Longevity Papers

Cellular calcium (Ca

Brain aging is not an independent process, yet how systemic aging drives neural decline remains unclear. Here, we identified a circulating miR-4433b-3p, packaged within extracellular vesicles (EVs), as a trans-organ effector bridging cardiac aging with central nervous system (CNS) decline. Small RNA sequencing and human cohort validation revealed selective enrichment of miR-4433b-3p in aged plasma EVs (Op-EVs), correlating with blood biomarkers of brain aging. Source tracing in mice identified the aged heart as the major origin of miR-4433b-3p-laden EVs. Functionally, aged cardiac EVs (Oc-EVs) accumulated in the hippocampus, impaired memory and induced neuronal senescence. Mechanistically, miR-4433b-3p suppressed TP53INP2, a facilitator of autophagic flux, leading to disrupted autophagosome maturation. Restoring TP53INP2 or inhibiting miR-4433b-3p rescued neuronal autophagy and improved cognition. Collectively, these findings uncover a heart-brain axis by EV-mediated miRNA signaling, positioning cardiac EV-miR-4433b-3p as a circulating biomarker and potential therapeutic target for age-related cognitive decline.

Background: It is an everyday observation that people of the same chronological age differ with respect to their physical and mental capacity. However, assessing these differences in biological age remains challenging. Methods: Here, we aggregate 89 age-associated variables from the Berlin Aging Study II (BASE-II, n=1,631) to generate MultiAge, a new marker of biological age that summarizes information from ten domains reflecting organ health and global biological age. We then used methylation data obtained from an Illumina MethylationEPIC array and supervised machine learning to translate MultiAge into a DNA methylation signature, MultiAgeEpi (309 CpGs), which was subsequently validated in four independent external validation cohorts (KORA FF4, KORA Age, SHIP-TREND, BiDirect, total n=4,339). MultiAgeEpi results were compared with previously published epigenetic clocks (GrimAge, DunedinPACE, SystemsAge). Results: We report that MultiAgeEpi showed similar, and in several cases, stronger associations with age-associated outcomes such as diabetes, metabolic syndrome, multimorbidity, frailty and mortality (q < 0.05) compared to the other clocks. Conclusions: MultiAge and MultiAgeEpi thus provide a comprehensive assessment of biological age through aggregation of numerous age-associated variables and the use of the high-resolution methylomics data makes transfer of this marker to other cohorts possible.

Aging research has made remarkable progress in describing aging through the genetic architecture of longevity, epigenetic clocks, proteomic signatures, and systems-level analyses. Yet a critical dimension remains underrepresented: the role of genome integrity, germline and somatic mutation accumulation in individual-specific vulnerability, frailty, and multimorbidity across the life course. The need for individual-level thinking has deep roots, from Darwin's emphasis on individual variation in natural selection, to Garrod's chemical individuality, to Lewontin's genotype-phenotype (G-P) map and reaction norms. This tradition in evolutionary biology and medicine treats the individual as a primary unit of both selection and intervention. Here, we argue for an N-of-1 framework in aging research. Population-level epidemiology and genetics of aging based on means and variances can produce a "curse of the average," obscuring the individual genetic variation that impacts relative aging among individuals. The individual-centered N-of-1 framework would integrate longitudinal tracking of mutation accumulation ranging from individual cells, tissues, and organs into comprehensive individual aging profiles aligned with the G-P map concept. The emerging idea of "mosaic aging" further emphasizes that cells, cell types, tissues, organs, and organ systems within an individual reflect heterogeneous aging trajectories. We discuss how somatic mutations, operating through Muller's ratchet-like dynamics in stem cell populations, generate hierarchical vulnerabilities across biological scales. The extreme rarity of centenarians who may maintain superior genome integrity illustrates the relevance of this framework. We suggest that an integrated G-P map approach, grounded in evolutionary genetics, would advance both precision medicine and geroscience.

The decline of organ function during aging limits healthspan. Despite the potential of lifestyle interventions to improve health, sustained maintenance of healthspan is challenging, and no gerotherapeutic drugs have been approved. Here, we demonstrated that aged and geriatric male and female mice treated with muscle-directed adeno-associated viral (AAV) vector-mediated fibroblast growth factor 21 (FGF21) gene therapy extended healthspan and lifespan with sustained organ benefits. This treatment normalized body weight and adiposity, improved insulin sensitivity and glucose homeostasis, preserved hepatic detoxification capacity, counteracted age-related kidney disease, promoted cardiac health, and muscular function, and enhanced cognition. Transcriptomic and histopathological analyses indicated improved whole-body energy homeostasis and cellular fitness, which were mediated by tissue-specific adaptations, including enhanced mitochondrial function, restored proteostasis, and reversion of inflammation, fibrosis and amyloidosis. AAV-FGF21 treatment also activated AMPK signaling. These results highlight FGF21 gene therapy as a potential strategy to promote healthspan and delay age-related deterioration.

The DREAM complex has emerged as a central repressor of DNA repair, raising questions as to whether such repression exerts long-term effects on human health. Here we establish that DREAM-associated activity significantly impacts lifetime somatic mutation burden, and that such effects are linked to altered lifespan and age-related disease pathology. First, joint profiling of DREAM-associated activity (quantified from the expression of genes transcriptionally repressed by DREAM) and somatic mutations across a single-cell atlas of 21 mouse tissues shows that cellular niches with lower DREAM-associated activity have decreased mutation rates. Second, DREAM-associated activity predicts the varied lifespans observed across 92 mammals, with low activity marking longer-lived species. Third, reduced DREAM-associated activity in individuals with Alzheimer's disease predicts late disease onset and decreased risk for severe neuropathology. Finally, DREAM knockout in mice protects against mutation accumulation, reducing single-base substitutions by 4.2% and insertion/deletions by 19.6% in the brain. These findings position DREAM as a key regulator of aging.

Time-restricted feeding (TRF) aligned with an organism's circadian rhythm has been shown to improve health, but its long-term effects on healthspan and lifespan in mammals, especially under standard dietary conditions that do not promote obesity, remain unclear. Here, we examined the impact of 12-h and 8-h nightly TRF windows in 264 male and 264 female C57BL/6 J mice fed regular chow. TRF improved multiple health measures, including behavioral rhythmicity, body weight and composition, frailty, and disease onset. These effects were most pronounced in the 8-h TRF group, which exhibited voluntary caloric restriction in addition to time restriction. A composite Healthspan Index revealed that TRF extended healthspan in both sexes, though the benefits were more prolonged in female mice relative to their total lifespan. Median lifespan was significantly extended in male mice under 8-h TRF by 12%, whereas female mice showed no significant lifespan extension. These results demonstrate sex-specific effects of TRF on mammalian aging.

Aging is a complex biological process characterized by progressive functional decline, driving the incidence of age-related diseases such as neurodegeneration, metabolic disorders, and cardiovascular diseases. Therapeutic strategies targeting aging hallmarks can delay aging and mitigate disease risk. Emerging interventions focus on modulating core aging mechanisms, including cellular senescence, metabolic dysfunction, epigenetic alterations, and mitochondrial impairment, etc. Recent advances have focused on three strategies: senolytics (eliminating senescent cells, e.g., dasatinib + quercetin), senomorphics (inhibiting the senescence-associated secretory phenotype, e.g., rapamycin), and senoreversion (rejuvenating senescent cells via epigenetic reprogramming). Additionally, metabolic interventions such as caloric restriction mimetics (e.g., spermidine, α-ketoglutarate, ergothioneine) enhance mitochondrial function, activate autophagy, and reprogram energy metabolism, demonstrating lifespan extension and healthspan improvement in preclinical models. Collectively, these approaches hold promise for delaying aging and alleviating age-related pathologies, facilitating the transition to precision longevity medicine. Concurrently, artificial intelligence (AI) accelerates discovery by integrating multiomics data, predicting candidate compounds, identifying biomarkers, and enabling personalized interventions. Despite advancements, challenges remain in target specificity, off-target effects, and clinical translation. The convergence of AI, multitarget strategies, and precision medicine signals a transformative era in extending healthspan and combating aging-associated diseases. This review systematically summarizes current breakthroughs, clinical landscapes, and future directions in aging therapeutics, underscoring interdisciplinary strategies to redefine healthy aging.

Sarcopenia, the age-related loss of muscle mass and function, poses a significant health burden in aging societies. Although mitochondrial dysfunction is a recognized driver, the upstream molecular regulators remain poorly defined. Here, we identify the mitochondrial translocator protein (TSPO) as a novel negative regulator of myogenesis that is consistently upregulated in aged and sarcopenic muscle. Using gain- and loss-of-function approaches in C2C12 myoblasts, we show that TSPO overexpression disrupts mitochondrial homeostasis, impairs proliferation and differentiation, while TSPO knockdown produces opposite effects-establishing TSPO as a critical modulator of myogenic capacity. Mechanistically, TSPO suppresses the Wnt/β-catenin pathway, and this effect is partially mediated by ROS accumulation. Importantly, in vivo AAV9-mediated TSPO knockdown in aged mice not only restores mitochondrial integrity but also significantly improves muscle mass, strength, and exercise performance. Collectively, our findings uncover a TSPO-Wnt/β-catenin axis that links mitochondrial dysfunction to impaired muscle regeneration in aging. Targeting TSPO may offer a dual-action therapeutic strategy to combat sarcopenia by simultaneously enhancing mitochondrial bioenergetics and reactivating pro-myogenic signaling.