Aging Cell

Peripheral nervous system (PNS) ageing is marked by structural and functional decline, yet it remains unclear whether ageing constitutes a distinct biological programme or reflects a chronic injury-like state. To address this, we performed an unbiased, comparative molecular analysis of PNS ageing, neuroprotective dietary restriction (DR), and nerve injury. We conducted transcriptomic and proteomic profiling of peripheral nerves from young, old and geriatric mice fed ad libitum or subjected to long-term DR, and proteomics of nerves collected at multiple time points following injury. Age-associated molecular changes followed both linear and non-linear trajectories, and DR partially attenuated these ageing-related alterations. Notably, ageing-and injury-induced proteomic signatures showed considerable similarities, supporting the concept that an aged nerve resembles an injured nerve. Together, our study provides the most comprehensive molecular resource of PNS changes during ageing, DR, and injury, enabling the definition of key molecular signatures underlying PNS physiology. All datasets are integrated into the "PNS-omics Viewer", a Shiny web application designed to facilitate data mining of the herein presented datasets (tba).

Metabolic ageing and associated changes in lipid mobilisation have been most heavily studied in humans and model taxa, yet remain poorly understood in farmed animals, with potentially important uncharacterised implications for health and welfare outcomes in food production systems. Here, we study both processes in domesticated Atlantic salmon (Salmo salar), the worlds most commercially valuable farmed fish, comparing three stages of aquaculture production. Our sampling captures a key life-cycle change where juvenile fish transition from freshwater into seawater (smoltification), followed by the ongoing ageing process during a final period of growth in seawater. Integrating lipidomics and proteomics of visceral adipose and skeletal muscle tissue, we firstly identified a metabolic-ageing profile akin to that observed in humans, which was distinct from lipid-associated remodelling associated with earlier smoltification. This was marked by impaired triglyceride storage, dysfunctional autophagy-lysosomal pathways, inflammation, fibrosis and reduced pathogen clearance pathways in visceral adipose tissue. In skeletal muscle, ageing was accompanied by reduced metabolic flexibility together with triglyceride and fatty acid accumulation, depletion of phospholipids, and a reduction in free fatty acids required for ATP production. We go on to provide experimental in vivo evidence that dietary spermidine supplementation suppresses adipose inflammation and reverses age-associated metabolic flexibility by re-establishing the buffering role of adipose tissue and enhancing fatty acid metabolism in skeletal muscle. Importantly, spermidine appears to reprogram lipid flux to counter metabolic ageing. As farmed Atlantic salmon exhibit key features of metabolic ageing observed in humans that appear linked to its recent domestication history, this species offers a novel model for ageing related studies of vertebrate metabolism.

Frailty, defined by progressive loss of physiological resilience, neuromuscular function, and cognitive capacity, is a central manifestation of biological aging yet remains difficult to quantify in scalable experimental systems. Here, we introduce a Composite Frailty Index (CFI) in the house cricket (Acheta domesticus) that integrates automated measures of locomotion, exploratory behavior, and freezing into a unified, quantitative framework of functional decline. Ten behavioral parameters derived from automated open-field tracking, including locomotor performance, exploratory behavior, and freezing were integrated into the CFI. Locomotor states were classified using k-means clustering (k = 2) of velocity distributions, and all features were normalized to age- or treatment-matched reference populations, discretized into quintiles, and summed to generate a 0-40 frailty score. Aging cohorts (young adult: 4-6 weeks; geriatric: 10-12 weeks, N = 103) and pharmacological cohorts treated at mid-life (8-10 weeks) with rapamycin (14 ppm), acarbose (1000 ppm), or phenylbutyrate (1000 ppm) were evaluated (N = 122). Across chronological aging cohorts, CFI increased from young adults to geriatrics in both females (d = 1.14 [95% CI: 0.53, 1.76], P = 0.0003) and males (d = -1.17 [95% CI: -1.75 to -0.59], P < 0.0001). Using pharmacological intervention cohorts, mid-life rapamycin treatment reduced late-life frailty relative to controls in both females (d = -1.31 [95% CI: -2.09, -0.53], P = 0.0017) and males (d = -1.33 [95% CI: -2.09, -0.58], P = 0.0004), whereas acarbose and phenylbutyrate produced inconclusive effects (ds = -0.54 to -0.03; Ps > 0.05). Together, these findings establish the cricket CFI as a scalable, high-throughput platform for quantifying multidimensional functional aging and prioritizing candidate geroprotective interventions based on clinically relevant endpoints beyond lifespan.

Ageing is characterised by the accumulation of senescent cells. Owing to their irreversible cell-cycle arrest, these cells lack the capacity to replenish the stem cell pool and regenerate tissue, while their pro-inflammatory secretome propagates senescence in a paracrine manner. Much of the senescent phenotype has been attributed to dysregulated mTORC1 signalling, a key regulator of protein synthesis implicated in organismal ageing. Nonetheless, the mechanism underlying this dysregulation is poorly understood and limited to a few selected cell types. Here, we show that mTORC1 dysregulation is also a characteristic of senescent muscle precursor cells, and in contrast to reports in other cell types, senescent myoblasts do not rely on lysosomal nutrient liberation to sustain mTORC1 activity. Instead, they appear to depend on the PI3K/Akt pathway, which is upregulated in these cells. Exogenous antioxidants were identified to alleviate PI3K/Akt/mTORC1 signalling, while exogenous ROS has the capacity to activate mTORC1, supporting a model in which ROS acts upstream of this pathway in senescent myoblasts. Moreover, antioxidants were able to suppress the expression of pro-inflammatory cytokines and enhance the differentiation of senescent myoblasts. Interestingly, prolonged antioxidant treatment led to increased cell death in senescent but not proliferating myoblasts, suggesting they are more prone to reductive stress-induced cell death. We propose that, in vitro, the antioxidant capacity of many plant-derived compounds may underlie their reported benefits as therapeutics targeting senescent cells (senotherapeutics). Together, our findings provide novel insights into mTORC1-dependent regulation of the senescent phenotype and highlight the role of redox modulation in senotherapeutic strategies.

In humans, aging is associated with an increased risk of developing neurodegenerative diseases such as Parkinsons disease and Alzheimers disease. In neurons, the effect of aging on intrinsic molecular processes, and how they tie to age-related neurodegeneration remains unclear. Animal studies have shown that mitochondrial function decline, autophagy impairment and defective elimination of damaged mitochondria by mitophagy are all central features of neuronal aging. However, very few studies have investigated such events in human neurons, due to a lack of models showing aging features, therefore leaving a crucial need for a better understanding of the effect of aging on neuronal health. Here, we use direct neuronal reprogramming, which maintains signatures of cellular aging, to study the effect of aging on mitochondrial health and mitophagy in human neurons. We show age-related mitochondrial impairment, as well as accumulation of mitochondria targeted for degradation in autophagosomes and unacidified autolysosomes following mitophagy induction in neurites of induced neurons (iNs) derived from older donors. These impairments culminate into incomplete elimination of damaged mitochondria. By showing age-dependant mitophagy impairment in human neurons, this study paves the way for more in-depth mechanistic studies that would allow for the identification of therapeutic targets for anti-aging treatment and in the context of age-associated neurodegenerative diseases.

Aging is one of the most important risk factors for Intervertebral disc degeneration, a major contributor to chronic low back and neck pain. Recently, we demonstrated a critical role for SIRT6, a nuclear NAD- dependent deacetylase and defatty acylase, in maintaining intervertebral disc health with aging. We therefore investigated whether pharmacological activation of SIRT6 improves disc health by examining the spinal phenotype of 24-month-old mice treated with the well-studied agonist MDL-800 for 6 months. Histological studies revealed healthy disc tissue morphology, enhanced cell viability, and lower degeneration scores in mice treated with MDL-800. Further mechanistic insights revealed that SIRT6 activation decreased H3K9ac levels, improved cell phenotype and matrix quality, and reduced the SASP burden in the disc, characterized by decreased abundance of p21, IL-6, and TGF-{beta}. Tissue RNA-Seq, in vitro measurements of histone 3 modifications, and multi-omics ATAC-seq/RNA-seq analyses revealed that SIRT6 activation altered the epigenetic status (decreased H3K9ac, H3K36me3, and H3K79me2) and transcriptomic landscape of disc cells. Notably, MDL-800 treatment increased LC3II levels in disc cells, indicating enhanced autophagic flux. Furthermore, plasma LC-MS and nuclear magnetic resonance (NMR) analyses revealed minimal systemic metabolomic changes. ScRNA-sequencing of splenocytes and bone marrow cells and systemic cytokine profiling indicated good tolerance and the absence of systemic inflammation following MDL-800 treatment. Our study demonstrates that SIRT6 activation modulates autophagy, cell senescence, and matrix homeostasis in the disc, underscoring the feasibility of targeting SIRT6 activation as a promising pharmacological strategy to maintain disc health in the aging spine.

Age-related reductions in whole-muscle function are attributed, in part, to pronounced atrophy of muscle fibers expressing the fast myosin heavy chain (MyHC) II isoforms. Senescence, a state of irreversible cell cycle arrest that can be characterized by DNA damage ({gamma}H2AX) and chromatin remodeling (loss of nuclear HMGB1), may contribute to skeletal muscle aging. Muscle nuclei (myonuclei) maintain fiber size and function and could exhibit senescence-associated features; however, the prevalence of senescent myonuclei and whether they contribute to fast fiber atrophy in older adults remains unknown. Vastus lateralis biopsies from 20 young (19-34yr; 10 females) and 20 older (65-84yr; 10 females) adults were analyzed via immunohistochemistry for myonuclei positive for {gamma}H2AX ({gamma}H2AX+) and negative for HMGB1 (HMGB1-). MyHC II cross-sectional area (CSA) was [~]70% larger in young compared with old, whereas MyHC I CSA did not differ with age. The relative abundance of {gamma}H2AX+/HMGB1- myonuclei did not differ with age and was not associated with CSA in either fiber type. Single-nucleus RNA-sequencing corroborated no age-related difference in the prevalence of myonuclei with senescence-associated features. Myonuclear content of MyHC II fibers was [~]30% higher in young compared with old and was closely associated with CSA in both fiber types. Size-cluster analysis revealed a pronounced age-related leftward shift in MyHC II CSA that paralleled the reductions in myonuclear number, consistent with myonuclear loss. These data suggest that age-related fast fiber atrophy is not attributed to an increased prevalence of senescent myonuclei but instead occurs concomitantly with fiber type-specific myonuclear loss across the lifespan.

1Manual frailty index (FI) assessment in mice is a strong predictor of morbidity and mortality, and is frequently used in mechanistic and translational geroscience. However, it is labor-intensive, requires expert training, and is vulnerable to scorer variability. We previously developed a visual frailty index (vFI) that objectively predicts age and frailty using expert-defined, supervised behavioral features extracted from open-field videos. However, relying solely on human-defined features may miss subtle, latent behavioral signatures of aging. Here, we test whether unsupervised behavioral discovery using Keypoint-MoSeq (KPMS) could uncover these hidden signatures and improve the prediction of aging-related outcomes. Using a large dataset of isogenic C57BL/6J (B6J) and genetically diverse Diversity Outbred (DO) mice, we find that unsupervised features are highly predictive of chronological age, biological frailty, and the proportion of life lived. Notably, while supervised features overall outperformed unsupervised features in these tasks, combining both feature sets yielded the highest predictive accuracy across all outcomes. Despite these improvements, models trained on either feature set failed to generalize across strains, confirming that behavioral manifestations of aging are strongly population-specific. These findings demonstrate that supervised and unsupervised machine vision provide complementary information, establishing a highly sensitive, scalable, and non-invasive framework for objective and scalable geroscience in rodents.

Perineuronal nets (PNNs), specialised extracellular matrix structures enriched in chondroitin sulphate proteoglycans (CSPGs), are key regulators of synaptic plasticity, learning, and memory. Aging is characterised by a shift in chondroitin sulphate composition toward increased chondroitin-4-sulfation (C4S) and reduced C6S, a pattern associated with declining cognitive flexibility. Here, we investigated how selective reduction of C4S affects PNN structure, PV-interneuron connectivity, and cognitive performance across the lifespan. Conditional deletion of the C4-sulfotransferase Chst11 markedly reduced C4S levels and diminished dendritic PNN complexity while preserving somatic PNN structure. This partial destabilisation of PNNs increased excitatory synaptic input onto PV interneurons in both young and aged mice, without major alterations in basal hippocampal transmission or long-term potentiation. Behaviourally, Chst11 knockout mice showed robust and persistent protection against age-related cognitive decline. Working memory performance remained stable across aging, short-term spatial memory was enhanced from early adulthood onward, and object recognition memory was significantly prolonged at all retention delays, even in old age. Sociability and social novelty preference were also preserved longer in aging knockouts compared with controls. These improvements occurred despite an overall preservation of PNN architecture, indicating that modifying sulphation rather than removing CSPGs is sufficient to enhance plasticity. Our findings demonstrate that reducing C4S through Chst11 deletion confers long-lasting enhancements in cognitive function and mitigates aging-related decline. Targeting CS-GAG sulphation patterns may therefore represent a promising strategy for maintaining cognitive resilience and restoring plasticity in aging or neurodegenerative conditions.

Human aging is the process through which numerous biological changes occur during life, affecting various processes. In some elderly individuals, this functional decline becomes more pronounced, leading to frailty, a condition characterised by reduced physiological reserves and increased vulnerability to stress. With the global rise of life expectancy, identification of biomarkers for healthspan and frailty are becoming more important. In this study, we directly compare two molecular readouts, namely the T cell receptor (TCR) repertoire and epigenetic clocks, on their ability to discern healthy aging. On blood samples from sixteen individuals, across age-matched healthy elderly and frail individuals, both TCR sequencing and epigenetic profiling were performed. A significantly higher TCR repertoire diversity in the CD4+ T cells differentiated the healthy elderly individuals from the frailty ones. Epigenetic clock signatures of biological relative to chronological ageing rate, did not show a clear difference between both groups. However, when taking into account the CMV-serostatus, a significant increase in epigenetic aging could be observed in the CMV-seropositive individuals. Our results support a clear hypothesis on the role of CMV infection in the healthy aging of the immune system. In healthy elderly, CMV is typically controlled by CD4+ T cells, however, in the frail elderly, the burden of managing the infection shifts to the CD8+ T cells. This change is marked by two key changes: a decrease in TCR diversity for seropositive individuals compared to seronegative individuals, as well as an increase in the fraction of CMV-associated TCRs within the CD8+ T cells. These findings contribute to our understanding of aging and provide insight into how CMV-infection may affect healthy aging and frailty. They also underline the crucial role of the immune system in healthy aging and the value of further investigating ageing-related health/disease patterns in the TCR repertoire to determine healthspan/lifespan.

Ageing is considered as a process were molecular, cellular and tissular function is impaired. One classic cellular phenotype that increases during ageing is cellular senescence. Upon senescence, the cells stop proliferating and release a variety of cytokines, chemokines and extracellular vesicles. However, the implication of biomolecules derived from lipids such as resolvins are not well characterised in senescence and ageing. Here, we find that the resolvin E and D biosynthesis pathway is activated as observed by an increase in their corresponding receptors and enzymes implicated. Furthermore, knockdown of the resolvins E and D receptors impairs the induction of senescence. This pathway is conserved not only during senescence but also in fibroblasts derived from aged human individuals, aged mice and during other inflammatory responses. A metabolomics analyses shows an increase in different precursors of resolvins in senescence. In accordance with prior data, we find that small extracellular vesicles (sEV) isolated from young human donors ameliorate inflammation and the biogenesis of resolvins both in different cell models and in aged mice. In summary, here we present data showing that the resolvins biogenesis pathway is induced in ageing and cellular senescence.

DNA methylation changes predictably with age across taxa, but in most species these patterns are confounded by genetic variation. As a result, age-predictive methylation models have mostly been developed in genetically heterogeneous, cross-fertilizing organisms, limiting inference about epigenetic aging per se. Disentangling epigenetic and genetic effects is therefore essential for understanding aging, adaptation, and evolution. Here, we exploit the mangrove rivulus (Kryptolebias marmoratus), one of only two known self-fertilizing vertebrates (together with K. hermaphroditus), to examine epigenetic aging in a system of naturally occurring near-isogenic individuals. Using reduced-representation bisulfite sequencing of 90 brain samples spanning 60-1100 days of age, we identified 40 CpG sites whose methylation levels predict chronological age with high accuracy (R2 > 0.96, Median Absolute Error of 28.7 days). These 40 age-associated CpG sites were linked to nearby genes with known roles in cellular maintenance and neurodegeneration. These include genes implicated in aging and neurodegenerative processes across vertebrates, such as lamin-A, the aryl hydrocarbon receptor, and genes associated with Alzheimers disease in humans. By leveraging a self-fertilizing vertebrate, this study demonstrates that DNA methylation undergoes consistent, age-associated changes across the lifespan in the near absence of genetic variation. Our results establish self-fertilizing vertebrates as powerful models for disentangling epigenetic aging from genetic effects and provide a foundation for comparative and evolutionary studies of aging. STATEMENTSO_ST_ABSData availabilityC_ST_ABSThe datasets generated and/or analyzed during the current study are available in the NCBI repository, under the ID BioProject ID PRJNA1331489. Funding statementThis work was supported by the FNRS project J.0189.24 "Epigenome Stability in Mangrove Rivulus". Ethics approvalAll research reported in this manuscript was conducted in accordance with institutional and national ethical standards for animal care and use. Experimental procedures involving Kryptolebias marmoratus were approved by the Animal Experimentation Ethics Committee (UN PM KE 23/020). Authors contributionsJB designed the experimental process, conceptualized the article, generated and analyzed the data and wrote the manuscript. FS designed the experimental process, reviewed and edited the manuscript and did validation and supervision. All authors read and approved of the final manuscript. Conflict of interestThe authors declare that they have no competing interests. Patient consent statementNot applicable. Permission to reproduce material from other sourcesNot applicable. Clinical trial registrationNot applicable.

Age-related cognitive decline in learning and decision-making may arise from increased variability of neural responses. Here, we investigated how ageing affects behavioral and neural variability by recording >18,000 neurons across 16 brain regions (including cortex, hippocampus, thalamus, midbrain, and basal ganglia) in younger and older mice performing a visual decision-making task. Older mice showed more variable response times, reproducing a common finding in human ageing studies. Ageing globally increased firing rates, post-stimulus neural variability (quantified using the Fano Factor), and decreased variability quenching-the reduction in neural variability upon stimulus presentation. Older animals showed higher overall firing rates across areas of visual and motor cortex, striatum, midbrain, and hippocampus, but lower firing rates in thalamic areas. Age-related attenuation in stimulus-induced variability quenching was most prominent in visual and motor cortex, striatum, and thalamic area. These findings show how large-scale neural recordings can help uncover regional specificity of ageing effects in single neurons, ultimately improving our understanding of the neural basis of age-related cognitive decline.

Aging is associated with a progressive loss of skeletal muscle function, known as sarcopenia; however, the molecular mechanisms coordinating cellular stress responses and structural adaptations permissive of sarcopenia remain incompletely understood. In our previous studies, we found aging differentially impacted mitochondrial networks by muscle, suggesting unique stress thresholds and response activation. Here, we investigate the role of activating transcription factor 4 (ATF4), a master regulator of the integrated stress response (ISR), in aged quadriceps muscle using complementary patient and aging mouse models. Older adults exhibited a marked decrease in aerobic capacity, muscle strength, and endurance when compared with young participants. These results paralleled findings in aged mice, with significant loss of muscle mass across multiple hindlimb muscles. Ultrastructural analysis revealed substantial age-related changes in mitochondrial morphology, including increased volume, surface area, and branching index, as well as a shift toward larger, more complex mitochondria. Our data indicate that ATF4 binds directly to the promoter region of the gene encoding TFAM, suggesting a transcriptional regulatory relationship to support DNA stability. These structural and transcriptional changes likely impair oxidative capacity and drive a feed-forward cycle of mitochondrial dysfunction and ISR activation. Our findings indicate that ATF4 coordinates transcriptomic and structural adaptations in aging muscle, identifying the ISR pathway as a potential therapeutic target for preserving muscle function in older adults.

BackgroundAdvanced ageing has been associated with an increased risk of serious disease endpoints in people with HIV (PWH). We conducted a longitudinal analysis to assess advanced proteomic ageing during untreated HIV infection and the effect of antiretroviral therapy (ART) on it by comparing the plasma proteome before and after ART initiation. Methods416 protein abundance estimates were used to train a linear regression model predicting chronological age on 727 samples from Swiss HIV Cohort Study (SHCS) participants on long-term suppressive ART (median ART duration, 11.7 years). Advanced ageing was defined as age predicted by the proteomic ageing clock (PAC) minus chronological age. We evaluated the effect of successful ART on advanced proteomic ageing in an independent set of 80 PWH who had 4 longitudinal samples available, that is 2 samples during untreated HIV infection (>3 years apart, median interval between samples, 8{middle dot}08 years (IQR 4{middle dot}83-11{middle dot}09)) and 2 samples during suppressive ART (>3 years apart, median interval between samples, 9{middle dot}81 years (7{middle dot}16-11{middle dot}01)). FindingsIn the longitudinal test cohort, participants showed significantly higher proteomic age during untreated HIV infection than during suppressive ART, with a mean difference of 5.99 years (95% CI 4.25, 7.72), p = 0.0001. Thus, ART was associated with a marked reduction in proteomic advanced ageing. Although proteomic age remained higher than chronological age at all time points, linear interpolation of per-participant advanced ageing showed progressive normalisation towards chronological age during long-term suppressive ART. We validated these findings with our previously published epigenetic ageing study in the same cohort and extended those observations to the functional proteome, showing that proteomic data can capture acute immune signatures. Further, mediation analysis suggests that reversal of advanced ageing under ART is not driven by CD4+ or CD8+ T cell counts, indicating that the proteome captures ageing signals beyond immune reconstitution. InterpretationsIn a longitudinal study spanning more than 17 years, the advanced proteomic ageing observed during untreated HIV infection showed immediate and persistent deceleration under suppressive ART, demonstrating the importance of minimising the duration of untreated HIV infection. FundingSwiss HIV Cohort Study Research in contextO_ST_ABSEvidence before this studyC_ST_ABSCurrent guidelines recommend prompt antiretroviral therapy (ART) initiation after HIV diagnosis, making it now difficult to quantify the potential effects of untreated HIV on advanced ageing. Biological ageing clocks serve as proxies for individual-level disease impact and are associated with serious disease endpoints in people with HIV (PWH). We searched PubMed for English-language reports from database inception to February 24, 2026, using combinations of the terms "HIV infection," "antiretroviral therapy," "proteomic ageing," "proteomic clocks," "proteomic advanced ageing," and "age advancement." We identified one study reporting that virally suppressed HIV infection is associated with a significant increase in proteomic ageing. We have previously shown in the well established longitudinal SHCS cohort with blood samples spanning >17 years and available both pre-ART and post-ART, that telomere length attrition and epigenetic ageing is accelerated during untreated HIV infection and that initiation of successful ART is associated with a significant reduction in accelerated ageing. Added value of this studyTo our knowledge, this is the first study to examine the impact of untreated HIV on the proteome using a proteomic ageing clock. Our results demonstrate that proteomic age is elevated before ART initiation and decreases significantly following successful viral suppression on ART. This reduction was not mediated by standard immunological markers (CD4+ and CD8+ T-cell counts,CD4:8 ratio). Compared with our previous epigenetics study, the proteome appears more responsive: advanced ageing increases more sharply during untreated HIV infection and is faster to decrease after ART initiation. Implications of all the available evidenceOur findings demonstrate the importance of prompt ART initiation for PWH and reveal HIV-related ageing signals in the proteome that extend beyond immune reconstitution. Further, given the established association between advanced ageing and serious disease endpoints, this evidence motivates future studies into persistent advanced ageing to enable identification and stratification of high-risk PWH.

Atherosclerosis (AS) is a chronic inflammatory disease closely linked to vascular senescence, yet the specific molecular mechanisms connecting aging processes to AS pathogenesis remain incompletely understood. This study integrated transcriptomic data from GEO datasets (GSE100927 and GSE43292) to identify vascular aging-related differentially expressed genes (VARDEGs). Following batch effect correction, 28 VARDEGs were screened and subjected to functional enrichment, protein-protein interaction (PPI) network analysis, and immune infiltration assessment. Seven hub genes (MMP9, APOE, TNF, ICAM1, PPARG, CYBA, and NCF2) were identified and experimentally validated via qRT-PCR, confirming their significant upregulation in AS samples. Receiver operating characteristic (ROC) analysis demonstrated high diagnostic accuracy for six of these genes (AUC > 0.7), with TNF exhibiting superior performance. Immune infiltration analysis revealed profound alterations in 28 immune cell types, particularly monocytes and T cells, which correlated strongly with hub gene expression. Furthermore, single-cell RNA sequencing analysis (GSE184073) localized the expression of core genes predominantly to monocytes and T cells, highlighting TNF overexpression in T cells as a potential critical driver. Finally, molecular docking simulations suggested that curcumin exhibits strong binding affinity to these hub genes, particularly PPARG, providing a mechanistic basis for its therapeutic potential. Collectively, this study elucidates the landscape of vascular aging-related genes in AS, identifies novel diagnostic biomarkers, and proposes potential therapeutic targets involving immune modulation and natural compounds.

Diet is an essential factor influencing biological aging, yet few exsiting dietary indices were specifically developed to target biological aging. We developed a data-driven food-based Empirical Dietary Index for Slower Epigenetic Aging (EDISEA) in the US Health and Retirement Study (HRS, n=7,398), which predicted deceleration of GrimAge, an established DNA methylation-based epigenetic clock. Participants in the highest versus lowest EDISEA quintile had 4.65-year deceleration in GrimAge (P value <0.001). We externally validated EDISEA in an independent US cohort (n=23,830), where it showed consistent associations with several epigenetic clocks and lower all-cause mortality risk. In HRS and a UK aging cohort (n=4,895), EDISEA was associated with lower risks of several aging-related diseases and functional limitations. Outcome-wide analyses in the UK Biobank (n=187,035), together with integrative proteomic, metabolic, and neuroimaging assessments, revealed biological signatures of EDISEA implicating broad vascular, inflammatory, metabolic, and brain-structural pathways through which EDISEA was associated with biological aging. EDISEA provides a scalable, biologically anchored tool to inform the development of precision nutrition strategies aimed at slowing epigenetic aging and mitigating aging-related disease burden.

Ageing biomarkers can predict mortality risk beyond chronological age. Recently, plasma proteins were used to estimate the biological ages of eleven human organs, including the brain, heart, liver, kidneys, and pancreas. Accelerated organ ageing is linked to higher all-cause mortality; however, systematic benchmarking against established ageing biomarkers is lacking. Here, we pursued two complementary aims. First, we benchmarked proteomic organ ages against multimodal ageing biomarkers for all-cause mortality (444 deaths; [&le;]17-year follow-up) using Cox regression in 861 Lothian Birth Cohort 1936 (LBC1936) participants. Ageing biomarkers included epigenetic age (GrimAge2), telomere length, neuroimaging, general cognitive function (g), and physical function (grip strength, walk time, and respiratory function). Among proteomic organ ageing biomarkers, accelerated liver (HRperSD [95%CI] = 1.43 [1.30-1.58]), immune (1.42 [1.29-1.57]), and heart (1.38 [1.25-1.53]) ageing were most strongly associated with higher mortality risk. However, GrimAge2 acceleration, total brain volume (TBV), grey matter volume, respiratory function, and g exhibited higher hazard estimates (HRperSD = 1.44-1.62) than organ ageing biomarkers. In a Cox model including all biomarkers, only TBV, white matter hyperintensity volume, g, and walk time associated with mortality. Second, survival analyses of SomaScan 11K plasma proteins identified 202 proteins associated with mortality and enriched for the liver and immune-related biological processes, with the strongest effects observed for GDF15 (HRperSD [95%CI] = 1.53 [1.37-1.72]), CST3 (1.48 [1.29-1.69]), and COL18A1 (1.47 [1.30-1.68]). These findings provide a systematic, cross-modal benchmarking of proteomic organ ages against established ageing biomarkers and highlight plasma proteomic signatures of mortality. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/26347914v1_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@188af79org.highwire.dtl.DTLVardef@b86609org.highwire.dtl.DTLVardef@32f90aorg.highwire.dtl.DTLVardef@7c1e66_HPS_FORMAT_FIGEXP M_FIG C_FIG

Aging is the gradual accumulation of structural and functional changes in an organism over time, including immune remodeling and a progressive increase in basal inflammation, or inflammaging. The mTOR pathway is a central driver of aging-related diseases, such as cancer, chronic inflammation and neurodegeneration; pharmacological inhibition with rapamycin is associated with reduced aged-related morbidity and increased lifespan across species. Nonetheless, concerns remain about the use of rapamycin, a well-established immunosuppressant in transplant medicine, as an anti-aging intervention. Here, we evaluated the impact of prolonged low-dose dietary rapamycin on the aging immune system. Treatment did not significantly alter innate or adaptive immune cell populations, including brain resident microglia; however, it attenuated the age-associated accumulation of IL-17-producing {gamma}{delta} T cells, particularly in the peritoneal cavity. After a peripheral inflammatory LPS challenge, circulating IL-17 levels were significantly reduced and correlated with an attenuation of microglia inflammatory phenotype. These findings suggest that prolonged low-dose rapamycin exposure exerts minor systemic immune changes, while selectively limiting age-related {gamma}{delta} T cell expansion and neuroinflammation associated with systemic inflammation.

Age-related hearing loss (ARHL), or presbycusis, is one of the most prevalent sensory deficits in older adults and has been increasingly implicated in cognitive decline and dementia. This study characterizes ARHL in a rhesus macaque model by combining histological, physiological, and cognitive assessments. Aged macaques exhibited progressive cochlear degeneration, with marked outer hair cell loss at mid-to-high frequencies, elevated auditory thresholds, reduced distortion product otoacoustic emissions, and impaired auditory brainstem responses including amplitude reduction, latency prolongation, and diminished temporal precision. Despite modest reductions in inner hair cell ribbon synapse counts, hypertrophic changes were observed. These auditory deficits correlated with subtle impairments in visual working memory, as measured by a delayed match-to-sample task, underscoring a potential sensory-cognitive link. By capturing cross-domain aging markers in a translationally relevant primate model, this work lays a foundation for mechanistic studies and therapeutic interventions targeting both hearing and cognition in aging populations.