Longevity Papers

Cellular senescence restrains the expansion of neoplastic cells through several layers of regulation. We report that the histone H3-specific demethylase KDM4 is expressed as human stromal cells undergo senescence. In clinical oncology, upregulated KDM4 and diminished H3K9/H3K36 methylation correlate with poorer survival of patients with prostate cancer after chemotherapy. Global chromatin accessibility mapping via assay for transposase-accessible chromatin with high-throughput sequencing, and expression profiling through RNA sequencing, reveals global changes of chromatin openness and spatiotemporal reprogramming of the transcriptomic landscape, which underlie the senescence-associated secretory phenotype (SASP). Selective targeting of KDM4 dampens the SASP of senescent stromal cells, promotes cancer cell apoptosis in the treatment-damaged tumor microenvironment, and prolongs survival of experimental animals. Our study supports dynamic changes of H3K9/H3K36 methylation during senescence, identifies an unusually permissive chromatin state, and unmasks KDM4 as a key SASP modulator. KDM4 targeting presents a new therapeutic avenue to manipulate cellular senescence and limit its contribution to age-related pathologies, including cancer.

The increasing number of forensic cases and solitary deaths ("kodokushi") involving older adults warrants targeted methods to serve this growing and vulnerable group. However, age-at-death estimation past midlife remains challenging due to diminished accuracy of traditional macroscopic age markers, often resulting in a single categorization of older age groups as "50 + ." This study evaluates the utility of cortical bone speed of sound (SoS), measured by quantitative ultrasound (QUS), as an alternative biomarker to quantify age-related changes in cortical bone quality and to estimate age-at-death in older adult skeletons. Using QUS, we collected SoS from three peripheral long bones (the radius, tibia, and third phalanx) of 168 anatomical and reference skeletal samples aged 18-103 years. Bayesian linear and generalized additive models were used to model the shift in cortical bone quality from early to late adulthood. Age-at-death predictive model performance was evaluated using correlation (r), mean absolute error (MAE), and credible intervals (CIs). Skeletal SoS reflected nonlinear, sex-specific age-related changes in cortical bone from accrual to loss beyond 40 years. SoS-based age-at-death estimates showed a strong correlation (r ≈ 0.7) with chronological ages, with the lowest MAEs (7.4-8.8 years) observed in the 40-49 and 70-79 age groups. In males, the lowest MAE was observed in the 60-69 age group (3.8 years), and, in females, in the 30-39 age group (5.6 years), followed by the 70-79 age group (6.24 years). This study demonstrates that skeletal SoS offers a biologically justified, non-destructive, fieldwork-suitable alternative to traditional methods for age estimation in older adults.

Premature ovarian insufficiency (POI) and age-related natural-aging ovarian insufficiency (ARNA-OI) pose pressing global health challenges, necessitating effective therapeutic strategies and a deep understanding of their underlying mechanisms. This study investigates how HEP14, a PKC pathway activator, boosts the regenerative potential of human adipose-derived stem cells (hADSCs) for ovarian regeneration. Transcriptome analysis reveals that HEP14 modulates gene expression profile in hADSCs, enhancing their regenerative capacity. In mouse models of POI and ARNA-OI, co-administration of HEP14-empowered hADSCs (h-hADSCs) with HEP14/PLGA microspheres significantly improves ovarian regeneration and function. These effects are attributed to increased h-hADSC retention and transdifferentiation, enhanced antifibrotic and proangiogenic capability, along with an optimized dosing strategy. The upregulation of MMP1, PDGFD, and STC1 through the HEP14-activated PKC-ERK1/2 signaling pathway is crucial for these effects. Our findings highlight the pivotal role of h-hADSCs and the HEP14-activated PKC-ERK1/2 pathway in ovarian regeneration and provide a promising advancement in treating ovarian insufficiency.

Traditional Chinese Medicine (TCM), as a globally recognized phytomedicinal approach, has made significant contributions to healthcare and anti-aging research worldwide. Jingfang Granule (JFG), an established TCM preparation in China, was demonstrated to exert effects on prolonging lifespan and healthspan via the Caenorhabditis elegans model in this study. We employed RNA-seq analysis to investigate the complex genetic interactions through which JFG extends the lifespan of C. elegans. We observed that administering JFG to adult nematodes increased the transcription levels of extracellular matrix (ECM)-related genes (including collagen genes), reproduction-related genes (e.g., egg-1, lin-41), and stress-activated transcription factor-1 (atfs-1). JFG treatment slowed down the functional degradation of organs, such as the cuticle, reproductive system, and mitochondria, leading to enhanced innate immunity and fecundity. Our findings demonstrate that JFG protects nematodes from age-related physiological decline and extends both lifespan and healthspan. This study not only highlights the effects of JFG on delaying aging but also provides a deep understanding of the genetic interactions underlying its anti-aging benefits.

Aging is a complex biochemical phenomenon that considerably impacts both individual health and societal dynamics. Recent researches have emphasized the essential function of metabolism in the processes of aging and longevity. Metabolites-chemical byproducts produced by the host organism and its symbiotic partners, including the microbiota, are generated through numerous metabolic pathways. In the last fifteen years, major progress has been made in elucidating the metabolism of BCAAs and the detailed molecular mechanisms that connect BCAAs homeostasis to the aging process. The growing body of literature presents a comprehensive view of the tissue- and disease-specific regulatory mechanisms governing BCAAs and their activation of various molecular pathways. These pathways link fluctuations in BCAA levels to the onset and progression of age-related diseases. This review seeks to consolidate current knowledge on the factors influencing BCAA levels and their metabolic pathways. It further aims to elucidate the molecular mechanisms linking dysregulated BCAA homeostasis to age-related diseases, evaluate epidemiological evidence correlating BCAAs with various cardiovascular conditions, and identify gaps in current understanding that warrant further investigation.

In this study, the anti-aging potential of melibiose was examined, and its molecular mechanism was elucidated using

The cerebellum supports higher-order cognition, such as working memory and executive function (EF) both directly and through connection with prefrontal areas via cortical loops. Thus, age-related degradation to white matter connectivity comprising cerebello-thalamo-cortical (CTC) loops may underlie age-related differences in EF. In 190 healthy adults (aged 20-94 years) we collected diffusion tensor imaging scans and multiple tests of working memory and EF. Deterministic tractography was used to generate CTC tracts from which white matter metrics (mean, radial, axial diffusivities) were extracted. General linear model results indicated that reduced white matter integrity (i.e., higher diffusivity) was associated with significantly poorer EF performance in an age-dependent fashion. Higher mean, radial, and axial diffusivities in fronto-cerebellar white matter was associated with lower EF scores in older, but not younger, adults. These findings suggest CTC white matter connectivity is important for executive function performance and lend mechanistic evidence to the role of the cerebellum in age-related differences in higher-order cognitive operations.

Immunosenescence, the age-related decline in immune function, profoundly impacts cancer progression and therapeutic outcomes by fostering a tumor-promoting microenvironment and impairing immune surveillance. This review delineates eleven molecular hallmarks of immunosenescence, including genomic instability, telomere attrition, epigenetic dysregulation, mitochondrial dysfunction, and chronic inflammation, which collectively drive immune cell dysfunction and systemic immunosuppression. Aging reshapes the tumor microenvironment (TME) through recruitment of immunosuppressive cells, senescence-associated secretory phenotypes (SASP), and metabolic reprogramming, contributing to therapy resistance and poor prognosis in elderly patients. While immunotherapies such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell immunotherapy (CAR-T) cells show promise, their efficacy in aging populations is limited by T cell exhaustion, myeloid bias, and altered intercellular communication. Emerging strategies-including senolytics, epigenetic modulators (e.g., histone deacetylase (HDAC) inhibitor), and metabolic interventions (e.g., spermidine, nicotinamide mononucleotide (NMN))-highlight potential avenues to rejuvenate aged immunity. Single-cell multi-omics (single cell RNA-seq, single cell ATAC-seq) further unravel immune cell heterogeneity, revealing tissue-specific chromatin accessibility dynamics and novel targets like interleukin-34 (IL-34) for microglia-mediated neuroinflammation. However, challenges persist in translating preclinical findings to clinical practice, necessitating age-tailored trials and biomarker-driven approaches. By integrating mechanistic insights with translational innovations, this review underscores the urgency of addressing immunosenescence to optimize cancer immunotherapy for aging populations, ultimately bridging the gap between aging biology and precision oncology.

Obesity and aging are key research topics in contemporary biomedical science. While studies have explored the effects of obesity on various health indicators, the precise mechanisms through which obesity may affect leukocyte telomere length (LTL)-and whether this impact contributes to accelerated immune cell senescence-remain unclear and warrant further investigation. In this study, we employed single nucleotide polymorphisms (SNPs) associated with four obesity indices-body mass index (BMI), body fat percentage (BFP), waist circumference (WC), and waist-hip ratio (WHR)-as instrumental variables (IVs) to assess the causal relationship between these indices and LTL through Mendelian randomization (MR) analysis. Additionally, we analyzed transcriptome sequencing data from peripheral blood mononuclear cells (PBMCs) across three groups: lean individuals, individuals with obesity before undergoing bariatric surgery, and individuals with obesity after surgery, and focus on the expression changes of cellular senescence and telomere dynamics related genes in PBMCs of individuals with obesity before and after weight loss intervention. The results showed a negative causal relationship between BMI (B=-0.04, P < 0.0001), BFP (B=-0.06, P < 0.0001) and LTL without being impacted by lipid profiles and T2D. The negative causal relationship between WC (B=-0.04, P < 0.0001) and LTL may be dependent on lipid levels, but not on T2D. WHR had no significant causal relationship (P > 0.05). Transcriptomic analysis further revealed that individuals with obesity had higher expression of cellular senescence-related genes such as ID2, LMNA, and TENT4B in PBMCs compared to lean individuals, with expression levels of these genes significantly decreasing after bariatric surgery. These findings underscore the detrimental impact of obesity on telomere attrition and immune cell senescence, highlighting the potential benefits of obesity management for slowing the biological process of cellular and immune aging.

Stem cells play a crucial role in tissue repair, not only by differentiating into progeny that directly replace damaged tissues, but also by secreting diverse factors that support host regeneration. Among these regenerative signals, extracellular vesicles released by stem cells (SC-EVs) have emerged as key mediators of intercellular communication. SC-EVs contribute to tissue repair by delivering their molecular cargo to recipient cells, modulating signaling pathways, metabolic processes, and gene expression. Recent findings suggest that various extracellular proteins dynamically associate with the EV surface, forming a context-dependent layer known as the protein corona. The protein corona interacts with cell-surface receptors and promotes the targeted uptake of SC-EVs, thereby enhancing their therapeutic potential. In this review, we explore the molecular mechanisms underlying the formation of the protein corona and highlight its unique roles in modulating SC-EVs to regulate aging processes, promote regeneration, and maintain tissue homeostasis. We also discuss emerging strategies to engineer the protein corona of SC-EVs through surface cargo modulation, aimed at enhancing their therapeutic potential. This review offers novel insights into the protein corona of SC-EVs as a modulable nanoplatform for their application. A deeper understanding of its properties will be crucial for optimizing cell-free therapies, opening new avenues for advancing regenerative medicine.

Sarcopenia, the age-related loss of muscle mass and function, may be a hidden driver of chronic low back pain (CLBP). This study explores the link between declining muscle quality and persistent back pain, highlighting the importance of early detection, exercise, and nutrition in prevention and treatment. A stronger back starts with stronger muscles. #Sarcopenia #LowBackPain #ChronicPain #MuscleHealth #HealthyAging.

Musculoskeletal disorders (MSDs), notably sarcopenia and osteoporosis, profoundly affect aging individuals. This review explores lipid metabolism's role in age-related MSD pathophysiology, highlighting fatty acid uptake, lipid signaling, and lipotoxicity in muscle deterioration. It further addresses lipid-mediated regulation of osteoclasts, osteoblasts, and bone remodeling, emphasizing age-associated metabolic shifts exacerbating bone loss. Emerging therapeutic strategies targeting lipid pathways for MSD treatment are also discussed. This review integrates recent findings in muscle and bone lipid metabolism to deepen understanding of lipid dysregulation in musculoskeletal disorders and explore potential metabolic intervention strategies.

This review tracks the discovery of circadian biology in cardiovascular science, starting with early clinical observations of daily changes in heart rate, blood pressure, and cardiovascular events. These patterns suggested that time of day matters, but it was not until the past two decades that the mechanisms and knowledge translation of these rhythms were uncovered. We describe the heart's intrinsic circadian properties and importantly how this leads to regulation of cardiac gene and protein expression, neuroendocrine and vascular rhythms, metabolism, cellular electrophysiology, and cell signaling pathways. Next, we explore emerging themes, including the impact of circadian timing on ischemic injury, cardiac aging, and trends in circadian desynchrony, sex, and interorgan crosstalk. Building on these discoveries, circadian medicine is beginning to reshape clinical care including timing of surgery, chronotherapies, biomarkers, ICU design, novel molecular drugs targeting the circadian clock, the role of the microbiome and time restricted eating, the new field of rest, and the concept of One Health and applications to veterinary medicine. Looking ahead we address new frontiers such as epigenetics, gene editing, and spaceflight. Together, these advances offer a roadmap for how circadian rhythms can be harnessed to improve cardiovascular health and disease outcomes, supporting longer and healthier lives.

Histidine containing dipeptides (HCDs) such as N-acetylcarnosine are endogenous metabolites that are ergogenic and mitigate metabolic dysfunction. We previously demonstrated that short-term N-acetylcarnosine treatment is highly efficacious in protecting muscle atrophy induced by disuse. Here we demonstrate that a 6-months treatment of N-acetylcarnosine attenuates a broad spectrum of age-associated maladies and improved survival by ~50% in female mice. A comprehensive survey of organ systems revealed that N-acetylcarnosine prevents decline in adiposity, diastolic function, vasodilation, muscle strength, and bone density. Together, N-acetylcarnosine substantially delays the onset of system-wide end-stage pathology to prolong lifespan. As an endogenously present metabolite, treatment with N-acetylcarnosine may be a safe and promising intervention to promote healthy aging in humans.

Forkhead box-O (FOXO) transcription factors are evolutionarily conserved regulators of several biological processes, including development, stress responses, metabolism and ageing. As downstream effectors of nutrient-dependent cell signalling pathways, including insulin/IGF signalling, they integrate signals from multiple stimuli to orchestrate appropriate transcriptional responses to changes in the nutritional environment. Traditionally, FOXO-dependent responses have been attributed to target gene regulation through direct interactions with regulatory regions by DNA-binding via the conserved Forkhead (FH) domain. However, emerging evidence suggests that FOXO proteins may also influence gene expression through DNA-binding-independent mechanisms. However, differences in transcriptional outputs between DNA-binding dependent and independent FOXO functions have yet to be explored. Here, we have used genomic engineering of the endogenous Drosophila foxo locus to disrupt the DNA-binding activity of the single fly FOXO orthologue, allowing us to dissect the in vivo contributions of canonical and non-canonical dFOXO functions. We show that while DNA-binding is essential for several dFOXO-mediated phenotypes including female fecundity, lifespan, and resistance to oxidative and xenobiotic stress, other traits such as adult body size and survival during starvation remain intact. Notably, DNA-binding-deficient dFOXO flies exhibit defective lipid mobilisation under starvation, implicating a DNA-binding-independent role for dFOXO in metabolic regulation. Differential gene expression analysis during starvation in these mutants revealed key transcriptional changes in genes encoding metabolic regulators as well as regulators of transcription and chromatin structure. Together, these findings reveal distinct modes of dFOXO transcriptional regulation that depend on its direct association with DNA.

A class of persistent organic pollutants, polychlorinated biphenyls (PCBs), are ubiquitous in the environment and human tissues which are continuously and long-term threatened. We aim to investigate the toxic effects and the underlying mechanisms of PCB153 using Caenorhabditis elegans as a model organism. Our findings demonstrated that exposure to an optimized concentration of 2 µmol/L PCB153 had adverse effects on C. elegans, led to reduction of lifespan, body length, frequency of body bending, and head wiggling. Additionally, this exposure led to an increase in the accumulation of reactive oxygen species, superoxide dismutase, lipofuscin and fat content within the organism. Furthermore, gene set enrichment analysis and whole transcriptome sequencing revealed, a significant up-regulation of Cytochrome P450 (CYP) family genes, which are crucial for the xenobiotics metabolism in C. elegans. Knocking down specific genes within the CYPs family, including cyp-35C1, cyp-35A5, cyp-35A3, cyp-34A1, and cyp-34A10, via RNA interference were able to reverse the shortening of lifespan and fat accumulation induced by PCB153 exposure. Moreover, a comprehensive a competing endogenous RNA network was constructed by integrating qPCR-validated differentially expressed mRNA along with lncRNA, circRNA, and miRNA identified by transcriptomic sequencing. This study emphasizes that PCB153 exposure leads to the physiological impairments, particularly fat accumulation and a shorter lifespan, through the modulation of CYP450 family genes. These findings contribute to our understanding of environmental pollutants and their impact on biological systems and provide valuable information on the toxic effects and potential risks associated with PCB153 exposure.

Arsenic, a widespread environmental contaminant, threatens millions globally through contaminated water, soil, and food. While arsenic compounds are used to treat acute promyelocytic leukemia, their toxic legacy includes cancers, cardiovascular disease, diabetes, and neurodegeneration, primarily driven by oxidative stress, mitochondrial dysfunction, and epigenetic instability. Sirtuins, a family of NAD⁺-dependent enzymes, are central to cellular defense, orchestrating metabolism, stress resistance, DNA repair, and longevity. Arsenic disrupts sirtuin function, particularly SIRT1, SIRT2, and SIRT3, via microRNA-mediated silencing and post-translational modifications, impairing antioxidant defenses, disturbing energy metabolism, and accelerating cellular injury across organ systems. However, activating sirtuins with agents like resveratrol, metformin, or berberine, as well as through lifestyle interventions, can counteract arsenic toxicity, restore cellular resilience, and provide new therapeutic strategies. This review synthesizes current knowledge on the interplay between arsenic exposure and sirtuin biology, examining how arsenic alters sirtuin expression and activity, the downstream consequences for cellular signaling and organ health, and emerging interventions targeting sirtuin pathways. By bridging molecular insights with translational potential, we highlight the promise of sirtuins as therapeutic targets in combating arsenic toxicity and guide future research directions.

One of the major challenges in modern biogerontology is understanding the accumulation of molecular damage and the manifestation of phenotypic heterogeneity during aging. Notably, genomic instability caused by impaired DNA damage repair along with telomere attrition are primary drivers of aging. However, how these aging-related characteristics differ in individuals who age healthily without developing major age-associated diseases remains unclear. Here, whole genome sequencing (WGS) was performed on 100 healthy agers (≥ 60 years old, no age-related diseases) and 100 unhealthy agers (≥ 60 years old, at least one age-related disease/condition) based on a case-control study. Telomere length was measured using TelSeq and Computel. High-functional impact germline variant (gHFI) burden and alteration pattern at the pathway level were also analyzed. The GTEx dataset including 751 individuals was used to observe the functional impact of identified germline variants at the molecular level. Telomere length showed minimal differences before 65 years of age but declined rapidly in unhealthy agers beyond this age. Additionally, healthy agers had lower gHFI burden, particularly in DNA repair genes such as BLM. Pathway analysis revealed enrichment of oxidative stress-related mutations in healthy agers, correlated with reduced oxidative stress and upregulated antioxidant enzymes (SOD1 and SOD2). Overall, genomic instability preserved through slow telomere attrition and reduced DNA repair defects plays a key role in healthy aging. Improved oxidative stress resistance may contribute to healthier aging, highlighting the role of genetic factors in reducing age-related decline and supporting overall well-being in later life.

Air pollution is a major environmental and health concern. It has been linked to diseases and contributes to aging. However, there is a lack of studies on the effects of realistic mixtures of air pollutants, notably solvents. Therefore, we investigated the aging effects of benzene, toluene, ethylbenzene, and xylenes (BTEX) airborne exposure using the Caenorhabditis elegans (C. elegans) model, simulating a real scenario. Nematodes at larval stage four (L4) were exposed to benzene (0.9 ppm), toluene (40 ppm), ethylbenzene (25 ppm), and xylenes (17 ppm), either individually or in combination, for seven days in a chamber designed to contain volatile compounds. The results showed that the mixture caused early aging in nematodes, with decreased mobility and mitochondrial function on days 4 (15 % and 40 %), 7 (27 % and 10 %), and 10 (30 % and 5 %). The mixture also increased the damage to physiological and neuronal parameters on days 4 (26 % and 5 %), 7 (70 % and 43 %), and 10 (95 % and 25 %). The Frailty Index analysis revealed elevated values (index above 0.5) on all days in the mixture group compared to the control and isolated groups. The combination index demonstrated that synergism was predominant among the majority of the endpoints assayed. Our findings showed that low-level exposure to BTEX compounds could reduce the healthspan of C. elegans, reinforcing the utility of this model for aging and ecotoxicological studies, and underscoring the risks associated with prolonged exposure to BTEX pollutants in association.

Resistance training is commonly used to prevent the decline in muscle power associated with aging.

An aging population presents significant challenges to cognitive health. Although previous studies have linked hobby participation to improved cognitive health, most focus on specific regions or types of hobbies, lacking cross-cultural exploration. This study examines global trends in hobby participation and their relationship to cognitive function. It also explores how consistent participation in hobbies influences cognitive function over time.

Cardiovascular ageing is a progressive loss of physiological reserve, modified by environmental and genetic risk factors, that contributes to multi-morbidity due to accumulated damage across diverse cell types, tissues, and organs. Obesity is implicated in premature ageing, but the effect of body fat distribution in humans is unknown. This study determined the influence of sex-dependent fat phenotypes on human cardiovascular ageing.

Healthy ageing is a multidimensional process shaped by physical, mental, social and environmental factors across the life course. However, the lack of a standardised framework and inconsistent interpretations of key constructs hinder meaningful comparison across studies and contexts. This article presents a systematically derived framework and structured dataset that capture the constructs, measurement approaches and methodological advancements involved in operationalising healthy ageing. The framework and dataset originate from the systematic review conducted by Piriu et al. (2025), which comprehensively maps the range of concepts, constructs and operational dimensions - measures, metrics, instruments and scales - used in 55 empirical studies that operationalise healthy ageing, each addressing at least two of the three core domains identified by the World Health Organization: intrinsic capacity (IC), functional ability (FA) and the environment (ENV). The Piriu et al. (2025) framework (hereafter PIETHA) introduces a multilayered categorisation of the healthy ageing construct, articulating it into three domains (IC, FA, ENV), 15 sub-domains, and 84 themes. This structure reflects both conceptual and measurement considerations (e.g. subjective vs. objective categories, self-reported vs. assessed/tested) while also providing a novel, detailed organisation of the environmental factors shaping healthy ageing at different levels of analysis (micro, meso and macro). Reflecting this multidimensional structure, the dataset complements the framework by documenting the specific tools employed in healthy ageing operationalisation, including assessment scales, validated instruments and measurement methodologies. By systematically analysing how healthy ageing is operationalised across disciplines, the PIETHA framework and related dataset support the identification of conceptual, empirical and methodological gaps in healthy ageing research. This enables researchers to generate new hypotheses, explore underrepresented areas - such as environmental and psychosocial dimensions - and advance integrative metrics. The framework and dataset also enhance methodological transparency and data reuse due to a structured design anchored in thematic identification, construct classification and comprehensive mapping of measurement practices. This facilitates replication, comparison and innovation in the field by enabling the systematic evaluation of interconnected factors and measurement strategies across studies and contexts. The framework and dataset offer a foundational resource to support the harmonisation of healthy ageing metrics and research strategies. They allow researchers and practitioners to: (i) obtain a structured overview of the concepts, constructs and measurement approaches used in healthy ageing research; (ii) assess the strengths and limitations of existing frameworks and methods, and compare approaches across domains and contexts to ensure we measure what matters; and (iii) address persistent gaps and develop the operational evidence base, especially concerning the contextual factors that enable healthy ageing and longevity. Ultimately, the dataset supports the continued development of robust, context-sensitive knowledge and methods for monitoring healthy ageing globally.

Cellular senescence is a critical process involved in aging and related disorders, yet the molecular triggers of early senescence remain elusive. Here, we identify DNA methyltransferase 1 (DNMT1) downregulation as a key trigger of early senescence and establish serine protease inhibitor Kunitz type 2 (SPINT2) as its critical downstream effector. Using replicative and oxidative stress-induced senescence models of primary human diploid fibroblast, we observed persistent upregulation of SPINT2 and inverse downregulation of DNMT1, preceding senescence-associated β-galactosidase activity, a conventional senescence marker. Pharmacological inhibition and siRNA-mediated knockdown of DNMT1 significantly increased SPINT2 expression and induced senescence, showing mitigated effects by SPINT2 knockdown. Furthermore, SPINT2 overexpression alone induced senescence. Methylation-specific sequencing identified four CpG sites in SPINT2 promoter, that became hypomethylated at early transition of senescence and upon DNMT1 suppression. Functional analyses revealed that DNMT1-mediated SPINT2 expression induced c-Met inhibition, triggering senescence. Transcriptomic profiling identified 17 commonly deregulated c-Met signaling genes in both senescence models, with COL27A1, STAM2, and CBL validated as key downstream targets of SPINT2/c-Met signaling. These findings establish DNMT1-mediated SPINT2 upregulation as a novel epigenetic mechanism driving senescence initiation via c-Met inhibition, providing insights into the early stage of senescence and potential therapeutic targets for aging-related diseases.

Aging is associated with a progressive decline in tissue function and regenerative capacity, partly due to genomic instability, one of the hallmarks of aging

Lifespan extension has not prevented age-related decline. We propose that diet acts as a molecular modulator of aging, influencing inflammation, the microbiome, and systemic resilience. Biological age markers and AI-powered multi-omics reveal actionable dietary targets, including food-derived signals and Nutrition Dark Matter. We highlight precision nutrition and the EIT Food Healthy Aging Think & Do Tank as pathways to align science, policy, and practice for healthy aging.

Pancreatic β-cell function declines with age, but the underlying mechanism is poorly understood. In this study, we attempted to address how to reverse β-cell aging. Our data showed that sirtuin 6 (SIRT6) overexpression can reduce age-associated DNA damage, cell death, and functional decline in β-cells. Our findings suggest that improving Sirt6 gene expression and function may slow down β-cell decline in older patients.

Chronic respiratory diseases impart a huge global disease burden. Many cases of adult chronic respiratory disorders are recognised to originate early in life during critical phases of lung growth and development. We therefore reviewed the longitudinal evolution of common childhood respiratory diseases across the lifespan. We included studies relating childhood respiratory health (preterm birth, asthma, low lung function or bronchiectasis) to respiratory health in adolescents and adults, including COPD.The negative impact of preterm birth (with or without bronchopulmonary dysplasia) on future respiratory health has now been quantified, with many having increasing deviation of lung function from the norm over their life course. While previous studies report children with asthma frequently "outgrow their disease" by adolescence or early adulthood, recent data describe asthma trajectories that include relapse, early-onset adult-remitting, and early-onset persistent childhood asthma. Evidence is emerging in adults of the negative impact of chronic productive cough, breathlessness and lower lung function on future respiratory and cardiovascular health and all-cause mortality. In addition, we found that in general, childhood respiratory health and adverse lung function trajectories are inextricably linked to adult respiratory health and cardiovascular events, as well as cardiovascular and all-cause mortality. Thus, we highlight the importance of pulmonary assessments in high-risk groups during childhood (

This study explores the relationships between biochemical phenotypes identified using machine learning, and key health outcomes, including body composition, physical function, and mortality risk. Data were collected from 536 physically active Spanish participants aged over 65 years (76.5% women) enrolled in the EXERNET cohort (2017-2018), with a 6-year mortality follow-up. Principal component analysis, and hierarchical and k-means clustering was used to identify distinct biochemical profiles. Associations between clusters and health outcomes were assessed using analysis of covariance and Cox proportional hazards models. Three distinct clusters emerged: 'Healthy', characterized by biochemical values within the normal range and used as the reference group; 'Metabolic', marked by dysregulated metabolic parameters; and 'Hepatic', which exhibited impaired liver function markers. Notably, all clusters showed subclinical levels of dysfunction. The 'Healthy Cluster' demonstrated the highest levels of organized physical activity (90%, p < 0.001), whereas the 'Metabolic Cluster' showed poorer body composition and reduced physical performance. Both the 'Metabolic' and 'Hepatic' clusters demonstrated a higher mortality risk, as confirmed through Cox regression analyses. Adjusted hazard ratios were significantly elevated when considering physical activity and adiposity, with values of 3.45 and 3.71 for the 'Metabolic Cluster', and 3.01 and 3.85 for the 'Hepatic Cluster' (p < 0.05). This study underscores the strong link between metabolic health, physical activity, body composition and 6-years mortality risk in older adults. Machine learning techniques for identifying phenotypic clusters offers a promising tool for early detection and targeted interventions to improve aging outcomes.

Aging is associated with changes in brain structure and connectivity and decrements in certain cognitive abilities. The benefits of active lifestyles in the aging brain and cognition in older adults have been widely described. This work aimed to explore the associations between brain parameters and cognitive performance in a sample of cognitively active adults who participate in University Programs for Seniors (UPS).

Background We used a genome-wide polygenic lifespan score (PLS) to investigate whether genetic predisposition to a longer lifespan is associated with lower mortality risk and how this association compares with associations between long-term lifestyle factors and mortality. Methods A PLS was computed for the Older Finnish Twin Cohort (mean age 57{middle dot}4 years; 45{middle dot}2% males; N=5575). Cox regression models were used to analyse the effects of the PLS on all-cause mortality risk before and after adding covariates (sex, physical activity, BMI, alcohol consumption, smoking, and education level). Differences between concordance indices (C-indices) were used to evaluate each predictor's contribution to the model's discriminatory performance. Findings Over a mean follow-up of 17{middle dot}5{+/-}8{middle dot}3 years, 1405 deaths (25{middle dot}2%) were recorded. A one standard deviation increase in the PLS was statistically significantly associated with a lower all-cause mortality risk (hazard ratio [HR]=0{middle dot}838, 95% confidence interval [CI]=0{middle dot}792-0{middle dot}887) and remained relatively unchanged after adding all covariates (HR=0{middle dot}863, 95% CI=0{middle dot}816-0{middle dot}912). Smoking 20 or more cigarettes per day showed the strongest association with increased mortality risk (HR=3{middle dot}341, 95% CI=2{middle dot}751-4{middle dot}056), whereas female sex was linked to the greatest risk reduction (HR=0{middle dot}678, 95% CI=0{middle dot}597-0{middle dot}770). Smoking had the largest impact on model discrimination ({Delta}C-index=0{middle dot}027), whereas all other covariates increased the C-index by less than 0{middle dot}006. Interpretation Genetic predisposition to a longer lifespan was associated with a small decrease in all-cause mortality risk. This association remained after adjusting for lifestyle factors and covariates. Smoking behaviour and female sex were stronger predictors of mortality than genetic scores for lifespan. Funding This study was funded by the Research Council of Finland (341750, 346509, and 361981 for ES) and the Juho Vainio, and Paivikki and Sakari Sohlberg Foundation (ES). Finnish Twin Cohort data collection was supported by the Research Council of Finland (264146, 308248, 336823, and 352792 for JK), the Wellcome Trust Sanger Institute, the Broad Institute, ENGAGE, and FP7-HEALTH-F4-2007 (201413).

Black older adults experience worse brain and cognitive aging than White older adults, on average. Racially patterned psychosocial stressors may contribute to these disparities. Maintaining white matter health is important for cognitive aging, particularly among Black older adults, and it is uniquely vulnerable to stress. Examining associations between racial discrimination and white matter may elucidate mechanisms of disparities. A sample of Black older adults in the Washington Heights-Inwood Columbia Aging project were included (N = 217). Everyday and major life discrimination were self-reported on well-validated scales. Diffusion tensor imaging quantified white matter fractional anisotropy (FA). Multivariable regressions revealed more major life discrimination was associated with lower FA in the cingulum cingulate gyrus, forceps major, forceps minor, and inferior fronto-occipital fasciculus but greater FA in the superior longitudinal fasciculus temporal projection. Everyday discrimination was not associated with FA. Findings suggest that institutional racism may have a stronger effect on white matter tracts corresponding to cognitive and emotional/affective processing than interpersonal racism. White matter health may be a mechanism through which racially patterned stressors contribute to disparities in brain and cognitive aging.

Energy restriction is closely related to cellular senescence and species longevity. Here, based on the structure and function of ATP synthase, a key enzyme for energy generation, we develop energy metabolism-engaged nanomedicines (EM-eNMs) to rejuvenate aged stromal/stem cells, and help to prevent skeletal ageing. We show that EM-eNMs infiltrate the mitochondria of aged bone marrow mesenchymal stromal/stem cells (BMMSCs), driving mitochondrial fission, mitophagy, glycolysis and maintaining BMMSC stemness and multifunction. The EM-eNMs directly bind to the ATP synthase and promote mitophagy through induction of the dynamin-related protein 1 (DRP1) gene. Remarkably, EM-eNMs selectively target bone tissues through systemic delivery and significantly reverse osteoporotic bone loss in aged mice by enhancing mitochondrial fission and mitophagy, while simultaneously restoring the stemness and osteogenic potential of aged BMMSCs in situ. Taken together, our findings highlight the potential of the EM-eNMs as a targeted therapy to alleviate cellular senescence and age-related diseases.

Aging is a multi-modal process, leaving distinct signatures across molecular layers, including the epigenome. DNA methylation changes are among the most robust markers of biological aging. Yet, most studies rely on models assuming linear relationships with age and often analyze mixed-sex cohorts, overlooking well-known sex differences in the timing and nature of aging phases. Such approaches risk obscuring critical, non-linear transitions and sex-specific trajectories that may better capture the biology of aging. We developed a computational approach to detect complex, non-linear trajectories and disentangle shared from sex-divergent patterns. Applied to whole-blood deconvoluted methylomes from 252 females and 246 males spanning ages 19-90 years, this analysis revealed convergent and divergent epigenetic aging pathways independent of immune cell composition. These non-linear trajectories were enriched for developmental transcription factor binding motifs, including NF1/CTF and REST, which are known for their oncogenic potential. Strikingly, a female-specific non-linear cluster was robustly associated with cancer onset and systemic inflammation. Our results uncover sex-specific, non-linear aging programs that better capture the dynamics of epigenetic change than linear models. These findings nominate candidate biomarkers for early disease risk and offer mechanistic insight into how aging trajectories diverge between the sexes.

Understanding cellular and molecular drivers of age-related cognitive decline is necessary to identify targets to restore cognition at old age. Here we identify ferritin light chain 1 (FTL1), an iron-associated protein, as a pro-aging neuronal factor that impairs cognition. Using transcriptomic and mass spectrometry approaches, we detect an increase in neuronal FTL1 in the hippocampus of aged mice, the levels of which correlate with cognitive decline. Mimicking an age-related increase in neuronal FTL1 in young mice alters labile iron oxidation states and promotes synaptic and cognitive features of hippocampal aging. Targeting neuronal FTL1 in the hippocampi of aged mice improves synaptic-related molecular changes and cognitive impairments. Using neuronal nuclei RNA sequencing, we detect changes in metabolic processes, such as ATP synthesis, and boosting these metabolic functions through NADH supplementation mitigated pro-aging effects of neuronal FTL1 on cognition. Our data identify neuronal FTL1 as a key molecular mediator of cognitive rejuvenation.

Caloric restriction (CR) can enhance human health, though underlying mechanisms, particularly related to energy expenditure, remain unclear. This ancillary investigation of the only randomized controlled trial of long-term CR in normal-weight adults, aimed to quantify metabolic adaptation following weight loss by assessing changes in energy-expending tissues and organs using magnetic resonance imaging (MRI). Participants in the CR group were prescribed 24-month 25% CR causing a ~ 13% weight loss at 12 months followed by 12 month weight maintenance, whereas the control group maintained ad libitum food intake throughout. The CR group experienced reductions in adipose tissue and skeletal muscle mass compared to the control group. Sleeping energy expenditure decreased more than predicted at 12 months, regardless of whether predictions were based on body mass, dual x-ray absorptiometry (DXA)-derived body composition, or MRI-derived tissue mass. MRI-derived models explained slightly more variation in energy expenditure at baseline and detected greater metabolic adaptation than simpler models based on body mass only. At 24 months, only the models based on DXA and MRI were indicative of persistent metabolic adaptation. These findings highlight the complexity of metabolic responses to CR. Further, advanced imaging techniques hold potential to provide insight into organ-specific contributions to energy metabolism during CR.

The gut microbiota of centenarians plays a vital role in promoting healthy longevity. We performed a cross-sectional study of 224 people from Jiaoling, China, which is globally recognised for the longevity of its residents. Compared with younger people, centenarians showed significantly increased alpha-diversity, enrichment of the beneficial bacteria Lactobacillus, Akkermansia, and Christensenella, and increased redox capacity in the gut microbiota. Serum metabolomics of centenarians showed significant enrichment of antioxidant metabolites, including L-ascorbic acid 2-sulphate and lipoic acid. Finally, we isolated and screened a strain of Lactobacillus plantarum 124 (LP124) with a good antioxidant effect on the gut microbiota of centenarians. Animal experiments further verified that mesaconic acid from LP124 regulates the gut microbiota, is anti-inflammatory, relieves oxidative stress, maintains the intestinal barrier, and is the best-known anti-aging molecule. LP124 derived from the gut microbiota of centenarians and its metabolite mesaconic acid, have a significant positive effect on health and longevity.

Parthanatos, a form of programmed cell death that is heavily dependent on redox imbalance, is gaining attention for its important role in cardiovascular disease (CVD) and myocardial aging. Its core mechanism involves hyperactivation of poly (ADP-ribose) polymerase-1 (PARP1), triggered primarily by oxidative stress-induced DNA damage. This hyperactivation initiates a detrimental cascade: excessive consumption of NAD+ and ATP leads to cellular energy crisis, while the resultant accumulation of poly (ADP-ribose) (PAR) polymers facilitates the nuclear translocation of apoptosis-inducing factor (AIF), culminating in large-scale DNA fragmentation and cell demise. Crucially, this pathway intertwines with oxidative stress, forming a vicious cycle that amplifies cellular damage. Within CVD, parthanatos is implicated in the pathogenesis of myocardial ischemia/reperfusion (MI/R) injury, atherosclerosis, and heart failure. Furthermore, in myocardial aging, the age-related accumulation of oxidative stress and DNA damage promotes parthanatos activation, contributing to cardiomyocyte loss, fibrosis, and functional decline. Understanding this redox-dependent death pathway reveals novel therapeutic targets, including PARP1 inhibitors, strategies to block AIF translocation, NAD+ precursors to restore redox and energy balance, and exercise interventions that enhance antioxidant defenses. Elucidating the intricate interplay between parthanatos and redox signaling offers significant potential for developing interventions to combat CVD and age-related cardiac dysfunction.

As we age, our brain is influenced by experience and intrinsic biological changes. This combination of external and internal factors shapes the way in which our brain functions. Neuronal plasticity processes can store information about the sensory world and regulate neural-circuit activity levels to maintain stable neural-circuit function. These learning- and homeostasis-related plasticity processes exhibit age-related changes. Developing a better understanding of such age-related changes may open opportunities for rejuvenation strategies that promote plasticity and improve neurological health in later life. Here we review some of the latest work investigating age-related plasticity changes with a specific focus on sensory cortices. We propose that a better understanding of age-related tipping points in the context of plasticity could facilitate timed intervention strategies that may promote resilience during aging, by boosting the efficacy of endogenous plasticity mechanisms.

Both air pollution and lifestyle are associated with cognitive function, with air pollution being detrimental and positive lifestyles being beneficial. The extent to which a favorable lifestyle can mitigate the harmful effects of air pollution on cognitive function in later life warrants further investigation.

This study aimed to evaluate the predictive capacity of the Body Roundness Index (BRI), Abdominal Body Shape Index (ABSI), Waist-to-Weight Index (WWI), and Waist-to-Height Ratio (WHtR) for sarcopenic obesity (SO) incidence among older adults in China using data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). The cohort included 3,919 participants aged 65 and older, with a mean follow-up of 2.79 years. Sarcopenic obesity was defined by low muscle mass and high body fat. Multivariate Cox proportional hazards regression models and Generalized Additive Models (GAMs) based on the Poisson distribution were used to assess the associations and predictive performance of these indices. After adjustment, BRI (HR: 1.037, 95% CI: 1.014, 1.060), ABSI (HR: 13.247, 95% CI: 1.677, 104.660), WWI (HR: 1.023, 95% CI: 1.006, 1.040), and WHtR (HR: 1.007, 95% CI: 1.003, 1.010) were significant predictors of SO incidence. Threshold effect analyses revealed non-linear relationships for BRI and WHtR. The predictive model based on GAMs demonstrated strong discrimination (C-index: 0.879 for the modeling set and 0.876 for the validation set) and good clinical utility. These findings highlight the importance of early intervention for individuals with abdominal obesity to prevent future sarcopenic obesity, thereby reducing disease and social burdens and improving the quality of life for the elderly.

A hallmark of aging is chronic systemic inflammation, which is exacerbated by the hypersecretory aging phenotype known as the senescence-associated secretory phenotype (SASP). How the SASP is initiated to accelerate tissue inflammation and aging is an outstanding question in aging biology. Here, we showed that phosphorylation of the Mediator subunit MED15 at T603 is able to control the SASP and aging. Transforming growth factor-β selectively induces CDK1-mediated MED15 T603 phosphorylation to control SASP gene expression. The MED15 T603 dephosphorylated mutant (T603A) inhibits the SASP and cell senescence, whereas the T603 phosphorylation-mimicking mutant (T603D) has the opposite effect. Mechanistically, forkhead box protein A1 preferentially binds to unphosphorylated but not phosphorylated MED15 at T603 to suppress SASP gene expression. Notably, aging mice harboring dephosphorylated mutation in this phosphosite exhibit improved learning and memory through the attenuation of the SASP across tissues. Overall, our study indicates that MED15 T603 phosphorylation serves as a control switch for SASP production, which underlies tissue aging and cognitive decline and provides a novel target for age-related pathogenesis.

The emergence of SARS-CoV-2 has posed significant threats to global health, particularly for the older population. Similarly, common human coronaviruses, such as HCoV-229E, which typically cause mild cold-like symptoms, have also been linked to severe diseases, underscoring the need to understand virus-host interactions and identify host factors contributing to viral pathogenesis and disease progression. In this study, we performed a genome-wide CRISPR knockout screen using HCoV-229E and identified Ubiquitin-like with PHD and RING finger domain 1 (UHRF1) as a potent restriction factor. Mechanistically, UHRF1 suppressed HCoV-229E infection by downregulating the expression of its cell entry receptor, aminopeptidase N (APN), through promoter hypermethylation. Focused CRISPR activation screens of UHRF1-downregulated genes confirmed the critical role of APN in HCoV-229E infection and identified additional genes (e.g., SIGLEC1, PLAC8, and heparan sulfate biosynthesis genes) contributing to the restrictive functions of UHRF1. Transcriptomic and single-cell RNA sequencing analysis revealed that UHRF1 expression decreases with age, negatively correlating with increased APN expression. This age-related decline in UHRF1 was further validated in primary alveolar macrophages isolated from elderly individuals, which exhibited heightened susceptibility to HCoV-229E infection compared to those from younger individuals. Our findings highlight UHRF1 as a key age-related host defense factor against coronavirus infection and provide novel insights into the epigenetic regulation of viral entry receptors.

Cell cycle progression presents a fundamental challenge to genome integrity, particularly due to the need to reestablish post-translational histone modifications (PTMs) following DNA replication. Although proliferative and differentiating tissues exhibit markedly different cell cycle dynamics, how these differences shape the histone modification landscape in vivo remains largely unexplored. Here, we show that levels of H3K27ac, H3K27me3, and H3K9me3 are tightly linked to cell cycle dynamics in the Drosophila wing imaginal disc. We demonstrate that both physiological and pathological elongation of the cell cycle led to an accumulation of H3K9me3 and H3K27me3, whereas cell cycle acceleration reduces their levels. In contrast, H3K27ac exhibits the opposite pattern: levels decrease in arrested cells and increase with faster cycling. Genome-wide CUT&Tag analysis reveals that these changes predominantly affect genomic loci already modified in normally proliferating tissue. Importantly, the regulation of methylation levels at H3K9 and H3K27 is not solely mediated by the cell cycle machinery but reflects a metabolically guided process in which the rate of methylation is coupled to the rate of cell proliferation through metabolic activity, including signaling via the Insulin/PI3K/Akt pathway. Our study thus reveals key principles for understanding histone methylation in proliferating, senescent, and differentiating cells. In contrast, H3K27 acetylation is regulated through a distinct, cell cycle-coupled mechanism. We find that CBP/Nejire-mediated acetylation of H3K27 peaks during S-phase and is reversed by HDAC1, as cells exit replication. Disruption of this acetylation cycle leads to replication stress and a G2 cell cycle arrest via a DNA damage checkpoint. Notably, this genome-protective function of CBP/Nejire depends specifically on acetylation of the H3K27 residue itself, revealing a novel role for H3K27ac beyond its well-established function in transcriptional activation. Together, our findings establish a robust link between cell cycle progression and histone modification dynamics, highlighting the necessity of maintaining balanced PTM levels under varying proliferative states. These insights have broad implications for our understanding of development, aging, and tumor growth.

Aging disrupts physiological and behavioral homeostasis, largely driven by one-carbon metabolism, mitochondrial, and metabolic imbalance. To elucidate the roles of conserved metabolic and mitochondrial genes in age-related decline, we employed genetic manipulations in vivo using Drosophila melanogaster models, in a cell-autonomous and non-cell-autonomous manner. By using panneuronal and indirect flight muscle (IFM) specific drivers, we assessed the impact of gene knockdown (KD) or overexpression (OE) on sleep-circadian rhythms, locomotion, and lipid metabolism in a cell-autonomous and non-cell-autonomous manner to address bidirectional neuro-muscle communications. KD of genes such as SdhD and Gnmt leads to a decrease in flight performance, especially in 6 weeks with both drivers. Panneuronal knockdown of genes did not impact the locomotory performance. Whereas knockdown of mAcon1, LSD2, Ampkα, Ald, and Adsl genes showed reduced flight performance, with only IFM-specific driver emphasizing the cell-autonomous role of metabolic genes. Panneuronal KD of Ald, GlyP, mAcon1, and Gnmt genes showed increased total sleep, reduced activity, while Adsl and Ogdh knockdown led to sleep fragmentation, in a mid-age suggests cell-autonomous impact. Functional analysis of AMPK signaling via overexpression and knockdown of Ampkα, as well as expression of the mutant overexpression SNF1A and its kinase-dead mutant, revealed kinase-dependent, age- and tissue-specific modulation of sleep and activity rhythms. Lipid analysis showed that panneuronal overexpression of Ampkα altered lipid droplet number and size in the brain, indicating disrupted lipid homeostasis during aging. These findings on various genes provide us with an understanding of their diverse effects on sleep-activity rhythms, locomotor effects, and communication in cell and non-cell-autonomous roles. Our study emphasizes Ampkα as a central regulator of behavioral and metabolic aging, linking neuronal energy sensing, motor function, and lipid dynamics, and offers mechanistic insights into tissue-specific metabolic regulation with potential relevance for interventions targeting age-related decline and neurodegeneration.

Brain aging significantly impairs cognitive and behavioral functions. While some nonlinear aging studies have identified age-specific aging peaks at certain ages, the influence of different cell types on brain aging fluctuations across the lifespan remains unclear. This study, approaching from the interdisciplinary perspective of brain aging and systems dynamics, extends the nonlinear aging analysis to the cellular level, using single-cell transcriptomic data to analyze 45 healthy elderly brain samples aged 29-94 years. Describing cellular and molecular differences in the aging process, neuron proportion is downregulated but relatively stable with low variability after aging, while glial cells are significantly upregulated and highly unstable. Notably, peaks in nonlinear molecular fluctuations are observed in aging at ages 60, 70, and 79. The nonlinear features prompted the introduction of a dynamic network biomarker and the identification of 56-60 years as the tipping point in the brain's healthy aging process, then suggesting that glia predominantly mediate this process and exploring the underlying features and mechanisms. This work investigates the tipping point of aging at single-cell resolution and provides new research strategies for early diagnosis and intervention of aging-related neurological diseases.

Acute kidney injury (AKI) can lead to chronic kidney disease (CKD), a transition driven by cellular senescence, a state of irreversible cell-cycle arrest. However, the molecular mechanisms promoting this pathological process remain unclear. Here we show that the channel protein Pannexin1 (Panx1) promotes this detrimental senescence and subsequent kidney fibrosis. We found that Panx1 functions in a noncanonical role as a calcium (Ca

Brain aging is a major risk for neurodegeneration, yet the underlying molecular mechanisms remain poorly understood. Here we performed an integrative proteo-transcriptomic analysis of the aging mouse brain, uncovering molecular signatures of aging through the assessment of protein aggregation, mRNA relocalization, and comparative proteomics across eight models of premature aging and neurodegeneration. We identified dynamic changes in physiological aging highlighting differences in synaptic maintenance and energy-allocation. These were linked to changes associated with fundamental protein biochemical properties such as size and net charge. Network analysis highlighted a decrease in mitochondrial complex I proteins not compensated at the mRNA level. Aggregation of 60S ribosome subunits indicated deteriorating translation efficiency and was accompanied by mitochondrial and proteasomal imbalance. The analysis of the nine models revealed key similarities and differences between physiological aging and pathology. Overall, our study provides an extensive resource on molecular aging, and offers insights into mechanisms predisposing to neurodegeneration, easily accessible at our Brain Aging and Molecular Atlas Project (BrainAging-MAP) website.

The 'INStitute for Prevention' 'healthy agIng' and 'medicine Rejuvenative' 'translational' (INSPIRE-T) study is a 10-year observational study. The primary objective of which is to study trajectories of aging across lifespan from the perspective of intrinsic capacity (IC) through deep clinical and biological phenotyping.

Background. Population aging is a major demographic challenge, particularly in low- and middle-income countries, where the burden of chronic and neurocognitive conditions is projected to grow sharply. Objectives. This scoping review aimed to synthesize scientific evidence on interventions that promote healthy aging across the life course. It was conducted following the Joanna Briggs Institute PCC framework. Methods. A systematic search was performed across PubMed, Scielo, EMBASE, PsycINFO, Cochrane, and LiLACS, without language or date restrictions. Results. From 5,808 records screened, 219 studies met the inclusion criteria, comprising systematic reviews, meta-analyses, clinical trials, quasi-experimental, and observational studies. Interventions were classified by thematic domains, including physical and mental health, social participation, education, technology, nutrition, public policy, and cultural aspects. Conclusions. Most studies focused on adult and older populations, with physical and mental health representing the predominant areas addressed, while other dimensions were less represented. Significant gaps remain regarding racially diverse populations, advanced-aged older adults, genetic stratification, and life-course perspectives, underscoring the need for diversified research designs to guide equitable and comprehensive healthy ageing strategies. Key words: Aging, healthy aging, life course, health interventions, aging.

Continuous metabolic monitoring is essential for assessing lifestyle-related disease risks. Hair, an easily accessible tissue, allows for long-term metabolic evaluation, with glycated proteins linked to diabetic complications found in hair. We established a mass spectrometry system to detect advanced glycation end products (AGEs) in hair samples from humans and rats, assessing their variations with aging and disease. Hair samples were hydrolyzed and processed using a cation-exchange column for mass spectrometric analysis. Regardless of temperature variations, the levels of AGEs [N

The search for drugs that extend lifespan in human-like biological models is a frontier area in biomedical research. In this study, we report a novel electrochemical approach using flufenamic acid (FFA), a widely known nonsteroidal anti-inflammatory drug (NSAID), to generate and detect its pharmacologically active metabolites. Electrochemical oxidation of FFA on multi-walled carbon nanotubes(MWCNT)-modified electrode yielded hydroxylated derivatives, primarily 4-hydroxy FFA (m/z 297.05 g/mol) and a polyhydroxylated product termed FFA-Redox (m/z 243.05 g/mol), as surface-confined species (MWCNT@FFA-Redox). To establish biological relevance, Caenorhabditis elegans (C. elegans) were exposed to FFA, resulting in in vivo formation of metabolites identical to those generated electrochemically. This confirmed the physiological significance of the electrosynthesized compounds. Lifespan assays demonstrated that FFA-Redox prolonged the survival of C. elegans by up to 40% under Klebsiella pneumoniae infection and by up to 80% under Staphylococcus aureus infection. This protective effect was attributed to reduced levels of intracellular reactive oxygen species (ROS). Mechanistic insights suggest that FFA-Redox induces a "de-aging" response by enhancing the expression of superoxide dismutase (SOD), a key antioxidant enzyme activated during oxidative stress.

Altered neuromuscular strategies are suggested to contribute to age-related decreases in postural stability. Current approaches tend to overlook global (whole body) neuromuscular postural control strategies, potentially due to methodological constraints or residual influence from a longstanding, but outdated, biomechanical view in which postural sway is represented by a single-jointed inverted pendulum. In this study, we investigate age-related differences in postural strategies during upright static balance maintenance by assessing global neuromuscular control. We collected simultaneous posturography and electromyography (EMG) data from young (18-35 years, n = 32) and older (65-85 years, n = 33) participants while they stood upright on a force plate or on foam pads thereon, with eyes open or closed. Postural instability was assessed by the standard deviation and velocity of the center of pressure. EMG sensors recorded the activity of thirty muscles (15 on each hemibody). Co-contraction across all muscle pairs was measured with Falconer's co-contraction index (CCI), and muscle synergy with non-negative matrix factorization. The older group possessed increased global co-contraction intensity, marked by more frequent use of a knee extensor synergy, and was more unstable than the younger group. Notably, advancing age modulated the variability of co-contraction intensity, where the oldest individuals consistently adopted a pure co-contraction strategy marked by the highest CCI values and lowest variability. Age-corrected correlations revealed that knee extensor CCI values were significantly related to postural instability. Taken together, global co-contraction appears to be a signature of elderly postural strategy and age-related instability may be directly related to the extent of knee extensor co-contraction. These results stress the importance of zooming out from classical agonist-antagonist muscle pair investigations in the endeavor to understand elderly postural control strategy.

Senescent cardiac fibroblasts (CFs), which are activated and acquire a pro-fibrotic phenotype, exacerbate age-related interstitial fibrosis and cardiac dysfunction by unclear mechanisms. Traditionally regarded as a central organ involved in regulating aging, the small intestine (SI) communicates with remote organs. However, the mechanisms underlying its role in CFs senescence remain undefined. We aimed to clarify whether the SI epithelium-derived exosomes (SI-exos) and their contained microRNAs could regulate CFs senescence and participate in deteriorating cardiac fibrosis during aging. Systemic administration of aged SI-exos exerted deleterious effects on the hearts of young recipient mice, as evidenced by exacerbated cardiac aging, inflammation, fibrosis, and the resulting poorer cardiac function. In vitro studies revealed that aged SI-exos could induce the activation and senescence of young CFs, while treatment with young SI-exos mitigated the activation and senescence of aged CFs. Mechanistic investigation identified that miR-223-3p was a common molecule significantly increased both in aged SI-exos and aged serum-exos. Incubation of young CFs with miR-223-3p mimics exacerbated cellular activation and senescence by cooperatively suppressing target genes: RASA1 and KLF15. In contrast, miR-223-3p inhibitor could rescue D-gal-induced CFs activation and senescence. Over-expression of RASA1 or KLF15 significantly rescued miR-223-3p-induced CFs activation and senescence. Summarily, our findings demonstrate for the first time that miR-223-3p enrichment in aged SI-exos, and its suppression of RASA1 and KLF15 in CFs, is a novel potential mechanism exacerbating cardiac aging and fibrosis. Targeting miR-223-3p mediated pathological communication between the aged SI epithelium and CFs might be an effective strategy for cardioprotection during aging.

Astrocytes play a critical role in neuroinflammation and the pathogenesis of neurodegenerative diseases. Here we found that human induced pluripotent stem cell (iPSC)-derived astrocytes responded differently to inflammatory triggers compared to rodent astrocytes, showing increased neurotoxicity when exposed to TNF- and IFN-{gamma}. Furthermore, astrocytes with senescent features showed even higher levels of neurotoxicity in the presence of TNF- and IFN-{gamma}, suggesting a potential link between aging and neurodegenerative diseases. It was also demonstrated that LPS-activated neuron/astrocyte/microglia tri-culture produced TNF-, leading to neurotoxicity in the tri-culture when IFN-{gamma} was present. Through compound screening, we identified Janus kinase inhibitors capable of preventing neurotoxicity in astrocytes induced by TNF- and IFN-{gamma}, demonstrating the potential use of neurotoxic astrocytes as a platform for drug screening. These results provide insight into the complex relationship between aging, inflammation, and neurodegenerative diseases, emphasizing the potential of targeting astrocytes as a novel therapeutic approach for addressing neurodegenerative diseases.

Patterns of brain aging are generally conserved among primates; however, there is marked variation in the observed rate among individuals, species, and brain regions. The hippocampus is a region particularly susceptible to the aging process. To better understand how the hippocampus changes over the lifespan, we measured gene expression in 96 banked hippocampus samples from adult male and female rhesus macaques aged 3-35 years old. Importantly, our dataset included representation across adulthood allowing us to characterize age-related patterns in gene expression during midlife, a period often underrepresented in studies of aging. We used autoregressive integrated moving average models to examine age-associated changes in gene expression to identify 2679 differentially expressed genes (FDR < 0.05) that fit four broad patterns of expression: linearly upregulated or downregulated across age, and two clusters with nonlinear patterns. Importantly, the nonlinear clusters highlight transitions in expression trajectories centered around ~ 10 years of age (~ 30 years of age in humans) indicating an important period that may have a critical impact on hippocampal aging. Changes in gene expression variance across age found that genes in individuals > 20 years of age (> 50 years of age in humans) have greater variance in expression than individuals aged 10-20 years (FDR < 0.05). Collectively, our results highlight molecular changes occurring during midlife which may shape brain aging in longer lived primates and may offer insight into increased susceptibility to neurodegenerative disease in humans.

Rapamycin (RPM) extends longevity in various species and combats vascular senescence related diseases. Selenium nanoparticles (SeNPs) have attracted attention as a potential therapy for cardiovascular diseases due to their excellent antioxidant and drug-carrying capacity. However, RPM coated SeNPs (RPM-SeNPs) have not been reported and their potential for preventing endothelial oxidative senescence remains unclear. In the present study, RPM-SeNPs were generated by selenite and RPM with ascorbic acid reduction. Stability and dispersity of SeNPs were increased by coating with RPM, resulting in an average diameter of 67.51 ± 2.07 nm with a RPM:Se molar ratio of 1:120. Notably, RPM-SeNPs exhibited ameliorative effects on oxidative endothelial senescence in mouse aortas or MAECs induced by paraquat or hydrogen peroxide, respectively. There were evidenced by decreased SA-β-gal activity, lower SASP levels, and decreased endothelial dysfunction. Mechanically, RPM-SeNPs reduced oxidative stress in endothelial cells by upregulating GPX4, particularly mitochondrial GPX4 (mtGPX4) that mitigated of ROS and relieved mitochondria dysfunction. By downregulating the PI3K/Akt/mTOR pathway, RPM-SeNPs inhibited ULK1 phosphorylation at Ser757, subsequently leading to the activation of mitophagy and the reversal of mitochondrial dysfunction, including mitochondrial membrane potential collapse and ATP deficiency. Thus, these results suggest that RPM-SeNPs rescue endothelial cells from oxidative stress induced senescence by upregulating mtGPX4 and activating mitophagy. These results provide insight into the mechanisms of functionalizing SeNPs for potentially treating senescence-related diseases.

The blood-brain barrier (BBB) serves as a critical boundary between the peripheral circulation and the brain. Brain endothelial cells (BECs), which form the inner lining of cerebral blood vessels, play a key role in maintaining this barrier. They express tight junction proteins that prevent molecules from leaking between cells into the brain and efflux transporters that actively remove substances from the brain. As we age, the BBB becomes leaky and dysfunctional, leading to cerebrovascular diseases and dementia. Here, we investigated how BECs become senescent, a major feature of aging, and change their metabolic profile. First, we demonstrate that both the chemotherapeutic doxorubicin, a known inducer of cellular senescence, as well as hydrogen peroxide, a mediator of oxidative stress, induce BEC senescence. This was indicated by positive senescence-associated {beta}-galactosidase staining (P = 0.002 and P = 0.001 for doxorubicin and H2O2, respectively) and increased P16 gene expression (both P = 0.004). Next, we analyzed the metabolic profile of the senescent cells using mass spectrometry. We identified 47 significantly altered metabolites (P < 0.05) in cells and 65 in the supernatant samples of doxorubicin-induced senescent cells, as well as, 53 significantly altered metabolites in cells and 82 in the supernatant samples of H2O2-induced senescent cells. There was an overlap of 10 and 44 metabolites between both treatments in the cell and supernatant samples, respectively. Of those, 9 cellular and 12 supernatant metabolites have already been reported in the literature to be changed during senescence in the brain or other organs. We also identified new metabolites and provide pathway analyses of the significantly altered metabolites. These analyses are the first to characterize BBB cell senescence at a metabolite level and provide the basis for the development of novel therapeutic interventions for age-related neurological disorders.

Sodium chloride (NaCl) is an essential nutrient, but it is toxic in excess. In humans, excessive dietary NaCl can cause high blood pressure, which contributes to age-related diseases, including stroke and heart disease. We used Caenorhabditis elegans to elucidate how NaCl levels influence animal aging. Most experiments on this animal are conducted in standard culture conditions: Nematode Growth Medium (NGM) agar with a lawn of E. coli. Here, we report that the supplemental NaCl in standard NGM, ∼50 mM, accelerates aging and decreases lifespan. For comparison, we prepared NGM with reduced NaCl or excess NaCl. Considering reduced NaCl as a baseline, wild-type worms on standard NGM displayed normal development and fertility but reduced lifespan and health span, indicating toxicity in old animals. The long-lived mutants daf-2, age-1, and nuo-6, cultured on standard NGM, also displayed reduced lifespan. Thus, NaCl in standard NGM accelerates aging in multiple genetic backgrounds. Wild-type worms on excess NaCl displayed delayed development and reduced fertility, and reduced lifespan and health span, indicating toxicity in both young and old animals. These results suggest that young animals are relatively resistant to NaCl toxicity, but that aging causes progressive sensitivity, such that old animals display toxicity to both standard and excess NaCl. We investigated pathways that respond to NaCl. Young animals cultured with excess NaCl activated gpdh-1, a specific response to NaCl stress. Old animals cultured with excess NaCl activated gpdh-1 and hsp-6, a reporter for the mitochondrial unfolded protein response. Thus, excess NaCl activates multiple stress response pathways in older animals.

Gerotherapeutic interventions that optimize the health and healthspan of biologically older, yet generally healthy adults are importance for reducing healthcare costs associated with ageing populations. It remains unclear whether recruiting middle-aged individuals with an older biological age is feasible in gerotherapeutic trials. The aim is to evaluate feasibility of recruiting biologically older yet generally healthy middle-aged adults for Alpha-ketoglutarate Supplementation and BiologicaL agE in middle-aged adults (ABLE) trial.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial component of the innate immune system, which senses abnormal double-stranded DNA in the cytoplasm and induces the type I interferon and pro-inflammatory cytokines expression. In cellular senescence, the cGAS-STING signaling pathway triggers the senescence-associated secretory phenotype, thereby exacerbating the senescence phenomenon and leading to age-related ocular diseases, including age-related macular degeneration and diabetic retinopathy. Herein, we outline the structure of cGAS-STING signaling pathway and its association with cellular senescence, and discuss the mechanism of behavior between cGAS-STING and ocular aging-related diseases. Finally, we summarize the relevant inhibitors of the cGAS-STING signaling pathway, thereby offering a novel direction for exploring the mechanism of ocular aging-related inflammatory diseases.