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Heart Rate and Heart Rate Variability Changes Are Not Related to Future Cardiovascular Disease and Death in People With and Without Dysglycemia: A Downfall of Risk Markers? The Whitehall II Cohort Study.
Hansen CS, Jørgensen ME, Malik M, Witte DR, Brunner EJ, Tabák AG, Kivimäki M, Vistisen D.
Diabetes Care. 2021 Feb 1:dc202490. doi: 10.2337/dc20-2490. Online ahead of print.
PMID: 33526428
Objective: Higher resting heart rate (rHR) and lower heart rate variability (HRV) are associated with increased risk of cardiovascular disease (CVD) and all-cause mortality in people with and without diabetes. It is unknown whether temporal changes in rHR and HRV may contribute to this risk. We investigated associations between 5-year changes in rHR and HRV and risk of future CVD and death, taking into account participants' baseline glycemic state.
Research design and methods: In this prospective, population-based cohort study we investigated 4,611 CVD-free civil servants (mean [SD] age, 60 [5.9] years; 70% men). We measured rHR and/or six indices of HRV. Associations of 5-year change in 5-min rHR and HRV with fatal and nonfatal CVD and all-cause mortality or the composite of the two were assessed, with adjustments made for relevant confounders. Effect modification by glycemic state was tested.
Results: At baseline, 63% of participants were normoglycemic, 29% had prediabetes, and 8% had diabetes. During a median (interquartile range) follow-up of 11.9 (11.4; 12.3) years, 298 participants (6.5%) experienced a CVD event and 279 (6.1%) died of non-CVD-related causes. We found no association between 5-year changes in rHR and HRV and future events. Only baseline rHR was associated with all-cause mortality. A 10 bpm-higher baseline HR level was associated with a 11.4% higher rate of all-cause mortality (95% CI 1.0-22.9%; P = 0.032). Glycemic state did not modify associations.
Conclusions: Changes in rHR and HRV and possibly also baseline values of these measures are not associated with future CVD or death in people with or without dysglycemia.

Dietary sodium restriction alters muscle lipidomics that relates to insulin resistance in mice.
Pinto PR, Yoshinaga MY, Del Bianco V, Bochi AP, Ferreira GS, Pinto IFD, Rodrigues LG, Nakandakare ER, Okamoto MM, Machado UF, Miyamoto S, Catanozi S, Passarelli M.
J Biol Chem. 2021 Jan 29:100344. doi: 10.1016/j.jbc.2021.100344. Online ahead of print.
PMID: 33524391
A low-sodium diet (LS) diet has been shown to reduce blood pressure (BP) and the incidence of cardiovascular diseases. However, severe dietary sodium restriction promotes insulin resistance (IR) and dyslipidemia in animal models and humans. Thus, further clarification of the long-term consequences of LS is needed. Here, we investigated the effects of chronic LS on gastrocnemius gene and protein expression and lipidomics and its association with IR and plasma lipids in LDL receptor knockout mice. Three-months old male mice were fed a normal sodium diet (NS; 0.5% Na; n=12-19) or LS (0.06% Na; n=14-20) over 90 days. Body mass (BM), BP, plasma total cholesterol, triacylglycerol (TG), glucose, hematocrit, and IR were evaluated. LS increased BM (9%), plasma TG (51%), blood glucose (19%) and IR (46%) when compared to the NS. RT-qPCR analysis revealed that genes involved in lipid uptake and oxidation were increased by the LS: Fabp3 (106%), Prkaa1 (46%) and Cpt1 (74%). Western blotting showed that genes and proteins involved in insulin signaling were not changed by the LS. Similarly, lipid species classically involved in muscle IR, such as diacylglycerols and ceramides detected by UHPLC-MS/MS, were also unchanged by LS. Species of phosphatidylcholines (68%), phosphatidylinositol (90%) and free fatty acids (59%) increased while cardiolipins (41%) and acylcarnitines (9%) decreased in gastrocnemius in response to LS and were associated with glucose disposal rate. Together these results suggest that chronic LS alters glycerophospholipid and fatty acids species in gastrocnemius that may contribute to glucose and lipid homeostasis derangements in mice.
Keywords: insulin resistance; lipid metabolism; lipidomics; low-sodium diet; skeletal muscle.

The Association of Preinfection Daily Oral Anticoagulation Use and All-Cause in Hospital Mortality From Novel Coronavirus 2019 at 21 Days: A Retrospective Cohort Study.
Harrison RF, Forte K, Buscher MG Jr, Chess A, Patel A, Moylan T, Mize CH, Werdmann M, Ferrigno R.
Crit Care Explor. 2021 Jan 22;3(1):e0324. doi: 10.1097/CCE.0000000000000324. eCollection 2021 Jan.
PMID: 33521644 Free PMC article.
Objectives: Practices regarding anticoagulation use in coronavirus disease 2019 focus primarily on its efficacy in the critically ill without a clear understanding of when to begin anticoagulation. We sought to understand the association of preinfection daily oral anticoagulation use and the short-term mortality of patients hospitalized with coronavirus disease 2019.
Design: Retrospective chart review.
Setting: Large health system with high coronavirus disease 2019 prevalence.
Patients: Patients 60 years or older admitted to the hospital with positive coronavirus disease 2019 polymerase chain reaction test.
Interventions: We compared both those on warfarin and those on a direct oral anticoagulant prior to admission and throughout disease course with those who were never exposed to an oral anticoagulant.
Results: Our primary outcome was inhospital mortality at 21 days from the first coronavirus disease 2019 test ordered. Patients in the direct oral anticoagulant group (n = 104) were found to have significantly lower 21-day all-cause in hospital mortality than patients in the control group (n = 894) both prior to adjustment (14.4% vs 23.8%; odds ratio, 0.57 [0.29-0.92]; p = 0.03) and after controlling for age, gender, and comorbidities (odds ratio, 0.44 [0.20-0.90]; p = 0.033). Patients on warfarin (n = 28) were found to have an elevated unadjusted mortality rate of 32% versus 23.8% in the control group (odds ratio, 1.51 [0.64-3.31]; p = 0.31). After adjustment, a reduction in mortality was observed but not found to be statistically significant (odds ratio, 0.29 [0.02-1.62]; p = 0.24). There was no statistical difference noted in the number of bleeding events in each group.
Conclusions: In this retrospective cohort study evaluating oral anticoagulant use among patients with coronavirus disease 2019, we found that patients who are on daily oral anticoagulation at the time of infection and throughout their disease course had significantly lower risk of all-cause mortality at 21 days. Validation of these findings should be performed on population-based levels. While research regarding anticoagulation algorithms is ongoing, we believe these results support future randomized control trials to understand the efficacy and risk of the use of early oral anticoagulation.
Keywords: anticoagulation; coronavirus; critical care; direct-acting oral anticoagulants; severe acute respiratory syndrome coronavirus; venous thromboembolism.

Protein signatures of centenarians and their offspring suggest centenarians age slower than other humans.
Sebastiani P, Federico A, Morris M, Gurinovich A, Tanaka T, Chandler KB, Andersen SL, Denis G, Costello K, Ferrucci L, Jennings L, Glass DJ, Monti S, Perls TT.
Aging Cell. 2021 Jan 29:e13290. doi: 10.1111/acel.13290. Online ahead of print.
PMID: 33512769
Using samples from the New England Centenarian Study (NECS), we sought to characterize the serum proteome of 77 centenarians, 82 centenarians' offspring, and 65 age-matched controls of the offspring (mean ages: 105, 80, and 79 years). We identified 1312 proteins that significantly differ between centenarians and their offspring and controls (FDR < 1%), and two different protein signatures that predict longer survival in centenarians and in younger people. By comparing the centenarian signature with 2 independent proteomic studies of aging, we replicated the association of 484 proteins of aging and we identified two serum protein signatures that are specific of extreme old age. The data suggest that centenarians acquire similar aging signatures as seen in younger cohorts that have short survival periods, suggesting that they do not escape normal aging markers, but rather acquire them much later than usual. For example, centenarian signatures are significantly enriched for senescence-associated secretory phenotypes, consistent with those seen with younger aged individuals, and from this finding, we provide a new list of serum proteins that can be used to measure cellular senescence. Protein co-expression network analysis suggests that a small number of biological drivers may regulate aging and extreme longevity, and that changes in gene regulation may be important to reach extreme old age. This centenarian study thus provides additional signatures that can be used to measure aging and provides specific circulating biomarkers of healthy aging and longevity, suggesting potential mechanisms that could help prolong health and support longevity.
Keywords: SomaLogic; aging; longevity; protein; senescence.

Visit-to-visit changes in fasting blood sugar and the risk for cardiovascular disease and mortality in the Korean population: a nationwide population-based cohort study.
An HM, Yeo SH, Chung HJ, Cho HS, Bae SJ, Kim JY, Kang DR, Lee MY, Lee JY.
Eur Rev Med Pharmacol Sci. 2021 Jan;25(1):263-272. doi: 10.26355/eurrev_202101_24392.
PMID: 33506915
Objective: The importance of continuous monitoring of fasting blood sugar (FBS) levels of diabetic patients has been established.
Materials and methods: An observational prospective study was conducted. Our analysis included 1,700,796 individuals from the nationwide South Korean National Health Insurance System cohort. FBS variability was measured by standard deviation (SD).
Results: Kaplan-Meier curves demonstrated elevated disease probability in the higher FBS fluctuation group compared with the lower FBS fluctuation group. After adjusting for confounding variables, Cox proportional hazards analysis showed that the hazard ratios of 411 individuals in the highest quartile of SD variation of FBS were 1.77 (95% confidence interval 1.37-2.28, p<0.001) compared with the lowest quartile of SD variation of FBS. The impact of FBS fluctuation on the risk of cardiovascular diseases (CVDs), cerebrovascular diseases, CVD mortality and all-cause mortality in the highest quartiles of diabetic and non-diabetic individuals was statistically significant.
Conclusions: Visit-to-visit FBS variability has prognostic value for predicting micro- and macrovascular disease, cardiovascular mortality, and all-cause mortality.

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Importance of Adipose Tissue NAD+ Biology in Regulating Metabolic Flexibility.
Franczyk MP, Qi N, Stromsdorfer KL, Li C, Yamaguchi S, Itoh H, Yoshino M, Sasaki Y, Brookheart RT, Finck BN, DeBosch BJ, Klein S, Yoshino J.
Endocrinology. 2021 Mar 1;162(3):bqab006. doi: 10.1210/endocr/bqab006.
PMID: 33543238
Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme that regulates cellular energy metabolism in many cell types. The major purpose of the present study was to test the hypothesis that NAD+ in white adipose tissue (WAT) is a regulator of whole-body metabolic flexibility in response to changes in insulin sensitivity and with respect to substrate availability and use during feeding and fasting conditions. To this end, we first evaluated the relationship between WAT NAD+ concentration and metabolic flexibility in mice and humans. We found that WAT NAD+ concentration was increased in mice after calorie restriction and exercise, 2 enhancers of metabolic flexibility. Bariatric surgery-induced 20% weight loss increased plasma adiponectin concentration, skeletal muscle insulin sensitivity, and WAT NAD+ concentration in people with obesity. We next analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) mice, which have markedly decreased NAD+ concentrations in WAT. ANKO mice oxidized more glucose during the light period and after fasting than control mice. In contrast, the normal postprandial stimulation of glucose oxidation and suppression of fat oxidation were impaired in ANKO mice. Data obtained from RNA-sequencing of WAT suggest that loss of NAMPT increases inflammation, and impairs insulin sensitivity, glucose oxidation, lipolysis, branched-chain amino acid catabolism, and mitochondrial function in WAT, which are features of metabolic inflexibility. These results demonstrate a novel function of WAT NAMPT-mediated NAD+ biosynthesis in regulating whole-body metabolic flexibility, and provide new insights into the role of adipose tissue NAD+ biology in metabolic health.
Keywords: NAD+; adiponectin; adipose tissue; insulin sensitivity; metabolic flexibility; obesity.

Effect of citrus peels-supplemented diet on longevity, memory index, redox status, cholinergic and monoaminergic enzymes in Drosophila melanogaster model.
Oboh G, Olatunde DM, Ademosun AO, Ogunsuyi OB.
J Food Biochem. 2021 Feb 3:e13616. doi: 10.1111/jfbc.13616. Online ahead of print.
PMID: 33533492
This study sought to determine the life span promoting effecof orange (Citrus sinensis), tangerine (Citrus maxima) and grapefruit (Citrus paradisi) peels in Drosophila melanogaster model. Flies (both gender, 3 to 5 days old) were divided into seven (7) groups (n = 5) containing 40 flies each; group I (control) flies were fed with basal diet, II-VII were flies were fed with basal diet containing 0.1 and 1.0% of tangerine peel (TP), orange peel (CP), and grapefruit peel (GP) respectively, for 14 days. Locomotor performance and memory index were assessed via negative geotaxis and aversive phototaxis suppression assays, respectively. Thereafter, the fly homogenates were assayed for activities of acetylcholinesterase (AChE), monoamine oxidase (MAO) and antioxidant enzymes as well as other indices of their redox. The results revealed that the citrus peels significantly improved longevity, locomotor performance, memory index, antioxidant status, and modulate cholinesterase and monoamine oxidase enzyme activities in treated flies when compared to the control. The results obtained suggest that the citrus peels offer potentials as dietary supplement with life span promoting properties in D. melanogaster model which could as well serve as a functional food additives. PRACTICAL APPLICATIONS: Citrus peels, although often considered agro-wastes, are used as food supplements and food ingredents especially in production of candies, jams and custards. This study suggests the use of orange (Citrus sinensis), tangerine (Citrus maxima), and grapefruit (Citrus paradisi) peels as dietary supplements which offers potential life span promoting properties.
Keywords: Drosophila melanogaster; acetylcholinesterase; aging; citrus; monoamine oxidase.

Association of ultra-processed food consumption with cardiovascular mortality in the US population: long-term results from a large prospective multicenter study.
Zhong GC, Gu HT, Peng Y, Wang K, Wu YQ, Hu TY, Jing FC, Hao FB.
Int J Behav Nutr Phys Act. 2021 Feb 3;18(1):21. doi: 10.1186/s12966-021-01081-3.
PMID: 33536027
Background: Ultra-processed foods have now become dominant in the global food system. Whether their consumption is associated with cardiovascular mortality remains controversial. Moreover, data on ultra-processed foods and cardiovascular outcomes are scarce in the US population. We aimed to examine the association of ultra-processed food consumption with cardiovascular mortality in a US population.
Methods: A population-based cohort of 91,891 participants was identified from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Dietary data were collected through a validated 137-item food frequency questionnaire. Ultra-processed foods were defined by the NOVA classification. Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for cardiovascular mortality. Restricted cubic spline regression was used to test nonlinearity. Subgroup analyses were conducted to identify the potential effect modifiers.
Results: After an average follow-up of 13.5 years (1,236,049.2 person-years), 5490 cardiovascular deaths were documented, including 3985 heart disease deaths and 1126 cerebrovascular deaths. In the fully adjusted model, participants in the highest vs. the lowest quintiles of ultra-processed food consumption had higher risks of death from cardiovascular disease (HRquintile 5 vs. 1, 1.50; 95% CI, 1.36-1.64) and heart disease (HRquintile 5 vs. 1, 1.68; 95% CI, 1.50-1.87) but not cerebrovascular disease (HRquintile 5 vs. 1, 0.94; 95% CI, 0.76-1.17). A nonlinear dose-response pattern was observed for overall cardiovascular and heart disease mortality (all Pnonlinearity < 0.05), with a threshold effect observed at ultra-processed food consumption of 2.4 servings/day and 2.3 servings/day, respectively; below the thresholds, no significant associations were observed for these two outcomes. Subgroup analyses showed that the increased risks of mortality from ultra-processed foods were significantly higher in women than in men (all Pinteraction < 0.05).
Conclusions: High consumption of ultra-processed foods is associated with increased risks of overall cardiovascular and heart disease mortality. These harmful associations may be more pronounced in women. Our findings need to be confirmed in other populations and settings.
Keywords: Cardiovascular mortality; Prospective study; Risk factor; Ultra-processed food.

Prolonged preoperative fasting induces postoperative insulin resistance by ER-stress mediated Glut4 down-regulation in skeletal muscles.
Lin MW, Chen CI, Cheng TT, Huang CC, Tsai JW, Feng GM, Hwang TZ, Lam CF.
Int J Med Sci. 2021 Jan 11;18(5):1189-1197. doi: 10.7150/ijms.52701. eCollection 2021.
PMID: 33526980 Free PMC article.
Preoperative fasting aims to prevent pulmonary aspiration and improve bowel preparation, but it may induce profound systemic catabolic responses that lead to protein breakdown and insulin-resistant hyperglycemia after operation. However, the molecular mechanisms of catabolic reaction induced by prolonged preoperative fasting and surgical stress are undetermined. In this study, anesthetized rats were randomly assigned to receive a sham operation or laparotomy cecectomy. Fasting groups were restricted from food and water for 12 h before operation, while the feeding group had free access to food throughout the study period. Twenty-four hours after operation, the animals were sacrificed to collect blood samples and soleus muscles for analysis. Postoperative blood glucose level was significantly increased in the fasting group with elevated serum insulin and C-peptide. Continuous feeding reduced serum myoglobin and lactate dehydrogenase concentrations. Preoperative fasting activated inositol-requiring transmembrane kinase/endoribonuclease (IRE)-1α and c-Jun N-terminal kinase (JNK) mediated endoplasmic reticulum (ER)-stress, and reduced glucose transporter type 4 (Glut4) expression in the soleus muscle. Phospholamban phosphorylation was reduced and intracellular calcium levels were increased in the isolated skeletal muscle cells. Similar results were found in ER stress-induced C1C12 myoblasts. The expression of Glut4 was suppressed in the stressed C1C12, but was potentiated following inhibition of ER stress and chelation of intracellular free calcium. This study provides evidence demonstrating that prolonged preoperative fasting induces ER stress and generates insulin resistance in the skeletal muscle through suppression of Glut4 and inactivation of Ca2+-ATPase, leading to intracellular calcium homeostasis disruption and peripheral insulin resistance.
Keywords: endoplasmic reticulum stress; fasting; insulin resistance; protein catabolism; skeletal muscle.

Effectiveness of ketogenic diet in treatment of patients with refractory chronic migraine.
Bongiovanni D, Benedetto C, Corvisieri S, Del Favero C, Orlandi F, Allais G, Sinigaglia S, Fadda M.
Neurol Sci. 2021 Feb 1. doi: 10.1007/s10072-021-05078-5. Online ahead of print.
PMID: 33527209
Background and purpose: Ketogenic diet (KD) is based on restriction of carbohydrate intake. Metabolism is forced to obtain energy starting from β-oxidation of fatty acids which, turned into ketone bodies, can also be used by central nervous system (CNS). KD use in treatment of chronic migraine has recently been considered. We set out to verify modification of symptoms in patients with refractory chronic migraine in response to KD.
Methods: Fifty patients were enrolled of which 38 completed the procedures the study and 23 were considered in the statistics. All of the patients considered in our study were affected by medication overuse headache (MOH). They were on a KD for 3 months. The following parameters have been checked at t = 0 and every 30 days for 6 months: migraine episode length (n. hours/day), frequency (n. days/month), level of pain of every episode measured on a scale from 1 to 3 (1 = mild; 2 = moderate; 3 = severe), and n. analgesic drugs taken/month.
Results: Days with symptoms decreased from 30 (median value) to 7.5 with p < 0.0001. The duration of the migraine episodes decreased from 24 h (median value) to 5.5 h with p < 0.0016. The patients' pain level, initially at maximum value for 83% of the participants, improved for 55% of them (p < 0.0024). The number of drugs taken in a month decreased from 30 doses (median value) to 6 doses.
Conclusions: It can be stated that a 3-month KD resulted in a reduction of painful symptoms of drug refractory chronic migraine. This result may suggest an improvement in quality of life of the patients, even without a tabulated data collection.
Keywords: Chronic migraine; Controlled ketosis; Drug resistance; Ketogenic diet; Meal replacements; Neurological diseases.

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More than 50 Long-term effects of COVID-19: a systematic review and meta-analysis.
Lopez-Leon S, Wegman-Ostrosky T, Perelman C, Sepulveda R, Rebolledo PA, Cuapio A, Villapol S.
medRxiv. 2021 Jan 30:2021.01.27.21250617. doi: 10.1101/2021.01.27.21250617. Preprint.
PMID: 33532785 Free PMC article.
COVID-19, caused by SARS-CoV-2, can involve sequelae and other medical complications that last weeks to months after initial recovery, which has come to be called Long-COVID or COVID long-haulers. This systematic review and meta-analysis aims to identify studies assessing long-term effects of COVID-19 and estimates the prevalence of each symptom, sign, or laboratory parameter of patients at a post-COVID-19 stage. LitCOVID (PubMed and Medline) and Embase were searched by two independent researchers. All articles with original data for detecting long-term COVID-19 published before 1st of January 2021 and with a minimum of 100 patients were included. For effects reported in two or more studies, meta-analyses using a random-effects model were performed using the MetaXL software to estimate the pooled prevalence with 95% CI. Heterogeneity was assessed using I2 statistics. The Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) reporting guideline was followed. A total of 18,251 publications were identified, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated, 21 meta-analyses were performed, and 47,910 patients were included. The follow-up time ranged from 15 to 110 days post-viral infection. The age of the study participants ranged between 17 and 87 years. It was estimated that 80% (95% CI 65-92) of the patients that were infected with SARS-CoV-2 developed one or more long-term symptoms. The five most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). All meta-analyses showed medium (n=2) to high heterogeneity (n=13). In order to have a better understanding, future studies need to stratify by sex, age, previous comorbidities, severity of COVID-19 (ranging from asymptomatic to severe), and duration of each symptom. From the clinical perspective, multi-disciplinary teams are crucial to developing preventive measures, rehabilitation techniques, and clinical management strategies with whole-patient perspectives designed to address long COVID-19 care.

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Egg and cholesterol consumption and mortality from cardiovascular and different causes in the United States: A population-based cohort study.
Zhuang P, Wu F, Mao L, Zhu F, Zhang Y, Chen X, Jiao J, Zhang Y.
PLoS Med. 2021 Feb 9;18(2):e1003508. doi: 10.1371/journal.pmed.1003508. eCollection 2021 Feb.
PMID: 33561122
Background: Whether consumption of egg and cholesterol is detrimental to cardiovascular health and longevity is highly debated. Data from large-scale cohort studies are scarce. This study aimed to examine the associations of egg and cholesterol intakes with mortality from all causes, cardiovascular disease (CVD), and other causes in a US population.
Methods and findings: Overall, 521,120 participants (aged 50-71 years, mean age = 62.2 years, 41.2% women, and 91.8% non-Hispanic white) were recruited from 6 states and 2 additional cities in the US between 1995 and 1996 and prospectively followed up until the end of 2011. Intakes of whole eggs, egg whites/substitutes, and cholesterol were assessed by a validated food frequency questionnaire. Cause-specific hazard models considering competing risks were used, with the lowest quintile of energy-adjusted intake (per 2,000 kcal per day) as the reference. There were 129,328 deaths including 38,747 deaths from CVD during a median follow-up of 16 years. Whole egg and cholesterol intakes were both positively associated with all-cause, CVD, and cancer mortality. In multivariable-adjusted models, the hazard ratios (95% confidence intervals) associated with each intake of an additional half of a whole egg per day were 1.07 (1.06-1.08) for all-cause mortality, 1.07 (1.06-1.09) for CVD mortality, and 1.07 (1.06-1.09) for cancer mortality. Each intake of an additional 300 mg of dietary cholesterol per day was associated with 19%, 16%, and 24% higher all-cause, CVD, and cancer mortality, respectively. Mediation models estimated that cholesterol intake contributed to 63.2% (95% CI 49.6%-75.0%), 62.3% (95% CI 39.5%-80.7%), and 49.6% (95% CI 31.9%-67.4%) of all-cause, CVD, and cancer mortality associated with whole egg consumption, respectively. Egg white/substitute consumers had lower all-cause mortality and mortality from stroke, cancer, respiratory disease, and Alzheimer disease compared with non-consumers. Hypothetically, replacing half a whole egg with equivalent amounts of egg whites/substitutes, poultry, fish, dairy products, or nuts/legumes was related to lower all-cause, CVD, cancer, and respiratory disease mortality. Study limitations include its observational nature, reliance on participant self-report, and residual confounding despite extensive adjustment for acknowledged dietary and lifestyle risk factors.
Conclusions: In this study, intakes of eggs and cholesterol were associated with higher all-cause, CVD, and cancer mortality. The increased mortality associated with egg consumption was largely influenced by cholesterol intake. Our findings suggest limiting cholesterol intake and replacing whole eggs with egg whites/substitutes or other alternative protein sources for facilitating cardiovascular health and long-term survival.

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(1):57. doi: 10.1186/s40795-020-00361-8.
PMID: 33557945
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.

Prospective Study of Engagement in Leisure Activities and All-Cause Mortality Among Older Japanese Adults.
Kobayashi T, Tani Y, Kino S, Fujiwara T, Kondo K, Kawachi I.
J Epidemiol. 2021 Feb 6. doi: 10.2188/jea.JE20200427. Online ahead of print.
PMID: 33551388
Background: Engagement in leisure activities among older people is associated with a lower risk of mortality. However, no studies have been conducted focusing on the difference of associations with mortality risk among multiple types of leisure activities.
Methods: We examined prospectively the association of engagement in leisure activities with all-cause mortality in a cohort of older Japanese adults. The Japan Gerontological Evaluation Study included 48,216 participants aged 65 years or older. During a mean follow-up period of 5.6 years, we observed 5,575 deaths (11.6%). We investigated the total number of leisure activities, as well as combinations of 25 different leisure activities with Cox proportional hazards models, adjusting for potential confounding factors.
Results: We found a linear relationship between the total number of leisure activities and mortality hazard (adjusted hazard ratio 0.93; 95% CI, 0.92-0.95). Furthermore, engagement in leisure activities involving physical activity, as well as group-based interactions, showed the strongest associations with lowered mortality. By contrast, engagement in cultural leisure activities and solitary leisure activities were not associated with all-cause mortality.
Conclusions: Although we cannot rule out residual confounding, our findings suggest that encouraging engagement in physically-active group-based leisure activities may promote longevity in older adults.
Keywords: Japan; aging; leisure activities; older people.

A compositional analysis of time spent in sleep, sedentary behaviour and physical activity with all-cause mortality risk.
Clarke AE, Janssen I.
Int J Behav Nutr Phys Act. 2021 Feb 6;18(1):25. doi: 10.1186/s12966-021-01092-0.
PMID: 33549100
Background: Daily time spent in sleep, sedentary behaviour (SED), light intensity physical activity (LIPA), and moderate-to-vigorous intensity physical activity (MVPA) are compositional, co-dependent variables. The objectives of this study were to use compositional data analysis to: (1) examine the relationship between the movement behaviour composition (daily time spent in sleep, SED, LIPA and MVPA) and all-cause mortality risk, and (2) estimate the extent to which changing time spent in any given movement behaviour (sleep, SED, LIPA, or MVPA) within the movement behaviour composition was associated with changes in risk of all-cause mortality.
Methods: 2838 adult participants from the 2005-2006 cycle of the U.S. National Health and Nutrition Examination Survey were studied using a prospective cohort design. Daily time spent in SED, LIPA and MVPA were determined by accelerometer. Nightly time spent sleeping was self-reported. Survey data were linked with mortality data through to the end of December 2015. Compositional data analysis was used to investigate relationships between the movement behaviour composition and mortality.
Results: The movement behaviour composition was significantly associated with mortality risk. Time spent in MVPA relative to other movement behaviours was negatively associated with mortality risk (HR = .74; 95% CI [.67, .83]) while relative time spent in SED was positively associated with mortality risk (HR = 1.75; 95% CI [1.10, 2.79]). Time displacement estimates revealed that the greatest estimated changes in mortality risk occurred when time spent in MVPA was decreased and replaced with sleep, SED, LIPA or a combination of these behaviours (HRs of 1.76 to 1.80 for 15 min/day displacements).
Conclusions: The daily movement behaviour composition was related to mortality. Replacing time in MVPA or SED with equivalent time from any other movement behaviour was associated with an increase and decrease in mortality risk, respectively.
Keywords: 24-h movement behaviours; Compositional data analysis; Physical activity; Public health; Sedentary behaviour; Sleep; Survival analysis.

Intermittent fasting promotes anxiolytic-like effects unrelated to synaptic mitochondrial function and BDNF support.
Carteri RB, Menegassi LN, Feldmann M, Kopczynski A, Rodolphi MS, Strogulski NR, Almeida AS, Marques DM, Porciúncula LO, Portela LV.
Behav Brain Res. 2021 Feb 4:113163. doi: 10.1016/j.bbr.2021.113163. Online ahead of print.
PMID: 33549686
Anxiety disorders are linked to mitochondrial dysfunction and decreased neurotrophic support. Since anxiolytic drugs target mitochondria, non-pharmacological approaches to improve mitochondrial metabolism such as intermittent fasting (IF) may cause parallel behavioral benefits against anxiety disorders. Here, we investigated whether a chronic IF regimen could induce anxiolytic-like effects concomitantly to modulation in mitochondrial bioenergetics and trophic signaling in mice brain. A total of 44 Male C57BL/6 J mice (180 days old) were assigned to two dietary regimens: a normal, ad libitum diet (AL group) and an alternate-day fasting (IF group), where animals underwent 10 cycles of 24 h food restriction followed by 24 h ad libitum access. Animals underwent the open field test, dark/light box and elevated plus maze tasks. Isolated nerve terminals were obtained from mice brain and used for mitochondrial respirometry, hydrogen peroxide production and assessment of membrane potential dynamics, calcium handling and western blotting. We showed that IF significantly alters total daily food intake and food consumption patterns but not body weight. There were no differences in the exploratory and locomotory parameters. Remarkably, animals from IF showed decreased anxiety-like behavior. Mitochondrial metabolic responses in different coupling states and parameters linked with H2O2 production, Ca2+ buffering and electric gradient were not different between groups. Finally, no alterations in molecular indicators of apoptotic death (Bax/Bcl-2 ratio) and neuroplasticity (proBDNF/BDNF and synaptophysin were observed). In conclusion, IF exerts anxiolytic-like effect not associated with modulation in synaptic neuronergetics or expression of neurotrophic proteins. These results highlight a potential benefit of intermittent fasting as a nutritional intervention in anxiety-related disorders.
Keywords: Anxiety; mitochondria; neurotrophic factors; nutritional intervention.

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Eicosapentaenoic Acid Is Associated with Decreased Incidence of Alzheimer's Dementia in the Oldest Old.
Melo van Lent D, Egert S, Wolfsgruber S, Kleineidam L, Weinhold L, Wagner-Thelen H, Maier W, Jessen F, Ramirez A, Schmid M, Scherer M, Riedel-Heller SG, Wagner M.
Nutrients. 2021 Jan 30;13(2):461. doi: 10.3390/nu13020461.
PMID: 33573174
Background: Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) may have different effects on cognitive health due to their anti- or pro-inflammatory properties.
Methods: We aimed to prospectively examine the relationships between n-3 and n-6 PUFA contents in serum phospholipids with incident all-cause dementia and Alzheimer's disease dementia (AD). We included 1264 non-demented participants aged 84 ± 3 years from the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe) multicenter-cohort study. We investigated whether fatty acid concentrations in serum phospholipids, especially eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), linoleic acid (LA), dihomo-γ-linolenic acid (DGLA), and arachidonic acid (AA), were associated with risk of incident all-cause dementia and AD.
Results: During the follow-up window of seven years, 233 participants developed dementia. Higher concentrations of EPA were associated with a lower incidence of AD (hazard ratio (HR) 0.76 (95% CI 0.63; 0.93)). We also observed that higher concentrations of EPA were associated with a decreased risk for all-cause dementia (HR 0.76 (95% CI 0.61; 0.94)) and AD (HR 0.66 (95% CI 0.51; 0.85)) among apolipoprotein E ε4 (APOE ε4) non-carriers but not among APOE ε4 carriers. No other fatty acids were significantly associated with AD or dementia.
Conclusions: Higher concentrations of EPA were associated with a lower risk of incident AD. This further supports a beneficial role of n-3 PUFAs for cognitive health in old age.
Keywords: Alzheimer’s disease dementia; apolipoprotein E ε4; dementia; eicosapentaenoic acid; fatty acids; oldest old; omega-3.

Alcohol Consumption and Incident Cataract Surgery in Two Large UK Cohorts.
Chua SY, Luben RN, Hayat S, Broadway DC, Khaw KT, Warwick A, Britten A, Day AC, Strouthidis N, Patel PJ, Khaw PT, Foster PJ, Khawaja AP; UK Biobank Eye and Vision Consortium.
Ophthalmology. 2021 Feb 8:S0161-6420(21)00114-7. doi: 10.1016/j.ophtha.2021.02.007. Online ahead of print.
PMID: 33571551
Purpose: To examine the association of alcohol consumption and type of alcoholic beverage with incident cataract surgery in two large cohorts.
Design: Longitudinal observational study PARTICIPANTS: We included 469,387 participants of UK Biobank with a mean age of 56 years, and 23,162 participants of EPIC-Norfolk with a mean age of 59 years.
Methods: Self-reported alcohol consumption at baseline was ascertained by a touchscreen questionnaire in UK Biobank and a food-frequency questionnaire in EPIC-Norfolk. Cases were defined as participants undergoing cataract surgery in either eye as ascertained via data linkage to National Health Service procedure statistics. We excluded participants with cataract surgery up to 1 year after the baseline assessment visit or those with self-reported cataract at baseline. Cox proportional hazards models were used to examine the associations of alcohol consumption with incident cataract surgery, adjusted for age, sex, ethnicity, Townsend deprivation index, body mass index, smoking and diabetes status.
Main outcome measures: Incident cataract surgery RESULTS: There were 19,011 (mean cohort follow-up of 95 months) and 4,573 (mean cohort follow-up of 193 months) incident cases of cataract surgery in UK Biobank and EPIC-Norfolk, respectively. Compared to non-drinkers, drinkers were less likely to undergo cataract surgery in UK Biobank (HR 0.89, 95% CI 0.85-0.93) and EPIC-Norfolk (HR 0.90, 95% CI 0.84-0.97) after adjusting for covariables. Among alcohol consumers, greater alcohol consumption was associated with a reduced risk of undergoing cataract surgery in EPIC-Norfolk (P<0.001), while a U-shaped association was observed in the UK Biobank. Compared with non-drinkers, sub-group analysis by type of alcohol beverage showed the strongest protective association with wine consumption; the risk of incident cataract surgery was 23% and 14% lower among those in the highest category of wine consumption in EPIC-Norfolk and UK Biobank, respectively.
Conclusion: Our findings suggest a lower risk of undergoing cataract surgery with low to moderate alcohol consumption. The association was particularly apparent with wine consumption. We cannot exclude the possibility of residual confounding and further studies are required to determine whether this association is causal in nature.
Keywords: Alcohol; Cataract; Cataract surgery; EPIC-Norfolk; Longitudinal observational cohort; UK Biobank; Wine.Alcohol Consumption and Incident Cataract Surgery in Two Large UK Cohorts.
Chua SY, Luben RN, Hayat S, Broadway DC, Khaw KT, Warwick A, Britten A, Day AC, Strouthidis N, Patel PJ, Khaw PT, Foster PJ, Khawaja AP; UK Biobank Eye and Vision Consortium.
Ophthalmology. 2021 Feb 8:S0161-6420(21)00114-7. doi: 10.1016/j.ophtha.2021.02.007. Online ahead of print.
PMID: 33571551

Evaluation of Various Starchy Foods: A Systematic Review and Meta-Analysis on Chemical Properties Affecting the Glycemic Index Values Based on In Vitro and In Vivo Experiments.
Afandi FA, Wijaya CH, Faridah DN, Suyatma NE, Jayanegara A.
Foods. 2021 Feb 8;10(2):364. doi: 10.3390/foods10020364.
PMID: 33567535
The chemical properties that serve as major determinants for the glycemic index (GI) of starchy food and recommended low-GI, carbohydrate-based foods have remained enigmatic. This present work performed a systematic assessment of linkages between chemical properties of foods and GI, and selected low-GI starchy foods. The data were sourced from literature published in various scientific journals. In total, 57 relevant studies and 936 data points were integrated into a database. Both in vitro and in vivo studies on GI values were included. The database was subsequently subjected to a meta-analysis. Meta-analysis from in vitro studies revealed that the two significant factors responsible for the GI of starchy foods were resistant starch and phenolic content (respectively, standardized mean difference (SMD): -2.52, 95% confidence interval (95%CI): -3.29 to -1.75, p (p-value) < 0.001; SMD: -0.72, 95%CI: -1.26 to -0.17, p = 0.005), while the lowest-GI crop type was legumes. Subgroup analysis restricted to the crop species with significant low GI found two crops, i.e., sorghum (SMD: -0.69, 95%CI: -2.33 to 0.96, p < 0.001) and red kidney bean (SMD: -0.39, 95%CI: -2.37 to 1.59, p = 0.001). Meta-analysis from in vivo studies revealed that the two significant factors responsible for the GI of starchy foods were flavonoid and phenolic content (respectively, SMD: -0.67, 95%CI: -0.87 to -0.47, p < 0.001; SMD: -0.63, 95%CI: -1.15 to -0.11, p = 0.009), while the lowest-GI crop type was fruit (banana). In conclusion, resistant starch and phenolic content may have a desirable impact on the GI of starchy food, while sorghum and red kidney bean are found to have low GI.
Keywords: bioactive compounds; carbohydrate foods; diabetes; glycemic index; meta-analysis.

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Effects of High and Low Sugar Diets on Cardiovascular Disease Risk Factors.
Ahmad A, Isherwood C, Umpleby M, Griffin B.
J Nutr Sci Vitaminol (Tokyo). 2020;66(Supplement):S18-S24. doi: 10.3177/jnsv.66.S18.
PMID: 33612591
It has been proposed that a high sugar intake was associated with cardiovascular disease (CVD) risk and metabolic syndrome depending on the amount of carbohydrate (CHO), other nutrients in foods, and underlying metabolic disturbances. This study aimed to investigate the effects of high (HS) and low sugar (LS) diets on metabolic profiles in 25 middle-aged men at increased CVD risk in a 12-week randomised cross-over intervention study. An isocaloric dietary exchanged model consisted of HS (24% energy from sugar) and LS (6% energy from sugar) with comparable total CHO, fat and fibre composition in normal foods was used. Anthropometric, blood pressure and plasma lipid profile were measured pre- and post-intervention. Body weight, waist circumference and fat mass increased and decreased significantly after HS (by 0.7±0.3 kg, 1.4±1.0 cm and 0.5±0.3 kg) and LS (by 2.1±0.5 kg, 2.0±0.8 cm and 1.4±0.3 kg) (p<0.05), respectively. Plasma TG increased significantly after HS by 0.26±0.07 mmol/L and decreased after LS by 0.35±0.16 mmol/L. Plasma HDL decreased by 0.11±0.03 mmol/L (p<0.05) after HS, whilst, plasma TC and LDL decreased significantly by 10% after LS. There was no significant change in other parameters after either diet. This study confirmed that a diet with a greater proportion of sugar increased CVD risk via negative changes in metabolic profiles including body weight, waist circumference and lipid parameters, whereas LS produced the positive effects. A restriction of sugar intake to lower than 10% energy intake is vital to reduce CVD risk.
Keywords: cardiovascular disease; high sugar; low sugar; risk factors.

Asparagine couples mitochondrial respiration to ATF4 activity and tumor growth.
Krall AS, Mullen PJ, Surjono F, Momcilovic M, Schmid EW, Halbrook CJ, Thambundit A, Mittelman SD, Lyssiotis CA, Shackelford DB, Knott SRV, Christofk HR.
Cell Metab. 2021 Feb 17:S1550-4131(21)00057-7. doi: 10.1016/j.cmet.2021.02.001. Online ahead of print.
PMID: 33609439
Mitochondrial respiration is critical for cell proliferation. In addition to producing ATP, respiration generates biosynthetic precursors, such as aspartate, an essential substrate for nucleotide synthesis. Here, we show that in addition to depleting intracellular aspartate, electron transport chain (ETC) inhibition depletes aspartate-derived asparagine, increases ATF4 levels, and impairs mTOR complex I (mTORC1) activity. Exogenous asparagine restores proliferation, ATF4 and mTORC1 activities, and mTORC1-dependent nucleotide synthesis in the context of ETC inhibition, suggesting that asparagine communicates active respiration to ATF4 and mTORC1. Finally, we show that combination of the ETC inhibitor metformin, which limits tumor asparagine synthesis, and either asparaginase or dietary asparagine restriction, which limit tumor asparagine consumption, effectively impairs tumor growth in multiple mouse models of cancer. Because environmental asparagine is sufficient to restore tumor growth in the context of respiration impairment, our findings suggest that asparagine synthesis is a fundamental purpose of tumor mitochondrial respiration, which can be harnessed for therapeutic benefit to cancer patients.
Keywords: asparaginase; asparagine; cancer metabolism; cancer treatment; dietary restriction; metformin; respiration.

A Mediterranean Diet and Low-Fat Vegan Diet to Improve Body Weight and Cardiometabolic Risk Factors: A Randomized, Cross-over Trial.
Barnard ND, Alwarith J, Rembert E, Brandon L, Nguyen M, Goergen A, Horne T, do Nascimento GF, Lakkadi K, Tura A, Holubkov R, Kahleova H.
J Am Coll Nutr. 2021 Feb 5:1-13. doi: 10.1080/07315724.2020.1869625. Online ahead of print.
PMID: 33544066
Objective: Evidence suggests that both Mediterranean and vegan diets improve body weight and cardiometabolic risk factors, but their relative efficacy has not been compared in a randomized trial. Methods: In a randomized crossover trial, 62 overweight adults were randomly assigned to a Mediterranean or vegan diet for a 16-week period. Body weight, plasma lipids, blood pressure, and body composition (dual X-ray absorptiometry) were measured. Secondary measures included insulin resistance (Homeostasis Model Assessment, HOMA-IR), oral glucose insulin sensitivity (OGIS), and predicted insulin sensitivity (PREDIM) indices. Thereafter, participants were asked to return to their baseline diets for 4 weeks, after which they began the opposite diet for 16 weeks. The same parameters were measured before and after this 2nd 16-week period. Results: Overall net weight changes were 0.0 (Mediterranean) and -6.0 kg (vegan), (treatment effect -6.0 kg [95% CI -7.5 to -4.5]; p < 0.001). HOMA-IR decreased and OGIS increased on the vegan diet with no significant change on the Mediterranean diet (treatment effect -0.7 [95% CI, -1.8 to +0.4]; p = 0.21; and +35.8 mL/min/m2 [95% CI, +13.2 to +58.3]; p = 0.003, respectively). PREDIM did not change significantly in either group. Among participants with no medication changes, total and LDL-cholesterol decreased 18.7 mg/dL (0.5 mmol/L) and 15.3 mg/dL (0.4 mmol/L), respectively, on the vegan diet, compared with no significant change on the Mediterranean diet (treatment effect -15.6 [-24.6 to -6.6]; p = 0.001 and -14.8 [-23.5 to -6.2]; p = 0.001, respectively); systolic and diastolic blood pressure decreased 9.3 and 7.3 mmHg on the Mediterranean diet, compared with 3.4 and 4.1 mmHg on the vegan diet (treatment effect +5.9 [95% CI +1.0 to +10.9]; p = 0.02; and +1.8 [95% CI -4.6 to +8.1]; p = 0.58, respectively). Conclusions: A low-fat vegan diet improved body weight, lipid concentrations, and insulin sensitivity, both from baseline and compared with a Mediterranean diet. Blood pressure decreased on both diets, more on the Mediterranean diet.
Keywords: Cardiometabolic; Mediterranean; diet; nutrition; vegan; weight.

Working memory and hippocampal expression of BDNF, ARC, and P-STAT3 in rats: effects of diet and exercise.
Sable HJ, MacDonnchadh JJ, Lee HW, Butawan M, Simpson RN, Krueger KM, Bloomer RJ.
Nutr Neurosci. 2021 Feb 16:1-14. doi: 10.1080/1028415X.2021.1885230. Online ahead of print.
PMID: 33593241
Objectives: Mounting evidence suggests diet and exercise influence learning and memory (LM). We compared a high-fat, high-sucrose Western diet (WD) to a plant-based, amylose/amylopectin blend, lower-fat diet known as the Daniel Fast (DF) in rats with and without regular aerobic exercise on a task of spatial working memory (WM).
Methods: Rats were randomly assigned to the WD or DF at 6 weeks of age. Exercised rats (WD-E, DF-E) ran on a treadmill 3 times/week for 30 min while the sedentary rats did not (WD-S, DF-S). Rats adhered to these assignments for 12 weeks, inclusive of ab libitum food intake, after which mild food restriction was implemented to encourage responding during WM testing. For nine months, WM performance was assessed once daily, six days per week, after which hippocampal sections were collected for subsequent analysis of brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeletal protein (ARC), and signal transducer and activator of transcription 3 (P-STAT3, Tyr705).
Results: DF-E rats exhibited the best DSA performance. Surprisingly, the WD-S group outperformed the WD-E group, but had significantly lower BDNF and ARC relative to the DF-S group, with a similar trend from the WD-E group. P-STAT3 expression was also significantly elevated in the WD-S group compared to both the DF-S and WD-E groups.
Discussion: These results support previous research demonstrating negative effects of the WD on spatial LM, demonstrate the plant-based DF regimen combined with chronic aerobic exercise produces measurable WM and neuroprotective benefits, and suggest the need to carefully design exercise prescriptions to avoid over-stressing individuals making concurrent dietary changes.
Keywords: Nutrition; aerobic exercise; cognition; delayed spatial alternation; high-fat diet; learning; neuroprotection; spatial working memory.

Aspirin Use on Incident Dementia and Mild Cognitive Decline: A Systematic Review and Meta-Analysis.
Li H, Li W, Zhang X, Ma XC, Zhang RW.
Front Aging Neurosci. 2021 Feb 4;12:578071. doi: 10.3389/fnagi.2020.578071. eCollection 2020.
PMID: 33613260 Free PMC article.
Background: More people with cognitive dysfunction and dementia also fall into the category of high vascular risk, for which aspirin is one of the most frequently used drugs. However, previous studies reporting that aspirin buffers against mild cognitive decline (MCI) and dementia remain controversial. We thus conducted an updated systematic review and meta-analysis to evaluate the association of aspirin use with the risk of MCI and dementia in older adults. Methods: Data sources from PubMed, Embase, Web of Science, and the Cochrane Database for randomized controlled trails (RCTs) and cohort studies (published between January 1, 2000 and April 11, 2020). Relative risks (RRs) and 95% confidence intervals (95% CIs) were used to pool data on the occurrence of dementia and MCI with random-effects models. Results: Of 3,193 identified articles, 15 studies (12 cohort studies and three RCTs) were eligible and were included in our analysis, which involved a total of 100,909 participants without cognitive dysfunctions or dementia at baseline. In pooled cohort studies, aspirin use did not reduce the incidence of MCI and dementia (the pooled RR = 0.97; 95% CI = 0.85-1.11; I2 for heterogeneity = 65%) compared with non-users. However, low-dose aspirin (75-100 mg/day) was associated with a decreased likelihood of developing dementia or MCI (the pooled RR = 0.75; 95% CI = 0.63-0.9; I2 for heterogeneity = 50.5%). This association existed in studies including all-cause dementia (the pooled RR = 0.82; 95% CI = 0.71-0.96) and Alzheimer's disease (AD) (the pooled RR = 0.54; 95% CI = 0.33-0.89), but not in MCI (the pooled RR = 0.58; 95% CI = 0.31-1.08). In RCTs, low-dose aspirin use was not significantly associated with less prevalence of dementia or MCI (RR = 0.94; 95% CI = 0.84-1.05; I2 for heterogeneity = 0.0%). Conclusions: In cohort studies, we found that low-dose aspirin use had a higher likelihood of reducing the incidence of dementia, which was not supported by RCTs. The evidence was insufficient to fully evaluate the effect of aspirin on cognitive function and dementia. Well-designed studies and innovative approaches are therefore needed to clarify whether the use of aspirin improves cognitive function and reduces the risk of dementia.
Keywords: aspirin; association; dementia; meta-analysis; mild cognitive decline.

Association between overall fruit and vegetable intake, and fruit and vegetable sub-types and blood pressure: the PRIME study (Prospective Epidemiological Study of Myocardial Infarction).
Elsahoryi NA, Neville CE, Patterson CC, Linden GJ, Moitry M, Biasch K, Kee F, Amouyel P, Bongard V, Dallongeville J, Ferrières J, Woodside JV.
Br J Nutr. 2021 Mar 14;125(5):557-567. doi: 10.1017/S0007114520001518. Epub 2020 May 4.
PMID: 32364085
Increased fruit and vegetable (FV) intake is associated with reduced blood pressure (BP). However, it is not clear whether the effect of FV on BP depends on the type of FV consumed. Furthermore, there is limited research regarding the comparative effect of juices or whole FV on BP. Baseline data from a prospective cohort study of 10 660 men aged 50-59 years examined not only the cross-sectional association between total FV intake but also specific types of FV and BP in France and Northern Ireland. BP was measured, and dietary intake assessed using FFQ. After adjusting for confounders, both systolic BP (SBP) and diastolic BP (DBP) were significantly inversely associated with total fruit, vegetable and fruit juice intake; however, when examined according to fruit or vegetable sub-type (citrus fruit, other fruit, fruit juices, cooked vegetables and raw vegetables), only the other fruit and raw vegetable categories were consistently associated with reduced SBP and DBP. In relation to the risk of hypertension based on SBP >140 mmHg, the OR for total fruit, vegetable and fruit juice intake (per fourth) was 0·95 (95 % CI 0·91, 1·00), with the same estimates being 0·98 (95 % CI 0·94, 1·02) for citrus fruit (per fourth), 1·02 (95 % CI 0·98, 1·06) for fruit juice (per fourth), 0·93 (95 % CI 0·89, 0·98) for other fruit (per fourth), 1·05 (95 % CI 0·99, 1·10) for cooked vegetable (per fourth) and 0·86 (95 % CI 0·80, 0·91) for raw vegetable intakes (per fourth). Similar results were obtained for DBP. In conclusion, a high overall intake of fruit, vegetables and fruit juice was inversely associated with SBP, DBP and risk of hypertension, but this differed by FV sub-type, suggesting that the strength of the association between FV sub-types and BP might be related to the type consumed, or to processing or cooking-related factors.
Keywords: Blood pressure; CVD risk; Dietary assessment; Fruit and vegetable sub-types.

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The impact of nutritive and non-nutritive sweeteners on the central nervous system: preliminary study.
López-Meza MS, Otero-Ojeda G, Estrada JA, Esquivel-Hernández FJ, Contreras I.
Nutr Neurosci. 2021 Feb 28:1-10. doi: 10.1080/1028415X.2021.1885239. Online ahead of print.
PMID: 33641634
Background: Human consumption of food and beverages containing added nutritive or non-nutritive sweeteners has increased worldwide.
Objective: The present study evaluated the possible impact of frequent sweetener consumption on human CNS activity and functions through neuropsychological testing and EEG/qEEG analysis.
Methods: A sample of 23 women and 16 men, aged 18-35, with a body mass index between 18 and 24.9 kg/m2 was evaluated. Participants underwent a 1-week washout period in which food with added sugars or sweeteners was restricted from their diet. Initial assessment of cognitive functions was performed with a validated neuropsychological test and EEG/qEEG analysis, prior to supplementation. Sucrose, sucralose, or steviol glycosides, in commercially available presentations, were randomly assigned to three experimental groups of 13 participants each. Sweeteners were supplemented in fixed amounts, daily, for six weeks. After supplementation, neurological tests were repeated and the initial and final results were compared.
Results: The results show no significant changes between final and initial measures in the steviol glycosides group. However, a significant decrease in encoding memory was found in the sucrose group in the final evaluation. Strikingly, the sucralose group showed a significant decrease in overall memory, encoding memory, and executive functions after supplementation. Furthermore, qEEG analysis showed an increase in theta wave absolute and relative power at the final evaluation in the same group.
Conclusion: These data show that frequent consumption of specific sweeteners is accompanied by measurable changes in EEG/qEEG activity and neuropsychological test performance in humans.
Keywords: Sweeteners; central nervous system; encoding memory; exeutive functions; neuropsychological testing; non-nutritive sweeteners; over all memory; qEEG.

Dietary Potassium Intake and 20-Year All-Cause Mortality in Older Adults: The Rancho Bernardo Study.
Davitte J, Laughlin GA, Kritz-Silverstein D, McEvoy LK.
J Nutr Gerontol Geriatr. 2021 Feb 26:1-12. doi: 10.1080/21551197.2021.1885559. Online ahead of print.
PMID: 33635744
We examined the association between dietary potassium intake and all-cause and cause-specific mortality among community-dwelling older adults. Potassium intake was assessed with a food frequency questionnaire administered to 1,363 older adults (mean age 71.0 ± 10.6 years). Cox proportional hazard regressions estimated hazard ratios for sex-specific quintiles of calorie-adjusted potassium in relation to all-cause and cause-specific (cardiovascular disease, CVD, and stroke) mortality, adjusting for numerous covariates. There were 855 deaths (63% mortality) during the 20-year follow-up. Relative to the third quintile, potassium intake in the lowest quintile only was associated with increased risk of all-cause mortality (fully-adjusted hazard ratio 1.33; 95% CI 1.06, 1.67). Potassium intake was not significantly associated with CVD or stroke mortality. These results suggest that low potassium intake is associated with increased risk of mortality independent of overall health status. Ensuring adequate potassium in the diet may be an important strategy for reducing risk of earlier mortality among older adults.
Keywords: Aging; cardiovascular disease; longevity; nutrition; stroke.

Vaccinating the oldest against COVID-19 saves both the most lives and most years of life.
Goldstein JR, Cassidy T, Wachter KW.
Proc Natl Acad Sci U S A. 2021 Mar 16;118(11):e2026322118. doi: 10.1073/pnas.2026322118.
PMID: 33632802
Many competing criteria are under consideration for prioritizing COVID-19 vaccination. Two criteria based on age are demographic: lives saved and years of future life saved. Vaccinating the very old against COVID-19 saves the most lives, but, since older age is accompanied by falling life expectancy, it is widely supposed that these two goals are in conflict. We show this to be mistaken. The age patterns of COVID-19 mortality are such that vaccinating the oldest first saves the most lives and, surprisingly, also maximizes years of remaining life expectancy. We demonstrate this relationship empirically in the United States, Germany, and South Korea and with mathematical analysis of life tables. Our age-risk results, under usual conditions, also apply to health risks.
Keywords: COVID-19; age; demography; vaccine; years of life lost.

Effects of chronic consumption of specific fruit (berries, citrus and cherries) on CVD risk factors: a systematic review and meta-analysis of randomised controlled trials.
Wang Y, Gallegos JL, Haskell-Ramsay C, Lodge JK.
Eur J Nutr. 2021 Mar;60(2):615-639. doi: 10.1007/s00394-020-02299-w. Epub 2020 Jun 13.
PMID: 32535781 Review.
Purpose: This review aims to compare the magnitude of the effects of chronic consumption of fruits; specifically berries, citrus and cherries on cardiovascular disease (CVD) risk factors.
Methods: PubMed, Web of Science, Scopus, and psycARTICLES were searched from inception until January 2020. Forty-five chronic (≥ 1 week) randomised controlled trials assessing CVD risk factors including endothelial (dys)function, blood pressure (BP), blood lipids and inflammatory biomarkers were included.
Results: Investigated interventions reported improvements in endothelial function (n = 8), inflammatory biomarkers and lipid status (n = 14), and BP (n = 10). Berries including juice of barberry, cranberry, grape, pomegranate, powder of blueberry, grape, raspberry and freeze-dried strawberry significantly reduced SBP by 3.68 mmHg (95% CI - 6.79 to - 0.58; P = 0.02) and DBP by 1.52 mmHg (95% CI - 2.87 to - 0.18, P = 0.04). In subgroup analysis, these associations were limited to cranberry juice (SBP by 1.52 mmHg [95% CI - 2.97 to - 0.07; P = 0.05], DBP by 1.78 mmHg [95% CI - 3.43 to - 0.12, P = 0.04] and cherry juice (SBP by 3.11 mmHg [95% CI - 4.06 to - 2.15; P = 0.02]). Berries also significantly elevated sVCAM-1 levels by 14.57 ng/mL (85% CI 4.22 to 24.93; P = 0.02).
Conclusion: These findings suggest that supplementing cranberry or cherry juice might contribute to an improvement in blood pressure. No other significant improvements were observed for other specified fruits. More research is warranted comparing different classes of fruit and exploring the importance of fruit processing on their cardiovascular-protective effects.
Keywords: CVD risk factors; Endothelial function; Fruit; Intervention; Meta-analysis; Systematic review.

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Visit-to-visit variability of serum uric acid measurements and the risk of all-cause mortality in the general population.
Tian X, Wang A, Zuo Y, Chen S, Zhang L, Wu S, Luo Y.
Arthritis Res Ther. 2021 Mar 4;23(1):74. doi: 10.1186/s13075-021-02445-7.
PMID: 33663587
Background: Evidence on longitudinal variability of serum uric acid (SUA) and risk of all-cause mortality in the general population is limited, as many prior studies focused on a single measurement of SUA.
Methods: A total of 53,956 participants in the Kailuan study who underwent three health examinations during 2006 to 2010 were enrolled. Variability of SUA was measured using the coefficient of variation (primary index), standard deviation, average real variability, and variability independent of the mean. Cox proportional hazard regressions were used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for the association of variability of SUA with subsequent risk of all-cause mortality, considering its magnitude and the direction and across different baseline SUA categories.
Results: Over a median follow-up of 7.04 years, 2728 participants died. The highest variability of SUA was associated with an increased risk of all-cause mortality, the HR was 1.33 (95% CI, 1.20-1.49) compared with the lowest variability. In this group, both a large fall (HR, 1.28; 95% CI, 1.14-1.44) and rise (HR, 1.18; 95% 1.05-1.32) in SUA were related to risk of all-cause mortality. These associations were similar across different baseline SUA categories. Consistent results were observed in alternative measures of SUA variability. Moreover, individuals with higher variability in SUA were more related to common risk factors than those with stable SUA.
Conclusions: Higher variability in SUA was independently associated with the risk of all-cause mortality irrespective of baseline SUA and direction of variability in the general population.
Keywords: All-cause mortality; Risk factors; Serum uric acid; Variability.

Growth Hormone and Aging: New Findings.
Bartke A, Hascup E, Hascup K, Masternak MM.
World J Mens Health. 2021 Feb 3. doi: 10.5534/wjmh.200201. Online ahead of print.
PMID: 33663025 Review.
Complex relationships between growth hormone (GH) signaling and mammalian aging continue to attract attention of many investigators. Recent results include evidence that the impact of GH on genome maintenance (DNA damage and repair) is drastically different in normal as compared to cancer cells, consistent with GH promoting aging and cancer progression. Impact of GH on DNA methylation was studied as a possible mechanism linking actions of GH during early life to the trajectory of aging. Animals with reduced or enhanced GH signaling and novel animals with adipocyte-specific deletion of GH receptors were used to elucidate the effects of GH on white and brown adipose tissue, including the impact of this hormone on lipolysis, fibrosis, and thermogenesis. Effects of GH on adipose tissue related to lipid and energy metabolism emerge as mechanistic links between GH, healthspan, and lifespan. Treatment of healthy men with a combination of GH, dehydroepiandrosterone, and metformin was reported to restore thymus function and reduce epigenetic age. Studies of human subjects with deficiency of GH or GH receptors and studies of mice with the same endocrine syndromes identified several phenotypic changes related (positively or negatively) to the previously reported predisposition to healthy aging. Results of these and other recent studies advance present understanding of the mechanisms by which GH influences aging and longevity and of the trade-offs involved.
Keywords: Aging; DNA methylation; Growth hormone; Healthy aging; Longevity.

Impact of Time-Restricted Feeding to Late Night on Adaptation to a 6 h Phase Advance of the Light-Dark Cycle in Mice.
Ren B, Ma C, Chen L, FitzGerald GA, Yang G.
Front Physiol. 2021 Feb 16;12:634187. doi: 10.3389/fphys.2021.634187. eCollection 2021.
PMID: 33664675 Free PMC article.
In modern society, more and more people suffer from circadian disruption, which in turn affects health. But until now, there are no widely accepted therapies for circadian disorders. Rhythmic feeding behavior is one of the most potent non-photic zeitgebers, thus it has been suggested that it was important to eat during specific periods of time (time-restricted feeding, TRF) so that feeding is aligned with environmental cues under normal light/dark conditions. Here, we challenged mice with a 6 h advanced shift, combined with various approaches to TRF, and found that food restricted to the second half of the nights after the shift facilitated adaptation. This coincided with improved resilience to sepsis. These results raise the possibility of reducing the adverse responses to jet lag by subsequent timing of food intake.
Keywords: adaptation; behavior; jet lag; sepsis; time-restricted feeding.

Impact of Intermittent Fasting on Lipid Profile-A Quasi-Randomized Clinical Trial.
Ahmed N, Farooq J, Siddiqi HS, Meo SA, Kulsoom B, Laghari AH, Jamshed H, Pasha F.
Front Nutr. 2021 Feb 1;7:596787. doi: 10.3389/fnut.2020.596787. eCollection 2020.
PMID: 33598473 Free PMC article.
Background: Sub-optimal HDL is a prognostic marker of cardiovascular disease. South Asia has a high prevalence of sub-optimal HDL compared to other parts of the world. Intermittent fasting (IF) is a type of energy restriction which may improve serum HDL and other lipids thereby reducing the risk of cardiovascular diseases. Objective: The aim of the study was to evaluate the effect of IF on lipid profile and HDL-cholesterol in a sample of South Asian adults. Methods: A 6-week quasi-experimental (non-randomized) clinical trial was conducted on participants with low HDL (< 40 mg/dl for men and < 50 mg/dl for women). Participants of the control group were recommended not to change their diet. The intervention group was recommended to fast for ~12 h during day time, three times per week for 6 weeks. Pulse rate, blood pressure, body weight, waist circumference, serum lipid profile, and blood glucose levels were measured at baseline and after 6 weeks. Result: A total of 40 participants were enrolled in the study (N = 20 in each group), while 35 (20 control and 15 intervention) completed the trial and were included in data analysis of the study. Body measurements, including body weight, BMI and waist circumference, showed significant interaction effects (p's < 0.001), indicating that there were larger reductions in the IF group than in the control group. Significant interaction effects were also observed for total (p = 0.033), HDL (p = 0.0001), and LDL cholesterol (p = 0.010) with larger improvements in the IF group. Conclusion: This study suggests that intermittent fasting may protect cardiovascular health by improving the lipid profile and raising the sub-optimal HDL. Intermittent fasting may be adopted as a lifestyle intervention for the prevention, management and treatment of cardiovascular disorders.
Keywords: cardioprotection; healthy life style; intermittent fasting; lipid profile; weight reduction.

Mar 2, 2021,11:00am EST|2,780 views
Intermittent Fasting Makes It Harder To Get Rid Of Belly Fat, Animal Study Finds
Misha Gajewski
Proteomics analysis of adipose depots after intermittent fasting reveals visceral fat preservation mechanisms.
Harney DJ, Cielesh M, Chu R, Cooke KC, James DE, Stöckli J, Larance M.
Cell Rep. 2021 Mar 2;34(9):108804. doi: 10.1016/j.celrep.2021.108804.
PMID: 33657384
Intermittent fasting is a beneficial dietary treatment for obesity. But the response of each distinct adipose depot is currently poorly defined. Here we explore the response of key adipose depots to every-other-day fasting (EODF) in mice using proteomics. A key change in subcutaneous white adipose tissue (scWAT) and visceral WAT (vWAT) depots is an increase in mitochondrial protein content after EODF. This effect is correlated with increased fatty acid synthesis enzymes in both WAT depots but not in brown adipose tissue. Strikingly, EODF treatment downregulates lipolysis specifically in vWAT, mediated by a large decrease in the abundance of the catecholamine receptor (ADRB3). Together, these changes are important for preservation of the visceral lipid store during EODF. Enrichment analysis highlights downregulation of inflammatory collagen IV specifically in vWAT, allowing improved insulin sensitivity. This resource for adipose-depot-specific fasting adaptations in mice is available using a web-based interactive visualization.
Keywords: ADRB3; adipose; browning; extracellular matrix; insulin sensitivity; intermittent fasting; lipogenesis; lipolysis; mitochondria; proteomics.

Urinary albumin-to-creatinine ratio levels are associated with subclinical atherosclerosis and predict CVD events and all-cause deaths: a prospective analysis.
Liu S, Niu J, Wu S, Xin Z, Zhao Z, Xu M, Lu J, Wang T, Chen Y, Wang S, Lin H, Xu Y, Ye L, Dai M, Wang W, Ning G, Bi Y, Xu Y, Li M.
BMJ Open. 2021 Mar 3;11(3):e040890. doi: 10.1136/bmjopen-2020-040890.
PMID: 33658258
Objective: We aimed to examine the associations of urinary albumin-to-creatinine ratio (ACR) levels with risks of subclinical atherosclerosis, cardiovascular events and all-cause deaths.
Methods: Data from a large population-based cohort were used, which included 9580 participants aged ≥40 years free from cardiovascular diseases. Carotid intima-media thickness, brachial-ankle pulse wave velocity and ankle-brachial index were measured at baseline to assess subclinical atherosclerosis. After a median of 4.53 years' follow-up, 486 cardiovascular events and 230 all-cause deaths were recorded.
Results: The urinary ACR levels were categorised into three groups. Compared with the normal group (0≤ACR <7.82 mg/g), people with low-grade albuminuria (7.82≤ACR <30 mg/g) and albuminuria (ACR ≥30 mg/g) had higher levels of subclinical atherosclerosis. In prospective analysis, people with low-grade albuminuria was not significantly associated with cardiovascular events (HR=1.18; 95% CI 0.95 to 1.46], whereas people with albuminuria had a 50% higher risk of cardiovascular events (HR=1.50; 95% CI 1.11 to 2.03). People with low-grade albuminuria and albuminuria had 43% (HR=1.43; 95% CI 1.05 to 1.93) and 87% (HR=1.87; 95% CI 1.24 to 2.81) higher risks of all-cause deaths during follow-up, respectively. In stratified analysis, the association of higher ACR with risks of cardiovascular events and all-cause deaths was stronger among individuals with concomitant subclinical atherosclerosis, the presence of diabetes and more cardiovascular risk factors, respectively.
Conclusions: ACR levels were positively associated with subclinical atherosclerosis and predicted the risks of cardiovascular events and all-cause deaths. Evaluation of ACR levels should be integrated into risk stratification and prevention of cardiovascular events and all-cause deaths, especially among those with pre-existing subclinical atherosclerosis and cardiometabolic abnormalities.
Keywords: cardiology; coronary heart disease; myocardial infarction.

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White Meat Consumption, All-Cause Mortality, and Cardiovascular Events: A Meta-Analysis of Prospective Cohort Studies.
Lupoli R, Vitale M, Calabrese I, Giosuè A, Riccardi G, Vaccaro O.
Nutrients. 2021 Feb 20;13(2):676. doi: 10.3390/nu13020676.
PMID: 33672599
The association of meat consumption with mortality and morbidity for non-communicable diseases has been extensively studied. However, the relation of white meat consumption with health outcomes remains controversial. The present meta-analysis was conducted to comprehensively analyze the available evidence on the consistency and strength of the association between the consumption of white meat, death from any cause and incidence of fatal and non-fatal cardiovascular (CV) events. PubMed, Web of Science, Scopus and Embase databases were searched for articles published up to April 30, 2020. We included prospective cohort studies reporting relative risks and pertinent 95% confidence intervals (CI) for all-cause mortality and/or CV events (fatal or non-fatal). A total of 22 studies were included in the meta-analysis. Eleven studies (14 data sets) reported data on all-cause mortality, 10 studies (15 datasets) on cardiovascular disease (CVD) mortality and 10 studies (11 datasets) on non-fatal CV events. When comparing the highest versus the lowest consumption of white meat, the pooled OR and pertinent 95% CI were 0.94 (0.90, 0.97, p < 0.001) for all-cause mortality, 0.95 (0.89, 1.01, p = 0.13) for CV mortality, and 0.99 (0.95, 1.02, p = 0.48) for non-fatal CV events. In conclusion, the study shows for the first time a robust and inverse association between white meat consumption and all-cause mortality and a neutral association with CV mortality and morbidity. This highlights the importance of differentiating the meat types for what concerns their health effects and suggests that white meat might be a healthier alternative to read and processed meat consumption.
Keywords: all-cause mortality; cardiovascular disease; cohort studies; coronary heart disease; meta-analysis; poultry; stroke; white meat.

The ketogenic diet preserves skeletal muscle with aging in mice.
Wallace MA, Aguirre NW, Marcotte GR, Marshall AG, Baehr LM, Hughes DC, Hamilton KL, Roberts MN, Lopez-Dominguez JA, Miller BF, Ramsey JJ, Baar K.
Aging Cell. 2021 Mar 6:e13322. doi: 10.1111/acel.13322. Online ahead of print.
PMID: 33675103
The causes of the decline in skeletal muscle mass and function with age, known as sarcopenia, are poorly understood. Nutrition (calorie restriction) interventions impact many cellular processes and increase lifespan and preserve muscle mass and function with age. As we previously observed an increase in life span and muscle function in aging mice on a ketogenic diet (KD), we aimed to investigate the effect of a KD on the maintenance of skeletal muscle mass with age and the potential molecular mechanisms of this action. Twelve-month-old mice were assigned to an isocaloric control or KD until 16 or 26 months of age, at which time skeletal muscle was collected for evaluating mass, morphology, and biochemical properties. Skeletal muscle mass was significantly greater at 26 months in the gastrocnemius of mice on the KD. This result in KD mice was associated with a shift in fiber type from type IIb to IIa fibers and a range of molecular parameters including increased markers of NMJ remodeling, mitochondrial biogenesis, oxidative metabolism, and antioxidant capacity, while decreasing endoplasmic reticulum (ER) stress, protein synthesis, and proteasome activity. Overall, this study shows the effectiveness of a long-term KD in mitigating sarcopenia. The diet preferentially preserved oxidative muscle fibers and improved mitochondrial and antioxidant capacity. These adaptations may result in a healthier cellular environment, decreasing oxidative and ER stress resulting in less protein turnover. These shifts allow mice to better maintain muscle mass and function with age.
Keywords: aging; ketogenic diet; mice; sarcopenia; skeletal muscle.

Splitting sleep between the night and a daytime nap reduces homeostatic sleep pressure and enhances long-term memory.
Cousins JN, Leong RLF, Jamaluddin SA, Ng ASC, Ong JL, Chee MWL.
Sci Rep. 2021 Mar 5;11(1):5275. doi: 10.1038/s41598-021-84625-8.
PMID: 33674679
Daytime naps have been linked with enhanced memory encoding and consolidation. It remains unclear how a daily napping schedule impacts learning throughout the day, and whether these effects are the same for well-rested and sleep restricted individuals. We compared memory in 112 adolescents who underwent two simulated school weeks containing 8 or 6.5 h sleep opportunities each day. Sleep episodes were nocturnal or split between nocturnal sleep and a 90-min afternoon nap, creating four experimental groups: 8 h-continuous, 8 h-split, 6.5 h-continuous and 6.5 h-split. Declarative memory was assessed with picture encoding and an educationally realistic factual knowledge task. Splitting sleep significantly enhanced afternoon picture encoding and factual knowledge under both 6.5 h and 8 h durations. Splitting sleep also significantly reduced slow-wave energy during nocturnal sleep, suggesting lower homeostatic sleep pressure during the day. There was no negative impact of the split sleep schedule on morning performance, despite a reduction in nocturnal sleep. These findings suggest that naps could be incorporated into a daily sleep schedule that provides sufficient sleep and benefits learning.

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Dose of aspirin to prevent preterm preeclampsia in women with moderate or high-risk factors: A systematic review and meta-analysis.
Van Doorn R, Mukhtarova N, Flyke IP, Lasarev M, Kim K, Hennekens CH, Hoppe KK.
PLoS One. 2021 Mar 9;16(3):e0247782. doi: 10.1371/journal.pone.0247782. eCollection 2021.
PMID: 33690642
Objective: To evaluate the effect of aspirin dose on the incidence of all gestational age preeclampsia and preterm preeclampsia.
Data sources: Electronic databases (Cochrane, PubMed, Scopus, ClinicalTrials.gov and the Web of Science) were searched for articles published between January 1985 and March 2019 with no language restrictions.
Methods: We followed the PRIMSA guidelines and utilized Covidence software. Articles were screened by 2 independent reviewers, with discrepancies settled by an independent 3rd party. Study selection criteria were randomized trials comparing aspirin for prevention of all gestational age and preterm preeclampsia to placebo or no antiplatelet treatment in women aged 15-55 years with moderate or high-risk factors according to the list of risk factors from American College of Obstetricians and Gynecologists and United States Preventive Services Task Force guidelines. The quality of trials was assessed using the Cochrane risk of bias tool. The data were pooled using a random-effects meta-analysis comparing aspirin at doses of <81, 81, 100, and 150 mg. Pre-specified outcomes were all gestational age and preterm preeclampsia.
Results: Of 1,609 articles screened, 23 randomized trials, which included 32,370 women, fulfilled the inclusion criteria. In preterm preeclampsia, women assigned at random to 150 mg experienced a significant 62% reduction in risk of preterm preeclampsia (RR = 0.38; 95% CI: 0.20-0.72; P = 0.011). Aspirin doses <150 mg produced no significant reductions. The number needed to treat with 150 mg of aspirin was 39 (95% CI: 23-100). There was a maximum 30% reduction in risk of all gestational age preeclampsia at all aspirin doses.
Conclusions: In this meta-analysis, based on indirect comparisons, aspirin at a dose greater than the current, recommended 81 mg was associated with the highest reduction in preterm preeclampsia. Our meta-analysis is limited due to the deficiency of homogeneous high evidence data available in the literature to date; however, it may be prudent for clinicians to consider that the optimal aspirin dose may be higher than the current guidelines advise. Future research to compare the efficacy aspirin doses greater than 81 mg is recommended.

Effect of temperature and/or sweetness of beverages on body composition in rats.
Ragi ME, El-Helou N, El-Mallah C, Eid A, Obeid OA.
Br J Nutr. 2021 Apr 28;125(8):934-942. doi: 10.1017/S0007114520003359. Epub 2020 Sep 1.
PMID: 32867865
Sweetened beverages are mainly consumed cold and various processes are activated in response to external temperature variations. However, the effect of internal temperature variations through the ingestion of cold beverages is far from clear. Two experiments were conducted to investigate the effect of beverage temperature on body composition. Sprague-Dawley rats (5-6-week-old males) had free access to food and beverage for 8 weeks. Energy intake, body weight and body composition were monitored. In Expt 1, two groups of rats (n 9) consumed water at room temperature (NW about 22°C) or cold (CW about 4°C). In Expt 2, rats were offered room-temperature (N) or cold (C) sweetened water (10 % sucrose CSu (n 7) and NSu (n 8); or 0·05 % acesulfame K CAk (n 6) and NAk (n 8)) for 12 h, followed by plain water. Our results show that in Expt 1, CW had higher lean body mass (P < 0·001) and lower body fat gain (P = 0·004) as compared with NW. In Expt 2, body weight (P = 0·013) and fat (P ≤ 0·001) gains were higher in the non-energetic sweetened groups, while lean body mass was not affected by the type of sweeteners or temperature. In conclusion, cold water ingestion improved lean body mass gain and decreased fat gain because of increased energy expenditure, while non-energetic sweetener (acesulfame K) increased body fat gain due to improved energy efficiency. Internal cold exposure failed to increase energy intake in contrast to that of external cold exposure.
Keywords: Body fat; Cold drink intake; Lean body mass; Sweeteners; Water.

No Clinically Relevant Effect of Heart Rate Increase and Heart Rate Recovery During Exercise on Cardiovascular Disease: A Mendelian Randomization Analysis.
Mensah-Kane J, Schmidt AF, Hingorani AD, Finan C, Chen Y, van Duijvenboden S, Orini M, Lambiase PD, Tinker A, Marouli E, Munroe PB, Ramírez J.
Front Genet. 2021 Feb 18;12:569323. doi: 10.3389/fgene.2021.569323. eCollection 2021.
PMID: 33679875 Free PMC article.
Background: Reduced heart rate (HR) increase (HRI), recovery (HRR), and higher resting HR are associated with cardiovascular (CV) disease, but causal inferences have not been deduced. We investigated causal effects of HRI, HRR, and resting HR on CV risk, all-cause mortality (ACM), atrial fibrillation (AF), coronary artery disease (CAD), and ischemic stroke (IS) using Mendelian Randomization.
Methods: 11 variants for HRI, 11 for HRR, and two sets of 46 and 414 variants for resting HR were obtained from four genome-wide association studies (GWASs) on UK Biobank. We performed a lookup on GWASs for CV risk and ACM in UK Biobank (N = 375,367, 5.4% cases and N = 393,165, 4.4% cases, respectively). For CAD, AF, and IS, we used publicly available summary statistics. We used a random-effects inverse-variance weighted (IVW) method and sensitivity analyses to estimate causality.
Results: IVW showed a nominally significant effect of HRI on CV events (odds ratio [OR] = 1.0012, P = 4.11 × 10-2) and on CAD and AF. Regarding HRR, IVW was not significant for any outcome. The IVW method indicated statistically significant associations of resting HR with AF (OR = 0.9825, P = 9.8 × 10-6), supported by all sensitivity analyses, and a nominally significant association with IS (OR = 0.9926, P = 9.82 × 10-3).
Conclusion: Our findings suggest no strong evidence of an association between HRI and HRR and any outcome and confirm prior work reporting a highly significant effect of resting HR on AF. Future research is required to explore HRI and HRR associations further using more powerful predictors, when available.
Keywords: GWAS; Mendelian randomization; UK Biobank; cardiovascular risk; exercise; heart rate; recovery.

Effect of tomato, lycopene and related products on blood pressure: A systematic review and network meta-analysis.
Rattanavipanon W, Nithiphongwarakul C, Sirisuwansith P, Chaiyasothi T, Thakkinstian A, Nathisuwan S, Pathomwichaiwat T.
Phytomedicine. 2021 Feb 16:153512. doi: 10.1016/j.phymed.2021.153512. Online ahead of print.
PMID: 33676812 Review.
Background: A number of randomized controlled trials (RCTs) have been conducted to evaluate the hypotensive effects of tomato, lycopene, and related products. However, the findings were conflicting, partly due to differences in the types of products investigated. Therefore, this study aimed to assess and compare the hypotensive effects of different tomato-related preparations through a network meta-analysis based on randomized controlled trials.
Study design: A systematic review and network meta-analysis.
Methods: A network meta-analysis based on a systematic review of RCTs comparing the effect of various tomato, lycopene and related products versus placebo on blood pressure in adults was performed. PubMed, EMBASE, SCOPUS, and Clinicaltrial.gov databases were searched up to October 2020 without language restrictions. The primary outcomes were systolic and diastolic blood pressure. Mean differences (MDs) along with 95% confidence intervals (CIs) were estimated and pooled using a random-effects model. Heterogeneity was assessed using the global inconsistency test.
Results: A total of 11 studies including six forms of tomato, lycopene and related products met the inclusion criteria. Among these trials, eight (N = 617) and seven trials (N = 501) were included in the analysis of systolic (SBP) and diastolic blood pressure (DBP) outcomes, respectively. The standardized tomato extract (STE) significantly decreased SBP compared to placebo, with a pooled MD (95% CI) of -5.89 (-9.13 to -2.64) mmHg. The effect on DBP was not significant, with a pooled MD (95% CI) of -3.51 (-7.39 to 0.38) mmHg. Subgroup analysis in hypertensive patients showed that STE significantly reduced both SBP and DBP with pooled MDs (95% CIs) of -8.09 (-11.52 to -4.67) and -4.25 (-6.97 to -1.53) mmHg, respectively, compared to placebo. Other forms of tomato, including other dose ranges of standardized tomato extract, tomato-containing diet, lycopene-free preparation, and synthetic lycopene, did not show consistent and significant effects on either SBP or DBP in all analyses.
Conclusion: Standardized tomato extract (STE) significantly decreased SBP compared to placebo in a mixed population of healthy volunteers and hypertensive patients. The BP-lowering effect was more pronounced among hypertensive patients. No significant BP effects were seen with other forms of tomato, lycopene and related products in the overall population or any subgroup of the population.
Keywords: Cardiovascular disease; Hypertension; Lycopene; Network meta-analysis; Tomato.

[I find that breathing through my nose helps, too.]
Why winter exercise can be especially hard on the lungs
Laura Glowacki · CBC News · Posted: Mar 07, 2021

Late-life intermittent fasting decreases aging-related frailty and increases renal hydrogen sulfide production in a sexually dimorphic manner.
Henderson YO, Bithi N, Link C, Yang J, Schugar R, Llarena N, Brown JM, Hine C.
Geroscience. 2021 Mar 6. doi: 10.1007/s11357-021-00330-4. Online ahead of print.
PMID: 33675469
Global average life expectancy continues to rise. As aging increases the likelihood of frailty, which encompasses metabolic, musculoskeletal, and cognitive deficits, there is a need for effective anti-aging treatments. It is well established in model organisms that dietary restriction (DR), such as caloric restriction or protein restriction, enhances health and lifespan. However, DR is not widely implemented in the clinic due to patient compliance and its lack of mechanistic underpinnings. Thus, the present study tested the effects of a somewhat more clinically applicable and adoptable DR regimen, every-other-day (EOD) intermittent fasting, on frailty in 20-month-old male and female C57BL/6 mice. Frailty was determined by a series of metabolic, musculoskeletal, and cognitive tasks performed prior to and toward the end of the 2.5-month dietary intervention. Late-life EOD fasting attenuated overall energy intake, hypothalamic inflammatory gene expression, and frailty in males. However, it failed to reduce overall caloric intake and had a little positive effect in females. Given that the selected benefits of DR are dependent on augmented production of the gasotransmitter hydrogen sulfide (H2S) and that renal H2S production declines with age, we tested the effects of EOD fasting on renal H2S production capacity and its connection to frailty in males. EOD fasting boosted renal H2S production, which positively correlated with improvements in multiple components of frailty tasks. Therefore, late-life initiated EOD fasting is sufficient to reduce aging-related frailty, at least in males, and suggests that renal H2S production capacity may modulate the effects of late-life EOD fasting on frailty.
Keywords: Aging; Cognition; Frailty; Hydrogen sulfide; Intermittent fasting; Sexual dimorphism.

Predictors of in-hospital mortality AND death RISK STRATIFICATION among COVID-19 PATIENTS aged ≥ 80 YEARs OLD.
Covino M, De Matteis G, Polla DAD, Santoro M, Burzo ML, Torelli E, Simeoni B, Russo A, Sandroni C, Gasbarrini A, Franceschi F.
Arch Gerontol Geriatr. 2021 Feb 25;95:104383. doi: 10.1016/j.archger.2021.104383. Online ahead of print.
PMID: 33676091
Introduction: To date, mainly due to age-related vulnerability and to coexisting comorbidities, older patients often face a more severe COVID-19. This study aimed to identify at Emergency Department (ED) admission the predictors of in-hospital mortality and suitable scores for death risk stratification among COVID-19 patients ≥ 80 years old.
Methods: Single-centre prospective study conducted in the ED of an university hospital, referral center for COVID-19 in central Italy. We included 239 consecutive patients ≥ 80 years old with laboratory-confirmed COVID-19. The primary study endpoint was all-cause in-hospital mortality. Multivariable Cox regression analysis was performed on significant variables at univariate analysis to identify independent risk factor for death. Overall performance in predicting mortality of WHO severity scale, APACHE II score, NEWS score, and CURB-65 was calculated.
Results: Median age was 85 [82-89] and 112 were males (46.9%). Globally, 77 patients (32.2%) deceased. The presence of consolidations at chest x-ray and the hypoxemic respiratory failure were significant predictors of poor prognosis. Moreover, age ≥ 85 years, dependency in activities of daily living (ADL), and dementia were risk factors for death, even after adjusting for clinical covariates and disease severity. All the evaluated scores showed a fairly good predictive value in identifying patients who could experience a worse outcome.
Conclusions: Among patients ≥ 80 years old hospitalized with COVID-19, not only a worse clinical and radiological presentation of the disease, but also the increasing age, dementia, and impairment in ADL were strong risk factors for in-hospital death, regardless of disease severity.
Keywords: Activities of Daily Living; COVID-19; Dementia; Emergency Department; Older people.

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Replacing the consumption of red meat with other major dietary protein sources and risk of type 2 diabetes mellitus: a prospective cohort study.
Würtz AML, Jakobsen MU, Bertoia ML, Hou T, Schmidt EB, Willett WC, Overvad K, Sun Q, Manson JE, Hu FB, Rimm EB.
Am J Clin Nutr. 2021 Mar 11;113(3):612-621. doi: 10.1093/ajcn/nqaa284.
PMID: 33094800
Background: Greater consumption of red meat has been associated with a higher risk of type 2 diabetes mellitus (T2DM). A decreased intake of red meat and simultaneous increased intake of other high-protein foods may be associated with a lower risk of T2DM. These analyses of specific food replacements for red meat may provide more accurate dietary advice.
Objective: We examined the association between a decrease in intake of red meat accompanied by an increase in other major dietary protein sources and risk of T2DM.
Methods: We prospectively followed 27,634 males in the Health Professionals Follow-up Study, 46,023 females in the Nurses' Health Study, and 75,196 females in the Nurses' Health Study II. Diet was assessed by a validated FFQ and updated every 4 y. Cox proportional hazards models adjusted for T2DM risk factors were used to model the food replacements. We calculated HRs and 95% CIs for the T2DM risk associated with replacements of 1 daily serving of red meat with another protein source.
Results: During 2,113,245 person-years of follow-up, we identified 8763 incident T2DM cases from 1990 to 2013. In the pooled analyses, a decrease in total red meat intake during a 4-y period replaced with another common protein food was associated with a lower risk of T2DM in the subsequent 4-y period. The HR (95% CI) per 1 serving/d was 0.82 (0.75, 0.90) for poultry, 0.87 (0.77, 0.98) for seafood, 0.82 (0.78, 0.86) for low-fat dairy, 0.82 (0.77, 0.86) for high-fat dairy, 0.90 (0.81, 0.99) for eggs, 0.89 (0.82, 0.98) for legumes, and 0.83 (0.78, 0.89) for nuts. The associations were present for both unprocessed and processed red meat, although stronger for the replacement of processed red meat.
Conclusions: Replacing red meat consumption with other protein sources was associated with a lower risk of T2DM.
Keywords: cohort study; diet change; follow-up study; food substitution; protein replacement; red meat; type 2 diabetes mellitus.

Health Effects of Alternate Day Fasting Versus Pair-Fed Caloric Restriction in Diet-Induced Obese C57Bl/6J Male Mice.
Henderson CG, Turner DL, Swoap SJ.
Front Physiol. 2021 Feb 26;12:641532. doi: 10.3389/fphys.2021.641532. eCollection 2021.
PMID: 33732170 Free PMC article.
Alternate day fasting (ADF) induces weight loss and improves various markers of health in rodents and humans. However, it is unclear whether the benefits of ADF are derived from the lower caloric intake of ADF or from the 24-h fasting period. Therefore, this study directly compared selected markers for health - such as glucose control, body weight, liver triglycerides, T cell frequencies, and others - in high-fat (60% calories from fat) diet-induced obese mice subjected to either ADF or caloric restriction (CR). Obese mice were randomly assigned to one of four groups: (1) ADF: remained on the high-fat diet, but fed on alternate days (n = 5), (2) PF: remained on the high-fat diet, but pair-fed to the ADF group (n = 5), (3) LF: moved to a chow ad libitum diet (n = 5; 17% calories from fat), and (4) HF: remained on the high-fat ad libitum diet (n = 5). An additional group of non-obese mice maintained on a chow diet since weaning were used as controls (CON: n = 5). After 10 weeks, ADF, PF, and LF mice ate fewer kcals, had a lower body mass, had smaller epididymal fat pads, improved glucose tolerance, and had a lower hepatic triglyceride content relative to HF mice (p < 0.05), but none reached that of CON mice in these measures. T cell frequencies of the spleen, blood, and mesenteric lymph nodes were reduced in ADF, PF, and HF compared to the CON group. Importantly, there were no significant differences between the ADF and PF groups in any of the measurements made in the current study. These data suggest that ADF, PF, and LF diets each lead to improved markers of health relative to high-fat diet-induced obese mice, and that the caloric restriction associated with ADF is the major factor for the noted improvements.
Keywords: ADF; CR; glucose; high-fat diet; intermittent fast; obesity.

Psychedelic therapy could 'reset' depressed brain
By Rachel Schraer
Health reporter

Interaction of Sirtuin 1 (SIRT1) candidate longevity gene and particulate matter (PM2.5) on all-cause mortality: a longitudinal cohort study in China.
Yao Y, Liu L, Guo G, Zeng Y, Ji JS.
Environ Health. 2021 Mar 14;20(1):25. doi: 10.1186/s12940-021-00718-x.
PMID: 33715628
Background: The SIRT1 gene was associated with the lifespan in several organisms through inflammatory and oxidative stress pathways. Long-term air particulate matter (PM) is detrimental to health through the same pathways.
Methods: We used the Chinese Longitudinal Healthy Longevity Survey (CLHLS) to investigate whether there is a gene-environment (G × E) interaction of SIRT1 and air pollution on mortality in an older cohort in China. Among 7083 participants with a mean age of 81.1 years, we genotyped nine SIRT1 alleles for each participant and assessed PM2.5 concentration using 3-year average concentrations around each participant's residence. We used Cox-proportional hazards models to estimate the independent and joint effects of SIRT1 polymorphisms and PM2.5 exposure on all-cause mortality, adjusting for a set of confounders.
Results: There were 2843 deaths over 42,852 person-years. The mortality hazard ratio (HR) and 95% confidence interval (CI) for each 10 μg/m3 increase in PM2·5 was 1.08 (1.05-1.11); for SIRT1_391 was 0.77 (0.61, 0.98) in the recessive model after adjustment. In stratified analyses, participants carrying two SIRT1_391 minor alleles had a significantly higher HR for each 10 μg/m3 increase in PM2.5 than those carrying zero minor alleles (1.323 (95% CI: 1.088, 1.610) vs. 1.062 (1.028, 1.096) p for interaction = 0.03). Moreover, the interaction of SIRT1 and air pollution on mortality is significant among women but not among men. We did not see significant relationships for SIRT1_366, SIRT1_773, and SIRT1_720.
Conclusion: We found a gene-environment interaction of SIRT1 and air pollution on mortality, future experimental studies are warranted to depict the mechanism observed in this study.
Keywords: Air pollution; CLHLS; Longevity gene; Sex difference.

Fitness, Fatness, and Mortality in Men and Women From the UK Biobank: Prospective Cohort Study.
Tarp J, Grøntved A, Sanchez-Lastra MA, Dalene KE, Ding D, Ekelund U.
J Am Heart Assoc. 2021 Mar 13:e019605. doi: 10.1161/JAHA.120.019605. Online ahead of print.
PMID: 33715383
Background Cardiorespiratory fitness may moderate the association between obesity and all-cause mortality (ie, the "fat-but-fit" hypothesis), but unaddressed sources of bias are a concern. Methods and Results Cardiorespiratory fitness was estimated as watts per kilogram from a submaximal bicycle test in 77 169 men and women from the UK Biobank cohort and combined with World Health Organization standard body mass index categories, yielding 9 unique fitness-fatness combinations. We also formed fitness-fatness combinations based on bioimpedance as a direct measure of body composition. All-cause mortality was ascertained from death registries. Multivariable-adjusted Cox regression models were used to estimate hazard ratios and 95% CIs. We examined the association between fitness-fatness combinations and all-cause mortality in models with progressively more conservative approaches for accounting for reverse causation, misclassification of body composition, and confounding. Over a median follow-up of 7.7 years, 1731 participants died. In our base model, unfit men and women had higher risk of premature mortality irrespective of levels of adiposity, compared with the normal weight-fit reference. This pattern was attenuated but maintained with more conservative approaches in men, but not in women. In analysis stratified by sex and excluding individuals with prevalent major chronic disease and short follow-up and using direct measures of body composition, mortality risk was 1.78 (95% CI, 1.17-2.71) times higher in unfit-obese men but not higher in obese-fit men (0.94 [95% CI, 0.60-1.48]). In contrast, there was no increased risk in obese-unfit women (1.09 [95% CI, 0.44-1.05]) as compared with the reference. Conclusions Cardiorespiratory fitness modified the association between obesity and mortality in men, but this pattern appeared susceptible to biases in women.
Keywords: adiposity; epidemiology; obesity; physical activity; physical exercise.

These symptoms and risk factors may predict whether you could become a 'COVID long hauler,' study suggests
Adrianna Rodriguez
USA TODAY Mar 11, 2021

Association of Balance Function With All-Cause and Cause-Specific Mortality Among US Adults.
Cao C, Cade WT, Li S, McMillan J, Friedenreich C, Yang L.
JAMA Otolaryngol Head Neck Surg. 2021 Mar 11. doi: 10.1001/jamaoto.2021.0057. Online ahead of print.
PMID: 33704356
Importance: Difficulty maintaining balance is common among individuals aged 40 years or older and increases the risk of falls. However, little is known about the association of balance function with long-term mortality outcomes in adults.
Objective: To investigate the association of balance function with all-cause and cause-specific mortality among US adults.
Design, setting, and participants: A prospective, population-based cohort study of a nationally representative sample of 5816 adults (weighted population, 92 260 641) from the US National Health and Nutrition Examination Survey was conducted from 1999 to 2004. Individuals aged 40 years or older who completed the modified Romberg Test of Standing Balance on Firm and Compliant Support Surfaces were included. Participants were linked to mortality data from the test date through December 31, 2015. Data analysis was conducted from February 1 to June 1, 2020.
Exposures: The modified Romberg Test of Standing Balance on Firm and Compliant Support Surfaces was used to measure balance function and define balance disorder according to sensory input.
Main outcomes and measures: Mortality associated with all causes, cardiovascular disease (CVD), and cancer.
Results: A total of 5816 adults (weighted mean [SE] age, 53.6 [0.2] years; 2897 [49.8%] women) were included in this cohort study. During up to 16.8 years of follow-up (median, 12.5 years; 68 919 person-years), 1530 deaths occurred, including 342 associated with CVD and 364 associated with cancer. Participants with balance disorder were at a higher risk of death from all causes, CVD, and cancer. After adjusting for sociodemographic characteristics, lifestyle factors, and chronic conditions, the hazard ratios (HRs) among participants with balance disorder compared with those without balance disorder were 1.44 (95% CI, 1.23-1.69) for all-cause mortality, 1.65 (95% CI, 1.17-2.31) for CVD mortality, and 1.37 (95% CI, 1.03-1.83) for cancer mortality. Furthermore, vestibular balance disorder was associated with increased mortality from all causes (HR, 1.31; 95% CI, 1.08-1.58), CVD (HR, 1.59; 95% CI, 1.12-2.27), and cancer (HR, 1.39; 95% CI, 1.04-1.86).
Conclusions and relevance: In this nationally representative sample of US adults, balance disorder was associated with an increased risk of all-cause, CVD, and cancer mortality. Further studies are needed to confirm these findings and evaluate whether the observed associations represent a causal biological phenomenon and, if so, whether the effect is modifiable with a multicomponent exercise program.

Body Mass Index and Risk for COVID-19-Related Hospitalization, Intensive Care Unit Admission, Invasive Mechanical Ventilation, and Death - United States, March-December 2020.
Kompaniyets L, Goodman AB, Belay B, Freedman DS, Sucosky MS, Lange SJ, Gundlapalli AV, Boehmer TK, Blanck HM.
MMWR Morb Mortal Wkly Rep. 2021 Mar 12;70(10):355-361. doi: 10.15585/mmwr.mm7010e4.
PMID: 33705371 Free article.
Obesity* is a recognized risk factor for severe COVID-19 (1,2), possibly related to chronic inflammation that disrupts immune and thrombogenic responses to pathogens (3) as well as to impaired lung function from excess weight (4). Obesity is a common metabolic disease, affecting 42.4% of U.S. adults (5), and is a risk factor for other chronic diseases, including type 2 diabetes, heart disease, and some cancers.† The Advisory Committee on Immunization Practices considers obesity to be a high-risk medical condition for COVID-19 vaccine prioritization (6). Using data from the Premier Healthcare Database Special COVID-19 Release (PHD-SR),§ CDC assessed the association between body mass index (BMI) and risk for severe COVID-19 outcomes (i.e., hospitalization, intensive care unit [ICU] or stepdown unit admission, invasive mechanical ventilation, and death). Among 148,494 adults who received a COVID-19 diagnosis during an emergency department (ED) or inpatient visit at 238 U.S. hospitals during March-December 2020, 28.3% had overweight and 50.8% had obesity. Overweight and obesity were risk factors for invasive mechanical ventilation, and obesity was a risk factor for hospitalization and death, particularly among adults aged <65 years. Risks for hospitalization, ICU admission, and death were lowest among patients with BMIs of 24.2 kg/m2, 25.9 kg/m2, and 23.7 kg/m2, respectively, and then increased sharply with higher BMIs. Risk for invasive mechanical ventilation increased over the full range of BMIs, from 15 kg/m2 to 60 kg/m2. As clinicians develop care plans for COVID-19 patients, they should consider the risk for severe outcomes in patients with higher BMIs, especially for those with severe obesity. These findings highlight the clinical and public health implications of higher BMIs, including the need for intensive COVID-19 illness management as obesity severity increases, promotion of COVID-19 prevention strategies including continued vaccine prioritization (6) and masking, and policies to ensure community access to nutrition and physical activities that promote and support a healthy BMI.

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Associations between calf, thigh, and arm circumference and cardiovascular and all-cause mortality in NHANES 1999-2004.
Abreo AP, Bailey SR, Abreo K.
Nutr Metab Cardiovasc Dis. 2021 Jan 29:S0939-4753(21)00031-4. doi: 10.1016/j.numecd.2021.01.011. Online ahead of print.
PMID: 33762151
Background and aims: Prior studies have described an association between calf circumference and cardiovascular disorders. We evaluated the associations between calf, thigh, and arm circumference and cardiovascular and all-cause mortality.
Methods and results: We performed a retrospective cohort study of 11,871 patients in the 1999-2004 National Health and Nutrition Examination Survey (NHANES) to determine the association between calf circumference and cardiovascular and all-cause mortality using univariate and multivariate Cox proportional hazards. We additionally examined the association between thigh and arm circumference and mortality. In the multivariable Cox regression for the female stratum, each centimeter increase in calf circumference was associated with a hazard ratio of 0.88 (95% CI 0.84-0.92), and a hazard ratio of 0.90 (95% CI 0.85-0.95) for cardiovascular death. In the model with males, the hazard ratio for higher calf circumference was 0.92 (95% CI 0.88-0.96) for all-cause mortality and 0.94 (95% CI 0.89-0.99) for cardiovascular death. There was a statistically significant association between higher thigh circumference and lower risk of all-cause and cardiovascular mortality. Arm circumference was not similarly associated with mortality in the multivariate model.
Conclusion: Calf and thigh circumference may provide important prognostic information regarding cardiovascular and all-cause mortality. Future prospective studies should examine the role of extremity circumference and cardiovascular events.
Keywords: Calf circumference; Cardiovascular disease; Clinical outcomes.

The effects of foods on LDL cholesterol levels: A systematic review of the accumulated evidence from systematic reviews and meta-analyses of randomized controlled trials.
Schoeneck M, Iggman D.
Nutr Metab Cardiovasc Dis. 2021 Jan 16:S0939-4753(21)00002-8. doi: 10.1016/j.numecd.2020.12.032. Online ahead of print.
PMID: 33762150
Aims: To systematically evaluate the evidence regarding the effects of foods on LDL cholesterol levels and to compare the findings with current guidelines.
Data synthesis: From inception through June 2019, we searched PubMed, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials for guidelines, systematic reviews, and RCTs (for coffee intake only) of at least 13 days duration. Additionally, we searched Trip database for guidelines from 2009 through Oct 2019. Language was restricted to English. The strength of evidence was evaluated using The Grading of Recommendations Assessment, Development, and Evaluation (GRADE). A total of 37 guidelines, 108 systematic reviews, and 20 RCTs were included. With high evidence, foods high in unsaturated and low in saturated and trans fatty acids (e.g. rapeseed/canola oil), with added plant sterols/stanols, and high in soluble fiber (e.g. oats, barley, and psyllium) caused at least moderate (i.e. 0.20-0.40 mmol/L) reductions in LDL cholesterol. Unfiltered coffee caused a moderate to large increase. Soy protein, tomatoes, flaxseeds, and almonds caused small reductions. With moderate evidence, avocados and turmeric caused moderate to large reductions. Pulses, hazelnuts, walnuts, high-fiber/wholegrain foods, and green tea caused small to moderate reductions, whereas sugar caused a small increase. Other identified foods were either neutral or had low or very low evidence regarding their effects.
Conclusions: Several foods distinctly modify LDL cholesterol levels. The results may aid future guidelines and dietary advice for hypercholesterolemia.
Keywords: Blood lipids; Diet; Food; Humans; LDL cholesterol; Lipoproteins.

Comparison between the impact of fermented and unfermented soy intake on the risk of liver cancer: the JPHC Study.
Abe SK, Sawada N, Ishihara J, Takachi R, Mori N, Yamaji T, Shimazu T, Goto A, Iwasaki M, Inoue M, Tsugane S; JPHC Study Group.
Eur J Nutr. 2020 Jul 27. doi: 10.1007/s00394-020-02335-9. Online ahead of print.
PMID: 32719984
Purpose: The aim of this study was to compare the impact of fermented and unfermented soy intake, based on the following soy-derived products: tofu, soymilk, natto, and miso, on the risk of liver cancer among Japanese adults.
Methods: 75,089 Participants of the Japan Public Health Center-based Prospective Study (JPHC Study) were followed from the time of the 5-year follow-up questionnaire until the end of 2012-2013. Subjects with available data on hepatitis B virus (HBV) and hepatitis C virus (HCV) infection status from blood samples (n = 14,016) and those who were anti-HCV antibody (anti-HCV) or hepatitis B virus antigen (HBsAg) positive (n = 1033) were also analyzed separately. Cox proportional hazard models were employed to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs).
Results: During 1,145,453 person-years, 534 newly diagnosed cases of liver cancer were identified in the JPHC Study. For miso intake among men, the multivariate-adjusted highest versus lowest quartile HR was 0.65 (95% CI, 0.48-0.89); p for trend = 0.006. Results were similar in those who were anti-HCV or HBsAg positive, 0.24 (0.08-0.70); p for trend = 0.004 highest versus lowest tertile. For the sub-analysis among only participants with known hepatitis infection status and HCV and HBsAg adjustment, a similar association was observed. In the multivariate complete cohort analysis, among women, the highest intake of fried tofu was inversely associated with the risk of liver cancer, HR = 0.45 (0.26-0.80); p for trend = 0.014.
Conclusions: We observed no association between total soy intake, fermented and unfermented, and risk of liver cancer, and only an inverse association between miso intake and liver cancer among men.
Keywords: Cohort study; Japan; Liver cancer; Soy.

Hydration for health hypothesis: a narrative review of supporting evidence.
Perrier ET, Armstrong LE, Bottin JH, Clark WF, Dolci A, Guelinckx I, Iroz A, Kavouras SA, Lang F, Lieberman HR, Melander O, Morin C, Seksek I, Stookey JD, Tack I, Vanhaecke T, Vecchio M, Péronnet F.
Eur J Nutr. 2020 Jul 6. doi: 10.1007/s00394-020-02296-z. Online ahead of print.
PMID: 32632658 Review.
Purpose: An increasing body of evidence suggests that excreting a generous volume of diluted urine is associated with short- and long-term beneficial health effects, especially for kidney and metabolic function. However, water intake and hydration remain under-investigated and optimal hydration is poorly and inconsistently defined. This review tests the hypothesis that optimal chronic water intake positively impacts various aspects of health and proposes an evidence-based definition of optimal hydration.
Methods: Search strategy included PubMed and Google Scholar using relevant keywords for each health outcome, complemented by manual search of article reference lists and the expertise of relevant practitioners for each area studied.
Results: The available literature suggest the effects of increased water intake on health may be direct, due to increased urine flow or urine dilution, or indirect, mediated by a reduction in osmotically -stimulated vasopressin (AVP). Urine flow affects the formation of kidney stones and recurrence of urinary tract infection, while increased circulating AVP is implicated in metabolic disease, chronic kidney disease, and autosomal dominant polycystic kidney disease.
Conclusion: In order to ensure optimal hydration, it is proposed that optimal total water intake should approach 2.5 to 3.5 L day-1 to allow for the daily excretion of 2 to 3 L of dilute (< 500 mOsm kg-1) urine. Simple urinary markers of hydration such as urine color or void frequency may be used to monitor and adjust intake.
Keywords: Arginine vasopressin; Copeptin; Metabolic; Renal; Water.

Midlife vascular risk factors and risk of incident dementia: Longitudinal cohort and Mendelian randomization analyses in the UK Biobank.
Malik R, Georgakis MK, Neitzel J, Rannikmäe K, Ewers M, Seshadri S, Sudlow CLM, Dichgans M.
Alzheimers Dement. 2021 Mar 22. doi: 10.1002/alz.12320. Online ahead of print.
PMID: 33749976
Introduction: Midlife clustering of vascular risk factors has been associated with late-life dementia, but causal effects of individual biological and lifestyle factors remain largely unknown.
Methods: Among 229,976 individuals (mean follow-up 9 years), we explored whether midlife cardiovascular health measured by Life's Simple 7 (LS7) is associated with incident all-cause dementia and whether the individual components of the score are causally associated with dementia.
Results: Adherence to the biological metrics of LS7 (blood pressure, cholesterol, glycemic status) was associated with lower incident dementia risk (hazard ratio = 0.93 per 1-point increase, 95% confidence interval [CI; 0.89-0.96]). In contrast, there was no association between the composite LS7 score and the lifestyle subscore (smoking, body mass index, diet, physical activity) and incident dementia. In Mendelian randomization analyses, genetically elevated blood pressure was associated with higher risk of dementia (odds ratio = 1.31 per one-standard deviation increase, 95% CI [1.05-1.60]).
Discussion: These findings underscore the importance of blood pressure control in midlife to mitigate dementia risk.
Keywords: Life's Simple 7; Mendelian randomization; blood pressure; dementia; epidemiology; genetics; hypertension; risk factors.

Whole-life body composition trajectory and longevity: role of insulin.
Lin YH, Tsai SC, Chuang SJ, Harris MB, Masodsai K, Chen PN, Hsieh CC, Killian T, Huang CY, Kuo CH.
Aging (Albany NY). 2021 Mar 19;13. doi: 10.18632/aging.202727. Online ahead of print.
PMID: 33744845
The present study assessed the body composition trajectory of rats (N = 96) placed into 5 groups according to lifespan, using dual-energy x-ray absorptiometry every 6 months until end-of-life. A striking linearity between lifespan and bone mass percentage (not absolute bone mass) was observed. Long-lived rats show a higher bone mass percentage with a delayed insulin rise to a similar peak level as short-lived counterparts, followed by insulin declines and bone mass loss. Decreasing insulin after streptozotocin (STZ) injection caused a rapid bone mass loss (-10.5%) with a decreased 5-day survival rate to 35% in old rats (20 months). Insulin replacement to STZ-injected rats completely blocked bone mass loss and increased the survival rate to 71%. Normal old rats (20 months) had faster lean mass loss despite greater myofiber regeneration (centronucleation) compared with the young rats (4 months). Increased CD68+ and CD163+ cell infiltration into insulin-depleted muscle suggests a bone marrow cell exhaustion by aging muscle. Bone produces stem cells and phagocytes to continuously rejuvenate peripheral tissues. Our data suggests that aging and unsustainable life is associated with development of disproportionality between bone and the growing body size, partly due to insulin reversal from hyperinsulinemia during late life.
Keywords: cachexia; frailty; longevity; osteopenia; sarcopenia.

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Selenium supplementation inhibits IGF-1 signaling and confers methionine restriction-like healthspan benefits to mice.
Plummer JD, Postnikoff SD, Tyler JK, Johnson JE.
Elife. 2021 Mar 30;10:e62483. doi: 10.7554/eLife.62483.
PMID: 33783357
Methionine restriction (MR) dramatically extends the healthspan of several organisms. Methionine-restricted rodents have less age-related pathology and increased longevity as compared with controls, and recent studies suggest that humans might benefit similarly. Mechanistically, it is likely that the decreased IGF-1 signaling that results from MR underlies the benefits of this regimen. Thus, we hypothesized that interventions that decrease IGF-1 signaling would also produce MR-like healthspan benefits. Selenium supplementation inhibits IGF-1 signaling in rats and has been studied for its putative healthspan benefits. Indeed, we show that feeding mice a diet supplemented with sodium selenite results in an MR-like phenotype, marked by protection against diet-induced obesity, as well as altered plasma levels of IGF-1, FGF-21, adiponectin, and leptin. Selenomethionine supplementation results in a similar, albeit less robust response, and also extends budding yeast lifespan. Our results indicate that selenium supplementation is sufficient to produce MR-like healthspan benefits for yeast and mammals.
Keywords: S. cerevisiae; aging; biochemistry; chemical biology; genetics; genomics; histone deacetylase; lifespan; metabolism; mitophagy; mouse; selenomethionine.

Food hardness influences the progression of age-related hearing loss in mice.
Oike H, Kohyama K, Mochizuki-Kawai H, Azami K.
Exp Gerontol. 2021 Mar 27:111335. doi: 10.1016/j.exger.2021.111335. Online ahead of print.
PMID: 33785396
C57BL/6J and DBA/2J mice are often used for hearing research because of their early onset and progression of age-related hearing loss (AHL). Here, we report that the hardness of the diet affects the progression of AHL in these mice. When C57BL/6J mice and DBA/2J mice were fed a pellet-type or powder-type standard AIN93M diet, the pellet diet significantly promoted AHL. AHL promotion was eliminated by crushing the pellet diet to a powder. Subsequently, when C57BL/6J mice were fed the pellet-type AIN93M diet obtained from three different manufacturers, two of them significantly promoted AHL. The hardness of the diets was measured, and it was found that the two diets that promoted AHL were significantly harder than the other diet. Next, we attempted to reduce diet hardness by replacing some nutritional ingredients with dried eggs or phosphatidylcholine (PC), and we succeeded in obtaining brittle diets with lower hardness values. Then, C57BL/6J mice were bred with brittle diets for 6 months and the promotion of AHL was suppressed to the equivalent level as the powder diet. Furthermore, when senescence-accelerated mice, SAMP8, were fed a brittle diet for one year, the progression of AHL was also suppressed; however, it did not affect other aging indexes, such as mental and physical performance. We also confirmed that a high-fat pellet diet, which is soft even in pellet form, did not promote AHL. Time-restricted feeding (tRF), which is a chrono-nutritional method to delay aging, ameliorated the promotion of AHL by the hard AIN93M pellets in C57BL/6J mice. These results indicate that the physical form and hardness of diets affect the progression of AHL in mouse models.
Keywords: Age-related hearing loss; Chrono-nutrition; Diet form; Mouse strain.

Association of Cycling with Risk of All-Cause and Cardiovascular Disease Mortality: A Systematic Review and Dose-Response Meta-analysis of Prospective Cohort Studies.
Zhao Y, Hu F, Feng Y, Yang X, Li Y, Guo C, Li Q, Tian G, Qie R, Han M, Huang S, Wu X, Zhang Y, Wu Y, Liu D, Zhang D, Cheng C, Zhang M, Yang Y, Shi X, Lu J, Hu D.
Sports Med. 2021 Mar 28. doi: 10.1007/s40279-021-01452-7. Online ahead of print.
PMID: 33774807
Background: Cycling has been suggested to be related to risk of all-cause and cardiovascular disease (CVD) mortality. However, a quantitative comprehensive assessment of the dose-response association of cycling with risk of all-cause and CVD mortality has not been reported. We performed a meta-analysis of cohort studies assessing the risk of all-cause and CVD mortality with cycling.
Methods: PubMed and Embase databases were searched for relevant articles published up to December 13, 2019. Random-effects models were used to estimate the summary relative risk (RR) of all-cause and CVD mortality with cycling. Restricted cubic splines were used to evaluate the dose-response association.
Results: We included 9 articles (17 studies) with 478,847 participants and 27,860 cases (22,415 from all-cause mortality and 5445 from CVD mortality) in the meta-analysis. Risk of all-cause mortality was reduced 23% with the highest versus lowest cycling level [RR 0.77, 95% confidence interval (CI) 0.67-0.88], and CVD mortality was reduced 24% (RR 0.76, 95% CI 0.65-0.89). We found a linear association between cycling and all-cause mortality (Pnon-linearity = 0.208); the risk was reduced by 9% (RR 0.91, 95% CI 0.86-0.96) with each five metabolic equivalent of task (MET)-h/week increase in cycling. We found an approximately U-shaped association between cycling and CVD mortality (Pnon-linearity = 0.034), with the lowest risk at approximately 15 MET-h/week of cycling.
Conclusions: Our findings based on quantitative data suggest that any level of cycling is better than none for all-cause mortality. However, for CVD mortality, one must choose an appropriate level of cycling, with an approximate optimum of 15 MET-h/week (equal to 130 min/week at 6.8 MET).

A fifty percent leucine-restricted diet reduces fat mass and improves glucose regulation.
Zhou Z, Yin H, Guo Y, Fang Y, Yuan F, Chen S, Guo F.
Nutr Metab (Lond). 2021 Mar 26;18(1):34. doi: 10.1186/s12986-021-00564-1.
PMID: 33771176
Background: Leucine deprivation modulates the dietary amino acid composition, reducing the fat content and improving the glucose tolerance, thus protecting the organism against obesity. However, a complete deprivation of leucine can lead to an extremely rapid fat loss in mice, accompanied by prolonged adverse effects such as weakness and mental fatigue. Therefore, in this study we aimed to seek the optimal concentration of dietary leucine that can reduce fat mass and improve the metabolism without the onset of severe effects.
Methods: To investigate whether there is a better concentration of diet leucine restriction (LR), based on the diet we conducted (A10021B), that can reduce fat mass and improve metabolism status without taking many negative effects, we fed 8 weeks old male C57Bl/6J mice with increasing degrees of leucine restriction diet 0% LR (control group), 25% LR, 50% LR, and 75% LR groups (4-6 mice each group). Fat mass and blood glucose levels were measured. The expression levels of genes involved in lipid metabolism in white adipose tissue (WAT) and liver, and proteins in insulin signaling were assessed in WAT, liver and muscle.
Results: We found that the 50% LR group is the most proper group here at the lowest leucine effective concentration, which reduced fat mass (p < 0.05) and improved glucose regulation in mice over a 90 days feeding. Further studies revealed that lipid synthesis pathway (Fas, Scd1and Srebp1, p < 0.05) was downregulated and lipolysis (Atgl, p < 0.05) was upregulated in WAT in 50% LR group, compared to that in control group. Furthermore, glucose regulation (glucose tolerance test, p < 0.05) was also improved, and insulin signaling (p < 0.05) in the muscle was enhanced in 50% LR group while in WAT and liver were not changed.
Conclusions: Collectively, a 50% LR in mice reduced fat mass and improved glucose regulation, which may function through modulating lipid synthesis and lipolysis pathway in adipose tissue as well as enhancing insulin signaling in muscle. So far, we provide a further consideration for carrying out the diet of leucine restriction to reduce fat and improve metabolism status before clinical study.
Keywords: Insulin signaling; Leucine restriction; Lipid metabolism pathway; Obesity.

Methionine restriction alleviates age-associated cognitive decline via fibroblast growth factor 21.
Ren B, Wang L, Shi L, Jin X, Liu Y, Liu RH, Yin F, Cadenas E, Dai X, Liu Z, Liu X.
Redox Biol. 2021 Mar 11;41:101940. doi: 10.1016/j.redox.2021.101940. Online ahead of print.
PMID: 33765615
Methionine restriction (MR) extends lifespan and delays the onset of aging-associated pathologies. However, the effect of MR on age-related cognitive decline remains unclear. Here, we find that a 3-month MR ameliorates working memory, short-term memory, and spatial memory in 15-month-old and 18-month-old mice by preserving synaptic ultrastructure, increasing mitochondrial biogenesis, and reducing the brain MDA level in aged mice hippocampi. Transcriptome data suggest that the receptor of fibroblast growth factor 21 (FGF21)-related gene expressions were altered in the hippocampi of MR-treated aged mice. MR increased FGF21 expression in serum, liver, and brain. Integrative modelling reveals strong correlations among behavioral performance, MR altered nervous structure-related genes, and circulating FGF21 levels. Recombinant FGF21 treatment balanced the cellular redox status, prevented mitochondrial structure damages, and upregulated antioxidant enzymes HO-1 and NQO1 expression by transcriptional activation of Nrf2 in SH-SY5Y cells. Moreover, knockdown of Fgf21 by i.v. injection of adeno-associated virus abolished the neuroprotective effects of MR in aged mice. In conclusion, the MR exhibited the protective effects against age-related behavioral disorders, which could be partly explained by activating circulating FGF21 and promoting mitochondrial biogenesis, and consequently suppressing the neuroinflammation and oxidative damages. These results demonstrate that FGF21 can be used as a potential nutritional factor in dietary restriction-based strategies for improving cognition associated with neurodegeneration disorders.
Keywords: Aging; Cognitive decline; Fibroblast growth factor 21; Methionine restriction; Nrf2; Oxidative stress.

Maintenance of muscle mass in adult male mice is independent of testosterone.
Davidyan A, Pathak S, Baar K, Bodine SC.
PLoS One. 2021 Mar 25;16(3):e0240278. doi: 10.1371/journal.pone.0240278. eCollection 2021.
PMID: 33764986
Testosterone is considered a potent anabolic agent in skeletal muscle with a well-established role in adolescent growth and development in males. However, the role of testosterone in the regulation of skeletal muscle mass and function throughout the lifespan has yet to be fully established. While some studies suggest that testosterone is important for the maintenance of skeletal muscle mass, an understanding of the role this hormone plays in young, adult, and old males with normal and low serum testosterone levels is lacking. We investigated the role testosterone plays in the maintenance of muscle mass by examining the effect of orchiectomy-induced testosterone depletion in C57Bl6 male mice at ages ranging from early postnatal through old age (1.5-, 5-, 12-, and 24-month old mice). Following 28 days of testosterone depletion, we assessed mass and fiber cross-sectional-area (CSA) of the tibialis anterior, gastrocnemius, and quadriceps muscles. In addition, we measured global rates of protein synthesis and degradation using the SuNSET method, western blots, and enzyme activity assays. Twenty-eight days of testosterone depletion resulted in reduced muscle mass in the two youngest cohorts, but had no effect in the two oldest cohorts. Mean CSA decreased only in the youngest cohort and only in the tibialis anterior muscle. Testosterone depletion resulted in a general increase in proteasome activity at all ages. No change in protein synthesis was detected at the terminal time point. These data suggest that within physiological serum concentrations, testosterone may not be critical for the maintenance of muscle mass in mature male mice; however, in young mice testosterone is crucial for normal growth.

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Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and lifespan in mice.
Richardson NE, Konon EN, Schuster HS, Mitchell AT, Boyle C, Rodgers AC, Finke M, Haider LR, Yu D, Flores V, Pak HH, Ahmad S, Ahmed S, Radcliff A, Wu J, Williams EM, Abdi L, Sherman DS, Hacker T, Lamming DW.
Nat Aging. 2021 Jan;1(1):73-86. doi: 10.1038/s43587-020-00006-2. Epub 2021 Jan 14.
PMID: 33796866
Protein restricted (PR) diets promote health and longevity in many species. While the precise components of a PR diet that mediate the beneficial effects to longevity have not been defined, we recently showed that many metabolic effects of PR 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 lifespan and a reduction in frailty in male, but not female, wild-type mice when fed lifelong. Our results demonstrate that restricting dietary BCAAs can increase healthspan and longevity in mice, and suggest that reducing dietary BCAAs may hold potential as a translatable intervention to promote healthy aging.
Keywords: branched-chain amino acids; healthspan; lifespan; mTOR; mTORC1; progeria; protein restriction; rapamycin.

17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex.
Harrison DE, Strong R, Reifsnyder P, Kumar N, Fernandez E, Flurkey K, Javors MA, Lopez-Cruzan M, Macchiarini F, Nelson JF, Bitto A, Sindler AL, Cortopassi G, Kavanagh K, Leng L, Bucala R, Rosenthal N, Salmon A, Stearns TM, Bogue M, Miller RA.
Aging Cell. 2021 Mar 31:e13328. doi: 10.1111/acel.13328. Online ahead of print.
PMID: 33788371
In genetically heterogeneous mice produced by the CByB6F1 x C3D2F1 cross, the "non-feminizing" estrogen, 17-α-estradiol (17aE2), extended median male lifespan by 19% (p < 0.0001, log-rank test) and 11% (p = 0.007) when fed at 14.4 ppm starting at 16 and 20 months, respectively. 90th percentile lifespans were extended 7% (p = 0.004, Wang-Allison test) and 5% (p = 0.17). Body weights were reduced about 20% after starting the 17aE2 diets. Four other interventions were tested in males and females: nicotinamide riboside, candesartan cilexetil, geranylgeranylacetone, and MIF098. Despite some data suggesting that nicotinamide riboside would be effective, neither it nor the other three increased lifespans significantly at the doses tested. The 17aE2 results confirm and extend our original reports, with very similar results when started at 16 months compared with mice started at 10 months of age in a prior study. The consistently large lifespan benefit in males, even when treatment is started late in life, may provide information on sex-specific aspects of aging.
Keywords: 17-α-estradiol; candesartan cilexetil; geranylgeranylacetone; heterogeneous mice; lifespan; macrophage migration inhibitory factor; nicotinamide riboside.

Caloric and nutrient restriction to augment chemotherapy efficacy for acute lymphoblastic leukemia: the IDEAL trial.
Orgel E, Framson C, Buxton R, Kim J, Li G, Tucci J, Freyer DR, Sun W, Oberley MJ, Dieli-Conwright C, Mittelman SD.
Blood Adv. 2021 Apr 13;5(7):1853-1861. doi: 10.1182/bloodadvances.2020004018.
PMID: 33792627
Being overweight or obese (OW/OB) during B-cell acute lymphoblastic leukemia (B-ALL) induction is associated with chemoresistance as quantified by minimal residual disease (MRD). We hypothesized that caloric and nutrient restriction from diet/exercise could lessen gains in fat mass (FM) and reduce postinduction MRD. The Improving Diet and Exercise in ALL (IDEAL) trial enrolled patients 10 to 21 years old, newly diagnosed with B-ALL (n = 40), in comparison with a recent historical control (n = 80). Designed to achieve caloric deficits ≥20% during induction, reduce fat intake/glycemic load, and increase activity, IDEAL's end points were FM gain (primary), MRD ≥0.01%, and adherence/feasibility. Integrated biology explored biomarkers of OW/OB physiology. IDEAL intervention did not significantly reduce median FM change from baseline overall (+5.1% [interquartile range [IQR], 15.8] vs +10.7% [IQR, 16.0]; P = .13), but stratified analysis showed benefit in those OW/OB (+1.5% [IQR, 6.6] vs +9.7% [IQR, 11.1]; P = .02). After accounting for prognostic factors, IDEAL intervention significantly reduced MRD risk (odds ratio, 0.30; 95% confidence interval, 0.09-0.92; P = .02). The trial exceeded its adherence (≥75% of overall diet) and feasibility (≥80% completed visits) thresholds. Integrated biology found the IDEAL intervention increased circulating adiponectin and reduced insulin resistance. The IDEAL intervention was feasible, decreased fat gain in those OW/OB, and reduced MRD. This is the first study in any hematologic malignancy to demonstrate potential benefit from caloric restriction via diet/exercise to augment chemotherapy efficacy and improve disease response. A prospective, randomized trial is warranted for validation. 

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Fluoride in Drinking Water, Diet, and Urine in Relation to Bone Mineral Density and Fracture Incidence in Postmenopausal Women.
Helte E, Donat Vargas C, Kippler M, Wolk A, Michaëlsson K, Åkesson A.
Environ Health Perspect. 2021 Apr;129(4):47005. doi: 10.1289/EHP7404. Epub 2021 Apr 6.
PMID: 33822648
Background: Although randomized controlled trials (RCTs) have demonstrated that high fluoride increases bone mineral density (BMD) and skeletal fragility, observational studies of low-dose chronic exposure through drinking water (<1.5mg/L, the maximum recommended by the World Health Organization) have been inconclusive.

Objective: We assessed associations of fluoride in urine, and intake via diet and drinking water, with BMD and fracture incidence in postmenopausal women exposed to drinking water fluoride ≤1mg/L.

Methods: Data were from participants in the Swedish Mammography Cohort-Clinical, a population-based prospective cohort study. At baseline (2004-2009), fluoride exposure was assessed based on urine concentrations (n
=4,306) and estimated dietary intake (including drinking water) (n=4,072), and BMD was measured using dual energy X-ray absorptiometry. Incident fractures were ascertained via register-linkage through 2017. Residential history was collected to identify women with long-term consistent drinking water exposures prior to baseline.

Results: At baseline, mean urine fluoride was 1.2mg/g creatinine (±1.9) and mean dietary intake was 2.2mg/d (±0.9), respectively. During follow-up, 850, 529, and 187 cases of any fractures, osteoporotic fractures, and hip fractures, respectively, were ascertained. Baseline BMD was slightly higher among women in the highest vs. lowest tertiles of exposure. Fluoride exposures were positively associated with incident hip fractures, with multivariable-adjusted hazard ratios of 1.50 (95% CI: 1.04, 2.17) and 1.59 (95% CI: 1.10, 2.30), for the highest vs. lowest tertiles of urine fluoride and dietary fluoride, respectively. Associations with other fractures were less pronounced for urine fluoride, and null for dietary fluoride. Restricting the analyses to women with consistent long-term drinking water exposures prior to baseline strengthened associations between fractures and urinary fluoride.
Discussion: In this cohort of postmenopausal women, the risk of fractures was increased in association with two separate indicators of fluoride exposure. Our findings are consistent with RCTs and suggest that high consumption of drinking water with a fluoride concentration of ∼1 mg/L may increase both BMD and skeletal fragility in older women. https://doi.org/10.1289/EHP7404.

Effect of 8-Day Fasting on Leukocytes Expression of Genes and Proteins Involved in Iron Metabolism in Healthy Men.
Borkowska A, Tomczyk M, Żychowska M, Pilis W, Zych M, Antosiewicz J.
Int J Mol Sci. 2021 Mar 23;22(6):3248. doi: 10.3390/ijms22063248.
PMID: 33806756
Anorexia Nervosa (AN) is a severe and often enduring disorder characterized by restriction of food intake, low body weight, fear of weight gain, and distorted body image. Investigations on cognition performance in AN patients have yielded conflicting results. Using an established and sensitive computerized cognitive test battery, we aimed to assess core aspects of cognitive function, including attention span, information processing, reasoning, working and episodic memory, in AN patients and controls. Patients were recruited from the Danish Prospective Longitudinal all-comer inclusion study in Eating Disorders (PROLED). Included were 26 individuals with AN and 36 healthy volunteers (HV). All were tested with CogTrack (an online cognitive assessment system) at baseline, and AN patients were tested again at a follow-up time point after weight increase (n = 13). At baseline, AN patients showed faster reaction times in the attention tasks, as well as increased accuracy in grammatical reasoning compared to HV. There were no differences in cognitive function between AN patients and HV in the other cognitive domains measured (sustained attention, working and episodic memory, speed of retrieval, and speed of grammatical reasoning). No differences were visible in the AN sample between baseline and follow-up. Performance did not correlate with any clinical variables in the AN sample. These findings supplement results from other studies suggesting increased concentration and reasoning accuracy in patients suffering from AN, who showed increased performance in cognitive tasks despite their illness.
Keywords: anorexia nervosa; cognitive functioning; cognitive performance; eating disorders; neuropsychology.

Associations of sleep duration and quality with incident cardiovascular disease, cancer, and mortality: a prospective cohort study of 407,500 UK biobank participants.
Tao F, Cao Z, Jiang Y, Fan N, Xu F, Yang H, Li S, Zhang Y, Zhang X, Sun L, Wang Y.
Sleep Med. 2021 Mar 15;81:401-409. doi: 10.1016/j.sleep.2021.03.015. Online ahead of print.
PMID: 33819843
Objective: Few studies have investigated the associations of sleep duration and sleep quality with incident cardiovascular diseases (CVDs), cancer, and mortality in the same large population. This study aimed at estimating the independent risk factors of long or short sleep durations and several typical characteristics of poor sleep quality for incident CVDs, cancer, and mortality.
Methods: In this prospective cohort study, 407 500 individuals were enrolled. Cox proportional hazards models were used to calculate the adjusted hazard ratios and 95% confidence intervals (HR, 95%CI) of associations of sleep duration and quality with incident CVDs, cancer, and mortality.
Results: Compared with the sleep duration of 7 h, sleep duration of ≤5 h and ≥9 h were both associated with higher risk of all-cause mortality (HR = 1.25, 95% CI: 1.16-1.34 and HR = 1.30, 95% CI: 1.22-1.38, respectively), CVD mortality (HR = 1.27, 95% CI: 1.09-1.49 and HR = 1.32, 95% CI: 1.16-1.50, respectively), and CVD incidence (HR = 1.23, 95% CI: 1.16-1.31 and HR = 1.08, 95% CI: 1.02-1.15, respectively). Additionally, long sleep duration (≥9 h) was associated with a higher risk of cancer mortality (HR = 1.19, 95% CI: 1.10-1.30) and cancer incidence (HR = 1.08, 95% CI: 1.04-1.12). Moreover, CVD incidence was significantly associated with snoring, insomnia and narcolepsy, increasing the risk by 7%, 26%, and 20%, respectively.
Conclusion: Long sleep durations may substantially increase the risk of mortality and morbidity. Snoring, insomnia, and narcolepsy were independent risk factors for incident CVD.
Keywords: Cancer; Cardiovascular disease; Mortality; Sleep duration; Sleep quality.

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10 hours ago, AlPater said:

Effect of 8-Day Fasting on Leukocytes Expression of Genes and Proteins Involved in Iron Metabolism in Healthy Men.
Borkowska A, Tomczyk M, Żychowska M, Pilis W, Zych M, Antosiewicz J.
Int J Mol Sci. 2021 Mar 23;22(6):3248. doi: 10.3390/ijms22063248.
PMID: 33806756

Anorexia Nervosa (AN) is a severe and often enduring disorder characterized by restriction of food intake, low body weight, fear of weight gain, and distorted body image. Investigations on cognition performance in AN patients have yielded conflicting results.   ETC.

The study title etc and the abstract don't  match.   This is the anorexia study:

Cognitive Function in Adults with Enduring Anorexia Nervosa

Nutrients  2021 Mar 5;13(3):859. 
PMID: 33808018  PMCID: PMC7998517  DOI: 10.3390/nu13030859
And this is the abstract for the Effect of 8-Day Fasting on Leukocytes etc study:


The popularity of fasting and restricted food intake is increasing. While the body's adaptability to dietary insufficiency is crucial for health, molecular mechanisms of adaptive changes are not well understood. Here, we compared the effects of fasting and exercise on the expression of leukocyte genes and proteins involved in the storage, export, and acquisition of iron, an essential element with physiological roles. Healthy men participated in the study (age, 30-70 years; body weight, 60-100 kg; body mass index, 20-29.9 kg/m2). The participants performed an exercise test with a gradually increasing intensity until the individual maximum exercise capacity was reached, before and after 8-d fast. Blood samples were collected before, immediately after, and 3 h after exercise. Gene expression was analyzed by reverse-transcription quantitative polymerase chain reaction and protein levels were analyzed by immunobloting. Eight days of total starvation diet affected the body composition and decreased exercise capacity. Further, fasting decreased the expression of genes associated with iron storage and export, and increased the expression of genes involved in iron acquisition. Conversely, only PCBP2 protein increased after fasting; however, an upward trend was apparent for all proteins. In conclusion, the body adapts to starvation by adjusting iron economy.

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Augmentation of the heat shock axis during exceptional longevity in Ames dwarf mice.
Trivedi R, Knopf B, Tripathi JK, Rakoczy S, Manocha GD, Brown-Borg H, Jurivich DA.
Geroscience. 2021 Apr 13. doi: 10.1007/s11357-021-00362-w. Online ahead of print.
PMID: 33846884
How the heat shock axis, repair pathways, and proteostasis impact the rate of aging is not fully understood. Recent reports indicate that normal aging leads to a 50% change in several regulatory elements of the heat shock axis. Most notably is the age-dependent enhancement of inhibitory signals associated with accumulated heat shock proteins and hyper-acetylation associated with marked attenuantion of heat shock factor 1 (HSF1)-DNA binding activity. Because exceptional longevity is associated with increased resistace to stress, this study evaluated regulatory check points of the heat shock axis in liver extracts from 12 months and 24 months long-lived Ames dwarf mice and compared these findings with aging wild-type mice. This analysis showed that 12M dwarf and wild-type mice have comparable stress responses, whereas old dwarf mice, unlike old wild-type mice, preserve and enhance activating elements of the heat shock axis. Old dwarf mice thwart negative regulation of the heat shock axis typically observed in usual aging such as noted in HSF1 phosphorylation at Ser307 residue, acetylation within its DNA binding domain, and reduction in proteins that attenuate HSF1-DNA binding. Unlike usual aging, dwarf HSF1 protein and mRNA levels increase with age and further enhance by stress. Together these observations suggest that exceptional longevity is associated with compensatory and enhanced HSF1 regulation as an adaptation to age-dependent forces that otherwise downregulate the heat shock axis.
Keywords: Aging; Ames dwarf; HSF; Heat shock; Longevity.

Fasting serum potassium and long-term mortality in healthy men.
Falk RS, Robsahm TE, Paulsen JE, Stocks T, Drake I, Heir T.
BMC Public Health. 2021 Apr 13;21(1):711. doi: 10.1186/s12889-021-10738-4.
PMID: 33849496
Background: Serum potassium levels have been positively associated with cardiovascular mortality, but little is known about the association with cancer mortality and death due to other causes. We examined whether serum levels of potassium were associated with long-term mortality in a healthy cohort.
Methods: Oslo Ischemia Study invited 2341 initially healthy men aged 40-59 years with no use of medication to a comprehensive health survey in 1972. Fasting serum level of potassium (mmol/L) was ascertained at baseline for 1989 men. We have complete follow-up for death throughout 2017. Cox proportional hazard models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) and adjusted for multiple confounders.
Results: After a median follow-up of 30 years (interquartile range 21.2-38.7), 1736 deaths were observed, of which 494 were cancer deaths, 688 cardiovascular deaths, and 536 deaths related to other causes. Restricted cubic spline analysis showed that potassium level was linearly and positively associated with long-term cancer mortality; HR per mmol/L 1.8, 95% CI 1.4-2.4. Compared with low levels of potassium (≤ 4.0 mmol/L), men with high levels (≥4.6 mmol/L) showed a significantly 78% higher risk of cancer death. A positive linear association was found for all-cause mortality (HR per mmol/L 1.6, 95% CI 1.4-1.8), and for cardiovascular (HR per mmol/L 1.4, 95% CI 1.1-1.7) and other cause mortality (HR per mmol/L 1.7, 95% CI 1.3-2.2).
Conclusions: These findings suggest that serum potassium level appears to predict long-term mortality in healthy middle-aged men, and it might imply future surveillance strategies for individuals with high serum potassium levels.
Keywords: Cancer; Cell proliferation; Mortality; Potassium levels; Prospective cohort study.

Non-aspirin NSAID use and mortality of endometrial cancer. A nationwide cohort study.
Sperling CD, Verdoodt F, Aalborg GL, Dehlendorff C, Friis S, Kjaer SK.
Cancer Causes Control. 2021 May;32(5):515-523. doi: 10.1007/s10552-021-01402-8. Epub 2021 Feb 23.
PMID: 33620641
Purpose: Laboratory studies have shown anti-neoplastic properties of non-aspirin NSAID; however, no studies have examined the influence of non-aspirin NSAIDs as potential adjuvant cancer therapy in women with endometrial cancer. We therefore examined the association between post-diagnostic use of non-aspirin NSAIDs and endometrial cancer mortality in Denmark.
Methods: We identified all women with a primary endometrial cancer diagnosis between 2000 and 2012, who were alive one year after the diagnosis. Information on drug use, cause-specific mortality and potential confounders was obtained from nationwide health- and demographic registries. Cox regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between post-diagnostic non-aspirin NSAID use and endometrial cancer mortality.
Results: Among 6 694 endometrial cancer patients with a maximum follow-up of 13 years, 753 women died from endometrial cancer. Post-diagnostic non-aspirin NSAID use (≥ 1 filled prescription) was associated with an overall HR of 1.15 (95% CI; 0.97-1.36) for endometrial cancer mortality, with higher HRs for the highest intensity of use (HR; 1.40, 95% CI; 1.11-1.77) and largest cumulative amount (HR; 1.56, 95% CI; 1.14-2.14).
Conclusion: Our findings yielded no evidence that use of non-aspirin NSAIDs was associated with reduced endometrial cancer. Rather, we observed that high-intensity and large cumulative amount of non-aspirin NSAID use may be associated with increased endometrial cancer mortality.
Keywords: Anti-neoplastic drugs; Cancer mortality; Chemoprevention; Endometrial cancer; Non-aspirin NSAID.

The association of skipping breakfast with cancer-related and all-cause mortality in a national cohort of United States adults.
Helo D, Appiah L, Bhende KM, Byrd TL, Appiah D.
Cancer Causes Control. 2021 May;32(5):505-513. doi: 10.1007/s10552-021-01401-9. Epub 2021 Feb 15.
PMID: 33590466
Purpose: Many lifestyle and dietary factors have been recognized as risk factors for cancer morbidity and mortality. However, investigations of the association of the frequency of breakfast consumption and cancer are limited. This study aimed to examine the association of skipping breakfast with all-cause and cancer-related mortality in a national cohort of United States men and women.
Methods: Data were from 7,007 adults aged ≥ 40 years who participated in the third National Health and Nutrition Examination Survey (1988-1994) and had follow-up information on mortality up until 31 December 2015. Cox proportional hazards regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI).
Results: The mean age of participants was 55.4 years, with 54.4% and 79% being women and non-Hispanic whites, respectively. Approximately, 16% of participants rarely consumed breakfast, 23.0% consumed breakfast some days, and 61% consumed breakfast every day. During a median follow-up of 22.2 years, 3,573 deaths occurred with 795 being related to cancer. In models adjusting for sociodemographic factors, smoking, physical activity, body mass index, hypertension, diabetes, cholesterol levels, total energy intake and diet quality, persons who rarely consumed breakfast had a higher risk of cancer-related mortality (HR = 1.52; CI:1.06-2.18) and all-cause (HR = 1.69; CI: 1.42-2.02) compared to those who took breakfast every day.
Conclusion: In this nationally representative sample, skipping breakfast was associated with elevated risks for all-cause and cancer-related mortality. This study provides evidence for the benefits of regular breakfast consumption in reducing the risk of all-cause and cancer mortality.
Keywords: Breakfast; Cancer; Diet; Epidemiology; Mortality.

Sunlight exposure in association with risk of lymphoid malignancy: a meta-analysis of observational studies.
Kim HB, Kim JH.
Cancer Causes Control. 2021 May;32(5):441-457. doi: 10.1007/s10552-021-01404-6. Epub 2021 Feb 19.
PMID: 33606147 Review.
Purpose: Several observational studies have shown contradictory results regarding the association between sunlight exposure and the risk of malignant lymphoma. Thus, we aimed to systematically determine the association between sunlight exposure and lymphoid malignancy risk through a meta-analysis.
Methods: A thorough search of four electronic databases (PubMed, Embase, Web of Science, and Scopus) was performed to identify eligible studies until 13 August 2020. A random-effects model was used to calculate risk estimates of sunlight exposure. The main outcome measure was the risk of lymphoid malignancy subtypes with odds ratios (ORs) and 95% confidence intervals (CIs) according to various forms of solar ultraviolet radiation.
Results: In total, 17 case-control studies and 9 cohort studies including 216,285 non-Hodgkin lymphoma (NHL) and 23,017 Hodgkin's lymphoma (HL) patients were included in the final analysis. Personal sunlight exposure was significantly associated with a decreased risk of HL (OR 0.77; 95% CI 0.68-0.87) and NHL (OR 0.81; 95% CI 0.71-0.92), including all subtypes except T-cell lymphoma. Ambient sunlight exposure at residence was associated with a reduced risk of HL (OR 0.88; 95% CI 0.81-0.95) and all NHL subtypes (OR 0.84; 95% CI 0.73-0.96), except for chronic lymphocytic leukemia/small lymphocytic lymphoma. As the number of sunburns and sunbaths increased, the risk of NHL tended to decrease.
Conclusion: While there was an observed protective effect both from case-control and prospective studies, substantial heterogeneity was found in the current study. Thus, more evidence is required to confirm that promoting sunlight exposure can prevent the development of lymphoid neoplasia.
Keywords: Hodgkin’s disease; Meta-analysis; Non-Hodgkin’s lymphoma; Observational study; Sunlight; Systematic review.

Association between intake of sweetened beverages with all-cause and cause-specific mortality: a systematic review and meta-analysis.
Li H, Liang H, Yang H, Zhang X, Ding X, Zhang R, Mao Y, Liu Z, Kan Q, Sun T.
J Public Health (Oxf). 2021 Apr 9:fdab069. doi: 10.1093/pubmed/fdab069. Online ahead of print.
PMID: 33837431
Background: Conclusions remain controversial between the consumption of sugar and artificially sweetened beverages (SSBs and ASBs) and mortality.
Methods: We systematically searched the PubMed, Embase, Cochrane Library and Web of Science databases from their inception date to 1st January 2020, prospective cohort studies researching the mortality risk and SSBs or ASBs consumption were included. Random effects meta-analyses and dose-response analyses were performed to measure the association. Subgroup analyses and sensitivity analyses were further performed to explore the source of heterogeneity. Publication bias was assessed by Funnel plots and Egger's regression test.
Results: Across all 15 cohorts, 1211 470 participants were included. High SSB consumption was associated with a higher risk of all-cause mortality (hazard ratio, {HR}, 1.12; 95% confidence interval [CI], 1.06-1.19, P < 0.001; and cardiovascular disease [CVD] mortality [HR 1.20, 95% CI, 1.05-1.38, P < 0.001]), and high ASBs consumption showed similar result (HR 1.12, 95% CI, 1.04-1.21, P = 0.001 for all-cause mortality and HR 1.23, 95% CI, 1.00-1.50, P = 0.049 for CVD mortality), both showed a linear dose-response relationship.

Conclusions: High consumption of both ASBs and SSBs showed significant associations with a higher risk of CVD mortality and all-cause mortality. This information may provide ideas for decreasing the global burden of diseases by reducing sweetened beverage intake.
Keywords: all-cause mortality; artificially sweetened beverage; global disease burden; meta-analysis; public health; sugar-sweetened beverage; sweetened beverage; systematic review.

Lifestyle as determinant of all-cause mortality and age at death. A middle-aged male population followed-up 60 years until the survivors were aged 100 years.
Menotti A, Puddu PE, Catasta G.
Aging Clin Exp Res. 2021 Apr 9. doi: 10.1007/s40520-021-01849-4. Online ahead of print.
PMID: 33835426
Objectives: To relate major lifestyle habits with all-cause mortality in an almost extinct male middle-aged population.
Material and methods: A 40-59 aged male population of 1712 subjects was enrolled and examined in 1960 and then followed-up for 60 years. Baseline smoking habits, working physical activity and dietary habits, each subdivided into 3 classes, were related to 60-year mortality, by Kaplan-Meier survival curves, Cox proportional hazards model and to age at death during 60 years by multiple linear regression.
Results: Death rate in 60 years was of 99.7% with only 5 survivors and 2 lost to follow-up after 50 years. Two out of three classes of each behavior were significantly protective versus the third class in all the statistical approaches. Cox hazard ratios (and their 95% confidence limits) of never smokers versus smokers was 0.71 (0.63-0.79); that of vigorous physical activity versus sedentary activity was 0.75 (0.64-0.89); that of Mediterranean diet versus Not Mediterranean diet was 0.74 (0.66-0.84). The gain of age at death for never smokers versus smokers was 3.32 years (2.05-4.54); of vigorous physical activity versus sedentary activity was 3.53 years (1.68-5.37); that of Mediterranean diet versus Not Mediterranean diet was 3.67 years (2.32-5.02). Age at death was more than 10 years longer for men with the 3 best behaviors than for those with the 3 worst behaviors.
Conclusions: Some lifestyle habits are strongly related to lifetime mortality and longevity.
Keywords: 60-year follow-up; Age at death; All-cause mortality; Lifestyle.

Body composition by computed tomography vs. dual energy x-ray absorptiometry: Long-term prediction of all-cause mortality in the Health ABC cohort.
Farsijani S, Xue L, Boudreau RM, Santanasto AJ, Kritchevsky SB, Newman AB.
J Gerontol A Biol Sci Med Sci. 2021 Apr 9:glab105. doi: 10.1093/gerona/glab105. Online ahead of print.
PMID: 33835154
Background: Body composition assessment by computed tomography (CT) predicts health outcomes in diverse populations. However, its performance in predicting mortality has not been directly compared to dual-energy-X-ray-absorptiometry (DXA). Additionally, the association between different body compartments and mortality, acknowledging the compositional nature of human body, is not well-studied. Compositional Data Analysis, that is applied to multivariate proportion-type dataset, may help to account for the inter-relationships of body compartments by constructing log-ratios of components. Here, we determined the associations of baseline CT-based measures of mid-thigh cross-sectional areas vs. DXA measures of body composition with all-cause mortality in Health ABC cohort, using both traditional (individual body compartments) and Compositional Data Analysis (using ratios of body compartments) approaches.
Methods: The Health ABC study assessed body composition in 2911 older adults in 1996-97. We investigated the individual and ratios of (by Compositional Analysis) body compartments assessed by DXA (lean, fat, and bone-mass) and CT (muscle, subcutaneous fat area, intermuscular fat (IMF), and bone) on mortality, using Cox proportional hazard models.
Results: Lower baseline muscle area by CT (HRmen=0.56 [95%CI: 0.48-0.67], HRwomen=0.60 [0.48-0.74]), fat-mass by DXA (HRmen=0.48 [0.24-0.95]) were predictors of mortality in traditional Cox-regression analysis. Consistently, Compositional Data Analysis revealed that lower muscle area vs. IMF, muscle area vs. bone area, and lower fat-mass vs. lean-mass were associated with higher mortality in both sexes.
Conclusion: Both CT measure of muscle area and DXA fat-mass (either individually or relative to other body compartments) were strong predictors of mortality in both sexes in a community research setting.
Keywords: Imaging; Longevity; Sarcopenia; Survival.

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Cooking oil/fat consumption and deaths from cardiometabolic diseases and other causes: prospective analysis of 521,120 individuals.
Zhang Y, Zhuang P, Wu F, He W, Mao L, Jia W, Zhang Y, Chen X, Jiao J.
BMC Med. 2021 Apr 15;19(1):92. doi: 10.1186/s12916-021-01961-2.
PMID: 33853582
Background: Increasing evidence highlights healthy dietary patterns and links daily cooking oil intake with chronic diseases including cardiovascular disease (CVD) and diabetes. However, food-based evidence supporting the consumption of cooking oils in relation to total and cardiometabolic mortality remains largely absent. We aim to prospectively evaluate the relations of cooking oils with death from cardiometabolic (CVD and diabetes) and other causes.
Methods: We identified and prospectively followed 521,120 participants aged 50-71 years from the National Institutes of Health-American Association of Retired Persons Diet and Health Study. Individual cooking oil/fat consumption was assessed by a validated food frequency questionnaire. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for mortality through the end of 2011.
Results: Overall, 129,328 deaths were documented during a median follow-up of 16 years. Intakes of butter and margarine were associated with higher total mortality while intakes of canola oil and olive oil were related to lower total mortality. After multivariate adjustment for major risk factors, the HRs of cardiometabolic mortality for each 1-tablespoon/day increment were 1.08 (95% CI 1.05-1.10) for butter, 1.06 (1.05-1.08) for margarine, 0.99 (0.95-1.03) for corn oil, 0.98 (0.94-1.02) for canola oil, and 0.96 (0.92-0.99) for olive oil. Besides, butter consumption was positively associated with cancer mortality. Substituting corn oil, canola oil, or olive oil for equal amounts of butter and margarine was related to lower all-cause mortality and mortality from certain causes, including CVD, diabetes, cancer, respiratory disease, and Alzheimer's disease.
Conclusions: Consumption of butter and margarine was associated with higher total and cardiometabolic mortality. Replacing butter and margarine with canola oil, corn oil, or olive oil was related to lower total and cardiometabolic mortality. Our findings support shifting the intake from solid fats to non-hydrogenated vegetable oils for cardiometabolic health and longevity.
Keywords: AARP Diet and Health Study; Cardiometabolic mortality; Cooking oils; Total mortality.

eIF5A hypusination, boosted by dietary spermidine, protects from premature brain aging and mitochondrial dysfunction.
Liang Y, Piao C, Beuschel CB, Toppe D, Kollipara L, Bogdanow B, Maglione M, Lützkendorf J, See JCK, Huang S, Conrad TOF, Kintscher U, Madeo F, Liu F, Sickmann A, Sigrist SJ.
Cell Rep. 2021 Apr 13;35(2):108941. doi: 10.1016/j.celrep.2021.108941.
PMID: 33852845
Mitochondrial function declines during brain aging and is suspected to play a key role in age-induced cognitive decline and neurodegeneration. Supplementing levels of spermidine, a body-endogenous metabolite, has been shown to promote mitochondrial respiration and delay aspects of brain aging. Spermidine serves as the amino-butyl group donor for the synthesis of hypusine (Nε-[4-amino-2-hydroxybutyl]-lysine) at a specific lysine residue of the eukaryotic translation initiation factor 5A (eIF5A). Here, we show that in the Drosophila brain, hypusinated eIF5A levels decline with age but can be boosted by dietary spermidine. Several genetic regimes of attenuating eIF5A hypusination all similarly affect brain mitochondrial respiration resembling age-typical mitochondrial decay and also provoke a premature aging of locomotion and memory formation in adult Drosophilae. eIF5A hypusination, conserved through all eukaryotes as an obviously critical effector of spermidine, might thus be an important diagnostic and therapeutic avenue in aspects of brain aging provoked by mitochondrial decline.
Keywords: CG8005; brain aging; deoxyhypusine synthase; eIF5A; eIF5A hypusination; learning and memory; locomotion; longevity; mitochondrial respiration; spermidine.

Dietary spermidine improves cognitive function.
Schroeder S, Hofer SJ, Zimmermann A, Pechlaner R, Dammbrueck C, Pendl T, Marcello GM, Pogatschnigg V, Bergmann M, Müller M, Gschiel V, Ristic S, Tadic J, Iwata K, Richter G, Farzi A, Üçal M, Schäfer U, Poglitsch M, Royer P, Mekis R, Agreiter M, Tölle RC, Sótonyi P, Willeit J, Mairhofer B, Niederkofler H, Pallhuber I, Rungger G, Tilg H, Defrancesco M, Marksteiner J, Sinner F, Magnes C, Pieber TR, Holzer P, Kroemer G, Carmona-Gutierrez D, Scorrano L, Dengjel J, Madl T, Sedej S, Sigrist SJ, Rácz B, Kiechl S, Eisenberg T, Madeo F.
Cell Rep. 2021 Apr 13;35(2):108985. doi: 10.1016/j.celrep.2021.108985.
PMID: 33852843
Decreased cognitive performance is a hallmark of brain aging, but the underlying mechanisms and potential therapeutic avenues remain poorly understood. Recent studies have revealed health-protective and lifespan-extending effects of dietary spermidine, a natural autophagy-promoting polyamine. Here, we show that dietary spermidine passes the blood-brain barrier in mice and increases hippocampal eIF5A hypusination and itochondrial function. Spermidine feeding in aged mice affects behavior in homecage environment tasks, improves spatial learning, and increases hippocampal respiratory competence. In a Drosophila aging model, spermidine boosts mitochondrial respiratory capacity, an effect that requires the autophagy regulator Atg7 and the mitophagy mediators Parkin and Pink1. Neuron-specific Pink1 knockdown abolishes spermidine-induced improvement of olfactory associative learning. This suggests that the maintenance of mitochondrial and autophagic function is essential for enhanced cognition by spermidine feeding. Finally, we show large-scale prospective data linking higher dietary spermidine intake with a reduced risk for cognitive impairment in humans.
Keywords: Pink1; aging; autophagy; cognitive function; dietary spermidine; memory; mitochondria; mitophagy.

COVID-19: Clinical Presentation and Prognostic Factors of Severe Disease and Mortality in the Oldest-Old Population: A Cohort Study.
Gálvez-Barrón C, Arroyo-Huidobro M, Miňarro A, Añaños G, Chamero A, Martín M, Gris C, Avalos JL, Capielo AM, Ventosa E, Tremosa G, Rodríguez-Molinero A; COVID-19 research group of CSAPG.
Gerontology. 2021 Apr 14:1-14. doi: 10.1159/000515159. Online ahead of print.
PMID: 33853067
Introduction: The oldest-old population (80 years or older) has the highest lethality from COVID-19. There is little information on the clinical presentation and specific prognostic factors for this group. This trial evaluated the clinical presentation and prognostic factors of severe disease and mortality in the oldest-old population.
Methods: This is an ambispective cohort study of oldest-old patients hospitalized for respiratory infection associated with COVID-19 and with a positive test by RT-PCR. The clinical presentation and the factors associated with severe disease and mortality were evaluated (logistic regression). All patients were followed up until discharge or death.
Results: A total of 103 patients (59.2% female) were included. The most frequent symptoms were fever (68.9%), dyspnoea (60.2%), and cough (39.8%), and 11.7% presented confusion. Fifty-nine patients (57.3%) presented severe disease, and 59 died, with 43 patients (41.7%) presenting both of these. In the multivariate analysis, female sex (odds ratio [OR] 0.31, 95% confidence interval [95% CI] 0.13-0.73, p 0.0074) and serum lactate dehydrogenase (LDH) (OR 2.55, 95% CI 1.21-5.37, p 0.0139) were associated with severe disease, and serum sodium was associated with mortality (OR 3.12, 95% CI 1.18-8.26, p 0.0222). No chronic disease or pharmacological treatment was associated with worse outcomes.
Conclusions: The typical presenting symptoms of respiratory infection in COVID-19 are less frequent in the oldest-old population. Male sex and LDH level are associated with severe disease, and the serum sodium level is associated with mortality in this population.
Keywords: COVID-19; Epidemiology; Mortality; Oldest-old population; Risk factors.

Complex Mechanisms Link Dietary Sulfur Amino Acid Restriction to Health Improvement.
Bruhat A, Papet I, Fafournoux P.
J Nutr. 2021 Apr 8;151(4):749-750. doi: 10.1093/jn/nxaa457.
PMID: 33693727 No abstract available.
Physiologic Responses to Dietary Sulfur Amino Acid Restriction in Mice Are Influenced by Atf4 Status and Biological Sex.
Jonsson WO, Margolies NS, Mirek ET, Zhang Q, Linden MA, Hill CM, Link C, Bithi N, Zalma B, Levy JL, Pettit AP, Miller JW, Hine C, Morrison CD, Gettys TW, Miller BF, Hamilton KL, Wek RC, Anthony TG.
J Nutr. 2021 Apr 8;151(4):785-799. doi: 10.1093/jn/nxaa396.
PMID: 33512502
Background: Dietary sulfur amino acid restriction (SAAR) improves body composition and metabolic health across several model organisms in part through induction of the integrated stress response (ISR).
Objective: We investigate the hypothesis that activating transcription factor 4 (ATF4) acts as a converging point in the ISR during SAAR.
Methods: Using liver-specific or global gene ablation strategies, in both female and male mice, we address the role of ATF4 during dietary SAAR.
Results: We show that ATF4 is dispensable in the chronic induction of the hepatokine fibroblast growth factor 21 while being essential for the sustained production of endogenous hydrogen sulfide. We also affirm that biological sex, independent of ATF4 status, is a determinant of the response to dietary SAAR.
Conclusions: Our results suggest that auxiliary components of the ISR, which are independent of ATF4, are critical for SAAR-mediated improvements in metabolic health in mice.
Keywords: DNA synthesis; gene expression; liver; methionine restriction; nutrient sensing; protein synthesis.

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Effect of glutamine supplementation on cardiometabolic risk factors and inflammatory markers: a systematic review and meta-analysis.
Hasani M, Mansour A, Asayesh H, Djalalinia S, Mahdavi Gorabi A, Ochi F, Qorbani M.
BMC Cardiovasc Disord. 2021 Apr 17;21(1):190. doi: 10.1186/s12872-021-01986-8.
PMID: 33865313
Background: Evidence exists that glutamine plays multiple roles in glucose metabolism, insulin sensitivity, and anti-inflammatory effects. This systematic review and meta-analysis of controlled trials aimed to assess the effect of glutamine supplementation on cardio-metabolic risk factors and inflammatory markers.
Methods: The processes of systematic reviews and meta-analyses were performed according to the PRISMA checklist. PubMed, Web of Sciences, Cochrane library, and Scopus databases were search for relevant studies without time or language restrictions up to December 30, 2020. All randomized clinical trials which assessed the effect of glutamine supplementation on "glycemic indices", "level of triglyceride, "and "inflammatory markers" were included in the study. The effect of glutamine supplementation on cardio-metabolic risk factors and inflammatory markers was assessed using a standardized mean difference (SMD) and 95% confidence interval (CI). Heterogeneity between among studies was assessed using Cochran Q-statistic and I-square. Random/fixed-effects meta-analysis method was used to estimate the pooled SMD. The risk of bias for the included trials was evaluated using the Cochrane quality assessment tool.
Results: In total, 12 studies that assessed the effect of glutamine supplementation on cardio-metabolic risk factors were included in the study. Meta-analysis showed that glutamine supplementation significantly decreased significantly serum levels of FPG [SMD: - 0.73, 95% CI - 1.35, - 0.11, I2: 84.1%] and CRP [SMD: - 0.58, 95% CI - 0.1, - 0.17, I2: 0%]. The effect of glutamine supplementation on other cardiometabolic risk factors was not statistically significant (P > 0.05).
Conclusion: Our findings showed that glutamine supplementation might have a positive effect on FPG and CRP; both of which are crucial as cardio-metabolic risk factors. However, supplementation had no significant effect on other cardio-metabolic risk factors.
Keywords: Cardiometabolic risk factors; Glutamine; Meta-analysis; Systematic review.

Heterochronic blood exchange attenuates age-related neuroinflammation and confers cognitive benefits: do microvascular protective effects play a role?
Huffman DM, Csiszar A, Ungvari Z.
Geroscience. 2021 Feb;43(1):111-113. doi: 10.1007/s11357-021-00324-2. Epub 2021 Jan 28.
PMID: 33511487 No abstract available.
Heterochronic parabiosis regulates the extent of cellular senescence in multiple tissues.
Yousefzadeh MJ, Wilkinson JE, Hughes B, Gadela N, Ladiges WC, Vo N, Niedernhofer LJ, Huffman DM, Robbins PD.
Geroscience. 2020 Jun;42(3):951-961. doi: 10.1007/s11357-020-00185-1. Epub 2020 Apr 13.
PMID: 32285290 Free PMC article.
An increase in the burden of senescent cells in tissues with age contributes to driving aging and the onset of age-related diseases. Genetic and pharmacologic elimination of senescent cells extends both health span and life span in mouse models. Heterochronic parabiosis in mice has been used to identify bloodborne, circulating pro- and anti-geronic factors able to drive or slow aging, respectively. However, whether factors in the circulation also regulate senescence is unknown. Here, we measured the expression of senescence and senescence-associated secretory phenotype (SASP) markers in multiple tissues from 4- to 18-month-old male mice that were either isochronically or heterochronically paired for 2 months. In heterochronic parabionts, the age-dependent increase in senescence and SASP marker expression was reduced in old mice exposed to a young environment, while senescence markers were concurrently increased in young heterochronic parabionts. These findings were supported by geropathology analysis using the Geropathology Grading Platform that showed a trend toward reduced hepatic lesions in old heterochronic parabionts. In summary, these results demonstrate that senescence is regulated in part by circulating geronic factors and suggest that one of the possible mediators of the rejuvenating effects with heterochronic parabiosis is through the reduction of the senescent cell burden.
Keywords: Aging; Cellular senescence; Geropathology; Parabiosis; SASP.

Plasma dilution improves cognition and attenuates neuroinflammation in old mice.
Mehdipour M, Mehdipour T, Skinner CM, Wong N, Liu C, Chen CC, Jeon OH, Zuo Y, Conboy MJ, Conboy IM.
Geroscience. 2021 Feb;43(1):1-18. doi: 10.1007/s11357-020-00297-8. Epub 2020 Nov 15.
PMID: 33191466
Our recent study has established that young blood factors are not causal, nor necessary, for the systemic rejuvenation of mammalian tissues. Instead, a procedure referred to as neutral blood exchange (NBE) that resets signaling milieu to a pro-regenerative state through dilution of old plasma, enhanced the health and repair of the muscle and liver, and promoted better hippocampal neurogenesis in 2-year-old mice (Mehdipour et al., Aging 12:8790-8819, 2020). Here we expand the rejuvenative phenotypes of NBE, focusing on the brain. Namely, our results demonstrate that old mice perform much better in novel object and novel texture (whisker discrimination) tests after a single NBE, which is accompanied by reduced neuroinflammation (less-activated CD68+ microglia). Evidence against attenuation/dilution of peripheral senescence-associated secretory phenotype (SASP) as the main mechanism behind NBE was that the senolytic ABT 263 had limited effects on neuroinflammation and did not enhance hippocampal neurogenesis in the old mice. Interestingly, peripherally acting ABT 263 and NBE both diminished SA-βGal signal in the old brain, demonstrating that peripheral senescence propagates to the brain, but NBE was more robustly rejuvenative than ABT 263, suggesting that rejuvenation was not simply by reducing senescence. Explaining the mechanism of the positive effects of NBE on the brain, our comparative proteomics analysis demonstrated that dilution of old blood plasma yields an increase in the determinants of brain maintenance and repair in mice and in people. These findings confirm the paradigm of rejuvenation through dilution of age-elevated systemic factors and extrapolate it to brain health and function.
Keywords: Memory and Cognition; Neuroinflammation; Neutral blood exchange; Plasma dilution; Rejuvenation; Senolytics.

Independent and joint associations between leisure time physical activity and strength activities with mortality outcomes in older adults 65 years-of-age: a prospective cohort study.
Nie J, Haberstroh M, Acosta T, Huang W, Wang Y, Barengo NC.
J Gerontol A Biol Sci Med Sci. 2021 Apr 15:glab114. doi: 10.1093/gerona/glab114. Online ahead of print.
PMID: 33858013
Scientific evidence regarding the combined effect of both aerobic leisure time physical activity (LTPA) and muscle strengthening activities on all-cause, CVD or cancer mortality in older adults is scant. The aim of the study was to investigate the associations between recommended physical activity and mortality in older adults ≥65 years-of-age. This prospective cohort study used data from the National Health Interview Surveys from 1997-2013 linked with mortality files through December 31, 2015 (n=89,962). The main outcomes included all-cause, cardiovascular disease (CVD) and cancer mortality. The main exposure variables were aerobic leisure time physical activity and guideline-concordant strength training during leisure time. Cox regression models were used to calculate the hazard ratios (HR) and the corresponding 95% confidence intervals (CI). Muscle-strengthening activity at least twice per week were associated with lower hazards of all-cause mortality (HR 0.92; 95% CI 0.88-0.96), CVD mortality (HR 0.90; 95% CI 0.81-0.99) and cancer mortality (HR 0.87; 95% CI 0.79-0.96). Those who reached the recommended weekly amount of LTPA, had lower hazard of all-cause mortality by 35% (HR 0.66; 95% CI 0.63-0.67), the hazard of CVD 38% (HR 0.62; 95% CI 0.58-0.67), and cancer mortality by 22% (HR 0.78; 95% CI 0.73-0.84). The hazard of death among those who were physically active in both leisure time and engaged in muscle-strengthening activities were 0.57 (95% CI 0.54-0.60) for all-cause mortality, 0.53 (95% CI 0.47-0.61) for CVD mortality, and 0.66 (95% CI 0.58-0.75) for cancer mortality. Thus, engaging in muscle-strengthening activity ≥2 times/week may provide additional benefits among physically active older adults.
Keywords: Survival; cohort study; guidelines; physical activity.

Association of sugary drink consumption with all-cause and cause-specific mortality: The Japan public health center-based prospective study.
Huang HL, Abe SK, Sawada N, Takachi R, Ishihara J, Iwasaki M, Yamaji T, Iso H, Mizoue T, Noda M, Hashizume M, Inoue M, Tsugane S; JPHC Study Group.
Prev Med. 2021 Apr 15:106561. doi: 10.1016/j.ypmed.2021.106561. Online ahead of print.
PMID: 33865863
Background: Few epidemiologic studies have assessed the associations of sugary drink consumption with mortality outcomes among Asian populations.
Methods: This study included 70,486 participants in the Japan Public Health Center-based Prospective Study at the age of 45-74 years in 1995-1999. A validated food frequency questionnaire was used to assess the consumption of sugary drinks. We estimated the risk of total and cause-specific mortality associated with sugary drink consumption using Cox proportional hazards regression model.
Results: Mean follow-up was 17.1 years, during which 11,811 deaths were documented. Sugary drink consumption was associated with higher total mortality, with multivariate HR of 1.06 (95% CI 1.00-1.13) for quintile 3, 1.07 (95% CI 1.01-1.13) for quintile 4, and 1.15 (95% CI 1.09-1.22) for quintile 5, compared with quintile 1 (P < 0.001 for trend). Additionally, positive associations with cause-specific mortality were observed, including death from circulatory system diseases (quintile 5 vs quintile 1; HR, 1.23; 95% CI 1.09-1.38) and heart disease (quintile 5 vs quintile 1; HR, 1.35; 95% CI 1.14-1.60).
Conclusion: In this large Japanese prospective study, sugary drink consumption was associated with all-cause and cause-specific mortality.
Keywords: JPHC study; Japan; Mortality; Prospective cohort study; Sugary drinks.

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Underweight rather than adiposity is an important predictor of death in rural Chinese adults: a cohort study.
Chen Y, Wang N, Dong X, Wang X, Zhu J, Chen Y, Jiang Q, Fu C.
J Epidemiol Community Health. 2021 Apr 20:jech-2020-214821. doi: 10.1136/jech-2020-214821. Online ahead of print.
PMID: 33879539
Background: To assess the associations of body mass index (BMI) with all-cause and cause-specific mortalities among rural Chinese.
Methods: A prospective study of 28 895 individuals was conducted from 2006 to 2014 in rural Deqing, China. Height and weight were measured. The association of BMI with mortality was assessed by using Cox proportional hazards model and restricted cubic spline regression.
Results: There were a total of 2062 deaths during an average follow-up of 7 years. As compared with those with BMI of 22.0-24.9 kg/m2, an increased risk of all-cause mortality was found for both underweight men (BMI <18.5 kg/m2) (adjusted HR (aHR): 1.45, 95% CI: 1.18 to 1.79) and low normal weight men (BMI of 18.5-21.9 kg/m2) (aHR: 1.20, 95% CI: 1.03 to 1.38). A J-shaped association was observed between BMI and all-cause mortality in men. Underweight also had an increased risk of cardiovascular disease and cancer mortalities in men. The association of underweight with all-cause mortality was more pronounced in ever smokers and older men (60+ years). The results remained after excluding participants who were followed up less than 1 year.
Conclusion: The present study suggests that underweight is an important predictor of mortality, especially for elderly men in the rural community of China.
Keywords: cohort studies; mortality; obesity.

Adverse associations of sedentary behavior with cancer incidence and all-cause mortality: A prospective cohort study: Sedentary behavior, cancer and mortality.
Lin Y, Liu Q, Liu F, Huang K, Li J, Yang X, Wang X, Chen J, Liu X, Cao J, Shen C, Yu L, Lu F, Wu X, Zhao L, Li Y, Hu D, Lu X, Huang J, Gu D.
J Sport Health Sci. 2021 Apr 17:S2095-2546(21)00046-6. doi: 10.1016/j.jshs.2021.04.002. Online ahead of print.
PMID: 33878448
Background: Inconsistent results have been reported in developed countries for relationships between sedentary behavior and cancer incidence and mortality, but evidence from the Chinese population is scarce. This study aimed to investigate such relationships in large Chinese population-based prospective cohorts and to explore the joint effect and interaction of sedentary behavior and moderate-to-vigorous physical activity (MVPA) on these relationships.
Methods: We included 95,319 Chinese adults without cancer from 3 large cohorts and assessed their sedentary behavior and physical activity with a unified questionnaire. Cancer incidence and mortality were confirmed by interviewing participants or their proxies and checking hospital records and death certificates. Hazard ratios (HRs) and 95% confidence intervals (95%CIs) for cancer and mortality were estimated using Cox proportional hazards regression models.
Results: During 559,002 person-years of follow-up, 2388 cancer events, 1571 cancer deaths, and 4562 all-cause deaths were recorded. Sedentary behavior was associated with increased risk of developing cancer and deaths in a dose-response manner. The multivariable-adjusted HRs (95%CIs) were: HR = 1.16, 95%CI: 1.01‒1.33; HR = 1.24, 95%CI: 1.04‒1.48; and HR = 1.15, 95%CI: 1.04‒1.28 for cancer incidence, cancer mortality, and all-cause mortality, respectively, for those having ≥10 h/day of sedentary time compared to those having <6 h/day of sedentary time. Sedentary populations (≥10 h/day) developed cancer or died 4.09 and 2.79 years earlier, respectively, at the index age of 50 years. Failure to achieve the recommended level of MVPA may further aggravate the adverse associations, with the highest cancer and mortality risks being observed among participants with both ≥10 h/day of sedentary time and <150 min/week of MVPA. Limitations of this study include the fact that physical activity information was obtained via questionnaire instead of objective measurement and that there were insufficient incident cases for the analysis of associations between sedentary behavior and site-specific cancers.
Conclusion: Sedentary behavior was associated with an increased risk of cancer and all-cause mortality among Chinese adults, especially for those with ≥10 h/day of sedentary time. It is necessary to reduce sedentary time, in addition to increasing MVPA levels, for the prevention of cancer and premature death.
Keywords: All-cause mortality; Cancer; Chinese population; Cohort study; Sedentary behavior.

The Effects of a 6-Week Controlled, Hypocaloric Ketogenic Diet, With and Without Exogenous Ketone Salts, on Body Composition Responses.
Buga A, Kackley ML, Crabtree CD, Sapper TN, Mccabe L, Fell B, LaFountain RA, Hyde PN, Martini ER, Bowman J, Pan Y, Scandling D, Brownlow ML, O'Connor A, Simonetti OP, Kraemer WJ, Volek JS.
Front Nutr. 2021 Mar 24;8:618520. doi: 10.3389/fnut.2021.618520. eCollection 2021.
PMID: 33869263 Free PMC article.
Background: Ketogenic diets (KDs) that elevate beta-hydroxybutyrate (BHB) promote weight and fat loss. Exogenous ketones, such as ketone salts (KS), also elevate BHB concentrations with the potential to protect against muscle loss during caloric restriction. Whether augmenting ketosis with KS impacts body composition responses to a well-formulated KD remains unknown. Purpose: To explore the effects of energy-matched, hypocaloric KD feeding (<50 g carbohydrates/day; 1.5 g/kg/day protein), with and without the inclusion of KS, on weight loss and body composition responses. Methods: Overweight and obese adults were provided a precisely defined hypocaloric KD (~75% of energy expenditure) for 6 weeks. In a double-blind manner, subjects were randomly assigned to receive ~24 g/day of a racemic BHB-salt (KD + KS; n = 12) or placebo (KD + PL; n = 13). A matched comparison group (n = 12) was separately assigned to an isoenergetic/isonitrogenous low-fat diet (LFD). Body composition parameters were assessed by dual x-ray absorptiometry and magnetic resonance imaging. Results: The KD induced nutritional ketosis (>1.0 mM capillary BHB) throughout the study (p < 0.001), with higher fasting concentrations observed in KD + KS than KD + PL for the first 2 weeks (p < 0.05). There were decreases in body mass, whole body fat and lean mass, mid-thigh muscle cross-sectional area, and both visceral and subcutaneous adipose tissues (p < 0.001), but no group differences between the two KDs or with the LFD. Urine nitrogen excretion was significantly higher in KD + PL than LFD (p < 0.01) and trended higher in KD + PL compared to KD + KS (p = 0.076), whereas the nitrogen excretion during KD + KS was similar to LFD (p > 0.05). Conclusion: Energy-matched hypocaloric ketogenic diets favorably affected body composition but were not further impacted by administration of an exogenous BHB-salt that augmented ketosis. The trend for less nitrogen loss with the BHB-salt, if manifested over a longer period of time, may contribute to preserved lean mass.
Keywords: advanced imaging; body composition; exogenous ketones; ketogenic diet; obesity.

Associations of Skeletal Muscle Mass and Fat Mass With Incident Cardiovascular Disease and All-Cause Mortality: A Prospective Cohort Study of UK Biobank Participants.
Knowles R, Carter J, Jebb SA, Bennett D, Lewington S, Piernas C.
J Am Heart Assoc. 2021 Apr 19:e019337. doi: 10.1161/JAHA.120.019337. Online ahead of print.
PMID: 33870707
Background There is debate whether body mass index is a good predictor of health outcomes because different tissues, namely skeletal muscle mass (SMM) and fat mass (FM), may be differentially associated with risk. We investigated the association of appendicular SMM (aSMM) and FM with fatal and nonfatal cardiovascular disease (CVD) and all-cause mortality. We compared their prognostic value to that of body mass index. Methods and Results We studied 356 590 UK Biobank participants aged 40 to 69 years with bioimpedance analysis data for whole-body FM and predicted limb muscle mass (to calculate aSMM). Associations between aSMM and FM with CVD and all-cause mortality were examined using multivariable Cox proportional hazards models. Over 3 749 501 person-years of follow-up, there were 27 784 CVD events and 15 844 all-cause deaths. In men, aSMM was positively associated with CVD incidence (hazard ratio {HR} per 1 SD 1.07; 95% CI, 1.06-1.09) and there was a curvilinear association in women. There were stronger positive associations between FM and CVD with HRs per SD of 1.20 (95% CI, 1.19-1.22) and 1.25 (95% CI, 1.23-1.27) in men and women respectively. Within FM tertiles, the associations between aSMM and CVD risk largely persisted. There were J-shaped associations between aSMM and FM with all-cause mortality in both sexes. Body mass index was modestly better at discriminating CVD risk. Conclusions FM showed a strong positive association with CVD risk. The relationship of aSMM with CVD risk differed between sexes, and potential mechanisms need further investigation. Body fat and SMM bioimpedance measurements were not superior to body mass index in predicting population-level CVD incidence or all-cause mortality.

Keywords: all‐cause mortality; cardiovascular disease; cohort study; fat mass; skeletal muscle mass.

Associations of Visceral Adipose Tissue and Skeletal Muscle Density With Incident Stroke, Myocardial Infarction, and All-Cause Mortality in Community-Dwelling 70-Year-Old Individuals: A Prospective Cohort Study.
Ballin M, Nordström P, Niklasson J, Nordström A.
J Am Heart Assoc. 2021 Apr 17:e020065. doi: 10.1161/JAHA.120.020065. Online ahead of print.
PMID: 33870709
Background Aging leads to increased visceral adipose tissue (VAT) and reduced skeletal muscle density. To which extent these are associated with the risk of stroke, myocardial infarction (MI), and all-cause mortality in older adults is unknown. Methods and Results A total of 3294 70-year-old individuals (49.6% women) underwent a health examination in Umeå, Sweden, during 2012 to 2018. VAT and muscle density were measured using dual-energy x-ray absorptiometry and peripheral quantitative computed tomography. Cases of stroke, MI, and all-cause mortality were collected through national registers. Cox regressions were used to calculate hazard ratios (HRs) and 95% CIs per SD greater VAT and per SD lower muscle density. During a mean follow-up of 3.6 years, there were 108 cases of stroke or MI, and 97 deaths. Greater VAT (adjusted HR [aHR], 1.56; 95% CI, 1.09-2.22), but not lower muscle density (aHR, 1.14; 95% CI, 0.97-1.34), was associated with increased risk of stroke or MI. Neither VAT (aHR, 0.95; 95% CI, 0.65-1.41) nor muscle density (aHR, 1.11; 95% CI, 0.92-1.34) was associated with all-cause mortality. The association of VAT with stroke or MI was only significant in men (aHR, 1.86; 95% CI, 1.19-2.91) but not women (aHR, 0.60; 95% CI, 0.25-1.42) (Pinteraction=0.038). Conclusions With the limitation of being an observational study, these findings suggest that VAT is an important obesity-related predictor of cardiovascular risk in 70-year-old men, and by implication, that decreasing VAT may potentially reduce their risk of cardiovascular disease.
Keywords: body composition; cardiovascular disease; ectopic fat; obesity.

Edited by AlPater
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Physical activity is associated with reduced risk of liver disease in the prospective UK Biobank cohort.
Schneider CV, Zandvakili I, Thaiss CA, Schneider KM.
JHEP Rep. 2021 Mar 2;3(3):100263. doi: 10.1016/j.jhepr.2021.100263. eCollection 2021 Jun.
PMID: 33898961 Free PMC article.
Background & aims: Previous studies have identified physical activity as an important lifestyle factor in the pathogenesis of chronic liver diseases (CLD). However, most studies were short in follow-up, and based on self-reported activity. Moreover, it is unknown whether physical activity affects the risk of liver disease development in the general population. Herein, we aimed to clarify the association between physical activity and CLD by examining the risk of liver disease and progression in relation to accelerometer-based physical activity in a large subset of prospectively recruited participants in the UK Biobank.
Methods: We analysed data from 96,688 participants that recorded their physical activity through the use of a wrist accelerometer. Relative risks for development of liver diseases were calculated using multivariable-adjusted Cox regression models. In a subgroup of participants without any previously diagnosed liver disease (n = 95,974), a total of 374 liver disease cases were diagnosed during follow-up (mean = 5.5 years).
Results: Participants in the top compared with the bottom quartile of physical activity had a reduced risk of both overall CLD (hazard ratio HR}: 0.41 [0.29-0.59]) and NAFLD (HR: 0.39 [0.21-0.70]). An activity increase of an additional 2,500 steps per day, was associated with a 38% reduction in CLD and a 47% reduction in NAFLD development, independent of adiposity. In the subgroup of participants with previously diagnosed liver disease (n = 714), participants in the top compared with the bottom quartile of physical activity had a striking 89% risk reduction in liver-related death (HR: 0.11 [0.02-0.86]), and 85% risk reduction in all-cause mortality (adjusted HR: 0.15 [0.05-0.44]). Walking an additional 2,500 steps per day was associated with 44% reduction in liver disease progression.
Conclusions: Greater physical activity is associated with a dose-dependent reduction in liver disease, which appears to be independent of adiposity.
Lay summary: In this study, we aimed to clarify the association between accelerometer-measured physical activity and chronic liver disease by examining risk of overall and specific liver diseases and their progression in relation to accelerometer-based physical activity in 96,688 participants in the UK Biobank. Our results show a clear, dose-dependent protective association between accelerometer-measured physical activity and liver disease development and progression. The linkage of device-measured activity could therefore create a framework for using wearables for personalised prevention of liver diseases.
Keywords: Accelerometer; CLD, chronic liver disease; DM, diabetes mellitus; HR, hazard ratio; ICD-10, International Classification of Diseases 10th edition; Liver disease progression; Liver-related death; MET, metabolic equivalent of task; MRI, magnetic resonance imaging; NAFLD; NAFLD, non-alcoholic fatty liver disease; OR, odds ratio; Survival.

Coffee Consumption and the Risk of All-Cause and Cause-Specific Mortality in the Korean Population.
Kim SA, Tan LJ, Shin S.
J Acad Nutr Diet. 2021 Apr 21:S2212-2672(21)00225-2. doi: 10.1016/j.jand.2021.03.014. Online ahead of print.
PMID: 33895098
Background: There is a dearth of information regarding the association between coffee consumption and its health effects with respect to mortality among Korean people.
Objective: The aim of this study was to examine the association between coffee consumption and all-cause mortality and cause-specific mortality risks in the Korean population.
Design: This prospective cohort study had a median follow-up period of 9.1 years.
Participants/setting: In total, 173,209 participants aged 40 years and older from the Health Examinees study were enrolled between 2004 and 2013. The analytic sample included 110,920 participants without diabetes, cardiovascular disease (CVD), or cancer at baseline who could be linked with their death information.
Main outcome measures: Deaths of participants until December 31, 2018 were ascertained using the death certificate database of the National Statistical Office. Cause of death was classified according to the International Classification of Diseases, 10th Revision.
Statistical analyses performed: Participants were categorized according to the amount and type of coffee consumed. Cox proportional hazards regression analysis was performed to estimate the hazard ratio (HR) and 95%CI of all-cause mortality and cause-specific mortality, such as CVD and cancer mortality.
Results: Compared with nonconsumers of coffee, participants who consumed > 3 cups/day had a reduced risk of all-cause mortality (HR 0.79, 95% CI 0.66 to 0.95). Participants who consumed ≤1 cup/day and 1 to 3 cups/day had a reduced risk of CVD mortality (≤1 cup/day: HR 0.58, 95% CI 0.69 to 0.94; 1 to 3 cups/day: HR 0.62, 95% CI 0.41 to 0.96).
Conclusions: This study provides evidence that greater coffee consumption is associated with a decreased risk of all-cause mortality and moderate coffee consumption (approximately 3 cups/day) is associated with a decreased risk of CVD mortality, regardless of the type of coffee, in a Korean population.
Keywords: 3-in-1 coffee; Black coffee; Cardiovascular disease; Coffee; Mortality.

Protective Effects of N(1)-Methylnicotinamide Against High-Fat Diet- and Age-Induced Hearing Loss via Moderate Overexpression of Sirtuin 1 Protein.
Miwa T.
Front Cell Neurosci. 2021 Apr 6;15:634868. doi: 10.3389/fncel.2021.634868. eCollection 2021.
PMID: 33889076 Free PMC article.
Age-related hearing loss (ARHL) is the most common form of hearing loss and the predominant neurodegenerative disease associated with aging. Sirtuin 1 (SIRT1) is associated with the most complex physiological processes, including metabolism, cancer onset, and aging. SIRT1 protein levels are enhanced by the conversion of nicotinamide to N1-methylnicotinamide (MNAM), independent of its mRNA levels. Moreover, MNAM has implications in increased longevity achieved through its mitohormetic effects. Nicotinamide N-methyltransferase (Nnmt) is an enzyme involved in MNAM metabolism, and its level increases under caloric restriction (CR) conditions. The CR condition has implications in delaying ARHL onset. In this study, we aimed to determine the relationship between diet, hearing function, SIRT1 and SIRT3 expression levels in the inner ear, and cochlear morphology. Mice fed with a high-fat diet (HFD), HFD + 1% MNAM, and low-fat diet (LFD) were monitored for age-related auditory-evoked brainstem responses, and changes in cochlear histology, metabolism, and protein and mRNA expressions were analyzed. Our results revealed that the HFD- and aging-mediated downregulated expression of SIRT1 and SIRT3 promoted hearing loss that was obfuscated by MNAM supplementation-induced upregulated expression of cochlear SIRT1 and SIRT3. Thus, our results suggest that MNAM can be used as a therapeutic agent for preventing ARHL.
Keywords: N1-methylnicotinamide; auditory brain stem responses; hearing loss; high-fat diet; sirtuin 1.

mTOR attenuation with rapamycin reverses neurovascular uncoupling and memory deficits in mice modeling Alzheimer's disease.
Van Skike CE, Hussong SA, Hernandez SF, Banh AQ, DeRosa N, Galvan V.
J Neurosci. 2021 Apr 20:JN-RM-2144-20. doi: 10.1523/JNEUROSCI.2144-20.2021. Online ahead of print.
PMID: 33888602
Vascular dysfunction is a universal feature of aging and decreased cerebral blood flow has been identified as an early event in the pathogenesis of Alzheimer's disease (AD). Cerebrovascular dysfunction in AD includes deficits in neurovascular coupling, a mechanism that ensures rapid delivery of energy substrates to active neurons through the blood supply. The mechanisms underlying NVC impairment in AD, however, are not well understood. We have previously shown that mechanistic/mammalian target of rapamycin (mTOR) drives cerebrovascular dysfunction in models of AD by reducing the activity of endothelial nitric oxide synthase (eNOS), and that attenuation of mTOR activity with rapamycin is sufficient to restore eNOS-dependent cerebrovascular function. Here we show mTOR drives NVC impairments in an AD model through the inhibition of neuronal NOS and non-NOS dependent components of NVC, and that mTOR attenuation with rapamycin is sufficient to restore NVC and even enhance it above WT responses. Restoration of NVC and concomitant reduction cortical amyloid-beta levels effectively treated memory deficits in 12-month-old hAPP(J20) mice. These data indicate mTOR is a critical driver of NVC dysfunction and underlies cognitive impairment in an AD model. Together with our previous findings, the present studies suggest that mTOR promotes cerebrovascular dysfunction in AD, which is associated with early disruption of nNOS activation, through its broad negative impact on nNOS as well as on non-NOS components of NVC. Our studies highlight the potential of mTOR attenuation as an efficacious treatment for AD and potentially other neurological diseases of aging.SIGNIFICANCE STATEMENT:Failure of the blood flow response to neuronal activation (neurovascular coupling, NVC) in a model of AD precedes the onset of AD-like cognitive symptoms and is driven, to a large extent, by mTOR-dependent inhibition of nitric oxide synthase activity. Our studies show that mTOR also drives AD-like failure of non-NO-mediated components of NVC, and importantly that it suppresses NVC in non-diseased animals. Thus, mTOR attenuation may serve to treat AD, where we find that nNOS is profoundly reduced early in disease progression, and potentially other neurological diseases of aging with cerebrovascular dysfunction as part of their etiology. Our studies also provide, to our knowledge, the first evidence for a role of mTOR in regulating NVC in non-diseased conditions in mice.

Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies.
Harris WS, Tintle NL, Imamura F, Qian F, Korat AVA, Marklund M, Djoussé L, Bassett JK, Carmichael PH, Chen YY, Hirakawa Y, Küpers LK, Laguzzi F, Lankinen M, Murphy RA, Samieri C, Senn MK, Shi P, Virtanen JK, Brouwer IA, Chien KL, Eiriksdottir G, Forouhi NG, Geleijnse JM, Giles GG, Gudnason V, Helmer C, Hodge A, Jackson R, Khaw KT, Laakso M, Lai H, Laurin D, Leander K, Lindsay J, Micha R, Mursu J, Ninomiya T, Post W, Psaty BM, Risérus U, Robinson JG, Shadyab AH, Snetselaar L, Sala-Vila A, Sun Y, Steffen LM, Tsai MY, Wareham NJ, Wood AC, Wu JHY, Hu F, Sun Q, Siscovick DS, Lemaitre RN, Mozaffarian D; Fatty Acids and Outcomes Research Consortium (FORCE).
Nat Commun. 2021 Apr 22;12(1):2329. doi: 10.1038/s41467-021-22370-2.
PMID: 33888689
The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.

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Occupational physical activity and longevity in working men and women in Norway: a prospective cohort study.
Dalene KE, Tarp J, Selmer RM, Ariansen IKH, Nystad W, Coenen P, Anderssen SA, Steene-Johannessen J, Ekelund U.
Lancet Public Health. 2021 Apr 28:S2468-2667(21)00032-3. doi: 10.1016/S2468-2667(21)00032-3. Online ahead of print.
PMID: 33932334
Background: Studies suggest that high occupational physical activity increases mortality risk. However, it is unclear whether this association is causal or can be explained by a complex network of socioeconomic and behavioural factors. We aimed to examine the association between occupational physical activity and longevity, taking a complex network of confounding variables into account.
Methods: In this prospective cohort study, we linked data from Norwegian population-based health examination surveys, covering all parts of Norway with data from the National Population and Housing Censuses and the Norwegian Cause of Death Registry. 437 378 participants (aged 18-65 years; 48·7% men) self-reported occupational physical activity (mutually exclusive groups: sedentary, walking, walking and lifting, and heavy labour) and were followed up from study entry (between February, 1974, and November, 2002) to death or end of follow-up on Dec 31, 2018, whichever came first. We estimated differences in survival time (death from all causes, cardiovascular disease, and cancer) between occupational physical activity categories using flexible parametric survival models adjusted for confounding factors.
Findings: During a median of 28 years (IQR 25-31) from study entry to the end of follow-up, 74 203 (17·0%) of the participants died (all-cause mortality), of which 20 111 (27·1%) of the deaths were due to cardiovascular disease and 29 886 (40·3%) were due to cancer. Crude modelling indicated shorter mean survival times among men in physically active occupations than in those with sedentary occupations. However, this finding was reversed following adjustment for confounding factors (birth cohort, education, income, ethnicity, prevalent cardiovascular disease, smoking, leisure-time physical activity, body-mass index), with estimates suggesting that men in occupations characterised by walking, walking and lifting, and heavy labour had life expectancies equivalent to 0·4 (95% CI -0·1 to 1·0), 0·8 (0·3 to 1·3), and 1·7 (1·2 to 2·3) years longer, respectively, than men in the sedentary referent category. Results for mortality from cardiovascular disease and cancer showed a similar pattern. No clear differences in survival times were observed between occupational physical activity groups in women.
Interpretation: Our results suggest that moderate to high occupational physical activity contributes to longevity in men. However, occupational physical activity does not seem to affect longevity in women. These results might inform future physical activity guidelines for public health.

Egg consumption, overall diet quality, and risk of type 2 diabetes and coronary heart disease: A pooling project of US prospective cohorts.
Djoussé L, Zhou G, McClelland RL, Ma N, Zhou X, Kabagambe EK, Talegawkar SA, Judd SE, Biggs ML, Fitzpatrick AL, Clark CR, Gagnon DR, Steffen LM, Gaziano JM, Lee IM, Buring JE, Manson JE.
Clin Nutr. 2021 Mar 11;40(5):2475-2482. doi: 10.1016/j.clnu.2021.03.003. Online ahead of print.
PMID: 33932789
Background and aims: Data on the relation of egg consumption with risk of type 2 diabetes (T2D) and coronary heart disease (CHD) are limited and inconsistent. Few studies have controlled for overall dietary patterns in egg-T2D or egg-CHD analyses, and it is unclear whether any observed elevated risks of T2D and CHD with frequent egg consumption is real or due to confounding by dietary habits. We tested the hypothesis that frequent egg consumption is associated with a higher risk of T2D and CHD risk after adjustment for overall dietary patterns among adults.
Design: We used prospective cohort design to complete time-to-event analyses.
Methods: We pooled de novo, harmonized, individual-level analyses from nine US cohorts (n = 103,811). Cox regression was used to estimate hazard ratios separately in each cohort adjusting for age, ethnicity, body mass index (BMI), exercise, smoking, alcohol intake, and dietary patterns. We pooled cohort-specific results using an inverse-variance weighted method to estimate summary relative risks.
Results: Median age ranged from 25 to 72 years. Median egg consumption was 1 egg per week in most of the cohorts. While egg consumption up to one per week was not associated with T2D risk, consumption of ≥2 eggs per week was associated with elevated risk [27% elevated risk of T2D comparing 7+ eggs/week with none (95% CI: 16%-37%)]. There was little evidence for heterogeneity across cohorts and we observed similar conclusions when stratified by BMI. Overall, egg consumption was not associated with the risk of CHD. However, in a sensitivity analysis, there was a 30% higher risk of CHD (95% CI: 3%-56%) restricted to older adults consuming 5-6 eggs/week.
Conclusions: Our data showed an elevated risk of T2D with egg consumption of ≥2 eggs per week but not with <2 eggs/week. While there was no overall association of egg consumption with CHD risk, the elevated CHD observed with consumption of 5-6 eggs/week in older cohorts merits further investigation.
Keywords: CHD; Diet quality; Epidemiology; Nutrition; Type 2 diabetes.

Adiponectin preserves metabolic fitness during aging.
Li N, Zhao S, Zhang Z, Zhu Y, Gliniak CM, Vishvanath L, An YA, Wang MY, Deng Y, Zhu Q, Shan B, Sherwood A, Onodera T, Oz OK, Gordillo R, Gupta RK, Liu M, Horvath TL, Dixit VD, Scherer PE.
Elife. 2021 Apr 27;10:e65108. doi: 10.7554/eLife.65108. Online ahead of print.
PMID: 33904399
Adiponectin is essential for the regulation of tissue substrate utilization and systemic insulin sensitivity. Clinical studies have suggested a positive association of circulating adiponectin with healthspan and lifespan. However, the direct effects of adiponectin on promoting healthspan and lifespan remain unexplored. Here, we are using an adiponectin null mouse and a transgenic adiponectin overexpression model. We directly assessed the effects of circulating adiponectin on the aging process and found that adiponectin null mice display exacerbated age-related glucose and lipid metabolism disorders. Moreover, adiponectin null mice have a significantly shortened lifespan on both chow and high-fat diet (HFD). In contrast, a transgenic mouse model with elevated circulating adiponectin levels has a dramatically improved systemic insulin sensitivity, reduced age-related tissue inflammation and fibrosis, and a prolonged healthspan and median lifespan. These results support a role of adiponectin as an essential regulator for healthspan and lifespan.
Keywords: cell biology; mouse.

Physical activity and all-cause mortality and mediators of the association in the very old.
Osawa Y, Abe Y, Takayama M, Oguma Y, Arai Y.
Exp Gerontol. 2021 Apr 24:111374. doi: 10.1016/j.exger.2021.111374. Online ahead of print.
PMID: 33905878
Background and objective: Physical activity (PA) confers protection to individuals from the risk of death. However, in the very old, the dose-response relationship between PA and all-cause mortality and the possible biological mediators of this association are less known. We investigated whether PA predicts 6-year all-cause mortality and what biomarkers mediate the association.
Design: Prospective cohort data from the Tokyo Oldest Old Survey on Total Health study.
Setting: Community-dwelling population.
Participants: A total of 441 women and men aged over 85 years.
Measurements: Questionnaire-based PA was assessed at baseline and 3-year and 6-year follow-up visits. Survival status was confirmed up to the 6-year follow-up visit (153 deaths, 34.7%). Data of plasma albumin, cholinesterase, NT-proBNP, interleukin-6, cystatin C, and HbA1c levels were collected. For mediation analysis for survival analysis, we used the baseline PA and biomarkers with Weibull distribution accelerated failure time model and linear regression model adjusted for age, sex, body mass index, smoking, education level, and Mini-Mental State Examination.
Results: A curvilinear relationship was observed in the association between baseline PA and all-cause mortality. Compared to the inactive (0 METs*h/week), light amount of PA was associated with a lower risk of mortality. Compared to the highest tertile of PA (11.2 METs*h/week), higher PA did not reduce the risk of death. Circulation levels of albumin and cholinesterase mediated the association between baseline PA and all-cause mortality (proportion mediated, 54%, both; p < 0.05).
Conclusions: Compared to completely inactive, light PA reduces the risk of all-cause mortality in the very old population. Mediation analysis suggests that protein synthesis in the liver may mediate the association between PA and all-cause mortality. Further studies are needed to understand the underlying association between PA, nutrition, and death.
Keywords: Albumin; Cholinesterase; Death; Exercises.

Association of sleep duration in middle and old age with incidence of dementia.
Sabia S, Fayosse A, Dumurgier J, van Hees VT, Paquet C, Sommerlad A, Kivimäki M, Dugravot A, Singh-Manoux A.
Nat Commun. 2021 Apr 20;12(1):2289. doi: 10.1038/s41467-021-22354-2.
PMID: 33879784 Free article.
Sleep dysregulation is a feature of dementia but it remains unclear whether sleep duration prior to old age is associated with dementia incidence. Using data from 7959 participants of the Whitehall II study, we examined the association between sleep duration and incidence of dementia (521 diagnosed cases) using a 25-year follow-up. Here we report higher dementia risk associated with a sleep duration of six hours or less at age 50 and 60, compared with a normal (7 h) sleep duration, although this was imprecisely estimated for sleep duration at age 70 (hazard ratios (HR) 1.22 (95% confidence interval 1.01-1.48), 1.37 (1.10-1.72), and 1.24 (0.98-1.57), respectively). Persistent short sleep duration at age 50, 60, and 70 compared to persistent normal sleep duration was also associated with a 30% increased dementia risk independently of sociodemographic, behavioural, cardiometabolic, and mental health factors. These findings suggest that short sleep duration in midlife is associated with an increased risk of late-onset dementia.

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Predictive value of attended automated office blood pressure and resting pulse rate for mortality in community-dwelling octogenarians: Minhang study.
Wang Y, Chen L, Cheng M, Wang Y, An D, Cai E, Wang Y, Zhang J, Tang X, Li Y, Zhu D.
J Clin Hypertens (Greenwich). 2021 May 5. doi: 10.1111/jch.14251. Online ahead of print.
PMID: 33949090
Systolic blood pressure (SBP) and resting pulse rate (RPR) have been linked to mortality and cardiovascular events in younger population. Till now, no studies simultaneously investigate the non-linear association of SBP and RPR with all-cause and cardiovascular mortality among population aged 80 and older. Data of 2828 eligible participants were selected from electronic health records linked attended automated office blood pressure measurement system. The dose-response relationship between the SBP, RPR, and the risk of all-cause and cardiovascular mortality was analyzed by Cox model with restricted cubic splines. During the 3.6-year follow-up, 442 deaths occurred. Comparing with the optimal SBP (117-145 mmHg), the lower (HR: 1.39, 95% CI: 1.07-1.81) and higher SBP (HR: 1.34, 95% CI: 1.08-1.65) were significantly associated with an increasing risk of all-cause mortality. The higher SBP (>144 mmHg) was associated with cardiovascular mortality, with the HR (95% CI) as 1.51 (1.07-2.12). The faster RPR showed the higher risk of all-cause (HR: 1.36, 95% CI: 1.05-1.76) and cardiovascular (HR: 1.51, 95% CI: 1.07-2.13) mortality. We found both higher SBP and faster RPR were independently associated with all-cause and cardiovascular mortality, and lower SBP was only associated with the increased risk of all-cause mortality in oldest old community-dwelling Chinese population. Our results demonstrate the prognostic importance of both SBP and RPR in the elderly.
Keywords: all-cause mortality; cardiovascular mortality; old elders; resting pulse rate; systolic blood pressure.

Effect of longevity genetic variants on the molecular aging rate.
Gurinovich A, Song Z, Zhang W, Federico A, Monti S, Andersen SL, Jennings LL, Glass DJ, Barzilai N, Millman S, Perls TT, Sebastiani P.
Geroscience. 2021 May 4. doi: 10.1007/s11357-021-00376-4. Online ahead of print.
PMID: 33948810
We conducted a genome-wide association study of 1320 centenarians from the New England Centenarian Study (median age = 104 years) and 2899 unrelated controls using >9 M genetic variants imputed to the HRC panel of ~65,000 haplotypes. The genetic variants with the most significant associations were correlated to 4131 proteins that were profiled in the serum of a subset of 224 study participants using a SOMAscan array. The genetic associations were replicated in a genome-wide association study of 480 centenarians and ~800 controls of Ashkenazi Jewish descent. The proteomic associations were replicated in a proteomic scan of approximately 1000 Ashkenazi Jewish participants from a third cohort. The analysis replicated a protein signature associated with APOE genotypes and confirmed strong overexpression of BIRC2 (p < 5E-16) and under-expression of APOB in carriers of the APOE2 allele (p < 0.05). The analysis also discovered and replicated associations between longevity variants and slower changes of protein biomarkers of aging, including a novel protein signature of rs2184061 (CDKN2A/CDKN2B in chromosome 9) that suggests a genetic regulation of GDF15. The analyses showed that longevity variants correlate with proteome signatures that could be manipulated to discover healthy-aging targets.
Keywords: Extreme human longevity; Genetic variants; Molecular aging rate; SOMAscan array.

Myostatin Inhibition-Induced Increase in Muscle Mass and Strength Was Amplified by Resistance Exercise Training, and Dietary Essential Amino Acids Improved Muscle Quality in Mice.
Jang J, Park S, Kim Y, Jung J, Lee J, Chang Y, Lee SP, Park BC, Wolfe RR, Choi CS, Kim IY.
Nutrients. 2021 Apr 29;13(5):1508. doi: 10.3390/nu13051508.
PMID: 33947024
It has been frequently reported that myostatin inhibition increases muscle mass, but decreases muscle quality (i.e., strength/muscle mass). Resistance exercise training (RT) and essential amino acids (EAAs) are potent anabolic stimuli that synergistically increase muscle mass through changes in muscle protein turnover. In addition, EAAs are known to stimulate mitochondrial biogenesis. We have investigated if RT amplifies the anabolic potential of myostatin inhibition while EAAs enhance muscle quality through stimulations of mitochondrial biogenesis and/or muscle protein turnover. Mice were assigned into ACV (myostatin inhibitor), ACV+EAA, ACV+RT, ACV+EAA +RT, or control (CON) over 4 weeks. RT, but not EAA, increased muscle mass above ACV. Despite differences in muscle mass gain, myofibrillar protein synthesis was stimulated similarly in all vs. CON, suggesting a role for changes in protein breakdown in muscle mass gains. There were increases in MyoD expression but decreases in Atrogin-1/MAFbx expression in ACV+EAA, ACV+RT, and ACV+EAA+RT vs. CON. EAA increased muscle quality (e.g., grip strength and maximal carrying load) without corresponding changes in markers of mitochondrial biogenesis and neuromuscular junction stability. In conclusion, RT amplifies muscle mass and strength through changes in muscle protein turnover in conjunction with changes in implicated signaling, while EAAs enhance muscle quality through unknown mechanisms.
Keywords: deuterium oxide; essential amino acids; mass spectrometry; protein turnover; resistance exercise training; soluble activin receptor type IIB.

Dietary Micronutrients and Risk of Chronic Kidney Disease: A Cohort Study with 12 Year Follow-Up.
Lee J, Oh KH, Park SK.
Nutrients. 2021 Apr 30;13(5):1517. doi: 10.3390/nu13051517.
PMID: 33946331
We investigated the association between dietary micronutrient intakes and the risk of chronic kidney disease (CKD) in the Ansan-Ansung study of the Korean Genome and Epidemiologic Study (KoGES), a population-based prospective cohort study. Of 9079 cohort participants with a baseline estimate glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and a urine albumin to creatinine ratio (UACR) <300 mg/g and who were not diagnosed with CKD, we ascertained 1392 new CKD cases over 12 year follow-up periods. The risk of CKD according to dietary micronutrient intakes was presented using hazard ratios (HRs) and 95% confidence intervals (95% CIs) in a full multivariable Cox proportional hazard models, adjusted for multiple micronutrients and important clinico-epidemiological risk factors. Low dietary intakes of phosphorus (<400 mg/day), vitamin B2 (<0.7 mg/day) and high dietary intake of vitamin B6 (≥1.6 mg/day) and C (≥100 mg/day) were associated with an increased risk of CKD stage 3B and over, compared with the intake at recommended levels (HR = 6.78 [95%CI = 2.18-21.11]; HR = 2.90 [95%CI = 1.01-8.33]; HR = 2.71 [95%CI = 1.26-5.81]; HR = 1.83 [95%CI = 1.00-3.33], respectively). In the restricted population, excluding new CKD cases defined within 2 years, an additional association with low folate levels (<100 µg/day) in higher risk of CKD stage 3B and over was observed (HR = 6.72 [95%CI = 1.40-32.16]). None of the micronutrients showed a significant association with the risk of developing CKD stage 3A. Adequate intake of micronutrients may lower the risk of CKD stage 3B and over, suggesting that dietary guidelines are needed in the general population to prevent CKD.
Keywords: chronic kidney disease; micronutrient; minerals intake; vitamins intake.

Whole-genome sequencing analysis of semi-supercentenarians.
Garagnani P, Marquis J, Delledonne M, Pirazzini C, Marasco E, Kwiatkowska KM, Iannuzzi V, Bacalini MG, Valsesia A, Carayol J, Raymond F, Ferrarini A, Xumerle L, Collino S, Mari D, Arosio B, Casati M, Ferri E, Monti D, Nacmias B, Sorbi S, Luiselli D, Pettener D, Castellani G, Sala C, Passarino G, De Rango F, D'Aquila P, Bertamini L, Martinelli N, Girelli D, Olivieri O, Giuliani C, Descombes P, Franceschi C.
Elife. 2021 May 4;10:e57849. doi: 10.7554/eLife.57849.
PMID: 33941312
Extreme longevity is the paradigm of healthy aging as individuals who reached the extreme decades of human life avoided or largely postponed all major age-related diseases. In this study, we sequenced at high coverage (90X) the whole genome of 81 semi-supercentenarians and supercentenarians [105+/110+] (mean age: 106.6 ± 1.6) and of 36 healthy unrelated geographically matched controls (mean age 68.0 ± 5.9) recruited in Italy. The results showed that 105+/110+ are characterized by a peculiar genetic background associated with efficient DNA repair mechanisms, as evidenced by both germline data (common and rare variants) and somatic mutations patterns (lower mutation load if compared to younger healthy controls). Results were replicated in a second independent cohort of 333 Italian centenarians and 358 geographically matched controls. The genetics of 105+/110+ identified DNA repair and clonal haematopoiesis as crucial players for healthy aging and for the protection from cardiovascular events.
Keywords: ageing; clonal hematopoiesis; genetics; genomics; geroscience; human; longevity; semi-supercentenarians; sequencing.

Interaction between APOE epsilon4 and dietary protein intake on cognitive decline: A longitudinal cohort study.
Zhang Y, Jin X, Lutz MW, Ju SY, Liu K, Guo G, Zeng Y, Yao Y.
Clin Nutr. 2021 Mar 16;40(5):2716-2725. doi: 10.1016/j.clnu.2021.03.004. Online ahead of print.
PMID: 33933737
Objective: To exam the association of cognitive decline with APOE ε4 allele carriage and dietary protein intake and investigate whether there is a gene-diet (GxD) interaction of APOE ε4 allele carriage and dietary protein intake on cognitive decline in a nationwide cohort of older adults.
Methods: A cohort study of participants from Chinese Longitudinal Healthy Longevity Survey was conducted from 2008 to 2014. A total of 3029 participants (mean age of 77.0 years, SD = 9.0; 49.3% were women) was enrolled. We genotyped APOE ε4 allele for each participant and calculated the diversity of dietary protein intake (DDPI) by summing up the frequency of intake of the 6 protein-rich foods (meats, fish, eggs, nuts, dairy products, and bean products). We assessed cognitive function using the Mini-Mental State Examination (MMSE). We used ordinal regression model to estimate the independent and joint effects of APOE ε4 carrier and dietary protein intake on cognitive decline, adjusting for potential confounders of age, sex, education, socio-economic status, lifestyles, BMI, and cardiometabolic conditions.
Results: There was significant association between carrying APOE ε4 allele and faster cognitive decline (Odds ratio: 1.19, 95% CI = 1.00-1.42), independent of potential confounders. While the associations of DDPI and the intake of 6 protein-rich foods with cognitive decline did not reach any statistical significance. We observed significant interactions of APOE ε4 with DDPI and fish intake, at multiple correction-adjusted Ps < 0.05. In those who were APOE ε4 carriers rather than non-carriers, both high DDPI (OR = 0.54, 95% CI: 0.34-0.88) and daily fish intake (OR = 0.43, 95% CI: 0.22-0.78) were significantly associated with slower cognitive decline, respectively. We also found that frequent intake of fish benefits women more than men regarding the mitigating of cognitive decline among APOE ε4 allele carriers (P for interaction = 0.016).
Conclusions: The results of this study support the hypothesis that diversified protein food intake in addition to frequent fish intake may reduce the detrimental effect of APOE ε4 on cognitive health.
Keywords: APOE; Cognitive decline; Fish intake; Gender differences; Gene-diet interaction; Protein-rich diet.

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Blood-based biomarkers and long-term risk of frailty - experience from the Swedish AMORIS cohort.
Wennberg AM, Ding M, Ebeling M, Hammar N, Modig K.
J Gerontol A Biol Sci Med Sci. 2021 May 12:glab137. doi: 10.1093/gerona/glab137. Online ahead of print.
PMID: 33979435
Background: Frailty is associated with reduced quality of life, poor health outcomes, and death. Past studies have investigated how specific biomarkers are associated with frailty but understanding biomarkers in concert with each other and the associated risk of frailty is critical for clinical application.
Methods: Using a sample aged ≥59 years at baseline from the Swedish AMORIS cohort (n=19341), with biomarkers measured at baseline (1985-1996), we conducted latent class analysis with 18 biomarkers and used Cox models to determine the association between class and frailty and all-cause mortality.
Results: Four classes were identified. Compared to the largest class, the Reference class (81.7%), all other classes were associated with increased risk of both frailty and mortality. The Anemia class (5.8%), characterized by comparatively lower iron markers and higher inflammatory markers, had HR=1.54, 95% CI 1.38, 1.73 for frailty and HR=1.76, 95% CI 1.65, 1.87 for mortality. The Diabetes class (6.5%) was characterized by higher glucose and fructosamine, and had HR=1.59, 95% CI 1.43, 1.77 for frailty and HR=1.74, 95% CI 1.64, 1.85 for mortality. Finally, the Liver class (6.0%), characterized by higher liver enzyme levels, had HR=1.15, 95% CI 1.01, 1.30 for frailty and HR=1.40, 95% CI 1.31, 1.50 for mortality. Sex-stratified analyses did not show any substantial differences between men and women.
Conclusions: Distinct sets of commonly available biomarkers were associated with development of frailty and monitoring these biomarkers in patients may allow for earlier detection and possible prevention of frailty, with the potential for improved quality of life.
Keywords: death; frail; longitudinal; population-based.

Energy and macronutrient intakes at breakfast and cognitive declines in community-dwelling older adults: a 9-year follow-up cohort study.
Shang X, Hill E, Li Y, He M.
Am J Clin Nutr. 2021 May 8;113(5):1093-1103. doi: 10.1093/ajcn/nqaa403.
PMID: 33675345
Background: It is unclear whether breakfast consumption and breakfast composition are independently associated with changes in cognition over a long-term period in older adults.
Objectives: We aimed to examine the associations between energy and macronutrient intakes at breakfast and cognitive declines.
Methods: We included 2935 participants aged 55-93 y at baseline from the China Health and Nutrition Survey in our analysis. Cognition was assessed in 1997, 2000, 2004, 2006, and 2015. Dietary intake was assessed using weighing methods in combination with 24-h food records.
Results: Breakfast contributed to 25.9% of total energy intake of the day and percentages of breakfast energy intake from protein, fat, and carbohydrates were 12.8%, 11.5%, and 75.7%, respectively. During a median follow-up of 9 y, the β values for changes in global cognitive z-scores for Quintile 5 of protein and fat intakes at breakfast, with Quintile 1 as the reference, were 0.13 (95% CI: 0.01-0.25) and 0.17 (95% CI: 0.04-0.30), respectively. Substitution of 5% energy from carbohydrates with equivalent energy from protein (β, 0.06; 95% CI: 0.01-0.11) or fat (β, 0.05; 95% CI: 0.02-0.08) at breakfast was positively associated with the change in the global cognitive z-score. Energy intake at breakfast was not significantly associated with the global cognitive z-score. Similar results were found for the verbal memory z-score. The positive association of breakfast fat intake and the inverse association of breakfast carbohydrate intake with cognitive declines were stronger in urban residents.
Conclusions: Higher intakes of protein and fat and lower intake of carbohydrates at breakfast were associated with a lower rate of cognitive decline in older adults. Substitution of carbohydrates with protein or fat intake at breakfast may help to delay or prevent cognitive declines.
Keywords: breakfast; cognitive decline; dietary carbohydrates; dietary fat; dietary protein; energy.

Excessive Unbalanced Meat Consumption in the First Year of Life Increases Asthma Risk in the PASTURE and LUKAS2 Birth Cohorts.
Hose AJ, Pagani G, Karvonen AM, Kirjavainen PV, Roduit C, Genuneit J, Schmaußer-Hechfellner E, Depner M, Frei R, Lauener R, Riedler J, Schaub B, Fuchs O, von Mutius E, Divaret-Chauveau A, Pekkanen J, Ege MJ.
Front Immunol. 2021 Apr 27;12:651709. doi: 10.3389/fimmu.2021.651709. eCollection 2021.
PMID: 33986744 Free PMC article.
A higher diversity of food items introduced in the first year of life has been inversely related to subsequent development of asthma. In the current analysis, we applied latent class analysis (LCA) to systematically assess feeding patterns and to relate them to asthma risk at school age. PASTURE (N=1133) and LUKAS2 (N=228) are prospective birth cohort studies designed to evaluate protective and risk factors for atopic diseases, including dietary patterns. Feeding practices were reported by parents in monthly diaries between the 4th and 12th month of life. For 17 common food items parents indicated frequency of feeding during the last 4 weeks in 4 categories. The resulting 153 ordinal variables were entered in a LCA. The intestinal microbiome was assessed at the age of 12 months by 16S rRNA sequencing. Data on feeding practice with at least one reported time point was available in 1042 of the 1133 recruited children. Best LCA model fit was achieved by the 4-class solution. One class showed an elevated risk of asthma at age 6 as compared to the other classes (adjusted odds ratio (aOR): 8.47, 95% CI 2.52-28.56, p = 0.001) and was characterized by daily meat consumption and rare consumption of milk and yoghurt. A refined LCA restricted to meat, milk, and yoghurt confirmed the asthma risk effect of a particular class in PASTURE and independently in LUKAS2, which we thus termed unbalanced meat consumption (UMC). The effect of UMC was particularly strong for non-atopic asthma and asthma irrespectively of early bronchitis (aOR: 17.0, 95% CI 5.2-56.1, p < 0.001). UMC fostered growth of iron scavenging bacteria such as Acinetobacter (aOR: 1.28, 95% CI 1.00-1.63, p = 0.048), which was also related to asthma (aOR: 1.55, 95% CI 1.18-2.03, p = 0.001). When reconstructing bacterial metabolic pathways from 16S rRNA sequencing data, biosynthesis of siderophore group nonribosomal peptides emerged as top hit (aOR: 1.58, 95% CI 1.13-2.19, p = 0.007). By a data-driven approach we found a pattern of overly meat consumption at the expense of other protein sources to confer risk of asthma. Microbiome analysis of fecal samples pointed towards overgrowth of iron-dependent bacteria and bacterial iron metabolism as a potential explanation.
Keywords: Infancy; asthma; cow's milk; gut microbiome; introduction of solid foods; latent class analysis; meat; nutritional immunity.

Dairy consumption and hepatocellular carcinoma risk.
Melnik BC.
Ann Transl Med. 2021 Apr;9(8):736. doi: 10.21037/atm-2020-ubih-06.
PMID: 33987434 Free PMC article. Review.
This review provides epidemiological and translational evidence for milk and dairy intake as critical risk factors in the pathogenesis of hepatocellular carcinoma (HCC). Large epidemiological studies in the United States and Europe identified total dairy, milk and butter intake with the exception of yogurt as independent risk factors of HCC. Enhanced activity of mechanistic target of rapamycin complex 1 (mTORC1) is a hallmark of HCC promoted by hepatitis B virus (HBV) and hepatitis C virus (HCV). mTORC1 is also activated by milk protein-induced synthesis of hepatic insulin-like growth factor 1 (IGF-1) and branched-chain amino acids (BCAAs), abundant constituents of milk proteins. Over the last decades, annual milk protein-derived BCAA intake increased 3 to 5 times in Western countries. In synergy with HBV- and HCV-induced secretion of hepatocyte-derived exosomes enriched in microRNA-21 (miR-21) and miR-155, exosomes of pasteurized milk as well deliver these oncogenic miRs to the human liver. Thus, milk exosomes operate in a comparable fashion to HBV- or HCV- induced exosomes. Milk-derived miRs synergistically enhance IGF-1-AKT-mTORC1 signaling and promote mTORC1-dependent translation, a meaningful mechanism during the postnatal growth phase, but a long-term adverse effect promoting the development of HCC. Both, dietary BCAA abundance combined with oncogenic milk exosome exposure persistently overstimulate hepatic mTORC1. Chronic alcohol consumption as well as type 2 diabetes mellitus (T2DM), two HCC-related conditions, increase BCAA plasma levels. In HCC, mTORC1 is further hyperactivated due to RAB1 mutations as well as impaired hepatic BCAA catabolism, a metabolic hallmark of T2DM. The potential HCC-preventive effect of yogurt may be caused by lactobacilli-mediated degradation of BCAAs, inhibition of branched-chain α-ketoacid dehydrogenase kinase via production of intestinal medium-chain fatty acids as well as degradation of milk exosomes including their oncogenic miRs. A restriction of total animal protein intake realized by a vegetable-based diet is recommended for the prevention of HCC.
Keywords: Branched-chain amino acids (BCAAs); dairy products; exosomal microRNAs; hepatocellular carcinoma (HCC); mechanistic target of rapamycin complex 1 (mTORC1).

Biomarkers representing key aging-related biological pathways are associated with subclinical atherosclerosis and all-cause mortality: The Framingham Study.
Castro-Diehl C, Ehrbar R, Obas V, Oh A, Vasan RS, Xanthakis V.
PLoS One. 2021 May 14;16(5):e0251308. doi: 10.1371/journal.pone.0251308. eCollection 2021.
PMID: 33989340
Background: Increased oxidative stress, leukocyte telomere length (LTL) shortening, endothelial dysfunction, and lower insulin-like growth factor (IGF)-1 concentrations reflect key molecular mechanisms of aging. We hypothesized that biomarkers representing these pathways are associated with measures of subclinical atherosclerosis and all-cause mortality.
Methods and results: We evaluated up to 2,314 Framingham Offspring Study participants (mean age 61 years, 55% women) with available biomarkers of aging: LTL, circulating concentrations of IGF-1, asymmetrical dimethylarginine (ADMA), and urinary F2-Isoprostanes indexed to urinary creatinine. We evaluated the association of each biomarker with coronary artery calcium [ln (CAC+1)] and carotid intima-media thickness (IMT). In multivariable-adjusted linear regression models, higher ADMA levels were associated with higher CAC values (βADMA per 1-SD increase 0.25; 95% confidence interval [CI] [0.11, 0.39]). Additionally, shorter LTL and lower IGF-1 values were associated with higher IMT values (βLTL -0.08, 95%CI -0.14, -0.02, and βIGF-1 -0.04, 95%CI -0.08, -0.01, respectively). During a median follow-up of 15.5 years, 593 subjects died. In multivariable-adjusted Cox regression models, LTL and IGF-1 values were inversely associated with all-cause mortality (hazard ratios {HR} per SD increase in biomarker, 0.85, 95% CI 0.74-0.99, and 0.90, 95% CI 0.82-0.98 for LTL and IGF-1, respectively). F2-Isoprostanes and ADMA values were positively associated with all-cause mortality (HR per SD increase in biomarker, 1.15, 95% CI, 1.10-1.22, and 1.10, 95% CI, 1.02-1.20, respectively).
Conclusion: In our prospective community-based study, aging-related biomarkers were associated with measures of subclinical atherosclerosis cross-sectionally and with all-cause mortality prospectively, supporting the concept that these biomarkers may reflect the aging process in community-dwelling adults.

Edited by AlPater
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Impaired fecundity as a marker of health and survival: a Danish twin cohort study.
Ahrenfeldt LJ, Möller S, Wensink MJ, Eisenberg ML, Christensen K, Jensen TK, Lindahl-Jacobsen R.
Hum Reprod. 2021 May 1:deab077. doi: 10.1093/humrep/deab077. Online ahead of print.
PMID: 34009293
Study question: Is fecundity, measured as self-reported time to first pregnancy (TTP), a marker for subsequent health and survival?
Summary answer: Long TTP was a marker for increased mortality among women and higher hospitalization rates for both women and men.
What is known already: Poor semen quality has been linked to increased mortality and morbidity from a wide range of diseases. Associations among fecundity, health and survival among women are still uncertain and studies on actual measures of fecundity and health outcomes are rare.
Study design, size, duration: We performed a prospective cohort study of 7825 women and 6279 men, aged 18 and above with measures on first TTP, who participated in one of the Danish nation-wide twin surveys in 1994 (twins born 1953-1976) and 1998 (twins born 1931-1952). They were followed-up for mortality and hospital admissions from the interview until 2018.
Participants/materials, setting, methods: Twins were identified in the Danish Twin Registry and linked to Danish registers. TTP was restricted to the first pregnancy as a categorical outcome with cut-off points at 2, 10 and 18 months. We analysed the association between TTP and survival using a Cox proportional hazards model estimating hazards ratios (HRs) with 95% confidence intervals (CIs). Fine-Gray survival models were used to estimate sub-hazard ratios for specific causes of death allowing for competing risks. Using negative binomial regression, we estimated incidence rate ratios (IRRs) with 95% CIs for all-cause and cause-specific hospitalizations. All analyses were stratified by sex and adjusted for age at interview, birth cohorts, age at first attempt to become pregnant, smoking, years in school and BMI.
Main results and the role of chance: In the total study population, 49.9% of women and 52.7% of men reported a TTP of less than 2 months, 30.8% of women and 29.6% of men reported a TTP of 2-9 months, 6.6% of women and 5.7% of men reported a TTP of 10-17 months, and 13.3% of women and 12.0% of men reported a TTP of 18 months or more. Among 1305 deaths, we found a higher mortality for women (HR = 1.46; 95% CI 1.15, 1.87) with a TTP of ≥18 months relative to those with a TTP of <2 months, while the highest mortality was indicated for men with a TTP of 10-17 months (HR = 1.31; 95% CI 0.98, 1.74). Among 53 799 hospitalizations, we found an increased hospitalization rate among women (HR = 1.21; 95% CI 1.0-1.41) and men (HR = 1.16; 95% CI 1.00-1.35) with a TTP of ≥18 months, and for men with a TTP of 2-9 months (HR = 1.14; 95% CI 1.01-1.30). A dose-response relationship was found for women regarding both mortality (P = 0.022) and hospitalizations (P = 0.018). Impaired fecundity was associated with a wide range of diseases and some causes of death, indicating a multi-factorial causal influence on fecundity, especially among women.
Limitations, reasons for caution: A major limitation was that fecundity depends on both partners, which was not considered in this study. Moreover, we could not obtain information on a number of potential confounders.
Wider implications of the findings: Fecundity seems positively correlated with overall health and may be a universal marker of future health and survival. These results add knowledge to the limited findings showing that reduced fecundity in women and poor semen quality in men may reflect worse health and a shorter life, particularly among women.
Keywords: hospitalization; infertility; mortality; subfertility; time to pregnancy.

Association between iron exposures and stroke in adults: Results from National Health and Nutrition Examination Survey during 2007-2016 in United States.
Xu J, Xu G, Fang J.
Int J Environ Health Res. 2021 May 18:1-10. doi: 10.1080/09603123.2021.1926440. Online ahead of print.
PMID: 34003723
The available findings on the association between iron status and risk of stroke remain controversial. We used multivariable logistic regression and restricted cubic spline models to explore the association between iron exposures and risk of stroke in the US National Health and Nutrition Examination Survey (NHANES 2007-2016, n = 24,627). A total of 941 (3.82%) stroke cases were identified in this study. In women, the ORs with 95% CIs of prevalence of stroke were 0.92 (0.65-1.28), 0.66 (0.44-0.98) and 0.72 (0.49-1.08) across quartiles 2-4 compared with quartile 1 of iron intake, respectively. An inverse and L-shaped association between iron intake and risk of stroke in women was observed, and the curve plateaued at 20 mg/day. However, neither serum iron concentrations nor iron intake were significantly associated with riskof stroke in men. Our study found that iron intake was inversely associated with risk of stroke in a sex-dependent fashion.
Keywords: Iron; National Health and Nutrition Examination Survey; diet; stroke.

Activation of GCN2 in macrophages promotes white adipose tissue browning and lipolysis under leucine deprivation.
Wang F, Xiao F, Du L, Niu Y, Yin H, Zhou Z, Jiang X, Jiang H, Yuan F, Liu K, Chen S, Duan S, Guo F.
FASEB J. 2021 Jun;35(6):e21652. doi: 10.1096/fj.202100061RR.
PMID: 34004054
We have previously shown that leucine deprivation stimulates browning and lipolysis in white adipose tissue (WAT), which helps to treat obesity. Adipose tissue macrophages (ATMs) significantly influence WAT browning and lipolysis. However, it is unclear whether ATMs are involved in leucine deprivation-induced browning and lipolysis in WAT; the associated signals remain to be elucidated. Here, we investigated the role of ATMs and the possible mechanisms involved in WAT browning and lipolysis under leucine-deprivation conditions. In this study, macrophages were depleted in mice by injecting clodronate-liposomes (CLOD) into subcutaneous white adipose tissues. Then, mice lacking general control nonderepressible 2 kinase (GCN2), which is a sensor of amino acid starvation, specifically in Lyz2-expressing cells, were generated to investigate the changes in leucine deprivation-induced WAT browning and lipolysis. We found leucine deprivation decreased the accumulation and changed the polarization of ATMs. Ablation of macrophages by CLOD impaired WAT browning and lipolysis under leucine-deprivation conditions. Mechanistically, leucine deprivation activated GCN2 signals in macrophages. Myeloid-specific abrogation of GCN2 in mice blocked leucine deprivation-induced browning and lipolysis in WAT. Further analyses revealed that GCN2 activation in macrophages reduced the expression of monoamine oxidase A (MAOA), resulting in increased norepinephrine (NE) secretion from macrophages to adipocytes, and this resulted in enhanced WAT browning and lipolysis. Moreover, the injection of CL316,243, a β3-adrenergic receptor agonist, and inhibition of MAOA effectively increased the level of NE, leading to the enhancement of browning and lipolysis of WAT in myeloid GCN2 knockout mice under leucine deprivation. Collectively, our results demonstrate a novel function of GCN2 signals in macrophages, that is, regulating WAT browning and lipolysis under leucine deprivation. Our study provides important hints for possible treatment for obesity.
Keywords: GCN2; leucine deprivation; lipolysis; macrophage; white adipose tissue browning.

Sarcopenia and mortality in different clinical conditions: A meta-analysis.
Koon-Yee Lee G, Chun-Ming Au P, Hoi-Yee Li G, Chan M, Li HL, Man-Yung Cheung B, Chi-Kei Wong I, Ho-Fun Lee V, Mok J, Hon-Kei Yip B, King-Yip Cheng K, Wu CH, Cheung CL.
Osteoporos Sarcopenia. 2021 Mar;7(Suppl 1):S19-S27. doi: 10.1016/j.afos.2021.02.001. Epub 2021 Mar 11.
PMID: 33997305 Free PMC article.
Objectives: Sarcopenia is recognized to be a health problem which is as serious as obesity, but its relevance to mortality is unclear. We conducted a meta-analysis of cohort studies on lean mass and mortality in populations with different health conditions.
Methods: In this study, a systematic search of PubMed, Cochrane Library and Embase was performed for cohort studies published before Dec 20, 2017 which examined the relationship between lean mass and mortality. We included studies reporting lean mass measurement by dual-energy X-ray absorptiometry, bioimpedance analysis or computed tomography, as continuous (per standard deviation [SD] decrease) or binary variables (using sarcopenia cutoffs). We excluded studies which used muscle mass surrogates, anthropometric measurement of muscle, rate of change in muscle mass, and sarcopenia defined by composite criteria. The primary study outcome was all-cause mortality. Pooled hazard ratio estimates were calculated using a random effects model.
Results: A total of 9602 articles were identified from the systematic search, and 188 studies with 98 468 participants from 34 countries were included in the meta-analysis. Of the 68 studies included in the present meta-analysis, the pooled HR was 1.36 and 1.74 for every SD decrease in lean mass and in people with low lean mass (cutoffs), respectively. Significant associations were also observed in elderly and all disease subgroups, irrespective of the measurement modalities.
Conclusions: Lower lean mass is robustly associated with increased mortality, regardless of health conditions and lean mass measurement modalities. This meta-analysis highlighted low lean mass as a key public health issue.
Keywords: Chronic diseases; Meta-analysis; Mortality; Sarcopenia; Systematic review.

Joint association between accelerometry-measured daily combination of time spent in physical activity, sedentary behaviour and sleep and all-cause mortality: a pooled analysis of six prospective cohorts using compositional analysis.
Chastin S, McGregor D, Palarea-Albaladejo J, Diaz KM, Hagströmer M, Hallal PC, van Hees VT, Hooker S, Howard VJ, Lee IM, von Rosen P, Sabia S, Shiroma EJ, Yerramalla MS, Dall P.
Br J Sports Med. 2021 May 18:bjsports-2020-102345. doi: 10.1136/bjsports-2020-102345. Online ahead of print.
PMID: 34006506
Objective: To examine the joint associations of daily time spent in different intensities of physical activity, sedentary behaviour and sleep with all-cause mortality.
ethods: Federated pooled analysis of six prospective cohorts with device-measured time spent in different intensities of physical activity, sedentary behaviour and sleep following a standardised compositional Cox regression analysis.
Participants: 130 239 people from general population samples of adults (average age 54 years) from the UK, USA and Sweden.
Main outcome: All-cause mortality (follow-up 4.3-14.5 years).
Results: Studies using wrist and hip accelerometer provided statistically different results (I2=92.2%, Q-test p<0.001). There was no association between duration of sleep and all-cause mortality, HR=0.96 (95% CI 0.67 to 1.12). The proportion of time spent in moderate to vigorous physical activity was significantly associated with lower risk of all-cause mortality (HR=0.63 (95% CI 0.55 to 0.71) wrist; HR=0.93 (95% CI 0.87 to 0.98) hip). A significant association for the ratio of time spent in light physical activity and sedentary time was only found in hip accelerometer-based studies (HR=0.5, 95% CI 0.42 to 0.62). In studies based on hip accelerometer, the association between moderate to vigorous physical activity and mortality was modified by the balance of time spent in light physical activity and sedentary time.
Conclusion: This federated analysis shows a joint dose-response association between the daily balance of time spent in physical activity of different intensities and sedentary behaviour with all-cause mortality, while sleep duration does not appear to be significant. The strongest association is with time spent in moderate to vigorous physical activity, but it is modified by the balance of time spent in light physical activity relative to sedentary behaviour.
Keywords: health; physical activity; sleep.

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