Longevity Papers

Familial longevity, quantified using the Longevity Relatives Count (LRC) score indicating the proportion of ancestral long-lived family members, associates with a pronounced 13 years delayed onset of cardiometabolic disease (CMD). Understanding the molecular basis of familial longevity therefore provides critical insights into mechanisms of cardiometabolic resilience. However, the combined metabolomics and proteomics profile associated with the delayed CMD onset observed in such long-lived family members is not understood yet. Hence, we integrated plasma metabolomics and proteomics in 495 participants from the Leiden Longevity Study to identify molecular signatures associated with (a contrast in) the LRC score. Metabolomics profiling captured 429 features, including amino acid derivatives, nucleosides, and lipid mediators, while proteomics quantified 374 proteins related to cardiovascular, metabolic, and inflammatory pathways. Three within-family analysis approaches were examined and overlapping findings were interpreted. We identified ten metabolites and nine proteins that are associated with increased familial longevity, exemplified by a high LRC score. High LRC scoring individuals exhibited lower levels of amino acid derivatives (prolylhydroxyproline, 5-hydroxy-tryptophan, asymmetric dimethylarginine), nucleosides (2-methylguanosine, 7-methylguanosine, pseudouridine), N-acetylneuraminic acid and quinolinic acid, indicating optimized extracellular matrix integrity, vascular function, and reduced neuroinflammatory activity. Lipid mediators, including elevated 6-keto-PGF1a and reduced 9-HOTrE/alpha-linolenic acid ratio, reflected preserved endothelial homeostasis and attenuated inflammatory signaling. At the proteome level, strong ancestral familial longevity is associated with immune regulators (RETN, NPPB, IGSF8), extracellular matrix components (EFEMP1, EPHB4), and adhesion/signaling molecules (LRP11, ICAM3, KIT, ADGRG2), highlighting coordinated regulation of inflammation, tissue remodeling, and regenerative capacity. Multi-omics pathway analyses indicated convergence on amino acid and nucleotide metabolism, lipid signaling, extracellular matrix remodeling, and receptor-mediated communication. Collectively, these multi-omics systemic signatures define a molecular framework of ancestral familial longevity characterized by reduced inflammation, preserved tissue integrity, and enhanced metabolic and regenerative processes. Our findings provide mechanistic insight into the biology of familial longevity and potentially cardiometabolic resilience.

Aging is accompanied by a progressive decline in skeletal muscle mass and function, culminating in sarcopenia, a major contributor to frailty, disability, and mortality in older adults. While skeletal muscle aging has traditionally been attributed to cell-autonomous and local tissue mechanisms, increasing evidence suggests that systemic, cell non-autonomous processes play a central role in coordinating aging across organs. The brain, particularly the hypothalamus, has emerged as a key regulator of organismal aging, yet its contribution to skeletal muscle aging remains poorly defined. Here, we tested the hypothesis that senescence confined to the brain is sufficient to induce aging-like molecular remodeling in skeletal muscle via systemic mechanisms. To model brain senescence, young mice were subjected to fractionated whole-brain irradiation (WBI), a well-established approach that induces widespread cellular senescence and neuroinflammation in the brain while sparing peripheral tissues. Two months after WBI, transcriptomic profiling of quadriceps muscle was performed and compared with that of naturally aged mice. WBI-induced robust gene expression changes in skeletal muscle that closely mirrored those observed during chronological aging. Pathway-level analyses revealed marked downregulation of mitochondrial organization, respiratory chain assembly, and metabolic processes, alongside enrichment of remodeling- and stress-associated pathways. Upstream regulator analysis identified FOXO1, FOXO3, KLF15, and STAT3, which are key drivers of muscle catabolism and atrophy, as central mediators of the observed transcriptional program. Semantic similarity analysis further demonstrated a high concordance between WBI-induced and aging-associated biological processes. Collectively, these findings demonstrate that brain senescence is sufficient to drive sarcopenia-like transcriptomic remodeling in skeletal muscle, implicating central nervous system aging as an upstream regulator of peripheral muscle decline. This brain-muscle aging axis may contribute to frailty in individuals with accelerated brain aging and in cancer survivors exposed to cranial irradiation, highlighting brain senescence as a potential therapeutic target to mitigate systemic aging and skeletal muscle dysfunction.

Organs age at different rates, yet the protective mechanisms contributing to decelerated aging in certain tissues remain unclear. Applying cross-tissue comparisons to molecular readouts of aging, here we report that the intervertebral disc (IVD) ages slowly. We link the rate of aging to the persistently hypoxic environment of the IVD, and its unique ability to degrade hypoxia-inducible factor-1α (HIF-1α) in nucleus pulposus cells through optineurin-mediated selective autophagy, thereby uncoupling hypoxia from HIF-1α accumulation and limiting cellular stress. Further, we developed a small-molecule HIF-1α-targeting autophagy-tethering compound (HATC) to pharmacologically export the protective mechanism to other tissues. In aged mice, systemic weekly administration of HATC reduced HIF-1α levels across multiple organs, ameliorated a range of age-related pathologies and significantly extended both median (~14%) and maximum lifespan (~12%). These findings define a regulatory axis in which HIF-1α degradation under hypoxia contributes to longevity, and support HATC as a geroprotective strategy to improve healthspan.

Aging is the primary driver of chronic disease and mortality, requiring comprehensive frameworks for quantification of aging and nomination of longevity interventions. We developed mAge (multimodal age), a biological aging framework that integrates plasma proteomics, wearables, and mortality hazard to predict biological age, intrinsic capacity, and mortality risk. By combining proteomic and wearable data in UK Biobank samples, mAge exceeds unimodal baseline age prediction to 0.87 test R2 and 2.3 years mean error, and reduces unimodal baseline mortality prediction error by 21%. We further constructed organ- and cell type-specific biological clocks that quantify aging across 49 distinct subsystems, revealing that cardiac, immune, and intracellular protein signatures benefit most from wearable integration. By mapping data to FDA-approved drug targets, we identified interventions, such as GLP-1 receptor agonists, gabapentin, and ACE inhibitors, that are associated with lower overall and subsystem-specific proteomic age and mortality risk or are associated with longer time-to-death and later age-at-death in longitudinal and deceased cohorts. mAge establishes a scalable framework for nominating and validating personalized longevity interventions, bridging continuous digital monitoring with molecular aging diagnostics.

Aging is characterized by progressive loss of physiological resilience accompanied by increased susceptibility to chronic diseases. Among the interconnected hallmarks of aging, cellular senescence has emerged as a central driver of systemic inflammation through the senescence-associated secretory phenotype (SASP). Senescent cells accumulate across multiple tissues with advancing age and secrete complex mixtures of cytokines, growth factors, and proteases that reshape tissue microenvironments and propagate inflammatory signaling locally and systemically. Increasing evidence indicates that SASP composition is highly heterogeneous and depends on cell lineage, metabolic state, and the nature of the senescence-inducing stressor. Recent discoveries further demonstrate that inflammatory signaling in senescent cells is sustained by multiple nucleic acid-sensing pathways, including both cGAS-STING-dependent DNA sensing and mitochondrial RNA-mediated activation of RIG-I-like receptors. Concurrently, senescent cells deploy immune-evasion mechanisms that limit clearance by cytotoxic lymphocytes and natural killer cells, facilitating their persistence within aging tissues. Accumulation of senescent cells therefore represents a critical mechanistic link between molecular damage and the systemic inflammatory state known as inflammaging. This review synthesizes current understanding of tissue-specific SASP programs across immune, vascular, metabolic, hepatic, and neural systems. Particular emphasis is placed on mechanisms that amplify local senescence into organism-wide inflammation, including endocrine signaling, extracellular vesicle trafficking, and sex-dependent modulation of senescence pathways.