Nature Aging

Multimorbidity is highly prevalent in ageing populations, yet its shared molecular basis remains poorly defined, limiting the development of therapies that target multiple conditions. We systematically integrated measurements of 1,954 circulating proteins from 54,219 individuals in discovery and 35,559 in replication, focusing on ten common age-related diseases: coronary artery disease, chronic kidney disease, chronic obstructive pulmonary disease, dementia, heart failure, major depressive disorder, osteoarthritis, Parkinson's disease, stroke, and type 2 diabetes. Coronary artery disease emerged as a central condition in the multimorbidity network, sharing circulating protein signatures with seven other diseases. Through genetic causal-inference analyses, we identified 40 circulating proteins with cross-disease relevance, of which four were further supported by colocalization of genetic variant associations. Among these, complement C1r, encoded by C1R, emerged as a key link between coronary artery disease and dementia, supported by independent colocalization evidence (PP.H4 = 0.86). Phenome-wide association analyses of C1R variants suggested that this signal was not driven by widespread unrelated genetic effects, but instead may reflect a more specific contribution to coronary artery disease-dementia pathogenesis. In vitro experiments further suggested that fibroblast-derived C1R promotes endothelial inflammation and neuronal apoptosis, providing mechanistic plausibility. Together, these findings position C1R as a biologically plausible and therapeutically relevant molecular link between coronary artery disease and dementia.

Aging is a major risk factor for neurological disease, yet the molecular architecture of human brain aging remains poorly defined. Here, we analyzed more than 10,000 cerebrospinal fluid (CSF) proteomes across multiple cohorts and proteomic platforms to develop a 249-protein CSF aging clock that accurately predicted chronological age and generalized across independent datasets. CSF brain-age acceleration was increased across diverse neurological diseases, associated with blood-brain barrier (BBB) dysfunction, and predictive of longitudinal cognitive decline, neuroimaging progression and dementia conversion. A simplified 30-protein panel retained similar prognostic performance. Biologically, the clock resolved two opposing programs: pro-aging activation of immune, vascular/BBB, extracellular matrix and coagulation pathways, marked by CHI3L1, CD14, VWF, LRG1 and LTBP2, and collapse of anti-aging neuronal-maintenance programs, marked by NPTX2, COL1A2, NID1, CDH8 and PENK. Brain-wide single-cell and regional mapping linked these programs to disease-vulnerable compartments. These findings establish a CSF-based molecular framework for quantifying biological brain aging and predicting neurological disease progression.

How tissue-resident T cells are organized to provide immune surveillance in healthy peripheral tissues and how this organization changes with age remains largely unknown. Here we use intravital imaging in zebrafish to identify a previously undescribed, appendage-specific mode of adaptive immune organization: fin-resident T cells undergo coordinated collective "streaming" migration within connective tissue compartments. T cells colonize the developing fin prior to lymphatic or blood vessel formation, indicating that initial residency can be established independently of classical immune conduits. However, collective streaming is not immediate; it emerges during juvenile maturation, coincident with maturation of fin architecture, and is restricted to T cells rather than other leukocyte populations. After fin amputation, young adults restore streaming within regenerated tissue once spatial compartments are re-established, whereas middle-aged fish following thymic involution repopulate the fin yet fail to promptly recover coordinated streaming and show broader tissue dispersion and altered motility in comparable times. Transcriptomic profiling across ages, regenerative states, and immune-altered microenvironments reveals coupled regulation of stromal remodeling programs and antigen presentation pathways, including differential expression of MHC class I and II components with strong microenvironmental dependence. These data define an age-regulated, tissue-instructed program that organizes resident T cell dynamics and immune potential in situ, providing a framework for understanding how tissue specific stromal environments constrain immune surveillance. Significance StatementT cells patrol most organs, but we know surprisingly little about how they are arranged inside healthy tissues over an animals lifetime. By imaging zebrafish in vivo, we discovered that fin-resident T cells do not move independently: they organize into coordinated "streams" that migrate collectively through fin connective tissue. This collective behavior appears during juvenile maturation, re-forms after regeneration in young adults, and is delayed or disrupted in older fish as age-related thymus decline reduces new T cell production. In parallel, aging and the tissue microenvironment reshape the expression of genes involved in antigen presentation. These results reveal a tissue-specific, age-regulated architecture for adaptive immune surveillance that links aging to impaired immune organization during regeneration.

Systemic aging and metabolic overload remodel the vasculature; however, how endothelial cells integrate these stresses across organs remains unclear. Using multi-organ single-cell and spatial transcriptomics with functional validation, we mapped endothelial and hematopoietic responses in adipose tissue, skeletal muscle, liver, and heart. Organ-specific endothelial transcriptional features were relatively preserved, whereas chronic stress selectively reconfigured regulatory programs: aging induced a conserved Irf/Stat-centered endothelial program, while high-fat diet engaged organ-biased lipid and remodeling programs. Spatial analysis revealed perivascular niches centered on aging-associated interferon-stimulated endothelial activation, with neighboring immune and stromal cells expressing C3 and LRP1-associated signals. Rather than simply amplifying inflammation, these niches contained mechanisms that restrained IFN activation, as C3 depletion upregulated vascular IRF7 expression. In parallel, the IFN downstream effector BST2 promoted anti-inflammatory macrophage differentiation and suppressed atherosclerosis. These findings define vascular inflammaging as an organ-resolved niche process in which endothelial IFN activation is coupled to local inflammatory restraint. HighlightsO_LIAging induces a shared endothelial type I IFN program across organs. C_LIO_LIA high-fat diet triggers organ-biased endothelial remodeling programs. C_LIO_LIPerivascular interferon niches couple inflammation with local restraint. C_LIO_LIIFN-induced endothelial BST2 promotes CD200R-associated macrophage regulatory features. C_LI

Spatial chromatin organization dictates cellular function and resilience, yet scalable imaging methods to quantify chromatin states in situ across aging and interventions are lacking. While ATAC-see can visualize accessible chromatin, its broader application is hindered by protocol variability, low throughput, and incompatibility with complex tissues. Here, we systematically optimize the ATAC-see workflow for robust, high-throughput quantitative imaging in fixed, adherent mammalian cells and fresh frozen tissues. We validate the platforms sensitivity to pharmacologic remodeling and apply it to replicative, chronological, and pathological aging in primary human fibroblasts, revealing progressive age-associated chromatin opening and heterochromatin remodeling. Furthermore, we demonstrate that our optimized ATAC-see captures rapid, reversible chromatin reorganization during OSK(M)-driven partial reprogramming of aged fibroblasts. Finally, we extend a cost-effective and accessible protocol to murine tissue sections, quantifying in situ age-dependent remodeling. This standardized framework establishes chromatin accessibility as a highly scalable, sequencing-compatible imaging biomarker for evaluating aging and rejuvenation. Summary StatementATAC-see was optimized for scalable, quantitative imaging of chromatin remodeling during aging and cellular reprogramming, and extended to characterize age-associated epigenetic changes across organs.

Age-associated inflammation varies across tissues, but whether distinct visceral adipose tissue (VAT) depots undergo inflammatory remodeling in a depot-specific manner remains unclear. Here we profiled human peri-organ VAT, comparing kidney-associated fat (KF, from kidney transplantation donors) and gallbladder-associated fat (GBF, from asymptomatic cholecystectomy patients with incidental polyps), using single-cell RNA sequencing, flow cytometry, intracellular protein profiling and in situ analysis. GBF showed broad tissue-residency and granzyme K-associated remodeling across conventional, regulatory and innate-like lymphocyte compartments, whereas KF showed stronger B cell remodeling, greater myeloid representation and more compartmentalized changes within resident effector-like CD8 T cell states. We further identified age-associated CD20 T cells with features consistent with local B-T cell interaction and an antigen-experienced, granzyme K-associated inflammatory memory phenotype. In situ analysis revealed age-associated myeloid accumulation and crown-like structure remodeling, accompanied by distinct myeloid inflammatory programs in KF and GBF. Finally, depot-specific immune signatures associated with clinical indices of adjacent kidney and liver function. These findings indicate that age-associated distinct immune programs within peri-organ VAT depots track with local tissue context and the state of the adjacent organ.

Environmental exposures are major modifiable determinants of human aging, yet the evidence remains fragmented across organ-agnostic summaries and rarely confronts population inequity. Here we present an exposomic atlas of pan-organ aging in ~300,000 UK Biobank adults, mapping 164 environmental and behavioural exposures onto biological aging of the whole body and nine organ subsystems. Comprising 1,476 systematically tested exposure-subsystem associations, the atlas reveals that environmental effects on human aging are pervasively organ-specific, with 65.9% of exposures acting divergently across organ subsystems. This landscape resolves into nine navigable modules that preserve organ selectivity, predict 23 major age-related diseases, and expose distinct dimensions of health inequity. In-silico analyses further show that priorities for ameliorating aging are target-dependent rather than universal, diverge markedly from the whole-body ranking (Kendall's {tau} = 0.52 to 0.39), reorder substantially across population strata, with findings externally validated in an ethnically distinct cohort. The atlas establishes an organ-resolved and target-aware foundation for precision environmental health.

Cells release membrane-bound extracellular vesicles into the bloodstream laden with proteins that may reflect their physiological state. How this circulating EV proteome changes across life remains poorly understood. Identifying molecular signatures of aging in accessible biofluids could facilitate earlier intervention and monitoring of age-related disease. Many circulating aging proteome studies rely on affinity-based platforms which suffer from poor cross-species translation, ambiguous signal attribution, and inconsistent agreement between platforms. Here, we present a characterization of the aging plasma EV proteome from a cross-sectional cohort of 86 male and female C57BL/6J mice (5-31 months). We leveraged a species-agnostic EV enrichment (Mag-Net) and mass spectrometry to detect 2,575 protein groups from 15,969 peptides. Protein abundance heterogeneity increased with age and the abundance of 272 proteins were significantly correlated with chronological age including established senescence and frailty markers. Proteins increasing with age were enriched in genome maintenance pathways, while those decreasing were associated with the extracellular matrix organization and lipid metabolism. Notably, several of the strongest age-increased proteins converged on Alzheimer's and Parkinson's disease pathology. We observed sexual divergence in the aging EV proteome not previously characterized at this resolution. A proteomic clock built from this data accurately predicts chronological age, and peptide-level analysis reveals aging signals invisible at protein-level. These findings demonstrate that EV-enriched plasma proteomics can identify known aging markers, reveal novel sex-specific age-related changes, and generate predictive models of chronological age. This study provides a species-agnostic foundation for proteomic clocks that complement epigenetic approaches to monitor aging and evaluate healthspan.

Endothelial cells (ECs) express organ-specific gene programs supporting tissue homeostasis and resilience. However, the mechanisms by which aging reshapes these organ-specific endothelial programs and how the resulting changes affect tissue homeostasis, resilience, and disease susceptibility remain largely unknown. Herein, we performed single-cell RNA sequencing of ECs harvested from five organs across the lifespan and found that aging progressively erodes organ-specific endothelial programs while inducing shared interferon-responsive and antigen-presentation programs across organs. Although vascular subtype identity and conserved capillary subset identity were mostly preserved, these organ-specific transcriptional programs were broadly attenuated with aging, indicating erosion of organ-specific endothelial identity to be a fundamental feature of endothelial aging. Importantly, these alterations were associated with declines in specialized EC functions, including alveolar barrier maintenance in the lung, scavenging activity in the liver, angiogenic capacity in the heart, and homeostatic programs in the kidneys and the brain, suggesting that age-related EC alterations compromise tissue homeostasis and resilience in multiple organs. Furthermore, we established a single-cell aging index for alveolar capillary ECs in mice and humans, revealing stress-associated endothelial activation to potentially be an intermediate state linking functional deterioration to cellular senescence, and also demonstrating marked heterogeneity in aging states among ECs of the same chronological age. Notably, alveolar capillary ECs exhibited progressive functional decline before reaching a senescent-like state, suggesting endothelial dysfunction to precede overt cellular senescence as the organism ages. Collectively, our findings establish progressive erosion of organ-specific endothelial programs as a central feature of vascular aging and provide a conceptual framework for elucidating how endothelial aging contributes to tissue dysfunction and reduced resilience across organs.

Dementia is a progressive condition that impairs cognitive processes such as memory, decision making, and the ability to manage daily activities. Recent estimates suggest that more than half of all dementia cases could be preventable by addressing their risk factors, including disease comorbidities such as diabetes and vision loss. Yet, we lack a comprehensive molecular map of dementia comorbidities. In this work, we analyzed Austrian nationwide hospital claims data, comprising 13 million hospital stays from 2015 to 2019, to systematically assess dementia-related risk across disease comorbidity patterns, covering both their molecular relationships and their epidemiological overrepresentation. We identified disease trajectories occurring before and at the time of dementia diagnosis, revealing both sex-specific and shared comorbidity patterns. Overall, we identified 51 potential risk factors, with a prominent contribution from endocrine and metabolic disorders. While Parkinson's disease emerged as a strong molecularly related driver of dementia, we also identified emerging and previously under chracterized risk factors, including vitamin D deficiency. This integrative framework provides a comprehensive view of dementia associated disease networks and identifies novel, potentially modifiable risk factors. These results offer new opportunities for targeted prevention strategies and advance our understanding of the complex interplay between comorbidities and dementia development.

Circadian timing influences human physiology and disease risk, yet scalable measures of molecular circadian phase are lacking. Here we infer circadian phase from circulating blood biomarkers in UK Biobank. Among 3,228 plasma biomarkers, 58% exhibit significant diurnal variation, with harmonic modeling identifying acrophase clustering consistent with canonical circadian patterns and independent constant-routine datasets. Machine-learning models trained on plasma proteomics predict sampling time (R2=0.68) and retain substantial accuracy with ~60 proteins. We define a novel construct, circadian acceleration (CA), as deviation from the population-average phase; CA is temporally stable, associates with chronotype and shift work, and responds to environmental perturbation. CA is heritable (h2SNP=0.10) and genetically correlated with chronotype and accelerometry-derived sleep traits. These results establish plasma proteomics as a scalable approach for population-level molecular circadian phenotyping.

Epigenetic clocks estimate biological age from DNA methylation patterns but perform poorly in cancer due to extensive epigenetic reprogramming, limiting the study of ageing in tumour biology.Here, we develop GepiClock, an epigenetic clock trained on DNA methylation data from 32 cancer types in The Cancer Genome Atlas. Based on 4,862 CpG sites, GepiClock accurately predicts age across both tumour and normal samples, indicating that core ageing-associatedmethylation programmes remain detectable despite malignant transformation.Applying GepiClock to molecularly profiled cancer cell lines with matched drug response and CRISPR screening data revealed age-associated vulnerabilities. Younger-predicted cell lines were more sensitive to mTOR, MEK1/2 and HSP90 inhibitors, whereas older lines showed increased sensitivity to AKT and PI3K inhibitors. Additional cancer-type-specific patterns and age-associated genetic dependencies were identified.These findings establish a framework to quantify biological age in cancer and link ageing-associated states to therapeutic vulnerabilities.

Skeletal muscle can release endocrine stress signals during aging and wasting, but the upstream mechanisms that restrain this response remain incompletely defined. Here we identify March5 as a muscle proteostatic checkpoint that limits ATF4-dependent GDF15 production. March5 expression declined in aged and atrophic muscle, whereas muscle-specific March5 deletion induced ATF4 accumulation, marked GDF15 elevation, reduced food intake and progressive loss of body, muscle and bone mass. Restoration of feeding, GDF15 neutralization or muscle Atf4 deletion substantially attenuated the wasting phenotype. Mechanistically, March5 interacted with ATF4 and promoted its ubiquitination at K92, thereby limiting ATF4 stability and Gdf15 expression. Conversely, muscle March5 gain-of-function or pharmacological attenuation of ATF4 signaling improved feeding, body composition and physical performance in aged mice. These findings define a March5-ATF4-GDF15 endocrine stress axis linking muscle proteostatic control to feeding suppression and systemic body-composition remodeling.

Rapamycin extends lifespan across species, yet its cell-type-specific benefits and vulnerabilities remain unclear at whole-organism scale. Here, we present the Rapamycin Fly Cell Atlas (Rapa-FCA), a whole-organism single-nucleus transcriptomic atlas of Drosophila spanning both sexes, multiple ages, 18 cell classes, and 181 cell types. Rapamycin elicited a highly heterogeneous response, with prominent effects in reproductive, digestive, and neuromuscular systems and modest responses in most neuronal populations. Across diverse tissues, we identified a rapamycin-sensitive Convergent Aging Trajectory (CAT), marked by Fkbp12 enrichment and mTORC1-linked metabolic programs, including glycolysis and lipid synthesis. CAT-high nuclei accumulated with age and were preferentially reduced by rapamycin, especially in females, consistent with stronger female lifespan extension. By integrating CAT abundance, aging-clock predictions, and nucleus-ratio changes, we mapped sex- and cell-type-specific geroprotection effects of rapamycin. Together, the Rapa-FCA provides an organism-wide framework for resolving how rapamycin reshapes cellular aging across sex, tissue, and cellular state.

Lysosomal damage is increasingly recognized as a hallmark of aging. Understanding lysosomal quality control may open new therapeutic strategies to enhance lysosomal resilience. Here, we identify SOLAR (SQSTM1/p62 Oligomer-mediated Lysosomal Antioxidant Defense And Membrane Repair), a lysosomal quality control pathway that links CASM (conjugation of ATG8 to single membranes) to p62-driven membrane repair and redox signaling. In this pathway, CASM, but not macroautophagy, recruited p62 to damaged lysosomes. Efficient lysosomal recruitment of p62 required its ATG8-binding and self-oligomerizing domains, enabling p62 assemblies to promote membrane repair. p62 mutations associated with neurodegeneration interfered with p62 recruitment and compromised lysosomal repair. Besides membrane repair, the SOLAR pathway also activated the p62-KEAP1-NRF2 redox signaling axis, driving transcriptional upregulation of antioxidative genes and cholesterol biosynthesis. By integrating membrane repair and redox defense, SOLAR establishes a coordinated lysosomal quality control pathway with implications for aging and degenerative disease.

Most plasma proteomic studies in Alzheimer's disease (AD) compare cases and controls cross-sectionally, leaving unresolved which AD-associated proteins mark diagnostic states and which are linked to disease progression. Using longitudinal SomaScan profiling from the Global Neurodegeneration Proteomics Consortium (13,449 participants, 17,269 samples, 7,362 aptamers), we separated baseline AD differences from AD-specific change over time. Linear mixed-effects models requiring concordant baseline and AD-by-time effects defined a 30-protein signature. We prioritized proteins across five evidence domains: clinical progression, AD biomarker alignment, cerebrospinal fluid concordance, independent prospective replication in UK Biobank and genetic support from Mendelian randomization and rare-variant burden. Thirteen proteins were supported in two or more domains and six in three. EDA2R, HPGDS, ITGAV and CLEC3B converged across clinical, biomarker and prospective evidence. Signature proteins aligned more strongly with tau and neuronal-injury markers than with Ab42/40. ANTXR1 showed direction-concordant plasma pQTL Mendelian randomization and nominal rare-variant burden signals, supporting its prioritization within the longitudinal AD signature. By distinguishing diagnostic-state markers from progression-linked changes, this longitudinal, multi-domain approach prioritizes proteins for validation as markers of AD progression and for mechanistic and therapeutic follow-up.

Type 2 diabetes is linked to systemic inflammation driven by metabolic stress and aging. Although pancreatic inflammation associated with these factors is well documented, the dynamics of immune cell populations and their molecular changes remain poorly understood. We characterized immune cell alterations in the pancreas and pancreatic islets during Western diet (WD) feeding and aging using imaging mass cytometry (IMC) and single-cell RNA sequencing (scRNA-seq). Spatial and transcriptional analyses were performed to define immune cell subtype composition, activation states, and inferred cell-cell communication programs under metabolic and age-related stress conditions. Our analyses identified expansion of an F4/80low macrophage subtype and activated effector-like CD8+ T cells throughout the pancreas during WD feeding and aging. Within pancreatic islets, single-cell RNA sequencing identified a type 1 interferon-responsive macrophage population with low F4/80 expression that expanded during overnutrition. Notably, the type 1 interferon responses elicited by these stressors diverged: aging was associated with a more canonical type 1 interferon response, whereas overnutrition induced a broader response that included STAT3-associated transcriptional programs. We further provide evidence for enhanced cytokine-mediated communication between macrophages and a CD8+ cytotoxic T-cell population under overnutrition and aging. These findings show that metabolic stress and aging remodel pancreatic inflammation through overlapping but distinct immune mechanisms, involving expansion of F4/80low macrophages, activation of divergent type 1 interferon programs, and enhanced macrophage-CD8+ T-cell communication. Together, these findings suggest that distinct therapeutic approaches may be required to preserve islet function in type 2 diabetes driven by metabolic stress versus aging.

Disease tolerance limits infectious disease severity through tissue damage control mechanisms that do not target pathogens directly. Here we demonstrate that age-dependent decline in adipose tissue lipolysis compromises disease tolerance to SARS-CoV-2 infection. Young adult mice exhibited robust adipocyte lipolysis and 80% survival, whereas old mice showed impaired adipocyte lipolysis and only 20% survival. Genetic repression of adipocyte lipolysis eliminated this age-dependent survival advantage without affecting viral titers, revealing that adipocyte lipolysis is essential for disease tolerance to SARS-CoV-2 in young adults. Impaired adipocyte lipolysis in aged mice was associated with a plasma lipidomic signature that predicts COVID-19 severity and mortality in three independent human cohorts. Mechanistically, adipocyte lipolysis provides free fatty acids (FFA) to support bone marrow emergency myelopoiesis, through CD36- and CPT1-dependent FFA cellular uptake and mitochondrial import, respectively. Bone marrow derived monocytes migrate to the lung via CCL2/CCR2-dependent mechanism where they enforce an immune-metabolic communication network with parenchymal cells to sustain lung structure and function. This circuit is not required to confer protection against influenza infection, revealing pathogen-specific disease tolerance mechanisms. These findings reveal adipose tissue catabolism as a central age-dependent factor responsible for exacerbated COVID-19 mortality in aged populations.

Proteostasis declines with lung aging, while the role of the Unfolded Protein Response (UPR) in lung aging and age-associated pulmonary diseases remains understudied. We investigated how deficiency in the UPR sensor ATF6 affects physiological and smoke exposure-accelerated lung aging. ATF6 -deficient mice exhibited accelerated alveolar simplification, a sign of lung parenchymal aging, which was exacerbated by smoking. Nevertheless, small airway vascular fibrotic remodeling, a prominent smoking induced pathology, was not evident in smoke-exposed ATF6 -deficient mice. Mechanistically, these divergent phenotypes arose from cell-type-specific ATF6 programs. In alveolar epithelial type 2 cells (AEC2s), the facultative progenitors of the lung parenchyma, ATF6 maintained mitochondrial bioenergetics and sustained efficient re-differentiation into alveolar epithelial type 1 cells (AEC1s). In lung pericytes, ATF6 promoted extravasation, re-differentiation into myofibroblast-like cells, and production of collagens 1 and 3. These findings identify ATF6 as a cell-type-specific regulator of differentiation programs during lung aging and highlight the need to study ATF6 under defined physiological and pathological contexts before therapeutically targeting this pathway.

INTRODUCTIONNeuroticism is an established risk factor for Alzheimers disease (AD), yet the molecular mechanisms linking this personality trait to neurodegeneration remain poorly understood. METHODSWe leveraged single-nucleus RNA-sequencing data from longitudinal cohort studies of cognitive aging (n = 655) to investigate the mechanisms mediating the association between neuroticism and AD. RESULTSWe identified two genes associated with neuroticism, both of which are downregulated in excitatory neurons: ADRA1B and LY6E-DT. In addition, we found that neuroticism is associated with enrichment of a specific excitatory neuron subpopulation: Exc.12. Further analysis revealed that Exc.12 partially mediates the relationship between neuroticism and AD, accounting for 12.2% of the total effect. DISCUSSIONThe dysregulation of excitatory neurons may represent a key cellular change that links neuroticism to AD.