Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder. Impaired neuronal bioenergetics and neuroinflammation are thought to play key roles in the progression of AD, but their interplay is not clear. Nicotinamide adenine dinucleotide (NAD+) is an important metabolite in all human cells in which it is pivotal for multiple processes including DNA repair and mitophagy, both of which are impaired in AD neurons. Here, we report that levels of NAD+ are reduced and markers of inflammation increased in the brains of APP/PS1 mutant transgenic mice with beta-amyloid pathology. Treatment of APP/PS1 mutant mice with the NAD+ precursor nicotinamide riboside (NR) for 5 mo increased brain NAD+ levels, reduced expression of proinflammatory cytokines, and decreased activation of microglia and astrocytes. NR treatment also reduced NLRP3 inflammasome expression, DNA damage, apoptosis, and cellular senescence in the AD mouse brains. Activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) are associated with DNA damage and senescence. cGAS–STING elevation was observed in the AD mice and normalized by NR treatment. Cell culture experiments using microglia suggested that the beneficial effects of NR are, in part, through a cGAS–STING-dependent pathway. Levels of ectopic (cytoplasmic) DNA were increased in APP/PS1 mutant mice and human AD fibroblasts and down-regulated by NR. NR treatment induced mitophagy and improved cognitive and synaptic functions in APP/PS1 mutant mice. Our findings suggest a role for NAD+ depletion-mediated activation of cGAS–STING in neuroinflammation and cellular senescence in AD.
Many but not all cognitive abilities decline during ageing. Some even improve due to lifelong experience. The critical capacities of attention and executive functions have been widely posited to decline. However, these capacities are composed of multiple components, so multifaceted ageing outcomes might be expected. Indeed, prior findings suggest that whereas certain attention/executive functions clearly decline, others do not, with hints that some might even improve. We tested ageing effects on the alerting, orienting and executive (inhibitory) networks posited by Posner and Petersen’s influential theory of attention, in a cross-sectional study of a large sample (N = 702) of participants aged 58–98. Linear and nonlinear analyses revealed that whereas the efficiency of the alerting network decreased with age, orienting and executive inhibitory efficiency increased, at least until the mid-to-late 70s. Sensitivity analyses indicated that the patterns were robust. The results suggest variability in age-related changes across attention/executive functions, with some declining while others improve.
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.
Background We have shown previously that low‐density lipoprotein (LDL) can be oxidized in the lysosomes of macrophages, that this oxidation can be inhibited by cysteamine, an antioxidant that accumulates in lysosomes, and that this drug decreases atherosclerosis in LDL receptor–deficient mice fed a high‐fat diet. We have now performed a regression study with cysteamine, which is of more relevance to the treatment of human disease. Methods and Results LDL receptor–deficient mice were fed a high‐fat diet to induce atherosclerotic lesions. They were then reared on chow diet and drinking water containing cysteamine or plain drinking water. Aortic atherosclerosis was assessed, and samples of liver and skeletal muscle were analyzed. There was no regression of atherosclerosis in the control mice, but cysteamine caused regression of between 32% and 56% compared with the control group, depending on the site of the lesions. Cysteamine substantially increased markers of lesion stability, decreased ceroid, and greatly decreased oxidized phospholipids in the lesions. The liver lipid levels and expression of cluster of differentiation 68, acetyl–coenzyme A acetyltransferase 2, cytochromes P450 (CYP)27, and proinflammatory cytokines and chemokines were decreased by cysteamine. Skeletal muscle function and oxidative fibers were increased by cysteamine. There were no changes in the plasma total cholesterol, LDL cholesterol, high‐density lipoprotein cholesterol, or triacylglycerol concentrations attributable to cysteamine. Conclusions Inhibiting the lysosomal oxidation of LDL in atherosclerotic lesions by antioxidants targeted at lysosomes causes the regression of atherosclerosis and improves liver and muscle characteristics in mice and might be a promising novel therapy for atherosclerosis in patients.
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.
The enormous mammal’s lifespan variation is the result of each species’ adaptations to their own biological trade-offs and ecological conditions. Comparative genomics have demonstrated that genomic factors underlying both, species lifespans and longevity of individuals, are in part shared across the tree of life. Here, we compared protein-coding regions across the mammalian phylogeny to detect individual amino acid (AA) changes shared by the most long-lived mammals and genes whose rates of protein evolution correlate with longevity. We discovered a total of 2,737 AA in 2,004 genes that distinguish long- and short-lived mammals, significantly more than expected by chance (P = 0.003). These genes belong to pathways involved in regulating lifespan, such as inflammatory response and hemostasis. Among them, a total 1,157 AA showed a significant association with maximum lifespan in a phylogenetic test. Interestingly, most of the detected AA positions do not vary in extant human populations (81.2%) or have allele frequencies below 1% (99.78%). Consequently, almost none of these putatively important variants could have been detected by genome-wide association studies. Additionally, we identified four more genes whose rate of protein evolution correlated with longevity in mammals. Crucially, SNPs located in the detected genes explain a larger fraction of human lifespan heritability than expected, successfully demonstrating for the first time that comparative genomics can be used to enhance interpretation of human genome-wide association studies. Finally, we show that the human longevity-associated proteins are significantly more stable than the orthologous proteins from short-lived mammals, strongly suggesting that general protein stability is linked to increased lifespan.
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.
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.