Longevity Papers

Chronic systemic inflammation and DNA methylation changes are two major hallmarks of aging, yet their interaction is poorly known. We investigated the relation between circulating inflammatory proteome and epigenetic age acceleration as assessed by DNA methylation in four independent cohorts of different ages and health conditions. Epigenetic age scores known to predict human health span (GrimAge and PhenoAge) were more strongly associated with age-associated inflammatory proteins, frailty, and multimorbidity when compared to epigenetic age scores associated with lifespan (Horvath and Hannum). Mendelian randomization analyses showed that blood concentrations of important inflammatory cytokines associated with the interferon pathway (CXCL9, CXCL10, CCL11, and IL-18) increase with age and are causal drivers of epigenetic age acceleration and age-related diseases. Furthermore, aging was associated with dysregulation of cytokine production capacity in immune cells in response to microbial stimulation. These findings argue that the interferon pathway may represent a target for anti-aging interventions.

This study aimed to investigate the effects of Mediterranean and Western diet models on telomere length, oxidative stress, inflammatory markers, and total hippocampal cell count in rats.

The global aging population presents a pressing challenge, highlighting the urgent need for interventions that target the fundamental mechanisms of aging. Gene therapy, leveraging its success in treating monogenic and aging-related diseases such as progeria and neurodegenerative disorders, has emerged as a promising strategy. It holds the potential not only to mitigate specific age-related pathologies but also to robustly extend healthspan. Although preclinical studies have shown encouraging results in mitigating aging phenotypes across multiple organ systems such as nervous, muscular, circulatory, and immune systems, existing research remains fragmented. This review comprehensively synthesizes evidence supporting gene therapy as a systemic strategy to combat core aging processes, promote multi-organ rejuvenation, and prolong healthspan. A deeper understanding of the role of gene therapy in delaying aging and extending lifespan could provide critical insights to guide translational strategies and revolutionize the treatment of age-related decline. Furthermore, we critically examine the formidable barriers to clinical implementation, including immunogenicity, off-target effects, and the complex socioeconomic and regulatory hurdles that must be navigated to transition these therapies from bench to bedside.

Loss of proteostasis and the accumulation of insoluble protein aggregates are features of aging across model organisms and occur in all major age-related neurodegenerative diseases; yet how aggregation proceeds during normal human brain aging remains unknown. Here, using detergent-fractionation proteomics, we show that brain aging does not involve uniform aggregate accumulation; rather, the insoluble proteome undergoes asymmetric remodeling beginning in midlife, with maximum-stability aggregates declining sharply by old age and intermediate-stability aggregates accumulating progressively before accelerating after age 80. Intermediate-stability aggregates are prone to liquid-liquid phase separation and are enriched among Alzheimer's disease plaque and tangle constituents. Proteasome and cytosolic chaperone capacity predict individual differences in aggregate burden as strongly as chronological age, offering human-level evidence in support of therapies targeting these pathways. These findings establish aggregate remodeling as a feature of normal brain aging and position intermediate-stability aggregate accumulation as a molecular event on the path to neurodegenerative disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. Its core pathologies include the deposition of amyloid-β plaques, the formation of neurofibrillary tangles composed of hyperphosphorylated tau protein, chronic neuroinflammation, and neuronal loss. With the rapidly aging global population, the prevalence of AD continues to rise. Current pharmacological treatments offer only limited symptomatic relief and cannot modify the underlying disease trajectory, leaving a significant unmet clinical need. In this context, cell-based therapy has emerged as a promising therapeutic strategy, leveraging its unique multi-targeted and regenerative capacities. This review systematically examines the therapeutic potential of various cell types, including mesenchymal stem cells, neural stem cells, immune cells, and engineered cells. We elaborate on their mechanisms of action, which encompass neurotrophic support, immunomodulation, and clearance of pathological proteins. These concerted actions contribute to remodeling the hostile brain microenvironment and promoting neuroregeneration in AD. Although preclinical evidence is robust, the clinical translation of cellular therapies faces considerable challenges. These hurdles include selecting the optimal cell source, developing efficient delivery strategies, determining the ideal intervention timing, and establishing standardized manufacturing protocols. Looking forward, we discuss how the development of precise disease models, the integration of gene editing and engineering strategies, advances in combination therapies, and the establishment of personalized treatment regimens are poised to position cell therapy at the forefront of comprehensive AD management. These innovations hold new promise for achieving true disease modification.

The global incidence of chronic kidney diseases (CKD) continues to rise annually, with renal fibrosis (RF) identified as the primary pathological mechanism leading to end-stage renal disease. The senescence of renal tubular epithelial cells (RTECs) has been established as a significant factor driving the progression of RF. Cellular senescence represents a fundamental cellular response to stress, characterized by irreversible cell cycle arrest and the emergence of senescent secretory phenotypes (SASP). Traditional studies have predominantly treated RTECs as homogeneous entities, complicating the understanding of their functional differences throughout the aging process and their specific regulatory roles within the microenvironment. Recent advancements in Single-cell Sequencing (sc-seq) and Spatial Omics technologies have equipped researchers with robust tools to analyze the heterogeneous characteristics of aging in RTECs, identify their spatial distribution patterns, and elucidate the causal relationships with fibrosis. This article systematically reviews the application of sc-seq and spatial omics techniques in uncovering the aging heterogeneity of RTECs, while thoroughly analyzing the molecular characteristics and spatial distribution patterns of aging subpopulations, as well as the mechanisms by which they influence RF. These findings will offer new insights for further investigations into RF and CKD, providing a theoretical foundation and technical support for the precise diagnosis and targeted treatment of CKD.

Background Poor physical function has been associated with higher cardiovascular disease (CVD) risk. However, the association between physical function and atrial fibrillation (AF) remains understudied. The comprehensive investigation of the association between physical function and incident AF risk could highlight a novel target for AF prevention. Methods A total of 4,803 participants without diagnosed AF from the Atherosclerosis Risk in Communities (ARIC) Study cohort with physical function assessed in 2011-2013 were studied. Physical function was measured using Short Physical Performance Battery (SPPB), 4-meter walk time, and grip strength. Hospital discharge codes and death certificates were used to ascertain incident AF through 2022, and through 2020 for participants from Jackson. Cox regression was used to assess the association between physical function and incident AF risk, adjusting for multiple covariates. Z-score transformations were performed to identify the physical function measure most strongly associated with incident AF risk, and SPPB component analysis was performed to identify the most influential SPPB component. Results Mean age of the study participants was 75.1 {+/-} 5.0 years, with 41.2% being male participants and 22.2% being black participants. During a median follow-up of 9.2 years, there were 809 incident AF events. SPPB (HR: 0.93, 95% CI: 0.90-0.96, per 1-point increase) and grip strength (HR: 0.87, 95% CI: 0.78-0.96, per 10kg increase) were inversely associated with incident AF risk, while 4-meter walk time (HR: 1.08, 95% CI: 1.03-1.13, per 1-second increase) was positively associated with incident AF risk. SPPB had the strongest association with incident AF risk. Within SPPB, only the chair stand component was significantly associated with incident AF risk. Conclusions The findings suggest that better physical function is associated with reduced incident AF risk, with higher SPPB having the strongest association. Given the modifiable nature of physical function, these findings highlight a potential novel target for AF prevention in aging populations.

Air pollution and extreme heat are adverse health risks, especially for aging populations. However, the associations between air pollution, heat exposure, and cognitive impairment remain unclear. This study examines these associations in China and compares the period before and during the COVID-19 pandemic. We found that higher temperature, CO

Background: Among cardiac measures, diastolic parameters demonstrate the earliest and most consistent age-related changes. This can be leveraged to develop a continuous left ventricular (LV) Diastolic Age from routine echocardiographic parameters. Analogous to how epigenetic clocks weight molecular markers against mortality risk, we calibrated Diastolic Age by weighting echocardiographic features against the validated PREVENT-Heart Failure (HF) risk score. Methods: We analyzed 1,952 participants from the Project Baseline Health Study (median age 50 [36-64] years, 54% female). The measure was derived using partial least-squares regression anchored on PREVENT-HF and calibrated within a healthy reference subgroup. External validation was performed in the WASE (n=1,708) and Stanford Cardiovascular Aging (n=313) cohorts. Associations with ASE-defined LV diastolic dysfunction (LVDD), epigenetic clocks, and major adverse cardiovascular events (MACE) were examined. Results: Diastolic Age correlated strongly with chronological age (r=0.78) with robust external validation (WASE r=0.76; Stanford r=0.82; calibration slopes {approx}1.0). It increased progressively across grades of diastolic dysfunction and discriminated LVDD with an AUC of 0.89 (95% CI 0.87-0.92), and was independently associated with hypertension, diabetes, and elevated C-reactive protein. While correlated with the Levine (r=0.76) and Horvath (r=0.41) epigenetic clocks, residual analyses indicated that Diastolic Age captures a distinct cardiac-specific dimension of biological aging. Over median follow-up of 4.2 years, it independently predicted MACE (HR 2.30, 95% CI 1.70-3.18), with accelerated diastolic aging across all age groups among those with events. Discrimination was comparable to ASE-defined LVDD (C-index 0.83 vs. 0.82). Conclusion: Diastolic Age provides a continuous, echocardiography-derived measure of cardiac biological aging that complements categorical diastolic grading and epigenetic aging clocks, and independently predicts cardiovascular outcomes.

Identifying robust, non-invasive biomarkers of biological age is key to preventive medicine. While gut aging clocks exist, the oral microbiome remains underexplored as a quantitative biomarker. Using oral microbiome data from two NHANES cohorts (N = 4,675), we identified 64 age-dependent bacterial genera and developed a machine learning model predicting chronological age, with generalizability in an independent external cohort (N = 1,293). We derived an Oral Microbiome Aging Acceleration (OMAA) Score as the residual of predicted age against chronological age. The OMAA Score independently predicted all-cause mortality (HR = 1.05, P = 0.024) and frailty (OR = 1.05, P = 0.008), correlated with impaired kidney function (lower eGFR: β = -0.066, P = 5.22×10

Ageing leads to diurnal misalignment with a global reduction in physiological fitness, yet the mechanisms underlying such age-related diurnal reprogramming and its role in ageing remain poorly understood. Here we generate diurnal transcriptomes across eight peripheral tissues and reveal that disrupted redox oscillations are common diurnal alterations in organismal ageing. Restoring redox rhythms through the time-restricted application of antioxidants and pro-oxidants markedly improved glucose metabolism, motor performance and ageing-related characteristics of liver and skeletal muscle in male aged mice. Through multi-omics analyses we further reveal that restoring redox rhythms partially rejuvenates the hepatic transcriptome and chromatin accessibility in ageing-associated functional pathways and involves redox modification of CLOCK protein. Perturbing redox-sensitive cysteine 195 of CLOCK causes premature ageing phenotypes and hepatic reprogramming. Overall, our study reveals that redox rhythms ameliorate functional decline by modulating ageing-relevant reprogramming in liver and skeletal muscle and indicates that redox rhythm-based interventions might promote healthy ageing.

ImportanceAge-related eye diseases, such as cataract, glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR), are leading causes of irreversible vision loss globally. Chronic inflammation is a shared pathogenic pathway, but the role of systemic inflammatory drivers like clonal hematopoiesis of indeterminate potential (CHIP) is unknown. ObjectiveTo investigate the association of CHIP, including its major genetic subtypes and clone sizes, with the risk of four major age-related eye diseases. Design, Setting, and ParticipantsThis was a prospective cohort study conducted using data from the UK Biobank, a large-scale, population-based cohort. A total of 436,469 participants free of the four eye diseases at baseline were included in the analysis. Data were collected from 2006 to 2010, with follow-up extending to March 2022. ExposuresCHIP status was ascertained from whole-exome sequencing data, defined by the presence of a somatic driver mutation with a variant allele fraction of 2% or greater. Main Outcomes and MeasuresThe primary outcomes were incident cases of cataract, glaucoma, AMD, and DR, identified through linked electronic health records. Associations were assessed using multivariable Cox proportional hazards regression models. ResultsOf 436,469 participants (mean [SD] age, 56.4 [8.1] years; 54.5% women), 14,110 (3.2%) had CHIP. Over a median follow-up of 13.1 years, CHIP was significantly associated with an increased risk of incident cataract (Hazard Ratio [HR], 1.08; 95% CI, 1.03-1.14), AMD (HR, 1.12; 95% CI, 1.04-1.21), and DR (HR, 1.41; 95% CI, 1.20-1.64). No significant association was found with glaucoma (HR, 1.08; 95% CI, 0.99-1.17). The risk for AMD was primarily associated with smaller clones (VAF <10%), while the risk for DR was highest with non-DNMT3A mutations. Systemic inflammation, particularly neutrophil count, partially mediated the associations. Conclusions and RelevanceIn this study, CHIP was independently associated with a higher risk of developing cataract, AMD, and DR, but not glaucoma. These findings establish a link between hematopoietic somatic mutations and the pathogenesis of several major age-related eye diseases, suggesting that CHIP-driven inflammation is a potential target for risk stratification and prevention. Key PointsO_ST_ABSQuestionC_ST_ABSIs clonal hematopoiesis of indeterminate potential (CHIP) associated with the risk of major age-related eye diseases? FindingsIn this cohort study of 436,469 participants, CHIP was associated with an increased risk of incident cataract (HR, 1.08; 95% CI, 1.03-1.14), age-related macular degeneration (HR, 1.12; 95% CI, 1.04-1.21), and diabetic retinopathy (HR, 1.41; 95% CI, 1.20-1.64), but not glaucoma. MeaningThese findings identify CHIP as an independent, non-ocular risk factor for cataract, AMD, and diabetic retinopathy, suggesting that systemic inflammation driven by CHIP contributes to the pathogenesis of these conditions and may represent a novel target for preventive strategies.

Understanding age-related cellular dysfunction in the brain is essential for developing strate-gies to promote healthy ageing. Towards this aim, we took advantage of a previously estab-lished mild dissociation method to profile cells in the cerebral cortex grey matter of adult and aged mice. This revealed glial cells with largely up-regulated and other glia and neurons with largely down-regulated gene expression upon ageing. Astrocytes were involved in increased interactions with microglia and decreased interaction with neurons, highlighting potent age-induced changes in their regulatory roles. Single cell RNA-seq and single nuclei multiome analysis of astrocytes uncovered down-regulation of Wnt-signalling with increased expression of its inhibitors and reduced RNA and protein levels of its effectors JunB/D, acting down-stream of Wnt signalling in ageing. This was confirmed by RNA-scope and immunostainings, as well as in human data. Notably, injection of JunD-expressing viral vectors in astrocytes increased their proliferation and HMGB1 levels in the aged brain, indicative of a more youthful astrocyte state.

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.

Antibody-secreting cells (ASCs) provide humoral immunity that can mediate lifelong protection against pathogens. Current classifications cannot delineate the heterogenous functionalities, tissue residencies, and lifespans of human ASC subsets, impeding clinical translation. We applied multi-omic sequencing, spatial proteomics, and functional assays to discover and characterize human bone marrow (BM) ASC subsets. We identified two peripheral subsets (ASCp) also present in blood and three BM-resident subsets (ASCr), comprising a maturation continuum associated with increased mitochondrial networking, diminished antibody secretion, differential transcription factor motif accessibility, and preferential co-localization in homotypic niches. CD19+9+ASCr and CD19-ASCr exhibited poor recovery years after BM transplantation, indicating a strong dependence on supportive niches. Childhood vaccine antigens were recognized by long-lived ASCr subsets in adults, as well as by immature HLA DR+ASCp, implying ASCs can differentiate without recent antigen exposure. Our results provide new insights into ASC identity, maturation, and longevity and a generalizable framework for study and manipulation of human ASCs.

Aging at the subcellular level involves the simultaneous decline in the cell's ability to maintain protein homeostasis and rise in misfolded proteins through a positive feedback loop. Here, we test if a widespread class of protein misfolding could contribute to proteome aging by examining if statistical associations exist between age-related changes in protein structure, measured by limited proteolysis mass spectrometry data of the aging Saccharomyces cerevisiae proteome, with structural annotations and molecular simulations. We find that globular proteins that are likely to exhibit entanglement misfolding are 121% more likely to exhibit age-related structural changes, and these changes are 59% more likely to be localized to natively entangled regions. Proteins containing native entanglements are seven-fold more likely to misfold, according to simulations, and populate long-lived, near-native misfolded states. Thus, the age-related structural changes in yeast proteins can be explained in part by the accumulation of misfolded proteins involving entanglements.

Metabolic processes shape ageing and longevity at multiple levels. Emerging evidence shows that many of these processes are orchestrated within and between cellular organelles. Organelles function not only as metabolic reactors but also as signalling hubs, and their coordination plays crucial roles in maintaining cellular homeostasis and promoting organismal fitness. Rather than acting in isolation, organelles engage in dynamic crosstalk through membrane contact sites, metabolite exchange and signalling interplay. In recent years, organelles have been increasingly recognized as critical regulators of ageing and longevity. Here we summarize age-related organellar changes, highlight organelle-mediated intra- and intercellular signalling communication in lifespan and healthspan regulation, and discuss the active roles of organelles in microbiome-host interactions and transgenerational inheritance in regulating longevity. We further outline how longevity-promoting interventions influence organelles, and provide perspectives on how future technological advances may further accelerate progress in this emerging research topic.

Aging is characterized by coordinated molecular and physiological changes across multiple biological systems, yet the ability to quantify these processes non-invasively within individuals remains limited. Here, we establish a framework for quantifying hallmark-level features of aging in mice using serum protein array profiles obtained from a single blood draw. Serum protein expression was profiled in groups of CB6F1J and C57BL/6J male mice at 8 and 32 months of age and mapped to established hallmarks of aging. Hallmark-level analyses revealed coordinated, pathway-specific changes in inflammatory, vascular, intercellular signaling, metabolic, and regenerative processes, with distinct patterns observed between strains. CB6F1J mice exhibited directional shifts across multiple pathways, while C57BL/6J mice showed broader but more heterogeneous changes. Cross-strain comparisons demonstrated shared pathway-level trends alongside variable protein-level concordance. This approach enables non-terminal assessment of aging within individuals and resolves heterogeneity in aging trajectories using minimally invasive sampling. These findings support the use of circulating protein signatures to quantify biological aging and provide a framework for translating non-invasive proteome-based assessment of aging to human studies.

Intervertebral disc degeneration (IVDD) is a major contributor to low back pain (LBP) and one of the foremost causes of disability worldwide. Oxidative stress-induced senescence of nucleus pulposus progenitor cells (NPPC) and mitochondrial dysfunction are key drivers of IVDD. The mitochondrial unfolded protein response (UPR

Alterations in the composition and functional potential of the skin microbiome are closely associated with aging. Nevertheless, integrative analyses that concurrently examine microbial composition, functional gene profiles, and skin surface metabolomics remain limited, particularly among Asian populations. In this study, we performed a comprehensive multi-omics analysis integrating skin microbiome and surface metabolomic data from Korean women to explore metabolites associated with youthful skin state. Twenty-three healthy female participants in their 20s and 60s were recruited. Skin physiological parameters were assessed, and microbiome and metabolite samples were collected from the cheek area. Unsupervised clustering of microbiome functional profiles revealed three microbial community patterns that were not strictly aligned with chronological age. Based on these patterns, samples were grouped into three functional groups. The cluster enriched in participants in their 20s showed higher relative abundance of Cutibacterium and enrichment of microbial pathways related to carbohydrate and energy metabolism. Metabolomic profiling showed that phenyllactic acid (PLA) and hydroxyphenyllactic acid were more abundant in participants in their 20s and in the functionally young cluster. These metabolite patterns were accompanied by higher abundance of genes associated with phenylalanine metabolism. In vitro experiments further showed that PLA increased procollagen production and reduced the secretion of collagen-degrading enzymes in human dermal fibroblasts under inflammatory conditions. Together, these findings suggest links between microbiome functional profiles, phenylalanine-related metabolites, and skin physiology. This study provides an integrated view of microbiome-metabolite relationships in Korean skin and identifies PLA as a candidate metabolite associated with youthful skin environments.

Foreign-born residents in high-income countries often outlive the native-born population, but it remains unclear how this advantage varies across countries and socioeconomic groups. We aimed to assess socioeconomic inequalities in the life expectancy advantage of foreign-born populations across 10 European countries.

The NAD+ dependent deacetylase sirtuin-1 (SIRT1) is known to elicit cellular defenses against aging, cancer, and other aberrant pathologies. Previous studies have identified an intrinsically disordered region of SIRT1 comprised of N-terminal residues 1-52, herein referred to as motif A, which activates SIRT1 activity, likely through intramolecular interactions. Additionally, phosphorylation of N-terminal residues Ser27 and Ser47 has been shown to be important for regulating SIRT1 activity and stability. The lack of in vitro characterization of these effects hampers our further understanding of the role of motif A in SIRT1 regulation. In this study, we elucidate the role phosphorylation plays in motif A structure as well as its regulatory effects on SIRT1 activity against Ac-p65. We find that phosphomimetic mutation at Ser27 significantly increases the activation effect of motif A towards SIRT1. This result is supported by molecular dynamics simulations of the phosphomimetics, which reveal stabilization of different transient structures for motif A depending on whether Ser27 and Ser47 have been modified. A key finding suggested by this study is that phosphorylation of S27 appears to activate SIRT1 by causing motif A, which is intrinsically disordered in the WT, to fold into an ordered structure. This conclusion is based on both the experimental findings and simulation results. These findings contribute to our understanding of SIRT1 regulation, specifically the role played by phosphorylation within the N-terminal disordered region.

The human brain varies across anatomical regions, cell types, development, ageing and disease states, yet existing single-cell transcriptomic resources remain fragmented and difficult to integrate into a unified biological model. Here we present DigitalBrain, a human brain-specific atlas and foundation-model framework for organizing diverse and fragmented human brain transcriptomic data across scales. We first built DigitalBrain-Atlas, a harmonized whole-brain single-cell resource comprising 16.35 million transcriptomes from 2,143 donors across 165 brain regions, spanning the human lifespan and multiple neurological and clinical conditions. We then developed DigitalBrain-M1, a Transformer-based model that jointly encodes gene identity and expression magnitude to learn a shared embedding space for cells and genes. Across held-out datasets, DigitalBrain supported robust single-cell integration, clustering and cell-type annotation while preserving major biological structure and reducing technical fragmentation. Beyond these benchmarks, the learned embeddings revealed emergent large-scale hierarchical organization of the human brain, linking anatomically distinct regions into higher-order patterns consistent with known functional systems. Applied to human hippocampal aging, DigitalBrain identified cell-type-specific aging sensitive gene sets, identified dentate gyrus granule cells as a particularly age-sensitive population, and discovered selective reorganization of gene programs related to synaptic transmission, postsynaptic structure, membrane excitability and axon guidance during aging. Cross-dataset convergence was strongest at the level of functional modules and recurrent aging sensitive genes. Together, these results demonstrate DigitalBrain as a brain-specific framework for mapping human brain organization across scales, and as an early step towards a complete virtual organ for the human brain.

Reduced insulin/IGF-1 signaling (IIS) can greatly extend lifespan in C. elegans. However, its effects on the duration of healthy life (healthspan) remain unclear, with several reports of either morbidity expansion or scaled effects, though none of morbidity compression. Moreover, life-extension by IIS reduction is particularly inter-individually variable within populations, confounding efforts to understand the intra-individual biology of such interventions. Here, we performed a longitudinal investigation at individual nematode resolution, of IIS reduction on aging-related health and lifespan, through temporally-controlled auxin-induced degradation (AID) of the DAF-2 insulin/IGF-1 receptor. Our results show how inter-individual variation in aging rate within control populations explains the complex demographic effects of age-specific DAF-2 AID on population lifespan. Strikingly, adult-limited IIS reduction causes an inter-individually homogeneous increase in lifespan (reducing Gompertz rather than {beta}) that is driven by healthspan expansion and compression of morbidity. Unexpectedly, cessation of DAF-2 AID in decrepit elderly individuals rejuvenates locomotory capacity and extends lifespan, showing that higher levels of IIS are optimal for health and survival towards the end of life. We also document a memory effect of transient IIS reduction during early adulthood, that is sufficient to fully extend lifespan (+189% median lifespan). Together, these findings demonstrate that both lifespan and healthspan can be maximized by appropriate temporal and directional modulation of IIS.

Mitochondrial biogenesis, the process by which cells generate new mitochondria, is crucial for maintaining cellular homeostasis, energy production, and overall health. Mitochondrial dysfunction is a key factor in both aging and cancer, where it contributes to the decline in cellular function and facilitates the progression of disease. In aging, mitochondrial alterations lead to impaired metabolic function, increased oxidative stress, and cellular senescence. Similarly, cancer cells often exhibit altered mitochondrial dynamics, which support rapid proliferation and resistance to apoptosis. Despite their differences, aging and cancer share common molecular mechanisms, particularly in mitochondrial dysregulation, that offer insights into potential therapeutic strategies. Recent research has highlighted the potential of medicinal plants and their bioactive compounds in modulating mitochondrial biogenesis and mitigating dysfunction. Phytochemicals have shown promise in enhancing mitochondrial function, promoting healthy aging, and inhibiting cancer progression. This review explores the molecular mechanisms underlying mitochondrial biogenesis, its dysregulation in aging and cancer, and the therapeutic potential of plant-based compounds in targeting mitochondrial dysfunction. By understanding the intricate relationship between mitochondria, aging, and cancer, novel therapeutic strategies can be developed to improve cellular health and combat age-related diseases and cancer.

During the aging process, the expression levels of numerous genes undergo significant changes, some of which in turn regulate the progression of aging. In this study, we identified the expression of EYA4 is upregulated during aging and demonstrated its critical role in modulating cellular senescence. Knockdown of EYA4 significantly delays both replicative and stress-induced cellular senescence. Mechanistic investigations showed that EYA4 interacts with the transcription factor SIX2 to promote the expression of p21, a key molecule in the senescence-signaling pathway, which accelerates cellular senescence. Interestingly, EYA4 possesses both transcriptional activation and phosphatase activities, yet experiments using phosphatase-deficient mutants revealed that its ability to enhance p21 expression is independent of its phosphatase activity. Further analysis demonstrated that the EYA4-SIX2-mediated regulation of p21 expression is p53-dependent, as the absence of p53 abolished this regulatory effect. In conclusion, our findings uncover a novel role of the EYA4-SIX2 complex in promoting cellular senescence through the transcriptional activation of p21. Targeting EYA4 may represent a promising strategy for delaying the aging process.

Klotho (KL) is an aging factor that has been associated with Alzheimer's Disease (AD) risk. Two common alleles circulate in human populations: the major allele FC and the minor allele VS, which is defined by two SNPs that cause two amino acid substitutions (F352V and C370S) in KL's second exon. To investigate the possibility that human KL variants influence brain aging and cognition, we developed a novel mouse model with humanized KL alleles. We used RNA-Seq to measure the whole brain transcriptome in four- and 12-month-old male and female C57Bl/6J mice carrying either the FC or the VS KL allele. We found that FC and VS carriers had widespread differences in gene expression in the brain at 12 months old, but not at four months old. The largest differences were in genes annotated to mitochondrial, ribosomal, and synaptic functions. Differential exon usage analysis identified differential splicing of synaptic genes, further supporting a role for KL on neuronal function. A more focused analysis of differential expression identified variation in glutamate receptors and amyloid precursor (APP) processing in particular, thereby linking human KL haplotypes to biological processes integral to AD pathogenesis. These results provide evidence that the human FC and VS KL haplotypes affect the function of the KL protein product in a manner that has widespread effects on gene expression in the brain and supports the hypothesis that these haplotypes may influence AD risk and pathogenesis.

The past decade has defined molecular hallmarks of aging, yet interventions that extend lifespan in short-lived organisms show limited and context-dependent translation to humans. Comparative studies of exceptional longevity remain largely genome-centric, although genomic instability alone cannot comprehensively explain aging-related pathologies. Many age-associated failures emerge at the level of cellular organelles whose stability underpins tissue function. The pathways that sustain these structures operate through proteomic, metabolic, and lipid networks that are insufficiently captured by genomic or transcriptomic analyses. Notably, longer organismal lifespan increases the requirement for sustained organelle functionality and fidelity. This Perspective proposes that the next conceptual advance in geroscience will come from comparative organelle biology. Examining mammals with divergent lifespans, including species evolutionarily closer to humans, can reveal how long-lived lineages evolved organelle-level architecture and resilience mechanisms that support cellular function over decades. I introduce the Comparative Metabolic Longevity Cell Atlas (CMLCA), a cross-mammalian platform integrating standardized cellular systems, organelle-resolved multi-omics, and computational analysis to identify conserved features of resilience and inform next-generation strategies to improve human healthspan.

Accelerated cellular senescence may be a key process in the progression of periodontitis, as it integrates the devastating effects of the major risk factors for periodontitis. Circadian rhythm disruption (CRD) affects the expression levels of multiple genes, such as brain and muscle ARNT-Like-1 (BMAL1), which is thought to be an important trigger or exacerbator of periodontitis. Even though CRD mechanisms are acknowledged to control cellular senescence, their effect on the senescence that happens during periodontitis is not well defined. This research aimed to explore the role and pathogenic mechanism of CRD in periodontitis and the involvement of cellular senescence, with the purpose of providing innovative ideas for the prevention and treatment of periodontitis. A rat model combining CRD and periodontitis was established. Periodontal lesions were assessed via histological staining. The expression levels of core circadian genes and senescence markers were evaluated. Inflammatory mediators related to the senescence-associated secretory phenotype (SASP) were quantified. The BMAL1 agonist SR8278 was employed to verify the key role of BMAL1 and the BMAL1/cryptochrome 2 (CRY2)/period circadian regulator 1 (PER1) signaling pathway. Finally, the effect of BMAL1 modulation on cellular senescence was examined in lipopolysaccharide (LPS)-induced human periodontal ligament cells (hPDLCs). CRD exacerbated experimental periodontitis lesions and aggravated the periodontal tissue senescence phenotype. BMAL1/CRY2/PER1 gene levels were down-regulated in a model of CRD-complexed periodontitis, and restoration of BMAL1 levels could alleviate CRD-exacerbated periodontitis by attenuating the periodontal tissue senescence phenotype. Interestingly, LPS exposure resulted in increased cellular senescence and decreased BMAL1/CRY2/PER1 in hPDLCs. Knockdown of BMAL1 resulted in further upregulation of cellular senescence in hPDLCs, whereas overexpression of BMAL1 inhibited LPS-induced cellular senescence. This study establishes a significant link between CRD and the aggravation of experimental periodontitis, within which a dysregulated BMAL1/CRY2/PER1 axis and an enhanced senescence phenotype are prominent features. This perspective opens new avenues for periodontitis intervention by focusing on circadian rhythm modulation.

Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare hereditary condition caused by germline de novo mutations of LMNA gene that synthesizes the toxic protein progerin and, therefore, compromises nuclear structure and expedites aging of cells. HGPS is fairly rare (estimated as 1 in 20 million people), but triggered a significant amount of academic interest due to the interplay between the disease and both research into rare diseases and studies of the aging process more generally.

Recent trends from Western countries indicate a stagnation of life expectancy gains, raising questions about the mechanisms that sustain healthy aging and morbidity compression. In this study, we focus on trends in cardiovascular diseases and diabetes and their determinants in the United States, as relevant contributors to potential morbidity compression and, consequently, to increases in healthy life expectancy. Using data from the Behavioral Risk Factor Surveillance System from 1990 to 2023, we apply a pseudo-panel approach to analyze morbidity patterns across birth cohorts in the United States. The models account for covariates such as BMI, smoking, ethnicity, gender, income, and education, including relevant nonlinearities and interactions to capture heterogeneity in disease risk. Findings show that, at comparable ages, more recent cohorts exhibit higher disease risk, for diabetes, a pattern that is not consistent with morbidity compression. These results are largely explained by the growing presence of behavioral and socioeconomic risk factors, such as overweight and low income, which disproportionately affect younger cohorts. Our study contributes to the growing literature documenting worsening population health trajectories in countries with advanced medical systems and highlights the need for public health strategies that address both behavioral and structural determinants to promote healthy aging.

Life-history theory and evolutionary theories of ageing predict that trade-offs between reproduction and somatic maintenance shape the evolution of ageing and lifespan. However, the significance of these trade-offs remains debated, as previous correlational studies have produced inconsistent results. Here, we used an experimental artificial selection approach in a precocial bird, the Japanese quail (Coturnix japonica), to directly test this fundamental tenet. We found that selection for divergent reproductive effort affected adult survival, with shorter lifespans in individuals selected for higher reproductive effort compared with individuals selected for lower reproductive effort at generations five and six. This difference in lifespan was driven by accelerated actuarial senescence rather than changes in baseline mortality. No differences in reproductive senescence were observed between the selection treatments. Our findings provide experimental evidence that vertebrate mortality trajectories can evolve rapidly in response to selection and demonstrate that increased reproductive effort is intrinsically linked to faster ageing and a shorter lifespan-thereby supporting a central tenet of life-history and ageing theory.

This study addresses key gaps in our understanding of the cognitive changes associated with normal brain aging and their underlying structural and functional correlates. Declining levels of brain endocannabinoids (eCB), particularly 2-arachidonoylglycerol (2-AG), are thought to contribute to age-related cognitive impairment, but the mechanisms involved remain poorly understood. Here, we show that levels of 2-AG and its synthesizing enzyme, diacylglycerol lipase- (DAGL-), are significantly reduced in the medial prefrontal cortex (mPFC) of aged mice. This decline is associated with impairments in mood and memory, as demonstrated by behavioral analyses. Immunofluorescence studies further revealed reduced expression of cannabinoid receptors CB1 and CB2 on microglia in aged brains, suggesting that diminished eCB signaling may contribute to enhanced neuroinflammation. Consistent with this idea, microglia from aged mice exhibited increased HMGB1-TLR4-NF-{kappa}B signaling, indicative of a pro-inflammatory state. LC-HR-MS analysis also showed elevated glutamate levels and reduced glutamine and GABA levels in the mPFC, linking impaired eCB signaling to excitotoxic imbalance during aging. Importantly, intraperitoneal administration of cannabidiol (CBD) to aged mice reversed mood and memory deficits, restored CB1 and CB2 receptor expression, attenuated HMGB1-TLR4-NF-{kappa}B signaling, and normalized the glutamate-glutamine/GABA balance in the mPFC. Collectively, these findings identify eCB signaling as a critical regulator of age-associated cognitive decline and support CBD as a potential therapeutic strategy to promote healthy brain aging.

Skeletal muscle has the impressive capacity to completely regenerate even after relatively severe injuries in young individuals, but this process is dysregulated in multiple cell types in the microenvironment in numerous diseases and aging. In this issue of the JCI, Cao et al., using an elegant set of genetic mouse models and pharmacological approaches, demonstrated that gasdermin E (GSDME) was required in myeloid cells after sterile muscle injury to normally regenerate muscle and that downstream IL-18 release prevented intramuscular ectopic fat deposition. GSDME expression was reduced in human muscles from aged individuals, and Gsdme was increased after muscle injury in young, but not old, mice. The ability of IL-18 to partially improve regeneration in aged GSDME-knockout mice demonstrates the potential clinical relevance of this finding in dysregulated muscle regeneration associated with aging.

As humans and other animals age, passive and active muscle properties change markedly, with reduced peak tension, peak strain rate, activation and deactivation rate, and increased parallel stiffness. It is thought that these alterations modify locomotor performance, but establishing causal links is difficult when many parameters vary at once. We developed a simplified model of an elbow joint with two antagonistic Hill-type muscles, and varied the associated muscle parameters combinatorially over a large range. For a given parameter combination, we found optimal joint movements that minimized cumulative squared error to a target while starting and ending at rest. Emergent behaviour from the optimisations compared well to ballistic point-to-point arm movements in humans. Age-associated reductions of maximum isometric force, maximum strain rate and activation rate all had detrimental effects on performance, independent of other parameters. In contrast, deactivation time and passive parallel stiffness had no effect on performance on their own, but pronounced interactive effects with each other. Increasing stiffness reduced joint movement time at fast deactivation rates, but increased movement time at slow deactivation rates. This occurs because antagonist muscles resist the passive tension at rest, but are stretched eccentrically by the agonist, amplifying their active resistive force. Fast-deactivating muscles can avoid this resistive effect, allowing the passive stiffness to amplify accelerating force and enhance performance. In all cases, coactivation emerged as optimal during and after the braking period, and during the acceleration phase when stiffness increased. As deactivation time increased, so too did coactivation levels- but coactivation was not generally associated with a reduction in performance. Our simulations offer evidence that age-related changes in muscle strength, activation time and maximum contraction velocity can reduce ballistic performance in a goal-directed task, but the effects of increased muscle stiffness and deactivation time depend on their relative values.

Alzheimer's disease (AD) is an aging-associated neurodegenerative disorder characterized by amyloid-β (Aβ) and tau accumulation and progressive cognitive decline. Increasing evidence implicates the glymphatic system, a brain-wide perivascular pathway involved in cerebrospinal fluid-interstitial fluid exchange and metabolic waste clearance, in the removal of Aβ, tau, and other solutes relevant to AD pathogenesis. Aging-related alterations in aquaporin-4 polarization, arterial pulsatility, sleep architecture, and cerebrovascular integrity may impair glymphatic transport and thereby promote protein retention and neurodegeneration. In this review, we summarize current knowledge of glymphatic anatomy and function and discuss its implications for AD, with particular emphasis on modifiable factors such as sleep, exercise, vascular health, and aging-associated decline. We further highlight emerging therapeutic and potential intervention strategies aimed at restoring glymphatic function, and critically evaluate current methods for assessing this system in humans together with the evidence obtained to date. Although human studies increasingly support the relevance of perivascular fluid transport to AD-related pathology and cognitive outcomes, mechanistic insights remain largely derived from animal models, and human assessment is still constrained by methodological and imaging limitations. Overall, the glymphatic system provides a useful framework for linking brain aging to impaired clearance in AD. Further refinement of human biomarkers and longitudinal translational studies will be essential for clarifying their clinical relevance and therapeutic potential.

Epigenetic aging prior to midlife is gaining interest as an intervenable period to address health and cognitive aging. Epigenetic changes may index DNA methylation aging rates, but methylation profiles may not be substitutable across tissues. We compared DNA methylation clocks and age acceleration in saliva, buffy coat (BC), and peripheral blood mononuclear cells (PBMC) collected in 91 individuals (7 unpaired, 20 siblings, 64 twins; 18 monozygotic (MZ), 14 dizygotic (DZ) pairs) from the Colorado Adoption/Twin Study of Lifespan behavioral development and cognitive aging (CATSLife1; Mean age = 30.90 years [range = 28.07-41.13]; 50.5% female). Across 15 DNA methylation clocks, chronological age and DNA methylation ages were moderately associated (mean Spearman correlations:

Cortical thinning and atrophy are hallmarks of brain aging that have been characterized using magnetic resonance imaging (MRI). Brain aging involves many neuroanatomic features whose effects on brain structure remain unexplored. To address this challenge, we trained interpretable deep neural networks (DNNs) to estimate brain age (BA) from T

Understanding how aging reshapes balance is essential for targeted assessment and rehabilitation. Because wobble boards impose continuous instability, their kinematics may provide a noninvasive readout of long-latency (transcortical) reflex function in ecologically valid conditions. We analyzed wobble-board dynamics in healthy younger adults (

Chronological age is a common and non-modifiable factor for chronic disease, but does not fully explain age-related changes. Biological clocks have been developed to explore biological aging mechanisms. They could help identify protective factors against accelerated aging and associated diseases. We aim to assess the association between reduced epigenetic or inflammatory aging and ideal cardiovascular health or cardiovascular risk. We conducted a cross-sectional analysis of participants from the INSPIRE-T cohort. Cardiovascular health (CVH) was assessed using the Life's Essential 8 score. Cardiovascular risk was assessed using the American Framingham risk score (FRS) and the European Systematic Coronary Risk Evaluation (SCORE2) score. Epigenetic and inflammatory aging was calculated from the residuals from linear regression of biological age (based on five epigenetic clocks and one inflammatory clock) and chronological age. Linear and logistic regression models were used. Better CVH has been associated with slower epigenetic aging, particularly in younger subjects and men. Accelerated epigenetic aging measured by GrimAge was associated with an increase cardiovascular risk (for SCORE2: OR = 1.10 95%CI [1.04; 1.16]). No persistent association was found with the inflammatory clock. Our study reported an association between ideal global CVH with reduced epigenetic aging after adjustment for chronological age and gender. This suggests that epigenetic aging may be modifiable through healthy lifestyle and cardiovascular risk management, although a potential underlying causal relationship remains to be established. Moreover, accelerated epigenetic aging is linked to worsening cardiovascular risk, and could be a new risk factor alongside chronological age.

Genetic background is a major determinant of disc degeneration, a leading cause of chronic back pain and disability. Herein, we demonstrate that premature disc cell senescence contributes to early-onset degeneration in SM/J mice and test two systemic senotherapeutic strategies to mitigate it: Navitoclax (Nav.) and a cocktail of Dasatinib and Quercetin (DQ). While Nav. treatment did not improve severe degeneration in SM/J mice or senescence status, DQ-treated mice showed lower grades of degeneration and a decreased abundance of senescence markers, including p19ARF, p21, and the senescence-associated secretory phenotype (SASP). DQ improved disc cell viability and phenotype retention and retarded fibrosis of the nucleus pulposus tissue. Transcriptomic analysis revealed tissue-specific effects of the treatment, with cell cycle regulation and JNK signaling being commonly affected across different tissue types. A comparison of SM/J data with DQ-mediated aging-dependent amelioration of disc degeneration in C57BL/6 N mice identified Junb and Zfp36l1 signaling as shared DQ targets in the mouse disc. Notably, the in vitro inhibition studies of the JUN pathway in human degenerated NP cells mimicked the benefits of DQ, namely, a reduction in senescence and SASP. This study reinforces the efficacy of senolytic treatment in ameliorating local senescence and intervertebral disc fibrosis.

Ménière's disease (MD), a chronic inflammatory disorder with age-related increased incidence, exhibits poorly understood pathogenesis and limited therapeutic options. Here, we demonstrate that cellular senescence, marked by mitochondrial damage, reactive oxygen species accumulation, and senescence-associated secretory phenotype (SASP), is prevalent in the vestibular tissue of MD patients and an endolymphatic hydrops mouse model. The transcription factor GATA4 is upregulated in MD and mice, and its genetic deletion in hair cells alleviates LPS-induced audio-vestibular dysfunction and cellular senescence in mice and HEI-OC1 cells. Mechanistically, HDAC6 interacts with GATA4 and restrains its nuclear transport, while RNA-seq and ChIP-seq identify HtrA1, a serine protease, as a direct transcriptional target of GATA4. Inhibition of HDAC6 or AAV-mediated HtrA1 overexpression exacerbates MD-like symptoms, whereas inhibition of HtrA1 by Galegenimab ameliorates these phenotypes in mice. In aged mice, GATA4 deletion reduces age-related audio-vestibular deficits and senescence markers. Collectively, our findings establish GATA4 as a critical regulator of cellular senescence and inflammaging in inner ear pathologies, providing promising therapeutic targets for MD and age-related audio-vestibular disorders.

Nanomaterials have been widely used to scavenge reactive oxygen species (ROS) and relieve mitochondria oxidative damage. However, developing nanomedicines that not only remove ROS but also accelerate the repair of dysfunctional mitochondria remains challenging. This study identifies polyvinylpyrrolidone (PVP)-modified palladium nanoparticles (PdP NPs) as mimics of cytochrome c oxidase (CcO) and superoxide dismutase (SOD), showcasing their potential as multifunctional nanoreactors to activate mitochondria for aging alleviation and neuroprotection. PdP NPs treatment enhances mitochondrial respiratory chain function, scavenges excessive ROS, thus alleviates cellular energy scarcity of aging individuals. Additionally, PdP NPs improve mitochondrial dynamics, promote biogenesis, and induce mitochondrial unfolded protein response (UPR

Several lines of evidence suggest that targeting dysfunctional calcium (Ca2+)-storing organelles and their defective connections may represent a promising therapeutic strategy counteracting neurodegeneration. Dysfunction in these compartments converges to promote oxidative and endoplasmic reticulum stress, energy failure, autophagy blockade or hyperactivation, and progressive neurodegeneration. Within the intracellular scenario, several dysfunctional organelles have been characterized in terms of their capability to hijack Ca2+ signaling during neurodegeneration to deadly impact on neuronal tasks in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, brain ischemia, and neonatal hypoxic injury. This review has focused on the endoplasmic reticulum, mitochondria, and lysosomes, as well as their functional interconnection able to maintain the physiological processes such as lysosomal-dependent autophagy and function, lipid trafficking, and protein quality control. Clinically, looking ahead from the already existing therapies, drugs that enhance mitochondrial Ca2+ efflux or modulate mitochondrial Ca2+ uniporter regulation at mitochondria-associated membranes-endoplasmic reticulum sites represent innovative opportunities for next-generation strategies aimed at restoring mitochondrial homeostasis and protecting dopaminergic neurons in Parkinson's disease. Furthermore, functional stabilization of the lysosomal channel transient receptor potential mucolipin 1 by the lipid-based formulation of PI(3,5)P2 may extend the lifespan of amyotrophic lateral sclerosis mice by stimulating the nuclear translocation of the master regulator of autophagy activated by lysosomal Ca2+ release, namely transcription factor EB. Moreover, dysfunction of lysosomal-dependent autophagy can cause mutant huntingtin accumulation in Huntington's disease through the repression of transcription factor EB and lysophagy induction. Collectively, this growing focus may highlight a shift toward recognizing mitochondria, lysosomes, and endoplasmic reticulum, as well as their ionic machinery and interconnections, as a unifying strategy to maintain neuronal viability and mitigate the neurodegeneration progression in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, lysosomal storage diseases, brain ischemia, and neonatal hypoxic insult.

In populations of many animal species, including humans, mortality rates increase exponentially with advancing age. The scale and rate of increase can be set by two parameters, α and β, respectively, of the Gompertz equation. Interventions that extend lifespan can reduce either or both parameters. A long-standing supposition is that β corresponds to biological ageing rate, and α to ageing-independent causes of mortality. Here, we investigate the biological basis of α and β using the nematode Caenorhabditis elegans, through the combined study in populations and individuals of effects of life-extending interventions on mortality and age-changes in health. We demonstrate that reductions in β arise not from slowed biological ageing, but rather from expansion of decrepitude (gerospan) in longer-lived population members. In contrast, reductions in α better reflect healthspan expansion, an indicator of slowed biological ageing. Thus, our investigation presents a new, empirical understanding of the Gompertz parameters that inverts their traditional interpretations.

Aging is the strongest risk factor for Alzheimer's disease (AD), yet the role of age-associated DNA methylation (DNAm) changes in blood and their relevance to AD remains poorly understood. We performed a meta-analysis of blood DNAm samples from 475 dementia-free subjects aged over 65 years across two independent cohorts, the Framingham Heart Study (FHS) at Exam 9 and the Alzheimer's Disease Neuroimaging Initiative (ADNI). We adjusted for sex and immune cell-type proportions and corrected batch effects and genomic inflation. Integrative analyses included pathway enrichment, mQTL analysis, colocalization with Alzheimer's disease and related dementia (ADRD) GWAS summary statistics, brain-blood DNAm correlations, and comparison to independent AD methylation studies. We identified 3758 CpGs and 556 differentially methylated regions (DMRs) consistently associated with chronological age in both cohorts at a 5% false discovery rate. Our pathway enrichment analyses highlighted metabolic regulation and synaptic signaling, processes previously implicated in Alzheimer's disease. Colocalization with ADRD GWAS summary statistics identified 32 genomic regions consistent with shared genetic signals for DNAm and ADRD risk. Roughly one-third of aging-associated CpGs overlapped CpGs associated with AD or AD neuropathology in external studies. Finally, we prioritized nine promoter CpGs (including those located in PDE1B, ELOVL2, and PODXL2) showing strong positive blood-to-brain methylation concordance and external AD associations, nominating them as candidate blood-based biomarkers. Our study demonstrated that late-life aging signatures in blood DNAm converge on processes implicated in AD and intersect with dementia genetics. A small set of CpGs with blood-brain concordance and external AD support offers promising candidate blood-based biomarkers for future validation.

Background: Dysregulation of phosphate homeostasis contributes to reduced longevity and vascular complications in chronic kidney disease and aging. This study investigates the role of TMEM174, a proximal tubule-specific protein, in regulating the phosphate co-transporter NPT2A and its subsequent impact on lifespan and vascular health. Methods: TMEM174 knockout (KO) mice (C57BL6/J and DBA/2J) were fed diets with varying phosphate concentrations (0.6% vs. 1.2%). In OKP cells, TIRF and FRET microscopy, alongside immunoprecipitation, were used to identify the TMEM174 protein regions essential for NPT2A binding and endocytosis. Results: TMEM174 KO mice exhibited significantly shorter lifespans than wild-type controls. High phosphate diets exacerbated vascular calcification, stiffness, and mortality, while low phosphate diets rescued these phenotypes. In vitro, TMEM174 siRNA blocked PTH-induced NPT2A endocytosis, increasing its apical membrane retention. FRET and biochemical assays revealed that the C-terminal region of TMEM174 is essential for its association with NPT2A. While intact TMEM174 and N-terminal mutants (TMEM174deltaN) facilitated NPT2A degradation, C-terminal deletions (TMEM174deltaC) failed to associate with or degrade NPT2A. Conclusions: TMEM174 is a critical regulator of phosphate homeostasis and longevity. The C-terminal region of TMEM174 is specifically required for NPT2A endocytosis and degradation, identifying it as a potential therapeutic target for managing phosphate-related vascular complications.

Chronic exposure to ultraviolet (UV) radiation, known as photoaging, accelerates skin aging by inducing molecular, histological, and functional changes. This study established a mouse model using SKH-1 hairless mice to investigate chronic UV-induced photoaging over eight weeks. SKH-1 hairless mice were exposed to a combination of UVA and UVB, and the progression of skin damage was monitored through physical, histological, and molecular parameters, with a focus on erythema, transepidermal water loss, and collagen and hyaluronan (HA) metabolism. Significant reductions in HA content and alterations in DNA repair markers, such as {gamma}H2AX, were observed, highlighting the impact of chronic UV exposure on skin structure and function. Reactive adipogenesis and increased epidermal thickness were noted, reflecting adaptive responses to UV-induced damage. By investigating these parameters over the evaluation period, we provide a comprehensive time-course analysis of the progressive impact of UV-induced photoaging, offering insights into the underlying mechanisms and potential therapeutic targets to prevent or delay photoaging.

Effective strategies must address functional decline among older adults resulting from aging and disease. We investigate the association between the number of different types of activities that older adults engaged in at community gathering places (CGPs) and their subsequent higher-level functional capacity in Japan.

Emerging evidence implicates premature placental senescence as a central driver of pregnancy complications, though its underlying mechanisms remain elusive. Here, we report marked downregulation of IL33 (interleukin 33) in villi from unexplained recurrent pregnancy loss (URPL) patients, concomitant with elevated trophoblast senescence. More importantly,

Aging is marked by a progressive breakdown of intestinal integrity and metabolic homeostasis, which together drive systemic decline in physiology and reduced lifespan. Here, we demonstrate that dietary lipids extracted from a genetically engineered long-lived yeast strain robustly extend lifespan in Drosophila by preserving gut function and modulating the gut brain axis. Using deuterium oxide probed stimulated Raman scattering microscopy, we show that these yeast-derived lipids restore age-related declines in gut lipid droplet abundance, enhance membrane lipid incorporation, and increase de novo lipid synthesis, thereby improving epithelial structure and barrier function. Single nucleus RNA sequencing reveals transcriptional remodeling in metabolically active enterocytes, including upregulation of autophagy and protein turnover genes, alongside reduction of unsaturated fatty acid biosynthesis. Complementary Raman spectroscopy and lipidomics demonstrate that the yeast lipids are enriched in shorter, more saturated fatty acids and phospholipids, contributing to increased membrane order and reduced lipid storage. Functionally, targeted dietary supplementation with these lipid components synergistically prolongs fly lifespan. In the brain, dietary lipids orchestrate a dual metabolic strategy, promoting energy conservation and enhanced signaling across most neuronal and glial populations, while selectively boosting mitochondrial function in memory-critical Kenyon cells. We also identify strengthened gut-to-glia communication, particularly through EGFR and FGFR pathways. Finally, a newly developed computational tool, FLY-MAP, reveals that yeast lipids restructure gut metabolic modules to coordinate energy production, redox balance, and nutrient flexibility. Our study uncovers a cross-kingdom mechanism of metabolic longevity regulation, paving the way for leveraging yeast-derived nutritional components to support tissue homeostasis and promote healthy aging.

In humans, aging is associated with an increased risk of developing neurodegenerative diseases such as Parkinson's disease and Alzheimer's 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.

Age-related cognitive and exploratory decline is a hallmark of brain aging across species, yet the evolutionary conservation of specific behavioral phenotypes remains unresolved. Thigmotaxis, the wall-following preference in open-field exploration, serves as a robust index of anxiety and cognitive vulnerability in humans and rodent models of aging and neurodegeneration. Here, we report that house crickets (Acheta domesticus) exhibit steep age-related increases in thigmotaxis, mirroring trajectories observed in C57BL/6 J mice, while CB6F1 hybrids remain resistant. Using lifespan- and maturity-normalized age metrics, we show that these patterns are robust across alternative scaling frameworks and independent of body size or sex. The conservation of exploratory decline across insects and mammals suggests that thigmotaxis reflects fundamental, evolutionarily ancient neurobehavioral processes of aging. Importantly, house crickets provide practical advantages (i.e., short lifespan, low cost, and responsiveness to established geroprotective drugs) positioning them as a powerful bridge model for scalable screening of interventions targeting age-related cognitive and behavioral decline.

Vascular smooth muscle cell (VSMC) senescence is a major driver of age-related vascular remodeling and functional decline, and is closely associated with lysosomal dysfunction. However, there remains a lack of small molecules capable of precisely targeting lysosomes to improve vascular remodeling.

Age-related cognitive decline (ARCD) is driven by conserved biological mechanisms of aging, yet no gerotherapeutic directly targets these processes in the brain. Glycyl-L-histidyl-L-lysine complexed with copper (GHK-Cu) is an endogenous peptide with regenerative and anti-inflammatory properties that declines with age. Whether its effects on cognitive aging depend on delivery route or exposure duration remains unclear. Aged C57BL/6J mice (20-21 months) received GHK-Cu (15 mg/kg) via short-term intraperitoneal (IP; 5 days) or longer-term intranasal (IN; 8 weeks) administration. Hippocampal-dependent escape learning was assessed using a spatial navigation task. Molecular effects were evaluated using hippocampal immunohistochemistry and bulk RNA sequencing. Differential gene expression was analyzed using DESeq2 with false discovery rate (FDR) correction, and pathway-level changes were assessed via gene set enrichment analysis (GSEA). IN GHK-Cu improved escape latency across Trials 2-4 in both sexes (P < 0.05), whereas IP dosing produced a transient improvement in males during Trial 2 (P < 0.05) without sustained effects or improvement in females. IN treatment increased synaptophysin in females (P < 0.001) and decreased GFAP in both sexes (P < 0.01), while IP treatment reduced TGF-{beta}, GFAP, and MCP-1 in males (P < 0.05) and decreased p21 in females (P < 0.0001). Transcriptomic analysis revealed distinct molecular programs. IN GHK-Cu induced coordinated suppression of oxidative phosphorylation (male NES -5.44, female NES -4.20; FDR < 0.0001) and MYC target pathways (female NES -4.31, FDR < 0.0001), with additional attenuation of PI3K-AKT-mTOR signaling in females (NES -3.15, FDR = 0.062). In contrast, IP treatment activated oxidative phosphorylation (female NES 4.97, FDR < 0.001), DNA repair (NES 5.58, FDR < 0.001), and MYC targets (NES 4.34, FDR = 0.002), indicating engagement of acute stress-response and repair pathways. GHK-Cu improves hippocampal-dependent learning in aged mice through distinct biological modes: IP exposure activates repair and stress-response pathways, whereas IN delivery induces sustained suppression of growth and mitochondrial metabolic signaling associated with aging biology. These findings demonstrate that functional cognitive improvement can arise from divergent molecular states and identify administrative route and exposure duration as key determinants of gerotherapeutic response.

Chronic wounds such as diabetic foot ulcers, venous leg ulcers, and pressure ulcers are characterized by impaired healing and persistent inflammation. Cellular senescence, defined as irreversible growth arrest with a pro-inflammatory secretory phenotype (senescence-associated secretory phenotype), has emerged as a potential driver of these nonhealing states. While transient induction of senescence may aid acute repair, chronic accumulation of senescent cells is thought to disrupt tissue regeneration, promote extracellular matrix degradation, and sustain inflammation.

Cardiac diseases are strongly associated with aging and pose a major threat to survival. This study evaluated the cardioprotective effects of oral eugenol and its nano-emulsion (20 mg/kg) in a D-galactose-induced aging model (300 mg/kg, i.p.) in male and female rats over 12 weeks. Particle size and zeta potential analyses confirmed the successful development of a stable, well-dispersed nano-emulsion system. At the end of treatment, echocardiography, biochemical assays, histopathology, and immunohistochemistry were performed. Cardiac dysfunction and dilatation were more pronounced in males than females following D-galactose administration, as evidenced by left ventricular internal diameter in diastole (LVIDd) and left ventricular internal diameter in systole (LVIDs), and reduced ejection fraction (EF) and fractional shortening (FS). Both eugenol and its nano-emulsion preserved cardiac architecture and mitigated histopathological alterations, including myofibrillar distortion, necrosis, vascular remodeling, and fibrosis. Treatment significantly reduced oxidative stress and mitochondrial dysfunction by restoring GSH, lowering MDA, and modulating the PINK1/Mfn2 pathway. Furthermore, eugenol and its nano-emulsion attenuated cardiac inflammation, apoptosis, and fibrosis through downregulation of TGF-β1, MMP-9, TNF-α, and caspase-3 expression. In conclusion, eugenol nano-emulsion demonstrates promising anti-aging potential against cardiac complications by regulating mitochondrial dynamics, mitophagy, oxidative stress, inflammatory and apoptotic responses, and the SIRT1/TGF-β/MMP9 signaling pathway.

Studies over the past 3 decades have shown decreased motor adaptation with age. The most widely supported theory for this change proposes that older adults fail to successfully implement cognitive strategies to facilitate performance. However, increased movement variability may also affect adaptation with age, but this has to date remained unstudied. Here, we examine whether age-related increases in movement variability influence adaptation. Healthy older adults (

Increased napping in later life is a common behaviour shaped by cultural, environmental and biological factors. Although brief naps can enhance alertness and memory, epidemiological evidence suggests that frequent or prolonged daytime sleep in older adults is associated with poorer physical health and accelerated cognitive decline, including episodic memory, possibly due to the underlying circadian disruption of the sleep-wake cycle. In this study, we tested whether restricting nap habits for 12 months would mitigate the age-related changes in cognitive functioning in healthy retirees (59-82 years). Fifty-eight habitual nappers were randomised either to a nap-control condition (n = 28), where they continued their usual nap routine, or to a nap-intervention condition (n = 30), where they received behavioural coaching to reduce the frequency and duration of daytime napping. A non-nappers group (n = 29) served as a reference. Cognitive performance, with a focus on episodic memory, was assessed at baseline and after the one-year intervention. Actimetric recordings showed that nap-intervention significantly decreased estimates of daytime nap frequency and duration throughout the study. Overall cognitive performance tended to decrease after a year in all participants, but the nap-control group exhibited a significantly greater decline in verbal episodic memory recall as compared to both non-nappers and nap-intervention participants. These results demonstrate that sleep-wake behaviour in older adults can be modified and suggest that targeted nap reduction may offer an accessible strategy to mitigate age-related decline in specific cognitive domains, regardless of whether habitual napping represents a causal or compensatory factor of neurobiological vulnerability.

Multiscale entropy (MSE) changes in relation to age, whereby aging is associated with an increasing bias towards fine scale entropy. This change is thought to represent a shift toward localized information processing in the brain as we age. However, this relationship has not been tested in large sample sizes alongside other demographic factors and cognitive behaviours. This study aimed to validate previously reported effects of aging on MSE in a large open access database (Cambridge Centre for Ageing and Neuroscience, N=587) and expand the findings to include an investigation of the effects of sex and a variety of cognitive behaviours. MSE curves and power spectrum densities (PSD) were calculated for each region of interest from the magnetoencephalography data. Multivariate partial least squares analyses were used to assess the relationship between MSE or PSD and 5 behavioural / demographic factors including: age, sex, fluid intelligence, visual short-term memory and a generalized measure of cognitive function. Age was associated with increased fine scale and decreased coarse scale entropy, as well as complementary spectral changes, including slowing of peak alpha rhythms, increased beta-band activity, and reduced gamma-band activity, which replicates prior MSE and PSD findings. In both domains, these age-related patterns differentiated based on sex with advancing age. Importantly, the unique effects of sex diverged between MSE and PSD. This result indicates that entropy-based measures can isolate aspects of temporal organization that are not clearly summarized by spectral structure alone.

ObjectiveCurrent lighting recommendations rely on Western laboratory studies, leaving the real-world mechanisms linking light exposure to sleep in Asian older adults unclear. This study aims to systematically analyze the complex relationships among daily light exposure, activity patterns, and sleep health in older adults living in residential environments.BackgroundExisting lighting guidance for sleep and circadian health is predominantly based on Western laboratory research, with no clear elucidation of the real-world associative mechanisms between light exposure and sleep among Asian older adults. This study targets this research gap by exploring the relevant correlations in real residential settings, to lay a foundation for targeted lighting improvement for the elderly population.MethodsWe employed a field investigation combining subjective and objective measurements in the living spaces of 116 elderly participants in Shanghai, China. Individual ocular light exposure and activity patterns were collected via luxmeters and interviews. Sleep quality and chronotype were assessed using the Pittsburgh Sleep Quality Index (PSQI) and Munich Chronotype Questionnaire (MCTQ). Hierarchical multiple linear regression was employed to examine associations, controlling for age and gender.ResultsField measurements confirmed that participants' indoor environments were pervasively light-deficient, lacking sufficient daytime stimulus for robust circadian entrainment. Age was the strongest negative predictor of sleep efficiency (β= -0.419, p < 0.001). After controlling for age, the light environment explained a significant 9.3% of additional variance (p = 0.012). Notably, higher maximum daytime ocular illuminance (Ev) was associated with lower sleep efficiency (β = -0.413, p = 0.015), while higher maximum evening ocular illuminance (Ev) was associated with higher sleep efficiency (β = 0.279, p = 0.008).ConclusionsThese findings challenge simplistic guidelines: high daytime light peaks likely represent uncomfortable glare rather than effective circadian stimulus, while evening light proxies for beneficial social activity. This underscores the urgent need for context-aware, glare-free residential lighting strategies to promote healthy aging among older adults.

Circadian clocks regulate a myriad of physiological processes rhythmically throughout the day in most organisms. Our study focuses on a relatively less-studied neuropeptide CCHamide1 (CCHa1), expressed in the Drosophila melanogaster gut and the central circadian clock in the brain. We investigated the role of ccha1 on sleep under altered dietary conditions, as well as its impact on metabolism and fitness in Drosophila. We assayed sleep under ad libitum fed, starved and altered protein diets using ccha1 mutant males and females. We found that both the mutant males and females showed sleep fragmentation when fed ad libitum. We also found that ccha1 specifically influences daytime sleep in males under starvation conditions and contributes strongly to sleep consolidation under normal and high-protein conditions, but to a lesser extent under low-protein diet conditions in male flies. Both ccha1 mutant males and females fared better under starvation stress and had higher triglyceride reserves. The ccha1 mutants also exhibited a delay in pupariation, likely because of an altered expression of the early ecdysone-responsive genes. In addition, the mutants had an increased mid-life fecundity and reduced lifespan. These results suggest a possible role for the protein sensing molecule ccha1 in integrating nutritional status with sleep, as well as in regulating triglyceride levels and some of the fitness related traits such as longevity and fecundity in Drosophila.