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  1. AlPater

    Oldest Man 111

    Gymnastics 'I love life': Oldest living Olympic champion turns 100 Agnes Keleti survived Holocaust, won 10 Olympic medals and is still celebrating life Justin Spike · The Associated Press · Posted: Jan 09, 2021 https://www.cbc.ca/sports/olympics/summer/gymnastics/agnes-keleti-oldest-olympian-turns-100-1.5867686
  2. L-Arginine Exerts Excellent Anti-Stress Effects on Stress-Induced Shortened Lifespan, Cognitive Decline and Depression. Pervin M, Unno K, Konishi T, Nakamura Y. Int J Mol Sci. 2021 Jan 6;22(2):E508. doi: 10.3390/ijms22020508. PMID: 33419170 Abstract The anti-stress potential of dietary L-arginine (Arg) was assessed in psychosocially stress-loaded senescence-accelerated (SAMP10) mice. Although this strain of mouse is sensitive to stress, daily administration of Arg at 3 mg/kg significantly suppressed aging-related cognitive decline and behavioral depression at nine months of age and counteracted stress-induced shortened lifespan. To investigate the mechanism of the anti-stress effect of Arg in the brain, early changes in oxidative damage and gene expression levels were measured using SAMP10 mice that were stress-loaded for three days. Increased lipid peroxidation in the brains of stressed mice was significantly lowered by Arg intake. Several genes associated with oxidative stress response and neuronal excitotoxic cell death, including Nr4a1, Arc, and Cyr61, remarkably increased in response to psychosocial stress; however, their expression was significantly suppressed in mice that ingested Arg even under stress conditions. In contrast, the genes that maintain mitochondrial functions and neuronal survival, including Hba-a2 and Hbb-b2, were significantly increased in mice that ingested Arg. These results indicate that Arg reduces oxidative damage and enhances mitochondrial functions in the brain. We suggest that the daily intake of Arg plays important roles in reducing stress-induced brain damage and slowing aging. Keywords: aging; arginine; brain; chronic psychosocial stress; depression; oxidative damage; shortened lifespan. Dietary carotenoids related to risk of incident Alzheimer dementia (AD) and brain AD neuropathology: a community-based cohort of older adults. Yuan C, Chen H, Wang Y, Schneider JA, Willett WC, Morris MC. Am J Clin Nutr. 2020 Nov 12;113(1):200-8. doi: 10.1093/ajcn/nqaa303. Online ahead of print. PMID: 33184623 Free PMC article. Abstract Background: Studies have reported a protective relation to cognitive decline with long-term intake of total and individual dietary carotenoids. However, the underlying mechanisms have not yet been clearly established in humans. Objectives: To evaluate the prospective association between intakes of total and individual carotenoids and risk of incident Alzheimer dementia (AD) and explore the underlying neuropathological basis. Methods: Among 927 participants from the Rush Memory and Aging Project who were free from AD at baseline and were followed up for a mean of 7 y, we estimated HRs for AD using Cox proportional hazards models by intakes of energy-adjusted carotenoids. Brain AD neuropathology was assessed in postmortem brain autopsies among 508 deceased participants. We used linear regression to assess the association of carotenoid intake with AD-related neuropathology. Results: Higher intake of total carotenoids was associated with substantially lower hazard of AD after controlling for age, sex, education, ApoE-ε4, participation in cognitively stimulating activities, and physical activity level. Comparing the top and bottom quintiles (median intake: 24.8 compared with 6.7 mg/d) of total carotenoids, the multivariate HR (95% CI) was 0.52 (0.33, 0.81), P-trend < 0.01. A similar association was observed for lutein-zeaxanthin, a weaker linear inverse association was observed for β-carotene, and a marginally significant linear inverse association was found for β-cryptoxanthin. Among the deceased participants, consumers of higher total carotenoids (top compared with bottom tertile, 18.2 compared with 8.2 mg/d) had less global AD pathology (b: -0.10; SE = 0.04; P-trend = 0.01). For individual carotenoids, lutein-zeaxanthin and lycopene were inversely associated with brain global pathology, whereas lutein-zeaxanthin showed additional inverse associations with AD diagnostic score, neuritic plaque severity, and neurofibrillary tangle density and severity. Conclusions: Our findings support a beneficial role of total carotenoid consumption, in particular lutein/zeaxanthin, on AD incidence that may be related to the inhibition of brain β-amyloid deposition and fibril formation. Keywords: Alzheimer dementia; cognitive function; dietary carotenoids; neuropathology; prospective cohort study. The neutrophil-lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials. Adamstein NH, MacFadyen JG, Rose LM, Glynn RJ, Dey AK, Libby P, Tabas IA, Mehta NN, Ridker PM. Eur Heart J. 2021 Jan 8:ehaa1034. doi: 10.1093/eurheartj/ehaa1034. Online ahead of print. PMID: 33417682 Abstract Aims: The neutrophil-lymphocyte ratio (NLR) is a readily available inflammatory biomarker that may associate with atherosclerosis and predict cardiovascular (CV) events. The aims of this study are to determine whether the NLR predicts incident major adverse cardiovascular events (MACE) and is modified by anti-inflammatory therapy. Methods and results: Baseline and on-treatment NLRs were calculated from complete blood counts among 60 087 participants randomized in the CANTOS, JUPITER, SPIRE-1, SPIRE-2, and CIRT trials to receive placebo or canakinumab, rosuvastatin, bococizumab, or methotrexate, respectively, and followed up for MACE. All analyses were performed first in CANTOS, and then externally validated in the other four trials. For the five trials, hazard ratios for major CV events and mortality comparing NLR quartiles were computed using Cox proportional hazards models, and the effect of each randomized intervention on the NLR was evaluated in comparison to placebo. The NLR modestly correlated with interleukin-6, C-reactive protein, and fibrinogen levels but minimally with lipids. In all five randomized trials, baseline NLR predicted incident CV events and death; the per-quartile increase in risk of MACE was 20% in CANTOS [95% confidence interval (CI) 14-25%, P < 0.0001], 31% in SPIRE-1 (95% CI 14-49%, P = 0.00007), 27% in SPIRE-2 (95% CI 12-43%, P = 0.0002), 9% in CIRT (95% CI 0.2-20%, P = 0.045), and 11% in JUPITER (95% CI 1-22%, P = 0.03). While lipid-lowering agents had no significant impact on the NLR, anti-inflammatory therapy with canakinumab lowered the NLR (P < 0.0001). Conclusion: The NLR, an easily obtained inflammatory biomarker, independently predicts CV risk and all-cause mortality, and is reduced by interleukin-1β blockade with canakinumab. Keywords: Atherosclerosis; Atherothrombosis; Inflammation; Lymphocyte; MACE; Neutrophil. Impact of oral anticoagulation on clinical outcomes of COVID-19: a nationwide cohort study of hospitalized patients in Germany. Fröhlich GM, Jeschke E, Eichler U, Thiele H, Alhariri L, Reinthaler M, Kastrati A, Leistner DM, Skurk C, Landmesser U, Günster C. Clin Res Cardiol. 2021 Jan 8. doi: 10.1007/s00392-020-01783-x. Online ahead of print. PMID: 33416918 Abstract Objectives: The aim of this study was to investigate the impact of concomitant long-term medication-with a focus on ACE inhibitors and oral anticoagulation-on clinical outcomes in patients hospitalized with coronavirus disease 2019. Methods: This is a retrospective cohort study using claims data of the biggest German health insurance company AOK, covering 26.9 million people all over Germany. In particular, patient-related characteristics and co-medication were evaluated. A multivariable logistic regression model was adopted to identify independent predictors for the primary outcome measure of all-cause mortality or need for invasive or non-invasive ventilation or extracorporeal membrane oxygenation. Results: 6637 patients in 853 German hospitals were included. The primary outcome occurred in 1826 patients (27.5%). 1372 patients (20.7%) died, 886 patients (13.3%) needed respiratory support, and 53 patients (0.8%) received extracorporeal membrane oxygenation. 34 of these patients survived (64.2%). The multivariable model demonstrated that pre-existing oral anticoagulation therapy with either vitamin-K antagonists OR 0.57 (95% CI 0.40-0.83, p = 0.003) or direct oral anticoagulants OR 0.71 (95% CI 0.56-0.91, p = 0.007)-but not with antiplatelet therapy alone OR 1.10 (95% CI 0.88-1.23, p = 0.66)-was associated with a lower event rate. This finding was confirmed in a propensity match analysis. Conclusions: In a multivariable analysis, a therapy with both direct oral anticoagulants or vitamin-K antagonists-but not with antiplatelet therapy-was associated with improved clinical outcomes. ACE inhibitors did not impact outcomes. Prospective randomized trials are needed to verify this hypothesis. Keywords: ACE inhibitors; Antiplatelet therapy; COVID-19; DOACs; ECMO; Vitamin-K-antagonist. Study estimates exposure to air pollution increases COVID-19 deaths by 15% worldwide 27 Oct 2020 https://www.escardio.org/The-ESC/Press-Office/Press-releases/study-estimates-exposure-to-air-pollution-increases-covid-19-deaths-by-15-world >>>>>>>>>>>>>>>>>> Regional and global contributions of air pollution to risk of death from COVID-19. Pozzer A, Dominici F, Haines A, Witt C, Münzel T, Lelieveld J. Cardiovasc Res. 2020 Dec 1;116(14):2247-2253. doi: 10.1093/cvr/cvaa288. PMID: 33236040 Abstract Aims: The risk of mortality from the coronavirus disease that emerged in 2019 (COVID-19) is increased by comorbidity from cardiovascular and pulmonary diseases. Air pollution also causes excess mortality from these conditions. Analysis of the first severe acute respiratory syndrome coronavirus (SARS-CoV-1) outcomes in 2003, and preliminary investigations of those for SARS-CoV-2 since 2019, provide evidence that the incidence and severity are related to ambient air pollution. We estimated the fraction of COVID-19 mortality that is attributable to the long-term exposure to ambient fine particulate air pollution. Methods and results: We characterized global exposure to fine particulates based on satellite data, and calculated the anthropogenic fraction with an atmospheric chemistry model. The degree to which air pollution influences COVID-19 mortality was derived from epidemiological data in the USA and China. We estimate that particulate air pollution contributed ∼15% (95% confidence interval 7-33%) to COVID-19 mortality worldwide, 27% (13 - 46%) in East Asia, 19% (8-41%) in Europe, and 17% (6-39%) in North America. Globally, ∼50-60% of the attributable, anthropogenic fraction is related to fossil fuel use, up to 70-80% in Europe, West Asia, and North America. Conclusion: Our results suggest that air pollution is an important cofactor increasing the risk of mortality from COVID-19. This provides extra motivation for combining ambitious policies to reduce air pollution with measures to control the transmission of COVID-19. Keywords: Air pollution; COVID-19; Fine particulate matter; comorbidity; mortality. Timing of Food Intake Drives the Circadian Rhythm of Blood Pressure. Zhang D, Colson JC, Jin C, Becker BK, Rhoads MK, Pati P, Neder TH, King MA, Valcin JA, Tao B, Kasztan M, Paul JR, Bailey SM, Pollock JS, Gamble KL, Pollock DM. Function (Oxf). 2021;2(1):zqaa034. doi: 10.1093/function/zqaa034. Epub 2020 Nov 24. PMID: 33415319 Free PMC article. Abstract Timing of food intake has become a critical factor in determining overall cardiometabolic health. We hypothesized that timing of food intake entrains circadian rhythms of blood pressure (BP) and renal excretion in mice. Male C57BL/6J mice were fed ad libitum or reverse feeding (RF) where food was available at all times of day or only available during the 12-h lights-on period, respectively. Mice eating ad libitum had a significantly higher mean arterial pressure (MAP) during lights-off compared to lights-on (113 ± 2 mmHg vs 100 ± 2 mmHg, respectively; P < 0.0001); however, RF for 6 days inverted the diurnal rhythm of MAP (99 ± 3 vs 110 ± 3 mmHg, respectively; P < 0.0001). In contrast to MAP, diurnal rhythms of urine volume and sodium excretion remained intact after RF. Male Bmal1 knockout mice (Bmal1KO) underwent the same feeding protocol. As previously reported, Bmal1KO mice did not exhibit a diurnal MAP rhythm during ad libitum feeding (95 ± 1 mmHg vs 92 ± 3 mmHg, lights-off vs lights-on; P > 0.05); however, RF induced a diurnal rhythm of MAP (79 ± 3 mmHg vs 95 ± 2 mmHg, lights-off vs lights-on phase; P < 0.01). Transgenic PERIOD2::LUCIFERASE knock-in mice were used to assess the rhythm of the clock protein PERIOD2 in ex vivo tissue cultures. The timing of the PER2::LUC rhythm in the renal cortex and suprachiasmatic nucleus was not affected by RF; however, RF induced significant phase shifts in the liver, renal inner medulla, and adrenal gland. In conclusion, the timing of food intake controls BP rhythms in mice independent of Bmal1, urine volume, or sodium excretion. Keywords: Bmal1; blood pressure; circadian rhythms; sodium excretion; time-restricted feeding.
  3. AlPater

    Al's CR updates

    Caloric Restriction Promotes Immunometabolic Reprogramming Leading to Protection from Tuberculosis. Palma C, La Rocca C, Gigantino V, Aquino G, Piccaro G, Di Silvestre D, Brambilla F, Rossi R, Bonacina F, Lepore MT, Audano M, Mitro N, Botti G, Bruzzaniti S, Fusco C, Procaccini C, De Rosa V, Galgani M, Alviggi C, Puca A, Grassi F, Rezzonico-Jost T, Norata GD, Mauri P, Netea MG, de Candia P, Matarese G. Cell Metab. 2021 Jan 4:S1550-4131(20)30671-9. doi: 10.1016/j.cmet.2020.12.016. Online ahead of print. PMID: 33421383 Abstract There is a strong relationship between metabolic state and susceptibility to Mycobacterium tuberculosis (MTB) infection, with energy metabolism setting the basis for an exaggerated immuno-inflammatory response, which concurs with MTB pathogenesis. Herein, we show that controlled caloric restriction (CR), not leading to malnutrition, protects susceptible DBA/2 mice against pulmonary MTB infection by reducing bacterial load, lung immunopathology, and generation of foam cells, an MTB reservoir in lung granulomas. Mechanistically, CR induced a metabolic shift toward glycolysis, and decreased both fatty acid oxidation and mTOR activity associated with induction of autophagy in immune cells. An integrated multi-omics approach revealed a specific CR-induced metabolomic, transcriptomic, and proteomic signature leading to reduced lung damage and protective remodeling of lung interstitial tightness able to limit MTB spreading. Our data propose CR as a feasible immunometabolic manipulation to control MTB infection, and this approach offers an unexpected strategy to boost immunity against MTB. Keywords: T cells; adipose tissue; body weight; caloric restriction; immune response; immunometabolism; infection; tuberculosis. Effects of dietary restriction on neuroinflammation in neurodegenerative diseases. Fontana L, Ghezzi L, Cross AH, Piccio L. J Exp Med. 2021 Feb 1;218(2):e20190086. doi: 10.1084/jem.20190086. PMID: 33416892 Abstract Recent and accumulating work in experimental animal models and humans shows that diet has a much more pervasive and prominent role than previously thought in modulating neuroinflammatory and neurodegenerative mechanisms leading to some of the most common chronic central nervous system (CNS) diseases. Chronic or intermittent food restriction has profound effects in shaping brain and peripheral metabolism, immunity, and gut microbiome biology. Interactions among calorie intake, meal frequency, diet quality, and the gut microbiome modulate specific metabolic and molecular pathways that regulate cellular, tissue, and organ homeostasis as well as inflammation during normal brain aging and CNS neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, among others. This review discusses these findings and their potential application to the prevention and treatment of CNS neuroinflammatory diseases and the promotion of healthy brain aging.
  4. Al adds: There are currently 1,933,522 (3%) Deaths from COVID-19, despite widespread extreme meassures to curtail infections. I believe that this year's flu deaths were almost irradicated by the extreme measures to curtail COVID-19.
  5. The greatest risk factor for the leading cause of death is ignored. Hayflick L. Biogerontology. 2020 Oct 14. doi: 10.1007/s10522-020-09901-y. Online ahead of print. PMID: 33058001 https://sci-hub.se/10.1007/s10522-020-09901-y Abstract All major United States institutional advocates for research on the biology of aging and for the leading causes of death assert that aging is the greatest risk factor for these deaths. Nevertheless, all fail to support research on the etiology of aging despite having mechanisms to do so. Aging is a problem in physics and not biology. It is a multibillion dollar miss-understanding to believe that the resolution of any or all age associated diseases will reveal information on the underlying aging process. The goal in research on the etiology of aging is to use the new revolutionary methods to study single molecules and their constituent atoms to uncover the qualitative and quantitative status of molecules in old cells that differ from that in young cells. These differences are the conditions that can explain why a common cause may exist for the risk factor for all age-associated diseases. The tyranny of the phrase "research on aging" could apply to almost any human institution. In the absence of a strict definition when used it has become a costly error in gerontology communication. Research on the biology of aging has become its greatest victim. Because aging is a universal manifestation of the fate of all matter, it is the provenance of the National Science Foundation because its stated purpose excludes research in the medical sciences. Keywords: AFAR; Aging; Alzheimer’s association; Etiology of aging; NIA; NIH; NSF; Risk factor; Tyranny of “research on aging”. Partial Replacement of Animal Proteins with Plant Proteins for 12 Weeks Accelerates Bone Turnover Among Healthy Adults: A Randomized Clinical Trial. Itkonen ST, Päivärinta E, Pellinen T, Viitakangas H, Risteli J, Erkkola M, Lamberg-Allardt C, Pajari AM. J Nutr. 2021 Jan 4;151(1):11-19. doi: 10.1093/jn/nxaa264. PMID: 32939557 Abstract Background: Plant-based diets may reduce the risk of chronic diseases, but can also lead to low calcium and vitamin D intakes, posing a risk for bone health. Objectives: We investigated whether partial replacement of animal proteins with plant-based proteins using a whole-diet approach affects bone and mineral metabolism in healthy adults in 3 groups fed diets differing in protein composition. Methods: This 12-week clinical trial was comprised of 107 women and 29 men (20-69 years old; BMI mean ± SD, 24.8 ± 3.9) randomly assigned to consume 1 of 3 diets designed to provide 17 energy percent (E%) protein: "animal" (70% animal protein, 30% plant protein of total protein intake), "50/50" (50% animal, 50% plant), and "plant" (30% animal, 70% plant) diets. We examined differences in bone formation [serum intact procollagen type I amino-terminal propeptide (S-iPINP)], bone resorption [serum collagen type 1 cross-linked C-terminal telopeptide (S-CTX)], mineral metabolism markers (primary outcomes), and nutrient intakes (secondary outcomes) by ANOVA/ANCOVA. Results: S-CTX was significantly higher in the plant group (mean ± SEM, 0.44 ± 0.02 ng/mL) than in the other groups (P values < 0.001 for both), and differed also between the animal (mean ± SEM, 0.29 ± 0.02 ng/mL) and 50/50 groups (mean ± SEM, 0.34 ± 0.02 ng/mL; P = 0.018). S-iPINP was significantly higher in the plant group (mean ± SEM, 63.9 ± 1.91 ng/mL) than in the animal group (mean ± SEM, 55.0 ± 1.82 ng/mL; P = 0.006). In a subgroup without a history of vitamin D supplement use, plasma parathyroid hormone was significantly higher in the plant than in the animal group (P = 0.018). Vitamin D and calcium intakes were below recommended levels in the plant group (mean ± SEM, 6.2 ± 3.7 μg/d and 733 ± 164 mg/d, respectively). Conclusions: Partial replacement of animal proteins with plant-based proteins for 12 weeks increased the markers of bone resorption and formation among healthy adults, indicating a possible risk for bone health. This is probably caused by lower vitamin D and calcium intakes from diets containing more plant-based proteins, but it is unclear whether differences in protein intake or quality play a major role. Keywords: animal protein; bone turnover; calcium; clinical trial; mineral metabolism; plant protein; vitamin D. Association of Objectively Measured Sleep with Frailty and 5-year Mortality in Community-Dwelling Older Adults. Guida JL, Alfini AJ, Gallicchio L, Spira AP, Caporaso NE, Green PA. Sleep. 2021 Jan 6:zsab003. doi: 10.1093/sleep/zsab003. Online ahead of print. PMID: 33406254 Abstract Study objectives: To determine whether actigraphy-measured sleep was independently associated with risk of frailty and mortality over a five-year period among older adults. Methods: We used data from Waves 2 (W2) and 3 (W3) (2010-2015) of the National Social Life, Health and Aging Project, a prospective cohort of community-dwelling older adults born between 1920 and 1947. One-third of W2 respondents were randomly selected to participate in a sleep study, of whom N=727 consented and N=615 were included in the analytic sample. Participants were instructed to wear a wrist actigraph for 72 hours (2.93±0.01 nights). Actigraphic sleep parameters were averaged across nights and included total sleep time, percent sleep, sleep fragmentation index, and wake after sleep onset (WASO). Subjective sleep was collected via questionnaire. Frailty was assessed using modified Fried Frailty Index. Vital status was ascertained at the time of the W3 interview. W3 frailty/mortality status were analyzed jointly with a four-level variable: robust, pre-frail, frail, and deceased. Associations were modeled per 10-unit increase. Results: After controlling for baseline frailty (robust and pre-frail categories), age, sex, education, body mass index, and sleep time preference, a higher sleep fragmentation index was associated with frailty (OR=1.70, 95% CI: 1.02-2.84) and mortality (OR=2.12, 95% CI: 1.09-4.09). Greater WASO (OR=1.24, 95% CI: 1.02-1.50) and lower percent sleep (OR=0.41, 95% CI: 0.17-0.97) were associated with mortality. Conclusions: Among community-dwelling older adults, actigraphic sleep is associated with frailty and all-cause mortality over a five-year period. Further investigation is warranted to elucidate the physiological mechanisms underlying these associations. Keywords: Actigraphy; Aging; Frailty; Mortality; Sleep. High vs. low-fat dairy and milk differently affects the risk of all-cause, CVD, and cancer death: A systematic review and dose-response meta-analysis of prospective cohort studies. Naghshi S, Sadeghi O, Larijani B, Esmaillzadeh A. Crit Rev Food Sci Nutr. 2021 Jan 5:1-15. doi: 10.1080/10408398.2020.1867500. Online ahead of print. PMID: 33397132 Abstract Considerable controversy exists regarding the association between milk and dairy consumption and mortality risk. The present systematic review and meta-analysis of prospective studies was undertaken to examine the association of high vs. low-fat dairy and milk consumption with mortality. We searched PubMed/Medline, ISI Web of Science, and Scopus databases through February 2020 for prospective cohort studies that reported the association between milk and dairy consumption and mortality risk. High-fat milk consumption was significantly associated with a greater risk of all-cause (Pooled ES: 1.15; 95% CI: 1.09-1.20, I2=24.5%, p = 0.22), CVD (Pooled ES: 1.09; 95% CI: 1.02-1.16, I2=4.5%, p = 0.38) and cancer mortality (Pooled ES: 1.17; 95% CI: 1.08-1.28, I2=30.1%, p = 0.19). However, total dairy consumption was associated with a lower risk of CVD mortality (Pooled ES: 0.93; 95% CI: 0.88-0.98, I2=59.7%, p = 0.001). Dose-response analysis revealed a significant non-linear association of total dairy consumption with all-cause and CVD mortality. Moreover, high-fat milk consumption was significantly associated with risk of cancer mortality in linear and non-linear dose-response analysis. In conclusion, we found high-fat milk consumption was associated with a higher risk of all-cause, CVD, and cancer mortality. However, total dairy consumption was associated with a lower risk of CVD mortality. Keywords: Mortality; cancer; cardiovascular disease; dairy; death; milk. Chocolate as a food matrix reduces the bioavailability of galloylated catechins from green tea in healthy women. Mukai R, Fukuda T, Ohnishi A, Nikawa T, Furusawa M, Terao J. Food Funct. 2021 Jan 4. doi: 10.1039/d0fo02485f. Online ahead of print. PMID: 33393957 Abstract In this study, we evaluated the food matrix effects of chocolate on the absorption of green tea catechins (GTCs), (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECg), and (-)-epigallocatechin gallate (EGCg), in five healthy 22-year-old women. In the single-intake experiment, the plasma concentrations of ECg (P < 0.05, at 1.5 h) and EGCg (P < 0.05, at 6 h) but not those of EC and EGC were reduced by the chocolate matrix. Regardless of the chocolate matrix, ECg and EGCg were mainly present as their aglycones in the plasma, whereas EGC and EC were found mostly as conjugated metabolites. After daily intake of GTCs mixed with chocolate for 14 days followed by overnight fasting, ECg but not EGCg was detected in the plasma. To compare the plasma profiles of ECg and EGCg, a mixture containing approximately equal amounts of ECg and EGCg was administered to nine rats for 14 days. Following treatment and overnight food deprivation, the plasma content of ECg was higher than that of EGCg. After a single injection of the same mixture in seven rats, ECg levels were higher than those of EGCg, and a greater amount of conjugated metabolites of ECg than those of EGCg was detected in the plasma 10 h after administration. In conclusion, the chocolate matrix affects the plasma profiles of GTCs, particularly ECg. ECg appears to persist in the plasma for a longer period, regardless of the chocolate matrix.
  6. AlPater

    Al's CR updates

    Skeletal muscle RBM3 expression is associated with extended lifespan in Ames dwarf and calorie restricted mice. Hettinger ZR, Confides AL, Vanderklish PW, Sidhom S, Masternak MM, Dupont-Versteegden EE. Exp Gerontol. 2020 Dec 29:111214. doi: 10.1016/j.exger.2020.111214. Online ahead of print. PMID: 33385482 Abstract RNA binding protein motif 3 (RBM3) is an RNA-binding and cold shock protein that protects myoblasts and promotes skeletal muscle hypertrophy by enhancing mRNA stability and translation. Muscle size is decreased during aging; however, it is typically delayed in models of extended lifespan such as the long-lived Ames Dwarf (df/df) mice and calorie restricted (CR) animals compared to age-match controls. In light of the protective and anabolic effects of RBM3 in muscle, we hypothesized that RBM3 expression is higher in long-lived animal models. Young and old df/df mice, and adult and old UM-HET3 CR mice were used to test this hypothesis. Gastrocnemius muscles were harvested and protein was isolated for RBM3 protein measurements. CR induced a 1.7 and 1.3-fold elevation in RBM3 protein abundance compared to adult and old male mice fed ad libitum (AL) diets, respectively; this effect was shared between males and females. Ames dwarfism induced a 4.6 and 2.7-fold elevation in RBM3 protein abundance in young and old df/df mice compared to normal control littermates, respectively. In contrast, there was an age-associated decrease in cold-inducible RNA-binding protein (CIRP), suggesting these effects are specific for RBM3. Lastly, there was an age-associated increase in RNA degradation marker decapping enzyme 2 (DCP2) in UM-HET3 mice that was mitigated by CR. These results show that muscle RBM3 expression is correlated with extended lifespan in both df/df and CR animals. Identifying how RBM3 exerts protective effects in muscle may yield new insights into healthy aging of skeletal muscle. Keywords: Aging; Longevity; RBM3; RNA; RNA-binding proteins; Skeletal muscle. Effect of Different Levels of Energy Diet Restriction on Energy Balance, Leptin and CL Development, Vascularization, and Function in South American Camelids. Norambuena C, Hernandez F, Alfaro J, Silva G, Topp S, Ratto M. Front Vet Sci. 2020 Dec 16;7:598147. doi: 10.3389/fvets.2020.598147. eCollection 2020. PMID: 33392291 Free PMC article. Abstract The objective was to determine the effect of energy diet restriction on energy balance, systemic leptin and corpus luteum (CL) vascularization, development, and function in South American camelids. In experiment 1, adult llamas were randomly assigned to receive a diet of 70% of their maintenance energy requirements (MER) (Restricted group, n = 7) or fed ad libitum (Control group, n = 7) during 28 days. Body live weight (BLW) and body condition score (BCS) were recorded, blood samples were collected every 2 weeks to measure plasma leptin concentrations, and energy metabolites were quantified. In experiment 2, adult alpacas were randomly assigned to receive a diet of 40% MER for 21 days (Restricted group, n = 7) or fed ad libitum (Control group, n = 7). Then, ovulation was induced with gonadorelin acetate (day = 0), and trans-rectal ultrasonography (7.5 MHz) was performed using B and Doppler mode to record the diameter of the pre-ovulatory follicle, ovulation, CL diameter, and vascularization from Days 0 to 13. Blood samples were collected every 48 h from Days 1 to 13 to quantify plasma leptin and progesterone concentrations. In experiment 1, energy diet restriction of 70% MER did not affect plasma leptin concentration and metabolic parameters of the Restricted group. In experiment 2, the Restricted group had a lower BCS (p < 0.001), a smaller diameter of the CL on Days 5 and 7 (p < 0.05), and a smaller maximum diameter of the CL (10.2 ± 0.6 mm) than the Control group (12.1 ± 0.6 mm; p = 0.04). Low energy restriction of 70% MER for 28 days did not affect the energy balance of llamas (Experiment 1). Moderate energy restriction of 40% MER for 21 days negatively affected energy balance (BCS), and CL development but not its vascularization, leptin, and progesterone concentrations. These species must be submitted to longer periods or a higher level of energy restriction to impair ovarian function. Keywords: alpaca; corpus luteum; diet restriction; leptin; llama; progesterone.
  7. (1) is a pretty good summary of COVID asymptomatic infections. Research early in the pandemic suggested that the rate of asymptomatic infections could be as high as 81%. But a meta-analysis published last month1, which included 13 studies involving 21,708 people, calculated the rate of asymptomatic presentation to be 17%. ... The review also found that asymptomatic individuals were 42% less likely to transmit the virus than symptomatic people. ... They “are not coughing or sneezing as much”. ... those without symptoms had similar initial levels of viral particles in a throat swab when compared with people with symptoms. But asymptomatic people seem to clear the virus faster and are infectious for a shorter period. ... people should continue to use measures to reduce viral spread, including social distancing and wearing masks, regardless of whether they have symptoms. 1. What the data say about asymptomatic COVID infections. Nogrady B. Nature. 2020 Nov;587(7835):534-535. doi: 10.1038/d41586-020-03141-3. PMID: 33214725 No abstract available. https://media.nature.com/original/magazine-assets/d41586-020-03141-3/d41586-020-03141-3.pdf
  8. Risk of metabolic syndrome and metabolic phenotypes in relation to biomarker-calibrated estimates of energy and protein intakes: an investigation from the Women's Health Initiative. Vasbinder A, Tinker LF, Neuhouser ML, Pettinger M, Hale L, Di C, Zaslavsky O, Hayman LL, Lin X, Eaton C, Wang D, Scherman A, Stefanick ML, Barrington WE, Reding KW. Am J Clin Nutr. 2020 Dec 31:nqaa334. doi: 10.1093/ajcn/nqaa334. Online ahead of print. PMID: 33381804 Abstract Background: Metabolic syndrome (MetS) is associated with increased mortality independent of BMI, resulting in discordant metabolic phenotypes, such as metabolically healthy obese and metabolically unhealthy normal-weight individuals. Studies investigating dietary intake in MetS have reported mixed results, due in part to the limitations of self-reported measures. Objectives: To investigate the role of biomarker-calibrated estimates of energy and protein in MetS and metabolic phenotypes. Methods: Postmenopausal participants from the Women's Health Initiative (WHI) study who were free of MetS at baseline, had available data from FFQs at baseline, and had components of MetS at Year 3 (n = 3963) were included. Dietary energy and protein intakes were estimated using biomarker calibration methods. MetS was defined as 3 or more of the following: elevated serum triglycerides (≥150 mg/dL), low HDL cholesterol (<50 mg/dL), hypertension [systolic blood pressure (BP) ≥130 or diastolic BP ≥85 mmHg], elevated serum glucose (>100 mg/dL), and abdominal adiposity (waist circumference > 89 cm). Models were adjusted for age, WHI study component, race/ethnicity, education, income, smoking, recreational physical activity, disease history, and parity. Results: For every 10% increment in total calibrated energy intake, women were at a 1.37-fold elevated risk of MetS (95% CI, 1.15-1.63); a 10% increment in calibrated total protein intake was associated with a 1.21-fold elevated risk of MetS (95% CI, 1.00-1.47). Specifically, animal protein intake was associated with MetS (OR, 1.08; 95% CI, 1.02-1.14), whereas vegetable protein intake was not (OR, 0.99; 95% CI, 0.95-1.03). No differences were seen when examining metabolic phenotypes. Conclusions: We found that higher calibrated total energy, total protein, and total animal protein intakes were strongly associated with MetS. If replicated in clinical trials, these results will have implications for the promotion of energy and animal protein restrictions for the reduction of MetS risks. Keywords: biomarker; body composition; diet; energy intake; metabolic syndrome; protein intake. Association Between Folate and Health Outcomes: An Umbrella Review of Meta-Analyses. Bo Y, Zhu Y, Tao Y, Li X, Zhai D, Bu Y, Wan Z, Wang L, Wang Y, Yu Z. Front Public Health. 2020 Dec 15;8:550753. doi: 10.3389/fpubh.2020.550753. eCollection 2020. PMID: 33384976 Free PMC article. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770110/pdf/fpubh-08-550753.pdf Abstract Background: There is no study that has systematically investigated the breadth and validity of the associations of folate and multiple health outcomes. We aimed to evaluate the quantity, validity, and credibility of evidence regarding associations between folate and multiple health outcomes by using umbrella review of meta-analysis. Methods: We searched the MEDLINE, EMBASE, and Cochrane Library databases from inception to May 20, 2018, to identify potential meta-analyses that examined the association of folate with any health outcome. For each included meta-analysis, we estimated the summary effect size and their 95% confidence interval using the DerSimonian and Laird random-effects model. We used the AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews) to assess methodological quality and the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation working group classification) to assess the quality of evidence for each outcome included in the umbrella review. Results: Overall, 108 articles reporting 133 meta-analyses of observational studies and 154 meta-analyses of randomized controlled trials (RCTs) were included in the study. Among them, 108 unique exposure-outcome-population triplets (referred to as unique meta-analyses hereafter) of RCTs and 87 unique meta-analyses of observational studies were reanalyzed. Beneficial effects of folate were observed in the all-cause mortality rate and in a number of chronic diseases, including several birth/pregnancy outcomes, several cancers, cardiovascular disease and metabolic-related outcomes, neurological conditions, and several other diseases. However, adverse effects of folate were observed for prostate cancer, colorectal adenomatous lesions, asthma or wheezing, and wheezing as an isolated symptom and depression. Conclusions: Current evidence allows for the conclusion that folate is associated with decreased risk of all-cause mortality and a wide range of chronic diseases. However, folate may be associated with an increased risk of prostate cancer. Further research is warranted to improve the certainty of the estimates. Keywords: chronic diseases; folate; meta-analysis; multiple health outcomes; umbrella review. Sleep duration and all-cause mortality in the elderly in China: a population-based cohort study. Ren Y, Miao M, Yuan W, Sun J. BMC Geriatr. 2020 Dec 30;20(1):541. doi: 10.1186/s12877-020-01962-5. PMID: 33380318 Abstract Background: Although a U-shaped association between sleep duration and all-cause mortality has been found in general population, its association in the elderly adults, especially in the oldest-old, is rarely explored. Methods: In present cohort study, we prospectively explore the association between sleep duration and all-cause mortality among 15,092 participants enrolled in the Chinese Longitudinal Healthy Longevity Survey (CLHLS) from 2005 to 2019. Sleep duration and death information was collected by using structured questionnaires. Cox regression model with sleep duration as a time-varying exposure was performed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). The dose-response association between them was explored via a restricted cubic spline function. Results: During an average follow-up of 4.51 (standard deviation, SD: 3.62) years, 10,768 participants died during the follow-up period. The mean (SD) age of the participants was 89.26 (11.56) years old. Compared to individuals with moderate sleep duration (7-8 hours), individuals with long sleep duration (> 8 hours) had a significantly higher risk of all-cause mortality (HR: 1.13, 95%CI: 1.09-1.18), but not among individuals with short sleep duration (≤ 6 hours) (HR: 1.02, 95%CI: 0.96-1.09). Similar results were observed in subgroup analyses based on age and gender. In the dose-response analysis, a J-shaped association was observed. Conclusions: Sleep duration was associated with all-cause mortality in a J-shaped pattern in the elderly population in China. Keywords: All-cause mortality; Cohort; Elderly; Sleep duration. Modified Fasting Compared to True Fasting Improves Blood Glucose Levels and Subjective Experiences of Hunger, Food Cravings and Mental Fatigue, But Not Cognitive Function: Results of an Acute Randomised Cross-Over Trial. Zajac I, Herreen D, Hunkin H, James-Martin G, Doyen M, Kakoschke N, Brindal E. Nutrients. 2020 Dec 28;13(1):E65. doi: 10.3390/nu13010065. PMID: 33379191 Abstract Recent dietary trends have prompted growing support for a variety of fasting paradigms involving extreme restriction or nil-caloric intake on fasting days. Some studies indicate that fasting may negatively influence factors including cognitive function through inducing fatigue, which may prove problematic in the context of completing a range of cognitively demanding activities required by daily obligations such as work. This randomised within-subjects cross-over trial explored the effects of true fasting (i.e., nil-caloric intake) versus modified fasting, the latter of which involved two sub-conditions: (1) extended distribution (three small meals distributed across the day; 522 kcal total); and (2) bulking (two meals eaten early in the day; 512 kcal total) over a period of 7.5 h on a single day with a 7-day washout period between conditions. Participants were n = 17 females (Body Mass Index (BMI) Mean (M) = 25.80, Standard Deviation (SD) = 2.30) aged 21-49 years. Outcomes included cognitive function, subjective mental fatigue, satiety, food cravings and blood glucose. Results showed that there were no differences in cognitive test performance between conditions;however, both modified fasting sub-conditions had improved blood glucose levels, cravings, hunger and fullness compared to true fasting. Moreover, subjective mental fatigue was significantly reduced in the modified fasting conditions relative to true fasting. Overall, results indicated that the subjective experience of true fasting and modified fasting is different, but that cognition does not appear to be impaired. Keywords: cognitive function; fasting; fatigue; satiety; weight loss. Prolonged nightly fasting and lower-extremity functioning in community-dwelling older adults. Estrada-deLeón DB, Struijk EA, Caballero FF, Sotos Prieto M, Rodríguez-Artalejo F, Lopez-Garcia E. Br J Nutr. 2020 Dec 29:1-26. doi: 10.1017/S0007114520005218. Online ahead of print. PMID: 33371909 Abstract It is unknown if time-restricted feeding confers a protective effect on the physical function of older adults. The aim of this study was to assess prolonged nightly fasting in association with performance-based lower-extremity function (LEF) in a large population of community-dwelling older adults. A cross-sectional study was carried out among 1,226 individuals ≥64 years from the Seniors-ENRICA-II cohort. In 2016-2017, habitual diet was assessed through a validated diet history. Fasting time was classified into the following categories: ≤9, 10-11, and ≥12hours/day, the latter being considered prolonged nightly fasting. Performance-based LEF was assessed with the Short Physical Performance Battery (SPPB). After adjusting for potential confounders, a longer fasting period was associated with a higher likelihood of impaired LEF [odds ratio (OR) and 95% confidence intervals (CI) for the second and third categories: 2.27 (1.56-3.33) and 2.70 (1.80-4.04), respectively, considering the ≤9 hours/day fasting group as reference; p-trend <0.001]. When assessing each SPPB subtest separately, fasting time showed a significant association with balance impairment (OR for highest vs. lowest fasting time: 2.48; 95% CI: 1.51-4.08; p-trend =0.001) and difficulty to rise from a chair (OR for highest vs. lowest fasting time: 1.47; 95% CI: 1.05-2.06; p-trend =0.01). The risk associated with ≥12 h fasting among those with the lowest levels of physical activity was three times higher than among those with ≤9 hours fasting with the same low level of physical activity. Prolonged nightly fasting was associated with a higher likelihood of impaired LEF, balance impairment, and difficulty to rise from a chair in older adults, especially among those with low levels of physical activity. Keywords: Short Physical Performance Battery; cross-sectional; intermittent fasting; older adults; physical function; time-restricted feeding.
  9. AlPater

    Al's CR updates

    Beyond calorie restriction: aging as a biological target for nutrient therapies. Austad SN, Hoffman JM. Curr Opin Biotechnol. 2020 Dec 23;70:56-60. doi: 10.1016/j.copbio.2020.11.008. Online ahead of print. PMID: 33360494 Review. Abstract Arguably, the most important discovery in the biology of aging to date was that simply reducing food intake extended life and improved many aspects of health in a diversity of animal species. The conventional wisdom that emerged from first 50 years of rodent food restriction studies included (1) that the longevity impact of restriction was greater the longer restriction was imposed, and (2) that restricting calories rather than any specific macronutrient was critical to its health and longevity benefits. However these assumptions began to crumble as more and more restriction research was performed on other species besides laboratory rodents. Recent investigations of flies, rodents, monkeys, and increasingly humans, has begun to parse how calorie restriction, protein restriction, intermittent fasting, and the temporal pattern of eating all impact the health benefits of food restriction. Fly research continues to inform, as it has repeatedly shown that genotype, age, sex, duration, and tempo restriction all affect the health impact. Ultimately, optimizing human diets will require a personalized approach using omics approaches.
  10. Association of low plasma antioxidant levels with all-cause mortality and coronary events in healthy middle-aged men from France and Northern Ireland in the PRIME study. McKay GJ, Lyner N, Linden GJ, Kee F, Moitry M, Biasch K, Amouyel P, Dallongeville J, Bongard V, Ferrières J, Gey KF, Patterson CC, Woodside JV. Eur J Nutr. 2020 Dec 23. doi: 10.1007/s00394-020-02455-2. Online ahead of print. PMID: 33355688 Abstract Background: The main underlying risk factors associated with coronary heart disease (CHD) are modifiable and oxidative injury and systemic inflammatory damage represent key aetiological factors associated with the development and progression of CHD and premature mortality. Objective: To examine associations of plasma antioxidant status with all-cause mortality and fatal or non-fatal cardiovascular events. Design: The PRIME study prospectively evaluated 9709 men aged 50-59 years between 1991 and 1993 in Northern Ireland and France who were free of CHD at recruitment and followed annually for deaths and cardiovascular events for 10 years. Serum concentrations of vitamin C, retinol, two forms of vitamin E (α- and γ-tocopherol) and six carotenoids were quantified by high-performance liquid chromatography. Baseline conventional risk factors were considered, as well as socioeconomic differences and lifestyle behaviours including diet, smoking habit, physical activity, and alcohol consumption through Cox regression analyses. Results: At 10 years, there were 538 deaths from any cause and 440 fatal or non-fatal cardiovascular events. After adjustment for country, age, systolic blood pressure, diabetes, body mass index, cholesterol, high density lipoprotein cholesterol, triglycerides, height, total physical activity, alcohol consumption and smoking habit, higher levels of all antioxidants were associated with significantly lower risk of all-cause mortality, with the exception of γ-tocopherol. Only retinol was significantly associated with decreased risk of cardiovascular events in a fully adjusted model. Conclusions: Low antioxidant levels contribute to the gradient of all-cause mortality and cardiovascular incidence independent of lifestyle behaviours and traditional cardiovascular and socioeconomic risk factors. Keywords: Antioxidant; Cardiovascular disease; Carotenoid; Premature mortality; Retinol; Vitamin. Sodium intake, life expectancy, and all-cause mortality. Messerli FH, Hofstetter L, Syrogiannouli L, Rexhaj E, Siontis GCM, Seiler C, Bangalore S. Eur Heart J. 2020 Dec 22:ehaa947. doi: 10.1093/eurheartj/ehaa947. Online ahead of print. PMID: 33351135 Abstract Aims : Since dietary sodium intake has been identified as a risk factor for cardiovascular disease and premature death, a high sodium intake can be expected to curtail life span. We tested this hypothesis by analysing the relationship between sodium intake and life expectancy as well as survival in 181 countries worldwide. Methods and results : We correlated age-standardized estimates of country-specific average sodium consumption with healthy life expectancy at birth and at age of 60 years, death due to non-communicable diseases and all-cause mortality for the year of 2010, after adjusting for potential confounders such as gross domestic product per capita and body mass index. We considered global health estimates as provided by World Health Organization. Among the 181 countries included in this analysis, we found a positive correlation between sodium intake and healthy life expectancy at birth (β = 2.6 years/g of daily sodium intake, R2 = 0.66, P < 0.001), as well as healthy life expectancy at age 60 (β = 0.3 years/g of daily sodium intake, R2 = 0.60, P = 0.048) but not for death due to non-communicable diseases (β = 17 events/g of daily sodium intake, R2 = 0.43, P = 0.100). Conversely, all-cause mortality correlated inversely with sodium intake (β = -131 events/g of daily sodium intake, R2 = 0.60, P < 0.001). In a sensitivity analysis restricted to 46 countries in the highest income class, sodium intake continued to correlate positively with healthy life expectancy at birth (β = 3.4 years/g of daily sodium intake, R2 = 0.53, P < 0.001) and inversely with all-cause mortality (β = -168 events/g of daily sodium intake, R2 = 0.50, P < 0.001). Conclusion : Our observation of sodium intake correlating positively with life expectancy and inversely with all-cause mortality worldwide and in high-income countries argues against dietary sodium intake being a culprit of curtailing life span or a risk factor for premature death. These data are observational and should not be used as a base for nutritional interventions. Keywords: Sodium intake • Salt • Diet • Life expectancy • All-cause mortality • Cardiovascular disease >>>>>>>>>>>>>>>>>> Salt Reduction to Prevent Hypertension and Cardiovascular Disease: JACC State-of-the-Art Review. He FJ, Tan M, Ma Y, MacGregor GA. J Am Coll Cardiol. 2020 Feb 18;75(6):632-647. doi: 10.1016/j.jacc.2019.11.055. PMID: 32057379 Review. https://sci-hub.se/10.1016/j.jacc.2019.11.055 Marine n-3 Fatty Acids, Sudden Cardiac Death, and Ischemic Heart Disease: Fish or Supplements? Schmidt EB, Calder PC. J Nutr. 2020 Dec 10;150(12):3055-3057. doi: 10.1093/jn/nxaa319. PMID: 33188414 No abstract available. Vitamin D(3) reduces risk of cardiovascular and liver diseases by lowering homocysteine levels: double-blinded, randomised, placebo-controlled trial. Al-Bayyari N, Hailat R, Subih H, Alkhalidy H, Eaton A. Br J Nutr. 2021 Jan 28;125(2):139-146. doi: 10.1017/S0007114520001890. Epub 2020 Jun 1. PMID: 32475360 Abstract The objective of this study was to evaluate the effect of vitamin D3 on total homocysteine (tHcy) and C-reactive protein (CRP) levels and liver and kidney function tests in overweight women with vitamin D deficiency. Therefore, a randomised, double-blind placebo, controlled clinical trial was conducted on 100 eligible women. Subjects were randomly divided into two groups: the placebo (n 50) and the vitamin D (n 50) which received 1250 µg vitamin D3 per week for 2 months. The participants' 25-hydroxyvitamin D (25(OH)D), tHcy, CRP, alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, creatinine and estimated glomerular filtration rate (eGFR) were measured and compared before and after treatment. Results showed that the tHcy, CRP, AST, ALT and eGFR levels after the 2nd month of vitamin D3 intervention were significantly (P < 0·001) decreased and the 25(OH)D, urea and creatinine levels were significantly (P < 0·001) increased in the treatment group. In the placebo group, no significant changes were identified throughout the follow-up period. In conclusion, vitamin D3 intervention with a treatment dose of 1250 µg/week for at least 2 months may help in lowering Hcy and CRP levels and may improve liver function tests, which in turn might help in minimising the risk of CVD and liver diseases among overweight women but negatively affect kidney function. Keywords: C-reactive protein; Homocysteine; Liver and kidney function; Overweight women; Vitamin D3. Association of diet with circulating trimethylamine-N-oxide concentration. Hamaya R, Ivey KL, Lee DH, Wang M, Li J, Franke A, Sun Q, Rimm EB. Am J Clin Nutr. 2020 Dec 10;112(6):1448-1455. doi: 10.1093/ajcn/nqaa225. PMID: 32936862 Abstract Background: Trimethylamine-N-oxide (TMAO) is a compound that is present in seafood and produced through human gut microbial metabolism of its precursors. Previous studies have suggested that elevated TMAO concentrations are associated with an increased risk of cardiovascular events. However, the association between diet and TMAO concentrations in free-living adult populations has not been adequately described. Objectives: The objective of this study was to identify dietary predictors of plasma TMAO concentrations. Methods: TMAO concentrations were assessed in 2 fasting plasma samples collected 6 mo apart among 620 healthy men. Short-term and long-term dietary intakes were assessed during the same time-frame of blood collections via repeated 7-d dietary records (7DDRs) and a semiquantitative food-frequency questionnaire (SFFQ), respectively. We grouped individual food items into 21 groups and regressed against averaged TMAO concentrations. We also assessed the association between dietary scores and TMAO concentrations. Results: In models adjusted for demographic characteristics and mutually adjusted for food groups, SFFQ-assessments of fish and egg intakes were significantly associated with increased TMAO concentration (β = 0.082; 95% CI: 0.021, 0.14; P = 0.009 for fish; β = 0.065; 95% CI: 0.004, 0.13; P = 0.039 for egg). The positive association between fish consumption and TMAO concentration was replicated in the 7DDR-assessments (β = 0.12; 95% CI: 0.060, 0.18; P < 0.001). There was no association between red meat intake and TMAO concentrations. The unhealthful plant-based diet index (uPDI) was inversely associated (β = -0.013; 95% CI: -0.021, -0.005; P = 0.001) and healthy dietary scores were positively correlated with TMAO concentration. Conclusions: TMAO concentration was significantly associated with fish intake, but not with red meat consumption. uPDI, an unhealthy dietary pattern, was inversely related to TMAO concentration. As such, this study suggests that in free-living populations, higher circulating concentrations of TMAO cannot simply be interpreted as a marker of unhealthy food intake or an unhealthy dietary pattern. Keywords: 7-d dietary records; fish; plant-based diet index; red meat; semiquantitative food-frequency questionnaire; trimethylamine-N-oxide. Selenium, antioxidants, cardiovascular disease, and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials. Jenkins DJA, Kitts D, Giovannucci EL, Sahye-Pudaruth S, Paquette M, Blanco Mejia S, Patel D, Kavanagh M, Tsirakis T, Kendall CWC, Pichika SC, Sievenpiper JL. Am J Clin Nutr. 2020 Dec 10;112(6):1642-1652. doi: 10.1093/ajcn/nqaa245. PMID: 33053149 Free PMC article. Abstract Background: Antioxidants have been promoted for cardiovascular disease (CVD) risk reduction and for the prevention of cancer. Our preliminary analysis suggested that only when selenium was present were antioxidant mixtures associated with reduced all-cause mortality. Objective: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the effect of selenium supplementation alone and of antioxidant mixtures with or without selenium on the risk of CVD, cancer, and mortality. Methods: We identified studies using the Cochrane Library, Medline, and Embase for potential CVD outcomes, cancer, and all-cause mortality following selenium supplementation alone or after antioxidant supplement mixtures with and without selenium up to June 5, 2020. RCTs of ≥24 wk were included and data were analyzed using random-effects models and classified by the Grading of Recommendations, Assessment, Development, and Evaluation approach. Results: The meta-analysis identified 9423 studies, of which 43 were used in the final analysis. Overall, no association of selenium alone or antioxidants was seen with CVD and all-cause mortality. However, a decreased risk with antioxidant mixtures was seen for CVD mortality when selenium was part of the mix (RR: 0.77; 95% CI: 0.62, 0.97; P = 0.02), with no association when selenium was absent. Similarly, when selenium was part of the antioxidant mixture, a decreased risk was seen for all-cause mortality (RR: 0.90; 95% CI: 0.82, 0.98; P = 0.02) as opposed to an increased risk when selenium was absent (RR: 1.09; 95% CI: 1.04, 1.13; P = 0.0002). Conclusion: The addition of selenium should be considered for supplements containing antioxidant mixtures if they are to be associated with CVD and all-cause mortality risk reduction. Keywords: all-cause mortality; antioxidants; cardiovascular disease; meta-analysis; selenium; supplements.
  11. The concrete and steel of engineering is more defined than human nutrition and biology. Human nutrition and biology studies are also science, just studies of a much more complex system.
  12. Associations of time-restricted eating with health-related quality of life and sleep in adults: a secondary analysis of two pre-post pilot studies. Kesztyüs D, Fuchs M, Cermak P, Kesztyüs T. BMC Nutr. 2020 Dec 17;6(1):76. doi: 10.1186/s40795-020-00402-2. PMID: 33327959 Free PMC article. Abstract Background: Therapeutic fasting may improve health-related quality of life (HRQoL) and sleep but is not applicable for everyone. Time-restricted eating (TRE) offers a low threshold alternative but research on associations with HRQoL and sleep is rare. Methods: We conducted a secondary analysis of two pilot studies in a pre-post design, which examined TRE in healthy employees at the Ulm University and in abdominal obese patients in a general practitioners office. Participants reported their HRQoL (EQ-5D visual analogue scale) before and after 3 months of restricting their daily eating to 8-9 h. They kept a diary to protocol timing of first and last meal, sleep quality (analogue scale) and duration. Pearson's correlation coefficient was applied to test bivariate correlations between continuous variables and linear regression analyses were conducted to identify associated factors with the pre-post differences in HRQoL and the differences in sleep quality. Results: Ninety-nine participants (aged aged 48.9 ± 1.1, 83.8% female) reached the fasting target of 15-16 h on average on 77.2 ± 18.7% of all recorded days. HRQoL increased by 7.8 ± 12.6 and sleep quality by 9.6 ± 13.9 points, but sleep duration was not extended. Regression analysis revealed mean fasting duration and baseline sleep quality as significant factors associated with changes in HRQoL. Improvements in sleep quality correlated with baseline sleep quality and HRQoL at follow-up but not with fasting. Changes in anthropometry did not correlate with the HRQoL or sleep quality. Conclusions: TRE correlates with increased HRQoL and sleep quality independent from weight loss. TRE is easily applicable with or without medical supervision. The potential effects of TRE on health and sleep should be further investigated in larger randomized trials. Keywords: Abdominal obesity; Employees; General practitioner; Patients; Pilot study; Sleep duration and quality; Time-restricted eating; health-related quality of life. Quercetin improves cognitive disorder in aging mice by inhibiting NLRP3 inflammasome activation. Li H, Chen FJ, Yang WL, Qiao HZ, Zhang SJ. Food Funct. 2020 Dec 18. doi: 10.1039/d0fo01900c. Online ahead of print. PMID: 33338087 Abstract Quercetin is one of the most abundant dietary flavonoid compounds, and its mechanism for combating age-related neurodegenerative diseases is unclear. In this study, quercetin (35 and 70 mg kg-1, orally administered for 4 weeks) was administered to 7-month-old aging mice (senescence-accelerated mouse prone 8 mice). As a result, it was found that quercetin could improve spatial learning and memory impairment displayed by aging mice in the Morris water maze. The results of immunoblotting reflected the protein expressions of the longevity factor (sirtuin1), inflammasomes (NLRP3 and ASC), synaptic marker (PSD95) and neurotrophic factors (BDNF and NGF) in the hippocampus of the brain. It indicated that the intervention of quercetin could increase the expression of sirtuin1 and prevent neuroinflammation, which was evident from the decrease in the protein levels of the astrocyte marker (GFAP) and inflammatory factors (cleaved-caspase 1, IL-1β and IL-18). In addition, quercetin could reduce the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in the hippocampus of aging mice. Current data indicated that quercetin might improve neuroinflammation in aging mice by regulating the Sirtuin1/NLRP3 pathway. High-density lipoprotein cholesterol and all-cause mortality by sex and age: a prospective cohort study among 15.8 million adults. Yi SW, Park SJ, Yi JJ, Ohrr H, Kim H. Int J Epidemiol. 2020 Dec 12:dyaa243. doi: 10.1093/ije/dyaa243. Online ahead of print. PMID: 33313654 Abstract Background: The associations between high-density lipoprotein cholesterol (HDL-C) levels and all-cause mortality are unclear in young adults (<45 years) and in Asian populations. Methods: In total, 15 860 253 Korean adults underwent routine health examinations during 2009-10 and were followed until June 2018 for all-cause mortality. Hazard ratios (HRs) were calculated using Cox proportional hazard models. Results: During a mean 8.4 years of follow-up, 555 802 individuals died. U-curve associations were found between HDL-C levels and mortality, irrespective of sex or age. The HDL-C ranges associated with the lowest mortality were 40-59 and 50-69 mg/dL (1.03-1.54 and 1.29-1.80 mmol/L) in men aged <65 and ≥65 years, respectively, and the corresponding ranges were 40-69 and 50-79 mg/dL (1.03-1.80 and 1.29-2.06 mmol/L) in women aged <45 and ≥45 years, respectively. For HDL-C ranges of 60-149 mg/dL (1.55-3.86 mmol/L), each 39 mg/dL (1 mmol/L) increase in HDL-C was associated with higher mortality [men: HR = 1.39; 95% confidence interval (CI) = 1.36-1.42; women: HR = 1.15, 95% CI = 1.11-1.18], adjusting for age. These positive associations were generally stronger at younger than older ages, whereas inverse associations for HDL-C ranges <60 mg/dL (1.55 mmol/L) were strongest in middle age (45-64 years). The U-curve associations were generally unchanged after adjustment for various confounders. Conclusions: Korean adults showed U-curve associations of HDL-C with mortality, regardless of sex, and age. Younger adults had a lower optimal range and a stronger positive association with mortality than older adults in the high HDL-C range. Even moderately high HDL-C levels are not necessarily a sign of good health, especially in young adults. Keywords: Asians; HDL-cholesterol; Lipids; epidemiology; general population; mortality. Physical Activity and Mortality Across Levels of Adiposity: A Prospective Cohort Study From the UK Biobank. Sanchez-Lastra MA, Ding D, Dalene KE, Ekelund U, Tarp J. Mayo Clin Proc. 2020 Dec 8:S0025-6196(20)30756-4. doi: 10.1016/j.mayocp.2020.06.049. Online ahead of print. PMID: 33309181 Abstract Objective: To examine the combined and stratified associations of physical activity and adiposity measures, modelled as body mass index (BMI), abdominal adiposity (waist circumference), and body fat percentage (BF) with all-cause mortality. Patients and methods: Using the UK Biobank cohort, we extracted quintiles of self-reported weekly physical activity. Categories of measured BMI, waist circumference, and BF were generated. Joint associations between physical activity-adiposity categories and mortality were examined using Cox proportional hazards models adjusted for demographic, behavioral, and clinical covariates. Physical activity-mortality associations were also examined within adiposity strata. Participants were followed from baseline (2006 to 2010) through January 31, 2018. Results: A total of 295,917 participants (median follow-up, 8.9 years, during which 6684 deaths occurred) were included. High physical activity was associated with lower risk of premature mortality in all strata of adiposity except for those with BMI ≥35 kg/m2. Highest risk (HR, 1.54; 95% CI; 1.33 to 1.79) was observed in individuals with low physical activity and high BF as compared with the high physical activity-low BF referent. High physical activity attenuated the risk of high adiposity when using BF (HR, 1.24; 95% CI; 1.04 to 1.49), but the association was weaker with BMI (HR, 1.45; 95% CI; 1.21 to 1.73). Physical activity also attenuated the association between mortality and high waist circumference. Conclusion: Low physical activity and adiposity were both associated with a higher risk of premature mortality, but high physical activity attenuated the increased risk with adiposity irrespective of adiposity metric, except in those with a BMI ≥35 kg/m2. Effects of low sodium diet versus high sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride. Graudal NA, Hubeck-Graudal T, Jurgens G. Cochrane Database Syst Rev. 2020 Dec 12;12:CD004022. doi: 10.1002/14651858.CD004022.pub5. PMID: 33314019 Review. Abstract Background: Recent cohort studies show that salt intake below 6 g is associated with increased mortality. These findings have not changed public recommendations to lower salt intake below 6 g, which are based on assumed blood pressure (BP) effects and no side-effects. Objectives: To assess the effects of sodium reduction on BP, and on potential side-effects (hormones and lipids) SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to April 2018 and a top-up search in March 2020: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions. The top-up search articles are recorded under "awaiting assessment." Selection criteria: Studies randomizing persons to low-sodium and high-sodium diets were included if they evaluated at least one of the outcome parameters (BP, renin, aldosterone, noradrenalin, adrenalin, cholesterol, high-density lipoprotein, low-density lipoprotein and triglyceride,. Data collection and analysis: Two review authors independently collected data, which were analysed with Review Manager 5.3. Certainty of evidence was assessed using GRADE. Main results: Since the first review in 2003 the number of included references has increased from 96 to 195 (174 were in white participants). As a previous study found different BP outcomes in black and white study populations, we stratified the BP outcomes by race. The effect of sodium reduction (from 203 to 65 mmol/day) on BP in white participants was as follows: Normal blood pressure: SBP: mean difference (MD) -1.14 mmHg (95% confidence interval (CI): -1.65 to -0.63), 5982 participants, 95 trials; DBP: MD + 0.01 mmHg (95% CI: -0.37 to 0.39), 6276 participants, 96 trials. Hypertension: SBP: MD -5.71 mmHg (95% CI: -6.67 to -4.74), 3998 participants,88 trials; DBP: MD -2.87 mmHg (95% CI: -3.41 to -2.32), 4032 participants, 89 trials (all high-quality evidence). The largest bias contrast across studies was recorded for the detection bias element. A comparison of detection bias low-risk studies versus high/unclear risk studies showed no differences. The effect of sodium reduction (from 195 to 66 mmol/day) on BP in black participants was as follows: Normal blood pressure: SBP: mean difference (MD) -4.02 mmHg (95% CI:-7.37 to -0.68); DBP: MD -2.01 mmHg (95% CI:-4.37, 0.35), 253 participants, 7 trials. Hypertension: SBP: MD -6.64 mmHg (95% CI:-9.00, -4.27); DBP: MD -2.91 mmHg (95% CI:-4.52, -1.30), 398 participants, 8 trials (low-quality evidence). The effect of sodium reduction (from 217 to 103 mmol/day) on BP in Asian participants was as follows: Normal blood pressure: SBP: mean difference (MD) -1.50 mmHg (95% CI: -3.09, 0.10); DBP: MD -1.06 mmHg (95% CI:-2.53 to 0.41), 950 participants, 5 trials. Hypertension: SBP: MD -7.75 mmHg (95% CI:-11.44, -4.07); DBP: MD -2.68 mmHg (95% CI: -4.21 to -1.15), 254 participants, 8 trials (moderate-low-quality evidence). During sodium reduction renin increased 1.56 ng/mL/hour (95%CI:1.39, 1.73) in 2904 participants (82 trials); aldosterone increased 104 pg/mL (95%CI:88.4,119.7) in 2506 participants (66 trials); noradrenalin increased 62.3 pg/mL: (95%CI: 41.9, 82.8) in 878 participants (35 trials); adrenalin increased 7.55 pg/mL (95%CI: 0.85, 14.26) in 331 participants (15 trials); cholesterol increased 5.19 mg/dL (95%CI:2.1, 8.3) in 917 participants (27 trials); triglyceride increased 7.10 mg/dL (95%CI: 3.1,11.1) in 712 participants (20 trials); LDL tended to increase 2.46 mg/dl (95%CI: -1, 5.9) in 696 participants (18 trials); HDL was unchanged -0.3 mg/dl (95%CI: -1.66,1.05) in 738 participants (20 trials) (All high-quality evidence except the evidence for adrenalin). Authors' conclusions: In white participants, sodium reduction in accordance with the public recommendations resulted in mean arterial pressure (MAP) decrease of about 0.4 mmHg in participants with normal blood pressure and a MAP decrease of about 4 mmHg in participants with hypertension. Weak evidence indicated that these effects may be a little greater in black and Asian participants. The effects of sodium reduction on potential side effects (hormones and lipids) were more consistent than the effect on BP, especially in people with normal BP.
  13. AlPater

    Al's CR updates

    Does calorie restriction improve cognition? Dias IR, Santos CS, Magalhães CODE, de Oliveira LRS, Peixoto MFD, De Sousa RAL, Cassilhas RC. IBRO Rep. 2020 Jun 1;9:37-45. doi: 10.1016/j.ibror.2020.05.001. eCollection 2020 Dec. PMID: 33336102 Free PMC article.] Abstract Calorie restriction (CR) has been considered the most effective non-pharmacological intervention to counteract aging-related diseases and improve longevity. This intervention has shown beneficial effects in the prevention and treatment of several chronic diseases and functional declines related to aging, such as Parkinson's, Alzheimer's, and neuroendocrine disorders. However, the effects of CR on cognition show controversial results since its effects vary according to intensity, duration, and the period of CR. This review focuses on the main studies published in the last ten years regarding the consequences of CR on cognition in different neurological diseases and conditions of experimental animals. Also, possible CR mimetics are discussed. These findings highlight the potential beneficial effects of CR of up to 40 % on cognition when started early in life in non human animals. Keywords: Aging; Calorie intake; Cognitive function; Memory; Neurodegenative diseases. <<>>>>>>>>>>>>>>> Nutrition to Prevent or Treat Cognitive Impairment in Older Adults: A GRADE Recommendation. Buckinx F, Aubertin-Leheudre M. J Prev Alzheimers Dis. 2021;8(1):110-116. doi: 10.14283/jpad.2020.40. PMID: 33336232 Abstract Aging is associated with cognitive declines leading to mild cognitive impairments or Alzheimer disease. Nutrition appear to protect from aging. Some dietary factors could either increase or protect against cognitive declines. This article aimed to provide GRADE recommendations related to nutrition aspects able to prevent or to treat cognitive impairments. A comprehensive literature review was performed using Medline database. The GRADE approach was used to classify quality of the existing evidence (systematic review or meta-analysis).The GRADE process led us to formulate seven key nutritional recommendations to manage cognitive declines, but did not allow us to do it for protein, vitamin B or antioxidants. Thus, 1) adherence to a Mediterranean diet (GRADE 1B); 2) high-level of consumption of mono- or poly- unsaturated fatty acids combined to a low consumption of saturated fatty acids (GRADE 1B); 3) high consumption of fruits and vegetables (GRADE 1B); 4) higher vitamin D intake (GRADE 1C) than the recommended daily allowance. In addition, a ketogenic diet, a low consumption of whole-fat dairy products or a caloric restriction are promising nutritional habits although the evidence does not yet support widespread uptake (GRADE 2C). In conclusion, nutrition is an important modifiable factor to prevent or protect against cognitive decline. Nevertheless, more studies are required to determine specific guidelines such as duration and amounts of nutrients to help older adult to maintain a healthy cognitive life. Keywords: GRADE process; aging; cognitive impairment; diet guidelines. Regulation of glucose homeostasis by calorie restriction and periodic fasting. Mezhnina V, Kondratov R. Aging (Albany NY). 2020 Dec 13. doi: 10.18632/aging.104217. Online ahead of print. PMID: 33318315 No abstract available. https://www.aging-us.com/article/104217/text
  14. AlPater

    Haven't been sick at all since taking Zinc

    The study https://www.sciencedirect.com/science/article/abs/pii/S0014483507000024 does not show excess zinc causes macular degeneration. They got samples from autopsies of those with the disease and found lots of zinc in the macula. As recommended a long time ago on these forums, I take my iron pills after waking with some vitamin C for maximum uptake and zinc later, including about two thirds of the RDA in pill form. Copper is overabundant in my vegan diet and I get blood tests on all three minerals to ensure that iron intake is adequate as are zinc and copper in about equal molar ratio.
  15. Objectively measured physical activity and all cause mortality: A systematic review and meta-analysis. Ramakrishnan R, He JR, Ponsonby AL, Woodward M, Rahimi K, Blair SN, Dwyer T. Prev Med. 2020 Dec 7:106356. doi: 10.1016/j.ypmed.2020.106356. Online ahead of print. PMID: 33301824 Review. Abstract Current physical activity recommendations have been based on evidence from systematic reviews of questionnaire-based data. Questionnaire-based physical activity data are subject to both random and non-random error. If the estimated association between physical activity and health outcomes was different when a more accurate, objective measure was used, this would have important health policy implications for physical activity. We conducted a systematic review and meta-analysis of published cohort studies that investigated the association between an objective measure of physical activity and all cause mortality. We searched PubMed, Scopus, Embase, Cochrane library, and SPORTDiscus for prospective cohort studies that examined the association between objectively measured (accelerometer, pedometer, or doubly labeled water method) physical activity and mortality in adults aged≥18 years, of either sex. Summary hazard ratios and 95% confidence interval [CI]s were computed using random-effects models. Thirty-three articles from 15 cohort studies were identified that together ascertained 3903 deaths. The mean years of follow-up ranged from 2.3-14.2 years. Individuals in the highest category of light, moderate-to-vigorous, and total physical activity had 40% (95%CI 20% to 55%), 56% (95%CI 41% to 67%), and 67% (95%CI 57% to 75%), respectively, lower risk for mortality compared to individuals in the lowest category of light, moderate-to-vigorous, and total physical activity. The summary hazard ratio for objectively measured physical activity and all cause mortality is lower than previously estimated from questionnaire based studies. Current recommendations for physical activity that are based on subjective measurement may underestimate the true reduction in mortality risk associated with physical activity. Keywords: Accelerometry; Exercise; Meta-analysis; Mortality; Objectively measured; Systematic review. Efficacy and harms of remdesivir for the treatment of COVID-19: A systematic review and meta-analysis. Piscoya A, Ng-Sueng LF, Parra Del Riego A, Cerna-Viacava R, Pasupuleti V, Roman YM, Thota P, White CM, Hernandez AV. PLoS One. 2020 Dec 10;15(12):e0243705. doi: 10.1371/journal.pone.0243705. eCollection 2020. PMID: 33301514 Abstract Background: Efficacy and safety of treatments for hospitalized COVID-19 are uncertain. We systematically reviewed efficacy and safety of remdesivir for the treatment of COVID-19. Methods: Studies evaluating remdesivir in adults with hospitalized COVID-19 were searched in several engines until August 21, 2020. Primary outcomes included all-cause mortality, clinical improvement or recovery, need for invasive ventilation, and serious adverse events (SAEs). Inverse variance random effects meta-analyses were performed. Results: We included four randomized controlled trials (RCTs) (n = 2296) [two vs. placebo (n = 1299) and two comparing 5-day vs. 10-day regimens (n = 997)], and two case series (n = 88). Studies used intravenous remdesivir 200mg the first day and 100mg for four or nine more days. One RCT (n = 236) was stopped early due to AEs; the other three RCTs reported outcomes between 11 and 15 days. Time to recovery was decreased by 4 days with remdesivir vs. placebo in one RCT (n = 1063), and by 0.8 days with 5-days vs. 10-days of therapy in another RCT (n = 397). Clinical improvement was better for 5-days regimen vs. standard of care in one RCT (n = 600). Remdesivir did not decrease all-cause mortality (RR 0.71, 95%CI 0.39 to 1.28, I2 = 43%) and need for invasive ventilation (RR 0.57, 95%CI 0.23 to 1.42, I2 = 60%) vs. placebo at 14 days but had fewer SAEs; 5-day decreased need for invasive ventilation and SAEs vs. 10-day in one RCT (n = 397). No differences in all-cause mortality or SAEs were seen among 5-day, 10-day and standard of care. There were some concerns of bias to high risk of bias in RCTs. Heterogeneity between studies could be due to different severities of disease, days of therapy before outcome determination, and how ordinal data was analyzed. Conclusions: There is paucity of adequately powered and fully reported RCTs evaluating effects of remdesivir in hospitalized COVID-19 patients. Until stronger evidence emerges, we cannot conclude that remdesivir is efficacious for treating COVID-19. Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort study. Johannesen CDL, Langsted A, Mortensen MB, Nordestgaard BG. BMJ. 2020 Dec 8;371:m4266. doi: 10.1136/bmj.m4266. PMID: 33293274 Abstract Objective: To determine the association between levels of low density lipoprotein cholesterol (LDL-C) and all cause mortality, and the concentration of LDL-C associated with the lowest risk of all cause mortality in the general population. Design: Prospective cohort study. Setting: Denmark; the Copenhagen General Population Study recruited in 2003-15 with a median follow-up of 9.4 years. Participants: Individuals randomly selected from the national Danish Civil Registration System. Main outcome measures: Baseline levels of LDL-C associated with risk of mortality were evaluated on a continuous scale (restricted cubic splines) and by a priori defined centile categories with Cox proportional hazards regression models. Main outcome was all cause mortality. Secondary outcomes were cause specific mortality (cardiovascular, cancer, and other mortality). Results: Among 108 243 individuals aged 20-100, 11 376 (10.5%) died during the study, at a median age of 81. The association between levels of LDL-C and the risk of all cause mortality was U shaped, with low and high levels associated with an increased risk of all cause mortality. Compared with individuals with concentrations of LDL-C of 3.4-3.9 mmol/L (132-154 mg/dL; 61st-80th centiles), the multivariable adjusted hazard ratio for all cause mortality was 1.25 (95% confidence interval 1.15 to 1.36) for individuals with LDL-C concentrations of less than 1.8 mmol/L (<70 mg/dL; 1st-5th centiles) and 1.15 (1.05 to 1.27) for LDL-C concentrations of more than 4.8 mmol/L (>189 mg/dL; 96th-100th centiles). The concentration of LDL-C associated with the lowest risk of all cause mortality was 3.6 mmol/L (140 mg/dL) in the overall population and in individuals not receiving lipid lowering treatment, compared with 2.3 mmol/L (89 mg/dL) in individuals receiving lipid lowering treatment. Similar results were seen in men and women, across age groups, and for cancer and other mortality, but not for cardiovascular mortality. Any increase in LDL-C levels was associated with an increased risk of myocardial infarction. Conclusions: In the general population, low and high levels of LDL-C were associated with an increased risk of all cause mortality, and the lowest risk of all cause mortality was found at an LDL-C concentration of 3.6 mmol/L (140 mg/dL). Food restriction reduces cortical bone mass and serum insulin-like growth factor-1 levels and promotes uterine atrophy in mice. Ito E, Sato Y, Kobayashi T, Nakamura S, Kaneko Y, Soma T, Matsumoto T, Kimura A, Miyamoto K, Matsumoto H, Matsumoto M, Nakamura M, Sato K, Miyamoto T. Biochem Biophys Res Commun. 2020 Dec 4:S0006-291X(20)32166-5. doi: 10.1016/j.bbrc.2020.11.122. Online ahead of print. PMID: 33288195 Abstract Low energy availability in female athletes often causes hypothalamic amenorrhea and osteoporosis, in turn promoting stress fractures. Mechanisms underlying these conditions remain unclear. Here we show that model mice subjected to food restriction (FR) or FR-plus-voluntary running exercise exhibit significantly reduced bone mineral density, cortical bone parameters and uterine weight than do control mice, and that these parameters worsen in the FR-plus-exercise group. Relative to controls, FR and FR-plus-exercise groups showed significantly lower mineral apposition rate and osteoclast number and significantly reduced serum insulin-like growth factor-1 (IGF1) levels. Outcomes were rescued by ED71 or 1.25(OH)2D3 treatment. Thus, we conclude that administration of active vitamin D analogues represents a possible treatment to prevent these conditions. Keywords: Cortical bone; Female athletes; Food restriction; IGF-1; Osteoporosis; Vitamin D. Adiposity change and mortality in middle-aged to older Chinese: an 8-year follow-up of the Guangzhou Biobank Cohort Study. Huang YY, Jiang CQ, Xu L, Zhang WS, Zhu F, Jin YL, Thomas GN, Cheng KK, Lam TH. BMJ Open. 2020 Dec 4;10(12):e039239. doi: 10.1136/bmjopen-2020-039239. PMID: 33277280 Abstract Objective: To examine the associations of change in body mass index (BMI) and waist circumference (WC) over an average of 4 years with subsequent mortality risk in middle-aged to older Chinese. Design: Prospective cohort study based on the Guangzhou Biobank Cohort Study. Setting: Community-based sample. Participants: 17 773 participants (12 956 women and 4817 men) aged 50+ years. Primary and secondary outcome measures: Primary outcome measure was all-cause mortality. Secondary outcome measures were cardiovascular disease (CVD) and cancer mortality. Causes of death were obtained via record linkage, and coded according to the International Classification of Diseases (tenth revision). Results: 1424 deaths (53.4% women) occurred in the 17 773 participants (mean age 61.2, SD 6.8 years) during an average follow-up of 7.8 (SD=1.5) years, and 97.7% of participants did not have an intention of weight loss . Compared with participants with stable BMI, participants with BMI loss (>5%), but not gain, had a higher risk of all-cause mortality (HR=1.49, 95% CI 1.31 to 1.71), which was greatest in those who were underweight (HR=2.45, 95% CI 1.31 to 4.59). Similar patterns were found for WC. In contrast, for participants with a BMI of ≥27.5 kg/m2, BMI gain, versus stable BMI, was associated with 89% higher risk of all-cause mortality (HR=1.89, 95% CI 1.25 to 2.88), 72% higher risk of CVD mortality (HR=1.72, 95% CI 0.80 to 3.72) and 2.27-fold risk of cancer mortality (HR=2.27, 95% CI 1.26 to 4.10). Conclusion: In older people, unintentional BMI/WC loss, especially in those who were underweight was associated with higher mortality risk. However, BMI gain in those with obesity showed excess risks of all-cause and cancer mortality, but not CVD mortality. Frequent monitoring of changes in body size can be used as an early warning for timely clinical investigations and interventions and is important to inform appropriate health management in older Chinese. Keywords: epidemiology; general endocrinology; geriatric medicine; public health. Essential Amino Acids and Protein Synthesis: Insights into Maximizing the Muscle and Whole-Body Response to Feeding. Church DD, Hirsch KR, Park S, Kim IY, Gwin JA, Pasiakos SM, Wolfe RR, Ferrando AA. Nutrients. 2020 Dec 2;12(12):E3717. doi: 10.3390/nu12123717. PMID: 33276485 Abstract Ingesting protein-containing supplements and foods provides essential amino acids (EAA) necessary to increase muscle and whole-body protein synthesis (WBPS). Large variations exist in the EAA composition of supplements and foods, ranging from free-form amino acids to whole protein foods. We sought to investigate how changes in peripheral EAA after ingesting various protein and free amino acid formats altered muscle and whole-body protein synthesis. Data were compiled from four previous studies that used primed, constant infusions of L-(ring-2H5)-phenylalanine and L-(3,3-2H2)-tyrosine to determine fractional synthetic rate of muscle protein (FSR), WBPS, and circulating EAA concentrations. Stepwise regression indicated that max EAA concentration (EAACmax; R2 = 0.524, p < 0.001), EAACmax (R2 = 0.341, p < 0.001), and change in EAA concentration (ΔEAA; R = 0.345, p < 0.001) were the strongest predictors for postprandial FSR, Δ (change from post absorptive to postprandial) FSR, and ΔWBPS, respectively. Within our dataset, the stepwise regression equation indicated that a 100% increase in peripheral EAA concentrations increases FSR by ~34%. Further, we observed significant (p < 0.05) positive (R = 0.420-0.724) correlations between the plasma EAA area under the curve above baseline, EAACmax, ΔEAA, and rate to EAACmax to postprandial FSR, ΔFSR, and ΔWBPS. Taken together our results indicate that across a large variety of EAA/protein-containing formats and food, large increases in peripheral EAA concentrations are required to drive a robust increase in muscle and whole-body protein synthesis. Keywords: aging; amino acid kinetics; anabolism; essential amino acids; muscle protein synthesis; nutrition; protein; protein quality; whole body protein synthesis. Mortality is not increased with Diabetes in hospitalised very old adults: a multi-site review. Smerdely P. BMC Geriatr. 2020 Dec 3;20(1):522. doi: 10.1186/s12877-020-01913-0. PMID: 33272212 Free PMC article. Abstract Background: Few data exist regarding hospital outcomes in people with diabetes aged beyond 75 years. This study aimed to explore the association of diabetes with hospital outcome in the very old patient. Methods: A retrospective review was conducted of all presentations of patients aged 65 years or more admitted to three Sydney teaching hospitals over 6 years (2012-2018), exploring primarily the outcomes of in-hospital mortality, and secondarily the outcomes of length of stay, the development of hospital-acquired adverse events and unplanned re-admission to hospital within 28 days of discharge. Demographic and outcome data, the presence of diabetes and comorbidities were determined from ICD10 coding within the hospital's electronic medical record. Logistic and negative binomial regression models were used to assess the association of diabetes with outcome. Results: A total of 139,130 separations (mean age 80 years, range 65 to 107 years; 51% female) were included, with 49% having documented comorbidities and 26.1% a diagnosis of diabetes. When compared to people without diabetes, diabetes was not associated with increased odds of mortality (OR: 0.89 SE (0.02), p < 0.001). Further, because of a significant interaction with age, diabetes was associated with decreased odds of mortality beyond 80 years of age. While people with diabetes overall had longer lengths of stay (10.2 days SD (13.4) v 9.4 days SD (12.3), p < 0.001), increasing age was associated with shorter lengths of stay in people aged more than 90 years. Diabetes was associated with increased odds of hospital-acquired adverse events (OR: 1.09 SE (0.02), p < 0.001) and but not 28-day re-admission (OR: 0.88 SE (0.18), p = 0.523). Conclusion: Diabetes has not been shown to have a negative impact on mortality or length of stay in hospitalised very old adults from data derived from hospital administrative records. This may allow a more measured application of diabetic guidelines in the very old hospitalised patient. Keywords: Diabetes; Health outcomes; Hospital; Older adults. The effect of a ketogenic diet and synergy with rapamycin in a mouse model of breast cancer. Zou Y, Fineberg S, Pearlman A, Feinman RD, Fine EJ. PLoS One. 2020 Dec 3;15(12):e0233662. doi: 10.1371/journal.pone.0233662. eCollection 2020. PMID: 33270630 https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0233662&type=printable Abstract Background: The effects of diet in cancer, in general, and breast cancer in particular, are not well understood. Insulin inhibition in ketogenic, high fat diets, modulate downstream signaling molecules and are postulated to have therapeutic benefits. Obesity and diabetes have been associated with higher incidence of breast cancer. Addition of anti-cancer drugs together with diet is also not well studied. Methods: Two diets, one ketogenic, the other standard mouse chow, were tested in a spontaneous breast cancer model in 34 mice. Subgroups of 3-9 mice were assigned, in which the diet were implemented either with or without added rapamycin, an mTOR inhibitor and potential anti-cancer drug. Results: Blood glucose and insulin concentrations in mice ingesting the ketogenic diet (KD) were significantly lower, whereas beta hydroxybutyrate (BHB) levels were significantly higher, respectively, than in mice on the standard diet (SD). Growth of primary breast tumors and lung metastases were inhibited, and lifespans were longer in the KD mice compared to mice on the SD (p<0.005). Rapamycin improved survival in both mouse diet groups, but when combined with the KD was more effective than when combined with the SD. Conclusions: The study provides proof of principle that a ketogenic diet a) results in serum insulin reduction and ketosis in a spontaneous breast cancer mouse model; b) can serve as a therapeutic anti-cancer agent; and c) can enhance the effects of rapamycin, an anti-cancer drug, permitting dose reduction for comparable effect. Further, the ketogenic diet in this model produces superior cancer control than standard mouse chow whether with or without added rapamycin.