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  1. Variants may proportionately selected in the viral population by vaccination: APRIL 11, 202110:18 AM; UPDATED 2 HOURS AGO South African variant may evade protection from Pfizer vaccine, Israeli study says By Maayan Lubell https://www.reuters.com/article/us-health-coronavirus-israel-study/south-african-variant-may-evade-protection-from-pfizer-vaccine-israeli-study-says-idUSKBN2BX0JZ?il=0
  2. Fluoride in Drinking Water, Diet, and Urine in Relation to Bone Mineral Density and Fracture Incidence in Postmenopausal Women. Helte E, Donat Vargas C, Kippler M, Wolk A, Michaëlsson K, Åkesson A. Environ Health Perspect. 2021 Apr;129(4):47005. doi: 10.1289/EHP7404. Epub 2021 Apr 6. PMID: 33822648 Abstract Background: Although randomized controlled trials (RCTs) have demonstrated that high fluoride increases bone mineral density (BMD) and skeletal fragility, observational studies of low-dose chronic exposure through drinking water (<1.5mg/L, the maximum recommended by the World Health Organization) have been inconclusive. Objective: We assessed associations of fluoride in urine, and intake via diet and drinking water, with BMD and fracture incidence in postmenopausal women exposed to drinking water fluoride ≤1mg/L. Methods: Data were from participants in the Swedish Mammography Cohort-Clinical, a population-based prospective cohort study. At baseline (2004-2009), fluoride exposure was assessed based on urine concentrations (n =4,306) and estimated dietary intake (including drinking water) (n=4,072), and BMD was measured using dual energy X-ray absorptiometry. Incident fractures were ascertained via register-linkage through 2017. Residential history was collected to identify women with long-term consistent drinking water exposures prior to baseline. Results: At baseline, mean urine fluoride was 1.2mg/g creatinine (±1.9) and mean dietary intake was 2.2mg/d (±0.9), respectively. During follow-up, 850, 529, and 187 cases of any fractures, osteoporotic fractures, and hip fractures, respectively, were ascertained. Baseline BMD was slightly higher among women in the highest vs. lowest tertiles of exposure. Fluoride exposures were positively associated with incident hip fractures, with multivariable-adjusted hazard ratios of 1.50 (95% CI: 1.04, 2.17) and 1.59 (95% CI: 1.10, 2.30), for the highest vs. lowest tertiles of urine fluoride and dietary fluoride, respectively. Associations with other fractures were less pronounced for urine fluoride, and null for dietary fluoride. Restricting the analyses to women with consistent long-term drinking water exposures prior to baseline strengthened associations between fractures and urinary fluoride. Discussion: In this cohort of postmenopausal women, the risk of fractures was increased in association with two separate indicators of fluoride exposure. Our findings are consistent with RCTs and suggest that high consumption of drinking water with a fluoride concentration of ∼1 mg/L may increase both BMD and skeletal fragility in older women. https://doi.org/10.1289/EHP7404. Effect of 8-Day Fasting on Leukocytes Expression of Genes and Proteins Involved in Iron Metabolism in Healthy Men. Borkowska A, Tomczyk M, Żychowska M, Pilis W, Zych M, Antosiewicz J. Int J Mol Sci. 2021 Mar 23;22(6):3248. doi: 10.3390/ijms22063248. PMID: 33806756 Abstract Anorexia Nervosa (AN) is a severe and often enduring disorder characterized by restriction of food intake, low body weight, fear of weight gain, and distorted body image. Investigations on cognition performance in AN patients have yielded conflicting results. Using an established and sensitive computerized cognitive test battery, we aimed to assess core aspects of cognitive function, including attention span, information processing, reasoning, working and episodic memory, in AN patients and controls. Patients were recruited from the Danish Prospective Longitudinal all-comer inclusion study in Eating Disorders (PROLED). Included were 26 individuals with AN and 36 healthy volunteers (HV). All were tested with CogTrack (an online cognitive assessment system) at baseline, and AN patients were tested again at a follow-up time point after weight increase (n = 13). At baseline, AN patients showed faster reaction times in the attention tasks, as well as increased accuracy in grammatical reasoning compared to HV. There were no differences in cognitive function between AN patients and HV in the other cognitive domains measured (sustained attention, working and episodic memory, speed of retrieval, and speed of grammatical reasoning). No differences were visible in the AN sample between baseline and follow-up. Performance did not correlate with any clinical variables in the AN sample. These findings supplement results from other studies suggesting increased concentration and reasoning accuracy in patients suffering from AN, who showed increased performance in cognitive tasks despite their illness. Keywords: anorexia nervosa; cognitive functioning; cognitive performance; eating disorders; neuropsychology. Associations of sleep duration and quality with incident cardiovascular disease, cancer, and mortality: a prospective cohort study of 407,500 UK biobank participants. Tao F, Cao Z, Jiang Y, Fan N, Xu F, Yang H, Li S, Zhang Y, Zhang X, Sun L, Wang Y. Sleep Med. 2021 Mar 15;81:401-409. doi: 10.1016/j.sleep.2021.03.015. Online ahead of print. PMID: 33819843 Abstract Objective: Few studies have investigated the associations of sleep duration and sleep quality with incident cardiovascular diseases (CVDs), cancer, and mortality in the same large population. This study aimed at estimating the independent risk factors of long or short sleep durations and several typical characteristics of poor sleep quality for incident CVDs, cancer, and mortality. Methods: In this prospective cohort study, 407 500 individuals were enrolled. Cox proportional hazards models were used to calculate the adjusted hazard ratios and 95% confidence intervals (HR, 95%CI) of associations of sleep duration and quality with incident CVDs, cancer, and mortality. Results: Compared with the sleep duration of 7 h, sleep duration of ≤5 h and ≥9 h were both associated with higher risk of all-cause mortality (HR = 1.25, 95% CI: 1.16-1.34 and HR = 1.30, 95% CI: 1.22-1.38, respectively), CVD mortality (HR = 1.27, 95% CI: 1.09-1.49 and HR = 1.32, 95% CI: 1.16-1.50, respectively), and CVD incidence (HR = 1.23, 95% CI: 1.16-1.31 and HR = 1.08, 95% CI: 1.02-1.15, respectively). Additionally, long sleep duration (≥9 h) was associated with a higher risk of cancer mortality (HR = 1.19, 95% CI: 1.10-1.30) and cancer incidence (HR = 1.08, 95% CI: 1.04-1.12). Moreover, CVD incidence was significantly associated with snoring, insomnia and narcolepsy, increasing the risk by 7%, 26%, and 20%, respectively. Conclusion: Long sleep durations may substantially increase the risk of mortality and morbidity. Snoring, insomnia, and narcolepsy were independent risk factors for incident CVD. Keywords: Cancer; Cardiovascular disease; Mortality; Sleep duration; Sleep quality.
  3. AlPater

    Al's CR updates

    LONG-TERM CHRONIC CALORIC RESTRICTION ALTERS miRNA PROFILES IN THE BRAIN OF AGEING MICE. Ozorhan U, Tuna BG, Cicekdal MB, Kuskucu A, Bayrak OF, Yilmaz B, Demirel PB, Cleary MP, Dogan S. Br J Nutr. 2021 Apr 7:1-32. doi: 10.1017/S0007114521001239. Online ahead of print. PMID: 33823947 Abstract Calorie restriction (CR) has been shown to be one of the most effective methods in alleviating the effects of ageing and age-related diseases such as increasing longevity and preventing dementia, and Alzheimer's Disease. Although the protective effects of CR have been reported, the exact molecular mechanism still needs to be clarified. This study aims to determine differentially expressed (DE) miRNAs and altered gene pathways due to long-term chronic (CCR) and intermittent (ICR) CR in the brain of mice to understand the preventive roles of miRNAs in long-term CR. Ten weeks old mice were enrolled into three different dietary groups; ad-libitum, CCR or ICR, and fed until 82 weeks old mice. miRNAs were analyzed using GeneChip 4.1 microarray and the target of DE miRNAs was determined using miRNA target databases. Out of a total 3,163 analyzed miRNAs, 55 of them were differentially expressed either by different CR protocols or by ageing. Brain samples from the CCR group had increased expression levels of mmu-miR-713 while decreasing expression levels of mmu-miR-184-3p and mmu-miR-351-5p compared to the other dietary groups. Also, current results indicated that CCR showed better preventive effects than that of ICR. Thus, CCR may perform its protective effects by modulating these specific miRNAs since they are shown to play roles in neurogenesis, chromatin, and histone regulation. In conclusion, these three miRNAs could be potential targets for neurodegenerative and ageing-related diseases and may play important roles in the protective effects of CR in the brain. Keywords: Ageing; Brain; Intermittent Calorie Restriction; Neurodegeneration; Neurogenesis; miRNA. Metabolic Reprogramming by Reduced Calorie Intake or Pharmacological Caloric Restriction Mimetics for Improved Cancer Immunotherapy. Eriau E, Paillet J, Kroemer G, Pol JG. Cancers (Basel). 2021 Mar 12;13(6):1260. doi: 10.3390/cancers13061260. PMID: 33809187 Review. Abstract Caloric restriction and fasting have been known for a long time for their health- and life-span promoting effects, with coherent observations in multiple model organisms as well as epidemiological and clinical studies. This holds particularly true for cancer. The health-promoting effects of caloric restriction and fasting are mediated at least partly through their cellular effects-chiefly autophagy induction-rather than reduced calorie intake per se. Interestingly, caloric restriction has a differential impact on cancer and healthy cells, due to the atypical metabolic profile of malignant tumors. Caloric restriction mimetics are non-toxic compounds able to mimic the biochemical and physiological effects of caloric restriction including autophagy induction. Caloric restriction and its mimetics induce autophagy to improve the efficacy of some cancer treatments that induce immunogenic cell death (ICD), a type of cellular demise that eventually elicits adaptive antitumor immunity. Caloric restriction and its mimetics also enhance the therapeutic efficacy of chemo-immunotherapies combining ICD-inducing agents with immune checkpoint inhibitors targeting PD-1. Collectively, preclinical data encourage the application of caloric restriction and its mimetics as an adjuvant to immunotherapies. This recommendation is subject to confirmation in additional experimental settings and in clinical trials. In this work, we review the preclinical and clinical evidence in favor of such therapeutic interventions before listing ongoing clinical trials that will shed some light on this subject. Keywords: caloric restriction; caloric restriction mimetics; cancer immunotherapy; fasting; metabolism. Long-Term Caloric Restriction Attenuates beta-Amyloid Neuropathology and Is Accompanied by Autophagy in APPswe/PS1delta9 Mice. Müller L, Power Guerra N, Stenzel J, Rühlmann C, Lindner T, Krause BJ, Vollmar B, Teipel S, Kuhla A. Nutrients. 2021 Mar 18;13(3):985. doi: 10.3390/nu13030985. PMID: 33803798 Abstract Caloric restriction (CR) slows the aging process, extends lifespan, and exerts neuroprotective effects. It is widely accepted that CR attenuates β-amyloid (Aβ) neuropathology in models of Alzheimer's disease (AD) by so-far unknown mechanisms. One promising process induced by CR is autophagy, which is known to degrade aggregated proteins such as amyloids. In addition, autophagy positively regulates glucose uptake and may improve cerebral hypometabolism-a hallmark of AD-and, consequently, neural activity. To evaluate this hypothesis, APPswe/PS1delta9 (tg) mice and their littermates (wild-type, wt) underwent CR for either 16 or 68 weeks. Whereas short-term CR for 16 weeks revealed no noteworthy changes of AD phenotype in tg mice, long-term CR for 68 weeks showed beneficial effects. Thus, cerebral glucose metabolism and neuronal integrity were markedly increased upon 68 weeks CR in tg mice, indicated by an elevated hippocampal fluorodeoxyglucose [18F] ([18F]FDG) uptake and increased N-acetylaspartate-to-creatine ratio using positron emission tomography/computer tomography (PET/CT) imaging and magnet resonance spectroscopy (MRS). Improved neuronal activity and integrity resulted in a better cognitive performance within the Morris Water Maze. Moreover, CR for 68 weeks caused a significant increase of LC3BII and p62 protein expression, showing enhanced autophagy. Additionally, a significant decrease of Aβ plaques in tg mice in the hippocampus was observed, accompanied by reduced microgliosis as indicated by significantly decreased numbers of iba1-positive cells. In summary, long-term CR revealed an overall neuroprotective effect in tg mice. Further, this study shows, for the first time, that CR-induced autophagy in tg mice accompanies the observed attenuation of Aβ pathology. Keywords: APPswe/PS1delta9; [18F]FDG-PET/CT; amyloid β; autophagy; caloric restriction; iba1.
  4. Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and lifespan in mice. Richardson NE, Konon EN, Schuster HS, Mitchell AT, Boyle C, Rodgers AC, Finke M, Haider LR, Yu D, Flores V, Pak HH, Ahmad S, Ahmed S, Radcliff A, Wu J, Williams EM, Abdi L, Sherman DS, Hacker T, Lamming DW. Nat Aging. 2021 Jan;1(1):73-86. doi: 10.1038/s43587-020-00006-2. Epub 2021 Jan 14. PMID: 33796866 Abstract Protein restricted (PR) diets promote health and longevity in many species. While the precise components of a PR diet that mediate the beneficial effects to longevity have not been defined, we recently showed that many metabolic effects of PR can be attributed to reduced dietary levels of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. Here, we demonstrate that restricting dietary BCAAs increases the survival of two different progeroid mouse models, delays frailty and promotes the metabolic health of wild-type C57BL/6J mice when started in midlife, and leads to a 30% increase in lifespan and a reduction in frailty in male, but not female, wild-type mice when fed lifelong. Our results demonstrate that restricting dietary BCAAs can increase healthspan and longevity in mice, and suggest that reducing dietary BCAAs may hold potential as a translatable intervention to promote healthy aging. Keywords: branched-chain amino acids; healthspan; lifespan; mTOR; mTORC1; progeria; protein restriction; rapamycin. 17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex. Harrison DE, Strong R, Reifsnyder P, Kumar N, Fernandez E, Flurkey K, Javors MA, Lopez-Cruzan M, Macchiarini F, Nelson JF, Bitto A, Sindler AL, Cortopassi G, Kavanagh K, Leng L, Bucala R, Rosenthal N, Salmon A, Stearns TM, Bogue M, Miller RA. Aging Cell. 2021 Mar 31:e13328. doi: 10.1111/acel.13328. Online ahead of print. PMID: 33788371 Abstract In genetically heterogeneous mice produced by the CByB6F1 x C3D2F1 cross, the "non-feminizing" estrogen, 17-α-estradiol (17aE2), extended median male lifespan by 19% (p < 0.0001, log-rank test) and 11% (p = 0.007) when fed at 14.4 ppm starting at 16 and 20 months, respectively. 90th percentile lifespans were extended 7% (p = 0.004, Wang-Allison test) and 5% (p = 0.17). Body weights were reduced about 20% after starting the 17aE2 diets. Four other interventions were tested in males and females: nicotinamide riboside, candesartan cilexetil, geranylgeranylacetone, and MIF098. Despite some data suggesting that nicotinamide riboside would be effective, neither it nor the other three increased lifespans significantly at the doses tested. The 17aE2 results confirm and extend our original reports, with very similar results when started at 16 months compared with mice started at 10 months of age in a prior study. The consistently large lifespan benefit in males, even when treatment is started late in life, may provide information on sex-specific aspects of aging. Keywords: 17-α-estradiol; candesartan cilexetil; geranylgeranylacetone; heterogeneous mice; lifespan; macrophage migration inhibitory factor; nicotinamide riboside. Caloric and nutrient restriction to augment chemotherapy efficacy for acute lymphoblastic leukemia: the IDEAL trial. Orgel E, Framson C, Buxton R, Kim J, Li G, Tucci J, Freyer DR, Sun W, Oberley MJ, Dieli-Conwright C, Mittelman SD. Blood Adv. 2021 Apr 13;5(7):1853-1861. doi: 10.1182/bloodadvances.2020004018. PMID: 33792627 Abstract Being overweight or obese (OW/OB) during B-cell acute lymphoblastic leukemia (B-ALL) induction is associated with chemoresistance as quantified by minimal residual disease (MRD). We hypothesized that caloric and nutrient restriction from diet/exercise could lessen gains in fat mass (FM) and reduce postinduction MRD. The Improving Diet and Exercise in ALL (IDEAL) trial enrolled patients 10 to 21 years old, newly diagnosed with B-ALL (n = 40), in comparison with a recent historical control (n = 80). Designed to achieve caloric deficits ≥20% during induction, reduce fat intake/glycemic load, and increase activity, IDEAL's end points were FM gain (primary), MRD ≥0.01%, and adherence/feasibility. Integrated biology explored biomarkers of OW/OB physiology. IDEAL intervention did not significantly reduce median FM change from baseline overall (+5.1% [interquartile range [IQR], 15.8] vs +10.7% [IQR, 16.0]; P = .13), but stratified analysis showed benefit in those OW/OB (+1.5% [IQR, 6.6] vs +9.7% [IQR, 11.1]; P = .02). After accounting for prognostic factors, IDEAL intervention significantly reduced MRD risk (odds ratio, 0.30; 95% confidence interval, 0.09-0.92; P = .02). The trial exceeded its adherence (≥75% of overall diet) and feasibility (≥80% completed visits) thresholds. Integrated biology found the IDEAL intervention increased circulating adiponectin and reduced insulin resistance. The IDEAL intervention was feasible, decreased fat gain in those OW/OB, and reduced MRD. This is the first study in any hematologic malignancy to demonstrate potential benefit from caloric restriction via diet/exercise to augment chemotherapy efficacy and improve disease response. A prospective, randomized trial is warranted for validation.
  5. AlPater

    Al's CR updates

    DNMT3.1 controls trade-offs between growth, reproduction, and life span under starved conditions in Daphnia magna. Nguyen ND, Matsuura T, Kato Y, Watanabe H. Sci Rep. 2021 Apr 1;11(1):7326. doi: 10.1038/s41598-021-86578-4. PMID: 33795753 Abstract The cladoceran crustacean Daphnia has long been a model of energy allocation studies due to its important position in the trophic cascade of freshwater ecosystems. However, the loci for controlling energy allocation between life history traits still remain unknown. Here, we report CRISPR/Cas-mediated target mutagenesis of DNA methyltransferase 3.1 (DNMT3.1) that is upregulated in response to caloric restriction in Daphnia magna. The resulting biallelic mutant is viable and did not show any change in growth rate, reproduction, and longevity under nutrient rich conditions. In contrast, under starved conditions, the growth rate of this DNMT3.1 mutant was increased but its reproduction was reciprocally reduced compared to the wild type when the growth and reproduction activities competed during a period from instar 4 to 8. The life span of this mutant was significantly shorter than that of the wild type. We also compared transcriptomes between DNMT3.1 mutant and wild type under nutrient-rich and starved conditions. Consistent with the DNMT3.1 mutant phenotypes, the starved condition led to changes in the transcriptomes of the mutant including differential expression of vitellogenin genes. In addition, we found upregulation of the I am not dead yet (INDY) ortholog, which has been known to shorten the life span in Drosophila, explaining the shorter life span of the DNMT3.1 mutant. These results establish DNMT3.1 as a key regulator for life span and energy allocation between growth and reproduction during caloric restriction. Our findings reveal how energy allocation is implemented by selective expression of a DNMT3 ortholog that is widely distributed among animals. We also infer a previously unidentified adaptation of Daphnia that invests more energy for reproduction than growth under starved conditions. Calorie Restriction Suppresses the Progression of Radiation-Induced Intestinal Tumours in C3B6F1 Apc (Min/+) Mice. Morioka T, Yamazaki S, Yanagihara H, Sunaoshi M, Kaminishi M, Kakinuma S. Anticancer Res. 2021 Mar;41(3):1365-1375. doi: 10.21873/anticanres.14894. PMID: 33788728 Abstract Background/aim: Progress in cancer treatment and diagnosis has made second cancer after medical radiation exposure a particular concern among childhood cancer survivors. Calorie restriction (CR) is a broadly effective cancer prevention strategy, although its effects on radiation-induced intestinal tumours are unclear. Here we examined the cancer-preventative efficacy of a CR diet at different starting ages on radiation induction of intestinal tumours in mice. Materials and methods: Male C3B6F1 ApcMin/+ mice were irradiated with 0 or 2 Gy of X-rays at 2 weeks of age. After an interval of 2, 8 or 18 weeks, mice were fed with a non-CR (95 kcal/week/mouse) or CR (65 kcal/week/mouse) diet. Intestinal tumours were evaluated for number, size distribution and malignancy. Results: CR suppressed the size and progression of both spontaneous and radiation-induced intestinal tumours depending on age at starting of CR. CR diets were effective even administered to adult mice. Conclusion: CR was effective for suppression of tumour progression, which was accelerated by radiation exposure. Use of CR might be a useful cancer-prevention strategy for radiation-induced tumours of the intestinal tract. Keywords: Calorie restriction; cancer prevention; radiation carcinogenesis. Olfactory perception of food abundance regulates dietary restriction-mediated longevity via a brain-to-gut signal. Zhang B, Jun H, Wu J, Liu J, Shawn Xu XZ. Nat Aging. 2021 Mar;1(3):255-268. doi: 10.1038/s43587-021-00039-1. Epub 2021 Mar 15. PMID: 33796867 Abstract The role of food nutrients in mediating the positive effect of dietary restriction (DR) on longevity has been extensively characterized, but how non-nutrient food components regulate lifespan is not well understood. Here, we show that food-associated odors shorten the lifespan of C. elegans under DR but not those fed ad libitum, revealing a specific effect of food odors on DR-mediated longevity. Food odors act on a neural circuit comprising the sensory neurons ADF and CEP, and the interneuron RIC. This olfactory circuit signals the gut to suppress DR-mediated longevity via octopamine, the mammalian homolog of norepinephrine, by regulating the energy sensor AMPK through a Gq-PLCβ-CaMKK-dependent mechanism. In mouse primary cells, we find that norepinephrine signaling regulates AMPK through a similar mechanism. Our results identify a brain-gut axis that regulates DR-mediated longevity by relaying olfactory information about food abundance from the brain to the gut.
  6. Viewpoint March 31, 2021 The Leading Causes of Death in the US for 2020 Farida B. Ahmad, MPH1; Robert N. Anderson, PhD2 JAMA. Published online March 31, 2021. doi:10.1001/jama.2021.5469 https://jamanetwork.com/journals/jama/fullarticle/2778234?guestAccessKey=0b94e087-4b87-458d-b869-a1aa164eb8a6&utm_source=silverchair&utm_medium=email&utm_campaign=article_alert-jama&utm_content=olf&utm_term=033121 Vital statistics data provide the most complete assessment of annual mortality burden and contribute key measurements of the direct and indirect mortality burden during a public health pandemic. While mortality statistics have historically been produced annually, the COVID-19 pandemic introduced a pressing need for the National Center for Health Statistics (NCHS) National Vital Statistics System (NVSS) to rapidly release reliable provisional mortality data. Provisional estimates indicate a 17.7% increase in the number of deaths in 2020 (the increase in the age-adjusted rate was 15.9%) compared with 2019, with increases in many leading causes of death.1 The provisional leading cause-of-death rankings for 2020 indicate that COVID-19 was the third leading cause of death in the US behind heart disease and cancer.1
  7. Selenium supplementation inhibits IGF-1 signaling and confers methionine restriction-like healthspan benefits to mice. Plummer JD, Postnikoff SD, Tyler JK, Johnson JE. Elife. 2021 Mar 30;10:e62483. doi: 10.7554/eLife.62483. PMID: 33783357 Abstract Methionine restriction (MR) dramatically extends the healthspan of several organisms. Methionine-restricted rodents have less age-related pathology and increased longevity as compared with controls, and recent studies suggest that humans might benefit similarly. Mechanistically, it is likely that the decreased IGF-1 signaling that results from MR underlies the benefits of this regimen. Thus, we hypothesized that interventions that decrease IGF-1 signaling would also produce MR-like healthspan benefits. Selenium supplementation inhibits IGF-1 signaling in rats and has been studied for its putative healthspan benefits. Indeed, we show that feeding mice a diet supplemented with sodium selenite results in an MR-like phenotype, marked by protection against diet-induced obesity, as well as altered plasma levels of IGF-1, FGF-21, adiponectin, and leptin. Selenomethionine supplementation results in a similar, albeit less robust response, and also extends budding yeast lifespan. Our results indicate that selenium supplementation is sufficient to produce MR-like healthspan benefits for yeast and mammals. Keywords: S. cerevisiae; aging; biochemistry; chemical biology; genetics; genomics; histone deacetylase; lifespan; metabolism; mitophagy; mouse; selenomethionine. Food hardness influences the progression of age-related hearing loss in mice. Oike H, Kohyama K, Mochizuki-Kawai H, Azami K. Exp Gerontol. 2021 Mar 27:111335. doi: 10.1016/j.exger.2021.111335. Online ahead of print. PMID: 33785396 Abstract C57BL/6J and DBA/2J mice are often used for hearing research because of their early onset and progression of age-related hearing loss (AHL). Here, we report that the hardness of the diet affects the progression of AHL in these mice. When C57BL/6J mice and DBA/2J mice were fed a pellet-type or powder-type standard AIN93M diet, the pellet diet significantly promoted AHL. AHL promotion was eliminated by crushing the pellet diet to a powder. Subsequently, when C57BL/6J mice were fed the pellet-type AIN93M diet obtained from three different manufacturers, two of them significantly promoted AHL. The hardness of the diets was measured, and it was found that the two diets that promoted AHL were significantly harder than the other diet. Next, we attempted to reduce diet hardness by replacing some nutritional ingredients with dried eggs or phosphatidylcholine (PC), and we succeeded in obtaining brittle diets with lower hardness values. Then, C57BL/6J mice were bred with brittle diets for 6 months and the promotion of AHL was suppressed to the equivalent level as the powder diet. Furthermore, when senescence-accelerated mice, SAMP8, were fed a brittle diet for one year, the progression of AHL was also suppressed; however, it did not affect other aging indexes, such as mental and physical performance. We also confirmed that a high-fat pellet diet, which is soft even in pellet form, did not promote AHL. Time-restricted feeding (tRF), which is a chrono-nutritional method to delay aging, ameliorated the promotion of AHL by the hard AIN93M pellets in C57BL/6J mice. These results indicate that the physical form and hardness of diets affect the progression of AHL in mouse models. Keywords: Age-related hearing loss; Chrono-nutrition; Diet form; Mouse strain. Association of Cycling with Risk of All-Cause and Cardiovascular Disease Mortality: A Systematic Review and Dose-Response Meta-analysis of Prospective Cohort Studies. Zhao Y, Hu F, Feng Y, Yang X, Li Y, Guo C, Li Q, Tian G, Qie R, Han M, Huang S, Wu X, Zhang Y, Wu Y, Liu D, Zhang D, Cheng C, Zhang M, Yang Y, Shi X, Lu J, Hu D. Sports Med. 2021 Mar 28. doi: 10.1007/s40279-021-01452-7. Online ahead of print. PMID: 33774807 Abstract Background: Cycling has been suggested to be related to risk of all-cause and cardiovascular disease (CVD) mortality. However, a quantitative comprehensive assessment of the dose-response association of cycling with risk of all-cause and CVD mortality has not been reported. We performed a meta-analysis of cohort studies assessing the risk of all-cause and CVD mortality with cycling. Methods: PubMed and Embase databases were searched for relevant articles published up to December 13, 2019. Random-effects models were used to estimate the summary relative risk (RR) of all-cause and CVD mortality with cycling. Restricted cubic splines were used to evaluate the dose-response association. Results: We included 9 articles (17 studies) with 478,847 participants and 27,860 cases (22,415 from all-cause mortality and 5445 from CVD mortality) in the meta-analysis. Risk of all-cause mortality was reduced 23% with the highest versus lowest cycling level [RR 0.77, 95% confidence interval (CI) 0.67-0.88], and CVD mortality was reduced 24% (RR 0.76, 95% CI 0.65-0.89). We found a linear association between cycling and all-cause mortality (Pnon-linearity = 0.208); the risk was reduced by 9% (RR 0.91, 95% CI 0.86-0.96) with each five metabolic equivalent of task (MET)-h/week increase in cycling. We found an approximately U-shaped association between cycling and CVD mortality (Pnon-linearity = 0.034), with the lowest risk at approximately 15 MET-h/week of cycling. Conclusions: Our findings based on quantitative data suggest that any level of cycling is better than none for all-cause mortality. However, for CVD mortality, one must choose an appropriate level of cycling, with an approximate optimum of 15 MET-h/week (equal to 130 min/week at 6.8 MET). A fifty percent leucine-restricted diet reduces fat mass and improves glucose regulation. Zhou Z, Yin H, Guo Y, Fang Y, Yuan F, Chen S, Guo F. Nutr Metab (Lond). 2021 Mar 26;18(1):34. doi: 10.1186/s12986-021-00564-1. PMID: 33771176 Abstract Background: Leucine deprivation modulates the dietary amino acid composition, reducing the fat content and improving the glucose tolerance, thus protecting the organism against obesity. However, a complete deprivation of leucine can lead to an extremely rapid fat loss in mice, accompanied by prolonged adverse effects such as weakness and mental fatigue. Therefore, in this study we aimed to seek the optimal concentration of dietary leucine that can reduce fat mass and improve the metabolism without the onset of severe effects. Methods: To investigate whether there is a better concentration of diet leucine restriction (LR), based on the diet we conducted (A10021B), that can reduce fat mass and improve metabolism status without taking many negative effects, we fed 8 weeks old male C57Bl/6J mice with increasing degrees of leucine restriction diet 0% LR (control group), 25% LR, 50% LR, and 75% LR groups (4-6 mice each group). Fat mass and blood glucose levels were measured. The expression levels of genes involved in lipid metabolism in white adipose tissue (WAT) and liver, and proteins in insulin signaling were assessed in WAT, liver and muscle. Results: We found that the 50% LR group is the most proper group here at the lowest leucine effective concentration, which reduced fat mass (p < 0.05) and improved glucose regulation in mice over a 90 days feeding. Further studies revealed that lipid synthesis pathway (Fas, Scd1and Srebp1, p < 0.05) was downregulated and lipolysis (Atgl, p < 0.05) was upregulated in WAT in 50% LR group, compared to that in control group. Furthermore, glucose regulation (glucose tolerance test, p < 0.05) was also improved, and insulin signaling (p < 0.05) in the muscle was enhanced in 50% LR group while in WAT and liver were not changed. Conclusions: Collectively, a 50% LR in mice reduced fat mass and improved glucose regulation, which may function through modulating lipid synthesis and lipolysis pathway in adipose tissue as well as enhancing insulin signaling in muscle. So far, we provide a further consideration for carrying out the diet of leucine restriction to reduce fat and improve metabolism status before clinical study. Keywords: Insulin signaling; Leucine restriction; Lipid metabolism pathway; Obesity. Methionine restriction alleviates age-associated cognitive decline via fibroblast growth factor 21. Ren B, Wang L, Shi L, Jin X, Liu Y, Liu RH, Yin F, Cadenas E, Dai X, Liu Z, Liu X. Redox Biol. 2021 Mar 11;41:101940. doi: 10.1016/j.redox.2021.101940. Online ahead of print. PMID: 33765615 Abstract Methionine restriction (MR) extends lifespan and delays the onset of aging-associated pathologies. However, the effect of MR on age-related cognitive decline remains unclear. Here, we find that a 3-month MR ameliorates working memory, short-term memory, and spatial memory in 15-month-old and 18-month-old mice by preserving synaptic ultrastructure, increasing mitochondrial biogenesis, and reducing the brain MDA level in aged mice hippocampi. Transcriptome data suggest that the receptor of fibroblast growth factor 21 (FGF21)-related gene expressions were altered in the hippocampi of MR-treated aged mice. MR increased FGF21 expression in serum, liver, and brain. Integrative modelling reveals strong correlations among behavioral performance, MR altered nervous structure-related genes, and circulating FGF21 levels. Recombinant FGF21 treatment balanced the cellular redox status, prevented mitochondrial structure damages, and upregulated antioxidant enzymes HO-1 and NQO1 expression by transcriptional activation of Nrf2 in SH-SY5Y cells. Moreover, knockdown of Fgf21 by i.v. injection of adeno-associated virus abolished the neuroprotective effects of MR in aged mice. In conclusion, the MR exhibited the protective effects against age-related behavioral disorders, which could be partly explained by activating circulating FGF21 and promoting mitochondrial biogenesis, and consequently suppressing the neuroinflammation and oxidative damages. These results demonstrate that FGF21 can be used as a potential nutritional factor in dietary restriction-based strategies for improving cognition associated with neurodegeneration disorders. Keywords: Aging; Cognitive decline; Fibroblast growth factor 21; Methionine restriction; Nrf2; Oxidative stress. Maintenance of muscle mass in adult male mice is independent of testosterone. Davidyan A, Pathak S, Baar K, Bodine SC. PLoS One. 2021 Mar 25;16(3):e0240278. doi: 10.1371/journal.pone.0240278. eCollection 2021. PMID: 33764986 Abstract Testosterone is considered a potent anabolic agent in skeletal muscle with a well-established role in adolescent growth and development in males. However, the role of testosterone in the regulation of skeletal muscle mass and function throughout the lifespan has yet to be fully established. While some studies suggest that testosterone is important for the maintenance of skeletal muscle mass, an understanding of the role this hormone plays in young, adult, and old males with normal and low serum testosterone levels is lacking. We investigated the role testosterone plays in the maintenance of muscle mass by examining the effect of orchiectomy-induced testosterone depletion in C57Bl6 male mice at ages ranging from early postnatal through old age (1.5-, 5-, 12-, and 24-month old mice). Following 28 days of testosterone depletion, we assessed mass and fiber cross-sectional-area (CSA) of the tibialis anterior, gastrocnemius, and quadriceps muscles. In addition, we measured global rates of protein synthesis and degradation using the SuNSET method, western blots, and enzyme activity assays. Twenty-eight days of testosterone depletion resulted in reduced muscle mass in the two youngest cohorts, but had no effect in the two oldest cohorts. Mean CSA decreased only in the youngest cohort and only in the tibialis anterior muscle. Testosterone depletion resulted in a general increase in proteasome activity at all ages. No change in protein synthesis was detected at the terminal time point. These data suggest that within physiological serum concentrations, testosterone may not be critical for the maintenance of muscle mass in mature male mice; however, in young mice testosterone is crucial for normal growth.
  8. AlPater

    Al's CR updates

    Cardioprotective effects of severe calorie restriction from birth in adult ovariectomized rats. Rodrigues CM, Domingues TE, de Sousa Santos C, Costa-Pereira LV, Mendes BF, Dos Santos JM, Costa KB, Silva G, Cantuária VL, Rocha-Vieira E, Peixoto MFD, Honorato-Sampaio K. Life Sci. 2021 Mar 24:119411. doi: 10.1016/j.lfs.2021.119411. Online ahead of print. PMID: 33774029 Abstract Aims: Menopause is a female condition induced by a reduction of ovarian hormone and is related to an increase in cardiovascular diseases in women. We have shown that severe calorie restriction (SCR) from birth reduces the cardiometabolic risk in adult male Wistar rats. In this study, we investigated the effects of SCR from birth to adulthood on cardiovascular function of ovariectomized rats. Main methods: From birth to adulthood, rats were daily fed ad libitum (control group - C) or with 50% of the amount consumed by the control group (calorie-restricted group - R). At 90 days, half of the rats in each group underwent bilateral ovariectomy (OVX), totaling 4 groups: C-Sham, C-OVX, R-Sham, R-OVX. Systolic blood pressure (SBP), heart rate (HR) and, double product (DP) index were recorded by tail-cuff plethysmography. Cardiac function was analyzed by the Langendorff technique and cardiomyocyte diameter was accessed by histologic analysis. Additionally, cardiac SERCA2 content and redox status were evaluated. Key findings: C-OVX rats exhibited reduced cardiac function and cardiac non-enzymatic total antioxidant capacity (TAC). R-Sham animals showed reduced SBP, DP, HR, improved cardiac function, reduced cardiac protein carbonyl derivatives and increased TAC, catalase, and superoxide dismutase activities. R-OVX rats maintained reduced SBP, DP, HR, and increased contractility and relaxation indexes. R-Sham and R-OVX rats exhibited preserved heart mass and reduced cardiomyocyte diameter. Cardiac SERCA2 content did not differ between the groups. Significance: Taken together, our findings show cardioprotective effects of SCR from birth in adult ovariectomized rats.
  9. Pfizer, Moderna COVID-19 vaccines highly effective after 1st shot in real-world, U.S. study suggests Findings add to evidence base supporting COVID-19 vaccines Thomson Reuters · Posted: Mar 29, 2021 https://www.cbc.ca/news/health/mrna-covid-19-vaccines-cdc-effectiveness-1.5968376 >>>>>>>>>>>>>>>> Interim Estimates of Vaccine Effectiveness of BNT162b2 and mRNA-1273 COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Health Care Personnel, First Responders, and Other Essential and Frontline Workers — Eight U.S. Locations, December 2020–March 2021 MMWR Early Release / March 29, 2021 / 70 Mark G. Thompson et al https://www.cdc.gov/mmwr/volumes/70/wr/mm7013e3.htm?s_cid=mm7013e3_w#T2_down [It was 80% after 2 weeks for first dose.]
  10. [mRNA-1273 vaccine is the Moderna vaccine. Variant B.1.1.7 is the UK variant. Variant B1.351 is the South Africa variant.] Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies. Planas D, Bruel T, Grzelak L, Guivel-Benhassine F, Staropoli I, Porrot F, Planchais C, Buchrieser J, Rajah MM, Bishop E, Albert M, Donati F, Prot M, Behillil S, Enouf V, Maquart M, Smati-Lafarge M, Varon E, Schortgen F, Yahyaoui L, Gonzalez M, De Sèze J, Péré H, Veyer D, Sève A, Simon-Lorière E, Fafi-Kremer S, Stefic K, Mouquet H, Hocqueloux L, van der Werf S, Prazuck T, Schwartz O. Nat Med. 2021 Mar 26. doi: 10.1038/s41591-021-01318-5. Online ahead of print. PMID: 33772244 https://www.nature.com/articles/s41591-021-01318-5.pdf Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.7 and B.1.351 variants were first identified in the United Kingdom and South Africa, respectively, and have since spread to many countries. These variants harboring diverse mutations in the gene encoding the spike protein raise important concerns about their immune evasion potential. Here, we isolated infectious B.1.1.7 and B.1.351 strains from acutely infected individuals. We examined sensitivity of the two variants to SARS-CoV-2 antibodies present in sera and nasal swabs from individuals infected with previously circulating strains or who were recently vaccinated, in comparison with a D614G reference virus. We utilized a new rapid neutralization assay, based on reporter cells that become positive for GFP after overnight infection. Sera from 58 convalescent individuals collected up to 9 months after symptoms, similarly neutralized B.1.1.7 and D614G. In contrast, after 9 months, convalescent sera had a mean sixfold reduction in neutralizing titers, and 40% of the samples lacked any activity against B.1.351. Sera from 19 individuals vaccinated twice with Pfizer Cominarty, longitudinally tested up to 6 weeks after vaccination, were similarly potent against B.1.1.7 but less efficacious against B.1.351, when compared to D614G. Neutralizing titers increased after the second vaccine dose, but remained 14-fold lower against B.1.351. In contrast, sera from convalescent or vaccinated individuals similarly bound the three spike proteins in a flow cytometry-based serological assay. Neutralizing antibodies were rarely detected in nasal swabs from vaccinees. Thus, faster-spreading SARS-CoV-2 variants acquired a partial resistance to neutralizing antibodies generated by natural infection or vaccination, which was most frequently detected in individuals with low antibody levels. Our results indicate that B1.351, but not B.1.1.7, may increase the risk of infection in immunized individuals. >>>>>>>>>>>>>>> Neutralizing Antibodies Against SARS-CoV-2 Variants After Infection and Vaccination. Edara VV, Hudson WH, Xie X, Ahmed R, Suthar MS. JAMA. 2021 Mar 19. doi: 10.1001/jama.2021.4388. Online ahead of print. PMID: 33739374 No abstract available. https://jamanetwork.com/journals/jama/fullarticle/2777898
  11. Associations between calf, thigh, and arm circumference and cardiovascular and all-cause mortality in NHANES 1999-2004. Abreo AP, Bailey SR, Abreo K. Nutr Metab Cardiovasc Dis. 2021 Jan 29:S0939-4753(21)00031-4. doi: 10.1016/j.numecd.2021.01.011. Online ahead of print. PMID: 33762151 Abstract Background and aims: Prior studies have described an association between calf circumference and cardiovascular disorders. We evaluated the associations between calf, thigh, and arm circumference and cardiovascular and all-cause mortality. Methods and results: We performed a retrospective cohort study of 11,871 patients in the 1999-2004 National Health and Nutrition Examination Survey (NHANES) to determine the association between calf circumference and cardiovascular and all-cause mortality using univariate and multivariate Cox proportional hazards. We additionally examined the association between thigh and arm circumference and mortality. In the multivariable Cox regression for the female stratum, each centimeter increase in calf circumference was associated with a hazard ratio of 0.88 (95% CI 0.84-0.92), and a hazard ratio of 0.90 (95% CI 0.85-0.95) for cardiovascular death. In the model with males, the hazard ratio for higher calf circumference was 0.92 (95% CI 0.88-0.96) for all-cause mortality and 0.94 (95% CI 0.89-0.99) for cardiovascular death. There was a statistically significant association between higher thigh circumference and lower risk of all-cause and cardiovascular mortality. Arm circumference was not similarly associated with mortality in the multivariate model. Conclusion: Calf and thigh circumference may provide important prognostic information regarding cardiovascular and all-cause mortality. Future prospective studies should examine the role of extremity circumference and cardiovascular events. Keywords: Calf circumference; Cardiovascular disease; Clinical outcomes. The effects of foods on LDL cholesterol levels: A systematic review of the accumulated evidence from systematic reviews and meta-analyses of randomized controlled trials. Schoeneck M, Iggman D. Nutr Metab Cardiovasc Dis. 2021 Jan 16:S0939-4753(21)00002-8. doi: 10.1016/j.numecd.2020.12.032. Online ahead of print. PMID: 33762150 Abstract Aims: To systematically evaluate the evidence regarding the effects of foods on LDL cholesterol levels and to compare the findings with current guidelines. Data synthesis: From inception through June 2019, we searched PubMed, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials for guidelines, systematic reviews, and RCTs (for coffee intake only) of at least 13 days duration. Additionally, we searched Trip database for guidelines from 2009 through Oct 2019. Language was restricted to English. The strength of evidence was evaluated using The Grading of Recommendations Assessment, Development, and Evaluation (GRADE). A total of 37 guidelines, 108 systematic reviews, and 20 RCTs were included. With high evidence, foods high in unsaturated and low in saturated and trans fatty acids (e.g. rapeseed/canola oil), with added plant sterols/stanols, and high in soluble fiber (e.g. oats, barley, and psyllium) caused at least moderate (i.e. 0.20-0.40 mmol/L) reductions in LDL cholesterol. Unfiltered coffee caused a moderate to large increase. Soy protein, tomatoes, flaxseeds, and almonds caused small reductions. With moderate evidence, avocados and turmeric caused moderate to large reductions. Pulses, hazelnuts, walnuts, high-fiber/wholegrain foods, and green tea caused small to moderate reductions, whereas sugar caused a small increase. Other identified foods were either neutral or had low or very low evidence regarding their effects. Conclusions: Several foods distinctly modify LDL cholesterol levels. The results may aid future guidelines and dietary advice for hypercholesterolemia. Keywords: Blood lipids; Diet; Food; Humans; LDL cholesterol; Lipoproteins. Comparison between the impact of fermented and unfermented soy intake on the risk of liver cancer: the JPHC Study. Abe SK, Sawada N, Ishihara J, Takachi R, Mori N, Yamaji T, Shimazu T, Goto A, Iwasaki M, Inoue M, Tsugane S; JPHC Study Group. Eur J Nutr. 2020 Jul 27. doi: 10.1007/s00394-020-02335-9. Online ahead of print. PMID: 32719984 Abstract Purpose: The aim of this study was to compare the impact of fermented and unfermented soy intake, based on the following soy-derived products: tofu, soymilk, natto, and miso, on the risk of liver cancer among Japanese adults. Methods: 75,089 Participants of the Japan Public Health Center-based Prospective Study (JPHC Study) were followed from the time of the 5-year follow-up questionnaire until the end of 2012-2013. Subjects with available data on hepatitis B virus (HBV) and hepatitis C virus (HCV) infection status from blood samples (n = 14,016) and those who were anti-HCV antibody (anti-HCV) or hepatitis B virus antigen (HBsAg) positive (n = 1033) were also analyzed separately. Cox proportional hazard models were employed to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs). Results: During 1,145,453 person-years, 534 newly diagnosed cases of liver cancer were identified in the JPHC Study. For miso intake among men, the multivariate-adjusted highest versus lowest quartile HR was 0.65 (95% CI, 0.48-0.89); p for trend = 0.006. Results were similar in those who were anti-HCV or HBsAg positive, 0.24 (0.08-0.70); p for trend = 0.004 highest versus lowest tertile. For the sub-analysis among only participants with known hepatitis infection status and HCV and HBsAg adjustment, a similar association was observed. In the multivariate complete cohort analysis, among women, the highest intake of fried tofu was inversely associated with the risk of liver cancer, HR = 0.45 (0.26-0.80); p for trend = 0.014. Conclusions: We observed no association between total soy intake, fermented and unfermented, and risk of liver cancer, and only an inverse association between miso intake and liver cancer among men. Keywords: Cohort study; Japan; Liver cancer; Soy. Hydration for health hypothesis: a narrative review of supporting evidence. Perrier ET, Armstrong LE, Bottin JH, Clark WF, Dolci A, Guelinckx I, Iroz A, Kavouras SA, Lang F, Lieberman HR, Melander O, Morin C, Seksek I, Stookey JD, Tack I, Vanhaecke T, Vecchio M, Péronnet F. Eur J Nutr. 2020 Jul 6. doi: 10.1007/s00394-020-02296-z. Online ahead of print. PMID: 32632658 Review. https://link.springer.com/article/10.1007/s00394-020-02296-z?utm_source&#x3D;toc&amp;utm_medium&#x3D;email&amp;utm_campaign&#x3D;toc_394_60_3&amp;utm_content&#x3D;etoc_springer_20210324 Abstract Purpose: An increasing body of evidence suggests that excreting a generous volume of diluted urine is associated with short- and long-term beneficial health effects, especially for kidney and metabolic function. However, water intake and hydration remain under-investigated and optimal hydration is poorly and inconsistently defined. This review tests the hypothesis that optimal chronic water intake positively impacts various aspects of health and proposes an evidence-based definition of optimal hydration. Methods: Search strategy included PubMed and Google Scholar using relevant keywords for each health outcome, complemented by manual search of article reference lists and the expertise of relevant practitioners for each area studied. Results: The available literature suggest the effects of increased water intake on health may be direct, due to increased urine flow or urine dilution, or indirect, mediated by a reduction in osmotically -stimulated vasopressin (AVP). Urine flow affects the formation of kidney stones and recurrence of urinary tract infection, while increased circulating AVP is implicated in metabolic disease, chronic kidney disease, and autosomal dominant polycystic kidney disease. Conclusion: In order to ensure optimal hydration, it is proposed that optimal total water intake should approach 2.5 to 3.5 L day-1 to allow for the daily excretion of 2 to 3 L of dilute (< 500 mOsm kg-1) urine. Simple urinary markers of hydration such as urine color or void frequency may be used to monitor and adjust intake. Keywords: Arginine vasopressin; Copeptin; Metabolic; Renal; Water. Midlife vascular risk factors and risk of incident dementia: Longitudinal cohort and Mendelian randomization analyses in the UK Biobank. Malik R, Georgakis MK, Neitzel J, Rannikmäe K, Ewers M, Seshadri S, Sudlow CLM, Dichgans M. Alzheimers Dement. 2021 Mar 22. doi: 10.1002/alz.12320. Online ahead of print. PMID: 33749976 Abstract Introduction: Midlife clustering of vascular risk factors has been associated with late-life dementia, but causal effects of individual biological and lifestyle factors remain largely unknown. Methods: Among 229,976 individuals (mean follow-up 9 years), we explored whether midlife cardiovascular health measured by Life's Simple 7 (LS7) is associated with incident all-cause dementia and whether the individual components of the score are causally associated with dementia. Results: Adherence to the biological metrics of LS7 (blood pressure, cholesterol, glycemic status) was associated with lower incident dementia risk (hazard ratio = 0.93 per 1-point increase, 95% confidence interval [CI; 0.89-0.96]). In contrast, there was no association between the composite LS7 score and the lifestyle subscore (smoking, body mass index, diet, physical activity) and incident dementia. In Mendelian randomization analyses, genetically elevated blood pressure was associated with higher risk of dementia (odds ratio = 1.31 per one-standard deviation increase, 95% CI [1.05-1.60]). Discussion: These findings underscore the importance of blood pressure control in midlife to mitigate dementia risk. Keywords: Life's Simple 7; Mendelian randomization; blood pressure; dementia; epidemiology; genetics; hypertension; risk factors. Whole-life body composition trajectory and longevity: role of insulin. Lin YH, Tsai SC, Chuang SJ, Harris MB, Masodsai K, Chen PN, Hsieh CC, Killian T, Huang CY, Kuo CH. Aging (Albany NY). 2021 Mar 19;13. doi: 10.18632/aging.202727. Online ahead of print. PMID: 33744845 Abstract The present study assessed the body composition trajectory of rats (N = 96) placed into 5 groups according to lifespan, using dual-energy x-ray absorptiometry every 6 months until end-of-life. A striking linearity between lifespan and bone mass percentage (not absolute bone mass) was observed. Long-lived rats show a higher bone mass percentage with a delayed insulin rise to a similar peak level as short-lived counterparts, followed by insulin declines and bone mass loss. Decreasing insulin after streptozotocin (STZ) injection caused a rapid bone mass loss (-10.5%) with a decreased 5-day survival rate to 35% in old rats (20 months). Insulin replacement to STZ-injected rats completely blocked bone mass loss and increased the survival rate to 71%. Normal old rats (20 months) had faster lean mass loss despite greater myofiber regeneration (centronucleation) compared with the young rats (4 months). Increased CD68+ and CD163+ cell infiltration into insulin-depleted muscle suggests a bone marrow cell exhaustion by aging muscle. Bone produces stem cells and phagocytes to continuously rejuvenate peripheral tissues. Our data suggests that aging and unsustainable life is associated with development of disproportionality between bone and the growing body size, partly due to insulin reversal from hyperinsulinemia during late life. Keywords: cachexia; frailty; longevity; osteopenia; sarcopenia.
  12. AlPater

    Al's CR updates

    Calorie restriction prevents age-related changes in the intestinal microbiota. Kurup K, Matyi S, Giles CB, Wren JD, Jones K, Ericsson A, Raftery D, Wang L, Promislow D, Richardson A, Unnikrishnan A. Aging (Albany NY). 2021 Mar 10;13(5):6298-6329. doi: 10.18632/aging.202753. Epub 2021 Mar 10. PMID: 33744869 Abstract The effect of calorie restriction (CR) on the microbiome, fecal metabolome, and colon transcriptome of adult and old male mice was compared. Life-long CR increased microbial diversity and the Bacteroidetes/Firmicutes ratio and prevented the age-related changes in the microbiota, shifting it to a younger microbial and fecal metabolite profile in both C57BL/6JN and B6D2F1 mice. Old mice fed CR were enriched in the Rikenellaceae, S24-7 and Bacteroides families. The changes in the microbiome that occur with age and CR were initiated in the cecum and further modified in the colon. Short-term CR in adult mice had a minor effect on the microbiome but a major effect on the transcriptome of the colon mucosa. These data suggest that CR has a major impact on the physiological status of the gastrointestinal system, maintaining it in a more youthful state, which in turn could result in a more diverse and youthful microbiome. Keywords: aging; calorie restriction; metabolome; microbiome; transcriptome.
  13. Replacing the consumption of red meat with other major dietary protein sources and risk of type 2 diabetes mellitus: a prospective cohort study. Würtz AML, Jakobsen MU, Bertoia ML, Hou T, Schmidt EB, Willett WC, Overvad K, Sun Q, Manson JE, Hu FB, Rimm EB. Am J Clin Nutr. 2021 Mar 11;113(3):612-621. doi: 10.1093/ajcn/nqaa284. PMID: 33094800 Abstract Background: Greater consumption of red meat has been associated with a higher risk of type 2 diabetes mellitus (T2DM). A decreased intake of red meat and simultaneous increased intake of other high-protein foods may be associated with a lower risk of T2DM. These analyses of specific food replacements for red meat may provide more accurate dietary advice. Objective: We examined the association between a decrease in intake of red meat accompanied by an increase in other major dietary protein sources and risk of T2DM. Methods: We prospectively followed 27,634 males in the Health Professionals Follow-up Study, 46,023 females in the Nurses' Health Study, and 75,196 females in the Nurses' Health Study II. Diet was assessed by a validated FFQ and updated every 4 y. Cox proportional hazards models adjusted for T2DM risk factors were used to model the food replacements. We calculated HRs and 95% CIs for the T2DM risk associated with replacements of 1 daily serving of red meat with another protein source. Results: During 2,113,245 person-years of follow-up, we identified 8763 incident T2DM cases from 1990 to 2013. In the pooled analyses, a decrease in total red meat intake during a 4-y period replaced with another common protein food was associated with a lower risk of T2DM in the subsequent 4-y period. The HR (95% CI) per 1 serving/d was 0.82 (0.75, 0.90) for poultry, 0.87 (0.77, 0.98) for seafood, 0.82 (0.78, 0.86) for low-fat dairy, 0.82 (0.77, 0.86) for high-fat dairy, 0.90 (0.81, 0.99) for eggs, 0.89 (0.82, 0.98) for legumes, and 0.83 (0.78, 0.89) for nuts. The associations were present for both unprocessed and processed red meat, although stronger for the replacement of processed red meat. Conclusions: Replacing red meat consumption with other protein sources was associated with a lower risk of T2DM. Keywords: cohort study; diet change; follow-up study; food substitution; protein replacement; red meat; type 2 diabetes mellitus. Health Effects of Alternate Day Fasting Versus Pair-Fed Caloric Restriction in Diet-Induced Obese C57Bl/6J Male Mice. Henderson CG, Turner DL, Swoap SJ. Front Physiol. 2021 Feb 26;12:641532. doi: 10.3389/fphys.2021.641532. eCollection 2021. PMID: 33732170 Free PMC article. Abstract Alternate day fasting (ADF) induces weight loss and improves various markers of health in rodents and humans. However, it is unclear whether the benefits of ADF are derived from the lower caloric intake of ADF or from the 24-h fasting period. Therefore, this study directly compared selected markers for health - such as glucose control, body weight, liver triglycerides, T cell frequencies, and others - in high-fat (60% calories from fat) diet-induced obese mice subjected to either ADF or caloric restriction (CR). Obese mice were randomly assigned to one of four groups: (1) ADF: remained on the high-fat diet, but fed on alternate days (n = 5), (2) PF: remained on the high-fat diet, but pair-fed to the ADF group (n = 5), (3) LF: moved to a chow ad libitum diet (n = 5; 17% calories from fat), and (4) HF: remained on the high-fat ad libitum diet (n = 5). An additional group of non-obese mice maintained on a chow diet since weaning were used as controls (CON: n = 5). After 10 weeks, ADF, PF, and LF mice ate fewer kcals, had a lower body mass, had smaller epididymal fat pads, improved glucose tolerance, and had a lower hepatic triglyceride content relative to HF mice (p < 0.05), but none reached that of CON mice in these measures. T cell frequencies of the spleen, blood, and mesenteric lymph nodes were reduced in ADF, PF, and HF compared to the CON group. Importantly, there were no significant differences between the ADF and PF groups in any of the measurements made in the current study. These data suggest that ADF, PF, and LF diets each lead to improved markers of health relative to high-fat diet-induced obese mice, and that the caloric restriction associated with ADF is the major factor for the noted improvements. Keywords: ADF; CR; glucose; high-fat diet; intermittent fast; obesity. Psychedelic therapy could 'reset' depressed brain By Rachel Schraer Health reporter https://www.bbc.com/news/health-56373202 Interaction of Sirtuin 1 (SIRT1) candidate longevity gene and particulate matter (PM2.5) on all-cause mortality: a longitudinal cohort study in China. Yao Y, Liu L, Guo G, Zeng Y, Ji JS. Environ Health. 2021 Mar 14;20(1):25. doi: 10.1186/s12940-021-00718-x. PMID: 33715628 Abstract Background: The SIRT1 gene was associated with the lifespan in several organisms through inflammatory and oxidative stress pathways. Long-term air particulate matter (PM) is detrimental to health through the same pathways. Methods: We used the Chinese Longitudinal Healthy Longevity Survey (CLHLS) to investigate whether there is a gene-environment (G × E) interaction of SIRT1 and air pollution on mortality in an older cohort in China. Among 7083 participants with a mean age of 81.1 years, we genotyped nine SIRT1 alleles for each participant and assessed PM2.5 concentration using 3-year average concentrations around each participant's residence. We used Cox-proportional hazards models to estimate the independent and joint effects of SIRT1 polymorphisms and PM2.5 exposure on all-cause mortality, adjusting for a set of confounders. Results: There were 2843 deaths over 42,852 person-years. The mortality hazard ratio (HR) and 95% confidence interval (CI) for each 10 μg/m3 increase in PM2·5 was 1.08 (1.05-1.11); for SIRT1_391 was 0.77 (0.61, 0.98) in the recessive model after adjustment. In stratified analyses, participants carrying two SIRT1_391 minor alleles had a significantly higher HR for each 10 μg/m3 increase in PM2.5 than those carrying zero minor alleles (1.323 (95% CI: 1.088, 1.610) vs. 1.062 (1.028, 1.096) p for interaction = 0.03). Moreover, the interaction of SIRT1 and air pollution on mortality is significant among women but not among men. We did not see significant relationships for SIRT1_366, SIRT1_773, and SIRT1_720. Conclusion: We found a gene-environment interaction of SIRT1 and air pollution on mortality, future experimental studies are warranted to depict the mechanism observed in this study. Keywords: Air pollution; CLHLS; Longevity gene; Sex difference. Fitness, Fatness, and Mortality in Men and Women From the UK Biobank: Prospective Cohort Study. Tarp J, Grøntved A, Sanchez-Lastra MA, Dalene KE, Ding D, Ekelund U. J Am Heart Assoc. 2021 Mar 13:e019605. doi: 10.1161/JAHA.120.019605. Online ahead of print. PMID: 33715383 https://www.ahajournals.org/doi/pdf/10.1161/JAHA.120.019605 Abstract Background Cardiorespiratory fitness may moderate the association between obesity and all-cause mortality (ie, the "fat-but-fit" hypothesis), but unaddressed sources of bias are a concern. Methods and Results Cardiorespiratory fitness was estimated as watts per kilogram from a submaximal bicycle test in 77 169 men and women from the UK Biobank cohort and combined with World Health Organization standard body mass index categories, yielding 9 unique fitness-fatness combinations. We also formed fitness-fatness combinations based on bioimpedance as a direct measure of body composition. All-cause mortality was ascertained from death registries. Multivariable-adjusted Cox regression models were used to estimate hazard ratios and 95% CIs. We examined the association between fitness-fatness combinations and all-cause mortality in models with progressively more conservative approaches for accounting for reverse causation, misclassification of body composition, and confounding. Over a median follow-up of 7.7 years, 1731 participants died. In our base model, unfit men and women had higher risk of premature mortality irrespective of levels of adiposity, compared with the normal weight-fit reference. This pattern was attenuated but maintained with more conservative approaches in men, but not in women. In analysis stratified by sex and excluding individuals with prevalent major chronic disease and short follow-up and using direct measures of body composition, mortality risk was 1.78 (95% CI, 1.17-2.71) times higher in unfit-obese men but not higher in obese-fit men (0.94 [95% CI, 0.60-1.48]). In contrast, there was no increased risk in obese-unfit women (1.09 [95% CI, 0.44-1.05]) as compared with the reference. Conclusions Cardiorespiratory fitness modified the association between obesity and mortality in men, but this pattern appeared susceptible to biases in women. Keywords: adiposity; epidemiology; obesity; physical activity; physical exercise. These symptoms and risk factors may predict whether you could become a 'COVID long hauler,' study suggests Adrianna Rodriguez USA TODAY Mar 11, 2021 https://www.usatoday.com/story/news/health/2021/03/11/covid-long-hauler-study-suggests-what-symptoms-look-out/6938043002/ Association of Balance Function With All-Cause and Cause-Specific Mortality Among US Adults. Cao C, Cade WT, Li S, McMillan J, Friedenreich C, Yang L. JAMA Otolaryngol Head Neck Surg. 2021 Mar 11. doi: 10.1001/jamaoto.2021.0057. Online ahead of print. PMID: 33704356 Abstract Importance: Difficulty maintaining balance is common among individuals aged 40 years or older and increases the risk of falls. However, little is known about the association of balance function with long-term mortality outcomes in adults. Objective: To investigate the association of balance function with all-cause and cause-specific mortality among US adults. Design, setting, and participants: A prospective, population-based cohort study of a nationally representative sample of 5816 adults (weighted population, 92 260 641) from the US National Health and Nutrition Examination Survey was conducted from 1999 to 2004. Individuals aged 40 years or older who completed the modified Romberg Test of Standing Balance on Firm and Compliant Support Surfaces were included. Participants were linked to mortality data from the test date through December 31, 2015. Data analysis was conducted from February 1 to June 1, 2020. Exposures: The modified Romberg Test of Standing Balance on Firm and Compliant Support Surfaces was used to measure balance function and define balance disorder according to sensory input. Main outcomes and measures: Mortality associated with all causes, cardiovascular disease (CVD), and cancer. Results: A total of 5816 adults (weighted mean [SE] age, 53.6 [0.2] years; 2897 [49.8%] women) were included in this cohort study. During up to 16.8 years of follow-up (median, 12.5 years; 68 919 person-years), 1530 deaths occurred, including 342 associated with CVD and 364 associated with cancer. Participants with balance disorder were at a higher risk of death from all causes, CVD, and cancer. After adjusting for sociodemographic characteristics, lifestyle factors, and chronic conditions, the hazard ratios (HRs) among participants with balance disorder compared with those without balance disorder were 1.44 (95% CI, 1.23-1.69) for all-cause mortality, 1.65 (95% CI, 1.17-2.31) for CVD mortality, and 1.37 (95% CI, 1.03-1.83) for cancer mortality. Furthermore, vestibular balance disorder was associated with increased mortality from all causes (HR, 1.31; 95% CI, 1.08-1.58), CVD (HR, 1.59; 95% CI, 1.12-2.27), and cancer (HR, 1.39; 95% CI, 1.04-1.86). Conclusions and relevance: In this nationally representative sample of US adults, balance disorder was associated with an increased risk of all-cause, CVD, and cancer mortality. Further studies are needed to confirm these findings and evaluate whether the observed associations represent a causal biological phenomenon and, if so, whether the effect is modifiable with a multicomponent exercise program. Body Mass Index and Risk for COVID-19-Related Hospitalization, Intensive Care Unit Admission, Invasive Mechanical Ventilation, and Death - United States, March-December 2020. Kompaniyets L, Goodman AB, Belay B, Freedman DS, Sucosky MS, Lange SJ, Gundlapalli AV, Boehmer TK, Blanck HM. MMWR Morb Mortal Wkly Rep. 2021 Mar 12;70(10):355-361. doi: 10.15585/mmwr.mm7010e4. PMID: 33705371 Free article. Abstract Obesity* is a recognized risk factor for severe COVID-19 (1,2), possibly related to chronic inflammation that disrupts immune and thrombogenic responses to pathogens (3) as well as to impaired lung function from excess weight (4). Obesity is a common metabolic disease, affecting 42.4% of U.S. adults (5), and is a risk factor for other chronic diseases, including type 2 diabetes, heart disease, and some cancers.† The Advisory Committee on Immunization Practices considers obesity to be a high-risk medical condition for COVID-19 vaccine prioritization (6). Using data from the Premier Healthcare Database Special COVID-19 Release (PHD-SR),§ CDC assessed the association between body mass index (BMI) and risk for severe COVID-19 outcomes (i.e., hospitalization, intensive care unit [ICU] or stepdown unit admission, invasive mechanical ventilation, and death). Among 148,494 adults who received a COVID-19 diagnosis during an emergency department (ED) or inpatient visit at 238 U.S. hospitals during March-December 2020, 28.3% had overweight and 50.8% had obesity. Overweight and obesity were risk factors for invasive mechanical ventilation, and obesity was a risk factor for hospitalization and death, particularly among adults aged <65 years. Risks for hospitalization, ICU admission, and death were lowest among patients with BMIs of 24.2 kg/m2, 25.9 kg/m2, and 23.7 kg/m2, respectively, and then increased sharply with higher BMIs. Risk for invasive mechanical ventilation increased over the full range of BMIs, from 15 kg/m2 to 60 kg/m2. As clinicians develop care plans for COVID-19 patients, they should consider the risk for severe outcomes in patients with higher BMIs, especially for those with severe obesity. These findings highlight the clinical and public health implications of higher BMIs, including the need for intensive COVID-19 illness management as obesity severity increases, promotion of COVID-19 prevention strategies including continued vaccine prioritization (6) and masking, and policies to ensure community access to nutrition and physical activities that promote and support a healthy BMI.
  14. AlPater

    Al's CR updates

    The effect of calorie intake, fasting, and dietary composition on metabolic health and gut microbiota in mice. Zhang Z, Chen X, Loh YJ, Yang X, Zhang C. BMC Biol. 2021 Mar 19;19(1):51. doi: 10.1186/s12915-021-00987-5. PMID: 33740961 Abstract Background: Calorie restriction (CR) and intermittent fasting (IF) can promote metabolic health through a process that is partially mediated by gut microbiota modulation. To compare the effects of CR and IF with different dietary structures on metabolic health and the gut microbiota, we performed an experiment in which mice were subjected to a CR or IF regimen and an additional IF control (IFCtrl) group whose total energy intake was not different from that of the CR group was included. Each regimen was included for normal chow and high-fat diet. Results: We showed that in normal-chow mice, the IFCtrl regimen had similar positive effects on glucose and lipid metabolism as the CR regimen, but the IF regimen showed almost no influence compared to the outcomes observed in the ad libitum group. IF also resulted in improvements, but the effects were less marked than those associate with CR and IFCtrl when the mice were fed a high-fat diet. Moreover, CR created a stable and unique gut microbial community, while the gut microbiota shaped by IF exhibited dynamic changes in fasting-refeeding cycles. At the end of each cycle, the gut microbiota of the IFCtrl mice was similar to that of the CR mice, and the gut microbiota of the IF mice was similar to that of the ad libitum group. When the abundance of Lactobacillus murinus OTU2 was high, the corresponding metabolic phenotype was improved regardless of eating pattern and dietary structure, which might be one of the key bacterial groups in the gut microbiota that is positively correlated with metabolic amelioration. Conclusion: There are interactions among the amount of food intake, the diet structure, and the fasting time on metabolic health. The structure and composition of gut microbiota modified by dietary regimens might contribute to the beneficial effects on the host metabolism. Keywords: Calorie restriction; Gut microbiota; High-fat diet; Intermittent fasting; Lactobacillus murinus. Dietary restriction transforms the mammalian protein persulfidome in a tissue-specific and cystathionine gamma-lyase-dependent manner. Bithi N, Link C, Henderson YO, Kim S, Yang J, Li L, Wang R, Willard B, Hine C. Nat Commun. 2021 Mar 19;12(1):1745. doi: 10.1038/s41467-021-22001-w. PMID: 33741971 Abstract Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein persulfidation (R-SSnH). Despite the known importance of persulfidation, tissue-specific persulfidome profiles and their associated functions are not well characterized, specifically under conditions and interventions known to modulate H2S production. We hypothesize that dietary restriction (DR), which increases lifespan and can boost H2S production, expands tissue-specific persulfidomes. Here, we find protein persulfidation enriched in liver, kidney, muscle, and brain but decreased in heart of young and aged male mice under two forms of DR, with DR promoting persulfidation in numerous metabolic and aging-related pathways. Mice lacking cystathionine γ-lyase (CGL) have overall decreased tissue protein persulfidation numbers and fail to functionally augment persulfidomes in response to DR, predominantly in kidney, muscle, and brain. Here, we define tissue- and CGL-dependent persulfidomes and how diet transforms their makeup, underscoring the breadth for DR and H2S to impact biological processes and organismal health. Effects of calorie restricted low carbohydrate high fat ketogenic vs. non-ketogenic diet on strength, body-composition, hormonal and lipid profile in trained middle-aged men. Vidić V, Ilić V, Toskić L, Janković N, Ugarković D. Clin Nutr. 2021 Feb 26;40(4):1495-1502. doi: 10.1016/j.clnu.2021.02.028. Online ahead of print. PMID: 33743284 Abstract Background & aims: The aim of this paper was to investigate and compare the effects of two iso-energetic hypo-caloric ketogenic hyper-ketonemic and non-ketogenic low carbohydrate high fat high cholesterol diets on body-composition, muscle strength and hormonal profile in experienced resistance-trained middle-aged men. Methods: Twenty non-competitive experienced resistance-trained middle-aged men were on the supervised calorie maintenance western diet and resistance-training regimen for 4 weeks and then divided into ketogenic and non-ketogenic groups for 8 weeks period. Keto bodies (β-hydroxybutyrate) levels were measured weekly, testosterone and insulin biweekly, strength and body-composition monthly, lipid profile and blood sugar level at the beginning and at the end of the study. Results: Both groups lost a similar amount of lean body mass and fat tissue (from F = 248.665, p < 0.001 to F = 21.943, p = 0.001), but preserved maximal upper and lower body strength (from F = 1.772, p = 0.238 to F = 0.595, p = 0.577). Basal testosterone and free testosterone increased (from F = 37.267, p = 0.001 to F = 16.261, p = 0.005) and insulin levels decreased significantly in both groups (F = 27.609, p = 0.001; F = 54.256, p < 0.001, respectively). No differences in lipid profile and blood sugar level were found (from F = 4.174, p = 0.058, to F = 0.065, p = 0.802). Conclusions: Ketogenic diet with sustained hyper-ketonemia above 1 mol/l has the same impact as low carbohydrate non-ketogenic diet on muscle strength, body-composition, and hormonal and lipid profile in hypo-caloric dietary conditions in strength-trained middle-aged men. Keywords: Body-composition; Insulin; Ketogenic diet; Middle-aged men; Resistance-training; Testosterone.
  15. None so blind as those who ... One expects more from this crowd. Effectiveness of Mask Wearing to Control Community Spread of SARS-CoV-2. Brooks JT, Butler JC. JAMA. 2021 Mar 9;325(10):998-999. doi: 10.1001/jama.2021.1505. PMID: 33566056 No abstract available. https://jamanetwork.com/journals/jama/fullarticle/2776536?utm_source=silverchair&utm_campaign=jama_network&utm_content=covid_weekly_highlights&utm_medium=email