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Mechanisms underlying familial aggregation of exceptional health and survival: A three-generation cohort study.
Christensen K, Wojczynski MK, Pedersen JK, Larsen LA, Kløjgaard S, Skytthe A, McGue M, Vaupel JW, Province MA.
Aging Cell. 2020 Sep 4:e13228. doi: 10.1111/acel.13228. Online ahead of print.
PMID: 32886847
The familial resemblance in length of adult life is very modest. Studies of parent-offspring and twins suggest that exceptional health and survival have a stronger genetic component than lifespan generally. To shed light on the underlying mechanisms, we collected information on Danish long-lived siblings (born 1886-1938) from 659 families, their 5379 offspring (born 1917-1982), and 10,398 grandchildren (born 1950-2010) and matched background population controls through the Danish 1916 Census, the Civil Registration System, the National Patient Register, and the Register of Causes of Death. Comparison with the background, population revealed consistently lower occurrence of almost all disease groups and causes of death in the offspring and the grandchildren. The expected incidence of hospitalization for mental and behavioral disorders was reduced by half in the offspring (hazard ratio 0.53, 95% confidence interval 0.45-0.62) and by one-third in the grandchildren (0.69, 0.61-0.78), while the numbers for tobacco-related cancer were 0.60 (0.51-0.70) and 0.71 (0.48-1.05), respectively. Within-family analyses showed a general, as opposed to specific, lowering of disease risk. Early parenthood and divorce were markedly less frequent in the longevity-enriched families, while economic and educational differences were small to moderate. The longevity-enriched families in this study have a general health advantage spanning three generations. The particularly low occurrence of mental and behavioral disorders and tobacco-related cancers together with indicators of family stability and only modest socioeconomic advantage implicate behavior as a key mechanism underlying familial aggregation of exceptional health and survival.
Keywords: family study; healthy aging; longevity; multi-generation study.

Association of Cardiovascular Risk Factors and APOE Polymorphism with Mortality in the Oldest Old: A 21-Year Cohort Study.
Vivian L, Bruscato NM, Werle BM, Carli W, Soares RAG, Santos PCJL, Moriguchi EH.
Arq Bras Cardiol. 2020 Aug 28:S0066-782X2020005010201. doi: 10.36660/abc.20190263. Online ahead of print.
PMID: 32876203 English, Portuguese.
Background Knowledge of environmental and genetic factors for healthy aging in elderly people is controversial. In addition to this evidence, few studies have been designed for this population. Objectives To investigate the relationship between the most frequent apolipoprotein E (APOE) genotypes and mortality in very elderly individuals living in a community and to evaluate survival according to cardiovascular risk factors. Methods A sample of 74 elderly individuals aged ≥ 80 years, from the Veranópolis Project cohort, was selected for APOE genotyping. At baseline, anthropometric variables, glucose and lipid levels, blood pressure, and lifestyle variables (smoking, alcohol consumption, and physical activity) were collected. The Bayer Activities of Daily Living Scale was applied to their caregivers. Total study follow-up was 21 years. Two-sided p < 0.05 was considered statistically significant. Results There was no association between APOE genotypes and mortality. However, the risk of death in elderly smokers was 2.30 times higher (hazard ratio {HR}, 95% CI 1.01 to 5.24); in individuals with diabetes, it was 3.95 times higher (HR, 95% CI 1.27 to 12.30) than in individuals without diabetes. Subjects who practiced vigorous physical activity had a 51% reduction in risk of death (HR = 0.49, 95% CI 0.27 to 0.88). For an increase of 1 mmHg in systolic blood pressure, there was a 2% reduction (HR = 0.98, 95% CI 0.97 to 0.99) in risk of death.Conclusion: In this sample population, APOE genotypes were not associated with mortality. However, classic cardiovascular risk factors may be important for overall mortality in the very elderly. 

Intermittent Fasting Attenuates Exercise Training-Induced Cardiac Remodeling.
Basilio PG, Oliveira APC, Castro ACF, Carvalho MR, Zagatto AM, Martinez PF, Okoshi MP, Okoshi K, Ota GE, Reis FAD, Oliveira-Junior SA.
Arq Bras Cardiol. 2020 Aug 28;115(2):184-193. doi: 10.36660/abc.20190349.
PMID: 32876182
Abstract in En , Portuguese
Background: The effects of non-pharmacological interventions such as calorie restriction and exercise training on health and prevention of cardiovascular diseases have been investigated in clinical and experimental studies.
Objective: To analyze the influence of intermittent fasting and exercise training on functional fitness, glycemia and cardiac remodeling.
Methods: Wistar rats (n=60) were randomly divided into four groups: control, exercise training (ET), intermittent fasting (IF) and exercise training plus intermittent fasting (ETI). Over 12 weeks, control and ET animals were fed daily a standard commercial diet ad libitum , while IF and ETI animals were fed every other day. In addition, the ET and ETI groups were submitted to a running protocol on a treadmill. After this period, functional fitness, nutritional parameters and blood glucose levels were analyzed. In addition to heart morphology, myocardial protein expression of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) was assessed by Western-blot. The results were analyzed using two-way ANOVA and Student-Newman-Keuls test. The level of significance considered was 5%.
Results: Exercise training increased functional fitness in the ET and ETI groups and promoted cardiac fibrosis. The combination of intermittent fasting and exercise training resulted in a smaller area under the blood glucose curve and reduced cardiomyocyte cross-sectional area and interstitial collagen fraction in the ETI group compared to ET. ERK and JNK expression levels were similar among groups (p>0.05).
Conclusions: Intermittent fasting is associated with improved glucose tolerance and attenuates cardiac remodeling induced by exercise training.

HNF4α regulates sulfur amino acid metabolism and confers sensitivity to methionine restriction in liver cancer.
Xu Q, Li Y, Gao X, Kang K, Williams JG, Tong L, Liu J, Ji M, Deterding LJ, Tong X, Locasale JW, Li L, Shats I, Li X.
Nat Commun. 2020 Aug 7;11(1):3978. doi: 10.1038/s41467-020-17818-w.
PMID: 32770044 Free PMC article
Methionine restriction, a dietary regimen that protects against metabolic diseases and aging, represses cancer growth and improves cancer therapy. However, the response of different cancer cells to this nutritional manipulation is highly variable, and the molecular determinants of this heterogeneity remain poorly understood. Here we report that hepatocyte nuclear factor 4α (HNF4α) dictates the sensitivity of liver cancer to methionine restriction. We show that hepatic sulfur amino acid (SAA) metabolism is under transcriptional control of HNF4α. Knocking down HNF4α or SAA enzymes in HNF4α-positive epithelial liver cancer lines impairs SAA metabolism, increases resistance to methionine restriction or sorafenib, promotes epithelial-mesenchymal transition, and induces cell migration. Conversely, genetic or metabolic restoration of the transsulfuration pathway in SAA metabolism significantly alleviates the outcomes induced by HNF4α deficiency in liver cancer cells. Our study identifies HNF4α as a regulator of hepatic SAA metabolism that regulates the sensitivity of liver cancer to methionine restriction.

Edited by AlPater

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Metabolic adaptation to calorie restriction.
Guijas C, Montenegro-Burke JR, Cintron-Colon R, Domingo-Almenara X, Sanchez-Alavez M, Aguirre CA, Shankar K, Majumder EL, Billings E, Conti B, Siuzdak G.
Sci Signal. 2020 Sep 8;13(648):eabb2490. doi: 10.1126/scisignal.abb2490.
PMID: 32900879
Calorie restriction (CR) enhances health span (the length of time that an organism remains healthy) and increases longevity across species. In mice, these beneficial effects are partly mediated by the lowering of core body temperature that occurs during CR. Conversely, the favorable effects of CR on health span are mitigated by elevating ambient temperature to thermoneutrality (30°C), a condition in which hypothermia is blunted. In this study, we compared the global metabolic response to CR of mice housed at 22°C (the standard housing temperature) or at 30°C and found that thermoneutrality reverted 39 and 78% of total systemic or hypothalamic metabolic variations caused by CR, respectively. Systemic changes included pathways that control fuel use and energy expenditure during CR. Cognitive computing-assisted analysis of these metabolomics results helped to prioritize potential active metabolites that modulated the hypothermic response to CR. Last, we demonstrated with pharmacological approaches that nitric oxide (NO) produced through the citrulline-NO pathway promotes CR-triggered hypothermia and that leucine enkephalin directly controls core body temperature when exogenously injected into the hypothalamus. Because thermoneutrality counteracts CR-enhanced health span, the multiple metabolites and pathways altered by thermoneutrality may represent targets for mimicking CR-associated effects.

The Association of Dietary Macronutrients with Lung Function in Healthy Adults Using the Ansan-Ansung Cohort Study.
Lee SA, Joshi P, Kim Y, Kang D, Kim WJ.
Nutrients. 2020 Sep 3;12(9):E2688. doi: 10.3390/nu12092688.
PMID: 32899146
This study is aimed to examine the association between macronutrient intake and lung function in healthy adults (n = 5880) using the Ansan-Ansung cohort study. To identify the index of lung function, we used the percentage difference of predicted Forced Expiratory Volume (%FEV1_diff) between baseline and follow-up. Based on the median %FEV1_diff, subjects were classified by two groups as "decreased vs. unchanged/improved". The dietary macronutrients were estimated and validated using the food-frequency questionnaire. Multiple logistic regression models were used to evaluate the association after adjusting for confounders. Advanced analysis examined the association after stratifying by age and obesity. The average of %FEV1 is 114.1 and 112.5 at baseline and follow-up, respectively. The positive association of protein and fiber intake with lung function was observed in men. Low fat and high carbohydrate intake decreased the lung function in women only. After stratification by age, the association of protein, fat, and carbohydrate intake with lung function was observed in young men and old women only. Otherwise, the association of protein and fiber with lung function was influenced by abdominal obesity. In conclusion, the lung function was positively associated with high protein and fat intake, but was negatively associated with high carbohydrate intake, which could be influenced by age and obesity.
Keywords: difference of FEV1; longitudinal study; lung function of healthy population; macronutrient; obese.

The Association Between Dietary Choline and Betaine With the Risk of Type 2 Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study.
Dibaba DT, Johnson KC, Kucharska-Newton AM, Meyer K, Zeisel SH, Bidulescu A.
Diabetes Care. 2020 Sep 8:dc200733. doi: 10.2337/dc20-0733. Online ahead of print.
PMID: 32900787
Objective: To examine the association between dietary intake of choline and betaine with the risk of type 2 diabetes.
Research design and methods: Among 13,440 Atherosclerosis Risk in Communities (ARIC) study participants, the prospective longitudinal association between dietary choline and betaine intake and the risk of type 2 diabetes was assessed using interval-censored Cox proportional hazards and logistic regression models adjusted for baseline potential confounding variables.
Results: Among 13,440 participants (55% women, mean age 54 [SD 7.4] years), 1,396 developed incident type 2 diabetes during median follow-up of 9 years from 1987 to 1998. There was no statistically significant association between every 1-SD increase in dietary choline and risk of type 2 diabetes (hazard ratio

1.01 [95% CI 0.87, 1.16]) nor between dietary betaine intake and the risk of type 2 diabetes (HR 1.01 [0.94, 1.10]). Those in the highest quartile of dietary choline intake did not have a statistically significant higher risk of type 2 diabetes than those in the lowest choline quartile (HR 1.09 [0.84, 1.42]); similarly, dietary betaine intake was not associated with the risk of type 2 diabetes comparing the highest quartile to the lowest (HR 1.06 [0.87, 1.29]). Among women, there was a higher risk of type 2 diabetes, comparing the highest to lowest dietary choline quartile (HR 1.54 [1.06, 2.25]), while in men, the association was null (HR 0.82 [0.57, 1.17]). Nevertheless, there was a nonsignificant interaction between high choline intake and sex on the risk of type 2 diabetes (P = 0.07). The results from logistic regression were similar.
Conclusions: Overall and among male participants, dietary choline or betaine intakes were not associated with the risk of type 2 diabetes. Among female participants, there was a trend for a modestly higher risk of type 2 diabetes among those with the highest as compared with the lowest quartile of dietary choline intake. Our study should inform clinical trials on dietary choline and betaine supplementation in relationship with the risk of type 2 diabetes.

Bisphosphonates and risk of cancers: a systematic review and meta-analysis.
Li YY, Gao LJ, Zhang YX, Liu SJ, Cheng S, Liu YP, Jia CX.
Br J Cancer. 2020 Sep 9. doi: 10.1038/s41416-020-01043-9. Online ahead of print.
PMID: 32901134
Background: It is unclear whether bisphosphonates are associated with risk of cancers. Therefore, this meta-analysis aimed to evaluate the effect of bisphosphonates on overall cancers.
Methods: A search in Pubmed, Embase, Cochrane Library and Web of Science databases was conducted, from the inception date of each resource to September 26, 2019. The summarised effect estimates with 95% CIs were calculated using a random-effect model. Heterogeneity and publication bias were explored.
Results: Thirty-four articles were included in this study (4,508,261 participants; 403,196 cases). The results revealed that bisphosphonates significantly decreased the risk of colorectal cancer (RR = 0.89, 95% CI: 0.81-0.98), breast cancer (RR = 0.87, 95% CI: 0.82-0.93) and endometrial cancer (RR = 0.75, 95% CI: 0.61-0.94), but no significant association was observed in all-cause cancer. Furthermore, nitrogen-containing bisphosphonates only had protective effects both on breast cancer (RR = 0.94, 95% CI: 0.90-0.99) and endometrial cancer (RR = 0.70, 95% CI: 0.54-0.92). Non-nitrogen-containing bisphosphonates tended to increase the risk of liver cancer (RR = 2.14, 95% CI: 1.23-3.72) and pancreas cancer (RR = 1.75, 95% CI: 1.32-2.33).
Conclusion: Bisphosphonates are significantly associated with risk reduction of colorectal, breast and endometrial cancer, especially nitrogen-containing bisphosphonates. It should be noted that non-nitrogen-containing bisphosphonates might increase the risk of liver and pancreas cancer. Large prospective cohort studies are needed to find the causal association between bisphosphonates and risk of cancers.

Body mass index change and estimated glomerular filtration rate decline in a middle-aged population: health check-based cohort in Japan.
Fukuma S, Ikenoue T, Bragg-Gresham J, Norton E, Yamada Y, Kohmoto D, Saran R.
BMJ Open. 2020 Sep 6;10(9):e037247. doi: 10.1136/bmjopen-2020-037247.
PMID: 32895282
Background: Obesity is a growing public health problem worldwide. We evaluated the mediators and association between changes in obesity metrics and renal outcomes in the general population.
Methods: Using the Japanese nationwide health check-based cohort from April 2011 to March 2019, we selected individuals aged 40-74 years, with a baseline estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2, whose body mass index (BMI) change was assessed. The primary outcome was combined 30% decline in eGFR, eGFR <15 mL/min/1.73 m2 and end-stage renal disease.
Results: During 245 147 person-years' follow-up among 50 604 participants (mean eGFR, 83.7 mL/min/1.73 m2; mean BMI, 24.1 kg/m2), 645 demonstrated eGFR decline (incidence rate 2.6/1000 person-years, 95% CI: 2.4 to 2.8). We observed continued initial changes in BMI for over 6 years and a U-shaped association between BMI change and eGFR decline. Compared with 0% change in BMI, adjusted HRs for changes of -10%, -4%, 4% and 10% were 1.53 (95% CI: 1.15 to 2.04), 1.14 (95% CI: 1.01 to 1.30), 1.16 (95% CI: 1.02 to 1.32) and 1.87 (95% CI: 1.25 to 2.80), respectively. The percentage of excess risk of BMI increase (>4%) mediated by three risk factors (blood pressure, haemoglobin A1c and total cholesterol), was 13.3%.
Conclusion: In the middle-aged Japanese population, both, increase and decrease in BMI were associated with subsequent eGFR decline. Changes in risk factors mediated a small proportion of the association between BMI increase and eGFR decline. Our findings support the clinical significance of monitoring BMI as a renal risk factor.
Keywords: epidemiology; nephrology; nutrition & dietetics; public health.

Fermented soy products intake and risk of cardiovascular disease and total cancer incidence: The Japan Public Health Center-based Prospective study.
Nozue M, Shimazu T, Charvat H, Mori N, Mutoh M, Sawada N, Iwasaki M, Yamaji T, Inoue M, Kokubo Y, Yamagishi K, Iso H, Tsugane S.
Eur J Clin Nutr. 2020 Sep 4. doi: 10.1038/s41430-020-00732-1. Online ahead of print.
PMID: 32887936
Background/objectives: The association of fermented soy products, separately from total soy products, with cardiovascular disease (CVD) and total cancer has not been reported. We examined this association in a population-based prospective cohort study in Japan.
Subjects/methods: We studied 79,648 participants (42,788 women; 36,860 men) aged 45-74 years without a history of cancer, myocardial infarction, or stroke. Participants completed a food frequency questionnaire (1995-1998) and were followed to 2009-2012. Cox proportional hazards regression analysis was used to calculate the hazard ratios (HR) and 95% confidence intervals (CI) of incidence of CVD and total cancer according to quartiles of total soy products, nonfermented soy products, fermented soy products, miso soup, natto, total isoflavones from soy products, isoflavones from nonfermented soy products, and isoflavones from fermented soy products.
Results: In women, we observed a significant inverse association between fermented soy product intake and the risk of CVD (multivariate HR in the highest compared with the lowest quartile of fermented soy product intake: 0.80; 95% CI: 0.68, 0.95; P for trend = 0.010), and also found significant inverse associations for natto and isoflavones among fermented soy products. In site-specific analysis, we observed a similar, significant inverse association between fermented soy product intake and the risk of stroke in women. We found no significant association between any soy product and risk of CVD in men or total cancer in both sexes.
Conclusions: Intake of fermented soy products such as natto was inversely associated with the risk of CVD in women.

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Obstructive Sleep Apnea and Risk for Incident Vertebral and Hip Fracture in Women.
Huang T, Tworoger SS, Redline S, Curhan GC, Paik JM.
J Bone Miner Res. 2020 Sep 9. doi: 10.1002/jbmr.4127. Online ahead of print.
PMID: 32909307
Recent studies suggest a positive association between obstructive sleep apnea (OSA), a disorder associated with intermittent hypoxia and sleep fragmentation, and derangements in bone metabolism. However, no prospective study to date has investigated the association between OSA and fracture risk in women. We conducted a prospective study examining the relation between OSA and risk of incident vertebral fracture (VF) and hip fracture (HF) in the Nurses' Health Study. History of physician-diagnosed OSA was assessed by self-reported questionnaires. A previous validation study demonstrated high concordance between self-reports and medical record identification of OSA. OSA severity was further categorized according to the presence or absence of self-reported sleepiness. Self-reports of VF were confirmed by medical record review. Self-reported HF was assessed by biennial questionnaires. Cox proportional-hazards models estimated the hazard ratio for fracture according to OSA status, adjusted for potential confounders, including BMI, physical activity, calcium intake, history of osteoporosis, and falls, and use of sleep medications. Among 55,264 women without prior history of fracture, physician-diagnosed OSA was self-reported in 1.3% in 2002 and increased to 3.3% by 2012. Between 2002 and 2014, 461 incident VF cases and 921 incident HF cases were documented. The multivariable-adjusted hazard ratio (HR) for confirmed VF for women with history of OSA was 2.00 (95% CI, 1.29-3.12) compared with no OSA history, with the strongest association observed for OSA with daytime sleepiness (HR 2.86; 95% CI, 1.31-6.21). No association was observed between OSA history and self-reported HF risk (HR 0.83; 95% CI, 0.49-1.43). History of OSA is independently associated with higher risk of confirmed VF but did not have a statistically significant association with self-reported HF in women. Further research is warranted in understanding the role of OSA and intermittent hypoxia in bone metabolism and health that may differ by fracture site. 

Intake of carbohydrates and SFA and risk of CHD in middle-age adults: the Hordaland Health Study (HUSK).
Haugsgjerd TR, Egeland GM, Nygård OK, Igland J, Sulo G, Lysne V, Vinknes KJ, Bjornevik K, Tell GS.
Public Health Nutr. 2020 Sep 10:1-15. doi: 10.1017/S1368980020003043. Online ahead of print.
PMID: 32907659
Objective: Limiting SFA intake may minimise the risk of CHD. However, such reduction often leads to increased intake of carbohydrates. We aimed to evaluate associations and the interplay of carbohydrate and SFA intake on CHD risk.
Design: Prospective cohort study.
Setting: We followed participants in the Hordaland Health Study, Norway from 1997-1999 through 2009. Information on carbohydrate and SFA intake was obtained from a FFQ and analysed as continuous and categorical (quartiles) variables. Multivariable Cox regression estimated hazard ratios (HR) and 95 % CI. Theoretical substitution analyses modelled the substitution of carbohydrates with other nutrients. CHD was defined as fatal or non-fatal CHD (ICD9 codes 410-414 and ICD10 codes I20-I25).
Participants: 2995 men and women, aged 46-49 years.
Results: Adjusting for age, sex, energy intake, physical activity and smoking, SFA was associated with lower risk (HRQ4 v. Q1 0·44, 95 % CI 0·26, 0·76, Ptrend = 0·002). For carbohydrates, the opposite pattern was observed (HRQ4 v. Q1 2·10, 95 % CI 1·22, 3·63, Ptrend = 0·003). SFA from cheese was associated with lower CHD risk (HRQ4 v. Q1 0·44, 95 % CI 0·24, 0·83, Ptrend = 0·006), while there were no associations between SFA from other food items and CHD. A 5 E% substitution of carbohydrates with total fat, but not SFA, was associated with lower CHD risk (HR 0·75, 95 % CI 0·62, 0·90).
Conclusions: Higher intake of predominantly high glycaemic carbohydrates and lower intake of SFA, specifically lower intake from cheese, were associated with higher CHD risk. Substituting carbohydrates with total fat, but not SFA, was associated with significantly lower risk of CHD.
Keywords: CHD; Carbohydrates; Cohort; SFA.

Association between high blood pressure and long term cardiovascular events in young adults: systematic review and meta-analysis.
Luo D, Cheng Y, Zhang H, Ba M, Chen P, Li H, Chen K, Sha W, Zhang C, Chen H.
BMJ. 2020 Sep 9;370:m3222. doi: 10.1136/bmj.m3222.
PMID: 32907799
Objective: To evaluate and quantify the future risk of cardiovascular events in young adults with high blood pressure.
Design: Systematic review and meta-analysis.
Data sources: Medline, Embase, and Web of Science were searched from inception to 6 March 2020. Relative risks were pooled using a random effects model and expressed with 95% confidence intervals. Absolute risk difference was calculated. Dose-response relations between blood pressure and individual outcomes were assessed by a restricted cubic spline model.
Eligibility criteria for selecting studies: Studies were selected that investigated the adverse outcomes of adults aged 18-45 with raised blood pressure. The primary study outcome was a composite of total cardiovascular events. Coronary heart disease, stroke, and all cause mortality were examined as secondary outcomes.
Results: Seventeen observational cohorts consisting of approximately 4.5 million young adults were included in the analysis. The average follow-up was 14.7 years. Young adults with normal blood pressure had increased risk of cardiovascular events compared with those with optimal blood pressure (relative risk 1.19, 95% confidence interval 1.08 to 1.31; risk difference 0.37, 95% confidence interval 0.16 to 0.61 per 1000 person years). A graded, progressive association was found between blood pressure categories and increased risk of cardiovascular events (high normal blood pressure: relative risk 1.35, 95% confidence interval 1.22 to 1.49; risk difference 0.69, 95% confidence interval 0.43 to 0.97 per 1000 person years; grade 1 hypertension: 1.92, 1.68 to 2.19; 1.81, 1.34 to 2.34; grade 2 hypertension: 3.15, 2.31 to 4.29; 4.24, 2.58 to 6.48). Similar results were observed for coronary heart disease and stroke. Generally, the population attributable fraction for cardiovascular events associated with raised blood pressure was 23.8% (95% confidence interval 17.9% to 28.8%). The number needed to treat for one year to prevent one cardiovascular event was estimated at 2672 (95% confidence interval 1639 to 6250) for participants with normal blood pressure, 1450 (1031 to 2326) for those with high normal blood pressure, 552 (427 to 746) for those with grade 1 hypertension, and 236 (154 to 388) for those with grade 2 hypertension.
Conclusions: Young adults with raised blood pressure might have a slightly increased risk of cardiovascular events in later life. Because the evidence for blood pressure lowering is limited, active interventions should be cautious and warrant further investigation.

The association of healthy behaviors with cognitive health expectancy in Chinese older adults: a population-based cohort study.
Hou C, Lin Y, Zimmer Z, Fang X.
Aging (Albany NY). 2020 Sep 9;12. doi: 10.18632/aging.103617. Online ahead of print.
PMID: 32903212
Objective: To examine how lifestyles and leisure activities are associated with cognitive health expectancy among older adults.
Results: For young-old (aged 65), an absolute increase in life years without cognitive impairment was found among those with a healthy diet, engaging in mental activities and in social activities. For old-old (aged 85), an absolute increase was found for men engaging in physical activities besides those. Compared with counterparts in a high risk group, the young-old in a medium-low risk group had a smaller proportion of years without cognitive impairment. Old-old in a low risk group had a greater proportion.
Conclusion: Extra years of life gained by a healthy dietary pattern, mental activities, and social activities are free of cognitive impairment for both sexes across ages. The beneficial impact of individual and combined modifiable factors on cognitive health is most prominent in old-old.
Methods: Data come from The Chinese Longitudinal Healthy Longevity Survey, a population-based cohort study of 27,193 participants aged 65+ conducted between 2002 and 2014. Smoking status, alcohol consumption, dietary pattern, marital status, physical, mental, social, and productive activities were assessed at baseline. Cognitive status was measured using the Chinese version of the MMSE.
Keywords: Markov multistate model; cognitive impairment; leisure activities; life expectancy; life styles.

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Plant- and Animal-Based Diet Quality and Mortality Among US Adults: A Cohort Study.
Keaver L, Ruan M, Chen F, Du M, Ding C, Wang J, Shan Z, Liu J, Zhang FF.
Br J Nutr. 2020 Sep 18:1-29. doi: 10.1017/S0007114520003670. Online ahead of print.
PMID: 32943123
Not all plant-based and animal foods exert the same health effects due to their various nutrient compositions. We aimed to assess the quality of plant-based vs. animal foods in relation to mortality in a prospective cohort study. Using data collected from a nationally representative sample of 36,825 adults in the National Health and Nutrition Examination Survey 1999-2014, we developed a de novo Comprehensive Diet Quality Index (cDQI) that assesses the quality of 17 foods based on the healthfulness, and separately scored the quality of 11 plant-based foods in a plant-based Diet Quality Index (pDQI) and 6 animal foods in an animal-based Diet Quality index (aDQI). Mortality from all causes, heart disease, and cancer were obtained from linkage to the National Death Index through December 31, 2015. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) after multivariable adjustments. During a median follow-up of 8.3 years, 4,669 all-cause deaths occurred, including 798 deaths due to heart disease and 1,021 due to cancer. Compared to individuals in the lowest quartile, those in the highest quartile of cDQI had a lower risk of all-cause mortality (HR=0.75, 95% CI: 0.65, 0.86; P-trend<0.001), which largely reflected the inverse relationship between quality of plant-based foods (pDQI) and all-cause mortality (HR=0.66; 95% CI: 0.58, 0.74, P-trend<0.001). No independent association was found for the quality of animal-foods (aDQI) and mortality. Our results suggest that consuming healthy plant-based foods is associated with lower all-cause mortality among US adults.
Keywords: animal foods; cancer; diet quality index; heart disease; mortality; plant-based foods.

Increased frequency of intentional weight loss associated with reduced mortality: a prospective cohort analysis.
Willis EA, Huang WY, Saint-Maurice PF, Leitzmann MF, Salerno EA, Matthews CE, Berndt SI.
BMC Med. 2020 Sep 17;18(1):248. doi: 10.1186/s12916-020-01716-5.
PMID: 32938465
Background: Due to the high prevalence of obesity and the difficulty in maintaining weight loss, repeated bouts of weight loss are a common occurrence. However, there are inconsistencies in epidemiological studies regarding repetitive weight fluctuations being associated with increased risk of mortality. Therefore, the purpose of this prospective cohort analysis was to determine the long-term association of the frequency of weight loss attempts on mortality.
Methods: This prospective cohort study used data collected from adult AARP members living in 6 states (California, Florida, Louisiana, New Jersey, North Carolina, or Pennsylvania) or 2 metropolitan areas (Atlanta, Georgia, or Detroit, Michigan) and participating in the National Institutes of Health-AARP Diet and Health Study between 2004 and 2006. Self-reported data were analyzed for 161,738 middle-aged adults. During an average 7 years of follow-up, 21,194 deaths were recorded. Hazard ratios of all-cause, cardiovascular, and cancer mortality were estimated adjusting for demographic, lifestyle, and behavioral risk factors.
Results: Increased frequency of weight loss attempts of at least five pounds was associated with lower mortality (ptrend < 0.010). Multivariate hazard ratios (95% confidence intervals) for all-cause death among individuals who successfully attempted weight loss compared with those who did not make any attempts were 0.94 (0.90-0.98) for 1-2 attempts, 0.96 (0.91-1.01) for 3-4 attempts, 0.91 (0.85-0.96) for 5-6 attempts, 0.91 (0.85-0.98) for 7-8 attempts, 0.87 (0.80-0.95) for 9-10 attempts, and 0.88 (0.82-0.94) for 11+ attempts. Similar results were noted for men and women, participants with healthy weight and overweight/obesity, and even among those who gained weight over time. Protective associations were also observed for deaths due to cardiovascular disease and cancer.
Conclusions: Increased frequency of intentionally losing at least five pounds in mid-life was associated with a lower risk of future death. Repeated attempts with moderate amounts of weight loss may provide benefit in terms of longevity.
Keywords: Mortality; Obesity; Prospective cohort; Weight loss.

Does insulin-like growth factor moderate the association between height and risk of cancer at 24 sites?
Parra-Soto S, Ho FK, Pell JP, Celis-Morales C.
Br J Cancer. 2020 Sep 14. doi: 10.1038/s41416-020-01059-1. Online ahead of print.
PMID: 32921791
Background: Whether the association of height with cancers differs by insulin-like growth factors has not been fully elucidated. Therefore, this study aimed to investigate the sex-specific associations between height and 24 site-specific cancers and to assess whether the association differed by IGF-1.
Methods: In total, 414,923 participants from the UK Biobank prospective cohort study were included. The association of height (per 5-cm increment) with incidence and mortality from 24 cancer sites was investigated by using Cox proportional hazard models.
Results: The median follow-up was 6.0 years. In men, height was positively associated with incidence risk of all-cause cancer and at five sites (lung, lymphatic, leukaemia, non-Hodgkin lymphoma and melanoma). In women, it was associated with breast, melanoma, lymphatic, non-Hodgkin lymphoma and all-cause cancer. The association was stronger in women than men for all-cause cancer incidence. The strength of the association did not differ by IGF-1 concentration.
Conclusions: Adult height was associated with risk of several cancer sites. However, some of these associations were sex-specific. There was no strong evidence to support IGF-1 moderating the association between height and cancer.

Circulating dehydroepiandrosterone sulfate level and cardiovascular or all-cause mortality in the elderly population: a meta-analysis.
Li R, E L, Zha N.
Ann Palliat Med. 2020 Sep 7:apm-20-441. doi: 10.21037/apm-20-441. Online ahead of print.
PMID: 32921089
Studies have yielded contradictory results concerning the association between dehydroepiandrosterone sulfate (DHEAS) and mortality in the elderly population. This meta-analysis aimed to evaluate the association of low serum DHEAS level with cardiovascular or all-cause mortality in the elderly population. A comprehensive literature search was conducted in PubMed and Embase databases up to 4 February, 2019. Longitudinal observational studies reporting multivariate adjusted risk ratio (RR) and corresponding 95% confidence intervals (CI) for cardiovascular or all-cause mortality with respect to baseline low DHEAS level were included. Both fixed-effect and random effect model were used to pool the overall risk estimate. Methodological quality of the included studies was evaluated using a 9-point Newcastle-Ottawa Scale. Six prospective studies enrolling 6,744 individuals were identified. Five studies were graded as high methodological quality. When compared the lowest to the reference higher circulating DHEAS level, the pooled RR of all-cause and cardiovascular mortality was 1.46 (95% CI: 1.25-1.70) and 1.49 (95% CI: 1.11-1.99), respectively. Subgroup analysis indicated that the association of low DHEAS level with all-cause mortality risk was only found in men (RR 1.41;95% CI: 1.18-1.69) but not in women (RR 1.72; 95% CI: 0.99-2.99). This meta-analysis provides evidence that low circulating DHEAS level is associated with increased risk all-cause mortality in the elderly population.
Keywords: Dehydroepiandrosterone sulfate (DHEAS); all-cause mortality; cardiovascular mortality; meta-analysis.

Middle-aged individuals may be in a perpetual state of H3N2 influenza virus susceptibility.
Gouma S, Kim K, Weirick ME, Gumina ME, Branche A, Topham DJ, Martin ET, Monto AS, Cobey S, Hensley SE.
Nat Commun. 2020 Sep 11;11(1):4566. doi: 10.1038/s41467-020-18465-x.
PMID: 32917903
Influenza virus exposures in childhood can establish long-lived memory B cell responses that can be recalled later in life. Here, we complete a large serological survey to elucidate the specificity of antibodies against contemporary H3N2 viruses in differently aged individuals who were likely primed with different H3N2 strains in childhood. We find that most humans who were first infected in childhood with H3N2 viral strains from the 1960s and 1970s possess non-neutralizing antibodies against contemporary 3c2.A H3N2 viruses. We find that 3c2.A H3N2 virus infections boost non-neutralizing H3N2 antibodies in middle-aged individuals, potentially leaving many of them in a perpetual state of 3c2.A H3N2 viral susceptibility.

Effects of Intermittent Fasting and Physical Activity on Salivary Expression of Reduced Glutathione and Interleukin-1β.
Allen C, Sellers B, Smith M, Edwards A, Gateless K, Aab B, Sherrard K, Bolyard C, Stover S.
Int J Exerc Sci. 2020 Aug 1;13(7):1063-1071. eCollection 2020.
PMID: 32922651 Free PMC article.
Previous research has consistently demonstrated that regular exercise promotes antioxidant production and decreases the expression of inflammation markers. However, there is very little research examining the effects of intermittent fasting (IF) on oxidative stress and inflammation. The present study investigated the hypothesis that a combination of IF and physical activity will reduce the need for glutathione (GSH) production by decreasing oxidative stress. In addition, it was hypothesized that a combination of IF and physical activity will significantly reduce inflammation, as indicated by a decrease in interleukin-1β (IL-1β) concentration. For three months, subjects practicing IF (n=7) ate only during an eight-hour window each day and fasted for the next 16 hours. A standard diet control group (n=18) maintained a normal, balanced diet spread out over the course of 14-18 hours each day. Based on data obtained from fitness-tracking devices, subjects were placed into one of three activity level groups: minimum, moderate, and maximum physical activity. Subjects provided fasting saliva samples monthly. The samples were subjected to a glutathione microplate assay and an interleukin ELISA test to determine salivary concentrations of GSH and IL-1β, respectively. For GSH concentration, there were no significant differences between the diets at any physical activity level. However, moderate to maximum physical activity, in conjunction with fasting, led to significant decreases in IL-1β concentration. In summary, results suggest that a combination of moderate physical activity and intermittent fasting promotes the maintenance of antioxidant function while inhibiting the inflammatory process.
Keywords: Cytokine; reactive oxygen species; time-restricted feeding.

Meal timing and subjective sleep disturbances in older men.
van Egmond LT, C Moulin T, Schiöth HB, Cederholm T, Benedict C.
Exp Gerontol. 2020 Sep 7;141:111089. doi: 10.1016/j.exger.2020.111089. Online ahead of print.
PMID: 32911034
Older adults often complain about sleep disturbances, such as difficulty falling asleep and difficulty maintaining sleep in the early morning hours. Here, we investigated whether meal timing is associated with sleep problems in a cohort of older Swedish men (n = 998, mean age 71). Each participant filled out a seven-day food diary used to determine the daily eating time window, daily eating midpoint, and meal timing variability (i.e., the variance in daily eating midpoints over seven days). Questionnaires were used to assess difficulty initiating sleep and difficulty maintaining sleep. As indicated by logistic regression adjusted for potential confounders (e.g., BMI, diabetes status), no significant associations were found between the meal timing parameters and subjective sleep problems (P ≥ 0.37). Similar results were obtained when restricting the analysis to adequate reporters of daily energy intake. Therefore, our findings suggest that meal timing variations do not contribute to subjective sleep problems in older men. Our results must be replicated in cohorts that also include women and other measures of sleep.
Keywords: Aging; Chrononutrition; Elderly; Insomnia; Sleep disturbances.

Associations of Cytomegalovirus Infection With All-Cause and Cardiovascular Mortality in Multiple Observational Cohort Studies of Older Adults.
Chen S, Pawelec G, Trompet S, Goldeck D, Mortensen LH, Slagboom PE, Christensen K, Gussekloo J, Kearney P, Buckley BM, Ford I, Jukema JW, Westendorp RGJ, Maier AB.
J Infect Dis. 2020 Sep 10:jiaa480. doi: 10.1093/infdis/jiaa480. Online ahead of print.
PMID: 32909605
Background: Whether latent cytomegalovirus (CMV) infection in older adults has any substantial health consequences is unclear. Here, we sought associations between CMV-seropositivity and IgG titer with all-cause and cardiovascular mortality in 5 longitudinal cohorts.
Methods: Leiden Longevity Study, Prospective Study of Pravastatin in the Elderly at Risk, Longitudinal Study of Aging Danish Twins, and Leiden 85-plus Study were assessed at median (2.8-11.4 years) follow-up . Cox regression and random effects meta-analysis were used to estimate mortality risk dependent on CMV serostatus and/or IgG antibody titer, in quartiles after adjusting for confounders.
Results: CMV-seropositivity was seen in 47%-79% of 10 122 white community-dwelling adults aged 59-93 years. Of these, 3519 had died on follow-up (579 from cardiovascular disease). CMV seropositivity was not associated with all-cause (hazard ratio {HR}, 1.05; 95% confidence interval [CI], .97-1.14) or cardiovascular mortality (HR, 0.97; 95% CI, .83-1.13). Subjects in the highest CMV IgG quartile group had increased all-cause mortality relative to CMV-seronegatives (HR, 1.16; 95% CI, 1.04-1.29) but this association lost significance after adjustment for confounders (HR, 1.13; 95% CI, .99-1.29). The lack of increased mortality risk was confirmed in subanalyses.

Conclusions: CMV infection is not associated with all-cause or cardiovascular mortality in white community-dwelling older adults.
Keywords: Herpesviridae; aged; cardiovascular; cytomegalovirus; immunoglobulin G; mortality; seroepidemiologic studies.

Substantial underestimation of SARS-CoV-2 infection in the United States.
Wu SL, Mertens AN, Crider YS, Nguyen A, Pokpongkiat NN, Djajadi S, Seth A, Hsiang MS, Colford JM Jr, Reingold A, Arnold BF, Hubbard A, Benjamin-Chung J.
Nat Commun. 2020 Sep 9;11(1):4507. doi: 10.1038/s41467-020-18272-4.
PMID: 32908126
Accurate estimates of the burden of SARS-CoV-2 infection are critical to informing pandemic response. Confirmed COVID-19 case counts in the U.S. do not capture the total burden of the pandemic because testing has been primarily restricted to individuals with moderate to severe symptoms due to limited test availability. Here, we use a semi-Bayesian probabilistic bias analysis to account for incomplete testing and imperfect diagnostic accuracy. We estimate 6,454,951 cumulative infections compared to 721,245 confirmed cases (1.9% vs. 0.2% of the population) in the United States as of April 18, 2020. Accounting for uncertainty, the number of infections during this period was 3 to 20 times higher than the number of confirmed cases. 86% (simulation interval: 64-99%) of this difference is due to incomplete testing, while 14% (0.3-36%) is due to imperfect test accuracy. The approach can readily be applied in future studies in other locations or at finer spatial scale to correct for biased testing and imperfect diagnostic accuracy to provide a more realistic assessment of COVID-19 burden.

l-Serine and EPA Relieve Chronic Low-Back and Knee Pain in Adults: A Randomized, Double-Blind, Placebo-Controlled Trial.
Sasahara I, Yamamoto A, Takeshita M, Suga Y, Suzuki K, Nishikata N, Takada M, Hashimoto M, Mine T, Kobuna Y, Nagao K.
J Nutr. 2020 Sep 1;150(9):2278-2286. doi: 10.1093/jn/nxaa156.
PMID: 32520991 Free PMC article.
Background: Multisite pain, including low-back and knee pain, is a major health issue that greatly decreases quality of life.
Objectives: This study analyzed the effects of l-serine, which provides necessary components for nerve function, and EPA, which exerts anti-inflammatory properties, on pain scores of adults with pain in at least the low back and knee for ≥3 mo.
Methods: This was a randomized, double-blind, placebo-controlled, parallel-group study. The Japan Low Back Pain Evaluation Questionnaire (JLEQ) and Japanese Knee Osteoarthritis Measure (JKOM) were applied as primary outcomes. The Brief Pain Inventory (BPI) and safety evaluation were secondary outcomes. We enrolled 120 participants aged ≥20 y (36 men and 84 women: mean ± SD age = 40.8 ± 10.9 y). The participants were randomly allocated to either the active group (daily ingestion of 594 mg l-serine and 149 mg EPA) or placebo group. The study period consisted of 8-wk dosing and 4-wk posttreatment observation. ANCOVA between groups for each time point was conducted using the baseline scores as covariates.
Results: The JLEQ scores (active compared with placebo: 14.2 ± 11.2 compared with 19.0 ± 10.2) at week 8 were lower in the active group (P < 0.001). The JKOM scores at week 4 (11.7 ± 9.0 compared with 13.9 ± 7.9), week 8 (10.4 ± 7.9 compared with 13.1 ± 7.1), and week 12 (10.3 ± 7.4 compared with 13.8 ± 7.5) were lower in the active group (P ≤ 0.04). Additionally, the active group had 11-27% better scores compared with the placebo group for BPI1 (worst pain), BPI3 (average pain), and BPI5D (pain during moving) at week 4 (P ≤ 0.028) and week 8 (P ≤ 0.019), respectively, and BPI5D was 23% better in the active group at week 12 (P = 0.007). No adverse events were observed.
Conclusions: l-Serine and EPA were effective for pain relief in adults with low-back and knee pain after multiplicity adjustment.This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry as UMIN000035056.
Keywords: Brief Pain Inventory (BPI); Japan Low Back Pain Evaluation Questionnaire (JLEQ); Japanese Knee Osteoarthritis Measure (JKOM); clinical; low-back and knee pain; multiple site pain; neuropathic pain.

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Circulating Thyroid Hormone Profile in Response to a Triiodothyronine Challenge in Familial Longevity.
Zutinic A, Blauw GJ, Pijl H, Ballieux BE, Westendorp RGJ, Roelfsema F, van Heemst D.
J Endocr Soc. 2020 Aug 20;4(10):bvaa117. doi: 10.1210/jendso/bvaa117. eCollection 2020 Oct 1.
PMID: 32964174 Free PMC article.
Context: Familial longevity is associated with higher circulating levels of thyrotropin (TSH), in the absence of differences in circulating thyroid hormones, and a lower thyroid responsivity to TSH, as previously observed in the Leiden Longevity Study (LLS). Further mechanisms underlying these observations remain unknown.
Objective: We hypothesized that members from long-lived families (offspring) have higher thyroid hormone turnover or less negative feedback effect on TSH secretion compared to controls.
Methods: In a case-control intervention study, 14 offspring and 13 similarly aged controls received 100 µg 3,5,3'-triiodothyronine (T3) orally. Their circulating T3, free T3 (fT3), and TSH levels were measured during 5 consecutive days. We compared profiles of circulating T3, fT3, and TSH between offspring and controls using general linear modeling (GLM) and calculated the percentage decline in TSH following T3 administration.
Results: Circulating T3 and fT3 levels increased to supraphysiologic values and normalized over the course of 5 days. There were no serious adverse events. T3 and fT3 concentration profiles over 5 days were similar between offspring and controls (T3 GLM P = .11, fT3 GLM P = .46). TSH levels decreased in a biphasic manner and started returning to baseline by day 5. The TSH concentration profile over 5 days was similar between offspring and controls (GLM P = .08), as was the relative TSH decline (%).
Conclusions: Members of long-lived families have neither higher T3 turnover nor diminished negative feedback of T3 on TSH secretion. The cause and biological role of elevated TSH levels in familial longevity remain to be elucidated.
Keywords: 3,5,3′-triiodothyronine; TSH; longevity; negative feedback; thyroid.

Mitochondrial DNA deletion mutations increase exponentially with age in human skeletal muscle.
Herbst A, Lee CC, Vandiver AR, Aiken JM, McKenzie D, Hoang A, Allison D, Liu N, Wanagat J.
Aging Clin Exp Res. 2020 Sep 23. doi: 10.1007/s40520-020-01698-7. Online ahead of print.
PMID: 32965609
Background: Mitochondrial DNA (mtDNA) deletion mutations lead to electron transport chain-deficient cells and age-induced cell loss in multiple tissues and mammalian species. Accurate quantitation of somatic mtDNA deletion mutations could serve as an index of age-induced cell loss. Quantitation of mtDNA deletion molecules is confounded by their low abundance in tissue homogenates, the diversity of deletion breakpoints, stochastic accumulation in single cells, and mosaic distribution between cells.
Aims: Translate a pre-clinical assay to quantitate mtDNA deletions for use in human DNA samples, with technical and biological validation, and test this assay on human subjects of different ages.
Methods: We developed and validated a high-throughput droplet digital PCR assay that quantitates human mtDNA deletion frequency.
Results: Analysis of human quadriceps muscle samples from 14 male subjects demonstrated that mtDNA deletion frequency increases exponentially with age-on average, a 98-fold increase from age 20-80. Sequence analysis of amplification products confirmed the specificity of the assay for human mtDNA deletion breakpoints. Titration of synthetic mutation mixtures found a lower limit of detection of at least 0.6 parts per million. Using muscle DNA from 6-month-old mtDNA mutator mice, we measured a 6.4-fold increase in mtDNA deletion frequency (i.e., compared to wild-type mice), biologically validating the approach.
Discussion/conclusions: The exponential increase in mtDNA deletion frequency is concomitant with the known muscle fiber loss and accelerating mortality that occurs with age. The improved assay permits the accurate and sensitive quantification of deletion mutations from DNA samples and is sufficient to measure changes in mtDNA deletion mutation frequency in healthy individuals across the lifespan and, therefore, patients with suspected mitochondrial diseases.
Keywords: Biomarker; Deletion; Mitochondria; MtDNA; Mutation; Sarcopenia.

Soy and isoflavone consumption and subsequent risk of prostate cancer mortality: the Japan Public Health Center-based Prospective Study.
Sawada N, Iwasaki M, Yamaji T, Shimazu T, Inoue M, Tsugane S.
Int J Epidemiol. 2020 Sep 23:dyaa177. doi: 10.1093/ije/dyaa177. Online ahead of print.
PMID: 32968784
Background: Although many epidemiological studies have reported the preventive effects of soy products and isoflavones on prostate cancer, our previous studies reported that the association between soy and isoflavones and prostate cancer incidence differed according to stage. It is more important to identify modifiable risk factors related to lethal prostate cancer. Here, we investigated the association between soy, soy products and isoflavones intake and prostate cancer mortality, in a prospective study in Japan.
Methods: We conducted a population-based prospective study in 43 580 Japanese men with no history of cancer or cardiovascular disease (aged 45-74 years). Participants completed a validated questionnaire which included 138 food items. We followed participants from 1995 to 2016. Hazard ratios (HRs) and 95% confidence intervals (CIs) of prostate cancer mortality were calculated according to quintiles of soy products and isoflavones intake, using Cox hazard proportional hazards regression.
Results: During 16.9 years follow-up, we registered 221 deaths from prostate cancer. Isoflavones and soy products intake was associated with an increased risk of prostate cancer death, with multivariate HRQ5 vs. Q1=1.39, 95% CI = 0.87-2.20, p for trend = 0.04 for isoflavones and multivariate HRQ5 vs. Q1=1.76, 95% CI = 1.10-2.82, p for trend = 0.04 for soy food.
Conclusions: Our study suggested that high intake of soy and isoflavones might increase the risk of prostate cancer mortality.
Keywords: JPHC Study; Soy; isoflavone; prospective; prostate cancer death.

Central fatness and risk of all cause mortality: systematic review and dose-response meta-analysis of 72 prospective cohort studies.
Jayedi A, Soltani S, Zargar MS, Khan TA, Shab-Bidar S.
BMJ. 2020 Sep 23;370:m3324. doi: 10.1136/bmj.m3324.
PMID: 32967840
Objective: To quantify the association of indices of central obesity, including waist circumference, hip circumference, thigh circumference, waist-to-hip ratio, waist-to-height ratio, waist-to-thigh ratio, body adiposity index, and A body shape index, with the risk of all cause mortality in the general population, and to clarify the shape of the dose-response relations.
Design: Systematic review and meta-analysis.
Data sources: PubMed and Scopus from inception to July 2019, and the reference lists of all related articles and reviews.
Eligibility criteria for selecting studies: Prospective cohort studies reporting the risk estimates of all cause mortality across at least three categories of indices of central fatness. Studies that reported continuous estimation of the associations were also included.
Data synthesis: A random effects dose-response meta-analysis was conducted to assess linear trend estimations. A one stage linear mixed effects meta-analysis was used for estimating dose-response curves.
Results: Of 98 745 studies screened, 1950 full texts were fully reviewed for eligibility. The final analyses consisted of 72 prospective cohort studies with 2 528 297 participants. The summary hazard ratios were as follows: waist circumference (10 cm, 3.94 inch increase): 1.11 (95% confidence interval 1.08 to 1.13, I2=88%, n=50); hip circumference (10 cm, 3.94 inch increase): 0.90 (0.81 to 0.99, I2=95%, n=9); thigh circumference (5 cm, 1.97 inch increase): 0.82 (0.75 to 0.89, I2=54%, n=3); waist-to-hip ratio (0.1 unit increase): 1.20 (1.15 to 1.25, I2=90%, n=31); waist-to-height ratio (0.1 unit increase): 1.24 (1.12 to 1.36, I2=94%, n=11); waist-to-thigh ratio (0.1 unit increase): 1.21 (1.03 to 1.39, I2=97%, n=2); body adiposity index (10% increase): 1.17 (1.00 to 1.33, I2=75%, n=4); and A body shape index (0.005 unit increase): 1.15 (1.10 to 1.20, I2=87%, n=9). Positive associations persisted after accounting for body mass index. A nearly J shaped association was found between waist circumference and waist-to-height ratio and the risk of all cause mortality in men and women. A positive monotonic association was observed for waist-to-hip ratio and A body shape index. The association was U shaped for body adiposity index.
Conclusions: Indices of central fatness including waist circumference, waist-to-hip ratio, waist-to-height ratio, waist-to-thigh ratio, body adiposity index, and A body shape index, independent of overall adiposity, were positively and significantly associated with a higher all cause mortality risk. Larger hip circumference and thigh circumference were associated with a lower risk. The results suggest that measures of central adiposity could be used with body mass index as a supplementary approach to determine the risk of premature death.

Improving rehabilitation in sarcopenia: a randomized-controlled trial utilizing a muscle-targeted food for special medical purposes.
Rondanelli M, Cereda E, Klersy C, Faliva MA, Peroni G, Nichetti M, Gasparri C, Iannello G, Spadaccini D, Infantino V, Caccialanza R, Perna S.
J Cachexia Sarcopenia Muscle. 2020 Sep 22. doi: 10.1002/jcsm.12532. Online ahead of print.
PMID: 32961041
Background: Sarcopenia is a disease associated with aging and a negative prognosis. Consensus-based treatment consists in targeting muscle mass and function through physical exercise, optimization of protein intake, and vitamin D supplementation, but evidence is lacking. We evaluated the safety and efficacy of a muscle-targeted nutritional support on the outcome of a physical exercise rehabilitation programme.
Methods: In a single-site, double-blind, randomized, controlled trial (NCT03120026; May 2017 to December 2018), old (≥65 years) adults [N = 140 (63% female patients; age, 81 ± 6 years)] without severe cognitive impairment, who were found to have sarcopenia by European Working Group on Sarcopenia in Older People 2010 criteria and hospitalized for physical rehabilitation, were randomized to receive until discharge (for at least 4 weeks and up to 8 weeks) a whey protein-based nutritional formula enriched with leucine and vitamin D or an iso-caloric control formula twice daily in addition to a standard hospital diet. The primary endpoint was the change in 4 m gait speed per month. Key secondary endpoints addressed the change in physical performance: chair-stand test, timed up and go test, and short physical performance battery. Other secondary outcomes were the change in functional status, muscle strength and mass, cognitive status, and quality of life. The proportion of patients who improved their rehabilitation intensity profile and overall economic benefits (using length of stay and duration of rehabilitation as surrogate measures) were also evaluated.
Results: A total of 161 patients were screened and 140 were randomized to study interventions. Thirteen patients (experimental, n = 6; placebo, n = 7) discontinued the intervention because they disliked the product and intention-to-treat analyses were based on patients reassessed at discharge [n = 127 (66% female patients; age, 81 ± 6 years)]. Supplementation with the experimental formula (n = 64) resulted in greater increase in mean gait speed {0.061 m/s/month [95% confidence interval (CI), 0.043 to 0.080]} than placebo [n = 63; -0.001 m/s/month (95%CI, -0.008 to 0.006)]: mean difference, 0.063 m/s/month (95%CI, 0.043 to 0.082) (P < 0.001). A significant effect was also found for muscle mass (P < 0.03) and all key secondary outcomes, functional and cognitive endpoints (P < 0.001 for all). Supplementation resulted also in higher proportion of patients improving their rehabilitation intensity profile (P = 0.003) and being discharged home (P = 0.002); shorter rehabilitation (P < 0.001); and hospital stay (P < 0.001).
Conclusions: In old adults with sarcopenia admitted to hospital for rehabilitation the consumption of a whey protein-based nutritional formula enriched with leucine and vitamin D improved physical performance and function, as well as muscle mass, and reduced the intensity and costs of care.
Keywords: Leucine; Nutritional support; Rehabilitation; Sarcopenia; Vitamin D; Whey protein; rehabilitation.

Visit-to-visit variability of lipid measurements and the risk of myocardial infarction and all-cause mortality: A prospective cohort study.
Liu X, Wu S, Song Q, Wang X.
Atherosclerosis. 2020 Sep 9:S0021-9150(20)30493-7. doi: 10.1016/j.atherosclerosis.2020.09.003. Online ahead of print.
PMID: 32958454
Background and aims: Previous studies suggested that increased visit-to-visit variability in lipid measurements is associated with cardiovascular disease in specific or high-risk populations. Because it is unknown whether this notion applies to the general population, we investigated whether lipid variability has additive effects on the risk of all-cause mortality and myocardial infarction (MI) in the general population.
Methods: We identified 51,620 subjects from the Kailuan cohort who had no history of MI, stroke and cancer and who underwent ≥3 health examinations from 2006 to 2010. Variability in total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) measurements was measured using the coefficient of variation (CV), standard deviation (SD), variability independent of the mean (VIM), and average real variability (ARV). Cox proportional hazards models were used to calculate the hazard ratios (HRs).
Results: During a median of 7.03 years of follow-up, 426 (1.21) incidents of MI and 2243 (6.45) incidents of all-cause mortality occurred. In the multivariable-adjusted model, the HRs comparing participants in the highest versus lowest quartile of the CV for HDL-C were 1.56 (95% CI, 1.17-2.08; p for trend<0.01) for MI and 1.22 (95% CI, 1.09-1.37; p for trend<0.01) for all-cause mortality. For the highest quartile compared with the lowest quartile of LDL-C variability, the risk of MI and all-cause mortality increased by 34% (HR, 1.34; 95% CI, 1.03-1.82; p for trend<0.05) and 19% (HR, 1.19; 95% CI, 1.04-1.36; p for trend<0.05), respectively. We did not observe any significant association between TG variability and MI or all-cause mortality.
Conclusions: These findings suggest that high visit-to-visit HDL-C and LDL-C variability is associated with an increased incidence of MI and all-cause mortality in a Chinese community population.
Keywords: All-cause mortality; Cohort study; Lipid; Myocardial infarction; Variability.

Effect of Coffee Consumption on Renal Outcome: A Systematic Review and Meta-Analysis of Clinical Studies.
Kanbay M, Siriopol D, Copur S, Tapoi L, Benchea L, Kuwabara M, Rossignol P, Ortiz A, Covic A, Afsar B.
J Ren Nutr. 2020 Sep 18:S1051-2276(20)30209-0. doi: 10.1053/j.jrn.2020.08.004. Online ahead of print.
PMID: 32958376 Review.
Objective: Drinking coffee is one of the most common daily habits, especially in the developed world. Along with caffeine, coffee has various ingredients that have been suggested to have beneficial effects, including antioxidant, antiinflammatory, anticarcinogenic, antithrombotic and antifibrotic effects. In this systematic review and meta-analysis, we investigated the relationship between coffee intake and chronic kidney disease (CKD) related outcomes.
Design and methods: Literature search was performed through PubMed/Medline, Web of Science, Embase (Elsevier), and the Cochrane Central Register of Controlled Trials (Wiley) from 1960 to February 2020. Incidence of CKD, the progression of CKD, and CKD-associated mortality have been evaluated in relation to coffee consumption and the amount of consumption. The Newcastle-Ottawa scale was used for quality assessment of included studies.
Results: 12 studies were included in the analysis (7 prospective, 5 cross-sectional) involving 505,841 subjects. 7 studies investigated the relationship between coffee consumption and incident CKD and showed that coffee consumption was associated with a significant decrease in the risk for incident CKD outcome (RR 0.86, 95% CI 0.76 to 0.97, P = .01) with a greater decrease in individuals taking ≥2 cups/day compared to those who drank ≤1 cup/day. There was a significantly lower risk of incident end stage kidney disease (ESKD) in coffee users (HR 0.82, 95% CI 0.72 to 0.94, P = .005). Coffee consumption was also associated with a lower risk of albuminuria (OR 0.81, 95% CI 0.68 to 0.97, P = .02). Overall, the risk of death related to CKD was lower in coffee users (HR 0.72, 95% CI 0.54 to 0.96, P = .02).
Conclusion: Coffee intake was dose-dependently associated with lower incident CKD, ESKD, and albuminuria.

Dietary Methionine Restriction Signals to the Brain Through Fibroblast Growth Factor 21 to Regulate Energy Balance and Remodeling of Adipose Tissue.
Forney LA, Fang H, Sims LC, Stone KP, Vincik LY, Vick AM, Gibson AN, Burk DH, Gettys TW.
Obesity (Silver Spring). 2020 Oct;28(10):1912-1921. doi: 10.1002/oby.22919.
PMID: 32959519
Objective: Restricting dietary methionine to 0.17% in mice increases energy expenditure (EE), reduces fat deposition, and improves metabolic health by increasing hepatic fibroblast growth factor 21 (FGF21). The goal of this study was to compare each of these responses in mice with the coreceptor for FGF21 deleted in either adipose tissue or the brain.
Methods: Methionine-restriction (MR) diets were fed to age-matched cohorts of mice with the coreceptor for FGF21 deleted in either adipose tissue or the brain. The physiological and transcriptional responses to MR were compared in the respective cohorts.
Results: Tissue-specific deletion of the FGF21 coreceptor in adipose tissue did not abrogate the ability of dietary MR to increase EE and reduce fat deposition. Tissue-specific deletion of the FGF21 coreceptor from the brain produced mice that were unable to respond to the effects of MR on EE or the remodeling of adipose tissue.
Conclusions: The increase in FGF21 produced by dietary MR acts primarily in the brain to produce its physiological effects on energy balance. In contrast, the effects of MR on hepatic gene expression were intact in both models, supporting a mechanism that directly links detection of reduced methionine in the liver to transcriptional mechanisms that alter gene expression in the liver.

The Influence of Cyclical Ketogenic Reduction Diet vs. Nutritionally Balanced Reduction Diet on Body Composition, Strength, and Endurance Performance in Healthy Young Males: A Randomized Controlled Trial.
Kysel P, Haluzíková D, Doležalová RP, Laňková I, Lacinová Z, Kasperová BJ, Trnovská J, Hrádková V, Mráz M, Vilikus Z, Haluzík M.
Nutrients. 2020 Sep 16;12(9):E2832. doi: 10.3390/nu12092832.
PMID: 32947920
(1) Background: The influence of ketogenic diet on physical fitness remains controversial. We performed a randomized controlled trial to compare the effect of cyclical ketogenic reduction diet (CKD) vs. nutritionally balanced reduction diet (RD) on body composition, muscle strength, and endurance performance. (2) Methods: 25 healthy young males undergoing regular resistance training combined with aerobic training were randomized to CKD (n = 13) or RD (n = 12). Body composition, muscle strength and spiroergometric parameters were measured at baseline and after eight weeks of intervention. (3) Results: Both CKD and RD decreased body weight, body fat, and BMI. Lean body mass and body water decreased in CKD and did not significantly change in RD group. Muscle strength parameters were not affected in CKD while in RD group lat pull-down and leg press values increased. Similarly, endurance performance was not changed in CKD group while in RD group peak workload and peak oxygen uptake increased. (4) Conclusions: Our data show that in healthy young males undergoing resistance and aerobic training comparable weight reduction were achieved by CKD and RD. In RD group; improved muscle strength and endurance performance was noted relative to neutral effect of CKD that also slightly reduced lean body mass.
Keywords: body composition; endurance; ketogenic diet; strength parameters; training.

The intestinal microbiome is a co-determinant of the postprandial plasma glucose response.
Søndertoft NB, Vogt JK, Arumugam M, Kristensen M, Gøbel RJ, Fan Y, Lyu L, Bahl MI, Eriksen C, Ängquist L, Frøkiær H, Hansen TH, Brix S, Nielsen HB, Hansen T, Vestergaard H, Gupta R, Licht TR, Lauritzen L, Pedersen O.
PLoS One. 2020 Sep 18;15(9):e0238648. doi: 10.1371/journal.pone.0238648. eCollection 2020.
PMID: 32947608
Elevated postprandial plasma glucose is a risk factor for development of type 2 diabetes and cardiovascular disease. We hypothesized that the inter-individual postprandial plasma glucose response varies partly depending on the intestinal microbiome composition and function. We analyzed data from Danish adults (n = 106), who were self-reported healthy and attended the baseline visit of two previously reported randomized controlled cross-over trials within the Gut, Grain and Greens project. Plasma glucose concentrations at five time points were measured before and during three hours after a standardized breakfast. Based on these data, we devised machine learning algorithms integrating bio-clinical, as well as shotgun-sequencing-derived taxa and functional potentials of the intestinal microbiome to predict individual postprandial glucose excursions. In this post hoc study, we found microbial and clinical features, which predicted up to 48% of the inter-individual variance of postprandial plasma glucose responses (Pearson correlation coefficient of measured vs. predicted values, R = 0.69, 95% CI: 0.45 to 0.84, p<0.001). The features were age, fasting serum triglycerides, systolic blood pressure, BMI, fasting total serum cholesterol, abundance of Bifidobacterium genus, richness of metagenomics species and abundance of a metagenomic species annotated to Clostridiales at order level. A model based only on microbial features predicted up to 14% of the variance in postprandial plasma glucose excursions (R = 0.37, 95% CI: 0.02 to 0.64, p = 0.04). Adding fasting glycaemic measures to the model including microbial and bio-clinical features increased the predictive power to R = 0.78 (95% CI: 0.59 to 0.89, p<0.001), explaining more than 60% of the inter-individual variance of postprandial plasma glucose concentrations. The outcome of the study points to a potential role of the taxa and functional potentials of the intestinal microbiome. If validated in larger studies our findings may be included in future algorithms attempting to develop personalized nutrition, especially for prediction of individual blood glucose excursions in dys-glycaemic individuals.

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Changes in Bone Turnover, Inflammatory, Oxidative Stress, and Metabolic Markers in Women Consuming Iron plus Vitamin D Supplements: a Randomized Clinical Trial.
Abiri B, Vafa M, Azizi-Soleiman F, Safavi M, Kazemi SM, Salehi M, Zaeri F, Sadeghi H.
Biol Trace Elem Res. 2020 Sep 25. doi: 10.1007/s12011-020-02400-8. Online ahead of print.
PMID: 32975739
We aimed to investigate whether combination of vitamin D and iron supplementation, comparing vitamin D alone, could modify bone turnover, inflammatory, oxidative stress, and metabolic markers. Eighty-seven women with hemoglobin (Hb) ≤ 12.7 g/dL and 25OHD ≤ 29 ng/mL vitamin D deficiency/insufficiency aged 18-45 years were randomly assigned into two groups: (1) receiving either 1000 IU/day vitamin D3 plus 27 mg/day iron (D-Fe); (2) vitamin D3 plus placebo supplements (D-P), for 12 weeks. In D-Fe group, significant decrease in red blood cells (RBC) (P = 0.001) and hematocrit (Hct) (P = 0.004) and increases in mean corpuscular hemoglobin concentration (MCHC) (P = 0.001), 25OHD (P < 0.001), osteocalcin (P < 0.001), high-density cholesterol (HDL) (P = 0.041), and fasting blood sugar (FBS) (P < 0.001) were observed. D-P group showed significant decrease in RBC (P < 0.001), Hb (P < 0.001), Hct (P < 0.001), mean corpuscular volume (MCV) (P = 0.004), mean corpuscular hemoglobin (MCH) (P < 0.001), MCHC (P = 0.005), serum ferritin (P < 0.001), and low-density cholesterol (LDL) (P = 0.016) and increases of 25OHD (P < 0.001), osteocalcin (P < 0.001), C-terminal telopeptide (CTX) (P = 0.025), triglyceride (TG) (P = 0.004), FBS (P < 0.001), and interleukin-6 (IL-6) (P = 0.001) at week 12. After the intervention, the D-P group had between-group increases in mean change in the osteocalcin (P = 0.007) and IL-6 (P = 0.033), and decreases in the RBC (P < 0.001), Hb (P < 0.001), Hct (P < 0.001), and MCV (P = 0.001), compared with the D-Fe group. There were significant between-group changes in MCH (P < 0.001), MCHC (P < 0.001), ferritin (P < 0.001), and serum iron (P = 0.018). Iron-vitamin D co-supplementation does not yield added benefits for improvement of bone turnover, inflammatory, oxidative stress, and metabolic markers, whereas, vitamin D alone may have some detrimental effects on inflammatory and metabolic markers. IRCT registration number: IRCT201409082365N9.
Keywords: Bone turnover; Inflammation; Iron; Oxidative stress; Vitamin D.

Association Between Fasting Blood Glucose and All-Cause Mortality in a Rural Chinese Population: 15-Year Follow-Up Cohort Study.
Cheng N, Zhang Y, Yang J, Li J, Ye L, Zhou Z, Wang Z, Liu L, Song Y, Yang Z, She G, Bai X, Huang X, Cheng X, Tang G, Wang B, Qin X, Zalloua P, Yan F, Xu X.
Diabetes Ther. 2020 Sep 25. doi: 10.1007/s13300-020-00927-6. Online ahead of print.
PMID: 32978754
Introduction: The worldwide prevalence of diabetes has been increasing for decades; diabetes can lead to serious health problems and even death, but the effects of maintaining low fasting blood glucose (FBG) remain controversial. The purpose of this study was to investigate the relationship between FBG levels and all-cause mortality in a long-term follow-up cohort and to find a relatively safe range of FBG levels.
Methods: This study included 17,902 adults from a community-based cohort study in rural China who were prospectively followed from 2003 to 2018. Generalized estimating equations were used to evaluate the association between FBG and all-cause mortality, adjusting for pertinent covariates and auto-correlations among siblings.
Results: A total of 1053 (5.9%) deaths occurred during 15 years of follow-up. There was a significant U-shaped association between all-cause mortality and FBG. Compared with the reference group (FBG of 5.6 - < 6.1 mmol/l), the risk of death among individuals with FBG levels < 5.6 mmol/l significantly increased by 38% (OR 1.34; 95% CI 1.13-1.59), while the risk of death among individuals with FBG ≥ 6.1 mmol/l or participants with a self-reported history of diabetes significantly increased by 51% (OR 1.49; 95% CI 1.20-1.85). Additionally, the U-shaped association remained steady in any stratification of risk factors.
Conclusion: Our study showed a significant U-shaped relationship between FBG levels and risk of all-cause mortality in this rural Chinese population. When FBG was within the range of 5.6 - < 6.1 mmol/l, the risk of all-cause mortality was the lowest.
Keywords: All-cause mortality; Fasting blood glucose; U-shaped relationship.

The Lipidome Fingerprint of Longevity.
Jové M, Mota-Martorell N, Pradas I, Galo-Licona JD, Martín-Gari M, Obis È, Sol J, Pamplona R.
Molecules. 2020 Sep 22;25(18):E4343. doi: 10.3390/molecules25184343.
PMID: 32971886 Review.
[pdf free from Medline abstact page.]
Lipids were determinants in the appearance and evolution of life. Recent studies disclose the existence of a link between lipids and animal longevity. Findings from both comparative studies and genetics and nutritional interventions in invertebrates, vertebrates, and exceptionally long-lived animal species-humans included-demonstrate that both the cell membrane fatty acid profile and lipidome are a species-specific optimized evolutionary adaptation and traits associated with longevity. All these emerging observations point to lipids as a key target to study the molecular mechanisms underlying differences in longevity and suggest the existence of a lipidome profile of long life.
Keywords: fatty acids; lipidomics; longevity; membrane unsaturation; peroxidation index.Association Between Midlife Physical Activity and Incident Kidney Disease: The Atherosclerosis Risk in Communities (ARIC) Study.
Parvathaneni K, Surapaneni A, Ballew SH, Palta P, Rebholz CM, Selvin E, Coresh J, Grams ME.
Am J Kidney Dis. 2020 Sep 10:S0272-6386(20)30940-9. doi: 10.1053/j.ajkd.2020.07.020. Online ahead of print.
PMID: 32971191
Rationale & objective: Physical activity is associated with lower risk of cardiovascular disease, diabetes, and hypertension, which have shared risk factor profiles with chronic kidney disease (CKD). However, there are conflicting findings regarding the relationship between physical activity and CKD. The objective was to evaluate the association between physical activity and CKD development over long-term follow-up using the Atherosclerosis Risk in Communities (ARIC) study.
Study design: Prospective cohort study.
Setting: & Participants: 14,537 participants aged 45 to 64 years old.
Predictors: Baseline physical activity status was assessed by the modified Baecke Physical Activity Questionnaire at visit 1 (1987-1989) and categorized according to the 2018 Physical Activity Guidelines for Americans to group participants as inactive, insufficiently active, active, and highly active.
Outcomes: Incident CKD defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at follow up and ≥25% decline in eGFR relative to baseline, CKD-related hospitalization or death, or end stage renal disease.
Analytical approach: Cox proportional hazards regression.
Results: At baseline, 37.8%, 24.2%, 22.7%, and 15.3% of participants were classified as inactive, insufficiently active, active, and highly active, respectively. During a median follow up of 24 years, 33.2% of participants developed CKD. After adjusting for age, sex, race-center, education, smoking status, diet quality, diabetes, coronary heart disease, hypertension, antihypertensive medication, body mass index, and baseline eGFR, higher categories of physical activity were associated with lower risk of CKD compared to the inactive group (HR for insufficiently active, 0.95 [95% CI, 0.88-1.02]; active, 0.93 [95% CI, 0.86-1.01]; highly active, 0.89 [95% CI, 0.81-0.97]; P for trend = 0.007).
Limitations: Observational design and self-reported physical activity that was based on leisure time activity only. Due to low numbers, non black and white participants were excluded.
Conclusions: Highly active participants had a lower risk of developing CKD compared to inactive participants. 
Index words (5 words): chronic kidney disease; physical activity; Atherosclerosis Risk in Communities Study; estimated glomerular filtration rate; cystatin C.

Edited by AlPater

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Importance of Dietary Phosphorus for Bone Metabolism and Healthy Aging.
Serna J, Bergwitz C.
Nutrients. 2020 Sep 30;12(10):E3001. doi: 10.3390/nu12103001.
PMID: 33007883 Review.
[pdf availed from Medline abstract.]
Inorganic phosphate (Pi) plays a critical function in many tissues of the body: for example, as part of the hydroxyapatite in the skeleton and as a substrate for ATP synthesis. Pi is the main source of dietary phosphorus. Reduced bioavailability of Pi or excessive losses in the urine causes rickets and osteomalacia. While critical for health in normal amounts, dietary phosphorus is plentiful in the Western diet and is often added to foods as a preservative. This abundance of phosphorus may reduce longevity due to metabolic changes and tissue calcifications. In this review, we examine how dietary phosphorus is absorbed in the gut, current knowledge about Pi sensing, and endocrine regulation of Pi levels. Moreover, we also examine the roles of Pi in different tissues, the consequences of low and high dietary phosphorus in these tissues, and the implications for healthy aging.

Keywords: absorption; dietary phosphorus; hyperphosphatemia; hypophosphatemia; inorganic phosphate (Pi); mineralization; paracellular; transcellular.

A prospective study on the role of smoking, environmental tobacco smoke, indoor painting and living in old or new buildings on asthma, rhinitis and respiratory symptoms.
Wang J, Janson C, Jogi R, Forsberg B, Gislason T, Holm M, Torén K, Malinovschi A, Sigsgaard T, Schlünssen V, Svanes C, Johannessen A, Bertelsen RJ, Franklin KA, Norbäck D.
Environ Res. 2020 Sep 27:110269. doi: 10.1016/j.envres.2020.110269. Online ahead of print.
PMID: 32997968
We studied associations between tobacco smoke, home environment and respiratory health in a 10 year follow up of a cohort of 11,506 adults in Northern Europe. Multilevel logistic regression models were applied to estimate onset and remission of symptoms. Current smokers at baseline developed more respiratory symptoms (OR=1.39-4.43) and rhinitis symptoms (OR=1.35). Starting smoking during follow up increased the risk of new respiratory symptoms (OR=1.54-1.97) and quitting smoking decreased the risk (OR=0.34-0.60). ETS at baseline increased the risk of wheeze (OR=1.26). Combined ETS at baseline or follow up increased the risk of wheeze (OR=1.27) and nocturnal cough (OR=1.22). Wood painting at baseline reduced remission of asthma (OR 95%CI: 0.61, 0.38-0.99). Floor painting at home increased productive cough (OR 95%CI: 1.64, 1.15-2.34) and decreased remission of wheeze (OR 95%CI: 0.63, 0.40-0.996). Indoor painting (OR 95%CI: 1.43, 1.16-1.75) and floor painting (OR 95%CI: 1.77, 1.11-2.82) increased remission of allergic rhinitis. Living in the oldest buildings (constructed before 1960) was associated with higher onset of nocturnal cough and doctor diagnosed asthma. Living in the newest buildings (constructed 1986-2001) was associated with higher onset of nocturnal breathlessness (OR=1.39) and rhinitis (OR=1.34). In conclusion, smoking, ETS and painting indoor can be risk factors for respiratory symptoms. Wood painting and floor painting can reduce remission of respiratory symptoms. Smoking can increase rhinitis. Living in older buildings can be a risk factor for nocturnal cough and doctor diagnosed asthma. Living in new buildings can increase nocturnal dyspnoea and rhinitis.
Keywords: Asthma; Environmental tobacco smoke; Onset and remission; Painting; Rhinitis; Smoking.

Immune response and endocytosis pathways are associated with the resilience against Alzheimer's disease.
Tesi N, van der Lee SJ, Hulsman M, Jansen IE, Stringa N, van Schoor NM, Scheltens P, van der Flier WM, Huisman M, Reinders MJT, Holstege H.
Transl Psychiatry. 2020 Sep 29;10(1):332. doi: 10.1038/s41398-020-01018-7.
PMID: 32994401
Developing Alzheimer's disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what extent each molecular mechanism associates with (i) the increased risk of AD and (ii) the resilience against AD until extreme old age, by comparing pathway-specific polygenic risk scores (pathway-PRS). We used 29 genetic variants associated with AD to develop pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in the Amsterdam Dementia Cohort of well-phenotyped AD patients (N = 1895), Dutch population controls from the Longitudinal Aging Study Amsterdam (N = 1654) and our unique 100-plus Study cohort of cognitively healthy centenarians who avoided AD (N = 293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and (in the opposite direction) with resilience against AD (except for angiogenesis, p < 0.05). The pathway that contributed most to the overall modulation of AD-risk was β-amyloid metabolism (29.6%), which was driven mainly by APOE-variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (except for angiogenesis, p < 0.05), while specifically immune response (p = 0.003) and endocytosis (p = 0.0003) associated with resilience against AD. Indeed, the variants in these latter two pathways became the main contributors to the overall modulation of genetic risk of AD (45.5% and 19.2%, respectively). The genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in general neuro-protection, which highlight the need to investigate these pathways, next to β-amyloid metabolism.

Spermidine, a caloric restriction mimetic, provides neuroprotection against normal and D-galactose-induced oxidative stress and apoptosis through activation of autophagy in male rats during aging.
Singh S, Kumar R, Garg G, Singh AK, Verma AK, Bissoyi A, Rizvi SI.
Biogerontology. 2020 Sep 26. doi: 10.1007/s10522-020-09900-z. Online ahead of print.
PMID: 32979155
Spermidine (SPD) is a natural polyamine present in all living organisms and is involved in the maintenance of cellular homeostasis by inducing autophagy in different model organisms. Its role as a caloric restriction mimetic (CRM) is still being investigated. We have undertaken this study to investigate whether SPD, acting as a CRM, can confer neuroprotection in D-galactose induced accelerated senescence model rat and naturally aged rats through modulation of autophagy and inflammation. Young male rats (4 months), D-gal induced (500 mg/kg b.w., subcutaneously) aging and naturally aged (22 months) male rats were supplemented with SPD (10 mg/kg b.w., orally) for 6 weeks. Standard protocols were employed to measure prooxidants, antioxidants, apoptotic cell death and electron transport chain complexes in brain tissues. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy and inflammatory marker genes. Our data demonstrate that SPD significantly (p ≤ 0.05) decreased the level of pro-oxidants and increased the level of antioxidants. SPD supplementation also augmented the activities of electron transport chain complexes in aged brain mitochondria thus proving its antioxidant potential at the level of mitochondria. RT-PCR data revealed that SPD up-regulated the expression of autophagy genes (ATG-3, Beclin-1, ULK-1 and LC3B) and down-regulated the expression of the inflammatory gene (IL-6) in aging brain. Our results provide first line of evidence that SPD provides neuroprotection against aging-induced oxidative stress by regulating autophagy, antioxidants level and also reduces neuroinflammation. These results suggest that SPD may be beneficial for neuroprotection during aging and age-related disorders.
Keywords: Aging; Apoptosis; Autophagy; Caloric restriction mimetics; Spermidine.

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Long-term aspirin use for primary cancer prevention: An updated systematic review and subgroup meta-analysis of 29 randomized clinical trials.
Wu Q, Yao X, Chen H, Liu Z, Li T, Fan X, Zhang G, Yu L, Chen M, Xu C, Zhang R, Chen B, Sui X, Leung EL.
J Cancer. 2020 Sep 14;11(21):6460-6473. doi: 10.7150/jca.49001. eCollection 2020.
PMID: 33033530 Free PMC article.
Background and objective: Long-term aspirin use for the primary prevention of cancer remains controversial, and variations in the effect of aspirin use on cancer outcomes by aspirin dose, follow-up duration, or study population have never been systematically evaluated. The objective of this study was to evaluate the effect of aspirin on primary cancer prevention and to determine whether the effect differed according to aspirin dose, follow-up duration, or study population. Materials and methods: Seven electronic databases were searched from inception to September 30, 2019. Randomized clinical trials (RCTs) that compared aspirin use versus no aspirin use in participants without pre-existing cancer and reported cancer outcomes were selected. Data were screened and extracted by different investigators. Analyses were performed using Review Manager 5.3 and Comprehensive Meta-Analysis 2.0. Total cancer incidence was defined as the primary clinical endpoint. Total cancer mortality, all-cause mortality, major bleeding, and total bleeding events were the secondary outcomes. Subgroup analyses were conducted based on aspirin dose, follow-up duration, and study populations. Results: Twenty-nine RCTs that randomized 200,679 participants were included. Compared with no aspirin, aspirin use was not associated with significant reductions in total cancer incidence (RR = 1.01, 95% CI: 0.97 to 1.04, P = 0.72), total cancer mortality (RR = 1.00, 95% CI: 0.93 to 1.07, P = 0.90), or all-cause mortality (RR = 0.98, 95% CI: 0.94 to 1.02, P =0.31); however, aspirin use was associated with a 44% increase in the risk of major bleeding (RR = 1.44, 95% CI: 1.32 to 1.57, P < 0.00001) and a 52% increase in the risk of total bleeding events (RR = 1.52, 95% CI: 1.33 to 1.74, P < 0.00001). Subgroup analyses demonstrated consistent results. Conclusions: Long-term aspirin use in individuals without pre-existing cancer was not associated with a significant reduction in total cancer incidence, cancer mortality, or all-cause mortality; however, aspirin use was associated with a significant increase in the risk of bleeding. Therefore, aspirin is not an appropriate choice for the primary cancer prevention.
Keywords: aspirin; cancer; long-term; primary prevention; randomized clinical trials; subgroup meta-analysis; systematic review.

Yogurt consumption and colorectal cancer incidence and mortality in the Nurses' Health Study and the Health Professionals Follow-Up Study.
Michels KB, Willett WC, Vaidya R, Zhang X, Giovannucci E.
Am J Clin Nutr. 2020 Oct 6:nqaa244. doi: 10.1093/ajcn/nqaa244. Online ahead of print.
PMID: 33022694
Background: Yogurt is a commonly consumed fermented food. Regular yogurt consumption may contribute to a favorable gut microbiome and gut health, but few epidemiologic studies have considered the relation between regular yogurt consumption and the incidence of and mortality from colorectal cancer.
Objectives: We used data from 2 large, prospective cohort studies, the Nurses' Health Study and the Health Professionals Follow-Up Study, to examine the role of yogurt consumption on colorectal cancer incidence and mortality.
Methods: During 32 years of follow-up in 83,054 women (mean age at baseline, 45.7 years) and 26 years of follow-up in 43,269 men (mean age at baseline, 52.3 years), we documented a total of 2666 newly diagnosed cases of colorectal cancer in these cohorts. We modeled yogurt consumption at baseline and cumulatively updated it throughout follow-up. Results: Baseline yogurt consumption was associated with a reduced risk of colon cancer in age-adjusted analyses (P for trend < 0.001). Associations remained statistically significant after adjusting for potential confounders, including calcium and fiber intake (P for trend = 0.03), and were restricted to proximal colon cancer. The consumption of 1 + servings per week of yogurt at baseline, compared to no yogurt consumption, was associated with a multivariable HR of 0.84 (95% CI, 0.70-0.99; P trend = 0.04) for the proximal colon cancer incidence. Latency analyses suggested that the most important window of opportunity for regular yogurt consumption to prevent colorectal cancer was 16-20 years in the past. When yogurt consumption was cumulatively updated, associations attenuated and were no longer significant. No statistically significant inverse trend was observed between yogurt consumption and the colorectal cancer mortality.
Conclusions: In these large cohorts, the frequency of yogurt consumption was associated with a reduced risk of proximal colon cancer with a long latency period. No significant inverse trend was observed for colorectal cancer mortality.
Keywords: colon cancer; fermentation; gut bacteria; microbiome; microbiota; mortality; rectal cancer; yogurt.

Randomized Trial Evaluation of Benefits and Risks of Menopausal Hormone Therapy Among Women Aged 50-59.
Prentice RL, Aragaki AK, Chlebowski RT, Rossouw JE, Anderson GL, Stefanick ML, Wactawski-Wende J, Kuller LH, Wallace R, Johnson KC, Shadyab AH, Gass M, Manson JAE.
Am J Epidemiol. 2020 Oct 7:kwaa210. doi: 10.1093/aje/kwaa210. Online ahead of print.
PMID: 33025002
The health benefits and risks of menopausal hormone therapy among women aged 50-59 years are examined in the Women's Health Initiative randomized, placebo-controlled trials using long-term follow-up data and a parsimonious statistical model that leverages data from older participants to increase precision. These trials enrolled 27,347 healthy post-menopausal women aged 50-79 at 40 U.S. clinical centers during 1993-1998, including 10,739 post-hysterectomy participants in a trial of conjugated equine estrogens, and 16,608 participants with uterus in the trial of these estrogens plus medroxyprogesterone acetate. Over an 18-year (median) follow-up period (1993-2016) risk for a global index, defined as the earliest of coronary heart disease, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and all-cause mortality, is reduced with conjugated equine estrogens with hazard ratio (95% confidence interval) of 0.82 (0.71, 0.95), and with nominally significant reductions for coronary heart disease, breast cancer, hip fracture and all-cause mortality. Corresponding global index hazard ratio estimates of 1.06 (0.95, 1.19) were non-significant for combined estrogens plus progestin, but increased breast cancer risk and reduced endometrial cancer risk were observed. These results, among women 50-59, substantially agree with the worldwide observational literature, with the exception of breast cancer for estrogens alone.

Keywords: benefits versus risks; estrogens; global index; hazard ratio; menopausal hormone therapy; multivariate failure times; progestin.

Dietary nicotine intake and risk of Parkinson disease: a prospective study.
Ma C, Molsberry S, Li Y, Schwarzschild M, Ascherio A, Gao X.
Am J Clin Nutr. 2020 Oct 1;112(4):1080-1087. doi: 10.1093/ajcn/nqaa186.
PMID: 32725131
Background: Tobacco use was observed to be associated with a lower risk of Parkinson disease (PD) in previous epidemiologic studies, with nicotine as a potential candidate. The association between dietary nicotine and PD risk has, however, not been examined in prospective studies yet.
Objectives: We aimed to examine prospectively the association between dietary nicotine intake and subsequent PD risk among never-smokers.
Methods: The current study was based on never-smoker participants from 2 large prospective cohorts: the Nurses' Health Study (n = 31,615) and the Health Professionals Follow-up Study (n = 19,523). The studies contained information on dietary nicotine intake from 1986 from validated FFQs. Dietary nicotine intake was calculated based on consumption of peppers, tomatoes, processed tomatoes, potatoes, and tea. Incident cases of PD were identified via questionnaires and subsequently confirmed by reviewing medical records. We used Cox proportional hazard models to calculate cohort-specific HRs, and used fixed-effects models to calculate the pooled HR.
Results: During 26 y of follow-up, we identified 601 incident PD cases (296 women and 305 men). After adjusting for potential covariates, the pooled HR for the highest compared with the lowest quintile of dietary nicotine intake was 0.70 (95% CI: 0.51, 0.94). The significant inverse association was, however, only observed in women (adjusted HR: 0.64; 95% CI: 0.42, 0.96), not in men (adjusted HR: 0.77; 95% CI: 0.50, 1.20). Further adjusting for environmental tobacco smoke exposure, family history of PD, and use of ibuprofen generated similar significant results in women. Consistently, greater consumption of peppers was associated with lower risk of PD (adjusted HR for ≥5 times/wk compared with ≤3 times/mo: 0.49; 95% CI: 0.25, 0.94) in women but not in men (adjusted HR: 1.04; 95% CI: 0.57, 1.90).
Conclusions: Women with greater dietary nicotine intake had a lower risk of PD than those with lower intake.
Keywords: Parkinson disease; cohort; dietary nicotine; neurodegenerative disease; prospective study.

Outcomes of thyroid dysfunction in people aged 80 years and older: an individual patient data meta-analysis of four prospective studies (TULIPS consortium).
Du Puy R, Poortvliet RKE, Mooijaart S, Den Elzen W, Jagger C, Pearce SH, Arai Y, Hirose N, Teh R, Menzies O, Rolleston A, Kerse N, Gussekloo J.
Thyroid. 2020 Oct 3. doi: 10.1089/thy.2020.0567. Online ahead of print.
PMID: 33012278
<b>Background</b> Subclinical and overt thyroid dysfunction is easily detectable, often modifiable and, in younger age groups, has been associated with clinically relevant outcomes. Robust associations in very old persons however are currently lacking. This study aimed to investigate the associations between (sub-)clinical thyroid dysfunction and disability in daily living, cognitive function, depressive symptoms, physical function and mortality in people aged 80 years and older. <b>Methods</b> Four prospective cohorts participating in the Towards Understanding Longitudinal International older People Studies (TULIPS) consortium were included. We performed a two-step Individual Participant Data meta-analysis on source data from community-dwelling participants aged 80 years and older from the Netherlands, New Zealand, United Kingdom and Japan. Outcome measures included disability in daily living (disability in activities of daily living questionnaires), cognitive function (MMSE), depressive symptoms (GDS), physical function (grip strength) at baseline and after 5 years of follow-up, and all-cause five-year mortality. <b>Results</b> Of the total 2116 participants at baseline (mean age 87 years, range 80-109 years), 105 participants (5.0%) were overtly hypothyroid, 136 (6.4%) subclinically hypothyroid, 1811 (85.6%) euthyroid, 60 (2.8%) subclinically hyperthyroid and 4 (0.2%) overtly hyperthyroid. Participants with thyroid dysfunction at baseline had non-significantly different activities of daily living scores compared to euthyroid participants at baseline and had similar MMSE scores, GDS scores and grip strength. There was no difference in the change of any of these functional measures in participants with thyroid dysfunction during five years of follow-up. Compared to the euthyroid participants, no 5-year survival differences were identified in participants with overt hypothyroidism (Hazard Ratio {HR} 1.0, 95% Confidence Interval [95%CI] 0.6 to 1.6), subclinical hypothyroidism (HR 0.9, 95%CI 0.7 to 1.2), subclinical hyperthyroidism (HR 1.1, 95%CI 0.8 to 1.7) and overt hyperthyroidism (HR 1.5, 95%CI 0.4 to 5.9). Results did not differ after excluding participants using thyroid-influencing medication. <b>Conclusions</b> In community dwelling people aged 80 years and older, (sub-)clinical thyroid dysfunction was not associated with functional outcomes or mortality and may therefore be of limited clinical significance.

Edited by AlPater

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Low carbohydrate diet and all cause and cause-specific mortality.
Akter S, Mizoue T, Nanri A, Goto A, Noda M, Sawada N, Yamaji T, Iwasaki M, Inoue M, Tsugane S; Japan Public Health Center-based Prospective Study Group.
Clin Nutr. 2020 Sep 23:S0261-5614(20)30478-7. doi: 10.1016/j.clnu.2020.09.022. Online ahead of print.
PMID: 33046262
Background: Evidence is limited regarding the association between low-carbohydrate diet (LCD) score and mortality among Asians, a population that consumes a large amount of carbohydrates.
Objective: The present study examined the association between low-carbohydrate diet (LCD) score (based on percentage of energy as carbohydrate, fat, and protein) and the risk of total and cause-specific mortality among Asians.
Design: This study was a prospective cohort study in Japan with follow-up for a median of 16.9 years involving 43008 men and 50646 women aged 45-75 years. Association of LCD score, LCD score based on animal sources of protein and fat, and LCD score based on plant sources of protein and fat with risk of mortality was assessed using Cox proportional hazards model.
Results: A U-shaped association was observed between LCD score and total mortality: the multivariable-adjusted hazard ratios (HRs) (95% CI) of total mortality for lowest through highest scores were 1.00, 0.95 (0.91, 1.01), 0.93 (0.88, 0.98), 0.93 (0.88, 0.98), and 1.01 (0.95, 1.07) (P-non-linearity <0.01). A similar association was found for mortality from cardiovascular disease (CVD) and heart disease. LCD score based on carbohydrate, animal protein, and animal fat also showed a U-shaped association for total mortality (P-non-linearity <0.01). In contrast, LCD score based on carbohydrate, plant protein, and plant fat was linearly associated with lower total (HR, 0.89; 95% CI: 0.83, 0.94 for highest versus lowest quintile), CVD [0.82 (0.73, 0.92)], heart disease [0.83 (0.71, 0.98)], and cerebrovascular disease [0.75 (0.62, 0.91) mortality.
Conclusions: Both LCD with high animal protein and fat and high-carbohydrate diet with low animal protein and fat were associated with higher risk of mortality. Meanwhile, LCD high in plant-based sources of protein and fat was associated with a lower risk of total and CVD mortality.
Keywords: Cancer mortality; Cardiovascular disease mortality; Low carbohydrate diet; Mortality.

Tea consumption and measures of attention and psychomotor speed in the very old: the Newcastle 85+ longitudinal study.
Okello EJ, Mendonça N, Stephan B, Muniz-Terrera G, Wesnes K, Siervo M.
BMC Nutr. 2020 Oct 6;6:57. doi: 10.1186/s40795-020-00361-8. eCollection 2020.
PMID: 33042566 Free PMC article.
Background: A number of studies have indicated a beneficial effect of tea consumption on the reduction of risk of cognitive impairment and dementia in older aged populations. However, there is a paucity of data on these associations in the very old, defined as individuals aged 85 years and over. We investigated the relationship between tea consumption in the very old and measures of global cognitive function, memory, attention and psychomotor speed.
Method: Longitudinal (5-years), population-based cohort study of individuals aged 85+ years in the North East of England, United Kingdom. Participants were community-dwelling and institutionalized men and women recruited through general medical practices (n = 676). Baseline tea consumption and longitudinal measures of global and domain specific (memory, speed and attention) cognitive function were assessed. Linear mixed models, controlling for demographic (e.g. age, sex and education) and health variables were used to determine whether tea consumption was protective against cognitive decline.
Results: Tea consumption was not associated with cognitive function at baseline on any measure (unadjusted and adjusted analyses). In the linear mixed effects models adjusted for age, sex, education and disease co-morbidity, higher tea consumption was associated with significantly better attention (focused and sustained attention), and psychomotor speed (complex tasks only) over five-years follow-up. However, there was no association between tea consumption and global cognitive function, memory or performance on simple speed tasks over time.
Conclusions: In this cohort study of non-demented very old adults we found that higher (vs. lower) tea consumption was associated with better performance over time on measures of focused and sustained attention and some psychomotor speed tasks. No associations with global cognition, memory or easy speed tasks (simple Reaction Time or Word Recognition) were detected. The results have implications for the development of possible diet-based interventions focused on improving cognitive function in the very old age group. These findings need to be confirmed in a sufficiently powered and well-designed RCT with non-demented very old adults.
Keywords: Cognition; Epidemiology; Tea; Very old.

Heart Rate Variability and Exceptional Longevity.
Hernández-Vicente A, Hernando D, Santos-Lozano A, Rodríguez-Romo G, Vicente-Rodríguez G, Pueyo E, Bailón R, Garatachea N.
Front Physiol. 2020 Sep 17;11:566399. doi: 10.3389/fphys.2020.566399. eCollection 2020.
PMID: 33041862 Free PMC article.
Centenarians are the paradigm of human extreme longevity and healthy aging, because they have postponed, if not avoided, mayor age-related diseases. The purpose of this study was to investigate potential differences in resting heart rate variability (HRV) between young adults, octogenarians, and centenarians and assess whether HRV variables are predictors of all-cause mortality in centenarians. To this end, three groups of participants: young adults (N = 20; 20.6 ± 2.3 years), octogenarians (N = 18; 84.1 ± 2.6 years), and centenarians (N = 17; 101.9 ± 1.9 years) were monitored for 15 min at rest (seated, without moving or talking) to measure RR intervals, from which HRV was evaluated. Our results showed a clear decrease with age in the main parasympathetic HRV variables, as well as in the standard deviation (SD) of the RR series [SD of normal-to-normal interval (SDNN)] and in low frequency (LF) heart rate (HR) oscillations, although differences between octogenarians and centenarians did not reach statistical significance. In 14 centenarians followed until death, only SDNN showed significant correlation (ρ = 0.536; p = 0.048) with survival prognosis. Additionally, SDNN <19 ms was associated with early mortality (≤1 year) in centenarians (Hazard Ratio = 5.72). In conclusion, HRV indices reflecting parasympathetic outflow as well as SDNN and LF all present an age-related reduction, which could be representative of a natural exhaustion of allostatic systems related to age. Moreover, low SDNN values (<19 ms) could be associated with early mortality in centenarians. HRV seems to play a role in exceptional longevity, which could be accounted for by centenarians' exposome.
Keywords: aging; autonomic nervous system; centenarians; electrocardiography; heart rate; heart rate variability; mortality; parasympathetic nervous system.

Adiposity and mortality in Korean adults: a population-based prospective cohort study.
Oh H, Kwak SY, Jo G, Lee J, Park D, Lee DH, Keum N, Lee JT, Giovannucci EL, Shin MJ.
Am J Clin Nutr. 2020 Sep 21:nqaa258. doi: 10.1093/ajcn/nqaa258. Online ahead of print.
PMID: 33037431
Background: The Asia-Pacific obesity classification recommends using lower BMI cutoffs in Asians compared with those in Western populations. However, the supporting evidence is scarce and little is known about the exact shape of the relations between adiposity and mortality in Asians.
Objectives: We investigated the relations of BMI (in kg/m2), waist circumference, and predicted body fat mass with mortality using a population-based prospective cohort of Korean men and women.
Methods: This analysis included 44,060 Korea National Health and Nutrition Examination Survey 2007-2014 participants who agreed to mortality follow-up through 31 December, 2016. At baseline, height, weight, and waist circumference were measured. Using DXA data, we derived predicted body fat and fat-free mass. Cox proportional hazards models were used to estimate HRs and 95% CIs for the associations with mortality, adjusting for potential confounders. We tested for nonlinearity using the likelihood ratio test comparing nonlinear restricted cubic spline models with linear models.
Results: During ≤9.5 y of follow-up, 1682 deaths were identified. The relations of BMI with all-cause and cardiovascular mortality were J-shaped with the nadir at BMI = 25.0-29.9 (P-nonlinearity < 0.001). Among participants without a history of cancer or cardiovascular disease, waist circumference (≥95 compared with 75.0-79.9 cm: HR: 2.10; 95% CI: 1.54, 2.86) and predicted body fat mass (highest compared with lowest sextiles: 2.55; 95% CI: 1.60, 4.06) were positively associated with all-cause mortality (all P-nonlinearity ≤ 0.03), as well as cancer and cardiovascular mortality. The highest mortality was observed among participants who had both high predicted fat mass and low fat-free mass.
Conclusions: Our data suggest a strong positive association between adiposity and mortality in a population without pre-existing disease. We observed the lowest mortality at BMI = 25.0-29.9, suggesting that the current cutoff for overweight (BMI ≥23) may require re-evaluation and that BMI alone may not be a useful measure for indicating adiposity in Asians.
Keywords: Asian; abdominal obesity; anthropometry; body composition; body fat; body mass index; death; obesity; overweight; waist circumference.

Dried fruit consumption and cardiometabolic health: a randomised crossover trial.
Sullivan VK, Petersen KS, Kris-Etherton PM.
Br J Nutr. 2020 Nov 14;124(9):912-921. doi: 10.1017/S0007114520002007. Epub 2020 Jun 9.
PMID: 32513313
Fruit intake is associated with lower risk of cardiometabolic diseases. However, effects of dried fruits on cardiometabolic health are not well researched. We investigated the effect of daily dried fruit consumption compared with a carbohydrate-rich snack on cardiometabolic disease risk factors in adults with increased cardiometabolic risk. A two-period randomised crossover trial was conducted in adults (n 55) with elevated BMI and at least one additional risk factor for cardiometabolic disease to compare the effects of consuming 3/4 cup/d mixed dried fruits (plums, figs, dates and raisins) or an energy- and carbohydrate-matched control snack for 4 weeks. The primary outcome was LDL-cholesterol; secondary outcomes included other lipids and lipoproteins, glucose and insulin, C-reactive protein, blood pressure and vascular stiffness. Linear mixed models were used for data analysis. Lipid and lipoprotein concentrations did not differ between conditions; however, dried fruit increased LDL-cholesterol (0·10 mmol/l, 95 % CI 0·01, 0·20) compared with baseline. Compared with the control, dried fruit increased mean fasting glucose (0·08 mmol/l, 95 % CI 0·005, 0·16; P = 0·038). Vascular outcomes, fasting insulin and C-reactive protein did not differ between conditions. Mean weight changes did not differ (P = 0·55) but tended to increase after both conditions (dried fruit 0·3 kg, 95 % CI -0·09, 0·65; control 0·4 kg, 95 % CI 0·01, 0·75). Thus, short-term daily consumption of a large portion of mixed dried plums, figs, dates and raisins, without structured dietary guidance, did not improve cardiometabolic risk factors, compared with carbohydrate-rich snacks, in adults with increased baseline cardiometabolic risk.
Keywords: Cardiometabolic risk; Cholesterol; Dried fruit; Fasting glucose; Phenolic compounds; Sugar; Vascular health.

Glucose control upon waking is unaffected by hourly sleep fragmentation during the night, but is impaired by morning caffeinated coffee.
Smith HA, Hengist A, Thomas J, Walhin JP, Heath P, Perkin O, Chen YC, Gonzalez JT, Betts JA.
Br J Nutr. 2020 Nov 28;124(10):1114-1120. doi: 10.1017/S0007114520001865. Epub 2020 Jun 1.
PMID: 32475359
Morning coffee is a common remedy following disrupted sleep, yet each factor can independently impair glucose tolerance and insulin sensitivity in healthy adults. Remarkably, the combined effects of sleep fragmentation and coffee on glucose control upon waking per se have never been investigated. In a randomised crossover design, twenty-nine adults (mean age: 21 (sd 1) years, BMI: 24·4 (sd 3·3) kg/m2) underwent three oral glucose tolerance tests (OGTT). One following a habitual night of sleep (Control; in bed, lights-off trying to sleep approximately 23.00-07.00 hours), the others following a night of sleep fragmentation (as Control but waking hourly for 5 min), with and without morning coffee approximately 1 h after waking (approximately 300 mg caffeine as black coffee 30 min prior to OGTT). Individualised peak plasma glucose and insulin concentrations were unaffected by sleep quality but were higher following coffee consumption (mean (normalised CI) for Control, Fragmented and Fragmented + Coffee, respectively; glucose: 8·20 (normalised CI 7·93, 8·47) mmol/l v. 8·23 (normalised CI 7·96, 8·50) mmol/l v. 8·96 (normalised CI 8·70, 9·22) mmol/l; insulin: 265 (normalised CI 247, 283) pmol/l; and 235 (normalised CI 218, 253) pmol/l; and 310 (normalised CI 284, 337) pmol/l). Likewise, incremental AUC for plasma glucose was higher in the Fragmented + Coffee trial compared with Fragmented. Whilst sleep fragmentation did not alter glycaemic or insulinaemic responses to morning glucose ingestion, if a strong caffeinated coffee is consumed, then a reduction in glucose tolerance can be expected.

Keywords: CYP1A2; Caffeine; Coffee; Glucose; Insulin; Polymorphisms; Sleep fragmentation.

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Serum testosterone is inversely, and sex hormone-binding globulin directly, associated with all-cause mortality in men.
Yeap BB, Marriott RJ, Antonio L, Chan YX, Raj S, Dwivedi G, Reid CM, Anawalt BD, Bhasin S, Dobs AS, Hankey GJ, Matsumoto AM, Norman PE, O'Neill TW, Ohlsson C, Orwoll ES, Vanderschueren D, Wittert GA, Wu FCW, Murray K.
J Clin Endocrinol Metab. 2020 Oct 16:dgaa743. doi: 10.1210/clinem/dgaa743. Online ahead of print.
PMID: 33059368
Context: Serum testosterone concentrations decline with age, while serum sex hormone-binding globulin (SHBG) concentrations increase.
Objective: To analyse associations of baseline serum testosterone and SHBG concentrations, and calculated free testosterone (cFT) values, with all-cause and cause-specific mortality in men.
Design, setting and participants: The UK Biobank prospective cohort study of community-dwelling men 40-69 years-old, followed for 11 years.
Main outcome measures: All-cause, atherosclerotic cardiovascular disease (CVD) and cancer-related mortality. Cox proportional hazards regression was performed, adjusting for age, waist circumference, medical conditions and other covariates. Models for testosterone included SHBG, and vice versa.
Results: In complete case analysis of 149,436 men with 10,053 deaths (1,925 CVD and 4,927 cancer-related), men with lower testosterone had higher mortality from any cause (lowest vs highest quintile, Q1 vs Q5, fully-adjusted hazard ratio HR =1.14, 95% confidence interval [CI]=1.06-1.22, overall trend P<0.001), and cancer (HR=1.20, CI=1.09-1.33, P<0.001), with no association for CVD deaths. Similar results were seen for cFT. Men with lower SHBG had lower mortality from any cause (Q1 vs Q5, HR=0.68, CI=0.63-0.73, P<0.001), CVD (HR=0.70, CI=0.59-0.83, P<0.001), and cancer (HR=0.80, CI=0.72-0.89, P<0.001). A multiply-imputed dataset (N=208,425, 15,914 deaths, 3,128 CVD and 7,468 cancer-related) and analysis excluding deaths within first two years (9,261, 1,734 and 4,534 events) yielded similar results.
Conclusions: Lower serum testosterone is independently associated with higher all-cause and cancer-related, but not CVD-related, mortality in middle-aged to older men. Lower SHBG is independently associated with lower all-cause, CVD-related and cancer-related mortality. Confirmation and determination of causality requires mechanistic studies and prospective trials.
Keywords: : Testosterone; cancer; cardiovascular disease; mortality; sex hormone-binding globulin.

Associations of Objectively Measured Physical Activity and Sedentary Time with the Risk of Stroke, Myocardial Infarction or All-Cause Mortality in 70-Year-Old Men and Women: A Prospective Cohort Study.
Ballin M, Nordström P, Niklasson J, Nordström A.
Sports Med. 2020 Oct 15. doi: 10.1007/s40279-020-01356-y. Online ahead of print.
PMID: 33063268
Objective: To study the associations of objectively measured physical activity (PA) and sedentary time (ST) with the combined outcome of incident stroke, myocardial infarction (MI) or all-cause mortality in older adults.
Methods: N = 3343 men and women aged 70 who participated in a health survey between 2012 and 2017 were included. Actigraph GT3X+ accelerometers were used to measure light-intensity PA (LPA), moderate-intensity PA (MPA) and ST for 1 week. Incident cases of cardiovascular disease (CVD) in terms of stroke or MI, and all-cause mortality were identified using national registers. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariable-adjusted Cox regressions.
Results: During a mean follow-up of 2.7 years (0.1-5.6), there were 124 events of CVD or all-cause mortality. After adjusting for potential confounders and mediators, every 30-min/day increment in LPA was associated with 11% lower risk of CVD or all-cause mortality (HR 0.89, 95% CI 0.82-0.97), and every 30-min/day increment in MPA was associated with 36% lower risk (HR 0.64, 95% CI 0.48-0.84). Every 1-h/day increment in ST increased the risk of the outcomes by 33% (HR 1.33, 95% CI 1.14-1.56), although there was no significant association among participants who performed ≥ 30 min/day MPA (HR 1.11, 95% CI 0.82-1.50, P = 0.034 for interaction). None of the associations were modified by sex (P > 0.4 for all).
Conclusion: Objectively measured LPA and MPA are each associated with lower risk of stroke, MI or all-cause mortality in 70-year-old individuals, while ST is associated with increased risk. The greatest risk reduction is observed for MPA, which also appears to attenuate some of the increased risks associated with ST.

Selenium, antioxidants, cardiovascular disease, and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials.
Jenkins DJA, Kitts D, Giovannucci EL, Sahye-Pudaruth S, Paquette M, Blanco Mejia S, Patel D, Kavanagh M, Tsirakis T, Kendall CWC, Pichika SC, Sievenpiper JL.
Am J Clin Nutr. 2020 Oct 14:nqaa245. doi: 10.1093/ajcn/nqaa245. Online ahead of print.
PMID: 33053149
Background: Antioxidants have been promoted for cardiovascular disease (CVD) risk reduction and for the prevention of cancer. Our preliminary analysis suggested that only when selenium was present were antioxidant mixtures associated with reduced all-cause mortality.
Objective: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the effect of selenium supplementation alone and of antioxidant mixtures with or without selenium on the risk of CVD, cancer, and mortality.
Methods: We identified studies using the Cochrane Library, Medline, and Embase for potential CVD outcomes, cancer, and all-cause mortality following selenium supplementation alone or after antioxidant supplement mixtures with and without selenium up to June 5, 2020. RCTs of ≥24 wk were included and data were analyzed using random-effects models and classified by the Grading of Recommendations, Assessment, Development, and Evaluation approach.
Results: The meta-analysis identified 9423 studies, of which 43 were used in the final analysis. Overall, no association of selenium alone or antioxidants was seen with CVD and all-cause mortality. However, a decreased risk with antioxidant mixtures was seen for CVD mortality when selenium was part of the mix (RR: 0.77; 95% CI: 0.62, 0.97; P = 0.02), with no association when selenium was absent. Similarly, when selenium was part of the antioxidant mixture, a decreased risk was seen for all-cause mortality (RR: 0.90; 95% CI: 0.82, 0.98; P = 0.02) as opposed to an increased risk when selenium was absent (RR: 1.09; 95% CI: 1.04, 1.13; P = 0.0002).
Conclusion: The addition of selenium should be considered for supplements containing antioxidant mixtures if they are to be associated with CVD and all-cause mortality risk reduction.
Keywords: all-cause mortality; antioxidants; cardiovascular disease; meta-analysis; selenium; supplements.

The Coffee-Acrylamide Apparent Paradox: An Example of Why the Health Impact of a Specific Compound in a Complex Mixture Should Not Be Evaluated in Isolation.
Nehlig A, Cunha RA.
Nutrients. 2020 Oct 14;12(10):E3141. doi: 10.3390/nu12103141.
PMID: 33066651 Free article.
The health implications of acrylamide in food are a matter of concern based on toxicological studies in rodents, which showed that doses of acrylamide more than 100 times higher than those estimated to result from dietary exposure in humans are carcinogenic; however, the cancer types reported in rodents are species-specific, and whether these results can be extrapolated to humans is still in question. In fact, human epidemiological studies revealed a general lack of association between dietary acrylamide exposure and the incidence of different cancer types. Even occupational exposure to acrylamide, resulting in acrylamide exposure nearly 10 times higher than dietary exposure, did not increase tumor occurrence. Furthermore, the consumption of coffee, which is a main contributor of dietary acrylamide exposure, actually decreases the overall incidence of cancer in humans and afford global health benefits, increasing both lifespan and healthspan on ageing. This paradox clearly illustrates the risk of evaluating an individual molecule independently of its complete food matrix, which may have other components that completely override the effects of the considered molecule.
Keywords: acrylamide; cancer; coffee; consumption; contaminant; exposure.

Short-term protein restriction at advanced age stimulates FGF21 signalling, energy expenditure and browning of white adipose tissue.
Dommerholt MB, Blankestijn M, Vieira-Lara MA, van Dijk TH, Wolters H, Koster MH, Gerding A, van Os RP, Bloks VW, Bakker BM, Kruit JK, Jonker JW.
FEBS J. 2020 Oct 22. doi: 10.1111/febs.15604. Online ahead of print.
PMID: 33089625
Dietary protein restriction has been demonstrated to improve metabolic health under various conditions. However, the relevance of ageing and age-related decline in metabolic flexibility on the effects of dietary protein restriction have not been addressed. Therefore, we investigated the effect of short-term dietary protein restriction on metabolic health in young and aged mice. Young adult (3 months old) and aged (18 months old) C57Bl/6J mice were subjected to a 3-month dietary protein restriction. Outcome parameters included FGF21 levels, muscle strength, glucose tolerance, energy expenditure, and transcriptomics of brown- and white adipose tissue. Here we report that a low protein diet had beneficial effects in aged mice by reducing some aspects of age-related metabolic decline. These effects were characterized by increased plasma levels of FGF21, browning of subcutaneous white adipose tissue, increased body temperature and energy expenditure, while no changes were observed in glucose homeostasis and insulin sensitivity. Moreover, the low protein diet used in this study was well tolerated in aged mice indicated by the absence of adverse effects on body weight, locomotor activity, and muscle performance. In conclusion, our study demonstrates that a short-term reduction in dietary protein intake can impact age-related metabolic health alongside increased FGF21 signalling, without negatively affecting muscle function. These findings highlight the potential of protein restriction as a strategy to induce energy expenditure and browning of white adipose tissue in aged individuals.
Keywords: Dietary protein restriction; FGF21 signalling; browning of white adipose tissue; energy metabolism; thermogenesis.

U.S. Decennial Life Tables for 2009-2011, United States Life Tables.
Arias E, Miniño A, Curtin S, Tejada-Vera B.
Natl Vital Stat Rep. 2020 Aug;69(8):1-73.
PMID: 33054929
Objectives-This report presents period life tables for the United States, based on age-specific death rates for the period 2009-2011. These tables are the most recent in a 110-year series of decennial life tables for the United States. Methods-This report presents complete life tables for the United States by race, Hispanic origin, and sex, based on age- specific death rates during 2009-2011. This is the first set of life tables by Hispanic origin presented in the U.S. decennial life table series. Data used to prepare these life tables include population estimates based on the 2010 decennial census; deaths occurring in the United States to U.S. residents in the 3 years 2009 through 2011; counts of U.S. resident births in the years 2007 through 2011; and population and death counts from the Medicare program for years 2009 through 2011. The methodology used to estimate life tables for the Hispanic population is based on the method first implemented with the 2006 annual U.S. life tables by Hispanic origin. The methodology used to estimate the life tables for all other groups is based on the method first implemented with the 2008 annual U.S. life tables. Results-During 2009-2011, life expectancy at birth was 78.60 years for the total U.S. population, representing an increase of 29.36 years from a life expectancy of 49.24 years in 1900. Between 1900 and 2010, life expectancy increased by 42.88 years for black females (from 35.04 to 77.92), by 39.21 years for black males (from 32.54 to 71.75), by 30.15 years for white females (from 51.08 to 81.23), and by 28.26 years for white males (from 48.23 to 76.49). During 2009-2011, Hispanic females had the highest life expectancy at birth (84.05), followed by non-Hispanic white females (81.06), Hispanic males (78.83), non-Hispanic black females (77.62), non-Hispanic white males (76.30), and non-Hispanic black males (71.41).

Time-restricted feeding prevents depressive-like and anxiety-like behaviors in male rats exposed to an experimental model of shift-work.
Guerrero-Vargas NN, Zárate-Mozo C, Guzmán-Ruiz MA, Cárdenas-Rivera A, Escobar C.
J Neurosci Res. 2020 Oct 20. doi: 10.1002/jnr.24741. Online ahead of print.
PMID: 33078850
Individuals who regularly shift their sleep timing, like night and/or shift-workers suffer from circadian desynchrony and are at risk of developing cardiometabolic diseases and cancer. Also, shift-work is are suggested to be a risk factor for the development of mood disorders such as the burn out syndrome, anxiety, and depression. Experimental and clinical studies provide evidence that food intake restricted to the normal activity phase is a potent synchronizer for the circadian system and can prevent the detrimental health effects associated with circadian disruption. Here, we explored whether adult male Wistar rats exposed to an experimental model of shift-work (W-AL) developed depressive and/or anxiety-like behaviors and whether this was associated with neuroinflammation in brain areas involved with mood regulation. We also tested whether time-restricted feeding (TRF) to the active phase could ameliorate circadian disruption and therefore would prevent depressive and anxiety-like behaviors as well as neuroinflammation. In male Wistar rats, W-AL induced depressive-like behavior characterized by hypoactivity and anhedonia and induced increased anxiety-like behavior in the open field test. This was associated with increased number of glial fibrillary acidic protein and IBA-1-positive cells in the prefrontal cortex and basolateral amygdala. Moreover W-AL caused morphological changes in the microglia in the CA3 area of the hippocampus indicating microglial activation. Importantly, TRF prevented behavioral changes and decreased neuroinflammation markers in the brain. Present results add up evidence about the importance that TRF in synchrony with the light-dark cycle can prevent neuroinflammation leading to healthy mood states in spite of circadian disruptive conditions.
Keywords: RRID:AB_10972670; RRID:AB_2109645; RRID:AB_2313606; RRID:AB_2336126; RRID:RGD_13508588; RRID:SCR_002285; RRID:SCR_003070; anxiety-like behavior; circadian; depression-like behavior; entrainment; neuroinflammation; time-restricted feeding.

High-sensitivity C-reactive protein, hemoglobin A1c and breast cancer risk: a nested case-control study from Alberta's Tomorrow Project cohort.
Price TR, Friedenreich CM, Robson PJ, Li H, Brenner DR.
Cancer Causes Control. 2020 Dec;31(12):1057-1068. doi: 10.1007/s10552-020-01329-6. Epub 2020 Sep 21.
PMID: 32959132
Purpose: Our aim is to examine the associations between high-sensitivity C-reactive protein (hsCRP) and hemoglobin A1c (HbA1c), common biomarkers of inflammation and insulin resistance, respectively, with breast cancer risk, while adjusting for measures of excess body size.
Methods: We conducted a nested case-control study within the Alberta's Tomorrow Project cohort (Alberta, Canada) including 197 incident breast cancer cases and 394 matched controls. The sample population included both pre- and postmenopausal women. Serum concentrations of hsCRP and HbA1c were measured from blood samples collected at baseline, along with anthropometric measurements, general health and lifestyle data. Conditional logistic regression was used to evaluate associations between hsCRP, HbA1c, and breast cancer risk adjusted for excess body size (body fat percentage) and other risk factors for breast cancer.
Results: Higher concentrations of hsCRP were associated with elevated breast cancer risk (odds ratio [OR] 1.27; 95% confidence interval [95% CI] 1.03-1.55). The observed associations were unchanged with adjustment for body fat percentage. Higher HbA1c concentrations were not significantly associated with an increased breast cancer risk (OR 1.22; 95% CI 0.17-8.75).
Conclusion: These data suggest that hsCRP may be associated with elevated breast cancer risk, independent of excess body size. However, elevated concentrations of HbA1c did not appear to increase breast cancer risk in apparently healthy women.
Keywords: Alberta’s Tomorrow Project cohort; Breast cancer; Hemoglobin A1c; High-sensitivity C-reactive protein; Nested case–control study.

Adiposity over the life course and prostate cancer: unraveling the complexities.
Giovannucci E.
Cancer Causes Control. 2020 Dec;31(12):1051-1055. doi: 10.1007/s10552-020-01353-6. Epub 2020 Oct 14.
PMID: 33057873
The association between obesity and prostate cancer has been extensively studied, but clear answers have evaded us. Most of the studies have been based on a single time-point measure, most commonly of body mass index (BMI) during adulthood. Emerging data suggest a complex pattern that may be better understood through a life course approach. The data suggest that early life adiposity, possibly before or during puberty, as being associated with lower risk of advanced prostate cancer. In contrast, moderate weight gain in men who were initially lean during pre-adulthood or early adulthood may increase risk of advanced prostate cancer. This pattern suggests competing factors associated with overall adiposity, some protective and some adverse. Factors that may increase risk appear to show more strongly in men who maintain a relatively low BMI but have a high waist circumference or waist:hip ratio. Possibly, this pattern may be associated with relatively high levels of factors associated with insulin resistance and related metabolic abnormalities (mostly central adiposity) while avoiding the protective factors (mostly generalized or subcutaneous adiposity). Broad measures at one time-point, such as adult BMI, are not likely to contribute further to our understanding. Instead, direct measures of visceral fat might be useful. For feasibility, combined measures, such as examining waist:hip ratio among men with normal BMI in relation to risk, might be useful. It may be informative to better determine the precise point in early life when adiposity may be protective and through what mechanisms, such as delay in puberty.
Keywords: Adiposity; Body mass index; Prostate cancer; Visceral fat.

Dietary Carbohydrates Restriction Inhibits The Development Of Cardiac Hypertrophy And Heart Failure.
Nakamura M, Odanovic N, Nakada Y, Dohi S, Zhai P, Ivessa A, Yang Z, Abdellatif M, Sadoshima J.
Cardiovasc Res. 2020 Oct 18:cvaa298. doi: 10.1093/cvr/cvaa298. Online ahead of print.
PMID: 33070172
Aims: A diet with modified components, such as a ketogenic low-carbohydrate (LC) diet, potentially extends longevity and healthspan. However, how a LC diet impacts on cardiac pathology during hemodynamic stress remains elusive. This study evaluated the effects of a LC diet high in either fat (Fat-LC) or protein (Pro-LC) in a mouse model of chronic hypertensive cardiac remodeling.
Methods and results: Wild-type mice were subjected to transverse aortic constriction, followed by feeding with the Fat-LC, the Pro-LC, or a high-carbohydrate control diet. After 4 weeks, echocardiographic, hemodynamic, histological and biochemical analyses were performed. LC diet consumption after pressure overload inhibited the development of pathological hypertrophy and systolic dysfunction compared to the control diet. An anti-hypertrophic serine/threonine kinase, GSK-3β, was re-activated by both LC diets; however, the Fat-LC, but not the Pro-LC, diet exerted cardioprotection in GSK-3β cardiac-specific knockout mice. β-hydroxybutyrate, a major ketone body in mammals, was increased in the hearts of mice fed the Fat-LC, but not the Pro-LC, diet. In cardiomyocytes, ketone body supplementation inhibited phenylephrine-induced hypertrophy, in part by suppressing mTOR signaling.
Conclusions: Strict carbohydrate restriction suppresses pathological cardiac growth and heart failure after pressure overload through distinct anti-hypertrophic mechanisms elicited by supplemented macronutrients.
Translational perspective: Hemodynamic stress, such as hypertension, induces pathological cardiac hypertrophy, leading to heart failure. There is growing evidence that modulating components of diet affects cardiac function in humans, although the causality and underlying mechanisms are poorly understood. Our study demonstrates that strict restriction of dietary carbohydrates supplemented with either fat or proteins during acute hemodynamic stress attenuates the development and progression of cardiac hypertrophy and heart failure by activating distinct anti-hypertrophic and cardioprotective signaling mechanisms. The study suggests that it would be useful to investigate the therapeutic benefit of carbohydrate restriction in patients with hypertension and cardiac hypertrophy in clinical studies.
Keywords: Low carbohydrate diet; cardiac hypertrophy; heart failure; ketone body.

Edited by AlPater

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Do I lose cognitive function as fast as my twin partner? Analyses based on classes of MMSE trajectories of twins aged 80 and older.
Muniz-Terrera G, Robitaille A, Goerdten J, Massa F, Johansson B.
Age Ageing. 2020 Oct 31:afaa239. doi: 10.1093/ageing/afaa239. Online ahead of print.
PMID: 33128547
Background: Aging is associated with an increasing risk of decline in cognitive abilities. The decline is, however, not a homogeneous process. There are substantial differences across individuals although previous investigations have identified individuals with distinct cognitive trajectories. Evidence is accumulating that lifestyle contributes significantly to the classification of individuals into various clusters. How and whether genetically related individuals, like twins, change in a more similar manner is yet not fully understood.
Methods: In this study, we fitted growth mixture models to Mini Mental State Exam (MMSE) scores from participants of the Swedish OCTO twin study of oldest-old monozygotic and same-sex dizygotic twins with the purpose of investigating whether twin pairs can be assigned to the same class of cognitive change.
Results: We identified four distinct groups (latent classes) whose MMSE trajectories followed different patterns of change over time: two classes of high performing individuals who remained stable and declined slowly, respectively, a group of mildly impaired individuals with a fast decline and a small group of impaired individuals who declined more rapidly. Notably, our analyses show no association between zygosity and class assignment.
Conclusions: Our study provides evidence for a more substantial impact of environmental, rather than genetic, influences on cognitive change trajectories in later life.
Keywords: Cognitive trajectories; Growth Mixture Models; Twins; older people.

Body size and weight change over adulthood and risk of breast cancer by menopausal and hormone receptor status: a pooled analysis of 20 prospective cohort studies.
van den Brandt PA, Ziegler RG, Wang M, Hou T, Li R, Adami HO, Agnoli C, Bernstein L, Buring JE, Chen Y, Connor AE, Eliassen AH, Genkinger JM, Gierach G, Giles GG, Goodman GG, Håkansson N, Krogh V, Le Marchand L, Lee IM, Liao LM, Martinez ME, Miller AB, Milne RL, Neuhouser ML, Patel AV, Prizment A, Robien K, Rohan TE, Sawada N, Schouten LJ, Sinha R, Stolzenberg-Solomon RZ, Teras LR, Tsugane S, Visvanathan K, Weiderpass E, White KK, Willett WC, Wolk A, Zeleniuch-Jacquotte A, Smith-Warner SA.
Eur J Epidemiol. 2020 Oct 30. doi: 10.1007/s10654-020-00688-3. Online ahead of print.
PMID: 33128203
Associations between anthropometric factors and breast cancer (BC) risk have varied inconsistently by estrogen and/or progesterone receptor (ER/PR) status. Associations between prediagnostic anthropometric factors and risk of premenopausal and postmenopausal BC overall and ER/PR status subtypes were investigated in a pooled analysis of 20 prospective cohorts, including 36,297 BC cases among 1,061,915 women, using multivariable Cox regression analyses, controlling for reproductive factors, diet and other risk factors. We estimated dose-response relationships and tested for nonlinear associations using restricted cubic splines. Height showed positive, linear associations for premenopausal and postmenopausal BC risk (6-7% RR increase per 5 cm increment), with stronger associations for receptor-positive subtypes. Body mass index (BMI) at cohort baseline was strongly inversely associated with premenopausal BC risk, and strongly positively-and nonlinearly-associated with postmenopausal BC (especially among women who never used hormone replacement therapy). This was primarily observed for receptor-positive subtypes. Early adult BMI (at 18-20 years) showed inverse, linear associations for premenopausal and postmenopausal BC risk (21% and 11% RR decrease per 5 kg/m2, respectively) with stronger associations for receptor-negative subtypes. Adult weight gain since 18-20 years was positively associated with postmenopausal BC risk, stronger for receptor-positive subtypes, and among women who were leaner in early adulthood. Women heavier in early adulthood generally had reduced premenopausal BC risk, independent of later weight gain. Positive associations between height, baseline (adult) BMI, adult weight gain and postmenopausal BC risk were substantially stronger for hormone receptor-positive versus negative subtypes. Premenopausal BC risk was positively associated with height, but inversely with baseline BMI and weight gain (mostly in receptor-positive subtypes). Inverse associations with early adult BMI seemed stronger in receptor-negative subtypes of premenopausal and postmenopausal BC.
Keywords: Body height; Body weight; Breast neoplasms; Cohort studies; Estrogen receptor; Weight change.

Sleep duration and mortality in Korean adults: a population-based prospective cohort study.
Kwon S, Lee H, Lee JT, Shin MJ, Choi S, Oh H.
BMC Public Health. 2020 Oct 28;20(1):1623. doi: 10.1186/s12889-020-09720-3.
PMID: 33115463
Background: Increasing evidence suggests that sleep duration is associated with risks of various diseases including type 2 diabetes, cardiovascular disease (CVD), and certain types of cancer. However, the relationship with mortality is not clear, particularly in non-European populations. In this study, we investigated the association between sleep duration and mortality in a population-based prospective cohort of Korean adults.
Methods: This analysis included 34,264 participants (14,704 men and 19,560 women) of the Korea National Health and Nutrition Examination Survey (KNHANES) 2007-2013 who agreed to mortality follow-up through December 31, 2016. Sleep duration was self-reported at baseline and was categorized into four groups: ≤4, 5-6, 7-8, and ≥ 9 h/day. Cox proportional hazards models were performed to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the associations with mortality (all-cause as well as CVD- and cancer-specific), adjusting for potential confounders.
Results: During up to 9.5 years of follow-up, we identified a total of 1028 deaths. We observed the lowest mortality at 5-6 h/day sleep. Compared with 7-8 h/day of sleep, short (≤4 h/day) and long (≥9 h/day) sleep were associated with a 1.05-fold (95% CI = 0.79-1.39) and 1.47-fold (95% CI = 1.15-1.87) higher all-cause mortality, respectively. After additional adjustment for self-rated health, the positive association with short sleep disappeared (HR = 0.99, 95% CI = 0.75-1.32) and the association with long sleep was slightly attenuated (HR = 1.38, 95% CI = 1.08-1.76). Long sleep was also nonsignificantly positively associated with both cancer-mortality (HR = 1.30, 95% CI = 0.86-1.98) and CVD-mortality (HR = 1.27, 95% CI = 0.73-2.21). There was no statistically significant evidence for nonlinearity in the relationships between sleep duration and mortality (all-cause as well as CVD- and cancer-specific). Effect modification by age, sex, education, and occupation were not statistically significant.
Conclusions: Our findings suggest that long sleep duration is associated with an increased all-cause mortality in Korean adults.
Keywords: Asian; Cohort study; Death; Mortality; Race; Sleep.

The Anabolic Response to Dietary Protein Is Not Limited by the Maximal Stimulation of Protein Synthesis in Healthy Older Adults: A Randomized Crossover Trial.
Park S, Jang J, Choi MD, Shin YA, Schutzler S, Azhar G, Ferrando AA, Wolfe RR, Kim IY.
Nutrients. 2020 Oct 26;12(11):E3276. doi: 10.3390/nu12113276.
PMID: 33114585
We have recently demonstrated in young adults that an anabolic response with mixed meal protein intake above ~35 g/meal, previously recognized as an "optimal" protein dose, was further stimulated. However, it is unknown if this applies to older adults. We therefore examined anabolic response to a mixed meal containing either 35 g (MOD, moderate amount of protein) or 70 g (HIGH, high amount of protein) in a randomized cross-over metabolic study in older adults (n = 8). Primed continuous infusions of L-[2H5] phenylalanine and L-[2H2]tyrosine were performed to determine whole-body protein kinetics and muscle protein fractional synthesis rate (MPS) in basal fasted and fed states. Whole-body protein kinetics (NB, net protein balance; PS, protein synthesis; PB, protein breakdown) and MPS was expressed as changes from the baseline post-absorptive state. Consistent with our previous findings in young adults, both feedings resulted in a positive NB, with HIGH being more positive than MOD. Furthermore, NB (expressed as g protein∙240 min) increased linearly with an increasing amount of protein intake, expressed relative to lean body mass. The positive NB was achieved due mainly to the suppression of PB in both MOD and to a greater extent HIGH, while PS was only increased in HIGH. Consistent with the whole-body data, MPS was significantly higher in HIGH than MOD. Plasma concentrations of essential amino acids and insulin were greater in HIGH vs. MOD. We conclude that in the context of mixed meals, whole-body anabolic response linearly increases with increasing protein intake primarily through the suppression of PB, and MPS was further stimulated with protein intake above the previously considered "optimal" protein dose in older adults.
Keywords: aging; anabolic response; essential amino acids; protein breakdown; protein synthesis; stable isotope tracers.

Association of body mass index with all-cause mortality in the elderly population of Taiwan: A prospective cohort study.
Lin YK, Wang CC, Yen YF, Chen LJ, Ku PW, Chen CC, Lai YJ.
Nutr Metab Cardiovasc Dis. 2020 Aug 20:S0939-4753(20)30352-5. doi: 10.1016/j.numecd.2020.08.014. Online ahead of print.
PMID: 33097409
Background and aims: The nutritional status of the elderly is different from that of young people. Body composition changes as people age, for example, fat mass increases, muscle mass decreases, and body fat distribution is changed. We aimed to investigate the association of body mass index (BMI) with cause-specific mortality in the elderly population.
Methods and results: The data of annual health examination for the older citizens (≥65 years old) from 2006 to 2011 in Taipei City Hospital were used. Information on baseline demographics, lifestyle behaviors, medical, and drug usage were collected by a self-administered questionnaire. Cause-specific mortality was ascertained from the National Registration of Death. Individuals were followed up until death or December 31, 2012, whichever was earlier. Univariable and multivariable Cox proportional hazard analyses were applied to investigate the association between BMI and all-cause mortality. Among 81,221 older people included in the analysis, 42,602 (52.45%) were men. The mean age was 73.85 ± 6.32 years. Among the 81,221 participants, 3398 (4.18%) were underweight, 36,476 (44.91%) were normal weight, 25,708 (31.65%) were overweight, and 15,639 (19.25%) were obese. Those in the BMI category 27 ≤ BMI<28 kg/m2 had the lowest all-cause mortality risk. The BMI of lowest cause-specific mortality was between 27 kg/m2 and 28 kg/m2 in infection mortality, between 28 kg/m2 and 29 kg/m2 in circulation mortality, between 29 kg/m2 and 30 kg/m2 in respiratory mortality, and between 31 kg/m2 and 32 kg/m2 in cancer mortality.
Conclusions: The current study found a J-shaped relation between BMI and cause-specific mortality in the elderly population of Taiwan.
Keywords: Body mass index; Mortality; Older people; Risk factors.

Dietary Intake of Nε-carboxymethyl-lysine, a Major Advanced Glycation End Product, is Not Associated with Increased Risk of Mortality in Japanese Adults in the Takayama Study.
Nagata C, Wada K, Yamakawa M, Nakashima Y, Koda S, Uji T, Oba S.
J Nutr. 2020 Oct 12;150(10):2799-2805. doi: 10.1093/jn/nxaa230.
PMID: 32840609
Background: Although endogenous advanced glycation end products (AGEs) have been implicated in the development of various chronic diseases, whether AGEs in foods represent a risk to human health remains unknown.
Objectives: We aimed to estimate the intake of Nε-carboxymethyl-lysine (CML), a major AGE product, using a database of CML contents on LC-MS methods, and to examine CML's association with total and cause-specific mortality in Japanese adults.
Methods: The analysis included 13,355 men and 15,724 women, aged 35 years and older, from the Takayama study. They responded to a self-administered questionnaire in 1992. Their diet, including the CML intake, was assessed using a food-frequency questionnaire at baseline. Mortality was ascertained during 16 years of follow-up. HRs and 95% CIs for mortality were estimated separately for men and women according to CMI quartiles.
Results: We noted 2901 deaths in men and 2438 deaths in women during the follow-up. In men, as compared with the lowest quartile of intake, the highest quartile of CML was inversely associated with the risks of both total and non-cancer, non-cardiovascular disease mortality after controlling for covariates [HR = 0.89 (95% CI, 0.79-1.00; P-trend = 0.047) and HR = 0.74 (95% CI, 0.58-0.94; P-trend = 0.03), respectively]. However, stratified analyses showed both inverse and positive associations between CML intake and cause-specific mortality in women, depending on their characteristics. For example, years of education had a modifying effect on both the CML intake and non-cancer, non-cardiovascular disease mortality in women. In men, the associations of CML intake with mortality depended on food sources.
Conclusions: Overall, the present study does not support a positive association between CML intake and mortality in Japanese adults. The potential relevance of the food source of CML to the link between dietary CML and mortality warrants further attention.
Keywords: Japanese; advanced glycation end products; cohort studies; diet; mortality.

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The association of weight change and all-cause mortality in older adults: a systematic review and meta-analysis.
Alharbi TA, Paudel S, Gasevic D, Ryan J, Freak-Poli R, Owen AJ.
Age Ageing. 2020 Nov 7:afaa231. doi: 10.1093/ageing/afaa231. Online ahead of print.
PMID: 33161429
Objective: there may be age-related differences in the impact of weight change on health. This study systematically reviewed the evidence on the relationship between weight change and all-cause mortality in adults aged 65 years and older.
Methods: MEDLINE, EMBASE and CINAHL were searched from inception to 11 June 2020, PROSPERO CRD 42019142268. We included observational studies reporting on the association between weight change and all-cause mortality in older community-dwelling adults. A random-effects meta-analysis was performed to calculate pooled hazard ratios and scored based on the Agency for Healthcare Research and Quality guidelines.
Results: a total of 30 studies, including 1,219,279 participants with 69,255 deaths, demonstrated that weight loss was associated with a 59% increase in mortality risk (hazard ratio (HR): 1.59; 95% confidence interval (CI): 1.45-1.74; P < 0.001). Twenty-seven studies that reported outcomes for weight gain (1,210,116 participants with 65,481 deaths) indicated that weight gain was associated with a 10% increase in all-cause mortality (HR: 1.10; 95%CI: 1.02, 1.17; P = 0.01). Four studies investigated weight fluctuation (2,283 events among 6,901 participants), which was associated with a 63% increased mortality risk (HR: 1.66; 95%CI: 1.28, 2.15). No evidence of publication bias was observed (all P > 0.05).
Conclusion: for community-dwelling older adults, weight changes (weight loss, gain or weight fluctuation) are associated with an increased risk of all-cause mortality risk relative to stable weight. Further research is needed to determine whether these associations vary depending upon initial weight, and whether or not the weight loss/gain was intentional.
Keywords: all-cause mortality; body mass index (BMI); meta-analysis; older people; systematic review; weight change.

Vascular protective effect of aspirin and rivaroxaban upon endothelial denudation of the mouse carotid artery.
Mastenbroek TG, Karel MFA, Nagy M, Chayoua W, Korsten EIJ, Coenen DM, Debets J, Konings J, Brouns AE, Leenders PJA, van Essen H, van Oerle R, Heitmeier S, Spronk HM, Kuijpers MJE, Cosemans JMEM.
Sci Rep. 2020 Nov 9;10(1):19360. doi: 10.1038/s41598-020-76377-8.
PMID: 33168914
While in recent trials the dual pathway inhibition with aspirin plus rivaroxaban has shown to be efficacious in patients with atherosclerotic cardiovascular disease, little is known about the effects of this combination treatment on thrombus formation and vascular remodelling upon vascular damage. The aim of this study was to examine the effects of aspirin and/or rivaroxaban on injury-induced murine arterial thrombus formation in vivo and in vitro, vessel-wall remodelling, and platelet-leukocyte aggregates. Temporary ligation of the carotid artery of C57BL/6 mice, fed a western type diet, led to endothelial denudation and sub-occlusive thrombus formation. At the site of ligation, the vessel wall stiffened and the intima-media thickened. Aspirin treatment antagonized vascular stiffening and rivaroxaban treatment led to a positive trend towards reduced stiffening. Local intima-media thickening was antagonized by both aspirin or rivaroxaban treatment. Platelet-leukocyte aggregates and the number of platelets per leukocyte were reduced in aspirin and/or rivaroxaban treatment groups. Furthermore, rivaroxaban restricted thrombus growth and height in vitro. In sum, this study shows vascular protective effects of aspirin and rivaroxaban, upon vascular injury of the mouse artery.

The Effects of Cannabis Use on Cognitive Function in Healthy Aging: A Systematic Scoping Review.
Pocuca N, Walter TJ, Minassian A, Young JW, Geyer MA, Perry W.
Arch Clin Neuropsychol. 2020 Nov 7:acaa105. doi: 10.1093/arclin/acaa105. Online ahead of print.
PMID: 33159510
Background: Older adults (≥50 years) represent the fastest-growing population of people who use cannabis, potentially due to the increasing promotion of cannabis as medicine by dispensaries and cannabis websites. Given healthy aging and cannabis use are both associated with cognitive decline, it is important to establish the effects of cannabis on cognition in healthy aging.
Objective: This systematic scoping review used preferred reporting items for systematic reviews and meta-analyses guidelines to critically examine the extent of literature on this topic and highlight areas for future research.
Method: A search of six databases (PubMed, EMBASE, PsycINFO, Web of Science, Family and Society Studies Worldwide, and CINAHL) for articles published by September 2019, yielded 1,014 unique results.
Results: Six articles reported findings for older populations (three human and three rodent studies), highlighting the paucity of research in this area. Human studies revealed largely null results, likely due to several methodological limitations. Better-controlled rodent studies indicate that the relationship between ∆9-tetrahydrocannabinol (THC) and cognitive function in healthy aging depends on age and level of THC exposure. Extremely low doses of THC improved cognition in very old rodents. Somewhat higher chronic doses improved cognition in moderately aged rodents. No studies examined the effects of cannabidiol (CBD) or high-CBD cannabis on cognition.
Conclusions: This systematic scoping review provides crucial, timely direction for future research on this emerging issue. Future research that combines neuroimaging and cognitive assessment would serve to advance understanding of the effects of age and quantity of THC and CBD on cognition in healthy aging.
Keywords: Cannabidiol; Cannabis; Cognitive function; Older adult; ∆9-Tetrahydrocannabinol.

Dietary casein, egg albumin, and branched-chain amino acids attenuate phosphate-induced renal tubulointerstitial injury in rats.
Shimada K, Matsui I, Inoue K, Matsumoto A, Yasuda S, Katsuma Y, Sakaguchi Y, Tanaka M, Sugimoto K, Kaimori JY, Takabatake Y, Isaka Y.
Sci Rep. 2020 Nov 4;10(1):19038. doi: 10.1038/s41598-020-76228-6.
PMID: 33149246
Dietary phosphate intake is closely correlated with protein intake. However, the effects of the latter on phosphate-induced organ injuries remain uncertain. Herein, we investigated the effects of low (10.8%), moderate (23.0%), and high (35.2%) dietary casein and egg albumin administration on phosphate-induced organ injuries in rats. The moderate and high casein levels suppressed renal tubulointerstitial fibrosis and maintained mitochondrial integrity in the kidney. The serum creatinine levels were suppressed only in the high casein group. Phosphate-induced muscle weakness was also ameliorated by high dietary casein. The urinary and fecal phosphate levels in the early experiment stage showed that dietary casein did not affect phosphate absorption from the intestine. High dietary egg albumin showed similar kidney protective effects, while the egg albumin effects on muscle weakness were only marginally significant. As the plasma branched-chain amino acid levels were elevated in casein- and egg albumin-fed rats, we analyzed their effects. Dietary supplementation of 10% branched-chain amino acids suppressed phosphate-induced kidney injury and muscle weakness. Although dietary protein restriction is recommended in cases of chronic kidney disease, our findings indicate that the dietary casein, egg albumin, and branched-chain amino acid effects might be reconsidered in the era of a phosphate-enriched diet.

[No offence but you seemed to come to mind, mccoy.]
Body dysmorphia: 'Bigorexia leading to depression' in gym-goers
By Gemma Dunstan
BBC Wales News

Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects.
Strong R, Miller RA, Bogue M, Fernandez E, Javors MA, Libert S, Marinez PA, Murphy MP, Musi N, Nelson JF, Petrascheck M, Reifsnyder P, Richardson A, Salmon AB, Macchiarini F, Harrison DE.
Aging Cell. 2020 Nov 4:e13269. doi: 10.1111/acel.13269. Online ahead of print.
PMID: 33145977
To see if variations in timing of rapamycin (Rapa), administered to middle aged mice starting at 20 months, would lead to different survival outcomes, we compared three dosing regimens. Initiation of Rapa at 42 ppm increased survival significantly in both male and female mice. Exposure to Rapa for a 3-month period led to significant longevity benefit in males only. Protocols in which each month of Rapa treatment was followed by a month without Rapa exposure were also effective in both sexes, though this approach was less effective than continuous exposure in female mice. Interpretation of these results is made more complicated by unanticipated variation in patterns of weight gain, prior to the initiation of the Rapa treatment, presumably due to the use of drug-free food from two different suppliers. The experimental design included tests of four other drugs, minocycline, β-guanidinopropionic acid, MitoQ, and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), but none of these led to a change in survival in either sex.
Keywords: 17-DMAG; MitoQ; minocycline; rapamycin; survival; β-GPA.

Television Viewing Time and the Risk of Colorectal Cancer Mortality among Japanese Population: The JACC Study.
Li Y, Eshak ES, Cui R, Shirai K, Liu K, Iso H, Satoyo K, Tamakoshi A, Ukawa S; JACC Study Group.
Cancer Res Treat. 2020 Oct 27. doi: 10.4143/crt.2020.327. Online ahead of print.
PMID: 33138348
Purpose: Sedentary behavior attributes to the increased risk of some cancers and all-cause mortality. The evidence is limited for the association between television (TV) viewing time, a major sedentary behavior, and risk of colorectal cancer death. We aimed to examine this association in Japanese population.
Methods and methods: A prospective cohort study encompassed of 90,834 men and women aged 40-79 years with no prior history of colorectal cancer who completed a self-administered food frequency questionnaire, and provided their TV viewing information. The participants were followed-up from 1988-1990 to the end of 2009. The hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated by the Cox proportional hazard regression for risk of colorectal cancer mortality according to TV viewing time.
Results: : During the median 19.1-year follow-up period, we documented 749 (385 men and 364 women) colorectal cancer deaths. The multivariable-adjusted HRs for mortality from colorectal cancer were 1.11 (0.88-1.41) for 1.5 to < 3 hr/day, 1.14 (0.91-1.42) for 3 to < 4.5 hr/day and 1.33 (1.02-1.73) for ≥ 4.5 hr/day in comparison to < 1.5 hr/day TV watching; p-trend=0.038, and that for 1-hour increment in TV viewing time was 1.06 (1.01-1.11). Moreover, the multivariable-adjusted HR (95%CI) of colon cancer for 1-hour increment in TV viewing time was 1.07 (1.02-1.13). Age, body mass index, and level of leisure-physical activity did not show significant effect modifications on the observed associations.
Conclusion: TV viewing time is associated with the increased risk of colorectal cancer mortality among Japanese population, more specifically colon rather than rectal cancer.
Keywords: Cohort study; Colorectal neoplasms; Japan; Sedentary behavior; Television viewing time.

Dietary intake of total, animal and plant proteins and the risk of coronary heart disease and hypertension: a systematic review and dose-response meta-analysis of prospective cohort studies.
Mousavi SM, Jayedi A, Jalilpiran Y, Hajishafiee M, Aminianfar A, Esmaillzadeh A.
Crit Rev Food Sci Nutr. 2020 Nov 2:1-14. doi: 10.1080/10408398.2020.1841730. Online ahead of print.
PMID: 33131293
Background & objectives: Previous findings assessing the association between long-term protein intake and cardiovascular diseases (CVDs) are inconsistent. This study aimed to summarize previous investigations on the association between total, animal and plant proteins intake and the risk of coronary heart disease (CHD) and hypertension (HTN) in adults.
Methods: Related papers were found by searching through PubMed/Medline, Scopus, and Google Scholar up to April 2020. Prospective cohort studies examined the association between consumption of the dietary protein from different sources and the risk of CHD and HTN in general population, were included. The random-effects model was used to pool the reported relative risks (RR). Dose-response associations were modeled by restricted cubic splines.
Results: Thirteen prospective studies, in total, including 547,303 participants- 11,590 cases with total CHD and 5,620 with HTN- were included. Dietary intake of total protein was not significantly associated with the risk of total CHD (RR: 0.97; 95%CI: 0.90-1.05) and HTN (RR: 1.01; 95% CI: 0.90-1.14). Moreover, consumption of both dietary plant and animal protein was not related to the risk of total CHD and HTN. Dose-response analysis indicated that the risk of CHD and HTN did not change significantly with increasing dietary total protein intake from 10% to 25% of total calorie intake.
Conclusions: Dietary protein intake from different sources had no significant association with risk of CHD and HTN. Further high-quality research is needed to examine the potential mechanistic links between dietary protein intake and health outcomes.
Keywords: Dietary protein; animal protein; coronary heart disease; hypertension; plant protein; prospective.

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Sleep duration and all-cause mortality: links to physical activity and prefrailty in a 27-year follow up of older adults in the UK.
Morgan K, Hartescu I.
Sleep Med. 2019 Feb;54:231-237. doi: 10.1016/j.sleep.2018.11.008. Epub 2018 Nov 24.
PMID: 30584984
Objectives: To assess sleep duration-mortality relationships across a 27-year follow-up period in a well characterized random sample of older people, and to test the hypothesis that mortality risks associated with long sleep duration confound with, and can be explained by, low levels of functional capacity indicative of frailty.
Methods: Face-to-face interviews conducted among 1002 randomly sampled older (65+) people in 1985 provided baseline profiles of health, functional capacity, physical activity, and sleep quality and duration. Health and functional status in each of 6 sleep duration categories (≤4, 5, 6, 7, 8, ≥9 h) was examined. At censorship in 2012, 927 deaths were recorded. Relationships between sleep duration and 27-year all-cause mortality were then examined in a series of incrementally adjusted Cox regression models.
Results: Associations between sleep duration and measures of sleep quality were predominantly linear, with longer sleep times indicating superior sleep quality. Relationships between sleep duration and functional capacity, on the other hand, were predominantly quadratic, with most approximating a U-shaped function. Adjusted for age, gender, social class, insomnia symptoms, physical health, depression, BMI and smoking status, long sleep duration and continuous hypnotic drug use at baseline were significantly and independently associated with elevated mortality risk (HR: 1.37; 95% CI: 1.05-1.78; HR: 1.24; 95% CI: 1.01-1.51). When indices of frailty were added to the model, hazard ratios for long sleep duration and hypnotic drug became non-significant, while the lowest physical activity quintile and very slow walking speed significantly increased mortality risk (HR: 1.79; 95% CI: 1.40-2.30; HR: 1.41; 95% CI: 1.15-1.73 respectively).
Conclusions: In analyses of sleep-related mortality outcomes long sleep durations confound with, and may be indicative of, incipient frailty among older participants.
Keywords: Frailty; Insomnia; Mortality; Physical activity; Sedentary behavior; Sleep duration.

Glycine supplementation extends lifespan of male and female mice.
Miller RA, Harrison DE, Astle CM, Bogue MA, Brind J, Fernandez E, Flurkey K, Javors M, Ladiges W, Leeuwenburgh C, Macchiarini F, Nelson J, Ryazanov AG, Snyder J, Stearns TM, Vaughan DE, Strong R.
Aging Cell. 2019 Jun;18(3):e12953. doi: 10.1111/acel.12953. Epub 2019 Mar 27.
PMID: 30916479 Free PMC article.
Diets low in methionine extend lifespan of rodents, though through unknown mechanisms. Glycine can mitigate methionine toxicity, and a small prior study has suggested that supplemental glycine could extend lifespan of Fischer 344 rats. We therefore evaluated the effects of an 8% glycine diet on lifespan and pathology of genetically heterogeneous mice in the context of the Interventions Testing Program. Elevated glycine led to a small (4%-6%) but statistically significant lifespan increase, as well as an increase in maximum lifespan, in both males (p = 0.002) and females (p < 0.001). Pooling across sex, glycine increased lifespan at each of the three independent sites, with significance at p = 0.01, 0.053, and 0.03, respectively. Glycine-supplemented females were lighter than controls, but there was no effect on weight in males. End-of-life necropsies suggested that glycine-treated mice were less likely than controls to die of pulmonary adenocarcinoma (p = 0.03). Of the 40 varieties of incidental pathology evaluated in these mice, none were increased to a significant degree by the glycine-supplemented diet. In parallel analyses of the same cohort, we found no benefits from TM5441 (an inhibitor of PAI-1, the primary inhibitor of tissue and urokinase plasminogen activators), inulin (a source of soluble fiber), or aspirin at either of two doses. Our glycine results strengthen the idea that modulation of dietary amino acid levels can increase healthy lifespan in mice, and provide a foundation for further investigation of dietary effects on aging and late-life diseases.
Keywords: anti-aging; life span; longevity regulation.

Glycolytic inhibition: an effective strategy for developing calorie restriction mimetics.
Ingram DK, Roth GS.
Geroscience. 2020 Nov 12. doi: 10.1007/s11357-020-00298-7. Online ahead of print.
PMID: 33184758
Calorie restriction mimetics encompass a growing research field directed toward developing treatments that mimic the anti-aging effects of long-term calorie restriction without requiring a change in eating habits. A wide range of approaches have been identified that include (1) intestinal inhibitors of fat and carbohydrate metabolism; (2) inhibitors of intracellular glycolysis; (3) stimulators of the AMPK pathway; (4) sirtuin activators; (5) inhibitors of the mTOR pathway, and (6) polyamines. Several biotech companies have been formed to pursue several of these strategies. The objective of this review is to describe the approaches directed toward glycolytic inhibition. This upstream strategy is considered an effective means to invoke a wide range of anti-aging mechanisms induced by CR. Anti-cancer and anti-obesity effects are important considerations in early development efforts. Although many dozens of candidates could be discussed, the compounds selected to be reviewed are the following: 2-deoxyglucose, 3-bromopyruvate, chrysin, genistein, astragalin, resveratrol, glucosamine, mannoheptulose, and D-allulose. Some candidates have been investigated extensively with both positive and negative results, while others are only beginning to be studied.
Keywords: Aging; Glucose; Glycolysis; Insulin; Longevity.

Do vigorous-intensity and moderate-intensity physical activities reduce mortality to the same extent? A systematic review and meta-analysis.
Rey Lopez JP, Sabag A, Martinez Juan M, Rezende LFM, Pastor-Valero M.
BMJ Open Sport Exerc Med. 2020 Oct 5;6(1):e000775. doi: 10.1136/bmjsem-2020-000775. eCollection 2020.
PMID: 33178440 Free PMC article. Review.
Objective: To examine whether vigorous-intensity physical activity confers additional reductions on all-cause and cause-specific mortality compared with moderate-intensity physical activity.
Design: A systematic review (registered in PROSPERO CRD42019138995) and meta-analysis.
Data sources: Three electronic databases up to April 14 2020.
Eligibility criteria: Inclusion criteria were prospective studies that contained information about (1) moderate-intensity (3-5.9 metabolic equivalent tasks (METs)) and vigorous-intensity (≥6 METs) physical activities and (2) all-cause and/or cause-specific mortality. Exclusion criteria were prospective studies that (1) exclusively recruited diseased patients (eg, hypertensive patients and diabetics) or (2) did not account for total physical activity in their multivariable models (3) or did not adjust or exclude individuals with comorbidities at baseline or (4) used physically inactive participants as reference group.
Results: Five studies (seven cohorts using sex-specific results) were pooled into a meta-analysis. For all-cause mortality and controlling by total physical activity, vigorous-intensity physical activity (vs moderate) was not associated with a larger reduction in mortality (HR 0.95, 95% CI 0.83 to 1.09). After the exclusion of one study judged with critical risk of bias (Risk Of Bias in Non randomized Studies, ROBINS tool) from meta-analysis, results remained similar (HR 0.98, 95% CI 0.85 to 1.12). Due to the limited number of studies, meta-analyses for cancer and cardiovascular mortality were not performed.
Conclusions: Prospective studies suggest that, for the same total physical activity, both vigorous-intensity and moderate-intensity physical activities reduce all-cause mortality to the same extent. However, absence of evidence must not be interpreted as evidence of absence due to the existing methodological flaws in the literature.
Keywords: Epidemiology; physical activity; prevention.

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The Relationship of Accelerometer-Assessed Standing Time With and Without Ambulation and Mortality: The WHI OPACH Study.
Jain P, Bellettiere J, Glass N, LaMonte MJ, Di C, Wild RA, Evenson KR, LaCroix AZ.
J Gerontol A Biol Sci Med Sci. 2020 Oct 12:glaa227. doi: 10.1093/gerona/glaa227. Online ahead of print.
PMID: 33225345
Background: Self-reported time spent standing has been associated with lower risk of mortality. No previous studies have examined this association using device-measured standing.
Method: This was a prospective cohort study of 5878 older (median age = 80 years), racial/ethnically diverse, community-dwelling women in the WHI Objective Physical Activity and Cardiovascular Health Study (OPACH). Women wore accelerometers for 1 week and were followed for mortality. The study applied previously validated machine learning algorithms to ActiGraph GT3X+ accelerometer data to separately measure time spent standing with and without ambulation. Cox proportional hazards models were used to estimate mortality risk adjusting for potential confounders. Effect modification by age, body mass index, moderate-to-vigorous physical activity, sedentary time, physical functioning, and race/ethnicity was evaluated.
Results: There were 691 deaths during 26 649 person-years of follow-up through March 31, 2018 (mean follow-up = 4.8 years). In fully adjusted models, all-cause mortality risk was lower among those with more standing without ambulation (quartile [Q] 4 vs Q1 HR = 0.63; 95% CI = 0.49-0.81, p-trend = .003) and more standing with ambulation (Q4 vs Q1 HR = 0.50; 95% CI = 0.35-0.71, p-trend < .001). Associations of standing with ambulation and mortality were stronger among women with above-median sedentary time (HR = 0.51; 95% CI = 0.38-0.68) compared to women with below-median sedentary time (HR = 0.80; 95% CI = 0.59-1.07; p-interaction = .02).
Conclusions: In this prospective study among older women, higher levels of accelerometer-measured standing were associated with lower risks of all-cause mortality. Standing is an achievable approach to interrupting prolonged sedentary time, and if not contraindicated, is a safe and feasible behavior that appears to benefit health in older ages.
Keywords: Accelerometer; Longevity; Physical activity.

Association of level of leisure-time physical activity with risks of all-cause mortality and cardiovascular disease in an elderly Chinese population: a prospective cohort study.
Zhao H, Zhang XN, Shi Z, Yin L, Zhang WL, He K, Xue HQ, Zhao XY, Shi SH.
J Geriatr Cardiol. 2020 Oct 28;17(10):628-637. doi: 10.11909/j.issn.1671-5411.2020.10.003.
PMID: 33224182 Free PMC article.
Background: Implementing the current guidelines for leisure-time physical activity (LTPA) provides significant health benefits, especially for middle-aged adults, but it is unclear whether LTPA also translates into cardiovascular health benefits among elderly people. Therefore, we aimed to assess the association of LTPA with the risks of cardiovascular disease (CVD), including coronary heart disease (CHD) and stroke, and all-cause mortality in an elderly population.
Methods: In this prospective cohort study, 32, 942 participants aged 60 years or older who participated in a health check-up programme in China between 2010 and 2018 were included. We evaluated the morbidity and mortality risks through the Cox regression model, competing risk model and restricted cubic spline model.
Results: During a median of 6.84 years of follow-up, there were 6, 857 elderly people with incident CVD; a total of 6, 324 deaths occurred due to all causes and 2, 060 deaths occurred due to CVD. Compared with the inactive group, reductions in CVD morbidity and mortality were observed, with hazard ratios (HRs) of 0.89 (95% CI: 0.83-0.96) and 0.81 (95% CI: 0.71-0.92) in the insufficiently active group, 0.86 (95% CI: 0.80-0.92) and 0.79 (95% CI: 0.69-0.90) in the sufficiently active group, and 0.79 (95% CI: 0.70-0.89) and 0.58 (95% CI: 0.45-0.76) in the highly active group, respectively; but no significant reductions were observed in the very highly active group, with HRs of 0.87 (95% CI: 0.71-1.06) and 0.99 (95% CI: 0.70-1.40), respectively. Compared with the inactive group, reductions in all-cause mortality were also observed, with a HR of 0.90 (95% CI: 0.84-0.97) in the insufficiently active group, 0.82 (95% CI: 0.77-0.89) in the sufficiently active group, 0.77 (95% CI: 0.67- 0.87) in the highly active group, and 0.80 (95% CI: 0.64-0.98) in the very highly active group. A restricted cubic spline diagram showed that there was an L-shaped association between LTPA and the risk of all-cause mortality but a U-shaped or reverse J-shaped relationship between LTPA and the risk of CVD morbidity and mortality, especially stroke. In addition, a subgroup analysis showed that elderly population who consistently performed LTPA for ten years or more had a lower risk of morbidity and mortality.
Conclusions: In an elderly population, even insufficient activity is associated with a decreased risk of all-cause mortality and CVD, and moderate levels of LTPA may be optimal for CVD prevention. In addition, elderly people who consistently perform LTPA over several years may experience greater health benefits.
Keywords: Cardiovascular disease; Chronic coronary disease; Leisure-time physical activity; Stroke.

Does Antihypertensive Use Moderate the Effect of Blood Pressure on Cognitive Decline in Older People?
Lennon MJ, Lam BCP, Crawford J, Brodaty H, Kochan NA, Trollor JN, Numbers K, Draper B, Thalamuthu A, Sachdev PS.
J Gerontol A Biol Sci Med Sci. 2020 Oct 12:glaa232. doi: 10.1093/gerona/glaa232. Online ahead of print.
PMID: 33225353
Background: While midlife hypertension is deleterious, late-life hypertension has been associated with better cognitive outcomes in several studies. Many questions remain, including the relative benefit or harm of a blood pressure (BP) target and antihypertensive therapy of <120 in very old individuals.
Methods: The Sydney Memory and Aging Study (n = 1015) comprises a cohort of 70- to 90-year-olds, who were followed biennially for 8 years. Global cognition was assessed with a battery of 10 neuropsychological tests. Blood pressure was measured at Waves 1 and 2 and classified into 3 systolic groupings: group 1 (≤120 mmHg), group 2 (121-140 mmHg), and group 3 (>140 mmHg). Multiple regression, linear mixed modeling, and Cox regression examined the effect of BP and antihypertensives.
Results: There were no overall significant differences in global cognition or dementia between the disparate BP groups. However, in those not taking antihypertensives, the systolic BP (SBP) > 140 mmHg group had a significantly worse global cognitive trajectory compared to SBP ≤ 120 mmHg (b = -0.067, 95% CI [-0.129, -0.006], p = .030). Within the SBP ≤ 120 mmHg group those taking antihypertensives had significantly worse global cognition trajectories compared to those not taking antihypertensives even when controlling for past history of hypertension (b = -0.077, 95% CI [-0.147, -0.007], p = .030).
Conclusions: Untreated hypertension in old age is related to worse global cognitive decline. However, ongoing treatment at new recommendations of lower SBP targets may be related to poorer cognitive decline and should be considered carefully in older populations.
Keywords: Aging; Cognition; Hypertension; Longitudinal studies; Medications.

High folic acid intake increases methylation-dependent expression of Lsr and dysregulates hepatic cholesterol homeostasis.
Leclerc D, Jelinek J, Christensen KE, Issa JJ, Rozen R.
J Nutr Biochem. 2020 Nov 18:108554. doi: 10.1016/j.jnutbio.2020.108554. Online ahead of print.
PMID: 33220403
Food fortification with folic acid and increased use of vitamin supplements have raised concerns about high folic acid intake. We previously showed that high folic acid intake was associated with hepatic degeneration, decreased levels of methylenetetrahydrofolate reductase (MTHFR), lower methylation potential, and perturbations of lipid metabolism. MTHFR synthesizes the folate derivative for methylation reactions. In this study, we assessed the possibility that high folic acid diets, fed to wild-type and Mthfr+/- mice, could alter DNA methylation and/or deregulate hepatic cholesterol homeostasis. Digital restriction enzyme analysis of methylation (DREAM) in liver revealed DNA hypomethylation of a CpG in the lipolysis-stimulated lipoprotein receptor (Lsr) gene, which is involved in hepatic uptake of cholesterol. Pyrosequencing confirmed this methylation change and identified hypomethylation of several neighboring CpG dinucleotides. Lsr expression was increased and correlated negatively with DNA methylation and plasma cholesterol. A putative binding site for E2F1 was identified. ChIP-qPCR confirmed reduced E2F1 binding when methylation at this site was altered, suggesting that it could be involved in increasing Lsr expression. Expression of genes in cholesterol synthesis, transport or turnover (Abcg5, Abcg8, Abcc2, Cyp46a1, Hmgcs1) was perturbed by high folic acid intake. We also observed increased hepatic cholesterol and increased expression of genes such as Sirt1, which might be involved in a rescue response to restore cholesterol homeostasis. Our work suggests that high folic acid consumption disturbs cholesterol homeostasis in liver. This finding may have particular relevance for MTHFR-deficient individuals, who represent ∼10% of many populations.
Keywords: 1-Carbon metabolism; Folic acid; Liver; Methyl donor; Methylenetetrahydrofolate reductase; Mouse model.

A randomized crossover trial on the effect of plant-based compared with animal-based meat on trimethylamine-N-oxide and cardiovascular disease risk factors in generally healthy adults: Study With Appetizing Plantfood-Meat Eating Alternative Trial (SWAP-MEAT).
Crimarco A, Springfield S, Petlura C, Streaty T, Cunanan K, Lee J, Fielding-Singh P, Carter MM, Topf MA, Wastyk HC, Sonnenburg ED, Sonnenburg JL, Gardner CD.
Am J Clin Nutr. 2020 Nov 11;112(5):1188-1199. doi: 10.1093/ajcn/nqaa203.
PMID: 32780794
Background: Despite the rising popularity of plant-based alternative meats, there is limited evidence of the health effects of these products.
Objectives: We aimed to compare the effect of consuming plant-based alternative meat (Plant) as opposed to animal meat (Animal) on health factors. The primary outcome was fasting serum trimethylamine-N-oxide (TMAO). Secondary outcomes included fasting insulin-like growth factor 1, lipids, glucose, insulin, blood pressure, and weight.
Methods: SWAP-MEAT (The Study With Appetizing Plantfood-Meat Eating Alternatives Trial) was a single-site, randomized crossover trial with no washout period. Participants received Plant and Animal products, dietary counseling, lab assessments, microbiome assessments (16S), and anthropometric measurements. Participants were instructed to consume ≥2 servings/d of Plant compared with Animal for 8 wk each, while keeping all other foods and beverages as similar as possible between the 2 phases.
Results: The 36 participants who provided complete data for both crossover phases included 67% women, were 69% Caucasian, had a mean ± SD age 50 ± 14 y, and BMI 28 ± 5 kg/m2. Mean ± SD servings per day were not different by intervention sequence: 2.5 ± 0.6 compared with 2.6 ± 0.7 for Plant and Animal, respectively (P = 0.76). Mean ± SEM TMAO concentrations were significantly lower overall for Plant (2.7 ± 0.3) than for Animal (4.7 ± 0.9) (P = 0.012), but a significant order effect was observed (P = 0.023). TMAO concentrations were significantly lower for Plant among the n = 18 who received Plant second (2.9 ± 0.4 compared with 6.4 ± 1.5, Plant compared with Animal, P = 0.007), but not for the n = 18 who received Plant first (2.5 ± 0.4 compared with 3.0 ± 0.6, Plant compared with Animal, P = 0.23). Exploratory analyses of the microbiome failed to reveal possible responder compared with nonresponder factors. Mean ± SEM LDL-cholesterol concentrations (109.9 ± 4.5 compared with 120.7 ± 4.5 mg/dL, P = 0.002) and weight (78.7 ± 3.0 compared with 79.6 ± 3.0 kg, P < 0.001) were lower during the Plant phase.
Conclusions: Among generally healthy adults, contrasting Plant with Animal intake, while keeping all other dietary components similar, the Plant products improved several cardiovascular disease risk factors, including TMAO; there were no adverse effects on risk factors from the Plant products.This trial was registered at clinicaltrials.gov as NCT03718988.
Keywords: cardiovascular disease risk factors; diet; meat; plant-based alternative meat; randomized controlled trial; trimethylamine-N-oxide.

Total and added sugar intakes, sugar types, and cancer risk: results from the prospective NutriNet-Sante cohort.
Debras C, Chazelas E, Srour B, Kesse-Guyot E, Julia C, Zelek L, Agaësse C, Druesne-Pecollo N, Galan P, Hercberg S, Latino-Martel P, Deschasaux M, Touvier M.
Am J Clin Nutr. 2020 Nov 11;112(5):1267-1279. doi: 10.1093/ajcn/nqaa246.
PMID: 32936868
Background: Excessive sugar intake is now recognized as a key risk factor for obesity, type 2 diabetes, and cardiovascular diseases. In contrast, evidence on the sugar-cancer link is less consistent. Experimental data suggest that sugars could play a role in cancer etiology through obesity but also through inflammatory and oxidative mechanisms and insulin resistance, even in the absence of weight gain.
Objective: The objective was to study the associations between total and added sugar intake and cancer risk (overall, breast, and prostate), taking into account sugar types and sources.
Methods: In total, 101,279 participants aged >18 y (median age, 40.8 y) from the French NutriNet-Santé prospective cohort study (2009-2019) were included (median follow-up time, 5.9 y). Sugar intake was assessed using repeated and validated 24-h dietary records, designed to register participants' usual consumption for >3500 food and beverage items. Associations between sugar intake and cancer risk were assessed by Cox proportional hazard models adjusted for known risk factors (sociodemographic, anthropometric, lifestyle, medical history, and nutritional factors).
Results: Total sugar intake was associated with higher overall cancer risk (n = 2503 cases; HR for quartile 4 compared with quartile 1: 1.17; 95% CI: 1.00, 1.37; Ptrend = 0.02). Breast cancer risks were increased (n = 783 cases; HRQ4vs.Q1 = 1.51; 95% CI: 1.14, 2.00; Ptrend = 0.0007). Results remained significant when weight gain during follow-up was adjusted for. In addition, significant associations with cancer risk were also observed for added sugars, free sugars, sucrose, sugars from milk-based desserts, dairy products, and sugary drinks (Ptrend ≤ 0.01).
Conclusions: These results suggest that sugars may represent a modifiable risk factor for cancer prevention (breast in particular), contributing to the current debate on the implementation of sugar taxation, marketing regulation, and other sugar-related policies.
Keywords: added sugars; breast cancer; cancer risk; prospective cohort; sucrose; sugars.

Grain and dietary fiber intake and bladder cancer risk: a pooled analysis of prospective cohort studies.
Yu EYW, Wesselius A, Mehrkanoon S, Brinkman M, van den Brandt P, White E, Weiderpass E, Le Calvez-Kelm F, Gunter M, Huybrechts I, Liedberg F, Skeie G, Tjonneland A, Riboli E, Giles GG, Milne RL, Zeegers MP.
Am J Clin Nutr. 2020 Nov 11;112(5):1252-1266. doi: 10.1093/ajcn/nqaa215.
PMID: 32778880
Background: Higher intakes of whole grains and dietary fiber have been associated with lower risk of insulin resistance, hyperinsulinemia, and inflammation, which are known predisposing factors for cancer.
Objectives: Because the evidence of association with bladder cancer (BC) is limited, we aimed to assess associations with BC risk for intakes of whole grains, refined grains, and dietary fiber.
Methods: We pooled individual data from 574,726 participants in 13 cohort studies, 3214 of whom developed incident BC. HRs, with corresponding 95% CIs, were estimated using Cox regression models stratified on cohort. Dose-response relations were examined using fractional polynomial regression models.
Results: We found that higher intake of total whole grain was associated with lower risk of BC (comparing highest with lowest intake tertile: HR: 0.87; 95% CI: 0.77, 0.98; HR per 1-SD increment: 0.95; 95% CI: 0.91, 0.99; P for trend: 0.023). No association was observed for intake of total refined grain. Intake of total dietary fiber was also inversely associated with BC risk (comparing highest with lowest intake tertile: HR: 0.86; 95% CI: 0.76, 0.98; HR per 1-SD increment: 0.91; 95% CI: 0.82, 0.98; P for trend: 0.021). In addition, dose-response analyses gave estimated HRs of 0.97 (95% CI: 0.95, 0.99) for intake of total whole grain and 0.96 (95% CI: 0.94, 0.98) for intake of total dietary fiber per 5-g daily increment. When considered jointly, highest intake of whole grains with the highest intake of dietary fiber showed 28% reduced risk (95% CI: 0.54, 0.93; P for trend: 0.031) of BC compared with the lowest intakes, suggesting potential synergism.
Conclusions: Higher intakes of total whole grain and total dietary fiber are associated with reduced risk of BC individually and jointly. Further studies are needed to clarify the underlying mechanisms for these findings.
Keywords: bladder cancer; cohort study; dietary fiber; dose-response analysis; grain.

Association of midlife body composition with old-age health-related quality of life, mortality, and reaching 90 years of age: a 32-year follow-up of a male cohort.
Jyväkorpi SK, Urtamo A, Kivimäki M, Salomaa V, Strandberg TE.
Am J Clin Nutr. 2020 Nov 11;112(5):1287-1294. doi: 10.1093/ajcn/nqaa230.
PMID: 32844221
Background: Overweight and obesity increase the risk of morbidity and mortality. The relations between body composition at midlife, health-related quality of life (HRQoL) in old age, and longevity are, however, less studied.
Objectives: We examined the association of midlife body composition with successful aging, defined as high HRQoL and reaching 90 y of age, during 32 y follow-up.
Methods: Participants were 1354 men from the Helsinki Businessmen Study, born 1919-1934. In 1985/1986 (mean age: 60 y) various health measurements were performed. Percentages of body fat (BF) and skeletal muscle mass (SM) were calculated using validated formulas (including waist and hip circumferences, weight, and age) and divided into quartiles. In 2000 and 2007 (mean ages: 74 and 80 y, respectively), HRQoL was assessed using RAND-36/Short Form-36 scales. Mortality was retrieved from registers through 2018, and longevity determined by calculating the proportion of participants reaching 90 y. Logistic regression was used to assess ORs with 95% CIs.
Results: Higher SM% at midlife in 1985/1986 was associated (P < 0.05) with higher scores in the RAND-36 scales of physical functioning, role limitations caused by physical health problems, vitality, social functioning, and general health in old age in 2000. In 2007 only the association with physical domain (physical functioning, role limitations caused by physical health problems) remained statistically significant (P < 0.01). BF% quartiles in 1985/1986 were inversely associated with several RAND-36 scales in 2000 and 2007. During the 32-y follow-up, 982 participants died and 281 reached 90 y of age. Being in the highest SM% quartile at midlife increased (adjusted OR: 2.32; 95% CI: 1.53, 3.53; lowest SM% quartile as reference) and being in the highest BF% quartile decreased (OR: 0.43; 95% CI: 0.28, 0.66; lowest BF% quartile as reference) the odds of reaching 90 y.
Conclusions: Desirable body composition in terms of both fat and skeletal muscle mass at midlife was associated with successful aging in men.
Keywords: body composition; body fat; longevity; quality of life; skeletal muscle; successful aging.

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Sarcopenia: prevalence, associated factors, and the risk of mortality and disability in Japanese older adults.
Kitamura A, Seino S, Abe T, Nofuji Y, Yokoyama Y, Amano H, Nishi M, Taniguchi Y, Narita M, Fujiwara Y, Shinkai S.
J Cachexia Sarcopenia Muscle. 2020 Nov 25. doi: 10.1002/jcsm.12651. Online ahead of print.
PMID: 33241660
Background: There is limited evidence on sarcopenia in Asian populations. This study aimed to clarify the prevalence, associated factors, and the magnitude of association with mortality and incident disability for sarcopenia and combinations of its components among Japanese community-dwelling older adults.
Methods: We conducted a 5.8 year prospective study of 1851 Japanese residents aged 65 years or older (50.5% women; mean age 72.0 ± 5.9) who participated in health check-ups. Sarcopenia was defined according to the Asian Working Group for Sarcopenia 2019 algorithm. Appendicular lean mass index (ALMI) was measured using direct segmental multi-frequency bioelectrical impedance analysis. A Cox proportional hazards regression model was used to identify associations of sarcopenia and the combinations of its components with all-cause mortality and incident disability.
Results: The prevalence of sarcopenia was 11.5% (105/917) in men and 16.7% (156/934) in women. Significant sarcopenia-related factors other than ageing were hypoalbuminaemia, cognitive impairment, low activity, and recent hospitalization (all P-values <0.05) among men and cognitive impairment (P = 0.004) and depressed mood (P < 0.001) among women. Individuals with sarcopenia had higher risks of mortality [hazard ratios (95% confidence interval): 2.0 (1.2-3.5) in men and 2.3 (1.1-4.9) in women] and incident disability [1.6 (1.0-2.7) in men and 1.7 (1.1-2.7) in women]. Compared with the individuals without any sarcopenia components, those having low grip strength and/or slow gait speed without low ALMI tended to have an increased risk of disability [1.4 (1.0-2.0), P = 0.087], but not mortality [1.3 (0.8-2.2)]. We did not find increased risks of these outcomes in participants having low ALMI in the absence of low grip strength and slow gait speed [1.2 (0.8-1.9) for mortality and 0.9 (0.6-1.3) for incident disability].
Conclusions: Japanese older men and women meeting Asian criteria of sarcopenia had increased risks of all-cause mortality and disability. There were no significant increased risks of death or incident disability for both participants with muscle weakness and/or low performance without low muscle mass and those with low muscle mass with neither muscle weakness nor low performance. Further studies are needed to examine the interaction between muscle loss, muscle weakness, and low performance for adverse health-related outcomes.
Keywords: Appendicular lean mass index; Community-based sample; Gait speed; Handgrip strength; Prospective study.

Joint associations of accelero-meter measured physical activity and sedentary time with all-cause mortality: a harmonised meta-analysis in more than 44 000 middle-aged and older individuals.
Ekelund U, Tarp J, Fagerland MW, Johannessen JS, Hansen BH, Jefferis BJ, Whincup PH, Diaz KM, Hooker S, Howard VJ, Chernofsky A, Larson MG, Spartano N, Vasan RS, Dohrn IM, Hagströmer M, Edwardson C, Yates T, Shiroma EJ, Dempsey P, Wijndaele K, Anderssen SA, Lee IM.
Br J Sports Med. 2020 Dec;54(24):1499-1506. doi: 10.1136/bjsports-2020-103270.
PMID: 33239356
Objectives: To examine the joint associations of accelerometer-measured physical activity and sedentary time with all-cause mortality.
Methods: We conducted a harmonised meta-analysis including nine prospective cohort studies from four countries. 44 370 men and women were followed for 4.0 to 14.5 years during which 3451 participants died (7.8% mortality rate). Associations between different combinations of moderate-to-vigorous intensity physical activity (MVPA) and sedentary time were analysed at study level using Cox proportional hazards regression analysis and summarised using random effects meta-analysis.
Results: Across cohorts, the average time spent sedentary ranged from 8.5 hours/day to 10.5 hours/day and 8 min/day to 35 min/day for MVPA. Compared with the referent group (highest physical activity/lowest sedentary time), the risk of death increased with lower levels of MVPA and greater amounts of sedentary time. Among those in the highest third of MVPA, the risk of death was not statistically different from the referent for those in the middle (16%; 95% CI 0.87% to 1.54%) and highest (40%; 95% CI 0.87% to 2.26%) thirds of sedentary time. Those in the lowest third of MVPA had a greater risk of death in all combinations with sedentary time; 65% (95% CI 1.25% to 2.19%), 65% (95% CI 1.24% to 2.21%) and 263% (95% CI 1.93% to 3.57%), respectively.
Conclusion: Higher sedentary time is associated with higher mortality in less active individuals when measured by accelerometry. About 30-40 min of MVPA per day attenuate the association between sedentary time and risk of death, which is lower than previous estimates from self-reported data.
Keywords: accelerometer; death; meta-analysis; sedentary.

Hypertension, hypotension, longevity and dementia.
Mossello E.
Monaldi Arch Chest Dis. 2020 Nov 20;90(4). doi: 10.4081/monaldi.2020.1674.
PMID: 33238701
High blood pressure at midlife has been consistently identified as a risk factor for dementia in late life, while dementia onset is typically associated with a subsequent decline of blood pressure values. A previous meta-analysis of randomized controlled studies of anti-hypertensive treatment in old age has shown a borderline effect of active treatment in reducing the risk of dementia. The cognitive sub-studies of SPRINT (SPRINT-MIND) and of HOPE-3, published in 2019, were aimed at assessing the cognitive effect of aggressive antihypertensive treatment. In SRINT-MIND, that included subjects with high vascular risk, the risk of dementia (primary outcome) did not differ between groups, but the risk of mild cognitive impairment was significantly reduced in the treatment group. Conversely in HOPE-3, that included subjects with intermediate vascular risk, no significant cognitive effect was observed, with a trend for a better outcome in the placebo arm in the subgroup with lower baseline systolic blood pressure. These data add to observational studies showing detrimental cognitive effect of lower blood pressure values in very old subjects, with cognitive impairment, disability, and complex health problems. Regarding longevity, observational studies confirm protective effects of lower blood pressure values, although systolic blood pressure <130 mmHg are associated with greater mortality risk in subjects with cognitive and/or motor impairment. On the whole antihypertensive treatment might decrease the risk of cognitive impairment in older, robust, high vascular risk subjects. Yet the presence of cognitive impairment might modify the prognostic effect of antihypertensive treatment and advise against aggressive blood pressure lowering.

Dose-response association between adult height and all-cause mortality: a systematic review and meta-analysis of cohort studies.
Li Q, Liu Y, Sun X, Li H, Cheng C, Liu L, Liu F, Zhou Q, Guo C, Tian G, Qie R, Han M, Huang S, Li L, Wang B, Zhao Y, Ren Y, Zhang M, Hu D, Wu J, Lu J.
Eur J Public Health. 2020 Nov 25:ckaa213. doi: 10.1093/eurpub/ckaa213. Online ahead of print.
PMID: 33236090
Background: We conducted a systematic review and meta-analysis from published cohort studies to examine the association of adult height and all-cause mortality and to further explore the dose-response association.
Methods: PubMed, The Cochrane Library, The Ovid, CNKI, CQVIP and Wanfang databases were searched for articles published from database inception to 6 February 2018. We used the DerSimonian-Laird random-effects model to estimate the quantitative association between adult height and all-cause mortality and the restricted cubic splines to model the dose-response association.
Results: We included 15 articles, with 1 533 438 death events and 2 854 543 study participants. For each 5-cm height increase below the average, the risk of all-cause mortality was reduced by 7% [relative risk (RR) = 0.93, 95% confidence interval (CI), 0.89-0.97] for men and 5% (RR = 0.95, 95% CI, 0.90-0.99) for women. All-cause mortality had a U-shaped association with adult height, the lowest risk occurring at 174 cm for men and 158 cm for women (both Pnonlinearity < 0.001). Relative to the shortest adult height (147 cm for men and 137 cm for women), men at 174 cm had a 47% lower likelihood of all-cause mortality and women at 158 cm a 33% lower risk of all-cause mortality.
Conclusions: Our study suggests that the relation between adult height and all-cause mortality is approximately U-shaped in both men and women.

Association of Antioxidant Vitamins A, C, E and Carotenoids with Cognitive Performance over Time: A Cohort Study of Middle-Aged Adults.
Beydoun MA, Canas JA, Fanelli-Kuczmarski MT, Maldonado AI, Shaked D, Kivimaki M, Evans MK, Zonderman AB.
Nutrients. 2020 Nov 20;12(11):E3558. doi: 10.3390/nu12113558.
PMID: 33233594
Carotenoids may strengthen the association of antioxidant vitamins A, C, and E with favorable cognitive outcomes over time, though a few prospective studies have examined this hypothesis. We evaluated the longitudinal data from 1251 participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study (Age at visit 1 in 2004-2009 (v1): 30-65 years). Vitamins A, C, and E dietary intakes and total and individual dietary carotenoids were computed using two 24-h recalls at v1. Cognitive tests, covering global mental status and domains of memory/learning, attention, psychomotor speed, visuo-spatial, language/verbal, and executive function were conducted at v1 and/or v2 (2009-2013); mean ± SD follow-up: 4.66 ± 0.93 years. Mixed-effects linear regression models detected an interaction between vitamin E and total (and individual) carotenoids for three of 11 cognitive tests at v1, with only one meeting the statistical significance upon multiple testing correction whereby vitamin E was linked with greater verbal memory performance in the uppermost total carotenoid tertile (γ0a = +0.26 ± 0.08, p = 0.002), a synergism largely driven by carotenoid lycopene. Vitamins A and C showed no consistent interactions with carotenoids. In conclusion, we provide partial evidence for synergism between vitamin E and carotenoids in relation to better baseline cognitive performance, pending further studies with time-dependent exposures and randomized trials directly examining this synergism.
Keywords: antioxidants; cognitive performance; dietary carotenoids; longitudinal studies; urban adults.

Eicosapentaenoic acid changes muscle transcriptome and intervenes in aging-related fiber type transition in male mice.
Yamazaki H, Nishimura M, Uehara M, Kuribara-Souta A, Yamamoto M, Yoshikawa N, Morohashi KI, Tanaka H.
Am J Physiol Endocrinol Metab. 2020 Nov 23. doi: 10.1152/ajpendo.00184.2020. Online ahead of print.
PMID: 33225720
Age-related sarcopenia is associated with a variety of changes in skeletal muscle. These changes are interrelated with each other and associated with systemic metabolism, the details of which, however, are largely unknown. Eicosapentaenoic acid (EPA) is a promising nutrient against sarcopenia and has multifaceted effects on systemic metabolism. In this study, we hypothesized that the aging process in skeletal muscle can be intervened by the administration of EPA. Seventy-five-week-old male mice were assigned to groups fed with EPA-deprived diet (EPA-) or EPA-enriched diet with 1wt% EPA (EPA+) for 12 weeks. Twenty-four-week-old male mice fed with normal chow were also analyzed. At baseline, the grip strength of the aging mice was lower than that of the young mice. After 12 weeks, EPA+ showed similar muscle mass but increased grip strength compared to EPA-. EPA+ displayed higher insulin sensitivity than EPA-. Immunohistochemistry and gene expression analysis of myosin heavy chains (MyHCs) revealed fast-to-slow fiber type transition in aging muscle, which was partially inhibited by EPA. RNA-seq analysis suggested that EPA supplementation exerts pathway-specific effects in skeletal muscle including the signatures of slow-to-fast fiber type transition. In conclusion, we revealed that aging skeletal muscle in male mice- shows lower grip strength and fiber type changes, both of which can be inhibited by EPA supplementation irrespective of muscle mass alteration.
Keywords: aging; eicosapentaenoic acid; fiber type transition; muscle strength; sarcopenia.

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Choline Metabolism and Risk of Atrial Fibrillation and Heart Failure in the PREDIMED Study.
Papandreou C, Bulló M, Hernández-Alonso P, Ruiz-Canela M, Li J, Guasch-Ferré M, Toledo E, Clish C, Corella D, Estruch R, Ros E, Fitó M, Alonso-Gómez A, Fiol M, Santos-Lozano JM, Serra-Majem L, Liang L, Martínez-González MA, Hu FB, Salas-Salvadó J.
Clin Chem. 2020 Nov 30:hvaa224. doi: 10.1093/clinchem/hvaa224. Online ahead of print.
PMID: 33257943
Background: Few studies have examined the associations of trimethylamine-N-oxide (TMAO) and its precursors (choline, betaine, dimethylglycine, and L-carnitine) with the risk of atrial fibrillation (AF) and heart failure (HF). This study sought to investigate these associations.
Methods: Prospective associations of these metabolites with incident AF and HF were examined among participants at high cardiovascular risk in the PREDIMED study (PREvención con DIeta MEDiterránea) after follow-up for about 10 years. Two nested case-control studies were conducted, including 509 AF incident cases matched to 618 controls and 326 HF incident cases matched to 426 controls. Plasma levels of TMAO and its precursors were semi-quantitatively profiled with liquid chromatography tandem mass spectrometry. Odds ratios were estimated with multivariable conditional logistic regression models.
Results: After adjustment for classical risk factors and accounting for multiple testing, participants in the highest quartile vs. the lowest quartile of baseline choline and betaine levels had a higher risk of AF [OR (95% CI): 1.85 (1.30-2.63) and 1.57 (1.09-2.24), respectively]. The corresponding OR for AF for extreme quartiles of dimethylglycine was 1.39 (0.99-1.96). One SD increase in log-transformed dimethylglycine was positively associated with AF risk (OR, 1.17; 1.03-1.33). The corresponding ORs for HF for extreme quartiles of choline, betaine, and dimethylglycine were 2.51 (1.57-4.03), 1.65 (1.00-2.71) and 1.65 (1.04-2.61), respectively. TMAO and L-carnitine levels were not associated with AF or HF.
Conclusions: Our findings support the role of the choline metabolic pathway in the pathogenesis of AF and HF.
Keywords: PREDIMED; Trimethylamine-N-oxide; atrial fibrillation; choline metabolism; heart failure.

Rice Bran and Vitamin B6 Suppress Pathological Neovascularization in a Murine Model of Age-Related Macular Degeneration as Novel HIF Inhibitors.
Ibuki M, Lee D, Shinojima A, Miwa Y, Tsubota K, Kurihara T.
Int J Mol Sci. 2020 Nov 25;21(23):E8940. doi: 10.3390/ijms21238940.
PMID: 33255657
Pathological neovascularization in the eye is a leading cause of blindness in all age groups from retinopathy of prematurity (ROP) in children to age-related macular degeneration (AMD) in the elderly. Inhibiting neovascularization via antivascular endothelial growth factor (VEGF) drugs has been used for the effective treatment. However, anti-VEGF therapies may cause development of chorioretinal atrophy as they affect a physiological amount of VEGF essential for retinal homeostasis. Furthermore, anti-VEGF therapies are still ineffective in some cases, especially in patients with AMD. Hypoxia-inducible factor (HIF) is a strong regulator of VEGF induction under hypoxic and other stress conditions. Our previous reports have indicated that HIF is associated with pathological retinal neovascularization in murine models of ROP and AMD, and HIF inhibition suppresses neovascularization by reducing an abnormal increase in VEGF expression. Along with this, we attempted to find novel effective HIF inhibitors from natural foods of our daily lives. Food ingredients were screened for prospective HIF inhibitors in ocular cell lines of 661W and ARPE-19, and a murine AMD model was utilized for examining suppressive effects of the ingredients on retinal neovascularization. As a result, rice bran and its component, vitamin B6 showed inhibitory effects on HIF activation and suppressed VEGF mRNA induction under a CoCl2-induced pseudo-hypoxic condition. Dietary supplement of these significantly suppressed retinal neovascularization in the AMD model. These data suggest that rice bran could have promising therapeutic values in the management of pathological ocular neovascularization.
Keywords: age-related macular degeneration; food ingredients; hypoxia-inducible factor; retinal pigment epithelium; rice bran; vascular endothelial growth factor; vitamin B6.

Effects of Matcha Green Tea Powder on Cognitive Functions of Community-Dwelling Elderly Individuals.
Sakurai K, Shen C, Ezaki Y, Inamura N, Fukushima Y, Masuoka N, Hisatsune T.
Nutrients. 2020 Nov 26;12(12):E3639. doi: 10.3390/nu12123639.
PMID: 33256220
Matcha Green Tea Powder contains a variety of active ingredients beneficial to health, such as tea catechins, lutein and vitamin K. It is also known that these ingredients confer benefits upon cognitive functions of elderly people. Therefore, we aimed to investigate the relationship between a daily supplementation of Matcha and the change in cognitive functions of community-dwelling elderly people. A randomized, double-blind, placebo-controlled 12-week trial was performed. Sixty-one participants were recruited and randomly assigned to receive test drink containing 3g powder from fresh Matcha or placebo powder per day. Changes in cognitive function were assessed utilizing a psychometric test battery. Daily food intake was assessed by a Brief-type Self-administered Diet History Questionnaire (BDHQ). In the gender-specific analysis, a significant cognitive enhancement was observed in the Montreal Cognitive Assessment (MoCA) score in the active group of women. In dietary analysis, we found a significant inverse correlation between consumption of vitamin K in daily diet, excluding test drinks, and change in MoCA. The present study suggests that daily supplementation of Matcha Green Tea Powder has protective effects against cognitive decline in community-dwelling elderly women.
Keywords: aging; cognitive function; green tea; impulsivity; memory function; vitamin K.

A high-protein total diet replacement increases energy expenditure and leads to negative fat balance in healthy, normal-weight adults.
Oliveira CLP, Boulé NG, Sharma AM, Elliott SA, Siervo M, Ghosh S, Berg A, Prado CM.
Am J Clin Nutr. 2020 Nov 18:nqaa283. doi: 10.1093/ajcn/nqaa283. Online ahead of print.
PMID: 33247306
Background: High-protein diets and total diet replacements are becoming increasingly popular for weight loss; however, further research is needed to elucidate their impact on the mechanisms involved in weight regulation.
Objective: The aim of this inpatient metabolic balance study was to compare the impact of a high-protein total diet replacement (HP-TDR) versus a control diet (CON) on select components of energy metabolism in healthy adults of both sexes.
Methods: The acute intervention was a randomized, controlled, crossover design with participants allocated to 2 isocaloric arms: 1) HP-TDR: 35% carbohydrate, 40% protein, and 25% fat achieved through a nutritional supplement; 2) CON: 55% carbohydrate, 15% protein, and 30% fat. Participants received the prescribed diets for 32 h while inside a whole-body calorimetry unit (WBCU). The first dietary intervention randomly offered in the WBCU was designed to maintain energy balance and the second matched what was offered during the first stay. Energy expenditure, macronutrient oxidation rates and balances, and metabolic blood markers were assessed. Body composition was measured at baseline using DXA.
Results: Forty-three healthy, normal-weight adults (19 females and 24 males) were included. Compared with the CON diet, the HP-TDR produced higher total energy expenditure [(EE) 81 ± 82 kcal/d, P <0.001], protein and fat oxidation rates (38 ± 34 g/d, P <0.001; 8 ± 20 g/d, P = 0.013, respectively), and a lower carbohydrate oxidation rate (-38 ± 43 g/d, P <0.001). Moreover, a HP-TDR led to decreased energy (-112 ± 85 kcal/d; P <0.001), fat (-22 ± 20 g/d; P <0.001), and carbohydrate balances (-69 ± 44 g/d; P <0.001), and increased protein balance (90 ± 32 g/d; P <0.001).
Conclusions: Our primary findings were that a HP-TDR led to higher total EE, increased fat oxidation, and negative fat balance. These results suggest that a HP-TDR may promote fat loss compared with a conventional isocaloric diet. These trials were registered at clinicaltrials.gov as NCT02811276 and NCT03565510.
Keywords: adults; energy metabolism; metabolic biomarkers; protein; total diet replacement.

A Novel Combination of Fruits and Vegetables Prevents Diet-Induced Hepatic Steatosis and Metabolic Dysfunction in Mice.
Guo W, Wu D, Dao MC, Li L, Lewis ED, Ortega EF, Eom H, Thomas M, Nikolova-Karakashian M, Meydani M, Meydani SN.
J Nutr. 2020 Nov 19;150(11):2950-2960. doi: 10.1093/jn/nxaa259.
PMID: 32939550
Background: Epidemiological studies suggest that higher fruits and vegetables (F&V) consumption correlates with reduced risk of hepatic steatosis, yet evidence for causality and the underlying mechanisms is lacking.
Objectives: We aimed to determine the causal relation between F&V consumption and improved metabolic disorders in mice fed high-fat (HF) (Experiment-1) or normal-fat (Experiment-2) diets and its underlying mechanisms.
Methods: Six-week-old male C57BL/6J mice were randomly grouped and fed diets supplemented at 0%-15% (wt:wt) with a freeze-dried powder composed of 24 commonly consumed F&V (human equivalent of 0-9 servings/d) for 20 wk. In Experiment-1, mice were fed an HF (45% kcal fat) diet with 0% (HF0), 5%, 10%, or 15% (HF15) F&V or a matched low-fat control diet (10% kcal fat). In Experiment-2, mice were fed an AIN-93 diet (basal) (B, 16% kcal fat) with 0% (B0), 5%, 10%, or 15% (B15) F&V supplementation. Body weight and composition, food intake, hepatic steatosis, inflammation, ceramide levels, sphingomyelinase activity, and gut microbiota were assessed.
Results: In Experiment-1, mice fed the HF15 diet had lower weight gain (17.9%), hepatic steatosis (48.4%), adipose tissue inflammation, blood (24.6%) and liver (33.9%) ceramide concentrations, and sphingomyelinase activity (38.8%) than HF0 mice (P < 0.05 for all). In Experiment-2, mice fed the B15 diet had no significant changes in weight gain but showed less hepatic steatosis (28.5%), blood and adipose tissue inflammation, and lower blood (30.0%) ceramide concentrations than B0 mice (P < 0.05 for all). These F&V effects were associated with favorable microbiota changes.
Conclusions: These findings represent the first evidence for a causal role of high F&V intake in mitigating hepatic steatosis in mice. These beneficial effects may be mediated through changes in ceramide and/or gut microbiota, and suggest that higher than currently recommended servings of F&V may be needed to achieve maximum health benefits.
Keywords: ceramide; fruits and vegetables; gut microbiota; hepatic steatosis; inflammation; nonalcoholic fatty liver disease.

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Objectively measured physical activity and all cause mortality: A systematic review and meta-analysis.
Ramakrishnan R, He JR, Ponsonby AL, Woodward M, Rahimi K, Blair SN, Dwyer T.
Prev Med. 2020 Dec 7:106356. doi: 10.1016/j.ypmed.2020.106356. Online ahead of print.
PMID: 33301824 Review.
Current physical activity recommendations have been based on evidence from systematic reviews of questionnaire-based data. Questionnaire-based physical activity data are subject to both random and non-random error. If the estimated association between physical activity and health outcomes was different when a more accurate, objective measure was used, this would have important health policy implications for physical activity. We conducted a systematic review and meta-analysis of published cohort studies that investigated the association between an objective measure of physical activity and all cause mortality. We searched PubMed, Scopus, Embase, Cochrane library, and SPORTDiscus for prospective cohort studies that examined the association between objectively measured (accelerometer, pedometer, or doubly labeled water method) physical activity and mortality in adults aged≥18 years, of either sex. Summary hazard ratios and 95% confidence interval [CI]s were computed using random-effects models. Thirty-three articles from 15 cohort studies were identified that together ascertained 3903 deaths. The mean years of follow-up ranged from 2.3-14.2 years. Individuals in the highest category of light, moderate-to-vigorous, and total physical activity had 40% (95%CI 20% to 55%), 56% (95%CI 41% to 67%), and 67% (95%CI 57% to 75%), respectively, lower risk for mortality compared to individuals in the lowest category of light, moderate-to-vigorous, and total physical activity. The summary hazard ratio for objectively measured physical activity and all cause mortality is lower than previously estimated from questionnaire based studies. Current recommendations for physical activity that are based on subjective measurement may underestimate the true reduction in mortality risk associated with physical activity.
Keywords: Accelerometry; Exercise; Meta-analysis; Mortality; Objectively measured; Systematic review.

Efficacy and harms of remdesivir for the treatment of COVID-19: A systematic review and meta-analysis.
Piscoya A, Ng-Sueng LF, Parra Del Riego A, Cerna-Viacava R, Pasupuleti V, Roman YM, Thota P, White CM, Hernandez AV.
PLoS One. 2020 Dec 10;15(12):e0243705. doi: 10.1371/journal.pone.0243705. eCollection 2020.
PMID: 33301514
Background: Efficacy and safety of treatments for hospitalized COVID-19 are uncertain. We systematically reviewed efficacy and safety of remdesivir for the treatment of COVID-19.
Methods: Studies evaluating remdesivir in adults with hospitalized COVID-19 were searched in several engines until August 21, 2020. Primary outcomes included all-cause mortality, clinical improvement or recovery, need for invasive ventilation, and serious adverse events (SAEs). Inverse variance random effects meta-analyses were performed.
Results: We included four randomized controlled trials (RCTs) (n = 2296) [two vs. placebo (n = 1299) and two comparing 5-day vs. 10-day regimens (n = 997)], and two case series (n = 88). Studies used intravenous remdesivir 200mg the first day and 100mg for four or nine more days. One RCT (n = 236) was stopped early due to AEs; the other three RCTs reported outcomes between 11 and 15 days. Time to recovery was decreased by 4 days with remdesivir vs. placebo in one RCT (n = 1063), and by 0.8 days with 5-days vs. 10-days of therapy in another RCT (n = 397). Clinical improvement was better for 5-days regimen vs. standard of care in one RCT (n = 600). Remdesivir did not decrease all-cause mortality (RR 0.71, 95%CI 0.39 to 1.28, I2 = 43%) and need for invasive ventilation (RR 0.57, 95%CI 0.23 to 1.42, I2 = 60%) vs. placebo at 14 days but had fewer SAEs; 5-day decreased need for invasive ventilation and SAEs vs. 10-day in one RCT (n = 397). No differences in all-cause mortality or SAEs were seen among 5-day, 10-day and standard of care. There were some concerns of bias to high risk of bias in RCTs. Heterogeneity between studies could be due to different severities of disease, days of therapy before outcome determination, and how ordinal data was analyzed.
Conclusions: There is paucity of adequately powered and fully reported RCTs evaluating effects of remdesivir in hospitalized COVID-19 patients. Until stronger evidence emerges, we cannot conclude that remdesivir is efficacious for treating COVID-19.

Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort study.
Johannesen CDL, Langsted A, Mortensen MB, Nordestgaard BG.
BMJ. 2020 Dec 8;371:m4266. doi: 10.1136/bmj.m4266.
PMID: 33293274
Objective: To determine the association between levels of low density lipoprotein cholesterol (LDL-C) and all cause mortality, and the concentration of LDL-C associated with the lowest risk of all cause mortality in the general population.
Design: Prospective cohort study.
Setting: Denmark; the Copenhagen General Population Study recruited in 2003-15 with a median follow-up of 9.4 years.
Participants: Individuals randomly selected from the national Danish Civil Registration System.
Main outcome measures: Baseline levels of LDL-C associated with risk of mortality were evaluated on a continuous scale (restricted cubic splines) and by a priori defined centile categories with Cox proportional hazards regression models. Main outcome was all cause mortality. Secondary outcomes were cause specific mortality (cardiovascular, cancer, and other mortality).
Results: Among 108 243 individuals aged 20-100, 11 376 (10.5%) died during the study, at a median age of 81. The association between levels of LDL-C and the risk of all cause mortality was U shaped, with low and high levels associated with an increased risk of all cause mortality. Compared with individuals with concentrations of LDL-C of 3.4-3.9 mmol/L (132-154 mg/dL; 61st-80th centiles), the multivariable adjusted hazard ratio for all cause mortality was 1.25 (95% confidence interval 1.15 to 1.36) for individuals with LDL-C concentrations of less than 1.8 mmol/L (<70 mg/dL; 1st-5th centiles) and 1.15 (1.05 to 1.27) for LDL-C concentrations of more than 4.8 mmol/L (>189 mg/dL; 96th-100th centiles). The concentration of LDL-C associated with the lowest risk of all cause mortality was 3.6 mmol/L (140 mg/dL) in the overall population and in individuals not receiving lipid lowering treatment, compared with 2.3 mmol/L (89 mg/dL) in individuals receiving lipid lowering treatment. Similar results were seen in men and women, across age groups, and for cancer and other mortality, but not for cardiovascular mortality. Any increase in LDL-C levels was associated with an increased risk of myocardial infarction.
Conclusions: In the general population, low and high levels of LDL-C were associated with an increased risk of all cause mortality, and the lowest risk of all cause mortality was found at an LDL-C concentration of 3.6 mmol/L (140 mg/dL).

Food restriction reduces cortical bone mass and serum insulin-like growth factor-1 levels and promotes uterine atrophy in mice.
Ito E, Sato Y, Kobayashi T, Nakamura S, Kaneko Y, Soma T, Matsumoto T, Kimura A, Miyamoto K, Matsumoto H, Matsumoto M, Nakamura M, Sato K, Miyamoto T.
Biochem Biophys Res Commun. 2020 Dec 4:S0006-291X(20)32166-5. doi: 10.1016/j.bbrc.2020.11.122. Online ahead of print.
PMID: 33288195
Low energy availability in female athletes often causes hypothalamic amenorrhea and osteoporosis, in turn promoting stress fractures. Mechanisms underlying these conditions remain unclear. Here we show that model mice subjected to food restriction (FR) or FR-plus-voluntary running exercise exhibit significantly reduced bone mineral density, cortical bone parameters and uterine weight than do control mice, and that these parameters worsen in the FR-plus-exercise group. Relative to controls, FR and FR-plus-exercise groups showed significantly lower mineral apposition rate and osteoclast number and significantly reduced serum insulin-like growth factor-1 (IGF1) levels. Outcomes were rescued by ED71 or 1.25(OH)2D3 treatment. Thus, we conclude that administration of active vitamin D analogues represents a possible treatment to prevent these conditions.
Keywords: Cortical bone; Female athletes; Food restriction; IGF-1; Osteoporosis; Vitamin D.

Adiposity change and mortality in middle-aged to older Chinese: an 8-year follow-up of the Guangzhou Biobank Cohort Study.
Huang YY, Jiang CQ, Xu L, Zhang WS, Zhu F, Jin YL, Thomas GN, Cheng KK, Lam TH.
BMJ Open. 2020 Dec 4;10(12):e039239. doi: 10.1136/bmjopen-2020-039239.
PMID: 33277280
Objective: To examine the associations of change in body mass index (BMI) and waist circumference (WC) over an average of 4 years with subsequent mortality risk in middle-aged to older Chinese.
Design: Prospective cohort study based on the Guangzhou Biobank Cohort Study.
Setting: Community-based sample.
Participants: 17 773 participants (12 956 women and 4817 men) aged 50+ years.
Primary and secondary outcome measures: Primary outcome measure was all-cause mortality. Secondary outcome measures were cardiovascular disease (CVD) and cancer mortality. Causes of death were obtained via record linkage, and coded according to the International Classification of Diseases (tenth revision).
Results: 1424 deaths (53.4% women) occurred in the 17 773 participants (mean age 61.2, SD 6.8 years) during an average follow-up of 7.8 (SD=1.5) years, and 97.7% of participants did not have an intention of weight loss . Compared with participants with stable BMI, participants with BMI loss (>5%), but not gain, had a higher risk of all-cause mortality (HR=1.49, 95% CI 1.31 to 1.71), which was greatest in those who were underweight (HR=2.45, 95% CI 1.31 to 4.59). Similar patterns were found for WC. In contrast, for participants with a BMI of ≥27.5 kg/m2, BMI gain, versus stable BMI, was associated with 89% higher risk of all-cause mortality (HR=1.89, 95% CI 1.25 to 2.88), 72% higher risk of CVD mortality (HR=1.72, 95% CI 0.80 to 3.72) and 2.27-fold risk of cancer mortality (HR=2.27, 95% CI 1.26 to 4.10).
Conclusion: In older people, unintentional BMI/WC loss, especially in those who were underweight was associated with higher mortality risk. However, BMI gain in those with obesity showed excess risks of all-cause and cancer mortality, but not CVD mortality. Frequent monitoring of changes in body size can be used as an early warning for timely clinical investigations and interventions and is important to inform appropriate health management in older Chinese.
Keywords: epidemiology; general endocrinology; geriatric medicine; public health.

Essential Amino Acids and Protein Synthesis: Insights into Maximizing the Muscle and Whole-Body Response to Feeding.
Church DD, Hirsch KR, Park S, Kim IY, Gwin JA, Pasiakos SM, Wolfe RR, Ferrando AA.
Nutrients. 2020 Dec 2;12(12):E3717. doi: 10.3390/nu12123717.
PMID: 33276485
Ingesting protein-containing supplements and foods provides essential amino acids (EAA) necessary to increase muscle and whole-body protein synthesis (WBPS). Large variations exist in the EAA composition of supplements and foods, ranging from free-form amino acids to whole protein foods. We sought to investigate how changes in peripheral EAA after ingesting various protein and free amino acid formats altered muscle and whole-body protein synthesis. Data were compiled from four previous studies that used primed, constant infusions of L-(ring-2H5)-phenylalanine and L-(3,3-2H2)-tyrosine to determine fractional synthetic rate of muscle protein (FSR), WBPS, and circulating EAA concentrations. Stepwise regression indicated that max EAA concentration (EAACmax; R2 = 0.524, p < 0.001), EAACmax (R2 = 0.341, p < 0.001), and change in EAA concentration (ΔEAA; R = 0.345, p < 0.001) were the strongest predictors for postprandial FSR, Δ (change from post absorptive to postprandial) FSR, and ΔWBPS, respectively. Within our dataset, the stepwise regression equation indicated that a 100% increase in peripheral EAA concentrations increases FSR by ~34%. Further, we observed significant (p < 0.05) positive (R = 0.420-0.724) correlations between the plasma EAA area under the curve above baseline, EAACmax, ΔEAA, and rate to EAACmax to postprandial FSR, ΔFSR, and ΔWBPS. Taken together our results indicate that across a large variety of EAA/protein-containing formats and food, large increases in peripheral EAA concentrations are required to drive a robust increase in muscle and whole-body protein synthesis.
Keywords: aging; amino acid kinetics; anabolism; essential amino acids; muscle protein synthesis; nutrition; protein; protein quality; whole body protein synthesis.

Mortality is not increased with Diabetes in hospitalised very old adults: a multi-site review.
Smerdely P.
BMC Geriatr. 2020 Dec 3;20(1):522. doi: 10.1186/s12877-020-01913-0.
PMID: 33272212 Free PMC article.
Background: Few data exist regarding hospital outcomes in people with diabetes aged beyond 75 years. This study aimed to explore the association of diabetes with hospital outcome in the very old patient.
Methods: A retrospective review was conducted of all presentations of patients aged 65 years or more admitted to three Sydney teaching hospitals over 6 years (2012-2018), exploring primarily the outcomes of in-hospital mortality, and secondarily the outcomes of length of stay, the development of hospital-acquired adverse events and unplanned re-admission to hospital within 28 days of discharge. Demographic and outcome data, the presence of diabetes and comorbidities were determined from ICD10 coding within the hospital's electronic medical record. Logistic and negative binomial regression models were used to assess the association of diabetes with outcome.
Results: A total of 139,130 separations (mean age 80 years, range 65 to 107 years; 51% female) were included, with 49% having documented comorbidities and 26.1% a diagnosis of diabetes. When compared to people without diabetes, diabetes was not associated with increased odds of mortality (OR: 0.89 SE (0.02), p < 0.001). Further, because of a significant interaction with age, diabetes was associated with decreased odds of mortality beyond 80 years of age. While people with diabetes overall had longer lengths of stay (10.2 days SD (13.4) v 9.4 days SD (12.3), p < 0.001), increasing age was associated with shorter lengths of stay in people aged more than 90 years. Diabetes was associated with increased odds of hospital-acquired adverse events (OR: 1.09 SE (0.02), p < 0.001) and but not 28-day re-admission (OR: 0.88 SE (0.18), p = 0.523).
Conclusion: Diabetes has not been shown to have a negative impact on mortality or length of stay in hospitalised very old adults from data derived from hospital administrative records. This may allow a more measured application of diabetic guidelines in the very old hospitalised patient.
Keywords: Diabetes; Health outcomes; Hospital; Older adults.

The effect of a ketogenic diet and synergy with rapamycin in a mouse model of breast cancer.
Zou Y, Fineberg S, Pearlman A, Feinman RD, Fine EJ.
PLoS One. 2020 Dec 3;15(12):e0233662. doi: 10.1371/journal.pone.0233662. eCollection 2020.
PMID: 33270630
Background: The effects of diet in cancer, in general, and breast cancer in particular, are not well understood. Insulin inhibition in ketogenic, high fat diets, modulate downstream signaling molecules and are postulated to have therapeutic benefits. Obesity and diabetes have been associated with higher incidence of breast cancer. Addition of anti-cancer drugs together with diet is also not well studied.
Methods: Two diets, one ketogenic, the other standard mouse chow, were tested in a spontaneous breast cancer model in 34 mice. Subgroups of 3-9 mice were assigned, in which the diet were implemented either with or without added rapamycin, an mTOR inhibitor and potential anti-cancer drug.
Results: Blood glucose and insulin concentrations in mice ingesting the ketogenic diet (KD) were significantly lower, whereas beta hydroxybutyrate (BHB) levels were significantly higher, respectively, than in mice on the standard diet (SD). Growth of primary breast tumors and lung metastases were inhibited, and lifespans were longer in the KD mice compared to mice on the SD (p<0.005). Rapamycin improved survival in both mouse diet groups, but when combined with the KD was more effective than when combined with the SD.
Conclusions: The study provides proof of principle that a ketogenic diet a) results in serum insulin reduction and ketosis in a spontaneous breast cancer mouse model; b) can serve as a therapeutic anti-cancer agent; and c) can enhance the effects of rapamycin, an anti-cancer drug, permitting dose reduction for comparable effect. Further, the ketogenic diet in this model produces superior cancer control than standard mouse chow whether with or without added rapamycin.

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Associations of time-restricted eating with health-related quality of life and sleep in adults: a secondary analysis of two pre-post pilot studies.
Kesztyüs D, Fuchs M, Cermak P, Kesztyüs T.
BMC Nutr. 2020 Dec 17;6(1):76. doi: 10.1186/s40795-020-00402-2.
PMID: 33327959 Free PMC article.
Background: Therapeutic fasting may improve health-related quality of life (HRQoL) and sleep but is not applicable for everyone. Time-restricted eating (TRE) offers a low threshold alternative but research on associations with HRQoL and sleep is rare.
Methods: We conducted a secondary analysis of two pilot studies in a pre-post design, which examined TRE in healthy employees at the Ulm University and in abdominal obese patients in a general practitioners office. Participants reported their HRQoL (EQ-5D visual analogue scale) before and after 3 months of restricting their daily eating to 8-9 h. They kept a diary to protocol timing of first and last meal, sleep quality (analogue scale) and duration. Pearson's correlation coefficient was applied to test bivariate correlations between continuous variables and linear regression analyses were conducted to identify associated factors with the pre-post differences in HRQoL and the differences in sleep quality.
Results: Ninety-nine participants (aged aged 48.9 ± 1.1, 83.8% female) reached the fasting target of 15-16 h on average on 77.2 ± 18.7% of all recorded days. HRQoL increased by 7.8 ± 12.6 and sleep quality by 9.6 ± 13.9 points, but sleep duration was not extended. Regression analysis revealed mean fasting duration and baseline sleep quality as significant factors associated with changes in HRQoL. Improvements in sleep quality correlated with baseline sleep quality and HRQoL at follow-up but not with fasting. Changes in anthropometry did not correlate with the HRQoL or sleep quality.
Conclusions: TRE correlates with increased HRQoL and sleep quality independent from weight loss. TRE is easily applicable with or without medical supervision. The potential effects of TRE on health and sleep should be further investigated in larger randomized trials.
Keywords: Abdominal obesity; Employees; General practitioner; Patients; Pilot study; Sleep duration and quality; Time-restricted eating; health-related quality of life.

Quercetin improves cognitive disorder in aging mice by inhibiting NLRP3 inflammasome activation.
Li H, Chen FJ, Yang WL, Qiao HZ, Zhang SJ.
Food Funct. 2020 Dec 18. doi: 10.1039/d0fo01900c. Online ahead of print.
PMID: 33338087
Quercetin is one of the most abundant dietary flavonoid compounds, and its mechanism for combating age-related neurodegenerative diseases is unclear. In this study, quercetin (35 and 70 mg kg-1, orally administered for 4 weeks) was administered to 7-month-old aging mice (senescence-accelerated mouse prone 8 mice). As a result, it was found that quercetin could improve spatial learning and memory impairment displayed by aging mice in the Morris water maze. The results of immunoblotting reflected the protein expressions of the longevity factor (sirtuin1), inflammasomes (NLRP3 and ASC), synaptic marker (PSD95) and neurotrophic factors (BDNF and NGF) in the hippocampus of the brain. It indicated that the intervention of quercetin could increase the expression of sirtuin1 and prevent neuroinflammation, which was evident from the decrease in the protein levels of the astrocyte marker (GFAP) and inflammatory factors (cleaved-caspase 1, IL-1β and IL-18). In addition, quercetin could reduce the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in the hippocampus of aging mice. Current data indicated that quercetin might improve neuroinflammation in aging mice by regulating the Sirtuin1/NLRP3 pathway.

High-density lipoprotein cholesterol and all-cause mortality by sex and age: a prospective cohort study among 15.8 million adults.
Yi SW, Park SJ, Yi JJ, Ohrr H, Kim H.
Int J Epidemiol. 2020 Dec 12:dyaa243. doi: 10.1093/ije/dyaa243. Online ahead of print.
PMID: 33313654
Background: The associations between high-density lipoprotein cholesterol (HDL-C) levels and all-cause mortality are unclear in young adults (<45 years) and in Asian populations.
Methods: In total, 15 860 253 Korean adults underwent routine health examinations during 2009-10 and were followed until June 2018 for all-cause mortality. Hazard ratios (HRs) were calculated using Cox proportional hazard models.
Results: During a mean 8.4 years of follow-up, 555 802 individuals died. U-curve associations were found between HDL-C levels and mortality, irrespective of sex or age. The HDL-C ranges associated with the lowest mortality were 40-59 and 50-69 mg/dL (1.03-1.54 and 1.29-1.80 mmol/L) in men aged <65 and ≥65 years, respectively, and the corresponding ranges were 40-69 and 50-79 mg/dL (1.03-1.80 and 1.29-2.06 mmol/L) in women aged <45 and ≥45 years, respectively. For HDL-C ranges of 60-149 mg/dL (1.55-3.86 mmol/L), each 39 mg/dL (1 mmol/L) increase in HDL-C was associated with higher mortality [men: HR = 1.39; 95% confidence interval (CI) = 1.36-1.42; women: HR = 1.15, 95% CI = 1.11-1.18], adjusting for age. These positive associations were generally stronger at younger than older ages, whereas inverse associations for HDL-C ranges <60 mg/dL (1.55 mmol/L) were strongest in middle age (45-64 years). The U-curve associations were generally unchanged after adjustment for various confounders.
Conclusions: Korean adults showed U-curve associations of HDL-C with mortality, regardless of sex, and age. Younger adults had a lower optimal range and a stronger positive association with mortality than older adults in the high HDL-C range. Even moderately high HDL-C levels are not necessarily a sign of good health, especially in young adults.
Keywords: Asians; HDL-cholesterol; Lipids; epidemiology; general population; mortality.

Physical Activity and Mortality Across Levels of Adiposity: A Prospective Cohort Study From the UK Biobank.
Sanchez-Lastra MA, Ding D, Dalene KE, Ekelund U, Tarp J.
Mayo Clin Proc. 2020 Dec 8:S0025-6196(20)30756-4. doi: 10.1016/j.mayocp.2020.06.049. Online ahead of print.
PMID: 33309181
Objective: To examine the combined and stratified associations of physical activity and adiposity measures, modelled as body mass index (BMI), abdominal adiposity (waist circumference), and body fat percentage (BF) with all-cause mortality.
Patients and methods: Using the UK Biobank cohort, we extracted quintiles of self-reported weekly physical activity. Categories of measured BMI, waist circumference, and BF were generated. Joint associations between physical activity-adiposity categories and mortality were examined using Cox proportional hazards models adjusted for demographic, behavioral, and clinical covariates. Physical activity-mortality associations were also examined within adiposity strata. Participants were followed from baseline (2006 to 2010) through January 31, 2018.
Results: A total of 295,917 participants (median follow-up, 8.9 years, during which 6684 deaths occurred) were included. High physical activity was associated with lower risk of premature mortality in all strata of adiposity except for those with BMI ≥35 kg/m2. Highest risk (HR, 1.54; 95% CI; 1.33 to 1.79) was observed in individuals with low physical activity and high BF as compared with the high physical activity-low BF referent. High physical activity attenuated the risk of high adiposity when using BF (HR, 1.24; 95% CI; 1.04 to 1.49), but the association was weaker with BMI (HR, 1.45; 95% CI; 1.21 to 1.73). Physical activity also attenuated the association between mortality and high waist circumference.
Conclusion: Low physical activity and adiposity were both associated with a higher risk of premature mortality, but high physical activity attenuated the increased risk with adiposity irrespective of adiposity metric, except in those with a BMI ≥35 kg/m2.

Effects of low sodium diet versus high sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride.
Graudal NA, Hubeck-Graudal T, Jurgens G.
Cochrane Database Syst Rev. 2020 Dec 12;12:CD004022. doi: 10.1002/14651858.CD004022.pub5.
PMID: 33314019 Review.
Background: Recent cohort studies show that salt intake below 6 g is associated with increased mortality. These findings have not changed public recommendations to lower salt intake below 6 g, which are based on assumed blood pressure (BP) effects and no side-effects.
Objectives: To assess the effects of sodium reduction on BP, and on potential side-effects (hormones and lipids) SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to April 2018 and a top-up search in March 2020: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions. The top-up search articles are recorded under "awaiting assessment."
Selection criteria: Studies randomizing persons to low-sodium and high-sodium diets were included if they evaluated at least one of the outcome parameters (BP, renin, aldosterone, noradrenalin, adrenalin, cholesterol, high-density lipoprotein, low-density lipoprotein and triglyceride,.
Data collection and analysis: Two review authors independently collected data, which were analysed with Review Manager 5.3. Certainty of evidence was assessed using GRADE.
Main results: Since the first review in 2003 the number of included references has increased from 96 to 195 (174 were in white participants). As a previous study found different BP outcomes in black and white study populations, we stratified the BP outcomes by race. The effect of sodium reduction (from 203 to 65 mmol/day) on BP in white participants was as follows: Normal blood pressure: SBP: mean difference (MD) -1.14 mmHg (95% confidence interval (CI): -1.65 to -0.63), 5982 participants, 95 trials; DBP: MD + 0.01 mmHg (95% CI: -0.37 to 0.39), 6276 participants, 96 trials. Hypertension: SBP: MD -5.71 mmHg (95% CI: -6.67 to -4.74), 3998 participants,88 trials; DBP: MD -2.87 mmHg (95% CI: -3.41 to -2.32), 4032 participants, 89 trials (all high-quality evidence). The largest bias contrast across studies was recorded for the detection bias element. A comparison of detection bias low-risk studies versus high/unclear risk studies showed no differences. The effect of sodium reduction (from 195 to 66 mmol/day) on BP in black participants was as follows: Normal blood pressure: SBP: mean difference (MD) -4.02 mmHg (95% CI:-7.37 to -0.68); DBP: MD -2.01 mmHg (95% CI:-4.37, 0.35), 253 participants, 7 trials. Hypertension: SBP: MD -6.64 mmHg (95% CI:-9.00, -4.27); DBP: MD -2.91 mmHg (95% CI:-4.52, -1.30), 398 participants, 8 trials (low-quality evidence). The effect of sodium reduction (from 217 to 103 mmol/day) on BP in Asian participants was as follows: Normal blood pressure: SBP: mean difference (MD) -1.50 mmHg (95% CI: -3.09, 0.10); DBP: MD -1.06 mmHg (95% CI:-2.53 to 0.41), 950 participants, 5 trials. Hypertension: SBP: MD -7.75 mmHg (95% CI:-11.44, -4.07); DBP: MD -2.68 mmHg (95% CI: -4.21 to -1.15), 254 participants, 8 trials (moderate-low-quality evidence). During sodium reduction renin increased 1.56 ng/mL/hour (95%CI:1.39, 1.73) in 2904 participants (82 trials); aldosterone increased 104 pg/mL (95%CI:88.4,119.7) in 2506 participants (66 trials); noradrenalin increased 62.3 pg/mL: (95%CI: 41.9, 82.8) in 878 participants (35 trials); adrenalin increased 7.55 pg/mL (95%CI: 0.85, 14.26) in 331 participants (15 trials); cholesterol increased 5.19 mg/dL (95%CI:2.1, 8.3) in 917 participants (27 trials); triglyceride increased 7.10 mg/dL (95%CI: 3.1,11.1) in 712 participants (20 trials); LDL tended to increase 2.46 mg/dl (95%CI: -1, 5.9) in 696 participants (18 trials); HDL was unchanged -0.3 mg/dl (95%CI: -1.66,1.05) in 738 participants (20 trials) (All high-quality evidence except the evidence for adrenalin).
Authors' conclusions: In white participants, sodium reduction in accordance with the public recommendations resulted in mean arterial pressure (MAP) decrease of about 0.4 mmHg in participants with normal blood pressure and a MAP decrease of about 4 mmHg in participants with hypertension. Weak evidence indicated that these effects may be a little greater in black and Asian participants. The effects of sodium reduction on potential side effects (hormones and lipids) were more consistent than the effect on BP, especially in people with normal BP.

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Association of low plasma antioxidant levels with all-cause mortality and coronary events in healthy middle-aged men from France and Northern Ireland in the PRIME study.
McKay GJ, Lyner N, Linden GJ, Kee F, Moitry M, Biasch K, Amouyel P, Dallongeville J, Bongard V, Ferrières J, Gey KF, Patterson CC, Woodside JV.
Eur J Nutr. 2020 Dec 23. doi: 10.1007/s00394-020-02455-2. Online ahead of print.
PMID: 33355688
Background: The main underlying risk factors associated with coronary heart disease (CHD) are modifiable and oxidative injury and systemic inflammatory damage represent key aetiological factors associated with the development and progression of CHD and premature mortality.
Objective: To examine associations of plasma antioxidant status with all-cause mortality and fatal or non-fatal cardiovascular events.
Design: The PRIME study prospectively evaluated 9709 men aged 50-59 years between 1991 and 1993 in Northern Ireland and France who were free of CHD at recruitment and followed annually for deaths and cardiovascular events for 10 years. Serum concentrations of vitamin C, retinol, two forms of vitamin E (α- and γ-tocopherol) and six carotenoids were quantified by high-performance liquid chromatography. Baseline conventional risk factors were considered, as well as socioeconomic differences and lifestyle behaviours including diet, smoking habit, physical activity, and alcohol consumption through Cox regression analyses.
Results: At 10 years, there were 538 deaths from any cause and 440 fatal or non-fatal cardiovascular events. After adjustment for country, age, systolic blood pressure, diabetes, body mass index, cholesterol, high density lipoprotein cholesterol, triglycerides, height, total physical activity, alcohol consumption and smoking habit, higher levels of all antioxidants were associated with significantly lower risk of all-cause mortality, with the exception of γ-tocopherol. Only retinol was significantly associated with decreased risk of cardiovascular events in a fully adjusted model.
Conclusions: Low antioxidant levels contribute to the gradient of all-cause mortality and cardiovascular incidence independent of lifestyle behaviours and traditional cardiovascular and socioeconomic risk factors.
Keywords: Antioxidant; Cardiovascular disease; Carotenoid; Premature mortality; Retinol; Vitamin.

Sodium intake, life expectancy, and all-cause mortality.
Messerli FH, Hofstetter L, Syrogiannouli L, Rexhaj E, Siontis GCM, Seiler C, Bangalore S.
Eur Heart J. 2020 Dec 22:ehaa947. doi: 10.1093/eurheartj/ehaa947. Online ahead of print.
PMID: 33351135
Aims : Since dietary sodium intake has been identified as a risk factor for cardiovascular disease and premature death, a high sodium intake can be expected to curtail life span. We tested this hypothesis by analysing the relationship between sodium intake and life expectancy as well as survival in 181 countries worldwide.
Methods and results : We correlated age-standardized estimates of country-specific average sodium consumption with healthy life expectancy at birth and at age of 60 years, death due to non-communicable diseases and all-cause mortality for the year of 2010, after adjusting for potential confounders such as gross domestic product per capita and body mass index. We considered global health estimates as provided by World Health Organization. Among the 181 countries included in this analysis, we found a positive correlation between sodium intake and healthy life expectancy at birth (β = 2.6 years/g of daily sodium intake, R2 = 0.66, P < 0.001), as well as healthy life expectancy at age 60 (β = 0.3 years/g of daily sodium intake, R2 = 0.60, P = 0.048) but not for death due to non-communicable diseases (β = 17 events/g of daily sodium intake, R2 = 0.43, P = 0.100). Conversely, all-cause mortality correlated inversely with sodium intake (β = -131 events/g of daily sodium intake, R2 = 0.60, P < 0.001). In a sensitivity analysis restricted to 46 countries in the highest income class, sodium intake continued to correlate positively with healthy life expectancy at birth (β = 3.4 years/g of daily sodium intake, R2 = 0.53, P < 0.001) and inversely with all-cause mortality (β = -168 events/g of daily sodium intake, R2 = 0.50, P < 0.001).
Conclusion : Our observation of sodium intake correlating positively with life expectancy and inversely with all-cause mortality worldwide and in high-income countries argues against dietary sodium intake being a culprit of curtailing life span or a risk factor for premature death. These data are observational and should not be used as a base for nutritional interventions.
Keywords: Sodium intake • Salt • Diet • Life expectancy • All-cause mortality • Cardiovascular disease
Salt Reduction to Prevent Hypertension and Cardiovascular Disease: JACC State-of-the-Art Review.
He FJ, Tan M, Ma Y, MacGregor GA.
J Am Coll Cardiol. 2020 Feb 18;75(6):632-647. doi: 10.1016/j.jacc.2019.11.055.
PMID: 32057379 Review.

Marine n-3 Fatty Acids, Sudden Cardiac Death, and Ischemic Heart Disease: Fish or Supplements?
Schmidt EB, Calder PC.
J Nutr. 2020 Dec 10;150(12):3055-3057. doi: 10.1093/jn/nxaa319.
PMID: 33188414 No abstract available.

Vitamin D(3) reduces risk of cardiovascular and liver diseases by lowering homocysteine levels: double-blinded, randomised, placebo-controlled trial.
Al-Bayyari N, Hailat R, Subih H, Alkhalidy H, Eaton A.
Br J Nutr. 2021 Jan 28;125(2):139-146. doi: 10.1017/S0007114520001890. Epub 2020 Jun 1.
PMID: 32475360
The objective of this study was to evaluate the effect of vitamin D3 on total homocysteine (tHcy) and C-reactive protein (CRP) levels and liver and kidney function tests in overweight women with vitamin D deficiency. Therefore, a randomised, double-blind placebo, controlled clinical trial was conducted on 100 eligible women. Subjects were randomly divided into two groups: the placebo (n 50) and the vitamin D (n 50) which received 1250 µg vitamin D3 per week for 2 months. The participants' 25-hydroxyvitamin D (25(OH)D), tHcy, CRP, alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, creatinine and estimated glomerular filtration rate (eGFR) were measured and compared before and after treatment. Results showed that the tHcy, CRP, AST, ALT and eGFR levels after the 2nd month of vitamin D3 intervention were significantly (P < 0·001) decreased and the 25(OH)D, urea and creatinine levels were significantly (P < 0·001) increased in the treatment group. In the placebo group, no significant changes were identified throughout the follow-up period. In conclusion, vitamin D3 intervention with a treatment dose of 1250 µg/week for at least 2 months may help in lowering Hcy and CRP levels and may improve liver function tests, which in turn might help in minimising the risk of CVD and liver diseases among overweight women but negatively affect kidney function.
Keywords: C-reactive protein; Homocysteine; Liver and kidney function; Overweight women; Vitamin D3.

Association of diet with circulating trimethylamine-N-oxide concentration.
Hamaya R, Ivey KL, Lee DH, Wang M, Li J, Franke A, Sun Q, Rimm EB.
Am J Clin Nutr. 2020 Dec 10;112(6):1448-1455. doi: 10.1093/ajcn/nqaa225.
PMID: 32936862
Background: Trimethylamine-N-oxide (TMAO) is a compound that is present in seafood and produced through human gut microbial metabolism of its precursors. Previous studies have suggested that elevated TMAO concentrations are associated with an increased risk of cardiovascular events. However, the association between diet and TMAO concentrations in free-living adult populations has not been adequately described.
Objectives: The objective of this study was to identify dietary predictors of plasma TMAO concentrations.
Methods: TMAO concentrations were assessed in 2 fasting plasma samples collected 6 mo apart among 620 healthy men. Short-term and long-term dietary intakes were assessed during the same time-frame of blood collections via repeated 7-d dietary records (7DDRs) and a semiquantitative food-frequency questionnaire (SFFQ), respectively. We grouped individual food items into 21 groups and regressed against averaged TMAO concentrations. We also assessed the association between dietary scores and TMAO concentrations.
Results: In models adjusted for demographic characteristics and mutually adjusted for food groups, SFFQ-assessments of fish and egg intakes were significantly associated with increased TMAO concentration (β = 0.082; 95% CI: 0.021, 0.14; P = 0.009 for fish; β = 0.065; 95% CI: 0.004, 0.13; P = 0.039 for egg). The positive association between fish consumption and TMAO concentration was replicated in the 7DDR-assessments (β = 0.12; 95% CI: 0.060, 0.18; P < 0.001). There was no association between red meat intake and TMAO concentrations. The unhealthful plant-based diet index (uPDI) was inversely associated (β = -0.013; 95% CI: -0.021, -0.005; P = 0.001) and healthy dietary scores were positively correlated with TMAO concentration.
Conclusions: TMAO concentration was significantly associated with fish intake, but not with red meat consumption. uPDI, an unhealthy dietary pattern, was inversely related to TMAO concentration. As such, this study suggests that in free-living populations, higher circulating concentrations of TMAO cannot simply be interpreted as a marker of unhealthy food intake or an unhealthy dietary pattern.
Keywords: 7-d dietary records; fish; plant-based diet index; red meat; semiquantitative food-frequency questionnaire; trimethylamine-N-oxide.

Selenium, antioxidants, cardiovascular disease, and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials.
Jenkins DJA, Kitts D, Giovannucci EL, Sahye-Pudaruth S, Paquette M, Blanco Mejia S, Patel D, Kavanagh M, Tsirakis T, Kendall CWC, Pichika SC, Sievenpiper JL.
Am J Clin Nutr. 2020 Dec 10;112(6):1642-1652. doi: 10.1093/ajcn/nqaa245.
PMID: 33053149 Free PMC article.
Background: Antioxidants have been promoted for cardiovascular disease (CVD) risk reduction and for the prevention of cancer. Our preliminary analysis suggested that only when selenium was present were antioxidant mixtures associated with reduced all-cause mortality.
Objective: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the effect of selenium supplementation alone and of antioxidant mixtures with or without selenium on the risk of CVD, cancer, and mortality.
Methods: We identified studies using the Cochrane Library, Medline, and Embase for potential CVD outcomes, cancer, and all-cause mortality following selenium supplementation alone or after antioxidant supplement mixtures with and without selenium up to June 5, 2020. RCTs of ≥24 wk were included and data were analyzed using random-effects models and classified by the Grading of Recommendations, Assessment, Development, and Evaluation approach.
Results: The meta-analysis identified 9423 studies, of which 43 were used in the final analysis. Overall, no association of selenium alone or antioxidants was seen with CVD and all-cause mortality. However, a decreased risk with antioxidant mixtures was seen for CVD mortality when selenium was part of the mix (RR: 0.77; 95% CI: 0.62, 0.97; P = 0.02), with no association when selenium was absent. Similarly, when selenium was part of the antioxidant mixture, a decreased risk was seen for all-cause mortality (RR: 0.90; 95% CI: 0.82, 0.98; P = 0.02) as opposed to an increased risk when selenium was absent (RR: 1.09; 95% CI: 1.04, 1.13; P = 0.0002).
Conclusion: The addition of selenium should be considered for supplements containing antioxidant mixtures if they are to be associated with CVD and all-cause mortality risk reduction.
Keywords: all-cause mortality; antioxidants; cardiovascular disease; meta-analysis; selenium; supplements.

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Risk of metabolic syndrome and metabolic phenotypes in relation to biomarker-calibrated estimates of energy and protein intakes: an investigation from the Women's Health Initiative.
Vasbinder A, Tinker LF, Neuhouser ML, Pettinger M, Hale L, Di C, Zaslavsky O, Hayman LL, Lin X, Eaton C, Wang D, Scherman A, Stefanick ML, Barrington WE, Reding KW.
Am J Clin Nutr. 2020 Dec 31:nqaa334. doi: 10.1093/ajcn/nqaa334. Online ahead of print.
PMID: 33381804
Background: Metabolic syndrome (MetS) is associated with increased mortality independent of BMI, resulting in discordant metabolic phenotypes, such as metabolically healthy obese and metabolically unhealthy normal-weight individuals. Studies investigating dietary intake in MetS have reported mixed results, due in part to the limitations of self-reported measures.
Objectives: To investigate the role of biomarker-calibrated estimates of energy and protein in MetS and metabolic phenotypes.
Methods: Postmenopausal participants from the Women's Health Initiative (WHI) study who were free of MetS at baseline, had available data from FFQs at baseline, and had components of MetS at Year 3 (n = 3963) were included. Dietary energy and protein intakes were estimated using biomarker calibration methods. MetS was defined as 3 or more of the following: elevated serum triglycerides (≥150 mg/dL), low HDL cholesterol (<50 mg/dL), hypertension [systolic blood pressure (BP) ≥130 or diastolic BP ≥85 mmHg], elevated serum glucose (>100 mg/dL), and abdominal adiposity (waist circumference > 89 cm). Models were adjusted for age, WHI study component, race/ethnicity, education, income, smoking, recreational physical activity, disease history, and parity.
Results: For every 10% increment in total calibrated energy intake, women were at a 1.37-fold elevated risk of MetS (95% CI, 1.15-1.63); a 10% increment in calibrated total protein intake was associated with a 1.21-fold elevated risk of MetS (95% CI, 1.00-1.47). Specifically, animal protein intake was associated with MetS (OR, 1.08; 95% CI, 1.02-1.14), whereas vegetable protein intake was not (OR, 0.99; 95% CI, 0.95-1.03). No differences were seen when examining metabolic phenotypes.
Conclusions: We found that higher calibrated total energy, total protein, and total animal protein intakes were strongly associated with MetS. If replicated in clinical trials, these results will have implications for the promotion of energy and animal protein restrictions for the reduction of MetS risks.
Keywords: biomarker; body composition; diet; energy intake; metabolic syndrome; protein intake.

Association Between Folate and Health Outcomes: An Umbrella Review of Meta-Analyses.
Bo Y, Zhu Y, Tao Y, Li X, Zhai D, Bu Y, Wan Z, Wang L, Wang Y, Yu Z.
Front Public Health. 2020 Dec 15;8:550753. doi: 10.3389/fpubh.2020.550753. eCollection 2020.
PMID: 33384976 Free PMC article.
Background: There is no study that has systematically investigated the breadth and validity of the associations of folate and multiple health outcomes. We aimed to evaluate the quantity, validity, and credibility of evidence regarding associations between folate and multiple health outcomes by using umbrella review of meta-analysis. Methods: We searched the MEDLINE, EMBASE, and Cochrane Library databases from inception to May 20, 2018, to identify potential meta-analyses that examined the association of folate with any health outcome. For each included meta-analysis, we estimated the summary effect size and their 95% confidence interval using the DerSimonian and Laird random-effects model. We used the AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews) to assess methodological quality and the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation working group classification) to assess the quality of evidence for each outcome included in the umbrella review. Results: Overall, 108 articles reporting 133 meta-analyses of observational studies and 154 meta-analyses of randomized controlled trials (RCTs) were included in the study. Among them, 108 unique exposure-outcome-population triplets (referred to as unique meta-analyses hereafter) of RCTs and 87 unique meta-analyses of observational studies were reanalyzed. Beneficial effects of folate were observed in the all-cause mortality rate and in a number of chronic diseases, including several birth/pregnancy outcomes, several cancers, cardiovascular disease and metabolic-related outcomes, neurological conditions, and several other diseases. However, adverse effects of folate were observed for prostate cancer, colorectal adenomatous lesions, asthma or wheezing, and wheezing as an isolated symptom and depression. Conclusions: Current evidence allows for the conclusion that folate is associated with decreased risk of all-cause mortality and a wide range of chronic diseases. However, folate may be associated with an increased risk of prostate cancer. Further research is warranted to improve the certainty of the estimates.
Keywords: chronic diseases; folate; meta-analysis; multiple health outcomes; umbrella review.

Sleep duration and all-cause mortality in the elderly in China: a population-based cohort study.
Ren Y, Miao M, Yuan W, Sun J.
BMC Geriatr. 2020 Dec 30;20(1):541. doi: 10.1186/s12877-020-01962-5.
PMID: 33380318
Background: Although a U-shaped association between sleep duration and all-cause mortality has been found in general population, its association in the elderly adults, especially in the oldest-old, is rarely explored.
Methods: In present cohort study, we prospectively explore the association between sleep duration and all-cause mortality among 15,092 participants enrolled in the Chinese Longitudinal Healthy Longevity Survey (CLHLS) from 2005 to 2019. Sleep duration and death information was collected by using structured questionnaires. Cox regression model with sleep duration as a time-varying exposure was performed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). The dose-response association between them was explored via a restricted cubic spline function.
Results: During an average follow-up of 4.51 (standard deviation, SD: 3.62) years, 10,768 participants died during the follow-up period. The mean (SD) age of the participants was 89.26 (11.56) years old. Compared to individuals with moderate sleep duration (7-8 hours), individuals with long sleep duration (> 8 hours) had a significantly higher risk of all-cause mortality (HR: 1.13, 95%CI: 1.09-1.18), but not among individuals with short sleep duration (≤ 6 hours) (HR: 1.02, 95%CI: 0.96-1.09). Similar results were observed in subgroup analyses based on age and gender. In the dose-response analysis, a J-shaped association was observed.
Conclusions: Sleep duration was associated with all-cause mortality in a J-shaped pattern in the elderly population in China.
Keywords: All-cause mortality; Cohort; Elderly; Sleep duration.

Modified Fasting Compared to True Fasting Improves Blood Glucose Levels and Subjective Experiences of Hunger, Food Cravings and Mental Fatigue, But Not Cognitive Function: Results of an Acute Randomised Cross-Over Trial.
Zajac I, Herreen D, Hunkin H, James-Martin G, Doyen M, Kakoschke N, Brindal E.
Nutrients. 2020 Dec 28;13(1):E65. doi: 10.3390/nu13010065.
PMID: 33379191
Recent dietary trends have prompted growing support for a variety of fasting paradigms involving extreme restriction or nil-caloric intake on fasting days. Some studies indicate that fasting may negatively influence factors including cognitive function through inducing fatigue, which may prove problematic in the context of completing a range of cognitively demanding activities required by daily obligations such as work. This randomised within-subjects cross-over trial explored the effects of true fasting (i.e., nil-caloric intake) versus modified fasting, the latter of which involved two sub-conditions: (1) extended distribution (three small meals distributed across the day; 522 kcal total); and (2) bulking (two meals eaten early in the day; 512 kcal total) over a period of 7.5 h on a single day with a 7-day washout period between conditions. Participants were n = 17 females (Body Mass Index (BMI) Mean (M) = 25.80, Standard Deviation (SD) = 2.30) aged 21-49 years. Outcomes included cognitive function, subjective mental fatigue, satiety, food cravings and blood glucose. Results showed that there were no differences in cognitive test performance between conditions;however, both modified fasting sub-conditions had improved blood glucose levels, cravings, hunger and fullness compared to true fasting. Moreover, subjective mental fatigue was significantly reduced in the modified fasting conditions relative to true fasting. Overall, results indicated that the subjective experience of true fasting and modified fasting is different, but that cognition does not appear to be impaired.
Keywords: cognitive function; fasting; fatigue; satiety; weight loss.

Prolonged nightly fasting and lower-extremity functioning in community-dwelling older adults.
Estrada-deLeón DB, Struijk EA, Caballero FF, Sotos Prieto M, Rodríguez-Artalejo F, Lopez-Garcia E.
Br J Nutr. 2020 Dec 29:1-26. doi: 10.1017/S0007114520005218. Online ahead of print.
PMID: 33371909
It is unknown if time-restricted feeding confers a protective effect on the physical function of older adults. The aim of this study was to assess prolonged nightly fasting in association with performance-based lower-extremity function (LEF) in a large population of community-dwelling older adults. A cross-sectional study was carried out among 1,226 individuals ≥64 years from the Seniors-ENRICA-II cohort. In 2016-2017, habitual diet was assessed through a validated diet history. Fasting time was classified into the following categories: ≤9, 10-11, and ≥12hours/day, the latter being considered prolonged nightly fasting. Performance-based LEF was assessed with the Short Physical Performance Battery (SPPB). After adjusting for potential confounders, a longer fasting period was associated with a higher likelihood of impaired LEF [odds ratio (OR) and 95% confidence intervals (CI) for the second and third categories: 2.27 (1.56-3.33) and 2.70 (1.80-4.04), respectively, considering the ≤9 hours/day fasting group as reference; p-trend <0.001]. When assessing each SPPB subtest separately, fasting time showed a significant association with balance impairment (OR for highest vs. lowest fasting time: 2.48; 95% CI: 1.51-4.08; p-trend =0.001) and difficulty to rise from a chair (OR for highest vs. lowest fasting time: 1.47; 95% CI: 1.05-2.06; p-trend =0.01). The risk associated with ≥12 h fasting among those with the lowest levels of physical activity was three times higher than among those with ≤9 hours fasting with the same low level of physical activity. Prolonged nightly fasting was associated with a higher likelihood of impaired LEF, balance impairment, and difficulty to rise from a chair in older adults, especially among those with low levels of physical activity.
Keywords: Short Physical Performance Battery; cross-sectional; intermittent fasting; older adults; physical function; time-restricted feeding.

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The greatest risk factor for the leading cause of death is ignored.
Hayflick L.
Biogerontology. 2020 Oct 14. doi: 10.1007/s10522-020-09901-y. Online ahead of print.
PMID: 33058001
All major United States institutional advocates for research on the biology of aging and for the leading causes of death assert that aging is the greatest risk factor for these deaths. Nevertheless, all fail to support research on the etiology of aging despite having mechanisms to do so. Aging is a problem in physics and not biology. It is a multibillion dollar miss-understanding to believe that the resolution of any or all age associated diseases will reveal information on the underlying aging process. The goal in research on the etiology of aging is to use the new revolutionary methods to study single molecules and their constituent atoms to uncover the qualitative and quantitative status of molecules in old cells that differ from that in young cells. These differences are the conditions that can explain why a common cause may exist for the risk factor for all age-associated diseases. The tyranny of the phrase "research on aging" could apply to almost any human institution. In the absence of a strict definition when used it has become a costly error in gerontology communication. Research on the biology of aging has become its greatest victim. Because aging is a universal manifestation of the fate of all matter, it is the provenance of the National Science Foundation because its stated purpose excludes research in the medical sciences.

Keywords: AFAR; Aging; Alzheimer’s association; Etiology of aging; NIA; NIH; NSF; Risk factor; Tyranny of “research on aging”.

Partial Replacement of Animal Proteins with Plant Proteins for 12 Weeks Accelerates Bone Turnover Among Healthy Adults: A Randomized Clinical Trial.
Itkonen ST, Päivärinta E, Pellinen T, Viitakangas H, Risteli J, Erkkola M, Lamberg-Allardt C, Pajari AM.
J Nutr. 2021 Jan 4;151(1):11-19. doi: 10.1093/jn/nxaa264.
PMID: 32939557
Background: Plant-based diets may reduce the risk of chronic diseases, but can also lead to low calcium and vitamin D intakes, posing a risk for bone health.
Objectives: We investigated whether partial replacement of animal proteins with plant-based proteins using a whole-diet approach affects bone and mineral metabolism in healthy adults in 3 groups fed diets differing in protein composition.
Methods: This 12-week clinical trial was comprised of 107 women and 29 men (20-69 years old; BMI mean ± SD, 24.8 ± 3.9) randomly assigned to consume 1 of 3 diets designed to provide 17 energy percent (E%) protein: "animal" (70% animal protein, 30% plant protein of total protein intake), "50/50" (50% animal, 50% plant), and "plant" (30% animal, 70% plant) diets. We examined differences in bone formation [serum intact procollagen type I amino-terminal propeptide (S-iPINP)], bone resorption [serum collagen type 1 cross-linked C-terminal telopeptide (S-CTX)], mineral metabolism markers (primary outcomes), and nutrient intakes (secondary outcomes) by ANOVA/ANCOVA.
Results: S-CTX was significantly higher in the plant group (mean ± SEM, 0.44 ± 0.02 ng/mL) than in the other groups (P values < 0.001 for both), and differed also between the animal (mean ± SEM, 0.29 ± 0.02 ng/mL) and 50/50 groups (mean ± SEM, 0.34 ± 0.02 ng/mL; P = 0.018). S-iPINP was significantly higher in the plant group (mean ± SEM, 63.9 ± 1.91 ng/mL) than in the animal group (mean ± SEM, 55.0 ± 1.82 ng/mL; P = 0.006). In a subgroup without a history of vitamin D supplement use, plasma parathyroid hormone was significantly higher in the plant than in the animal group (P = 0.018). Vitamin D and calcium intakes were below recommended levels in the plant group (mean ± SEM, 6.2 ± 3.7 μg/d and 733 ± 164 mg/d, respectively).
Conclusions: Partial replacement of animal proteins with plant-based proteins for 12 weeks increased the markers of bone resorption and formation among healthy adults, indicating a possible risk for bone health. This is probably caused by lower vitamin D and calcium intakes from diets containing more plant-based proteins, but it is unclear whether differences in protein intake or quality play a major role.
Keywords: animal protein; bone turnover; calcium; clinical trial; mineral metabolism; plant protein; vitamin D.

Association of Objectively Measured Sleep with Frailty and 5-year Mortality in Community-Dwelling Older Adults.
Guida JL, Alfini AJ, Gallicchio L, Spira AP, Caporaso NE, Green PA.
Sleep. 2021 Jan 6:zsab003. doi: 10.1093/sleep/zsab003. Online ahead of print.
PMID: 33406254
Study objectives: To determine whether actigraphy-measured sleep was independently associated with risk of frailty and mortality over a five-year period among older adults.
Methods: We used data from Waves 2 (W2) and 3 (W3) (2010-2015) of the National Social Life, Health and Aging Project, a prospective cohort of community-dwelling older adults born between 1920 and 1947. One-third of W2 respondents were randomly selected to participate in a sleep study, of whom N=727 consented and N=615 were included in the analytic sample. Participants were instructed to wear a wrist actigraph for 72 hours (2.93±0.01 nights). Actigraphic sleep parameters were averaged across nights and included total sleep time, percent sleep, sleep fragmentation index, and wake after sleep onset (WASO). Subjective sleep was collected via questionnaire. Frailty was assessed using modified Fried Frailty Index. Vital status was ascertained at the time of the W3 interview. W3 frailty/mortality status were analyzed jointly with a four-level variable: robust, pre-frail, frail, and deceased. Associations were modeled per 10-unit increase.
Results: After controlling for baseline frailty (robust and pre-frail categories), age, sex, education, body mass index, and sleep time preference, a higher sleep fragmentation index was associated with frailty (OR=1.70, 95% CI: 1.02-2.84) and mortality (OR=2.12, 95% CI: 1.09-4.09). Greater WASO (OR=1.24, 95% CI: 1.02-1.50) and lower percent sleep (OR=0.41, 95% CI: 0.17-0.97) were associated with mortality.
Conclusions: Among community-dwelling older adults, actigraphic sleep is associated with frailty and all-cause mortality over a five-year period. Further investigation is warranted to elucidate the physiological mechanisms underlying these associations.
Keywords: Actigraphy; Aging; Frailty; Mortality; Sleep.

High vs. low-fat dairy and milk differently affects the risk of all-cause, CVD, and cancer death: A systematic review and dose-response meta-analysis of prospective cohort studies.
Naghshi S, Sadeghi O, Larijani B, Esmaillzadeh A.
Crit Rev Food Sci Nutr. 2021 Jan 5:1-15. doi: 10.1080/10408398.2020.1867500. Online ahead of print.
PMID: 33397132
Considerable controversy exists regarding the association between milk and dairy consumption and mortality risk. The present systematic review and meta-analysis of prospective studies was undertaken to examine the association of high vs. low-fat dairy and milk consumption with mortality. We searched PubMed/Medline, ISI Web of Science, and Scopus databases through February 2020 for prospective cohort studies that reported the association between milk and dairy consumption and mortality risk. High-fat milk consumption was significantly associated with a greater risk of all-cause (Pooled ES: 1.15; 95% CI: 1.09-1.20, I2=24.5%, p = 0.22), CVD (Pooled ES: 1.09; 95% CI: 1.02-1.16, I2=4.5%, p = 0.38) and cancer mortality (Pooled ES: 1.17; 95% CI: 1.08-1.28, I2=30.1%, p = 0.19). However, total dairy consumption was associated with a lower risk of CVD mortality (Pooled ES: 0.93; 95% CI: 0.88-0.98, I2=59.7%, p = 0.001). Dose-response analysis revealed a significant non-linear association of total dairy consumption with all-cause and CVD mortality. Moreover, high-fat milk consumption was significantly associated with risk of cancer mortality in linear and non-linear dose-response analysis. In conclusion, we found high-fat milk consumption was associated with a higher risk of all-cause, CVD, and cancer mortality. However, total dairy consumption was associated with a lower risk of CVD mortality.
Keywords: Mortality; cancer; cardiovascular disease; dairy; death; milk.

Chocolate as a food matrix reduces the bioavailability of galloylated catechins from green tea in healthy women.
Mukai R, Fukuda T, Ohnishi A, Nikawa T, Furusawa M, Terao J.
Food Funct. 2021 Jan 4. doi: 10.1039/d0fo02485f. Online ahead of print.
PMID: 33393957
In this study, we evaluated the food matrix effects of chocolate on the absorption of green tea catechins (GTCs), (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECg), and (-)-epigallocatechin gallate (EGCg), in five healthy 22-year-old women. In the single-intake experiment, the plasma concentrations of ECg (P < 0.05, at 1.5 h) and EGCg (P < 0.05, at 6 h) but not those of EC and EGC were reduced by the chocolate matrix. Regardless of the chocolate matrix, ECg and EGCg were mainly present as their aglycones in the plasma, whereas EGC and EC were found mostly as conjugated metabolites. After daily intake of GTCs mixed with chocolate for 14 days followed by overnight fasting, ECg but not EGCg was detected in the plasma. To compare the plasma profiles of ECg and EGCg, a mixture containing approximately equal amounts of ECg and EGCg was administered to nine rats for 14 days. Following treatment and overnight food deprivation, the plasma content of ECg was higher than that of EGCg. After a single injection of the same mixture in seven rats, ECg levels were higher than those of EGCg, and a greater amount of conjugated metabolites of ECg than those of EGCg was detected in the plasma 10 h after administration. In conclusion, the chocolate matrix affects the plasma profiles of GTCs, particularly ECg. ECg appears to persist in the plasma for a longer period, regardless of the chocolate matrix.

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L-Arginine Exerts Excellent Anti-Stress Effects on Stress-Induced Shortened Lifespan, Cognitive Decline and Depression.
Pervin M, Unno K, Konishi T, Nakamura Y.
Int J Mol Sci. 2021 Jan 6;22(2):E508. doi: 10.3390/ijms22020508.
PMID: 33419170
The anti-stress potential of dietary L-arginine (Arg) was assessed in psychosocially stress-loaded senescence-accelerated (SAMP10) mice. Although this strain of mouse is sensitive to stress, daily administration of Arg at 3 mg/kg significantly suppressed aging-related cognitive decline and behavioral depression at nine months of age and counteracted stress-induced shortened lifespan. To investigate the mechanism of the anti-stress effect of Arg in the brain, early changes in oxidative damage and gene expression levels were measured using SAMP10 mice that were stress-loaded for three days. Increased lipid peroxidation in the brains of stressed mice was significantly lowered by Arg intake. Several genes associated with oxidative stress response and neuronal excitotoxic cell death, including Nr4a1, Arc, and Cyr61, remarkably increased in response to psychosocial stress; however, their expression was significantly suppressed in mice that ingested Arg even under stress conditions. In contrast, the genes that maintain mitochondrial functions and neuronal survival, including Hba-a2 and Hbb-b2, were significantly increased in mice that ingested Arg. These results indicate that Arg reduces oxidative damage and enhances mitochondrial functions in the brain. We suggest that the daily intake of Arg plays important roles in reducing stress-induced brain damage and slowing aging.
Keywords: aging; arginine; brain; chronic psychosocial stress; depression; oxidative damage; shortened lifespan.

Dietary carotenoids related to risk of incident Alzheimer dementia (AD) and brain AD neuropathology: a community-based cohort of older adults.
Yuan C, Chen H, Wang Y, Schneider JA, Willett WC, Morris MC.
Am J Clin Nutr. 2020 Nov 12;113(1):200-8. doi: 10.1093/ajcn/nqaa303. Online ahead of print.
PMID: 33184623 Free PMC article.
Background: Studies have reported a protective relation to cognitive decline with long-term intake of total and individual dietary carotenoids. However, the underlying mechanisms have not yet been clearly established in humans.
Objectives: To evaluate the prospective association between intakes of total and individual carotenoids and risk of incident Alzheimer dementia (AD) and explore the underlying neuropathological basis.
Methods: Among 927 participants from the Rush Memory and Aging Project who were free from AD at baseline and were followed up for a mean of 7 y, we estimated HRs for AD using Cox proportional hazards models by intakes of energy-adjusted carotenoids. Brain AD neuropathology was assessed in postmortem brain autopsies among 508 deceased participants. We used linear regression to assess the association of carotenoid intake with AD-related neuropathology.
Results: Higher intake of total carotenoids was associated with substantially lower hazard of AD after controlling for age, sex, education, ApoE-ε4, participation in cognitively stimulating activities, and physical activity level. Comparing the top and bottom quintiles (median intake: 24.8 compared with 6.7 mg/d) of total carotenoids, the multivariate HR (95% CI) was 0.52 (0.33, 0.81), P-trend < 0.01. A similar association was observed for lutein-zeaxanthin, a weaker linear inverse association was observed for β-carotene, and a marginally significant linear inverse association was found for β-cryptoxanthin. Among the deceased participants, consumers of higher total carotenoids (top compared with bottom tertile, 18.2 compared with 8.2 mg/d) had less global AD pathology (b: -0.10; SE = 0.04; P-trend = 0.01). For individual carotenoids, lutein-zeaxanthin and lycopene were inversely associated with brain global pathology, whereas lutein-zeaxanthin showed additional inverse associations with AD diagnostic score, neuritic plaque severity, and neurofibrillary tangle density and severity.
Conclusions: Our findings support a beneficial role of total carotenoid consumption, in particular lutein/zeaxanthin, on AD incidence that may be related to the inhibition of brain β-amyloid deposition and fibril formation.
Keywords: Alzheimer dementia; cognitive function; dietary carotenoids; neuropathology; prospective cohort study.

The neutrophil-lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials.
Adamstein NH, MacFadyen JG, Rose LM, Glynn RJ, Dey AK, Libby P, Tabas IA, Mehta NN, Ridker PM.
Eur Heart J. 2021 Jan 8:ehaa1034. doi: 10.1093/eurheartj/ehaa1034. Online ahead of print.
PMID: 33417682
Aims: The neutrophil-lymphocyte ratio (NLR) is a readily available inflammatory biomarker that may associate with atherosclerosis and predict cardiovascular (CV) events. The aims of this study are to determine whether the NLR predicts incident major adverse cardiovascular events (MACE) and is modified by anti-inflammatory therapy.
Methods and results: Baseline and on-treatment NLRs were calculated from complete blood counts among 60 087 participants randomized in the CANTOS, JUPITER, SPIRE-1, SPIRE-2, and CIRT trials to receive placebo or canakinumab, rosuvastatin, bococizumab, or methotrexate, respectively, and followed up for MACE. All analyses were performed first in CANTOS, and then externally validated in the other four trials. For the five trials, hazard ratios for major CV events and mortality comparing NLR quartiles were computed using Cox proportional hazards models, and the effect of each randomized intervention on the NLR was evaluated in comparison to placebo. The NLR modestly correlated with interleukin-6, C-reactive protein, and fibrinogen levels but minimally with lipids. In all five randomized trials, baseline NLR predicted incident CV events and death; the per-quartile increase in risk of MACE was 20% in CANTOS [95% confidence interval (CI) 14-25%, P < 0.0001], 31% in SPIRE-1 (95% CI 14-49%, P = 0.00007), 27% in SPIRE-2 (95% CI 12-43%, P = 0.0002), 9% in CIRT (95% CI 0.2-20%, P = 0.045), and 11% in JUPITER (95% CI 1-22%, P = 0.03). While lipid-lowering agents had no significant impact on the NLR, anti-inflammatory therapy with canakinumab lowered the NLR (P < 0.0001).
Conclusion: The NLR, an easily obtained inflammatory biomarker, independently predicts CV risk and all-cause mortality, and is reduced by interleukin-1β blockade with canakinumab.
Keywords: Atherosclerosis; Atherothrombosis; Inflammation; Lymphocyte; MACE; Neutrophil.

Impact of oral anticoagulation on clinical outcomes of COVID-19: a nationwide cohort study of hospitalized patients in Germany.
Fröhlich GM, Jeschke E, Eichler U, Thiele H, Alhariri L, Reinthaler M, Kastrati A, Leistner DM, Skurk C, Landmesser U, Günster C.
Clin Res Cardiol. 2021 Jan 8. doi: 10.1007/s00392-020-01783-x. Online ahead of print.
PMID: 33416918
Objectives: The aim of this study was to investigate the impact of concomitant long-term medication-with a focus on ACE inhibitors and oral anticoagulation-on clinical outcomes in patients hospitalized with coronavirus disease 2019.
Methods: This is a retrospective cohort study using claims data of the biggest German health insurance company AOK, covering 26.9 million people all over Germany. In particular, patient-related characteristics and co-medication were evaluated. A multivariable logistic regression model was adopted to identify independent predictors for the primary outcome measure of all-cause mortality or need for invasive or non-invasive ventilation or extracorporeal membrane oxygenation.
Results: 6637 patients in 853 German hospitals were included. The primary outcome occurred in 1826 patients (27.5%). 1372 patients (20.7%) died, 886 patients (13.3%) needed respiratory support, and 53 patients (0.8%) received extracorporeal membrane oxygenation. 34 of these patients survived (64.2%). The multivariable model demonstrated that pre-existing oral anticoagulation therapy with either vitamin-K antagonists OR 0.57 (95% CI 0.40-0.83, p = 0.003) or direct oral anticoagulants OR 0.71 (95% CI 0.56-0.91, p = 0.007)-but not with antiplatelet therapy alone OR 1.10 (95% CI 0.88-1.23, p = 0.66)-was associated with a lower event rate. This finding was confirmed in a propensity match analysis.
Conclusions: In a multivariable analysis, a therapy with both direct oral anticoagulants or vitamin-K antagonists-but not with antiplatelet therapy-was associated with improved clinical outcomes. ACE inhibitors did not impact outcomes. Prospective randomized trials are needed to verify this hypothesis.
Keywords: ACE inhibitors; Antiplatelet therapy; COVID-19; DOACs; ECMO; Vitamin-K-antagonist.

Study estimates exposure to air pollution increases COVID-19 deaths by 15% worldwide
27 Oct 2020
Regional and global contributions of air pollution to risk of death from COVID-19.
Pozzer A, Dominici F, Haines A, Witt C, Münzel T, Lelieveld J.
Cardiovasc Res. 2020 Dec 1;116(14):2247-2253. doi: 10.1093/cvr/cvaa288.
PMID: 33236040
Aims: The risk of mortality from the coronavirus disease that emerged in 2019 (COVID-19) is increased by comorbidity from cardiovascular and pulmonary diseases. Air pollution also causes excess mortality from these conditions. Analysis of the first severe acute respiratory syndrome coronavirus (SARS-CoV-1) outcomes in 2003, and preliminary investigations of those for SARS-CoV-2 since 2019, provide evidence that the incidence and severity are related to ambient air pollution. We estimated the fraction of COVID-19 mortality that is attributable to the long-term exposure to ambient fine particulate air pollution.
Methods and results: We characterized global exposure to fine particulates based on satellite data, and calculated the anthropogenic fraction with an atmospheric chemistry model. The degree to which air pollution influences COVID-19 mortality was derived from epidemiological data in the USA and China. We estimate that particulate air pollution contributed ∼15% (95% confidence interval 7-33%) to COVID-19 mortality worldwide, 27% (13 - 46%) in East Asia, 19% (8-41%) in Europe, and 17% (6-39%) in North America. Globally, ∼50-60% of the attributable, anthropogenic fraction is related to fossil fuel use, up to 70-80% in Europe, West Asia, and North America.
Conclusion: Our results suggest that air pollution is an important cofactor increasing the risk of mortality from COVID-19. This provides extra motivation for combining ambitious policies to reduce air pollution with measures to control the transmission of COVID-19.
Keywords: Air pollution; COVID-19; Fine particulate matter; comorbidity; mortality.

Timing of Food Intake Drives the Circadian Rhythm of Blood Pressure.
Zhang D, Colson JC, Jin C, Becker BK, Rhoads MK, Pati P, Neder TH, King MA, Valcin JA, Tao B, Kasztan M, Paul JR, Bailey SM, Pollock JS, Gamble KL, Pollock DM.
Function (Oxf). 2021;2(1):zqaa034. doi: 10.1093/function/zqaa034. Epub 2020 Nov 24.
PMID: 33415319 Free PMC article.
Timing of food intake has become a critical factor in determining overall cardiometabolic health. We hypothesized that timing of food intake entrains circadian rhythms of blood pressure (BP) and renal excretion in mice. Male C57BL/6J mice were fed ad libitum or reverse feeding (RF) where food was available at all times of day or only available during the 12-h lights-on period, respectively. Mice eating ad libitum had a significantly higher mean arterial pressure (MAP) during lights-off compared to lights-on (113 ± 2 mmHg vs 100 ± 2 mmHg, respectively; P < 0.0001); however, RF for 6 days inverted the diurnal rhythm of MAP (99 ± 3 vs 110 ± 3 mmHg, respectively; P < 0.0001). In contrast to MAP, diurnal rhythms of urine volume and sodium excretion remained intact after RF. Male Bmal1 knockout mice (Bmal1KO) underwent the same feeding protocol. As previously reported, Bmal1KO mice did not exhibit a diurnal MAP rhythm during ad libitum feeding (95 ± 1 mmHg vs 92 ± 3 mmHg, lights-off vs lights-on; P > 0.05); however, RF induced a diurnal rhythm of MAP (79 ± 3 mmHg vs 95 ± 2 mmHg, lights-off vs lights-on phase; P < 0.01). Transgenic PERIOD2::LUCIFERASE knock-in mice were used to assess the rhythm of the clock protein PERIOD2 in ex vivo tissue cultures. The timing of the PER2::LUC rhythm in the renal cortex and suprachiasmatic nucleus was not affected by RF; however, RF induced significant phase shifts in the liver, renal inner medulla, and adrenal gland. In conclusion, the timing of food intake controls BP rhythms in mice independent of Bmal1, urine volume, or sodium excretion.
Keywords: Bmal1; blood pressure; circadian rhythms; sodium excretion; time-restricted feeding.

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Fruit and Vegetable Intake and All-Cause Mortality in a Chinese Population: The China Health and Nutrition Survey.
Gu Y, He Y, Ali SH, Harper K, Dong H, Gittelsohn J.
Int J Environ Res Public Health. 2021 Jan 5;18(1):E342. doi: 10.3390/ijerph18010342.
PMID: 33466375
This study was to investigate the association of long-term fruit and vegetable (FV) intake with all-cause mortality. We utilized data from the China Health and Nutrition Survey (CHNS), a prospective cohort study conducted in China. The sample population included 19,542 adult respondents with complete mortality data up to 31 December 2011. Cumulative FV intake was assessed by 3 day 24 h dietary recalls. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause mortality. Covariates included sociodemographic characteristics, lifestyle factors, health-related factors, and urban index. A total of 1409 deaths were observed during follow-up (median: 14 years). In the fully adjusted model, vegetable intake of the fourth quintile (327~408 g/day) had the greatest negative association with death compared to the lowest quintile (HR = 0.63, 95% CI: 0.53-0.76). Fruit intake of the fifth quintile (more than 126 g/day) had the highest negative association (HR = 0.24, 95% CI: 0.15-0.40) and increasing general FV intake were also negatively associated with all-cause mortality which demonstrated the greatest negative association in the amount of fourth quintile (HR = 0.59, 95% CI: 0.49-0.70) compared to the lowest quintile. To conclude, greater FV intake is associated with a reduced risk of total mortality for Chinese adults. High intake of fruit has a stronger negative association with mortality than differences in intake of vegetables. Our findings support recommendations to increase the intake of FV to promote overall longevity.
Keywords: China; fruit; mortality; prospective studies; vegetables.

Leukocyte telomere length, cancer incidence and all-cause mortality among Chinese adults: Singapore Chinese Health Study.
Samavat H, Luu HN, Beckman KB, Jin A, Wang R, Koh WP, Yuan JM.
Int J Cancer. 2021 Jan 15;148(2):352-362. doi: 10.1002/ijc.33211. Epub 2020 Aug 5.
PMID: 33459354
Telomeres play a key role in chromosomal maintenance and stability. To date, few studies have investigated the association of leukocyte telomere length with risk of cancer incidence and all-cause mortality in a large prospective cohort, particularly of the Asian population. Relative telomere lengths in genomic DNA from peripheral blood samples were quantified using a validated quantitative real-time PCR among 26 540 middle-aged or older Chinese adults. Hazard ratios (HRs) and 95% confidence intervals (CIs) of cancer and deaths by quintiles of telomere length were calculated using the Cox proportional hazards regression method with adjustment for age, sex and other potential confounders. After baseline blood collection, 4353 persons developed cancer and 7609 died. Participants with the longest decile of telomeres had a 26% (95% CI: 11%-44%) higher risk of total cancer incidence compared to the shortest decile after controlling for age, sex and other potential founders (Ptrend < .0001). In contrast, longer telomeres were associated with lower risk of all-cause mortality (HR = 0.93; 95% CI: 0.84-1.03), noncancer death (HR = 0.81; 95% CI: 0.71-0.92), specifically, death from chronic obstructive pulmonary disease and pneumonia (HR = 0.79, 95% CI: 0.70-0.89) and digestive diseases (HR = 0.60, 95% CI: 0.42-0.88). Our findings demonstrated that longer telomeres are associated with increased risk of cancer development overall and several common cancer types including breast, rectal, prostate, pancreatic cancer and lung adenocarcinoma. Our study also confirmed that longer telomeres are associated with a reduced risk of noncancer related death.
Keywords: all‐cause mortality; biomarkers; cancer incidence; prospective cohort study; telomere length.

Cognitive Trajectories and Resilience in Centenarians-Findings From the 100-Plus Study.
Perls TT.
JAMA Netw Open. 2021 Jan 4;4(1):e2032538. doi: 10.1001/jamanetworkopen.2020.32538.
PMID: 33449091 No abstract available.
[Free full-text from PMID abstract.]
Association of Cognitive Function Trajectories in Centenarians With Postmortem Neuropathology, Physical Health, and Other Risk Factors for Cognitive Decline.
Beker N, Ganz A, Hulsman M, Klausch T, Schmand BA, Scheltens P, Sikkes SAM, Holstege H.
JAMA Netw Open. 2021 Jan 4;4(1):e2031654. doi: 10.1001/jamanetworkopen.2020.31654.
PMID: 33449094
Importance: Understanding mechanisms associated with prolonged cognitive health in combination with exceptional longevity might lead to approaches to enable successful aging.
Objective: To investigate trajectories of cognitive functioning in centenarians across domains, and to examine the association of these trajectories with factors underlying cognitive reserve, physical health, and postmortem levels of Alzheimer disease (AD)-associated neuropathology.
Design, setting, and participants: This cohort study used neuropsychological test data and postmortem neuropathological reports from Dutch centenarians who were drawn from the 100-plus Study between January 2013 and April 2019. Eligible participants self-reported being cognitively healthy, which was confirmed by a proxy. Data analysis was performed between June 2019 and June 2020.
Exposures: Age, sex, APOE ε genotype, factors of cognitive reserve, physical health, and AD-associated neuropathology (ie, amyloid-β, neurofibrillary tangles, and neuritic plaques).
Main outcomes and measures: In annual visits (until death or until participation was no longer possible), centenarians underwent an extensive neuropsychological test battery, from which an mean z score of global cognition, memory, executive functions, verbal fluency, visuospatial functions, and attention/processing speed was calculated. Linear mixed models with a random intercept and time as independent variable were used to investigate cognitive trajectories, adjusted for sex, age, education, and vision and hearing capacities. In a second step, linear mixed models were used to associate cognitive trajectories with factors underlying cognitive reserve, physical health at baseline, and AD-associated neuropathology.
Results: Of the 1023 centenarians approached, 340 were included in the study. We analyzed 330 centenarians for whom cognitive tests were available at baseline (239 [72.4%] women; median [interquartile range] age of 100.5 [100.2-101.7] years), with a mean (SD) follow-up duration of 1.6 (0.8) years. We observed no decline across investigated cognitive domains, with the exception of a slight decline in memory function (β, -0.10 SD per year; 95% CI, -0.14 to -0.05 SD; P < .001). Cognitive performance was associated with factors of physical health (eg, higher Barthel index: β, 0.37 SD per year; 95% CI, 0.24-0.49; P < .001) and cognitive reserve (eg, higher education: β, 0.41 SD per year; 95% CI, 0.29-0.53; P < .001), but none of these factors were associated with the rate of decline. Neuropathological reports were available for 44 participants. While centenarian brains revealed varying loads of postmortem neuropathological hallmarks of AD, this was not associated with cognitive performance or rate of decline.
Conclusions and relevance: While we observed a slight vulnerability for decline in memory function, centenarians maintained high levels of performance in all other investigated cognitive domains for up to 4 years despite the presence of risk factors of cognitive decline. These findings suggest that mechanisms of resilience may underlie the prolongation of cognitive health until exceptional ages.

Anti-ageing effects of protein restriction unpacked
Two animal studies show that restricting the dietary intake of branched-chain amino acids can extend lifespan by modulating the mTOR signalling pathway. But more research is needed before this diet should be recommended in people.
Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and life span in mice
Nicole E. Richardson, Elizabeth N. Konon, Haley S. Schuster, Alexis T. Mitchell, Colin Boyle, Allison C. Rodgers, Megan Finke, Lexington R. Haider, Deyang Yu, Victoria Flores, Heidi H. Pak, Soha Ahmad, Sareyah Ahmed, Abigail Radcliff, Jessica Wu, Elizabeth M. Williams, Lovina Abdi, Dawn S. Sherman, Timothy A. Hacker & Dudley W. Lamming 
Nature Aging volume 1, pages73–86(2021)
Protein-restricted diets promote health and longevity in many species. While the precise components of a protein-restricted diet that mediate the beneficial effects to longevity have not been defined, we recently showed that many metabolic effects of protein restriction can be attributed to reduced dietary levels of the branched-chain amino acids (BCAAs) leucine, isoleucine and valine. Here, we demonstrate that restricting dietary BCAAs increases the survival of two different progeroid mouse models, delays frailty and promotes the metabolic health of wild-type C57BL/6J mice when started in midlife, and leads to a 30% increase in life span and a reduction in frailty in male, but not female, wild-type mice when they undergo lifelong feeding. Our results demonstrate that restricting dietary BCAAs can increase health span and longevity in mice and suggest that reducing dietary BCAAs may hold potential as a translatable intervention to promote healthy aging.

An isocaloric moderately high-fat diet extends lifespan in male rats and Drosophila.
Shi D, Han T, Chu X, Lu H, Yang X, Zi T, Zhao Y, Wang X, Liu Z, Ruan J, Liu X, Ning H, Wang M, Tian Z, Wei W, Sun Y, Li Y, Guo R, Wang Y, Ling F, Guan Y, Shen D, Niu Y, Li Y, Sun C.
Cell Metab. 2021 Jan 7:S1550-4131(20)30672-0. doi: 10.1016/j.cmet.2020.12.017. Online ahead of print.
PMID: 33440166
The health effect of dietary fat has been one of the most vexing issues in the field of nutrition. Few animal studies have examined the impact of high-fat diets on lifespan by controlling energy intake. In this study, we found that compared to a normal diet, an isocaloric moderately high-fat diet (IHF) significantly prolonged lifespan by decreasing the profiles of free fatty acids (FFAs) in serum and multiple tissues via downregulating FFA anabolism and upregulating catabolism pathways in rats and flies. Proteomics analysis in rats identified PPRC1 as a key protein that was significantly upregulated by nearly 2-fold by IHF, and among the FFAs, only palmitic acid (PA) was robustly and negatively associated with the expression of PPRC1. Using PPRC1 transgenic RNAi/overexpression flies and in vitro experiments, we demonstrated that IHF significantly reduced PA, which could upregulate PPRC1 through PPARG, resulting in improvements in oxidative stress and inflammation and prolonging the lifespan.
Keywords: PPRC1; isocaloric moderately high-fat diet; lifespan; palmitic acid.

Associations between daily aspirin use and cancer risk across strata of major cancer risk factors in two large U.S. cohorts.
Hurwitz LM, Michels KA, Cook MB, Pfeiffer RM, Trabert B.
Cancer Causes Control. 2020 Oct 26. doi: 10.1007/s10552-020-01357-2. Online ahead of print.
PMID: 33104910
Purpose: Daily aspirin use has been shown to reduce risk of colorectal, and possibly other, cancers, but it is unknown if these benefits are consistent across subgroups of people with differing cancer risk factors. We investigated whether age, body mass index (BMI), smoking status, physical inactivity, and family history of cancer modify the effect of daily aspirin use on colorectal, ovarian, breast, endometrial and aggressive prostate cancer risk.
Methods: We pooled 423,495 individuals from two prospective, U.S.-based studies: the NIH-AARP Diet and Health Study (1995-2011) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (1993-2009). Using Cox proportional hazards regression, we examined associations between daily aspirin use (≥ 5 days/week) and risk of colorectal, ovarian, breast, endometrial, and aggressive prostate cancer, overall and across strata of risk factors.
Results: Daily aspirin use was associated with a 15% reduction in colorectal cancer risk (hazard ratio

: 0.85, 95% confidence interval [CI] 0.80-0.89). Risk reductions were generally consistent across strata of risk factors but attenuated with increasing BMI (p-interaction = 0.16). For ovarian cancer, there was no significant association overall (HR: 0.93, 95% CI 0.80-1.08) but reduced risk among obese women (HR: 0.73, 95% CI 0.52-0.98, p-interaction = 0.12). Weak or null associations were observed for breast, endometrial, and aggressive prostate cancer, with no strong effect modification observed.
Conclusions: Daily aspirin use appears to reduce colorectal cancer risk regardless of other risk factors, though the potential modifying effect of BMI warrants further investigation and may need to be considered in risk-benefit calculations for aspirin use.
Keywords: Anti-inflammatory agents; Aspirin; Cancer risk; Chemoprevention; Effect modification; Non-steroidal.

Physical activity and all-cause and cause-specific mortality: assessing the impact of reverse causation and measurement error in two large prospective cohorts.
Lee DH, Rezende LFM, Ferrari G, Aune D, Keum N, Tabung FK, Giovannucci EL.
Eur J Epidemiol. 2021 Jan 11. doi: 10.1007/s10654-020-00707-3. Online ahead of print.
PMID: 33428024
Most cohort studies have only a single physical activity (PA) measure and are thus susceptible to reverse causation and measurement error. Few studies have examined the impact of these potential biases on the association between PA and mortality. A total of 133,819 participants from Nurses' Health Study and Health Professionals Follow-up Study (1986-2014) reported PA through biennial questionnaires. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for PA and mortality using different analytic approaches comparing single (baseline, simple update = most recent) versus repeated (cumulative average) measures of PA and applying various lag times separating PA measurement and time at risk. Over 3.2 million person-years, we documented 47,273 deaths. The pooled multivariable-adjusted HR (95% CI) of all-cause mortality per 10 MET-hour/week was 0.95 (0.94-0.96) for baseline PA, 0.78 (0.77-0.79) for simple updated PA and 0.87 (0.86-0.88) for cumulative average PA in the range of 0-50 MET-hour/week. Simple updated PA showed the strongest inverse association, suggesting larger impact of reverse causation. Application of 2-year lag substantially reduced the apparent reverse causation (0.85 (0.84-0.86) for simple updated PA and 0.90 (0.89-0.91) for cumulative average PA), and 4-12-year lags had minimal additional effects. In the dose-response analysis, baseline or simple updated PA showed a J or U-shaped association with all-cause mortality while cumulative average PA showed an inverse association across a wide range of PA (0-150 MET-hour/week). Similar findings were observed for different specific mortality causes. In conclusion, PA measured at baseline or with short lag time was prone to bias. Cumulative average PA showed robust evidence that PA is inversely associated with mortality in a dose-response manner.
Keywords: Bias; Measurement error; Mortality; Physical activity; Reverse causation.

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Long-term exposure to ambient air pollution and risk of dementia: Results of the prospective Three-City Study.
Mortamais M, Gutierrez LA, de Hoogh K, Chen J, Vienneau D, Carrière I, Letellier N, Helmer C, Gabelle A, Mura T, Sunyer J, Benmarhnia T, Jacquemin B, Berr C.
Environ Int. 2021 Jan 20;148:106376. doi: 10.1016/j.envint.2020.106376. Online ahead of print.
PMID: 33484961
Background: Emerging epidemiological evidence suggests a relationship between exposure to air pollution and dementia. However, most of the existing studies relied on health administrative databases for the diagnosis of dementia. In a large French population-based cohort (the 3C Study), we assessed the effects of particulate matter ≤2.5 µm (PM2.5), nitrogen dioxide (NO2) and black carbon (BC) on the risk of dementia diagnosed with reliable tools.
Methods: Participants aged ≥65 years were recruited between 1999 and 2001 and followed for 12 years. At baseline and every 2 years, dementia was suspected on the basis of the neuropsychological and neurological examination and confirmed by an independent committee of clinicians. Exposure to NO2, BC and PM2.5 at the participants' residential address was estimated using land use regression models. For each pollutant and year of follow-up, the 10-year moving average of past exposure was estimated. Multilevel spatial random-effects Cox proportional hazards models were used in which exposure was included as a time-varying variable. Analyses were adjusted for individual (age, sex, education, APOE4 genotype, health behaviours) and contextual (neighbourhood deprivation index) confounders.
Results: At baseline, the median age of the 7066 participants was 73.4 years, and 62% were women. The median follow-up duration was 10.0 years during which 791 participants developed dementia (n = 541 Alzheimer's disease (AD) and n = 155 vascular/mixed dementia (VaD)). The 10-year moving average of PM2.5 concentrations ranged from 14.6 to 31.3 µg/m3. PM2.5 concentration was positively associated with dementia risk: HR = 1.20, 95% CI (1.08-1.32) for all-cause dementia, 1.20 (1.09-1.32) for AD, and 1.33 (1.05-1.68) for VaD per 5 µg/m3 PM2.5 increase. No association was detected between NO2 or BC exposure and dementia risk.
Conclusion: In this large cohort of older adults, long-term PM2.5 exposure was associated with increased dementia incidence. Reducing PM2.5 emissions might lessen the burden of dementia in aging populations.
Keywords: Air pollution; Black carbon; Cohort; Dementia; Elderly; Fine particulate matter; Incidence; Nitrogen dioxide.

High Serum Folate Concentrations Are Associated with Decreased Risk of Mortality among Japanese Adults.
Chen S, Honda T, Hata J, Sakata S, Furuta Y, Yoshida D, Shibata M, Ohara T, Hirakawa Y, Oishi E, Kitazono T, Ninomiya T.
J Nutr. 2021 Jan 20:nxaa382. doi: 10.1093/jn/nxaa382. Online ahead of print.
PMID: 33484141
Background: Folate and vitamin B-12 are essential nutrients for normal cell growth and replication, but the association of serum folate and vitamin B-12 concentrations with mortality risk remains uncertain.
Objective: This study was performed to investigate the associations of serum folate and vitamin B-12 concentrations with mortality risk and test whether the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism modifies these associations.
Methods: A total of 3050 Japanese community residents aged ≥40 y were prospectively followed-up for mortality between 2002 and 2012. Cox proportional hazards models and restricted cubic splines were used to estimate HRs and 95% CIs of mortality.
Results: During a median follow-up period of 10.2 y, 336 participants died. Higher serum folate concentrations were associated with lower risks of all-cause mortality [multivariable-adjusted HR: 0.73; 95% CI: 0.56, 0.96 for the second tertile (8.8-12.2 nmol/L; median 10.4 nmol/L) and HR: 0.61; 95% CI: 0.46, 0.80 for the third tertile (≥12.5 nmol/L; median 15.6 nmol/L) serum folate concentrations compared with the first tertile (≤8.6 nmol/L; median 7.0 nmol/L)]. This association remained significant in all sensitivity analyses. Spline analyses showed a steady decline in all-cause mortality risk with increasing serum folate concentrations up to 20-25 nmol/L. This association persisted regardless of the MTHFR C677T genotypes. For serum vitamin B-12, the multivariable-adjusted HR of 1.32 (95% CI: 0.97, 1.79) of all-cause mortality was marginally significantly greater in the first tertile compared with the second tertile. This association was attenuated and nonsignificant after the exclusion of participants with a history of cardiovascular disease or cancer, or participants aged ≥85 y at baseline, or deaths in the first 3 y of follow-up.
Conclusions: Serum folate concentrations were inversely associated with the risk of all-cause mortality in Japanese adults. Serum vitamin B-12 concentrations were not consistently associated with all-cause mortality risk after accounting for reverse-causation bias.
Keywords: Japanese; folate; mortality; nutritional biomarkers; prospective cohort; serum; vitamin B-12.

Colchicine reduces the risk of COVID-19-related complications
January 23, 2021
A gout drug shows promise for Covid-19, but skeptics worry about trusting science by press release
By MATTHEW HERPER @matthewherperJANUARY 23, 2021

Comparison of Deaths Rates for COVID-19 across Europe During the First Wave of the COVID-19 Pandemic.
Villani L, McKee M, Cascini F, Ricciardi W, Boccia S.
Front Public Health. 2020 Dec 11;8:620416. doi: 10.3389/fpubh.2020.620416. eCollection 2020.
PMID: 33425843 Free PMC article.
Background: Europe overall suffered greatly in the early stages of the COVID-19 pandemic but the impact of different countries varied. Italy was in the forefront, but there too there were differences, with the Lombardy region the epicentre of the pandemic. Methods: We report Crude Mortality Rates (CMRs) from deaths reported as due to COVID-19 and, in five countries where age-specific data are available, Standardized Mortality Rates (SMRs) in the European Union and United Kingdom. Results: As of 30th August 2020, Belgium was the country with the highest cumulative CMR (86.3/100,000), but the Lombardy region reached almost double this figure (167.6/100,000), far ahead of the corresponding figure for the rest of Italy at 37.0/100,000. SMRs could be calculated for five countries (Italy, Portugal, Sweden, Germany, and Netherlands). Among them, Sweden had the highest SMR (61.6/100,000). The corresponding figures for Italy, Netherlands, Portugal and Germany were 50.2, 41.4, 15.9, and 10.1 per 100,000, respectively. Conclusion: It is clear that countries within Europe have performed very differently in their responses to the COVID-19 pandemic, but the many limitations in the available data must be addressed before a definitive assessment of the reasons for these differences can be made.
Keywords: COVID-19; death rates; epidemics; pandemics; standardized mortality rate.

[Sodium raises blood pressure but they adjusted for hypertension. -- AP]
Higher Intakes of Potassium and Magnesium, but Not Lower Sodium, Reduce Cardiovascular Risk in the Framingham Offspring Study.
Pickering RT, Bradlee ML, Singer MR, Moore LL.
Nutrients. 2021 Jan 19;13(1):E269. doi: 10.3390/nu13010269.
PMID: 33477824
um to cardiovascular health.
Keywords: cardiovascular disease; potassium; sodium.

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Roles of Adiponectin and Leptin Signaling Related microRNAs in The Preventive Effects of Calorie Restriction in Mammary Tumor Development.
Dogan S, Cicekdal MB, Özorhan Ü, Karabiyik G, Kazan BT, Ekici ID, Yilmaz B, Demirel PB, Coban I, Tuysuz EC, Kuskucu A, Bayrak OF, Cleary MP, Tuna BG.
Appl Physiol Nutr Metab. 2021 Jan 25. doi: 10.1139/apnm-2020-1000. Online ahead of print.
PMID: 33493087
Calorie restriction (CR) is suggested preventing development of mammary tumors (MT) however the mechanism remains to be clarified. We aimed to determine the miRNA profile in mice applied to two different CR protocols; chronic (CCR) and intermittent (ICR) and follow the MT development. In addition, the roles of miRNAs involved in adiponectin and/or leptin signaling pathways were investigated. Mice were enrolled into ad-libitum (AL), CCR, or ICR which was three-weeks AL feeding followed by one-week of 60% CR in cyclic manner. Blood and tissue collection were performed at weeks 10, 17/18, 49/50 and 81/82. Long-term CCR provided better protection compared to ICR for MT development with a delay in the MT occurrence. Adiponectin expression in mammary fat pad were significantly higher in CCR group compared to AL. Using GeneChip™ Array, 250 of 3,195 miRNAs were differentially expressed among the dietary groups. 13 of 250 miRNAs were related to adiponectin and/or leptin signaling genes. Results were verified by RT-PCR. Specifically, miR-326-3p, miR-500-3p and miR-129-5p which are adiponectin and/or leptin signaling related may play important roles in the preventive effects of CR in MT development and in ageing. Thus, these miRNAs might be putative biomarkers to target for diagnostic and treatment purposes. Novelty Bullets • Type of Calorie restriction and micro RNA interaction is related to ageing. • miR-326-3p, miR-500-3p and miR-129-5p expression levels were differentially expressed in MT development and in ageing. • The adiponectin and/or leptin signaling pathways related genes are regulated by certain miRNAs in the protective effects of CR.

Overnight Caloric Restriction Prior to Cardiac Arrest and Resuscitation Leads to Improved Survival and Neurological Outcome in a Rodent Model.
Azadian M, Tian G, Bazrafkan A, Maki N, Rafi M, Chetty N, Desai M, Otarola I, Aguirre F, Zaher SM, Khan A, Suri Y, Wang M, Lopour BA, Steward O, Akbari Y.
Front Neurosci. 2021 Jan 12;14:609670. doi: 10.3389/fnins.2020.609670. eCollection 2020.
PMID: 33510613 Free PMC article.
While interest toward caloric restriction (CR) in various models of brain injury has increased in recent decades, studies have predominantly focused on the benefits of chronic or intermittent CR. The effects of ultra-short, including overnight, CR on acute ischemic brain injury are not well studied. Here, we show that overnight caloric restriction (75% over 14 h) prior to asphyxial cardiac arrest and resuscitation (CA) improves survival and neurological recovery as measured by, behavioral testing on neurological deficit scores, faster recovery of quantitative electroencephalography (EEG) burst suppression ratio, and complete prevention of neurodegeneration in multiple regions of the brain. We also show that overnight CR normalizes stress-induced hyperglycemia, while significantly decreasing insulin and glucagon production and increasing corticosterone and ketone body production. The benefits seen with ultra-short CR appear independent of Sirtuin 1 (SIRT-1) and brain-derived neurotrophic factor (BDNF) expression, which have been strongly linked to neuroprotective benefits seen in chronic CR. Mechanisms underlying neuroprotective effects remain to be defined, and may reveal targets for providing protection pre-CA or therapeutic interventions post-CA. These findings are also of high importance to basic sciences research as we demonstrate that minor, often-overlooked alterations to pre-experimental dietary procedures can significantly affect results, and by extension, research homogeneity and reproducibility, especially in acute ischemic brain injury models.
Keywords: caloric restriction; cardiac arrest; cerebral ischemia; dietary restriction; neurological recovery.

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