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.

Earlier menopause is a risk factor for several age-related diseases, including dementia. The biological pathways linking menopause timing to later-life brain aging are not understood. Leveraging large-scale plasma proteomics in postmenopausal women from the UK Biobank (N=15,012), earlier menopause was associated with upregulation of pro-inflammatory and extracellular matrix degradation pathways, plus accelerated aging across proteomic clocks of organ and cellular aging, including brain and oligodendrocyte aging. Elevated GDF15, a canonical aging marker, was the top protein correlate of earlier menopause. We observed robust replication of menopause timing proteomic shifts in the Womens Health Initiative Long Life Study (N=1,210). In UKB, proteins associated with earlier menopause, including GDF15, exhibited concordant associations with incident dementia risk and brain atrophy, cerebral small vessel disease burden, and white matter microstructural integrity. Collectively, our findings identify proteomic signatures linking ovarian aging to brain aging, providing a framework to inform interventions to reduce dementia risk.

BackgroundForeign bodies (FBs) can cause obstruction, infection, or injury, yet comprehensive global assessments remain limited. This study evaluated the burden of FBs from 1990-2021, projected trends to 2050, and identified high-risk populations. MethodsUsing Global Burden of Disease 2021 data, we estimated age-standardized incidence ratio (ASIR), death ratio (ASDR), and disability-adjusted life years (DALYs) by age, sex, and region. Temporal trends were assessed with estimated annual percentage change (EAPC) and Joinpoint regression; projections applied Bayesian age-period-cohort models; decomposition quantified the effects of aging, population, and epidemiological change. ResultsFrom 1990-2021, global ASIR declined from 660.75 to 561.16 per 100,000 (EAPC: -0.84), ASDR from 2.11 to 1.41 (-1.47), and DALYs from 145.14 to 77.87 (- 2.13). Males had consistently higher burden (2021: 725.96 versus 394.11 per 100,000 in females). Children under 5 and adults over 80 bore the highest risks, with intraocular FBs dominating incidence and pulmonary aspiration/airway FBs driving mortality. Western Europe had the highest ASIR, Andean Latin America the highest ASDR. Since 2019, the onset of the COVID-19 pandemic, intraocular FBs incidence has surged in East Asia, mainly China. Projections suggest ASIR will continue to rise through 2050, while ASDR and DALYs continue to decline, driven by global population growth (187.27%) and aging (46.82%) but offset by epidemiological improvements (-134.09%). ConclusionsDespite long-term declines, FB incidence is rebounding, with marked disparities across sex, age, and region. Targeted interventions, including workplace safety, pediatric and geriatric care, and region-specific policies, are needed to mitigate risks and reduce inequalities.

Background: While genetic factors strongly influence brain aging trajectories, variants conferring cognitive resilience remain poorly characterized. The neurokinin-3 receptor (NK3-R), encoded by Tachykinin Receptor 3 (TACR3), modulates cholinergic signaling in memory circuits vulnerable to aging. Previous studies linked the non-WT expression of the TACR3 variant rs2765 with cognitive decline and reduced volume of the hippocampus and basal forebrain, but systematic replication and mechanistic validation were lacking. Methods: We investigated rs2765 in the preregistered AgeGain cohort of cognitively healthy older adults (n=188) with independent validation in the ADNI cohort (n=809) which includes persons with and without Alzheimers Disease (AD) that show healthy cognition, mild cognitive impairment or dementia. Analyses integrated structural neuroimaging, longitudinal cognitive assessments, epigenetic aging (PhenoAge), genome-wide methylation profiling, and mechanistic validation through luciferase assays and cross-species protein expression studies. Results: The infrequent protective rs2765 WT variant, found in 12.8% of Europeans, conferred 49% slower cognitive decline (p = 0.002) for amyloid-positive individuals of the ADNI cohort and 3.7 years younger epigenetic age (p = 0.013, 95% CI: 0.79-6.67 years) in the cognitively healthy AgeGain cohort. WT carriers showed larger hippocampal and basal forebrain volumes across cohorts, with Allen Brain Atlas integration revealing these outcomes to occur exclusively in regions where TACR3 expression positively correlated with gray matter volume. Mechanistically, the non-WT variant ameliorated RBMX-mediated post-transcriptional regulation, reducing NK3-R protein expression by 25-40% in vitro and ex vivo murine brain slice models. Senescence-accelerated mice exhibited reduced endogenous NK3-R expression, phenocopying the predicted functional consequences of the variant. In AgeGain participants, genome-wide methylation profiling identified 2,313 differentially methylated CpGs affecting 228 pathways spanning glutamatergic signaling, acetylcholine receptor pathways, chromatin remodeling, and angiogenesis, suggesting coordinated molecular reprogramming from synaptic function to systemic aging. Conclusions: rs2765 WT confers resilience to age- and AD-related cognitive decline through RBMX-dependent regulation of NK3-R expression, with effects of remarkable size cascading from memory to systemic aging. rs2765 genotyping could stratify individuals for NK3-R modulator therapy (e.g., fezolinetant or senktides) and identify those maintaining function despite pathological burden, complementing APOE-based risk assessment in precision geromedicine.

The postmenopausal ovary is commonly viewed as a passive organ, and its biology and cell composition remain incompletely characterized. Here, we generated a single-nucleus atlas of the aging postmenopausal human ovary comprising 439,011 nuclei across 64 ovarian samples from 28 donors. We resolved 37 fine cell states, revealing extensive stromal, vascular, and immune heterogeneity in the postmenopausal ovary. Aging was associated with stromal stress-state expansion, vascular and immune depletion, and enrichment of steroidogenic programs consistent with ovarian androgenization. Several major age-associated compositional shifts were supported in an independent GTEx ovary bulk RNA-seq cohort. Notably, the number of live births broadly opposed age-associated transcriptional and compositional remodeling. Together, our findings show that the postmenopausal ovary remains an actively remodeled aging tissue and that reproductive history leaves durable molecular and cellular imprints on ovarian aging.

Epidemiological studies link aging and autoimmune diseases to increased herpes zoster (HZ) risk, yet their shared genetic basis remains unresolved. Here, we integrated large-scale genome-wide association studies (GWAS) of a multivariate aging latent factor (mvAge), rheumatoid arthritis (RA, representing autoimmunity), and HZ with multi-omics quantitative trait loci. Using linkage disequilibrium-aware colocalization and Mendelian randomization (MR), we identified a shared pleiotropic major histocompatibility complex (MHC) signal, tagged by rs1800628. Phenome-wide association studies (PheWAS) and network analyses revealed that the signal drives systemic immune remodeling, characterized by increased pro-inflammatory mediators, elevated T-cell regulation markers, and reduced lymphocyte counts. This pleiotropic genetic variation may alter the lifelong immune regulatory trajectory, accelerating aging and predisposing individuals to both autoimmunity and VZV reactivation. These findings support a life-course "high inflammatory burden-compensatory immune tolerance dysregulation" model that mechanistically underpins the epidemiological overlap of aging, autoimmunity, and HZ, providing a conceptual framework for early immune-rebalancing interventions.

BackgroundEpigenetic clocks are DNA methylation-based biomarkers increasingly used in aging research and clinical trials. A recent assessment of 18 clocks across multiple short-term perturbations concluded that most demonstrate only moderate biological reliability, raising concerns about their translational utility. However, epigenetic clocks differ substantially in their construction and in the biological signals they capture, and their sensitivity to physiological perturbation may not be a flaw but a consequence of the construction. To understand this more clearly, we undertook a focused investigation of biological reliability for a single, well-characterised perturbation, an overnight fast followed by acute refeeding, examining how and why clock estimates may shift with physiological state. MethodsWe evaluated 24 epigenetic clocks spanning five construction categories - first and second generation classical clocks (eg. Horvath, Hannum, PhenoAge), the PC versions of the classical clocks, SystemsAge organ-system clocks, mortality-trained clocks (GrimAge, PCGrimAge, OMICmAge), pace of aging clocks (DunedinPACE) and the IntrinClock, across three datasets: a within-person paired fasting design (n = 15 pairs), a cross-sectional cohort of fasted vs non-fasted (n = 2,895), and EPICv2custom technical replicates (n = 96 samples from 4 individuals). For each clock, we quantified the acute fasting effect with and without immune cell adjustment, decomposed between-person and within-person variance at successive adjustment levels (Raw, EAA, IAA), and benchmarked biological variability against the technical measurement floor. ResultsFasting followed by acute refeeding was associated with group-level shifts of 0.5-3 years in immune-sensitive clocks, while within-person reliability remained high (Raw clock ICC median ~0.96). These observations are compatible because fasting effects are small relative to the age-driven between-person variance that dominates the ICC denominator. The magnitude of the observed shift varied by clock. PC transformations showed larger effects than their classical counterparts in the paired cohort (PC Hannum -2.03 vs. Hannum -1.37 years; PC PhenoAge > PhenoAge; PC Horvath > Horvath), SystemsAge showed the largest effects (1.15-2.9 years younger when fasted), and mortality-trained clocks (GrimAge V1/V2, OMICmAge) and DunedinPACE showed no detectable acute effect (all FDR p > 0.10). Immune cell adjustment attenuated or eliminated the fasting effects in sensitive clocks (PC Hannum 88% attenuation; SystemsAge Blood 99.7%); no clock retained a significant fasting effect after FDR-corrected immune adjustment in either cohort. Within the cross-sectional cohort, a clocks immune content, which is the fraction of its age-independent variance explained by immune cell composition, was correlated with the degree to which immune adjustment attenuated its fasting effect (r = 0.68, p = 0.003). IntrinClock, designed to exclude immune-variable CpGs, showed no fasting effect in either cohort (immune R2 = 3.2%), serving as a negative control. Technical replicates confirmed near-perfect measurement reproducibility (median Raw ICC > 0.97), establishing that variance in fasting pairs reflects biology, not noise. Immune-adjusted ICCs behaved differently across clocks in ways consistent with their composition: for clocks where fasting generated within-person variance, immune adjustment removed it and ICC increased (SystemsAge EAA 0.768 to IAA 0.913); for clocks unaffected by fasting, immune adjustment removed between-person structure and ICC fell substantially (OMICmAge 0.922 to 0.160), reflecting the estimation cost of fitting many immune cell predictors to stable residuals. Cross-sectional replication (n = 2,895) confirmed immune cell redistribution at scale. Mortality clocks reached significance cross-sectionally despite resistance to acute fasting. ConclusionsEpigenetic clock responses to an overnight fast followed by acute refeeding varied systematically by training category in our data. PC-based clocks, which concentrate correlated CpG variance including that associated with immune cell composition, showed the largest shifts; mortality-trained clocks showed no detectable acute effect. A framework that summarises a clock by its ICC alone, without identifying the biological source of its within-person variation, can misread structured, perturbation-driven biology as measurement noise. ICC is not a fixed property of a clock, it is shaped by the study design, the population heterogeneity, the perturbation, and the adjustment applied. We recommend that clock reliability be assessed on a perturbation-specific, clock-by-clock basis, with variance decomposition at each adjustment level and explicit benchmarking against technical replicates.

Behavioral and psychological symptoms of dementia (BPSD) are common, profoundly troubling to patients and caregivers, and difficult to treat, yet their molecular underpinnings remain poorly understood. Here, we generated a large brain proteomic dataset with nine BPSD domains assessed in life from 376 donors from three cohorts. Protein associations with BPSD were examined using complementary approaches -- domain-specific BPSD, multi-domain BPSD, and latent factor modeling -- and integrated via cross-cohort meta-analysis. Four proteins (NMT1, DCAKD, DNPH1, and HIBADH) were associated with anxiety in dementia and five proteins (ABL1, SAP18, PLXND1, CTRB2, and LDHD) with multi-domain BPSD or BPSD latent factors after adjusting for sex, age, and other covariates (FDR < 0.05). Additionally, eight protein co-expression networks were associated with BPSD across cohorts. Together, these results link BPSD to dysregulation of synaptic signaling, protein folding, and humoral immune response, providing a molecular framework for therapeutic discovery.

Cerebrovascular dysfunction emerges early in neurodegeneration, yet how vascular structure, blood-brain barrier (BBB) failure, and cognition are linked remains undefined. Using VesselPro, a whole-brain pipeline integrating perfusion-resolved 3D imaging with spatial proteomics, we mapped vascular aging across the mouse lifespan. We identify two discrete trajectories: a hypovascular state and a previously unrecognized hyper-vascular, BBB-compromised state, defined relative to a young-adult vascular baseline. The hyper-vascular trajectory, concentrated in the cortex and hippocampus, was associated with marked spatial memory impairment and pervasive BBB leakage. Spatial proteomics revealed a coordinated program involving angiogenic activation, endothelial stress, cytoskeletal remodeling, and inflammatory signaling. Cross-species comparison with human proteomic biomarkers from the UK Biobank showed strong alignment between the mouse hypervascular signature and vascular dementia risk, but minimal concordance with Alzheimers disease, defining a vascular-specific dementia endotype. Transient Tie2 activation with AKB-9778 attenuated this trajectory, improving vessel organization, BBB integrity, and memory performance. Our findings show that endothelial instability is a key mechanistic driver of this heterogeneous vascular aging state. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/720441v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@39494aorg.highwire.dtl.DTLVardef@faa4acorg.highwire.dtl.DTLVardef@1511dd5org.highwire.dtl.DTLVardef@7db29b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIVesselPro: we developed a pipeline for capturing perfused blood vessels in the brain: unexpected bifurcation in vascular aging: traditional hypovascular state and a novel, hypervascular, BBB-compromised state. C_LIO_LIHypervascular pathology: Linked the hypervascular profile in the cortex and hippocampus to spatial memory impairment, pervasive BBB leakage, and angiogenic inflammatory signaling. C_LIO_LIClinical endotype: Cross-species analysis via the UK Biobank confirms this hypervascular signature aligns with vascular dementia risk rather than Alzheimers disease. C_LIO_LIPharmacological stabilization: Demonstrated that Tie2 signaling activation (AKB-9778) improves the vessel organization, BBB integrity, and memory performance. C_LI

Genome-wide association studies have identified risk loci for aging brain disorders, but mechanistic interpretation depends on linking these loci to genes and to the tissues, cell types, and molecular modalities in which those genes act. Here we introduce FunGen-xQTL Multi-Brain (FGMB), a multi-context regulome-wide association atlas for transcriptome-wide association studies (TWAS) built from molecular datasets assembled by the ADSP Functional Genomics Consortium. FGMB provides cis-genetic prediction models for 17,375 protein-coding genes across 36 molecular datasets, 18 contexts, and 3 regulatory modalities, yielding more than 293,000 imputable gene-level or splice-event models. FGMB evaluates eight established and newer Bayesian or multivariate prediction methods, including cross-context models that borrow information across tissues and cell types. Applied to Alzheimer's disease, FGMB identified 327 TWAS associations and used joint fine-mapping of variants and predicted molecular traits to prioritize 146 gene--molecular-trait pairs, distinguishing regulatory associations from linkage disequilibrium (LD) hitchhiking.

Dietary restriction extends lifespan across model organisms, but the plasma molecular changes mediating this effect remain incompletely characterized. We present a longitudinal multiomic analysis of 2,234 plasma samples from 960 Diversity Outbred mice subjected to intermittent fasting or caloric restriction and followed to natural death. Using mass spectrometry, we quantified 1,512 metabolites, lipids, and proteins and mapped their associations with diet, age and longevity. DR-induced molecular changes scale with caloric intake and modulate inflammatory, lipid catabolism, and oxidative stress pathways. Aging showed a biphasic signature with sharp acceleration beyond 85% of lifespan, demarcating terminal decline. Mediation and survival modeling both identified superoxide dismutase (SODE) and vascular cell adhesion molecule (VCAM1) as top lifespan predictors. Genetic analysis revealed 9,599 QTL, nine of which coincided with previously identified lifespan QTLs, and were largely related to immune regulation. These findings provide a rich multiomic and genetic resource for the aging research community.

Aging is often associated with progressive tissue degeneration and chronic inflammation, yet the role of immune cells in mediating structural and functional decline in organs remains poorly defined. Here, we investigated immune-tissue interactions in the aged lung and identified emphysematous remodeling characterized by alveolar loss. Notably, aged lungs exhibited a marked expansion of tissue-resident lymphocytes (TRLs) with senescent features, accompanied by a significant reduction in alveolar stem/progenitor cell (AT2) abundance. In vivo adoptive T cell transfer and 3D immune-stem cell organoid assays revealed that these expanded TRLs suppressed AT2 growth via secretion of oncostatin M and interferon gamma. In vivo blockade of IL-7 receptor (IL-7R) reduced TRL accumulation in the lungs and ameliorated age-related emphysematous changes, including restoration of alveolar density. Our findings identify TRLs as key drivers of alveolar degeneration in aging and propose IL-7R inhibition as a therapeutic strategy to mitigate pulmonary decline. TeaserBlocking IL-7R clears harmful lymphocytes and helps rebuild the damaged air sacs of the aging lung.

Aging is a major driver of tissue senescence, but little is known about the development of age-unrelated tissue senescence. Here we show that nucleocytosolic acetyl-CoA deficiency in colon epithelial cells, caused by Acly ablation and bacterial depletion, triggers age-independent, p53-dependent colonic senescence leading to severe systemic inflammation. Acetate supplementation, acetate-producing bacterial transplantation, targeted depletion of senescent cells or treatment with lysine deacetylase inhibitors blocks colonic senescence and inflammatory injury. Spontaneous colonic senescence develops following simultaneous deletion of epithelial Acly and Acss2, confirming that microbe-derived acetate maintains the epithelial acetyl-CoA pool via ACSS2 to avert colonic senescence. Mechanistically, acetyl-CoA deficiency deprives a cohort of mitochondrial and nuclear proteins of acetylation, leading to increased oxidative stress and DNA repair stress that trigger cellular senescence. Among these proteins, ATP5F1A-K161 acetylation and H4-K5/8 acetylation are required to protect colonic epithelial cells from developing senescence. These observations unveil a previously unknown mechanism that governs colonic senescence.

Measured hospital AI deployment expanded between 2022 and 2024, but did the geography of access converge, and did persistent access deserts overlap with greater health burden? Using two waves of the American Hospital Association (AHA) Annual Survey linked to 2020 Census block-group populations, we estimate contiguous-U.S. coverage for 329.3 million residents and full-frame transition profiles for 334.7 million residents. Measured AI-enabled status is identified using five binary workforce/workflow AI-use items in 2022 and fourteen ordinal clinical and operational AI implementation items in 2024 (primary 2024 threshold: expanding or fully integrated). The share of hospitals reporting active AI deployment rose from 18.3% to 28.6%. Contiguous-U.S. coverage within a 30-minute drive increased from 67.0% to 76.1%, yet spatial inequality grew: the population-weighted Gini coefficient of access distances rose from 0.739 to 0.767. In the full transition frame, 45.1 million people newly crossed the 30-minute threshold, while 67.9 million remained outside it in both waves: 37.2 million experienced no travel-time improvement and 30.7 million improved but still did not cross the threshold. These findings reveal a diffusion paradox: measured expansion coexists with persistent and, by some measures, rising inequality in who benefits. The communities left behind are not randomly distributed; they are more rural, lower-income, higher-poverty, older, more uninsured, and carry higher baseline premature-mortality burden than persistently served communities. A pre-diffusion Years of Potential Life Lost (YPLL) check showed that the mortality-burden gradient was already present before the 2022-2024 diffusion window, supporting a burden-overlap interpretation rather than causal mortality evidence. O_TEXTBOXSignificance StatementUsing two AHA survey waves (2022-2024), we estimate contiguous-U.S. 30-minute coverage for 329.3 million residents and full-frame transition profiles for 334.7 million residents. Coverage rose from 67.0% to 76.1%, yet spatial inequality increased (Gini 0.739 to 0.767; bootstrap p < 0.05). In the full transition frame, 67.9 million people remained outside 30-minute access in both waves, including 37.2 million with no travel-time improvement. Persistently excluded communities also carried higher baseline premature mortality, and a pre-diffusion check showed that this gradient was already present before the 2022-2024 diffusion window, making the access pattern a health-equity concern rather than only a geography-of-technology finding. C_TEXTBOX

The development of minimally invasive multi-organ aging clocks, established through the deconvolution of plasma proteomics, has provided a convenient tool to assess the organ heterogeneity of aging. However, prior studies relied on bulk transcriptomic data for organ marker identification, which may lead to the potential misidentification of protein markers, and their research scope was largely confined to a few common diseases. To address these limitations, this study integrated multi-dimensional data to refine organ-enriched marker panels by incorporating organ-specific proteome information, and developed Proteome-Aware Organ Proxy Proteome Aging Clock (PAOPAC). PAOPAC exhibited decelerated biological age corresponding to improved physiological phenotypes across two independent external datasets, demonstrating its generalizability. We then leveraged PAOPAC to generate a comprehensive disease-aging landscape and to investigate the process of chronological and biological aging. Our analyses revealed that the majority of diseases are associated with an accelerated aging phenotype.

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.

The mutation accumulation (MA) hypothesis posits that somatic mutations progressively escape selection and degrade tissue function during aging. Direct tests of this idea have been limited by the difficulty of predicting, at scale, the molecular consequences of individual somatic variants. Here I use AlphaGenome, a sequence-to-function deep learning model, to systematically score the predicted transcriptional impact of somatic mutations under a nested series of designs spanning individual variants, co-occurring variant bundles, and real mutation catalogues. First, I characterize the genome-wide effect-size baseline by scoring 4,000 random single-nucleotide variants (SNVs) in colon tissue, together with 1-Mb-window combined-effect tests. Second, I extend this baseline to gene-body resolution with a 60-cell x 4,000-SNV simulation and pseudobulk RNA-seq aggregation. Third, I analyze the real somatic mutation catalogue of Cagan et al. (Nature, 2022), scoring 54,158 substitutions and 9,799 indels from 54 mouse colonic crypts plus three human samples, together with region- and gene-level enrichment tests against GENCODE. Across all analyses, both random and real somatic variants, including single-nucleotide variants and indels, produce predicted expression changes whose distributions lie three to four orders of magnitude below the tissues endogenous aging transcriptional program. These results argue against a simple, direct mutation-accumulation explanation for the age-associated transcriptional signature of colonic epithelium and redirect attention to epigenetic and regulatory mechanisms.

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.