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183
Date Added: Nov 27, 2021
Date Added: Nov 27, 2021
Caloric restriction has been known for nearly a century to extend life span and delay age-associated pathology in laboratory animals. More recently, alternative “antiaging” diet modalities have been described that provide new mechanistic insights and potential clinical applications. These include intermittent fasting, fasting-mimicking diets, ketogenic diets, time-restricted feeding, protein restriction, and dietary restriction of specific amino acids. Despite mainstream popularization of some of these diets, many questions remain about their efficacy outside of a laboratory setting. Studies of these interventions support at least partially overlapping mechanisms of action and provide insights into what appear to be highly conserved mechanisms of biological aging.
93
Date Added: Jul 31, 2021
Date Added: Jul 31, 2021
Centenarians display decreased susceptibility to ageing-associated illness, chronic inflammation, and infectious disease1–3. Here we show that centenarians have a distinct gut microbiome enriched in microbes capable of generating unique secondary bile acids (BAs), including iso-, 3-oxo-, allo-, 3-oxoallo-, and isoallo-lithocholic acid (LCA). Among these BAs, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from a centenarian’s faecal microbiota, we identified Odoribacteraceae strains as effective producers of isoalloLCA both in vitro and in vivo. Furthermore, we found that the enzymes 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3βHSDH) were responsible for isoalloLCA production. IsoalloLCA exerted potent antimicrobial effects against gram-positive (but not gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecium. These findings suggest that specific bile acid metabolism may be involved in reducing the risk of pathobiont infection, thereby potentially contributing to the maintenance of intestinal homeostasis.
3
Date Added: May 17, 2021
Date Added: May 17, 2021
Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls. Using these data, we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) and discriminated between cases and controls of the discovery set with 89% sensitivity and specificity, and with 58% specificity and 60% sensitivity in an independent cohort of 341 controls and 253 genetically matched nonagenarians and centenarians (median age 100 years). Consistent with the hypothesis that the genetic contribution is largest with the oldest ages, the sensitivity of the model increased in the independent cohort with older and older ages (71% to classify subjects with an age at death>102 and 85% to classify subjects with an age at death>105). For further validation, we applied the model to an additional, unmatched 60 centenarians (median age 107 years) resulting in 78% sensitivity, and 2863 unmatched controls with 61% specificity. The 281 SNPs include the SNP rs2075650 in TOMM40/APOE that reached irrefutable genome wide significance (posterior probability of association = 1) and replicated in the independent cohort. Removal of this SNP from the model reduced the accuracy by only 1%. Further in-silico analysis suggests that 90% of centenarians can be grouped into clusters characterized by different “genetic signatures” of varying predictive values for exceptional longevity. The correlation between 3 signatures and 3 different life spans was replicated in the combined replication sets. The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity.
102
Date Added: Aug 5, 2021
Date Added: Aug 5, 2021
INTRODUCTION Obesity and its associated complications are serious global concerns. Despite growing public health initiatives, obesity rates continue to rise. Thus, there is a critical need to identify pathways that affect adiposity. Recent studies indicate that the immune system can regulate adipose tissue and its metabolic function. Type 2 immune cells, such as type 2 innate lymphoid cells (ILC2s) and eosinophils, increase the metabolic rate, whereas regulatory T cells (T reg cells) promote insulin sensitivity. RATIONALE Thymic stromal lymphopoietin (TSLP) is an epithelial cell cytokine that is expressed at barrier sites such as the skin, lung, and gut. Because TSLP has been shown to activate type 2 immune cells and expand T reg cells, we hypothesized that TSLP could counteract obesity and its associated complications. RESULTS The effect of TSLP on obesity was tested by administering a Tslp -expressing adeno-associated virus serotype 8 (TSLP-AAV) to mice. Compared with mice administered control-AAV, mice given TSLP-AAV displayed selective white adipose tissue (WAT) loss, which protected against diet-induced and genetic models of obesity, insulin resistance, and nonalcoholic steatohepatitis (NASH). Unexpectedly, TSLP-induced WAT loss was not dependent on ILC2s, eosinophils, or T reg cells. Rather, it resulted from direct activation of either CD4 + or CD8 + αβ T cell receptor (TCRαβ) T cells by TSLP in an antigen-independent manner. The adoptive transfer of T cells from the lymph nodes of TSLP-AAV–injected mice also caused WAT loss in TSLP receptor–deficient ( Tslpr –/– ) mice, suggesting that TSLP-stimulated T cells retain their ability to induce WAT loss. TSLP-induced WAT loss was not associated with decreased food intake, increased fecal caloric excretion, or increased energy metabolism. Instead, the WAT loss was associated with a notable greasy hair appearance. Thin-layer chromatography analysis of extracted hair lipids from TSLP-AAV–injected mice showed that the oleaginous substance was enriched for sebum-specific lipids. Sebum is a calorically dense substance produced by sebocytes in sebaceous glands (SGs) and helps form both the physical and immune-protective skin barrier. Skin histological analysis showed that TSLP promoted sebum secretion and turnover of sebocytes. Sebum hypersecretion was responsible for TSLP-induced WAT loss because TSLP did not induce WAT loss in asebia mice, which harbor hypomorphic SGs. TSLP also induced the migration of T cells to SGs, which was required for the enhanced sebum secretion. Inhibition of T cell migration prevented TSLP-induced sebum hypersecretion and subsequent WAT loss. At homeostasis, TSLP and T cells controlled steady-state sebum secretion. Both Tslpr –/– and T cell–deficient mice exhibited decreased sebum secretion at baseline. Many of the fatty acids within sebum have bactericidal properties, and antimicrobial peptides (AMPs) are also secreted as part of sebum for barrier protection. Accordingly, Tslpr –/– mice expressed lower levels of sebum-associated AMPs in the skin, suggesting that endogenous TSLP plays a role in skin barrier function. This TSLP-sebum axis was also applicable to humans because the expression of TSLP and sebum-associated genes were positively correlated in skin samples from healthy individuals. CONCLUSION Our findings support a model in which TSLP overexpression causes WAT loss by inducing skin T cell migration and increasing sebum hypersecretion. Additionally, TSLP and T cells homeostatically regulate sebum production and skin AMP expression, highlighting an unexpected role for the adaptive immune system in the maintenance of skin barrier function.
124
Date Added: Jul 4, 2021
Date Added: Jul 4, 2021
As the global elderly population grows, it is socioeconomically and medically critical to have diverse and effective means of mitigating the impact of aging on human health. Previous studies showed that adenovirus-associated virus (AAV) vector induced overexpression of certain proteins can suppress or reverse the effects of aging in animal models. Here, we sought to determine whether the high-capacity cytomegalovirus vector can be an effective and safe gene delivery method for two such-protective factors: telomerase reverse transcriptase (TERT) and follistatin (FST). We found that the mouse cytomegalovirus (MCMV) carrying exogenous TERT or FST (MCMV or MCMV ) extended median lifespan by 41.4% and 32.5%, respectively. This is the first report of CMV being used successfully as both an intranasal and injectable gene therapy system to extend longevity. Treatment significantly improved glucose tolerance, physical performance, and prevented loss of body mass and alopecia. Telomere shortening seen with aging was ameliorated by TERT, and mitochondrial structure deterioration was halted in both treatments. Intranasal and injectable preparations performed equally well in safely and efficiently delivering gene therapy to multiple organs, with long-lasting benefits and without carcinogenicity or unwanted side effects. Translating this research to humans could have significant benefits associated with increased health span.
161
Date Added: Aug 11, 2021
Date Added: Aug 11, 2021
The gut microbiota is increasingly recognized as an important regulator of host immunity and brain health. The aging process yields dramatic alterations in the microbiota, which is linked to poorer health and frailty in elderly populations. However, there is limited evidence for a mechanistic role of the gut microbiota in brain health and neuroimmunity during aging processes. Therefore, we conducted fecal microbiota transplantation from either young (3–4 months) or old (19–20 months) donor mice into aged recipient mice (19–20 months). Transplant of a microbiota from young donors reversed aging-associated differences in peripheral and brain immunity, as well as the hippocampal metabolome and transcriptome of aging recipient mice. Finally, the young donor-derived microbiota attenuated selective age-associated impairments in cognitive behavior when transplanted into an aged host. Our results reveal that the microbiome may be a suitable therapeutic target to promote healthy aging.
23
Date Added: Aug 10, 2021
Date Added: Aug 10, 2021
Exercise is a powerful driver of physiological angiogenesis during adulthood, but the mechanisms of exercise-induced vascular expansion are poorly understood. We explored endothelial heterogeneity in skeletal muscle and identified two capillary muscle endothelial cell (mEC) populations that are characterized by differential expression of ATF3/4. Spatial mapping showed that ATF3/4+ mECs are enriched in red oxidative muscle areas while ATF3/4low ECs lie adjacent to white glycolytic fibers. In vitro and in vivo experiments revealed that red ATF3/4+ mECs are more angiogenic when compared with white ATF3/4low mECs. Mechanistically, ATF3/4 in mECs control genes involved in amino acid uptake and metabolism and metabolically prime red (ATF3/4+) mECs for angiogenesis. As a consequence, supplementation of non-essential amino acids and overexpression of ATF4 increased proliferation of white mECs. Finally, deleting Atf4 in ECs impaired exercise-induced angiogenesis. Our findings illustrate that spatial metabolic angiodiversity determines the angiogenic potential of muscle ECs.
46
Date Added: Aug 2, 2021
Date Added: Aug 2, 2021
Background: Light-to-moderate alcohol consumption has been reported to be cardio-protective among apparently healthy individuals; however, it is unclear whether this association is also present in those with disease. To examine the association between alcohol consumption and prognosis in individuals with pre-existing cardiovascular disease (CVD), we conducted a series of meta-analyses of new findings from three large-scale cohorts and existing published studies. Methods: We assessed alcohol consumption in relation to all-cause mortality, cardiovascular mortality, and subsequent cardiovascular events via de novo analyses of 14,386 patients with a previous myocardial infarction, angina, or stroke in the UK Biobank Study (median follow-up 8.7 years, interquartile range [IQR] 8.0–9.5), involving 1640 deaths and 2950 subsequent events, and 2802 patients and 1257 deaths in 15 waves of the Health Survey for England 1994–2008 and three waves of the Scottish Health Survey 1995, 1998, and 2003 (median follow-up 9.5 years, IQR 5.7–13.0). This was augmented with findings from 12 published studies identified through a systematic review, providing data on 31,235 patients, 5095 deaths, and 1414 subsequent events. To determine the best-fitting dose-response association between alcohol and each outcome in the combined sample of 48,423 patients, models were constructed using fractional polynomial regression, adjusting at least for age, sex, and smoking status. Results: Alcohol consumption was associated with all assessed outcomes in a J-shaped manner relative to current non-drinkers, with a risk reduction that peaked at 7 g/day (relative risk 0.79, 95% confidence interval 0.73–0.85) for all-cause mortality, 8 g/day (0.73, 0.64–0.83) for cardiovascular mortality and 6 g/day (0.50, 0.26–0.96) for cardiovascular events, and remained significant up to 62, 50, and 15 g/day, respectively. No statistically significant elevated risks were found at higher levels of drinking. In the few studies that excluded former drinkers from the non-drinking reference group, reductions in risk among light-to-moderate drinkers were attenuated. Conclusions: For secondary prevention of CVD, current drinkers may not need to stop drinking. However, they should be informed that the lowest risk of mortality and having another cardiovascular event is likely to be associated with lower levels of drinking, that is up to approximately 105g (or equivalent to 13 UK units, with one unit equal to half a pint of beer/lager/cider, half a glass of wine, or one measure of spirits) a week.