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  • Birthday 06/09/1947

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    Polyunsaturated fatty acids and p38-MAPK link metabolic reprogramming to cytoprotective gene expression during dietary restriction. Chamoli M, Goyala A, Tabrez SS, Siddiqui AA, Singh A, Antebi A, Lithgow GJ, Watts JL, Mukhopadhyay A. Nat Commun. 2020 Sep 25;11(1):4865. doi: 10.1038/s41467-020-18690-4. PMID: 32978396 https://www.nature.com/articles/s41467-020-18690-4.pdf Abstract The metabolic state of an organism instructs gene expression modalities, leading to changes in complex life history traits, such as longevity. Dietary restriction (DR), which positively affects health and life span across species, leads to metabolic reprogramming that enhances utilisation of fatty acids for energy generation. One direct consequence of this metabolic shift is the upregulation of cytoprotective (CyTP) genes categorized in the Gene Ontology (GO) term of "Xenobiotic Detoxification Program" (XDP). How an organism senses metabolic changes during nutritional stress to alter gene expression programs is less known. Here, using a genetic model of DR, we show that the levels of polyunsaturated fatty acids (PUFAs), especially linoleic acid (LA) and eicosapentaenoic acid (EPA), are increased following DR and these PUFAs are able to activate the CyTP genes. This activation of CyTP genes is mediated by the conserved p38 mitogen-activated protein kinase (p38-MAPK) pathway. Consequently, genes of the PUFA biosynthesis and p38-MAPK pathway are required for multiple paradigms of DR-mediated longevity, suggesting conservation of mechanism. Thus, our study shows that PUFAs and p38-MAPK pathway function downstream of DR to help communicate the metabolic state of an organism to regulate expression of CyTP genes, ensuring extended life span. Resemblance and differences in dietary restriction nephroprotective mechanisms in young and old rats. Andrianova NV, Zorova LD, Pevzner IB, Popkov VA, Chernikov VP, Silachev DN, Plotnikov EY, Zorov DB. Aging (Albany NY). 2020 Sep 24;12. doi: 10.18632/aging.103960. Online ahead of print. PMID: 32970613 https://paperchase-aging.s3-us-west-1.amazonaws.com/pdf/eYPXbdLKxHZT7JgwD.pdf Abstract Dietary restriction (DR) is the strategy ameliorating the morbidity of various pathologies, including age-associated diseases. Acute kidney injury (AKI) remains a problem for the elderly with DR being a promising approach for diminishing its consequences. We evaluated the possible nephroprotective potential of short-term DR in young and old rats. DR in young rats resulted in pronounced beneficial effects normalizing lipid metabolism (triglycerides concentration, adiponectin level) activating autophagic-lysosomal system evaluated by LC3II/LC3I ratio, LAMP1, p62/SQSTM1 levels, and LysoTracker Green staining. DR had a remarkable recovering effect on mitochondrial structure and functions including regaining of mitochondrial membrane potential, the elevation of SIRT-3, PGC-1α, Bcl-XL levels and partial restoration of ultrastructure. The beneficial effects of DR resulted in the mitigation of oxidative stress including a decrease in levels of protein carbonylation and lipid peroxidation. Aging led to decreased activity of autophagy, elevated oxidative stress and impaired kidney regenerative capacity. Eventually, in old rats, even 8-week DR was not able to ameliorate AKI, but it caused some rejuvenating effects including elevation of mitochondrial membrane potential and Bcl-XL levels, as well as lowered severity of the oxidative stress. Thus, the age-associated decline of protective signaling demands extended DR to achieve nephroprotective potential in old animals. Keywords: aging; caloric restriction; ischemia/reperfusion; kidney injury; mitochondria. "In addition, we estimated the intensity of lipid peroxidation ... revealed the decrease in ... DR rats, but only in young animals (Figure 6G)."
  2. Changes in Bone Turnover, Inflammatory, Oxidative Stress, and Metabolic Markers in Women Consuming Iron plus Vitamin D Supplements: a Randomized Clinical Trial. Abiri B, Vafa M, Azizi-Soleiman F, Safavi M, Kazemi SM, Salehi M, Zaeri F, Sadeghi H. Biol Trace Elem Res. 2020 Sep 25. doi: 10.1007/s12011-020-02400-8. Online ahead of print. PMID: 32975739 Abstract We aimed to investigate whether combination of vitamin D and iron supplementation, comparing vitamin D alone, could modify bone turnover, inflammatory, oxidative stress, and metabolic markers. Eighty-seven women with hemoglobin (Hb) ≤ 12.7 g/dL and 25OHD ≤ 29 ng/mL vitamin D deficiency/insufficiency aged 18-45 years were randomly assigned into two groups: (1) receiving either 1000 IU/day vitamin D3 plus 27 mg/day iron (D-Fe); (2) vitamin D3 plus placebo supplements (D-P), for 12 weeks. In D-Fe group, significant decrease in red blood cells (RBC) (P = 0.001) and hematocrit (Hct) (P = 0.004) and increases in mean corpuscular hemoglobin concentration (MCHC) (P = 0.001), 25OHD (P < 0.001), osteocalcin (P < 0.001), high-density cholesterol (HDL) (P = 0.041), and fasting blood sugar (FBS) (P < 0.001) were observed. D-P group showed significant decrease in RBC (P < 0.001), Hb (P < 0.001), Hct (P < 0.001), mean corpuscular volume (MCV) (P = 0.004), mean corpuscular hemoglobin (MCH) (P < 0.001), MCHC (P = 0.005), serum ferritin (P < 0.001), and low-density cholesterol (LDL) (P = 0.016) and increases of 25OHD (P < 0.001), osteocalcin (P < 0.001), C-terminal telopeptide (CTX) (P = 0.025), triglyceride (TG) (P = 0.004), FBS (P < 0.001), and interleukin-6 (IL-6) (P = 0.001) at week 12. After the intervention, the D-P group had between-group increases in mean change in the osteocalcin (P = 0.007) and IL-6 (P = 0.033), and decreases in the RBC (P < 0.001), Hb (P < 0.001), Hct (P < 0.001), and MCV (P = 0.001), compared with the D-Fe group. There were significant between-group changes in MCH (P < 0.001), MCHC (P < 0.001), ferritin (P < 0.001), and serum iron (P = 0.018). Iron-vitamin D co-supplementation does not yield added benefits for improvement of bone turnover, inflammatory, oxidative stress, and metabolic markers, whereas, vitamin D alone may have some detrimental effects on inflammatory and metabolic markers. IRCT registration number: IRCT201409082365N9. Keywords: Bone turnover; Inflammation; Iron; Oxidative stress; Vitamin D. Association Between Fasting Blood Glucose and All-Cause Mortality in a Rural Chinese Population: 15-Year Follow-Up Cohort Study. Cheng N, Zhang Y, Yang J, Li J, Ye L, Zhou Z, Wang Z, Liu L, Song Y, Yang Z, She G, Bai X, Huang X, Cheng X, Tang G, Wang B, Qin X, Zalloua P, Yan F, Xu X. Diabetes Ther. 2020 Sep 25. doi: 10.1007/s13300-020-00927-6. Online ahead of print. PMID: 32978754 https://www.nature.com/articles/s41467-020-18690-4.pdf Abstract Introduction: The worldwide prevalence of diabetes has been increasing for decades; diabetes can lead to serious health problems and even death, but the effects of maintaining low fasting blood glucose (FBG) remain controversial. The purpose of this study was to investigate the relationship between FBG levels and all-cause mortality in a long-term follow-up cohort and to find a relatively safe range of FBG levels. Methods: This study included 17,902 adults from a community-based cohort study in rural China who were prospectively followed from 2003 to 2018. Generalized estimating equations were used to evaluate the association between FBG and all-cause mortality, adjusting for pertinent covariates and auto-correlations among siblings. Results: A total of 1053 (5.9%) deaths occurred during 15 years of follow-up. There was a significant U-shaped association between all-cause mortality and FBG. Compared with the reference group (FBG of 5.6 - < 6.1 mmol/l), the risk of death among individuals with FBG levels < 5.6 mmol/l significantly increased by 38% (OR 1.34; 95% CI 1.13-1.59), while the risk of death among individuals with FBG ≥ 6.1 mmol/l or participants with a self-reported history of diabetes significantly increased by 51% (OR 1.49; 95% CI 1.20-1.85). Additionally, the U-shaped association remained steady in any stratification of risk factors. Conclusion: Our study showed a significant U-shaped relationship between FBG levels and risk of all-cause mortality in this rural Chinese population. When FBG was within the range of 5.6 - < 6.1 mmol/l, the risk of all-cause mortality was the lowest. Keywords: All-cause mortality; Fasting blood glucose; U-shaped relationship. The Lipidome Fingerprint of Longevity. Jové M, Mota-Martorell N, Pradas I, Galo-Licona JD, Martín-Gari M, Obis È, Sol J, Pamplona R. Molecules. 2020 Sep 22;25(18):E4343. doi: 10.3390/molecules25184343. PMID: 32971886 Review. [pdf free from Medline abstact page.] Abstract Lipids were determinants in the appearance and evolution of life. Recent studies disclose the existence of a link between lipids and animal longevity. Findings from both comparative studies and genetics and nutritional interventions in invertebrates, vertebrates, and exceptionally long-lived animal species-humans included-demonstrate that both the cell membrane fatty acid profile and lipidome are a species-specific optimized evolutionary adaptation and traits associated with longevity. All these emerging observations point to lipids as a key target to study the molecular mechanisms underlying differences in longevity and suggest the existence of a lipidome profile of long life. Keywords: fatty acids; lipidomics; longevity; membrane unsaturation; peroxidation index.Association Between Midlife Physical Activity and Incident Kidney Disease: The Atherosclerosis Risk in Communities (ARIC) Study. Parvathaneni K, Surapaneni A, Ballew SH, Palta P, Rebholz CM, Selvin E, Coresh J, Grams ME. Am J Kidney Dis. 2020 Sep 10:S0272-6386(20)30940-9. doi: 10.1053/j.ajkd.2020.07.020. Online ahead of print. PMID: 32971191 Abstract Rationale & objective: Physical activity is associated with lower risk of cardiovascular disease, diabetes, and hypertension, which have shared risk factor profiles with chronic kidney disease (CKD). However, there are conflicting findings regarding the relationship between physical activity and CKD. The objective was to evaluate the association between physical activity and CKD development over long-term follow-up using the Atherosclerosis Risk in Communities (ARIC) study. Study design: Prospective cohort study. Setting: & Participants: 14,537 participants aged 45 to 64 years old. Predictors: Baseline physical activity status was assessed by the modified Baecke Physical Activity Questionnaire at visit 1 (1987-1989) and categorized according to the 2018 Physical Activity Guidelines for Americans to group participants as inactive, insufficiently active, active, and highly active. Outcomes: Incident CKD defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at follow up and ≥25% decline in eGFR relative to baseline, CKD-related hospitalization or death, or end stage renal disease. Analytical approach: Cox proportional hazards regression. Results: At baseline, 37.8%, 24.2%, 22.7%, and 15.3% of participants were classified as inactive, insufficiently active, active, and highly active, respectively. During a median follow up of 24 years, 33.2% of participants developed CKD. After adjusting for age, sex, race-center, education, smoking status, diet quality, diabetes, coronary heart disease, hypertension, antihypertensive medication, body mass index, and baseline eGFR, higher categories of physical activity were associated with lower risk of CKD compared to the inactive group (HR for insufficiently active, 0.95 [95% CI, 0.88-1.02]; active, 0.93 [95% CI, 0.86-1.01]; highly active, 0.89 [95% CI, 0.81-0.97]; P for trend = 0.007). Limitations: Observational design and self-reported physical activity that was based on leisure time activity only. Due to low numbers, non black and white participants were excluded. Conclusions: Highly active participants had a lower risk of developing CKD compared to inactive participants. Index words (5 words): chronic kidney disease; physical activity; Atherosclerosis Risk in Communities Study; estimated glomerular filtration rate; cystatin C.
  3. Circulating Thyroid Hormone Profile in Response to a Triiodothyronine Challenge in Familial Longevity. Zutinic A, Blauw GJ, Pijl H, Ballieux BE, Westendorp RGJ, Roelfsema F, van Heemst D. J Endocr Soc. 2020 Aug 20;4(10):bvaa117. doi: 10.1210/jendso/bvaa117. eCollection 2020 Oct 1. PMID: 32964174 Free PMC article. Abstract Context: Familial longevity is associated with higher circulating levels of thyrotropin (TSH), in the absence of differences in circulating thyroid hormones, and a lower thyroid responsivity to TSH, as previously observed in the Leiden Longevity Study (LLS). Further mechanisms underlying these observations remain unknown. Objective: We hypothesized that members from long-lived families (offspring) have higher thyroid hormone turnover or less negative feedback effect on TSH secretion compared to controls. Methods: In a case-control intervention study, 14 offspring and 13 similarly aged controls received 100 µg 3,5,3'-triiodothyronine (T3) orally. Their circulating T3, free T3 (fT3), and TSH levels were measured during 5 consecutive days. We compared profiles of circulating T3, fT3, and TSH between offspring and controls using general linear modeling (GLM) and calculated the percentage decline in TSH following T3 administration. Results: Circulating T3 and fT3 levels increased to supraphysiologic values and normalized over the course of 5 days. There were no serious adverse events. T3 and fT3 concentration profiles over 5 days were similar between offspring and controls (T3 GLM P = .11, fT3 GLM P = .46). TSH levels decreased in a biphasic manner and started returning to baseline by day 5. The TSH concentration profile over 5 days was similar between offspring and controls (GLM P = .08), as was the relative TSH decline (%). Conclusions: Members of long-lived families have neither higher T3 turnover nor diminished negative feedback of T3 on TSH secretion. The cause and biological role of elevated TSH levels in familial longevity remain to be elucidated. Keywords: 3,5,3′-triiodothyronine; TSH; longevity; negative feedback; thyroid. Mitochondrial DNA deletion mutations increase exponentially with age in human skeletal muscle. Herbst A, Lee CC, Vandiver AR, Aiken JM, McKenzie D, Hoang A, Allison D, Liu N, Wanagat J. Aging Clin Exp Res. 2020 Sep 23. doi: 10.1007/s40520-020-01698-7. Online ahead of print. PMID: 32965609 Abstract Background: Mitochondrial DNA (mtDNA) deletion mutations lead to electron transport chain-deficient cells and age-induced cell loss in multiple tissues and mammalian species. Accurate quantitation of somatic mtDNA deletion mutations could serve as an index of age-induced cell loss. Quantitation of mtDNA deletion molecules is confounded by their low abundance in tissue homogenates, the diversity of deletion breakpoints, stochastic accumulation in single cells, and mosaic distribution between cells. Aims: Translate a pre-clinical assay to quantitate mtDNA deletions for use in human DNA samples, with technical and biological validation, and test this assay on human subjects of different ages. Methods: We developed and validated a high-throughput droplet digital PCR assay that quantitates human mtDNA deletion frequency. Results: Analysis of human quadriceps muscle samples from 14 male subjects demonstrated that mtDNA deletion frequency increases exponentially with age-on average, a 98-fold increase from age 20-80. Sequence analysis of amplification products confirmed the specificity of the assay for human mtDNA deletion breakpoints. Titration of synthetic mutation mixtures found a lower limit of detection of at least 0.6 parts per million. Using muscle DNA from 6-month-old mtDNA mutator mice, we measured a 6.4-fold increase in mtDNA deletion frequency (i.e., compared to wild-type mice), biologically validating the approach. Discussion/conclusions: The exponential increase in mtDNA deletion frequency is concomitant with the known muscle fiber loss and accelerating mortality that occurs with age. The improved assay permits the accurate and sensitive quantification of deletion mutations from DNA samples and is sufficient to measure changes in mtDNA deletion mutation frequency in healthy individuals across the lifespan and, therefore, patients with suspected mitochondrial diseases. Keywords: Biomarker; Deletion; Mitochondria; MtDNA; Mutation; Sarcopenia. Soy and isoflavone consumption and subsequent risk of prostate cancer mortality: the Japan Public Health Center-based Prospective Study. Sawada N, Iwasaki M, Yamaji T, Shimazu T, Inoue M, Tsugane S. Int J Epidemiol. 2020 Sep 23:dyaa177. doi: 10.1093/ije/dyaa177. Online ahead of print. PMID: 32968784 Abstract Background: Although many epidemiological studies have reported the preventive effects of soy products and isoflavones on prostate cancer, our previous studies reported that the association between soy and isoflavones and prostate cancer incidence differed according to stage. It is more important to identify modifiable risk factors related to lethal prostate cancer. Here, we investigated the association between soy, soy products and isoflavones intake and prostate cancer mortality, in a prospective study in Japan. Methods: We conducted a population-based prospective study in 43 580 Japanese men with no history of cancer or cardiovascular disease (aged 45-74 years). Participants completed a validated questionnaire which included 138 food items. We followed participants from 1995 to 2016. Hazard ratios (HRs) and 95% confidence intervals (CIs) of prostate cancer mortality were calculated according to quintiles of soy products and isoflavones intake, using Cox hazard proportional hazards regression. Results: During 16.9 years follow-up, we registered 221 deaths from prostate cancer. Isoflavones and soy products intake was associated with an increased risk of prostate cancer death, with multivariate HRQ5 vs. Q1=1.39, 95% CI = 0.87-2.20, p for trend = 0.04 for isoflavones and multivariate HRQ5 vs. Q1=1.76, 95% CI = 1.10-2.82, p for trend = 0.04 for soy food. Conclusions: Our study suggested that high intake of soy and isoflavones might increase the risk of prostate cancer mortality. Keywords: JPHC Study; Soy; isoflavone; prospective; prostate cancer death. Central fatness and risk of all cause mortality: systematic review and dose-response meta-analysis of 72 prospective cohort studies. Jayedi A, Soltani S, Zargar MS, Khan TA, Shab-Bidar S. BMJ. 2020 Sep 23;370:m3324. doi: 10.1136/bmj.m3324. PMID: 32967840 https://www.bmj.com/content/bmj/370/bmj.m3324.full.pdf Abstract Objective: To quantify the association of indices of central obesity, including waist circumference, hip circumference, thigh circumference, waist-to-hip ratio, waist-to-height ratio, waist-to-thigh ratio, body adiposity index, and A body shape index, with the risk of all cause mortality in the general population, and to clarify the shape of the dose-response relations. Design: Systematic review and meta-analysis. Data sources: PubMed and Scopus from inception to July 2019, and the reference lists of all related articles and reviews. Eligibility criteria for selecting studies: Prospective cohort studies reporting the risk estimates of all cause mortality across at least three categories of indices of central fatness. Studies that reported continuous estimation of the associations were also included. Data synthesis: A random effects dose-response meta-analysis was conducted to assess linear trend estimations. A one stage linear mixed effects meta-analysis was used for estimating dose-response curves. Results: Of 98 745 studies screened, 1950 full texts were fully reviewed for eligibility. The final analyses consisted of 72 prospective cohort studies with 2 528 297 participants. The summary hazard ratios were as follows: waist circumference (10 cm, 3.94 inch increase): 1.11 (95% confidence interval 1.08 to 1.13, I2=88%, n=50); hip circumference (10 cm, 3.94 inch increase): 0.90 (0.81 to 0.99, I2=95%, n=9); thigh circumference (5 cm, 1.97 inch increase): 0.82 (0.75 to 0.89, I2=54%, n=3); waist-to-hip ratio (0.1 unit increase): 1.20 (1.15 to 1.25, I2=90%, n=31); waist-to-height ratio (0.1 unit increase): 1.24 (1.12 to 1.36, I2=94%, n=11); waist-to-thigh ratio (0.1 unit increase): 1.21 (1.03 to 1.39, I2=97%, n=2); body adiposity index (10% increase): 1.17 (1.00 to 1.33, I2=75%, n=4); and A body shape index (0.005 unit increase): 1.15 (1.10 to 1.20, I2=87%, n=9). Positive associations persisted after accounting for body mass index. A nearly J shaped association was found between waist circumference and waist-to-height ratio and the risk of all cause mortality in men and women. A positive monotonic association was observed for waist-to-hip ratio and A body shape index. The association was U shaped for body adiposity index. Conclusions: Indices of central fatness including waist circumference, waist-to-hip ratio, waist-to-height ratio, waist-to-thigh ratio, body adiposity index, and A body shape index, independent of overall adiposity, were positively and significantly associated with a higher all cause mortality risk. Larger hip circumference and thigh circumference were associated with a lower risk. The results suggest that measures of central adiposity could be used with body mass index as a supplementary approach to determine the risk of premature death. Improving rehabilitation in sarcopenia: a randomized-controlled trial utilizing a muscle-targeted food for special medical purposes. Rondanelli M, Cereda E, Klersy C, Faliva MA, Peroni G, Nichetti M, Gasparri C, Iannello G, Spadaccini D, Infantino V, Caccialanza R, Perna S. J Cachexia Sarcopenia Muscle. 2020 Sep 22. doi: 10.1002/jcsm.12532. Online ahead of print. PMID: 32961041 Abstract Background: Sarcopenia is a disease associated with aging and a negative prognosis. Consensus-based treatment consists in targeting muscle mass and function through physical exercise, optimization of protein intake, and vitamin D supplementation, but evidence is lacking. We evaluated the safety and efficacy of a muscle-targeted nutritional support on the outcome of a physical exercise rehabilitation programme. Methods: In a single-site, double-blind, randomized, controlled trial (NCT03120026; May 2017 to December 2018), old (≥65 years) adults [N = 140 (63% female patients; age, 81 ± 6 years)] without severe cognitive impairment, who were found to have sarcopenia by European Working Group on Sarcopenia in Older People 2010 criteria and hospitalized for physical rehabilitation, were randomized to receive until discharge (for at least 4 weeks and up to 8 weeks) a whey protein-based nutritional formula enriched with leucine and vitamin D or an iso-caloric control formula twice daily in addition to a standard hospital diet. The primary endpoint was the change in 4 m gait speed per month. Key secondary endpoints addressed the change in physical performance: chair-stand test, timed up and go test, and short physical performance battery. Other secondary outcomes were the change in functional status, muscle strength and mass, cognitive status, and quality of life. The proportion of patients who improved their rehabilitation intensity profile and overall economic benefits (using length of stay and duration of rehabilitation as surrogate measures) were also evaluated. Results: A total of 161 patients were screened and 140 were randomized to study interventions. Thirteen patients (experimental, n = 6; placebo, n = 7) discontinued the intervention because they disliked the product and intention-to-treat analyses were based on patients reassessed at discharge [n = 127 (66% female patients; age, 81 ± 6 years)]. Supplementation with the experimental formula (n = 64) resulted in greater increase in mean gait speed {0.061 m/s/month [95% confidence interval (CI), 0.043 to 0.080]} than placebo [n = 63; -0.001 m/s/month (95%CI, -0.008 to 0.006)]: mean difference, 0.063 m/s/month (95%CI, 0.043 to 0.082) (P < 0.001). A significant effect was also found for muscle mass (P < 0.03) and all key secondary outcomes, functional and cognitive endpoints (P < 0.001 for all). Supplementation resulted also in higher proportion of patients improving their rehabilitation intensity profile (P = 0.003) and being discharged home (P = 0.002); shorter rehabilitation (P < 0.001); and hospital stay (P < 0.001). Conclusions: In old adults with sarcopenia admitted to hospital for rehabilitation the consumption of a whey protein-based nutritional formula enriched with leucine and vitamin D improved physical performance and function, as well as muscle mass, and reduced the intensity and costs of care. Keywords: Leucine; Nutritional support; Rehabilitation; Sarcopenia; Vitamin D; Whey protein; rehabilitation. Visit-to-visit variability of lipid measurements and the risk of myocardial infarction and all-cause mortality: A prospective cohort study. Liu X, Wu S, Song Q, Wang X. Atherosclerosis. 2020 Sep 9:S0021-9150(20)30493-7. doi: 10.1016/j.atherosclerosis.2020.09.003. Online ahead of print. PMID: 32958454 Abstract Background and aims: Previous studies suggested that increased visit-to-visit variability in lipid measurements is associated with cardiovascular disease in specific or high-risk populations. Because it is unknown whether this notion applies to the general population, we investigated whether lipid variability has additive effects on the risk of all-cause mortality and myocardial infarction (MI) in the general population. Methods: We identified 51,620 subjects from the Kailuan cohort who had no history of MI, stroke and cancer and who underwent ≥3 health examinations from 2006 to 2010. Variability in total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) measurements was measured using the coefficient of variation (CV), standard deviation (SD), variability independent of the mean (VIM), and average real variability (ARV). Cox proportional hazards models were used to calculate the hazard ratios (HRs). Results: During a median of 7.03 years of follow-up, 426 (1.21) incidents of MI and 2243 (6.45) incidents of all-cause mortality occurred. In the multivariable-adjusted model, the HRs comparing participants in the highest versus lowest quartile of the CV for HDL-C were 1.56 (95% CI, 1.17-2.08; p for trend<0.01) for MI and 1.22 (95% CI, 1.09-1.37; p for trend<0.01) for all-cause mortality. For the highest quartile compared with the lowest quartile of LDL-C variability, the risk of MI and all-cause mortality increased by 34% (HR, 1.34; 95% CI, 1.03-1.82; p for trend<0.05) and 19% (HR, 1.19; 95% CI, 1.04-1.36; p for trend<0.05), respectively. We did not observe any significant association between TG variability and MI or all-cause mortality. Conclusions: These findings suggest that high visit-to-visit HDL-C and LDL-C variability is associated with an increased incidence of MI and all-cause mortality in a Chinese community population. Keywords: All-cause mortality; Cohort study; Lipid; Myocardial infarction; Variability. Effect of Coffee Consumption on Renal Outcome: A Systematic Review and Meta-Analysis of Clinical Studies. Kanbay M, Siriopol D, Copur S, Tapoi L, Benchea L, Kuwabara M, Rossignol P, Ortiz A, Covic A, Afsar B. J Ren Nutr. 2020 Sep 18:S1051-2276(20)30209-0. doi: 10.1053/j.jrn.2020.08.004. Online ahead of print. PMID: 32958376 Review. Abstract Objective: Drinking coffee is one of the most common daily habits, especially in the developed world. Along with caffeine, coffee has various ingredients that have been suggested to have beneficial effects, including antioxidant, antiinflammatory, anticarcinogenic, antithrombotic and antifibrotic effects. In this systematic review and meta-analysis, we investigated the relationship between coffee intake and chronic kidney disease (CKD) related outcomes. Design and methods: Literature search was performed through PubMed/Medline, Web of Science, Embase (Elsevier), and the Cochrane Central Register of Controlled Trials (Wiley) from 1960 to February 2020. Incidence of CKD, the progression of CKD, and CKD-associated mortality have been evaluated in relation to coffee consumption and the amount of consumption. The Newcastle-Ottawa scale was used for quality assessment of included studies. Results: 12 studies were included in the analysis (7 prospective, 5 cross-sectional) involving 505,841 subjects. 7 studies investigated the relationship between coffee consumption and incident CKD and showed that coffee consumption was associated with a significant decrease in the risk for incident CKD outcome (RR 0.86, 95% CI 0.76 to 0.97, P = .01) with a greater decrease in individuals taking ≥2 cups/day compared to those who drank ≤1 cup/day. There was a significantly lower risk of incident end stage kidney disease (ESKD) in coffee users (HR 0.82, 95% CI 0.72 to 0.94, P = .005). Coffee consumption was also associated with a lower risk of albuminuria (OR 0.81, 95% CI 0.68 to 0.97, P = .02). Overall, the risk of death related to CKD was lower in coffee users (HR 0.72, 95% CI 0.54 to 0.96, P = .02). Conclusion: Coffee intake was dose-dependently associated with lower incident CKD, ESKD, and albuminuria. Dietary Methionine Restriction Signals to the Brain Through Fibroblast Growth Factor 21 to Regulate Energy Balance and Remodeling of Adipose Tissue. Forney LA, Fang H, Sims LC, Stone KP, Vincik LY, Vick AM, Gibson AN, Burk DH, Gettys TW. Obesity (Silver Spring). 2020 Oct;28(10):1912-1921. doi: 10.1002/oby.22919. PMID: 32959519 Abstract Objective: Restricting dietary methionine to 0.17% in mice increases energy expenditure (EE), reduces fat deposition, and improves metabolic health by increasing hepatic fibroblast growth factor 21 (FGF21). The goal of this study was to compare each of these responses in mice with the coreceptor for FGF21 deleted in either adipose tissue or the brain. Methods: Methionine-restriction (MR) diets were fed to age-matched cohorts of mice with the coreceptor for FGF21 deleted in either adipose tissue or the brain. The physiological and transcriptional responses to MR were compared in the respective cohorts. Results: Tissue-specific deletion of the FGF21 coreceptor in adipose tissue did not abrogate the ability of dietary MR to increase EE and reduce fat deposition. Tissue-specific deletion of the FGF21 coreceptor from the brain produced mice that were unable to respond to the effects of MR on EE or the remodeling of adipose tissue. Conclusions: The increase in FGF21 produced by dietary MR acts primarily in the brain to produce its physiological effects on energy balance. In contrast, the effects of MR on hepatic gene expression were intact in both models, supporting a mechanism that directly links detection of reduced methionine in the liver to transcriptional mechanisms that alter gene expression in the liver. The Influence of Cyclical Ketogenic Reduction Diet vs. Nutritionally Balanced Reduction Diet on Body Composition, Strength, and Endurance Performance in Healthy Young Males: A Randomized Controlled Trial. Kysel P, Haluzíková D, Doležalová RP, Laňková I, Lacinová Z, Kasperová BJ, Trnovská J, Hrádková V, Mráz M, Vilikus Z, Haluzík M. Nutrients. 2020 Sep 16;12(9):E2832. doi: 10.3390/nu12092832. https://sci-hub.tw/10.3390/nu12092832 PMID: 32947920 Abstract (1) Background: The influence of ketogenic diet on physical fitness remains controversial. We performed a randomized controlled trial to compare the effect of cyclical ketogenic reduction diet (CKD) vs. nutritionally balanced reduction diet (RD) on body composition, muscle strength, and endurance performance. (2) Methods: 25 healthy young males undergoing regular resistance training combined with aerobic training were randomized to CKD (n = 13) or RD (n = 12). Body composition, muscle strength and spiroergometric parameters were measured at baseline and after eight weeks of intervention. (3) Results: Both CKD and RD decreased body weight, body fat, and BMI. Lean body mass and body water decreased in CKD and did not significantly change in RD group. Muscle strength parameters were not affected in CKD while in RD group lat pull-down and leg press values increased. Similarly, endurance performance was not changed in CKD group while in RD group peak workload and peak oxygen uptake increased. (4) Conclusions: Our data show that in healthy young males undergoing resistance and aerobic training comparable weight reduction were achieved by CKD and RD. In RD group; improved muscle strength and endurance performance was noted relative to neutral effect of CKD that also slightly reduced lean body mass. Keywords: body composition; endurance; ketogenic diet; strength parameters; training. The intestinal microbiome is a co-determinant of the postprandial plasma glucose response. Søndertoft NB, Vogt JK, Arumugam M, Kristensen M, Gøbel RJ, Fan Y, Lyu L, Bahl MI, Eriksen C, Ängquist L, Frøkiær H, Hansen TH, Brix S, Nielsen HB, Hansen T, Vestergaard H, Gupta R, Licht TR, Lauritzen L, Pedersen O. PLoS One. 2020 Sep 18;15(9):e0238648. doi: 10.1371/journal.pone.0238648. eCollection 2020. PMID: 32947608 Abstract Elevated postprandial plasma glucose is a risk factor for development of type 2 diabetes and cardiovascular disease. We hypothesized that the inter-individual postprandial plasma glucose response varies partly depending on the intestinal microbiome composition and function. We analyzed data from Danish adults (n = 106), who were self-reported healthy and attended the baseline visit of two previously reported randomized controlled cross-over trials within the Gut, Grain and Greens project. Plasma glucose concentrations at five time points were measured before and during three hours after a standardized breakfast. Based on these data, we devised machine learning algorithms integrating bio-clinical, as well as shotgun-sequencing-derived taxa and functional potentials of the intestinal microbiome to predict individual postprandial glucose excursions. In this post hoc study, we found microbial and clinical features, which predicted up to 48% of the inter-individual variance of postprandial plasma glucose responses (Pearson correlation coefficient of measured vs. predicted values, R = 0.69, 95% CI: 0.45 to 0.84, p<0.001). The features were age, fasting serum triglycerides, systolic blood pressure, BMI, fasting total serum cholesterol, abundance of Bifidobacterium genus, richness of metagenomics species and abundance of a metagenomic species annotated to Clostridiales at order level. A model based only on microbial features predicted up to 14% of the variance in postprandial plasma glucose excursions (R = 0.37, 95% CI: 0.02 to 0.64, p = 0.04). Adding fasting glycaemic measures to the model including microbial and bio-clinical features increased the predictive power to R = 0.78 (95% CI: 0.59 to 0.89, p<0.001), explaining more than 60% of the inter-individual variance of postprandial plasma glucose concentrations. The outcome of the study points to a potential role of the taxa and functional potentials of the intestinal microbiome. If validated in larger studies our findings may be included in future algorithms attempting to develop personalized nutrition, especially for prediction of individual blood glucose excursions in dys-glycaemic individuals.
  4. AlPater

    Al's CR updates

    Caloric restriction alleviates aging-related fibrosis of kidney through downregulation of miR-21 in extracellular vesicles. Liu JR, Cai GY, Ning YC, Wang JC, Lv Y, Guo YN, Fu B, Hong Q, Sun XF, Chen XM. Aging (Albany NY). 2020 Aug 27;12. doi: 10.18632/aging.103591. Online ahead of print. PMID: 32963130 Abstract Glomerulosclerosis and renal interstitial fibrosis occur with the aging kidney. In this study, we examined the expression of miR-21, peroxisome proliferator-activated receptor(PPARα), hypoxia-inducible factor(HIF-1α) in the kidney of 3-month-old rats fed ad libitum (YAL), 24-month-old rats fed ad libitum (OAL) and 24-month-old rats subjected to a 70% calorie-restricted diet for 8 months (OCR). We found long-term caloric restriction (CR) ameliorated aging and aging-related fibrosis. CR ameliorated the increment of miR-21 and HIF-1α, as well as the decrement of PPARα in old ad libitum group. Human proximal tubular cells (HPTCs) presented phenotypes of senescence and epithelial to mesenchymal transition (EMT) under high-glucose conditions, in which senescence occurred earlier than EMT. Senescent cells secreted extracellular vesicles (EVs) which contained miR-21 into the recipient cells. Inhibiting miR-21 of donor cells prevented the occurrence of EMT in recipient cells. In addition, miR-21 induced EMT through targeting PPARα protein and consequently enhancing HIF-1α expression, although other pathways cannot be ruled out. These findings demonstrated that miR-21-containing EVs derived from the senescent cells could facilitate EMT of HPTCs via PPARα-HIF-1α signaling pathway. Long-term caloric restriction and caloric restriction mimetics alleviated aging-related-fibrosis of kidney through downregulation of miR-21. Keywords: EMT; age; caloric restriction; extracellular vesicles; miR-21. Effects of caloric restriction on retinal aging and neurodegeneration. Adornetto A, Morrone LA, Satriano A, Laganà ML, Licastro E, Nucci C, Corasaniti MT, Tonin P, Bagetta G, Russo R. Prog Brain Res. 2020;256(1):189-207. doi: 10.1016/bs.pbr.2020.07.005. Epub 2020 Aug 18. PMID: 32958212 Abstract Glaucoma is the most common neurodegenerative cause of irreversible blindness worldwide. Restricted caloric regimens are an attractive approach for delaying the progression of neurodegenerative diseases. Here we review the current literature on the effects of caloric restriction on retinal neurons, under physiological and pathological conditions. We focused on autophagy as one of the mechanisms modulated by restricted caloric regimens and involved in the death of retinal ganglion cells (RGCs) over the course of glaucoma. Keywords: AMPK; Aging; Autophagy; Caloric restriction; Glaucoma; Neurodegeneration; Retina; SIRT1.
  5. We looked at every confirmed COVID-19 case in Canada. Here's what we found CBC News analyzed data on all confirmed cases of COVID-19 collected by Public Health Agency of Canada Dave Seglins, Andreas Wesley, Roberto Rocha · CBC News · Posted: Sep 23, 2020 https://www.cbc.ca/news/canada/public-health-agency-of-canada-covid-19-statistics-1.5733069
  6. Plant- and Animal-Based Diet Quality and Mortality Among US Adults: A Cohort Study. Keaver L, Ruan M, Chen F, Du M, Ding C, Wang J, Shan Z, Liu J, Zhang FF. Br J Nutr. 2020 Sep 18:1-29. doi: 10.1017/S0007114520003670. Online ahead of print. PMID: 32943123 https://sci-hub.tw/https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/plant-and-animalbased-diet-quality-and-mortality-among-us-adults-a-cohort-study/107CDCF21A89DBE9ADE0CCB2ADA08A04 Abstract Not all plant-based and animal foods exert the same health effects due to their various nutrient compositions. We aimed to assess the quality of plant-based vs. animal foods in relation to mortality in a prospective cohort study. Using data collected from a nationally representative sample of 36,825 adults in the National Health and Nutrition Examination Survey 1999-2014, we developed a de novo Comprehensive Diet Quality Index (cDQI) that assesses the quality of 17 foods based on the healthfulness, and separately scored the quality of 11 plant-based foods in a plant-based Diet Quality Index (pDQI) and 6 animal foods in an animal-based Diet Quality index (aDQI). Mortality from all causes, heart disease, and cancer were obtained from linkage to the National Death Index through December 31, 2015. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) after multivariable adjustments. During a median follow-up of 8.3 years, 4,669 all-cause deaths occurred, including 798 deaths due to heart disease and 1,021 due to cancer. Compared to individuals in the lowest quartile, those in the highest quartile of cDQI had a lower risk of all-cause mortality (HR=0.75, 95% CI: 0.65, 0.86; P-trend<0.001), which largely reflected the inverse relationship between quality of plant-based foods (pDQI) and all-cause mortality (HR=0.66; 95% CI: 0.58, 0.74, P-trend<0.001). No independent association was found for the quality of animal-foods (aDQI) and mortality. Our results suggest that consuming healthy plant-based foods is associated with lower all-cause mortality among US adults. Keywords: animal foods; cancer; diet quality index; heart disease; mortality; plant-based foods. Increased frequency of intentional weight loss associated with reduced mortality: a prospective cohort analysis. Willis EA, Huang WY, Saint-Maurice PF, Leitzmann MF, Salerno EA, Matthews CE, Berndt SI. BMC Med. 2020 Sep 17;18(1):248. doi: 10.1186/s12916-020-01716-5. PMID: 32938465 Abstract Background: Due to the high prevalence of obesity and the difficulty in maintaining weight loss, repeated bouts of weight loss are a common occurrence. However, there are inconsistencies in epidemiological studies regarding repetitive weight fluctuations being associated with increased risk of mortality. Therefore, the purpose of this prospective cohort analysis was to determine the long-term association of the frequency of weight loss attempts on mortality. Methods: This prospective cohort study used data collected from adult AARP members living in 6 states (California, Florida, Louisiana, New Jersey, North Carolina, or Pennsylvania) or 2 metropolitan areas (Atlanta, Georgia, or Detroit, Michigan) and participating in the National Institutes of Health-AARP Diet and Health Study between 2004 and 2006. Self-reported data were analyzed for 161,738 middle-aged adults. During an average 7 years of follow-up, 21,194 deaths were recorded. Hazard ratios of all-cause, cardiovascular, and cancer mortality were estimated adjusting for demographic, lifestyle, and behavioral risk factors. Results: Increased frequency of weight loss attempts of at least five pounds was associated with lower mortality (ptrend < 0.010). Multivariate hazard ratios (95% confidence intervals) for all-cause death among individuals who successfully attempted weight loss compared with those who did not make any attempts were 0.94 (0.90-0.98) for 1-2 attempts, 0.96 (0.91-1.01) for 3-4 attempts, 0.91 (0.85-0.96) for 5-6 attempts, 0.91 (0.85-0.98) for 7-8 attempts, 0.87 (0.80-0.95) for 9-10 attempts, and 0.88 (0.82-0.94) for 11+ attempts. Similar results were noted for men and women, participants with healthy weight and overweight/obesity, and even among those who gained weight over time. Protective associations were also observed for deaths due to cardiovascular disease and cancer. Conclusions: Increased frequency of intentionally losing at least five pounds in mid-life was associated with a lower risk of future death. Repeated attempts with moderate amounts of weight loss may provide benefit in terms of longevity. Keywords: Mortality; Obesity; Prospective cohort; Weight loss. Does insulin-like growth factor moderate the association between height and risk of cancer at 24 sites? Parra-Soto S, Ho FK, Pell JP, Celis-Morales C. Br J Cancer. 2020 Sep 14. doi: 10.1038/s41416-020-01059-1. Online ahead of print. PMID: 32921791 Abstract Background: Whether the association of height with cancers differs by insulin-like growth factors has not been fully elucidated. Therefore, this study aimed to investigate the sex-specific associations between height and 24 site-specific cancers and to assess whether the association differed by IGF-1. Methods: In total, 414,923 participants from the UK Biobank prospective cohort study were included. The association of height (per 5-cm increment) with incidence and mortality from 24 cancer sites was investigated by using Cox proportional hazard models. Results: The median follow-up was 6.0 years. In men, height was positively associated with incidence risk of all-cause cancer and at five sites (lung, lymphatic, leukaemia, non-Hodgkin lymphoma and melanoma). In women, it was associated with breast, melanoma, lymphatic, non-Hodgkin lymphoma and all-cause cancer. The association was stronger in women than men for all-cause cancer incidence. The strength of the association did not differ by IGF-1 concentration. Conclusions: Adult height was associated with risk of several cancer sites. However, some of these associations were sex-specific. There was no strong evidence to support IGF-1 moderating the association between height and cancer. Circulating dehydroepiandrosterone sulfate level and cardiovascular or all-cause mortality in the elderly population: a meta-analysis. Li R, E L, Zha N. Ann Palliat Med. 2020 Sep 7:apm-20-441. doi: 10.21037/apm-20-441. Online ahead of print. PMID: 32921089 Abstract Studies have yielded contradictory results concerning the association between dehydroepiandrosterone sulfate (DHEAS) and mortality in the elderly population. This meta-analysis aimed to evaluate the association of low serum DHEAS level with cardiovascular or all-cause mortality in the elderly population. A comprehensive literature search was conducted in PubMed and Embase databases up to 4 February, 2019. Longitudinal observational studies reporting multivariate adjusted risk ratio (RR) and corresponding 95% confidence intervals (CI) for cardiovascular or all-cause mortality with respect to baseline low DHEAS level were included. Both fixed-effect and random effect model were used to pool the overall risk estimate. Methodological quality of the included studies was evaluated using a 9-point Newcastle-Ottawa Scale. Six prospective studies enrolling 6,744 individuals were identified. Five studies were graded as high methodological quality. When compared the lowest to the reference higher circulating DHEAS level, the pooled RR of all-cause and cardiovascular mortality was 1.46 (95% CI: 1.25-1.70) and 1.49 (95% CI: 1.11-1.99), respectively. Subgroup analysis indicated that the association of low DHEAS level with all-cause mortality risk was only found in men (RR 1.41;95% CI: 1.18-1.69) but not in women (RR 1.72; 95% CI: 0.99-2.99). This meta-analysis provides evidence that low circulating DHEAS level is associated with increased risk all-cause mortality in the elderly population. Keywords: Dehydroepiandrosterone sulfate (DHEAS); all-cause mortality; cardiovascular mortality; meta-analysis. Middle-aged individuals may be in a perpetual state of H3N2 influenza virus susceptibility. Gouma S, Kim K, Weirick ME, Gumina ME, Branche A, Topham DJ, Martin ET, Monto AS, Cobey S, Hensley SE. Nat Commun. 2020 Sep 11;11(1):4566. doi: 10.1038/s41467-020-18465-x. PMID: 32917903 Abstract Influenza virus exposures in childhood can establish long-lived memory B cell responses that can be recalled later in life. Here, we complete a large serological survey to elucidate the specificity of antibodies against contemporary H3N2 viruses in differently aged individuals who were likely primed with different H3N2 strains in childhood. We find that most humans who were first infected in childhood with H3N2 viral strains from the 1960s and 1970s possess non-neutralizing antibodies against contemporary 3c2.A H3N2 viruses. We find that 3c2.A H3N2 virus infections boost non-neutralizing H3N2 antibodies in middle-aged individuals, potentially leaving many of them in a perpetual state of 3c2.A H3N2 viral susceptibility. Effects of Intermittent Fasting and Physical Activity on Salivary Expression of Reduced Glutathione and Interleukin-1β. Allen C, Sellers B, Smith M, Edwards A, Gateless K, Aab B, Sherrard K, Bolyard C, Stover S. Int J Exerc Sci. 2020 Aug 1;13(7):1063-1071. eCollection 2020. PMID: 32922651 Free PMC article. Abstract Previous research has consistently demonstrated that regular exercise promotes antioxidant production and decreases the expression of inflammation markers. However, there is very little research examining the effects of intermittent fasting (IF) on oxidative stress and inflammation. The present study investigated the hypothesis that a combination of IF and physical activity will reduce the need for glutathione (GSH) production by decreasing oxidative stress. In addition, it was hypothesized that a combination of IF and physical activity will significantly reduce inflammation, as indicated by a decrease in interleukin-1β (IL-1β) concentration. For three months, subjects practicing IF (n=7) ate only during an eight-hour window each day and fasted for the next 16 hours. A standard diet control group (n=18) maintained a normal, balanced diet spread out over the course of 14-18 hours each day. Based on data obtained from fitness-tracking devices, subjects were placed into one of three activity level groups: minimum, moderate, and maximum physical activity. Subjects provided fasting saliva samples monthly. The samples were subjected to a glutathione microplate assay and an interleukin ELISA test to determine salivary concentrations of GSH and IL-1β, respectively. For GSH concentration, there were no significant differences between the diets at any physical activity level. However, moderate to maximum physical activity, in conjunction with fasting, led to significant decreases in IL-1β concentration. In summary, results suggest that a combination of moderate physical activity and intermittent fasting promotes the maintenance of antioxidant function while inhibiting the inflammatory process. Keywords: Cytokine; reactive oxygen species; time-restricted feeding. Meal timing and subjective sleep disturbances in older men. van Egmond LT, C Moulin T, Schiöth HB, Cederholm T, Benedict C. Exp Gerontol. 2020 Sep 7;141:111089. doi: 10.1016/j.exger.2020.111089. Online ahead of print. PMID: 32911034 Abstract Older adults often complain about sleep disturbances, such as difficulty falling asleep and difficulty maintaining sleep in the early morning hours. Here, we investigated whether meal timing is associated with sleep problems in a cohort of older Swedish men (n = 998, mean age 71). Each participant filled out a seven-day food diary used to determine the daily eating time window, daily eating midpoint, and meal timing variability (i.e., the variance in daily eating midpoints over seven days). Questionnaires were used to assess difficulty initiating sleep and difficulty maintaining sleep. As indicated by logistic regression adjusted for potential confounders (e.g., BMI, diabetes status), no significant associations were found between the meal timing parameters and subjective sleep problems (P ≥ 0.37). Similar results were obtained when restricting the analysis to adequate reporters of daily energy intake. Therefore, our findings suggest that meal timing variations do not contribute to subjective sleep problems in older men. Our results must be replicated in cohorts that also include women and other measures of sleep. Keywords: Aging; Chrononutrition; Elderly; Insomnia; Sleep disturbances. Associations of Cytomegalovirus Infection With All-Cause and Cardiovascular Mortality in Multiple Observational Cohort Studies of Older Adults. Chen S, Pawelec G, Trompet S, Goldeck D, Mortensen LH, Slagboom PE, Christensen K, Gussekloo J, Kearney P, Buckley BM, Ford I, Jukema JW, Westendorp RGJ, Maier AB. J Infect Dis. 2020 Sep 10:jiaa480. doi: 10.1093/infdis/jiaa480. Online ahead of print. PMID: 32909605 Abstract Background: Whether latent cytomegalovirus (CMV) infection in older adults has any substantial health consequences is unclear. Here, we sought associations between CMV-seropositivity and IgG titer with all-cause and cardiovascular mortality in 5 longitudinal cohorts. Methods: Leiden Longevity Study, Prospective Study of Pravastatin in the Elderly at Risk, Longitudinal Study of Aging Danish Twins, and Leiden 85-plus Study were assessed at median (2.8-11.4 years) follow-up . Cox regression and random effects meta-analysis were used to estimate mortality risk dependent on CMV serostatus and/or IgG antibody titer, in quartiles after adjusting for confounders. Results: CMV-seropositivity was seen in 47%-79% of 10 122 white community-dwelling adults aged 59-93 years. Of these, 3519 had died on follow-up (579 from cardiovascular disease). CMV seropositivity was not associated with all-cause (hazard ratio {HR}, 1.05; 95% confidence interval [CI], .97-1.14) or cardiovascular mortality (HR, 0.97; 95% CI, .83-1.13). Subjects in the highest CMV IgG quartile group had increased all-cause mortality relative to CMV-seronegatives (HR, 1.16; 95% CI, 1.04-1.29) but this association lost significance after adjustment for confounders (HR, 1.13; 95% CI, .99-1.29). The lack of increased mortality risk was confirmed in subanalyses. Conclusions: CMV infection is not associated with all-cause or cardiovascular mortality in white community-dwelling older adults. Keywords: Herpesviridae; aged; cardiovascular; cytomegalovirus; immunoglobulin G; mortality; seroepidemiologic studies. Substantial underestimation of SARS-CoV-2 infection in the United States. Wu SL, Mertens AN, Crider YS, Nguyen A, Pokpongkiat NN, Djajadi S, Seth A, Hsiang MS, Colford JM Jr, Reingold A, Arnold BF, Hubbard A, Benjamin-Chung J. Nat Commun. 2020 Sep 9;11(1):4507. doi: 10.1038/s41467-020-18272-4. PMID: 32908126 Abstract Accurate estimates of the burden of SARS-CoV-2 infection are critical to informing pandemic response. Confirmed COVID-19 case counts in the U.S. do not capture the total burden of the pandemic because testing has been primarily restricted to individuals with moderate to severe symptoms due to limited test availability. Here, we use a semi-Bayesian probabilistic bias analysis to account for incomplete testing and imperfect diagnostic accuracy. We estimate 6,454,951 cumulative infections compared to 721,245 confirmed cases (1.9% vs. 0.2% of the population) in the United States as of April 18, 2020. Accounting for uncertainty, the number of infections during this period was 3 to 20 times higher than the number of confirmed cases. 86% (simulation interval: 64-99%) of this difference is due to incomplete testing, while 14% (0.3-36%) is due to imperfect test accuracy. The approach can readily be applied in future studies in other locations or at finer spatial scale to correct for biased testing and imperfect diagnostic accuracy to provide a more realistic assessment of COVID-19 burden. l-Serine and EPA Relieve Chronic Low-Back and Knee Pain in Adults: A Randomized, Double-Blind, Placebo-Controlled Trial. Sasahara I, Yamamoto A, Takeshita M, Suga Y, Suzuki K, Nishikata N, Takada M, Hashimoto M, Mine T, Kobuna Y, Nagao K. J Nutr. 2020 Sep 1;150(9):2278-2286. doi: 10.1093/jn/nxaa156. PMID: 32520991 Free PMC article. Abstract Background: Multisite pain, including low-back and knee pain, is a major health issue that greatly decreases quality of life. Objectives: This study analyzed the effects of l-serine, which provides necessary components for nerve function, and EPA, which exerts anti-inflammatory properties, on pain scores of adults with pain in at least the low back and knee for ≥3 mo. Methods: This was a randomized, double-blind, placebo-controlled, parallel-group study. The Japan Low Back Pain Evaluation Questionnaire (JLEQ) and Japanese Knee Osteoarthritis Measure (JKOM) were applied as primary outcomes. The Brief Pain Inventory (BPI) and safety evaluation were secondary outcomes. We enrolled 120 participants aged ≥20 y (36 men and 84 women: mean ± SD age = 40.8 ± 10.9 y). The participants were randomly allocated to either the active group (daily ingestion of 594 mg l-serine and 149 mg EPA) or placebo group. The study period consisted of 8-wk dosing and 4-wk posttreatment observation. ANCOVA between groups for each time point was conducted using the baseline scores as covariates. Results: The JLEQ scores (active compared with placebo: 14.2 ± 11.2 compared with 19.0 ± 10.2) at week 8 were lower in the active group (P < 0.001). The JKOM scores at week 4 (11.7 ± 9.0 compared with 13.9 ± 7.9), week 8 (10.4 ± 7.9 compared with 13.1 ± 7.1), and week 12 (10.3 ± 7.4 compared with 13.8 ± 7.5) were lower in the active group (P ≤ 0.04). Additionally, the active group had 11-27% better scores compared with the placebo group for BPI1 (worst pain), BPI3 (average pain), and BPI5D (pain during moving) at week 4 (P ≤ 0.028) and week 8 (P ≤ 0.019), respectively, and BPI5D was 23% better in the active group at week 12 (P = 0.007). No adverse events were observed. Conclusions: l-Serine and EPA were effective for pain relief in adults with low-back and knee pain after multiplicity adjustment.This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry as UMIN000035056. Keywords: Brief Pain Inventory (BPI); Japan Low Back Pain Evaluation Questionnaire (JLEQ); Japanese Knee Osteoarthritis Measure (JKOM); clinical; low-back and knee pain; multiple site pain; neuropathic pain.
  7. AlPater

    Al's CR updates

    Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers. Di Tano M, Raucci F, Vernieri C, Caffa I, Buono R, Fanti M, Brandhorst S, Curigliano G, Nencioni A, de Braud F, Longo VD. Nat Commun. 2020 May 11;11(1):2332. doi: 10.1038/s41467-020-16243-3. PMID: 32393788 Free PMC article. Abstract Fasting-mimicking diets delay tumor progression and sensitize a wide range of tumors to chemotherapy, but their therapeutic potential in combination with non-cytotoxic compounds is poorly understood. Here we show that vitamin C anticancer activity is limited by the up-regulation of the stress-inducible protein heme-oxygenase-1. The fasting-mimicking diet selectivity reverses vitamin C-induced up-regulation of heme-oxygenase-1 and ferritin in KRAS-mutant cancer cells, consequently increasing reactive iron, oxygen species, and cell death; an effect further potentiated by chemotherapy. In support of a potential role of ferritin in colorectal cancer progression, an analysis of The Cancer Genome Atlas Database indicates that KRAS mutated colorectal cancer patients with low intratumor ferritin mRNA levels display longer 3- and 5-year overall survival. Collectively, our data indicate that the combination of a fasting-mimicking diet and vitamin C represents a promising low toxicity intervention to be tested in randomized clinical trials against colorectal cancer and possibly other KRAS mutated tumors. >>>>>>>>>>>>>>>>>> A fasting-mimicking diet and vitamin C turning anti-aging strategies against cancer. Di Tano M, Longo VD. Mol Cell Oncol. 2020 Jul 29;7(5):1791671. doi: 10.1080/23723556.2020.1791671. eCollection 2020. PMID: 32944646 Abstract In search of anti-aging interventions with differential effects on normal and cancer cells, we show that cycles of a fasting-mimicking diet plus pharmacological doses of vitamin C can be effective in targeting KRAS-mutant cancers. This approach represents a promising strategy able to protect the organism while killing cancer cells. Keywords: Fasting-mimicking diet; KRAS-mutant cancers; iron metabolism; vitamin C. Effects of caloric restriction on human physiological, psychological, and behavioral outcomes: highlights from CALERIE phase 2. Dorling JL, van Vliet S, Huffman KM, Kraus WE, Bhapkar M, Pieper CF, Stewart T, Das SK, Racette SB, Roberts SB, Ravussin E, Redman LM, Martin CK. Nutr Rev. 2020 Sep 17:nuaa085. doi: 10.1093/nutrit/nuaa085. Online ahead of print. PMID: 3294069 Abstract Caloric restriction (CR) is a strategy that attenuates aging in multiple nonhuman species. The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trials are part of a research program aiming to test the effects of CR on aging and longevity biomarkers in humans. Building on CALERIE phase 1, CALERIE phase 2 (CALERIE 2) was the largest study to date to assess sustained CR in healthy humans without obesity. In a 24-month randomized controlled trial comprising 218 participants at baseline, CALERIE 2 showed that moderate CR, 11.9% on average, induced improvements in aging-related biomarkers without adversely affecting psychological or behavioral outcomes. The objectives of this report are to summarize and review the highlights of CALERIE 2 and report previously unpublished results on eating disorder symptoms and cognitive function. This article specifically summarizes the physiological, psychological, aging, behavioral, and safety results of the trial. Also provided are research directions beyond CALERIE 2 that highlight important opportunities to investigate the role of CR in aging, longevity, and health span in humans. Keywords: aging; longevity; metabolism; quality of life; randomized controlled trial. Long-term mid-onset dietary restriction rejuvenates hematopoietic stem cells and improves regeneration capacity of total bone marrow from aged mice. Tao S, Wang Y, Wu J, Zeng T, Cui H, Tao Z, Lei L, Yu L, Liu A, Wang H, Zhang L, Tang D. Aging Cell. 2020 Sep 15:e13241. doi: 10.1111/acel.13241. Online ahead of print. PMID: 32935456 Abstract Currently, the world's aging population is expanding rapidly, leading to a rise in aged hematopoietic cell transplantation (HCT) recipients and aged donors. However, the age of donors is negatively related to the prognosis after transplantation due to functional decline in hematopoietic stem cells (HSCs) during aging. Previously, we showed that an early-onset dietary restriction (DR) significantly retards early aging of HSCs. However, the effects of a mid-onset DR on HSCs remain unknown. In the current study, we performed 30% DR in 15- to 18-month-old mice (equivalent to 50-60 human years) for short-term (4 months) and long-term (9 months). We show that DR reduces and rectifies the imbalance of the HSC pool in aged mice. Short-term DR improves hematopoietic reconstitution in purified HSC transplantations, but not in bone marrow transplantations. Intriguingly, long-term mid-onset DR improves the hematopoietic regeneration of aging HSCs with a particular enhancement of lymphoid outputs even in total bone marrow transplantation settings. Mechanistically, long-term DR rejuvenates the aberrantly regulated mitochondrial pathways in aging HSCs and is accompanied by increased quiescence and reduced DNA damage signaling in HSCs. Short-term DR showed a similar trend of rescuing these aging hallmarks but to a much lesser extent. Together, the current study suggests that mid-onset DR ameliorates the function of aging HSCs and long-term DR even improved hematopoietic reconstitution in bone marrow transplantation, which could potentially have considerable implications in HCT of humans when only old donors are available. Keywords: aging; bone marrow transplantation; dietary restriction; hematopoietic stem cells.
  8. AlPater


    https://bmjopen.bmj.com/content/bmjopen/10/8/e036976.full.pdf "Adjusted for age, smoking, drinking, BMI, living alone status, household income, educational level, rural residence, ADL disability, hand grip strength, HDL-C, triglyceride, haemoglobin, hypertension, HBS/diabetes, history of stroke, cancer, heart disease, lung disease, liver disease, kidney disease, digestive disease, asthma, arthritis, psychological problem and memory problem."
  9. Obstructive Sleep Apnea and Risk for Incident Vertebral and Hip Fracture in Women. Huang T, Tworoger SS, Redline S, Curhan GC, Paik JM. J Bone Miner Res. 2020 Sep 9. doi: 10.1002/jbmr.4127. Online ahead of print. PMID: 32909307 Abstract Recent studies suggest a positive association between obstructive sleep apnea (OSA), a disorder associated with intermittent hypoxia and sleep fragmentation, and derangements in bone metabolism. However, no prospective study to date has investigated the association between OSA and fracture risk in women. We conducted a prospective study examining the relation between OSA and risk of incident vertebral fracture (VF) and hip fracture (HF) in the Nurses' Health Study. History of physician-diagnosed OSA was assessed by self-reported questionnaires. A previous validation study demonstrated high concordance between self-reports and medical record identification of OSA. OSA severity was further categorized according to the presence or absence of self-reported sleepiness. Self-reports of VF were confirmed by medical record review. Self-reported HF was assessed by biennial questionnaires. Cox proportional-hazards models estimated the hazard ratio for fracture according to OSA status, adjusted for potential confounders, including BMI, physical activity, calcium intake, history of osteoporosis, and falls, and use of sleep medications. Among 55,264 women without prior history of fracture, physician-diagnosed OSA was self-reported in 1.3% in 2002 and increased to 3.3% by 2012. Between 2002 and 2014, 461 incident VF cases and 921 incident HF cases were documented. The multivariable-adjusted hazard ratio (HR) for confirmed VF for women with history of OSA was 2.00 (95% CI, 1.29-3.12) compared with no OSA history, with the strongest association observed for OSA with daytime sleepiness (HR 2.86; 95% CI, 1.31-6.21). No association was observed between OSA history and self-reported HF risk (HR 0.83; 95% CI, 0.49-1.43). History of OSA is independently associated with higher risk of confirmed VF but did not have a statistically significant association with self-reported HF in women. Further research is warranted in understanding the role of OSA and intermittent hypoxia in bone metabolism and health that may differ by fracture site. Keywords: HIP FRACTURE; NURSES' HEALTH STUDY; OBSTRUCTIVE SLEEP APNEA; PROSPECTIVE STUDY; VERTEBRAL FRACTURE. Intake of carbohydrates and SFA and risk of CHD in middle-age adults: the Hordaland Health Study (HUSK). Haugsgjerd TR, Egeland GM, Nygård OK, Igland J, Sulo G, Lysne V, Vinknes KJ, Bjornevik K, Tell GS. Public Health Nutr. 2020 Sep 10:1-15. doi: 10.1017/S1368980020003043. Online ahead of print. PMID: 32907659 https://sci-hub.tw/https://www.cambridge.org/core/journals/public-health-nutrition/article/intake-of-carbohydrates-and-sfa-and-risk-of-chd-in-middleage-adults-the-hordaland-health-study-husk/7739244CD6380545DAC7687B66063A2C Abstract Objective: Limiting SFA intake may minimise the risk of CHD. However, such reduction often leads to increased intake of carbohydrates. We aimed to evaluate associations and the interplay of carbohydrate and SFA intake on CHD risk. Design: Prospective cohort study. Setting: We followed participants in the Hordaland Health Study, Norway from 1997-1999 through 2009. Information on carbohydrate and SFA intake was obtained from a FFQ and analysed as continuous and categorical (quartiles) variables. Multivariable Cox regression estimated hazard ratios (HR) and 95 % CI. Theoretical substitution analyses modelled the substitution of carbohydrates with other nutrients. CHD was defined as fatal or non-fatal CHD (ICD9 codes 410-414 and ICD10 codes I20-I25). Participants: 2995 men and women, aged 46-49 years. Results: Adjusting for age, sex, energy intake, physical activity and smoking, SFA was associated with lower risk (HRQ4 v. Q1 0·44, 95 % CI 0·26, 0·76, Ptrend = 0·002). For carbohydrates, the opposite pattern was observed (HRQ4 v. Q1 2·10, 95 % CI 1·22, 3·63, Ptrend = 0·003). SFA from cheese was associated with lower CHD risk (HRQ4 v. Q1 0·44, 95 % CI 0·24, 0·83, Ptrend = 0·006), while there were no associations between SFA from other food items and CHD. A 5 E% substitution of carbohydrates with total fat, but not SFA, was associated with lower CHD risk (HR 0·75, 95 % CI 0·62, 0·90). Conclusions: Higher intake of predominantly high glycaemic carbohydrates and lower intake of SFA, specifically lower intake from cheese, were associated with higher CHD risk. Substituting carbohydrates with total fat, but not SFA, was associated with significantly lower risk of CHD. Keywords: CHD; Carbohydrates; Cohort; SFA. Association between high blood pressure and long term cardiovascular events in young adults: systematic review and meta-analysis. Luo D, Cheng Y, Zhang H, Ba M, Chen P, Li H, Chen K, Sha W, Zhang C, Chen H. BMJ. 2020 Sep 9;370:m3222. doi: 10.1136/bmj.m3222. PMID: 32907799 Abstract Objective: To evaluate and quantify the future risk of cardiovascular events in young adults with high blood pressure. Design: Systematic review and meta-analysis. Data sources: Medline, Embase, and Web of Science were searched from inception to 6 March 2020. Relative risks were pooled using a random effects model and expressed with 95% confidence intervals. Absolute risk difference was calculated. Dose-response relations between blood pressure and individual outcomes were assessed by a restricted cubic spline model. Eligibility criteria for selecting studies: Studies were selected that investigated the adverse outcomes of adults aged 18-45 with raised blood pressure. The primary study outcome was a composite of total cardiovascular events. Coronary heart disease, stroke, and all cause mortality were examined as secondary outcomes. Results: Seventeen observational cohorts consisting of approximately 4.5 million young adults were included in the analysis. The average follow-up was 14.7 years. Young adults with normal blood pressure had increased risk of cardiovascular events compared with those with optimal blood pressure (relative risk 1.19, 95% confidence interval 1.08 to 1.31; risk difference 0.37, 95% confidence interval 0.16 to 0.61 per 1000 person years). A graded, progressive association was found between blood pressure categories and increased risk of cardiovascular events (high normal blood pressure: relative risk 1.35, 95% confidence interval 1.22 to 1.49; risk difference 0.69, 95% confidence interval 0.43 to 0.97 per 1000 person years; grade 1 hypertension: 1.92, 1.68 to 2.19; 1.81, 1.34 to 2.34; grade 2 hypertension: 3.15, 2.31 to 4.29; 4.24, 2.58 to 6.48). Similar results were observed for coronary heart disease and stroke. Generally, the population attributable fraction for cardiovascular events associated with raised blood pressure was 23.8% (95% confidence interval 17.9% to 28.8%). The number needed to treat for one year to prevent one cardiovascular event was estimated at 2672 (95% confidence interval 1639 to 6250) for participants with normal blood pressure, 1450 (1031 to 2326) for those with high normal blood pressure, 552 (427 to 746) for those with grade 1 hypertension, and 236 (154 to 388) for those with grade 2 hypertension. Conclusions: Young adults with raised blood pressure might have a slightly increased risk of cardiovascular events in later life. Because the evidence for blood pressure lowering is limited, active interventions should be cautious and warrant further investigation. The association of healthy behaviors with cognitive health expectancy in Chinese older adults: a population-based cohort study. Hou C, Lin Y, Zimmer Z, Fang X. Aging (Albany NY). 2020 Sep 9;12. doi: 10.18632/aging.103617. Online ahead of print. PMID: 32903212 Abstract Objective: To examine how lifestyles and leisure activities are associated with cognitive health expectancy among older adults. Results: For young-old (aged 65), an absolute increase in life years without cognitive impairment was found among those with a healthy diet, engaging in mental activities and in social activities. For old-old (aged 85), an absolute increase was found for men engaging in physical activities besides those. Compared with counterparts in a high risk group, the young-old in a medium-low risk group had a smaller proportion of years without cognitive impairment. Old-old in a low risk group had a greater proportion. Conclusion: Extra years of life gained by a healthy dietary pattern, mental activities, and social activities are free of cognitive impairment for both sexes across ages. The beneficial impact of individual and combined modifiable factors on cognitive health is most prominent in old-old. Methods: Data come from The Chinese Longitudinal Healthy Longevity Survey, a population-based cohort study of 27,193 participants aged 65+ conducted between 2002 and 2014. Smoking status, alcohol consumption, dietary pattern, marital status, physical, mental, social, and productive activities were assessed at baseline. Cognitive status was measured using the Chinese version of the MMSE. Keywords: Markov multistate model; cognitive impairment; leisure activities; life expectancy; life styles.
  10. AlPater

    Al's CR updates

    Dietary restriction and/or exercise training impairs spermatogenesis in normal rats. Li Y, Zhang L, Zheng X, Qian J, Li Y, Xie C, Zhang X, Zhou Y, Huang H. Appl Physiol Nutr Metab. 2020 Sep 9. doi: 10.1139/apnm-2020-0477. Online ahead of print. PMID: 32905708 Abstract Dietary restriction and/or exercise has been shown to have multiple benefits for health. However, its effects on reproductive health and the mechanisms by which it regulates reproductive function remain unclear. Here, in order to evaluate its effects on spermatogenesis and sperm function, rats were divided into four groups: ad libitum-fed sedentary control (CO), dietary restriction (DR), exercise training (ET), and dietary restriction plus exercise training (DR+ET) groups. Results indicated that body weight, epididymal fat pad weight, and sperm counts were significantly reduced in the DR, ET, and DR+ET groups. Moreover, sperm motility and capacitation-associated protein tyrosine phosphorylation were suppressed in the DR and DR+ET groups, but not the ET group. Microarray analysis revealed that the number of downregulated genes was higher than that of upregulated genes in the DR and/or ET groups. About half of the downregulated genes are common after exercise training and/or diet restriction. Gene ontology analysis showed that downregulated genes in the DR, ET, and DR+ET groups affected spermatogenesis through overlapping pathways, including glucocorticoid, corticosteroid, extracellular structure organization, and estradiol responses. Our findings suggest that diet restriction and/or exercise training may present potential risks to male reproductive dysfunction by disrupting normal gene expression patterns in the testis. Novelty bullets: 1. Dietary restriction and/or exercise can lead to the damage of spermatogenesis as well as sperm maturation. 2. Sperm functional changes are more sensitive to dietary restriction than exercise training. 3. Dietary restriction and exercise impair spermatogenesis through overlapping biological pathways in the testis.
  11. Metabolic adaptation to calorie restriction. Guijas C, Montenegro-Burke JR, Cintron-Colon R, Domingo-Almenara X, Sanchez-Alavez M, Aguirre CA, Shankar K, Majumder EL, Billings E, Conti B, Siuzdak G. Sci Signal. 2020 Sep 8;13(648):eabb2490. doi: 10.1126/scisignal.abb2490. PMID: 32900879 Abstract Calorie restriction (CR) enhances health span (the length of time that an organism remains healthy) and increases longevity across species. In mice, these beneficial effects are partly mediated by the lowering of core body temperature that occurs during CR. Conversely, the favorable effects of CR on health span are mitigated by elevating ambient temperature to thermoneutrality (30°C), a condition in which hypothermia is blunted. In this study, we compared the global metabolic response to CR of mice housed at 22°C (the standard housing temperature) or at 30°C and found that thermoneutrality reverted 39 and 78% of total systemic or hypothalamic metabolic variations caused by CR, respectively. Systemic changes included pathways that control fuel use and energy expenditure during CR. Cognitive computing-assisted analysis of these metabolomics results helped to prioritize potential active metabolites that modulated the hypothermic response to CR. Last, we demonstrated with pharmacological approaches that nitric oxide (NO) produced through the citrulline-NO pathway promotes CR-triggered hypothermia and that leucine enkephalin directly controls core body temperature when exogenously injected into the hypothalamus. Because thermoneutrality counteracts CR-enhanced health span, the multiple metabolites and pathways altered by thermoneutrality may represent targets for mimicking CR-associated effects. The Association of Dietary Macronutrients with Lung Function in Healthy Adults Using the Ansan-Ansung Cohort Study. Lee SA, Joshi P, Kim Y, Kang D, Kim WJ. Nutrients. 2020 Sep 3;12(9):E2688. doi: 10.3390/nu12092688. PMID: 32899146 Abstract This study is aimed to examine the association between macronutrient intake and lung function in healthy adults (n = 5880) using the Ansan-Ansung cohort study. To identify the index of lung function, we used the percentage difference of predicted Forced Expiratory Volume (%FEV1_diff) between baseline and follow-up. Based on the median %FEV1_diff, subjects were classified by two groups as "decreased vs. unchanged/improved". The dietary macronutrients were estimated and validated using the food-frequency questionnaire. Multiple logistic regression models were used to evaluate the association after adjusting for confounders. Advanced analysis examined the association after stratifying by age and obesity. The average of %FEV1 is 114.1 and 112.5 at baseline and follow-up, respectively. The positive association of protein and fiber intake with lung function was observed in men. Low fat and high carbohydrate intake decreased the lung function in women only. After stratification by age, the association of protein, fat, and carbohydrate intake with lung function was observed in young men and old women only. Otherwise, the association of protein and fiber with lung function was influenced by abdominal obesity. In conclusion, the lung function was positively associated with high protein and fat intake, but was negatively associated with high carbohydrate intake, which could be influenced by age and obesity. Keywords: difference of FEV1; longitudinal study; lung function of healthy population; macronutrient; obese. The Association Between Dietary Choline and Betaine With the Risk of Type 2 Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study. Dibaba DT, Johnson KC, Kucharska-Newton AM, Meyer K, Zeisel SH, Bidulescu A. Diabetes Care. 2020 Sep 8:dc200733. doi: 10.2337/dc20-0733. Online ahead of print. PMID: 32900787 Abstract Objective: To examine the association between dietary intake of choline and betaine with the risk of type 2 diabetes. Research design and methods: Among 13,440 Atherosclerosis Risk in Communities (ARIC) study participants, the prospective longitudinal association between dietary choline and betaine intake and the risk of type 2 diabetes was assessed using interval-censored Cox proportional hazards and logistic regression models adjusted for baseline potential confounding variables. Results: Among 13,440 participants (55% women, mean age 54 [SD 7.4] years), 1,396 developed incident type 2 diabetes during median follow-up of 9 years from 1987 to 1998. There was no statistically significant association between every 1-SD increase in dietary choline and risk of type 2 diabetes (hazard ratio 1.01 [95% CI 0.87, 1.16]) nor between dietary betaine intake and the risk of type 2 diabetes (HR 1.01 [0.94, 1.10]). Those in the highest quartile of dietary choline intake did not have a statistically significant higher risk of type 2 diabetes than those in the lowest choline quartile (HR 1.09 [0.84, 1.42]); similarly, dietary betaine intake was not associated with the risk of type 2 diabetes comparing the highest quartile to the lowest (HR 1.06 [0.87, 1.29]). Among women, there was a higher risk of type 2 diabetes, comparing the highest to lowest dietary choline quartile (HR 1.54 [1.06, 2.25]), while in men, the association was null (HR 0.82 [0.57, 1.17]). Nevertheless, there was a nonsignificant interaction between high choline intake and sex on the risk of type 2 diabetes (P = 0.07). The results from logistic regression were similar. Conclusions: Overall and among male participants, dietary choline or betaine intakes were not associated with the risk of type 2 diabetes. Among female participants, there was a trend for a modestly higher risk of type 2 diabetes among those with the highest as compared with the lowest quartile of dietary choline intake. Our study should inform clinical trials on dietary choline and betaine supplementation in relationship with the risk of type 2 diabetes. Bisphosphonates and risk of cancers: a systematic review and meta-analysis. Li YY, Gao LJ, Zhang YX, Liu SJ, Cheng S, Liu YP, Jia CX. Br J Cancer. 2020 Sep 9. doi: 10.1038/s41416-020-01043-9. Online ahead of print. PMID: 32901134 Abstract Background: It is unclear whether bisphosphonates are associated with risk of cancers. Therefore, this meta-analysis aimed to evaluate the effect of bisphosphonates on overall cancers. Methods: A search in Pubmed, Embase, Cochrane Library and Web of Science databases was conducted, from the inception date of each resource to September 26, 2019. The summarised effect estimates with 95% CIs were calculated using a random-effect model. Heterogeneity and publication bias were explored. Results: Thirty-four articles were included in this study (4,508,261 participants; 403,196 cases). The results revealed that bisphosphonates significantly decreased the risk of colorectal cancer (RR = 0.89, 95% CI: 0.81-0.98), breast cancer (RR = 0.87, 95% CI: 0.82-0.93) and endometrial cancer (RR = 0.75, 95% CI: 0.61-0.94), but no significant association was observed in all-cause cancer. Furthermore, nitrogen-containing bisphosphonates only had protective effects both on breast cancer (RR = 0.94, 95% CI: 0.90-0.99) and endometrial cancer (RR = 0.70, 95% CI: 0.54-0.92). Non-nitrogen-containing bisphosphonates tended to increase the risk of liver cancer (RR = 2.14, 95% CI: 1.23-3.72) and pancreas cancer (RR = 1.75, 95% CI: 1.32-2.33). Conclusion: Bisphosphonates are significantly associated with risk reduction of colorectal, breast and endometrial cancer, especially nitrogen-containing bisphosphonates. It should be noted that non-nitrogen-containing bisphosphonates might increase the risk of liver and pancreas cancer. Large prospective cohort studies are needed to find the causal association between bisphosphonates and risk of cancers. Body mass index change and estimated glomerular filtration rate decline in a middle-aged population: health check-based cohort in Japan. Fukuma S, Ikenoue T, Bragg-Gresham J, Norton E, Yamada Y, Kohmoto D, Saran R. BMJ Open. 2020 Sep 6;10(9):e037247. doi: 10.1136/bmjopen-2020-037247. PMID: 32895282 Abstract Background: Obesity is a growing public health problem worldwide. We evaluated the mediators and association between changes in obesity metrics and renal outcomes in the general population. Methods: Using the Japanese nationwide health check-based cohort from April 2011 to March 2019, we selected individuals aged 40-74 years, with a baseline estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2, whose body mass index (BMI) change was assessed. The primary outcome was combined 30% decline in eGFR, eGFR <15 mL/min/1.73 m2 and end-stage renal disease. Results: During 245 147 person-years' follow-up among 50 604 participants (mean eGFR, 83.7 mL/min/1.73 m2; mean BMI, 24.1 kg/m2), 645 demonstrated eGFR decline (incidence rate 2.6/1000 person-years, 95% CI: 2.4 to 2.8). We observed continued initial changes in BMI for over 6 years and a U-shaped association between BMI change and eGFR decline. Compared with 0% change in BMI, adjusted HRs for changes of -10%, -4%, 4% and 10% were 1.53 (95% CI: 1.15 to 2.04), 1.14 (95% CI: 1.01 to 1.30), 1.16 (95% CI: 1.02 to 1.32) and 1.87 (95% CI: 1.25 to 2.80), respectively. The percentage of excess risk of BMI increase (>4%) mediated by three risk factors (blood pressure, haemoglobin A1c and total cholesterol), was 13.3%. Conclusion: In the middle-aged Japanese population, both, increase and decrease in BMI were associated with subsequent eGFR decline. Changes in risk factors mediated a small proportion of the association between BMI increase and eGFR decline. Our findings support the clinical significance of monitoring BMI as a renal risk factor. Keywords: epidemiology; nephrology; nutrition & dietetics; public health. Fermented soy products intake and risk of cardiovascular disease and total cancer incidence: The Japan Public Health Center-based Prospective study. Nozue M, Shimazu T, Charvat H, Mori N, Mutoh M, Sawada N, Iwasaki M, Yamaji T, Inoue M, Kokubo Y, Yamagishi K, Iso H, Tsugane S. Eur J Clin Nutr. 2020 Sep 4. doi: 10.1038/s41430-020-00732-1. Online ahead of print. PMID: 32887936 Abstract Background/objectives: The association of fermented soy products, separately from total soy products, with cardiovascular disease (CVD) and total cancer has not been reported. We examined this association in a population-based prospective cohort study in Japan. Subjects/methods: We studied 79,648 participants (42,788 women; 36,860 men) aged 45-74 years without a history of cancer, myocardial infarction, or stroke. Participants completed a food frequency questionnaire (1995-1998) and were followed to 2009-2012. Cox proportional hazards regression analysis was used to calculate the hazard ratios (HR) and 95% confidence intervals (CI) of incidence of CVD and total cancer according to quartiles of total soy products, nonfermented soy products, fermented soy products, miso soup, natto, total isoflavones from soy products, isoflavones from nonfermented soy products, and isoflavones from fermented soy products. Results: In women, we observed a significant inverse association between fermented soy product intake and the risk of CVD (multivariate HR in the highest compared with the lowest quartile of fermented soy product intake: 0.80; 95% CI: 0.68, 0.95; P for trend = 0.010), and also found significant inverse associations for natto and isoflavones among fermented soy products. In site-specific analysis, we observed a similar, significant inverse association between fermented soy product intake and the risk of stroke in women. We found no significant association between any soy product and risk of CVD in men or total cancer in both sexes. Conclusions: Intake of fermented soy products such as natto was inversely associated with the risk of CVD in women.
  12. Mechanisms underlying familial aggregation of exceptional health and survival: A three-generation cohort study. Christensen K, Wojczynski MK, Pedersen JK, Larsen LA, Kløjgaard S, Skytthe A, McGue M, Vaupel JW, Province MA. Aging Cell. 2020 Sep 4:e13228. doi: 10.1111/acel.13228. Online ahead of print. PMID: 32886847 https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/acel.13228 Abstract The familial resemblance in length of adult life is very modest. Studies of parent-offspring and twins suggest that exceptional health and survival have a stronger genetic component than lifespan generally. To shed light on the underlying mechanisms, we collected information on Danish long-lived siblings (born 1886-1938) from 659 families, their 5379 offspring (born 1917-1982), and 10,398 grandchildren (born 1950-2010) and matched background population controls through the Danish 1916 Census, the Civil Registration System, the National Patient Register, and the Register of Causes of Death. Comparison with the background, population revealed consistently lower occurrence of almost all disease groups and causes of death in the offspring and the grandchildren. The expected incidence of hospitalization for mental and behavioral disorders was reduced by half in the offspring (hazard ratio 0.53, 95% confidence interval 0.45-0.62) and by one-third in the grandchildren (0.69, 0.61-0.78), while the numbers for tobacco-related cancer were 0.60 (0.51-0.70) and 0.71 (0.48-1.05), respectively. Within-family analyses showed a general, as opposed to specific, lowering of disease risk. Early parenthood and divorce were markedly less frequent in the longevity-enriched families, while economic and educational differences were small to moderate. The longevity-enriched families in this study have a general health advantage spanning three generations. The particularly low occurrence of mental and behavioral disorders and tobacco-related cancers together with indicators of family stability and only modest socioeconomic advantage implicate behavior as a key mechanism underlying familial aggregation of exceptional health and survival. Keywords: family study; healthy aging; longevity; multi-generation study. Association of Cardiovascular Risk Factors and APOE Polymorphism with Mortality in the Oldest Old: A 21-Year Cohort Study. Vivian L, Bruscato NM, Werle BM, Carli W, Soares RAG, Santos PCJL, Moriguchi EH. Arq Bras Cardiol. 2020 Aug 28:S0066-782X2020005010201. doi: 10.36660/abc.20190263. Online ahead of print. PMID: 32876203 English, Portuguese. Abstract Background Knowledge of environmental and genetic factors for healthy aging in elderly people is controversial. In addition to this evidence, few studies have been designed for this population. Objectives To investigate the relationship between the most frequent apolipoprotein E (APOE) genotypes and mortality in very elderly individuals living in a community and to evaluate survival according to cardiovascular risk factors. Methods A sample of 74 elderly individuals aged ≥ 80 years, from the Veranópolis Project cohort, was selected for APOE genotyping. At baseline, anthropometric variables, glucose and lipid levels, blood pressure, and lifestyle variables (smoking, alcohol consumption, and physical activity) were collected. The Bayer Activities of Daily Living Scale was applied to their caregivers. Total study follow-up was 21 years. Two-sided p < 0.05 was considered statistically significant. Results There was no association between APOE genotypes and mortality. However, the risk of death in elderly smokers was 2.30 times higher (hazard ratio {HR}, 95% CI 1.01 to 5.24); in individuals with diabetes, it was 3.95 times higher (HR, 95% CI 1.27 to 12.30) than in individuals without diabetes. Subjects who practiced vigorous physical activity had a 51% reduction in risk of death (HR = 0.49, 95% CI 0.27 to 0.88). For an increase of 1 mmHg in systolic blood pressure, there was a 2% reduction (HR = 0.98, 95% CI 0.97 to 0.99) in risk of death.Conclusion: In this sample population, APOE genotypes were not associated with mortality. However, classic cardiovascular risk factors may be important for overall mortality in the very elderly. Intermittent Fasting Attenuates Exercise Training-Induced Cardiac Remodeling. Basilio PG, Oliveira APC, Castro ACF, Carvalho MR, Zagatto AM, Martinez PF, Okoshi MP, Okoshi K, Ota GE, Reis FAD, Oliveira-Junior SA. Arq Bras Cardiol. 2020 Aug 28;115(2):184-193. doi: 10.36660/abc.20190349. PMID: 32876182 Abstract in En , Portuguese https://www.scielo.br/pdf/abc/v115n2/en_0066-782X-abc-115-02-0184.pdf Background: The effects of non-pharmacological interventions such as calorie restriction and exercise training on health and prevention of cardiovascular diseases have been investigated in clinical and experimental studies. Objective: To analyze the influence of intermittent fasting and exercise training on functional fitness, glycemia and cardiac remodeling. Methods: Wistar rats (n=60) were randomly divided into four groups: control, exercise training (ET), intermittent fasting (IF) and exercise training plus intermittent fasting (ETI). Over 12 weeks, control and ET animals were fed daily a standard commercial diet ad libitum , while IF and ETI animals were fed every other day. In addition, the ET and ETI groups were submitted to a running protocol on a treadmill. After this period, functional fitness, nutritional parameters and blood glucose levels were analyzed. In addition to heart morphology, myocardial protein expression of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) was assessed by Western-blot. The results were analyzed using two-way ANOVA and Student-Newman-Keuls test. The level of significance considered was 5%. Results: Exercise training increased functional fitness in the ET and ETI groups and promoted cardiac fibrosis. The combination of intermittent fasting and exercise training resulted in a smaller area under the blood glucose curve and reduced cardiomyocyte cross-sectional area and interstitial collagen fraction in the ETI group compared to ET. ERK and JNK expression levels were similar among groups (p>0.05). Conclusions: Intermittent fasting is associated with improved glucose tolerance and attenuates cardiac remodeling induced by exercise training. HNF4α regulates sulfur amino acid metabolism and confers sensitivity to methionine restriction in liver cancer. Xu Q, Li Y, Gao X, Kang K, Williams JG, Tong L, Liu J, Ji M, Deterding LJ, Tong X, Locasale JW, Li L, Shats I, Li X. Nat Commun. 2020 Aug 7;11(1):3978. doi: 10.1038/s41467-020-17818-w. PMID: 32770044 Free PMC article Abstract Methionine restriction, a dietary regimen that protects against metabolic diseases and aging, represses cancer growth and improves cancer therapy. However, the response of different cancer cells to this nutritional manipulation is highly variable, and the molecular determinants of this heterogeneity remain poorly understood. Here we report that hepatocyte nuclear factor 4α (HNF4α) dictates the sensitivity of liver cancer to methionine restriction. We show that hepatic sulfur amino acid (SAA) metabolism is under transcriptional control of HNF4α. Knocking down HNF4α or SAA enzymes in HNF4α-positive epithelial liver cancer lines impairs SAA metabolism, increases resistance to methionine restriction or sorafenib, promotes epithelial-mesenchymal transition, and induces cell migration. Conversely, genetic or metabolic restoration of the transsulfuration pathway in SAA metabolism significantly alleviates the outcomes induced by HNF4α deficiency in liver cancer cells. Our study identifies HNF4α as a regulator of hepatic SAA metabolism that regulates the sensitivity of liver cancer to methionine restriction.
  13. AlPater

    Al's CR updates

    Amyloidosis increase is not attenuated by long-term calorie restriction or related to neuron density in the prefrontal cortex of extremely aged rhesus macaques. Stonebarger GA, Urbanski HF, Woltjer RL, Vaughan KL, Ingram DK, Schultz PL, Calderazzo SM, Siedeman JA, Mattison JA, Rosene DL, Kohama SG. Geroscience. 2020 Sep 2. doi: 10.1007/s11357-020-00259-0. Online ahead of print. PMID: 32876855 Abstract As human lifespan increases and the population ages, diseases of aging such as Alzheimer's disease (AD) are a major cause for concern. Although calorie restriction (CR) as an intervention has been shown to increase healthspan in many species, few studies have examined the effects of CR on brain aging in primates. Using postmortem tissue from a cohort of extremely aged rhesus monkeys (22-44 years old, average age 31.8 years) from a longitudinal CR study, we measured immunohistochemically labeled amyloid beta plaques in Brodmann areas 32 and 46 of the prefrontal cortex, areas that play key roles in cognitive processing, are sensitive to aging and, in humans, are also susceptible to AD pathogenesis. We also evaluated these areas for cortical neuron loss, which has not been observed in younger cohorts of aged monkeys. We found a significant increase in plaque density with age, but this was unaffected by diet. Moreover, there was no change in neuron density with age or treatment. These data suggest that even in the oldest-old rhesus macaques, amyloid beta plaques do not lead to overt neuron loss. Hence, the rhesus macaque serves as a pragmatic animal model for normative human aging but is not a complete model of the neurodegeneration of AD. This model of aging may instead prove most useful for determining how even the oldest monkeys are protected from AD, and this information may therefore yield valuable information for clinical AD treatments. Keywords: Aging; Alzheimer’s disease; Amyloid plaques; Diet; Neurodegeneration; Neuron number. Improvement of intestinal stem cells and barrier function via energy restriction in middle-aged C57BL/6 mice. Di W, Lv Y, Xia F, Sheng Y, Liu J, Ding G. Nutr Res. 2020 Jun 26;81:47-57. doi: 10.1016/j.nutres.2020.06.015. Online ahead of print. PMID: 32877836 Abstract This study aimed to reveal the impact of energy restriction on the intestine via structural and molecular changes in terms of intestinal stem cell (ISC) function, ISC niche, intestinal epithelial barrier function, and intestinal immune function. Female C57BL/6J mice, aged 12 months, fed a commercial chow were used in this study. The ISC function, ISC niche, intestinal epithelial barrier function, and intestinal immune function were assessed. Energy restriction reversed aging-induced intestinal shortening and made the crypts shallower. The intestinal epithelial cells isolated from the intestine showed a significant increase in the expression levels of stem cell-associated genes in small intestinal epithelial cells as detected by flow cytometry. Despite the increase in the number of stem cells and the expression levels of markers, no increase or decrease was found in the enteroid complexity of the small intestine and colonic enteroid formation in vitro. The colonic mucous layer was measured in mice of the energy restricted (ER)-treated group to investigate the epithelial barrier function in the colon. The results revealed that the barrier was more complete. The fluorescence intensity of tight junction markers claudin-2 and zonula occludens-1 increased and the mRNA expression profiles of monocyte chemotactic protein 1 and interleukin-6 decreased in the colon of mice in the ER-treated group. The beneficial effects of ER on the colon in terms of the integrity of the mucosal barrier and alleviation of inflammation were confirmed, thus highlighting the importance of modulating the intestinal function in developing effective antiaging dietary interventions. Keywords: Aging; Energy restriction; Intestinal barrier; Intestinal epithelial cell; Intestinal epithelial stem cell.
  14. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S, Diaz JV, Slutsky AS, Villar J, Angus DC, Annane D, Azevedo LCP, Berwanger O, Cavalcanti AB, Dequin PF, Du B, Emberson J, Fisher D, Giraudeau B, Gordon AC, Granholm A, Green C, Haynes R, Heming N, Higgins JPT, Horby P, Jüni P, Landray MJ, Le Gouge A, Leclerc M, Lim WS, Machado FR, McArthur C, Meziani F, Møller MH, Perner A, Petersen MW, Savovic J, Tomazini B, Veiga VC, Webb S, Marshall JC. JAMA. 2020 Sep 2. doi: 10.1001/jama.2020.17023. Online ahead of print. PMID: 32876694 Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial. Tomazini BM, Maia IS, Cavalcanti AB, Berwanger O, Rosa RG, Veiga VC, Avezum A, Lopes RD, Bueno FR, Silva MVAO, Baldassare FP, Costa ELV, Moura RAB, Honorato MO, Costa AN, Damiani LP, Lisboa T, Kawano-Dourado L, Zampieri FG, Olivato GB, Righy C, Amendola CP, Roepke RML, Freitas DHM, Forte DN, Freitas FGR, Fernandes CCF, Melro LMG, Junior GFS, Morais DC, Zung S, Machado FR, Azevedo LCP; COALITION COVID-19 Brazil III Investigators. JAMA. 2020 Sep 2. doi: 10.1001/jama.2020.17021. Online ahead of print. PMID: 32876695
  15. Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice. Asadi Shahmirzadi A, Edgar D, Liao CY, Hsu YM, Lucanic M, Asadi Shahmirzadi A, Wiley CD, Gan G, Kim DE, Kasler HG, Kuehnemann C, Kaplowitz B, Bhaumik D, Riley RR, Kennedy BK, Lithgow GJ. Cell Metab. 2020 Sep 1;32(3):447-456.e6. doi: 10.1016/j.cmet.2020.08.004. PMID: 32877690