Aging Cell最新文献

Previous studies from our lab identified functional defects in antigen-specific peripheral T follicular helper cells (pTfh), characterized by low IL-21 and high IL-2 production, contributing to non-responsiveness to the influenza vaccine in both aging and HIV. This study investigated how IL-21-induced STAT3 and IL-2-induced STAT5 activation in pTfh cells affects vaccine responses in aging people with HIV (PWH) and those without HIV (PWoH). Ninety participants, including young (Y, ≤ 40 years) and old (O, ≥ 65 years) PWoH (YPWoH, n = 23; OPWoH, n = 25) and virally suppressed PWH (YPWH, n = 19; OPWH, n = 23), received the seasonal quadrivalent influenza vaccine. Samples were collected at pre-vaccination (day 0) and at days 14 and 28 post-vaccination. Participants were classified as vaccine responders (VR) or non-responders (VNR) based on serum antibody titers against vaccine antigens using the hemagglutination inhibition assay. Phosphoflow cytometry was performed on pre-vaccination PBMCs stimulated with IL-21 or IL-2, and high-dimensional analysis was performed using OMIQ software. Peripheral Tfh cells of young individuals showed greater IL-21-induced STAT3, reduced IL-2-induced STAT5 activity, and a reduced frequency of IL-2R+ pTfh cells compared to older individuals. IL-21-induced STAT3 in naïve CD4+ T cells in young participants correlated with the frequency of pTfh cells. Among VNR, IL-2-induced STAT5 in pTfh cells inversely correlated with day 28 vaccine titers. Our findings emphasize the essential role of IL-21 and IL-2-induced STAT signaling in orchestrating the immune response to vaccination. As individuals age, IL-2-induced STAT5 signaling in pTfh increases, potentially hindering Tfh cell differentiation and function, which may result in weaker vaccine responses.

Aging is a major risk factor for heart failure, yet the molecular mechanisms linking cardiac aging to the inflammatory pathophysiology of heart failure remain elusive. Mitochondrial dysfunction and defective organelle quality control are emerging hallmarks of the aging heart, but their biochemical underpinnings are poorly defined. Using comprehensive glycomics, we found that cardiac mitochondria from physiologically aged mice (≥ 20 months) are the major intracellular reservoirs of advanced glycation end products (AGEs), derived primarily from the chemical attack of some α-oxoaldehydes on proteins. This was associated with mild mitochondrial dysfunction and structural remodeling. Lysosomes in aged hearts were enlarged, more abundant, less acidic, and frequently loaded with lipofuscin. Notably, ~7% of cardiomyocytes showed proinflammatory senescence traits. In vitro, glycative stress in H9c2 myoblasts reproduced mitochondrial AGE buildup, dysfunction, and activation of the mitochondria-lysosome axis. However, AGE-modified mitochondria impaired lysosomal acidification and proteolysis, hindering mitophagic clearance and contributing to lipofuscin accumulation. This sequence of events ultimately led to proinflammatory senescence in a subset of cells. These findings identify mitochondrial AGE accumulation as a novel mechanism of sublethal nonsolved aging-associated stress that eventually triggers geroconversion in cardiomyocytes. This mechanism could facilitate the transition of the aging heart towards a failing phenotype.

Aging disrupts systemic metabolism, but the mechanisms by which gut microbial metabolites drive tissue-specific decline remain unclear. We conducted a multi-organ, multi-omics atlas across the gut, serum, liver, lung, and cortex in young and early-aged mice to address this. We identified a conserved aging signature marked by the microbiota-associated depletion of protective circulating metabolites, such as lysophosphatidylcholines (LPCs), concurrently with the systemic accumulation of pro-oxidative microbial catabolites, specifically trimethylamine N-oxide (TMAO) and indole-3-acetic acid (IAA). This microbial-metabolic drift disrupted systemic lipid transport and redox balance, leading to distinct organ-level vulnerabilities: hepatic lipid retention and ferroptosis susceptibility, pulmonary immune-redox activation, and cortical neurochemical dysregulation. To establish functional relevance, we conducted an integrated meta-analysis of 40 independent studies encompassing natural aging models, fecal microbiota transplantation (FMT), and probiotic interventions. This quantitative synthesis provided convergent evidence that microbial remodeling is a functionally relevant correlate associated with systemic aging phenotypes by restoring intestinal barrier integrity (upregulating ZO-1, MUC2), suppressing tissue inflammatory factors (IL-6, IL-1β, TNF-α), and mitigating oxidative stress (reducing MDA and restoring SOD/GSH). Together, our findings highlight gut-derived metabolic reprogramming as a modifiable, upstream driver of systemic aging, offering tractable targets for therapeutic intervention.

Protein phosphatase 2A (PP2A) regulates Tau hyperphosphorylation in Alzheimer's disease (AD). This study hypothesized that exercise increases adiponectin levels, activating PP2A to reduce Tau hyperphosphorylation and enhance hippocampal plasticity. The study utilized adiponectin knockout (Adipo^-/-) and hippocampal-specific PP2A knockdown (PP2A-KD) in mice with 3-week voluntary running and/or chronic stress to assess changes in Tau phosphorylation, adult neurogenesis, and cognitive performance. Running improved cognitive deficits and reduced Tau hyperphosphorylation in association with increased adiponectin levels and enhanced PP2A activity in stressed mice. Adiponectin deficiency impaired cognitive performance, increased Tau phosphorylation, and decreased PP2A activity. Mechanistically, adiponectin is dispensable for running to increase PP2A activity, reduce Tau hyperphosphorylation, and restore hippocampal neurogenesis, leading to cognitive improvement. Hippocampal-specific PP2A knockdown diminished the beneficial effects of running, indicating that PP2A is downstream of adiponectin's action. This study provides mechanistic insights into how exercise reduces AD-like neuropathology, emphasizing the critical role of the adiponectin-PP2A pathway in mitigating Tau hyperphosphorylation and suggesting a potential therapeutic target for AD through modulation of this pathway.

The increase in maternal age of pregnancies is a global phenomenon that may have wide-ranging implications for the future health of the next generations. We have previously shown that oocytes from females at advanced maternal age (AMA F0) accumulate intracytoplasmic lipid droplets (LDs), and that oxidative changes to lipids in oocytes from AMA F0 mice are maintained in preimplantation embryos. Here we explore whether oxidative changes are transmitted to the foetus, and what effects this has on neonatal and adult organ development, and the transgenerational inheritance of these changes. First, we show increased antioxidants in lipid-rich organs (liver and brain) of AMA-derived prenatal mice (AMA F1), indirectly showing increased oxidative stress. Then, we provide evidence of metabolic reprogramming in adult offspring of AMA and the accumulation of lipids in AMA-derived third generation (AMA F3) mouse oocytes. In particular, we demonstrate the accumulation of retinoids and other mediators of oxidative phosphorylation (OXPHOS) in AMA F0 and AMA F3 oocytes. Altogether, an altered oxidative metabolism of AMA F0 oocytes may constitute a base of oxidative changes in the organs of offspring and of their transgenerational inheritance to AMA F3 oocytes. Our findings indicate a remodelling of lipid homeostasis in oocytes of female mice derived from AMA great-grandmothers and highlight the need to take a closer look at the inheritance of metabolic changes from mothers of advanced age into their offspring.

Obesity and aging are converging health challenges, contributing to morbidity in older populations. However, the specific contribution of age to susceptibility to obesity is unclear. This study examined the impact of age on susceptibility to diet-induced obesity (DIO) and calorie restriction (CR) in male mice. Young (2-3 months) and old (17-24 months) lean C57BL/6J male mice were fed a standard chow diet (CD) or a high-fat diet (HFD) for 28 days, then underwent 18 days of CR. We monitored body weight, body composition, energy intake and expenditure, glucose tolerance, and gene expression in metabolically relevant tissues. HFD-fed old mice exhibited more fat mass gain but, surprisingly, protection from glucose intolerance. In comparison, young controls exhibited resistance to DIO due to reduced calorie storage efficiency. Gene expression analysis suggested reduced plasticity and lipid turnover in visceral adipose tissue but increased subcutaneous adipose tissue plasticity in old mice. The increased energy storage did not protect old mice from body weight loss following CR. Old mice exhibit increased susceptibility to DIO due to near optimal efficiency storing calories as fat. This susceptibility correlates with increased energy storage efficiency and the absence of energy demanding anabolic processes, like lean mass accrual, exhibited by young mice. Despite increased predisposition to obesity, lifelong leanness confers resilient glycemic control to old mice, emphasizing the importance of maintaining a healthy body weight and dietary habits throughout life to mitigate age-related metabolic risks.

Biomarkers of ageing are defined as age-related changes in body function or composition that could serve as a measure of 'biological' age and predict the onset of age-related diseases and/or residual life expectancy. We conducted the MARK-AGE Study, a European population study (3300 subjects aged 35-74) to identify a powerful set of biomarkers of ageing. A total of 362 clinical-chemistry, genetic, cellular or molecular biomarkers were analysed for each subject. Using statistical models as well as machine learning we derived mathematical formulas for females and for males that yield a 'bioage score' of an individual, based on sets of 10 biomarkers for females and 10 for males. Collectively, these biomarkers model chronological age of our study population and, thus yield the 'biological' age of a certain person. 'Age difference' (defined as biological minus chronological age) should then identify biologically older or younger individuals. Using our set of biomarkers, subjects with Down Syndrome and smoking females are biologically older, whereas postmenopausal females taking hormone replacement therapy are biologically younger. Strikingly, our data reveal that age difference of MARK-AGE subjects, but not chronological age, is linearly correlated with levels of HDL, 25-hydroxy-Vitamin D, and CD3+ CD4+/CD45+ ratio in such a way that biologically younger subjects display values that are favourable to good health, whereas other markers such as glucose and HbA1c are correlated with chronological age, but not age difference. This dichotomy of correlations may point to different roles of such markers, that is, drivers of the ageing process versus bystanders of ageing.

Aging is linked to a higher incidence of gut diseases such as inflammatory bowel disease (IBD), yet the underlying mechanisms remain unclear. We identified an age-related decline in magnesium (Mg) levels specifically in the gut across species, prompting investigation of its role in intestinal health. Functional studies demonstrated that Mg restriction accelerates gut aging in old but not in young mice and aggravates colitis severity. Multi-omics analysis of mouse tissues revealed that dietary Mg deficiency reshapes the phosphoproteome and N-glycoproteome, destabilizing adhesion complexes, a hallmark of intestinal aging and inflammation. In the UK Biobank cohort (n = 182,213), dietary Mg intake was inversely correlated with gut disorder risk, with 334.7-420.0 mg/day conferring significant protection against Crohn's disease, ulcerative colitis, irritable bowel syndrome, and diverticular disease. These findings identify Mg homeostasis as a key regulator of gut health and highlight Mg supplementation as a potential strategy to counteract age-related gut dysfunction.

Interventional therapy and surgery play important roles in the treatment of various diseases, but they cause varying degrees of vascular injury. Currently, the side effects are often overlooked. Here, we observed abnormal nuclear morphology (nuclear dysmorphism) and vascular aging in injured human and rodent arteries. Platelet-derived microvesicles (PMVs) adhere to injured blood vessels, leading to nuclear dysmorphism and cell senescence in vascular smooth muscle cells (VSMCs). This occurs because PMV adherence reduces intracellular Zn²⁺ levels, which impairs Zn²⁺-dependent processing of prelamin A by the enzyme ZMPSTE24. Consequently, prelamin A accumulates in VSMCs, contributing to the observed nuclear dysmorphism and cell senescence. RNA sequencing and loss-of-function assays revealed that Zinc transporter solute carrier family 39 member 4 (SLC39A4, also called ZIP4) deficiency accounts for the decreased Zinc concentration. Consistently, Zmpste24^+/- and Zmpste24^-/- mice displayed significant cumulative prelamin A, deteriorated nuclear dysmorphism and vascular aging. Whole genome bisulfite sequencing (WGBS) and bioinformatic analysis illustrated that demethylation of genes within Lamina-associated domains (LADs) participates in nuclear dysmorphism and cell senescence. Of note, Zinc supplementation, especially using platelet membrane-coated Zn-MOF nanoparticles, robustly alleviated nuclear dysmorphism and vascular aging. Our data established a novel and significant role of pMVs/ZIP4/zinc/prelamin A axis in promoting nuclear dysmorphism and vascular aging after injury.