Longevity Papers

The global demographic shift towards an aging population has amplified the public health challenge posed by immunosenescence, a progressive remodeling of the immune system that compromises host defenses. This age-related decline is characterized by a reduction in adaptive immunity, marked by a diminished pool of naïve T-cells and an increased susceptibility to infections and poor vaccine responses. Simultaneously, it is defined by a paradoxical state of chronic low-grade inflammation, or "inflammaging," which accelerates age-related pathologies. This review posits "immunopause" as a conceptual framework for a state of severe immune decline, a state often viewed as an inevitable consequence of aging. However, the evidence synthesized herein challenges this view by positioning physical exercise as a potent, non-pharmacological intervention capable of countering this process. The report systematically reviews the cellular, molecular, and systemic mechanisms through which exercise exerts its beneficial effects, including the rejuvenation of T-cell repertoires, the regulation of cytokine networks, and the modulation of multi-organ axes involving myokines and the gut microbiome. By improving the efficacy of existing immune cells and shifting the systemic inflammatory milieu, chronic physical activity promotes a more "youthful" and functional immune phenotype. This synthesis not only underscores exercise's potential to enhance vaccine efficacy and serve as an adjuvant therapy for age-related diseases but also argues for a paradigm shift: from viewing immune aging as an immutable process to recognizing it as a modifiable state. The report concludes that exercise provides a scientifically validated strategy to extend healthspan and prevent the pathological state of immunopause.

Aging impairs tissue function and regenerative capacity across multiple organs. This study demonstrates that extracellular vesicles derived from human nasal mucosa (nmEVs) exert systemic antiaging effects in aged mice. Treatment with nmEVs improves cognitive performance and alters hippocampal aging signatures related to synaptic signaling and the regulation of neuroplasticity. In parallel, transcriptomic analysis of five major aging-sensitive organs reveals that nmEVs broadly ameliorate age-associated transcriptional changes, notably by restoring circadian rhythmicity and suppressing cellular senescence-related pathways. At the cellular level, nmEVs alleviate senescence phenotypes in aged human bone marrow mesenchymal stem cells, restore proliferation and osteogenic capacity, and reactivate core clock gene expression. These effects are accompanied by modulation of the p53 pathway, suggesting its involvement in nmEV-mediated rejuvenation. Importantly, lacking the need for cell isolation and ex vivo expansion, nmEVs offer a practical, age-independent source of extracellular vesicles with high clinical accessibility. Together, these findings support the translational potential of nmEVs as a multifaceted therapeutic candidate for systemic aging intervention.

In many countries, lifespan has been increasing faster than healthspan, leading to more years spent with late-life disease and highlighting the need for reliable biomarkers to measure biological aging and to plan personalized interventions to extend healthspan. We used data from the Berlin Aging Study II (BASE-II, 60-80 years of age at baseline, average follow-up 7.4 +/- 1.5 years, range 3.9-10.4, n=1,083) to compare 14 biomarkers of aging recently consented by an expert panel for the use as outcome measures in intervention studies: Insulin-like growth factor 1 (IGF-1), growth-differentiating factor-15 (DNA methylation derived, DNAmGDF15), high sensitivity C-reactive protein (CRP), interleukin-6 (IL 6), muscle mass, muscle strength, hand grip strength (HGS), Timed-Up-and-Go (TUG), gait speed, standing balance test, frailty index (FI), cognitive health, blood pressure, and epigenetic age (DunedinPACE). Cox proportional hazard regression analyses were performed to investigate the predictive role for all-cause mortality and to identify subgroups of the three most frequent causes of death observed in BASE-II. Results were adjusted for age, sex, lifestyle factors, and genetic ancestry. In adjusted models of all-cause mortality, HGS, IL 6, standing balance, cognitive health, and epigenetic age (DunedinPACE) significantly predicted mortality, with the epigenetic age (DunedinPACE) emerging as the strongest predictor. In contrast, CRP, Gait Speed, IGF-1, blood pressure, muscle mass, DNAmGDF15, FI and TUG were not associated with mortality. These results were corroborated in subgroup analyses stratified by cause of death. Feature selection identified a minimal biomarker set comprising muscle mass, standing balance, and epigenetic age (DunedinPACE) that predicted mortality with nearly the same discriminative accuracy (C-index = 0.63) as the full model including all biomarkers (C-index = 0.65).

Decades of publicly available molecular studies have generated millions of samples testing diverse interventions, yet these datasets were rarely analyzed for their effects on aging. Aging clocks now enable biological age estimation and life outcome prediction from molecular data, creating an opportunity to systematically mine this untapped resource. We developed ClockBase Agent (www.clockbase.org), a publicly accessible platform that reanalyzes millions of human and mouse methylation and RNA-seq samples by integrating them with over 40 aging clock predictions. ClockBase Agent employs specialized AI agents that autonomously generate aging-focused hypotheses, evaluate intervention effects on biological age, conduct literature reviews, and produce scientific reports across all datasets. Reanalyzing 43,602 intervention-control comparisons through multiple aging biomarkers revealed thousands of age-modifying effects missed by original investigators, including over 500 interventions that significantly reduce biological age (e.g., ouabain, KMO inhibitor, fenofibrate, and NF1 knockout). Large-scale systematic analysis reveals fundamental patterns: significantly more interventions accelerate rather than decelerate aging, disease states predominantly accelerate biological age, and loss-of-function genetic approaches systematically outperform gain-of-function strategies in decelerating aging. As validation, we show that identified interventions converge on canonical longevity pathways and with strong concordance to independent lifespan databases. We further experimentally validated ouabain, a top-scoring AI-identified candidate, demonstrating reduced frailty progression, decreased neuroinflammation, and improved cardiac function in aged mice. ClockBase Agent establishes a paradigm where specialized AI agents systematically reanalyze all prior research to identify age-modifying interventions autonomously, transforming how we extract biological insights from existing data to advance human healthspan and longevity.

The lack of safe, durable therapeutics that act against both biological aging and Alzheimer's disease is an unmet clinical need. To bridge this gap, we devised an artificial intelligence (AI)-enabled approach that pairs rapid compound triage with mechanistic target deconvolution. Our AI-driven screening highlighted melatonin (MLT) as a promising candidate. Serum profiling of 161 human individuals confirmed an age-related fall in circulating MLT level, while subsequent in vivo and in vitro experiments showed that MLT rescues cognition, suppresses neuroinflammation, and alleviates senescence phenotypes. Proteolysis targeting chimera (PROTAC)-guided chemoproteomic deconvolution next pinpointed the histone acetyltransferase p300 as MLT's target. Integrated Cleavage Under Targets and Tagmentation, single-cell RNA sequencing, and spatial transcriptomics revealed that MLT-bound p300 cooperates with specificity protein 1 (SP1) at a brain and muscle ARNT-like protein 1 super-enhancer, elevating histone H3 lysine-27 acetylation and reengaging a circadian-epigenetic program that links redox resilience to neuroprotection. By combining AI-driven discovery with PROTAC-based target mapping and super-enhancer-centric mechanistic resolution, our study identifies MLT as a dual-action candidate and sets out a reproducible "AI-to-clinic" paradigm for multitarget drug innovation in aging-related neurodegeneration.

Commensal microbiota plays crucial roles in maintaining tissue homeostasis, yet its impact on cellular ageing and inflammaging across diverse cell types remains poorly understood. Here we present a comprehensive single-cell epigenomic and transcriptomic atlas of various tissues from mice aged under specific pathogen-free (SPF) or germ-free conditions, revealing context-dependent effects of microbiota on cellular ageing. Microbiota conferred beneficial effects in young mice but accelerated various ageing features in old, such as age-related AP-1 pathway upregulation, senescence and transcriptomic alterations, likely due to age-associated dysbiosis. Strikingly, inflammatory signatures persisted across cell types in aged germ-free mouse tissues, establishing sterile inflammation as an intrinsic feature of ageing. Age-associated B cells expanded equally under germ-free conditions and (SPF) conditions, raising the possibility that they function as intrinsic, microbiota-independent drivers of inflammageing and potential therapeutic targets. The atlas provides a resource for distinguishing intrinsic ageing features from those modulated by the microbiota, illuminating mechanisms of cellular ageing and potential anti-ageing interventions.

A systematic investigation of aging patterns across virtually all major tissues in nonhuman primates, our evolutionarily closest relatives, can provide valuable insights into tissue aging in humans, which is still elusive largely due to the difficulty in sampling. Here, we generated and analyzed multi-omics data, including transcriptome, proteome and metabolome, from 30 tissues of 17 female rhesus macaques (Macaca mulatta) aged 3-27 years. We found that certain molecular features, such as increased inflammation, are consistent across tissues and align with findings in mice and humans. We further revealed that tissue aging in macaques is asynchronous and can be classified into two distinct types, with one type exhibiting more pronounced aging degree, likely associated with decreased mRNA translation efficiency, and predominantly contributing to whole-body aging. This work provides a comprehensive molecular landscape of aging in nonhuman primate tissues and links translation efficiency to tissue-specific aging.

The short-lived and rapidly aging African turquoise killifish, Nothobranchius furzeri GRZ is a unique model to study vertebrate aging. Current genomic and full-length transcriptomic sequencing lacks full gene annotations, resulting in poor mapping in bulk and single-cell transcriptomic studies. In our efforts to reannotate the transcriptome of the killifish telencephalon, we combined long-read (Smrt-Isoseq) and short-read transcriptome sequencing approaches. A total of 17,008 full-length isoforms, including 6763 novel ones were obtained (51 bp to 7,500 bp). The killifish telencephalon comprises 25% multi-exon genes, while over 50% are mono-exon genes. We discovered novel non-coding and coding sequences in both young and aged telencephali. We integrated long-read and RNA-seq data to construct a comprehensive transcriptome and profiled expression dynamics across the aging telencephalon. Our gene models demonstrate greater detail and accuracy than Ensembl, with more precise polyA locations. Alternative splicing analysis revealed 29 events altered with aging, which involved changes in ribosome function, gap junction and mRNA surveillance pathways. These generated resources pave the way for future functional genomic studies in this biogerontology model.

Background: Defective cardiac relaxation (diastolic dysfunction) is common in heart failure, especially with diabetes, obesity, hypertension, and ageing, and is linked to increased mortality. No effective therapy specifically targets this dysfunction. Phosphorylation of troponin I by cAMP-dependent protein kinase A (PKA) promotes relaxation, but global PKA activation affects numerous downstream targets. Here we investigated whether selective enhancement of troponin I phosphorylation could improve relaxation without widespread PKA activation. Methods: To investigate cAMP signalling with subcellular resolution we used real-time detection of cAMP levels and FRET based genetically encoded reporters targeted to specific locations combined with biochemical and genetic approaches. We applied peptide array technology to study protein-protein interaction surfaces and develop a protein-protein interaction disruptor peptide. The impact of such peptide on cardiac myocyte function was investigated in vitro, using both mouse and human primary cardiac myocytes and biochemical approaches, real-time imaging, work-loop analysis. In vivo analysis involved echocardiography and hemodynamics measurements. Results: We discovered that the cAMP-hydrolysing enzyme PDE4D9 binds troponin I and locally degrades cAMP within a nanometre-scale domain, thereby selectively regulating troponin I phosphorylation. The association of PDE4D9 with troponin I is markedly increased in cardiac disease in rodents and humans. A peptide displacing PDE4D9 from troponin I selectively elevates troponin I phosphorylation, enhances cardiomyocyte relaxation, and prevents diastolic dysfunction in a mouse heart failure model. Conclusions: Our findings define a first-in-class, mechanism-based therapeutic approach to a major, unmet contributor to heart failure.

Arterial aging, marked by progressive vascular stiffening, is a contributor to cardiovascular disease. Photoplethysmography (PPG) waveforms offer an easily accessible signal of arterial function, enabling scalable assessment of arterial age at the population level. Here, we present a multimodal deep learning framework integrating raw PPG waveforms with hemodynamic features from UK Biobank participants to construct an arterial aging clock. From this model, we derived ArtAgeGap, an age-independent residual biomarker of arterial aging, which correlated with established measures of vascular stiffening, such as pulse pressure (r=0.60). ArtAgeGap was significantly elevated in individuals with a history of cardiovascular disease, and associated with diabetes (+0.93 years, 95%CI: 0.64-1.21) and hyperlipidemia (+0.49, [0.36-0.61]). In 96,615 participants followed for a median of 13 years, higher ArtAgeGap values predicted incident hypertension, major adverse cardiovascular events, and cardiovascular and all-cause mortality (hazard ratios per +1 year: 1.01-1.06), on top of chronological age. A genome-wide association study in 114,098 individuals identified 60 independent loci associated with ArtAgeGap, including variants previously associated with blood pressure (e.g. NPR3), arterial stiffness (CLCN6), aortic diameter (SLC24A3), and atherosclerosis (HDAC9), as well as 34 novel loci enriched for arterial tissue expression. Integrative analyses with transcriptomic data from human arteries prioritized 28 genes, such as RSG19 and ULK4, whose genetically proxied expression was associated with ArtAgeGap. Single-cell transcriptomic data from arterial tissue revealed strong enrichment of these genes in fibroblasts, implicating fibrotic remodeling mechanisms in arterial aging. Rare variant burden testing further implicated damaging variants in COL21A1, LMNA, TP53BP2, RXRB, and FLOT2, also converging to mechanisms related to extracellular matrix organization and fibrosis regulation. Lastly, Mendelian randomization analysis identified ArtAgeGap as an intermediate biomarker in-between vascular risk factors and outcomes, with central adiposity, higher blood pressure, and type 2 diabetes increasing ArtAgeGap, and higher ArtAgeGap elevating the risks of coronary heart disease and stroke. Together, these findings establish ArtAgeGap as a scalable PPG-based biomarker of arterial aging and provide mechanistic insights into potential therapeutic strategies to mitigate arterial aging.