Older adults face disproportionate fall risk during dual-task conditions, yet the neuromechanical basis remains elusive. We reveal a mechanistic paradox: aging reorganizes whole-body coordination through globally rigid, hyper-connected networks that paradoxically decouple the peripheral effectors critical for balance. Motion capture analysis (48 younger, 48 older adults; 21 markers) during stance on stable/unstable surfaces with and without cognitive load showed that younger adults dynamically reconfigure coordination architectures, with task-specific modulation of local clustering, global efficiency, and peripheral-to-center-of-mass coupling. Older adults instead exhibited chronically rigid networks—elevated local transitivity, global efficiency, and small-worldness, hallmarks of ostensibly superior organization—yet showed reduced inter-modular flexibility and, critically, weakened foot–ankle–shank-to-center-of-mass coupling during instability, precisely when distal control becomes essential. This rigidity persisted across mechanical and cognitive challenges and throughout sustained trials, independent of sway magnitude or fatigue, indicating chronic reorganization rather than transient compensation. Age-related motor decline thus reflects not component degradation but qualitative network rigidification: loss of context-sensitive reconfiguration capacity. These findings establish network flexibility metrics as mechanistic markers for fall risk and reframe intervention targets from component strengthening toward restoring organizational plasticity—the capacity to selectively assemble, dissolve, and reassemble coordination patterns as task demands evolve.
Age-related diseases (ARDs) have brought substantial ageing burdens and posed severe health challenges. However, evidence on the disease burden and risk factors of ARDs in Southeast Asia, East Asia, and Oceania is still insufficient over a long period. Data on the 310 diseases and injuries were retrieved and obtained from the Global Burden of Disease Study 2023. Based on the regional incidence or prevalence rates among individuals aged 25 years and older, a two-step regression framework was applied to identify ARDs. The disease burden and risk factors of ARDs were measured. 53 were identified as ARDs, and 42 were non-communicable diseases (NCDs). Among 33 countries and territories, China exhibited the lowest disease burden of ARDs, whereas Nauru (Naoero) showed the highest disease burden. Ischemic heart disease, intracerebral hemorrhage, ischemic stroke, chronic obstructive pulmonary disease, and Alzheimer’s disease and other dementias were the top five ARDs for disease burden. High systolic blood pressure, ambient particulate matter pollution, smoking, high LDL cholesterol, and lead exposure were the top five risks for total risk-ARD burden. Implementing healthy ageing policies and developing regional tailored interventions can mitigate disease burden and promote early prevention and disease management, especially in age-related NCDs and modifiable risk factors.
As the global population ages, understanding determinants of healthy aging requires evidence on whether the regularity of sleep and physical activity, beyond total duration or volume, is associated with health outcomes. In J-HAS, a prospective observational cohort study, we developed novel Wasserstein distance-based regularity metrics using wearable data and examined associations with cognitive and physical function among Japanese adults aged 80–96 years. Among 150 enrolled participants, 120 had complete follow-up data, contributing 46,720 person-days of sleep recordings and 28,180 person-days of physical activity recordings. Higher sleep Wasserstein regularity (SWR) and activity Wasserstein regularity (AWR) scores indicate greater temporal regularity. Higher all-day SWR was associated with better cognitive performance; each 1-unit increase in rescaled SWR corresponded to approximately 1.6- to 1.7-fold higher odds of being in the second and third MoCA-J tertiles than in the lowest tertile. All-day SWR was not associated with 5-times-sit-to-stand performance or grip strength. Higher midday and evening SWR were associated with faster sit-to-stand performance. All-day AWR showed no significant associations. Midday AWR was inversely associated with grip strength in secondary analyses. The SWR-cognition association remained robust after FDR correction in continuous outcome (q = 0.003) and absolute-scaling analyses (q = 0.045). Wasserstein-based wearable metrics may inform personalized healthy-aging strategies.
Human leukocyte antigen (HLA) genes regulate immune function and influence disease susceptibility, but their role in healthy aging is unclear. We investigated whether disease-associated HLA alleles affect the likelihood of becoming a cognitively healthy centenarian (CHC). Using imputed HLA genotypes from 3632 individuals—including 353 CHCs and 3279 middle-aged healthy Dutch individuals—we examined 59 HLA alleles previously linked to 12 diseases, including Alzheimer’s disease (AD), ten autoimmune disorders, and SARS-CoV-2. Six alleles were associated with reduced likelihood of becoming a CHC (ORs=0.59–0.74, FDR < 0.1), forming three haplotypes: a class II haplotype (HLA-DRB1*01:01, HLA-DQA1*01:01, HLA-DQB1*05:01), a class I haplotype (HLA-C*03:04, HLA-B*40:01), and HLA-A*02:01. These alleles showed pleiotropic effects, with AD-risk alleles strongly linked to lower CHC likelihood (5- to 10-fold). Our findings suggest HLA-driven immunity plays a complex role in longevity and may inform personalized strategies for age-related diseases with immunological components.
Current dietary patterns based on general consumption trends may not fully capture factors influencing arterial stiffness, a subclinical marker of cardiovascular disease (CVD). We aimed to identify data-driven dietary patterns and evaluate their associations with arterial stiffness in a population without known CVD. In this cross-sectional study of 1155 adults, food choices from a 16-item questionnaire were collected and brachial-ankle pulse wave velocity (baPWV) was measured as the arterial stiffness indicator. Multiple correspondence analysis followed by hierarchical clustering on principal components identified dietary patterns, and generalized linear models were used to assessed their associations with baPWV. Three dietary patterns were identified, mainly distinguished by whole grains, tubers, smoked foods, and salty foods. Compared with the Chinese-adapted Western diet (high smoked/salty foods intake), the Chinese-adapted Mediterranean diet (high whole grains/tubers intake, β = −0.30, 95% CI: −0.49 to −0.10) and conventional Chinese urban diet (low consumption of four key distinguishing components, β = −0.23, 95% CI: −0.40 to −0.07) were associated with lower baPWV. Despite complex dietary behaviors, simple food-choice data enabled identification of dietary patterns associated with arterial stiffness. However, given the cross-sectional design, these findings should be interpreted as exploratory associations rather than causal effects.
The FDA-approved fibrate, gemfibrozil, has been used clinically to treat hyperlipidaemia, showing efficacy both in lowering triglycerides and increasing high-density lipoproteins. However, in recent years, the drug has been increasingly investigated for potential clinical use in other diseases. Here, we show for the first time that gemfibrozil promotes healthy lifespan across multiple evolutionarily diverse species. Interestingly, we find this novel pro-longevity role to be independent of PPAR-$$\alpha$$, the canonical target of all fibrates, and instead through an inhibitory interaction with a cell-surface dipeptide transporter, Slc15a1 (PEPT1). In both PEPT1-expressing cells and in isolated murine intestinal segments, treatment with gemfibrozil displayed a significant decrease in global amino acid levels, reminiscent of protein restriction. In vitro, gemfibrozil treatment also lowered signalling through mTOR; a master regulator of metabolism that is responsive to cellular amino acid levels and a viable therapeutic target under investigation to recapitulate the beneficial effects of dietary restriction in a nutrient-replete environment. In aged 20-month old female mice, a 6-month gemfibrozil regimen resulted in an improvement in frailty, positively impacting parameters such as hearing loss, piloerection and grip strength. Finally, in a DSS-induced colitis mouse model, gemfibrozil appeared to alleviate symptoms; an effect often observed with PEPT1 inhibition. Overall, our study reveals a potential role of gemfibrozil, a largely safe clinically approved drug in circumventing the negative consequences of overnutrition often seen in a modern-day diet, and as an effective means to promote lifespan and healthspan.
Liver cancer incidences increase dramatically beyond 55 years of age, suggesting that age-associated changes contribute critically to tumor initiation. However, the mechanisms linking liver aging and cancer initiation remain incompletely defined. This study investigated the role of CD44, a marker of liver tumor-initiating cells (TICs), in age-associated liver pathophysiology. To define the role of CD44 in aged livers, we profiled CD44-expressing hepatocytes in young and aged livers by targeted and unbiased -omics methods, assessed their number and relationship to neighboring T cells by spatial transcriptomics, and validated key findings using hepatocyte-specific Cd44 knockout. Aged livers showed an accumulation of CD44-expressing hepatocytes enriched for immune modulatory genes and activation of the immunosuppressive IL-6/JAK/STAT3 pathway. Consistent with an immunosuppressive aged milieu, following their adoptive transfer antigen-exposed CD8+ T cells mounted a lower IFN-γ response in aged livers than in young livers. Concordantly, spatial analyses showed that neighborhoods proximal to Cd44-expressing hepatocytes are enriched in T cells exhibiting reduced cytokine and chemokine gene expression. Finally, hepatocyte-specific knockout of Cd44 mitigated the IL-6/JAK/STAT3 gene signature in aged livers. Overall, these findings suggest that CD44 expression in aged hepatocytes promotes activation of the immunosuppressive IL-6/JAK/STAT3 pathway associated with impaired T cell effector function, potentially, contributing to the increased incidence of liver cancer with age.
We developed an interpretable blood-based epigenetic clock to estimate DNA methylation age and identify disease-specific DNA methylation alterations. Using 8233 Illumina methylomes from healthy controls and nine age-associated diseases, we used ridge selection to retain 4855 CpG sites and benchmarked 20 regression architectures with Bayesian hyperparameter optimization. Tree-based boosting models performed best, and a weighted ensemble achieved a mean absolute error of 2.54 years on held-out test data, outperforming established clocks evaluated under the same conditions. External validation in the independent EPIC cohort GSE132203 provided initial cross-platform support for transferability (MAE 3.04 years) and a modest but significant association with GEO-reported age acceleration (r = 0.145, p = 0.041). PaCMAP embeddings revealed structured aging trajectories and disease-enriched neighborhoods. Model interpretation highlighted loci including ELOVL2, FHL2, KLF14, CD8A, LAG3, SMAD2, and NSD1, while Enrichr identified enrichment of REST, microRNA, and histone modification programs. The clock identified departures from the healthy control methylation age model across diseases, with the greatest absolute deviation observed in stroke patients.
Studying senescence in wild organisms reveals evolutionary trade-offs and life-history strategies that cannot be captured in laboratory settings. Long-lived seabirds from rare known-aged populations provide excellent models for examining aging under natural conditions. Because reproductive effort and self-maintenance are balanced throughout life, parental age can influence offspring phenotype through both genetic and non-genetic mechanisms. We investigated the effects of maternal and paternal age on offspring phenotype in the common gull (Larus canus), using known-aged breeders ranging from 3 to 18 years. We measured chick morphology (body size) and physiology, including corticosterone concentrations, telomere length, and immune parameters, in newly hatched chicks. Paternal age did not affect any offspring traits, whereas maternal age increased chick corticosterone concentrations, particularly in offspring of lower-quality females. Path analysis further showed that maternal age influenced chick body mass indirectly through corticosterone, suggesting that maternal senescence affects offspring quality via stress hormone–mediated pathways. These findings reveal sex-specific patterns of reproductive senescence in the wild, demonstrating that maternal—but not paternal—aging shapes offspring phenotype through endocrine mechanisms. Reduced growth in chicks of older, low-quality mothers may represent an adaptive adjustment to lower expected parental provisioning, resulting in development better matched to a constrained parental environment.
Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder caused by a CAG over-repetition in the ATXN3 gene, resulting in a toxic gain-of-function in the ataxin-3 protein. Despite all the advances, its molecular mechanisms remain unclear, and no disease-modifying treatments are available. Aging is the major risk factor for neurodegenerative diseases, including Alzheimer’s and Huntington’s. Nuclear membrane proteins (lamins) and related processing proteins like ZMPSTE24 are altered not only in aging but also in neurodegeneration. To explore aging’s role in MJD, we examined age-related markers in human and animal MJD models. Reduced levels of lamins B, C and ZMPSTE24 were observed, along with nuclear shape abnormalities - hallmark of aging. Additionally, overexpressing progerin (mutant lamin A that causes premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS)) in a relevant brain area of a lentiviral MJD mouse model, aggravated MJD-related neuropathology. These findings suggest that aging mechanisms may contribute to MJD progression, offering potential targets for therapy.
Aging is a major risk factor for metabolic liver disorders, yet the molecular mechanisms driving hepatic aging remain incompletely understood. Here, we identify the Hmgcs2-Pparα signaling pathway that regulates the prolongevity gene Cisd2 and liver aging. Using naturally aged mice, we show that late-life administration of the citrus flavonoid hesperetin restores hepatic Cisd2 expression, improves liver pathology, and partially reverses aging-associated transcriptomic alterations. Mechanistically, we identify Hmgcs2 as a candidate molecular target of hesperetin and demonstrate that Hmgcs2 interacts with Pparα to activate Cisd2 transcription through a Ppar response element (PPRE) in the Cisd2 promoter. Genetic and transcriptomic analyses reveal that the protective effects of hesperetin are largely Cisd2-dependent, as they are significantly attenuated in hepatocyte-specific Cisd2 knockout mice. Consistent with these findings, PPARα and CISD2 expression decline with age in human liver tissues. Together, our results define a signaling axis linking Hmgcs2, Pparα, and Cisd2 that regulates liver aging and suggest that targeting this pathway may represent a strategy to mitigate age-associated hepatic dysfunction.
Age-related skeletal muscle atrophy and the accompanying decline in muscle strength represent major societal challenges, highlighting the urgent need to identify bioactive compounds that can prevent such deterioration. Although in vitro muscle models are valuable tools for evaluating the effects of candidate compounds, a human in vitro system that faithfully reproduces age-related muscle atrophy and functional loss has not yet been established. This study established a human in vitro aged muscle model and examined whether quercetin, a dietary polyphenol, could alleviate atrophic and functional effects induced by aged human serum. Primary human myoblasts were cultured and treated with serum from healthy young or older individuals for 48 h. Exposure to aged serum reduced the MF20-positive cell area in the 2D model and diminished contractile force in the 3D model. Further analyses revealed that aged serum treatment upregulated muscle-specific E3 ubiquitin ligases, mainly through activation of NF-κB signaling. Quercetin also suppressed NF-κB activation and mitigated aged serum-induced muscle atrophy and contractile dysfunction. Together, these findings demonstrate the effectiveness of quercetin and confirm the establishment of a human in vitro model of age-related muscle atrophy.
Social environments affect health and longevity, yet biological pathways remain incompletely understood. Data from Midlife in the United States (MIDUS) study were used to examine whether social experiences predicted mortality and whether effects were mediated by epigenetic aging, allostatic load, and health status. Outcomes included epigenetic clocks (e.g., GrimAgeV2), allostatic load (e.g., immune/inflammatory biomarkers), health status, and all-cause mortality. Among 1309 participants, positive social experiences (e.g., attending meetings) were associated with reduced mortality risk, epigenetic age deceleration, and better health; negative social experiences (e.g., childhood adversities) were associated with shortened survival, epigenetic age acceleration, and poorer health. Epigenetic aging partially mediated the mortality risk of positive and negative social exposures; inflammation attenuated the associations of positive social experiences and childhood adversity with mortality. Epigenetic aging appears to be an influential pathway linking social experiences to survival. Social conditions that slow biological aging and reduce inflammation offer promise as approaches to enhance longevity.
While bacterial membrane-derived vesicles (MDVs) are known for immune functions, this study reveals their anti-aging properties. MDVs from E. coli ΔaroD extend lifespan and alleviate aging phenotypes in Caenorhabditis elegans. We identified Novel27, a miRNA-like sRNA in these MDVs, which increases longevity by 32.8% by directly downregulating the target gene unc-13. These findings reveal a novel MDV-mediated anti-aging mechanism and establish unc-13 as a key regulator of longevity.
Gait speed, known as the ‘sixth vital sign’ is an indicator of functional health and aging. Identifying drivers of midlife gait changes is critical for timely intervention, yet most evidence focuses on older adults and overlooks non-linear, heterogeneous effects. We applied machine learning with quantile regression to the Canadian Longitudinal Study on Aging (n = 23,419) to identify predictors of gait speed over 3 years. While higher BMI and comorbidity burden were consistently associated with slower gait across quantiles, distinct predictors emerged at distributional extremes. Among slower walkers, higher grip strength, vegetable consumption, and more frequent travel outside the local community predicted faster gait, with physical activity and lung function contributing at lower-to-middle quantiles. Among faster walkers, higher fruit consumption and cognitive performance predicted faster gait. These findings highlight the importance of distribution-sensitive modeling to identify modifiable, stage-specific predictors for tailored interventions to improve health span and quality of life in aging populations.
Aging induces muscle weakness and power decline in older adults, increasing the risk of falls. Adapted physical activity (APA) programs are effective in mitigating these declines. Recent innovations, including videoconferencing, offer alternative delivery modes, but their effectiveness in improving physical function remains underexplored. The objective was to evaluate the effects of a 12-week multi-component APA program via videoconferencing on physical capacity in older adults. Fifty older adults (73.20 ± 5.69 years) completed two testing sessions three months apart. Thirty-six participants underwent the APA program, while 14 served as controls. Physical capacities were assessed using: (i) Sit-to-Stand (STS), (ii) six-minute walk, (iii) unipedal balance, (iv) Timed-Up-and-Go (TUG), and (v) knee extensor strength and power tests. Accelerometers embedded in smart eyeglasses captured biomechanical data used to calculate a physical performance score (PPS) and categorize participants into three performance groups. Frailty status was assessed at baseline and post-intervention. The APA program significantly improved maximal knee extensor power, TUG performance, and PPS. A favorable shift in performance groups and frailty status was observed, with no participants remaining frail post-intervention. Adherence was high, and no adverse events were reported. While videoconferencing programs cannot replicate heavy-load or high-risk balance training, they provide a safe, accessible alternative to traditional programs, promoting healthy aging and functional independence.
Age-related deterioration of oocyte quality is a major cause of female infertility. Aged oocytes exhibit meiotic abnormalities and aneuploidy, yet the molecular mechanisms underlying these defects remain poorly defined. Here, we report that KIF14, a member of kinesin-3 family, is indispensable for meiosis in mouse and porcine oocytes, and KIF14 insufficiency drives maturation defects in oocytes during reproductive aging. We found that KIF14 expression is markedly downregulated in aged oocytes, and KIF14 depletion results in aberrant chromosome alignment and subsequent aneuploidy. This abnormality may be attributed to diminished polar ejection force and impaired spindle tension, which arise from altered tubulin acetylation levels modulated by HDAC6. Moreover, KIF14 deficiency reduces actin abundance by regulating multiple actin nucleation factors, thereby disrupting meiotic spindle migration and compromising FIS1-governed mitochondrial function. Additionally, loss of KIF14 induces abnormal mitochondrial distribution and perturbs microtubule-dependent RPS3 transport, which impairs the stability and translational efficiency of stored oocyte mRNAs. Importantly, exogenous supplementation of KIF14 in oocytes from aged mice effectively rescues aging-related deficiencies in polar body extrusion, chromosome alignment, spindle migration, mitochondrial function, and mRNA metabolism. In summary, our findings demonstrate that reduced KIF14 expression is a key contributor to maternal age-associated meiotic defects in mouse oocytes.
Age-related degeneration of articular cartilage is a key pathological hallmark of primary osteoarthritis (OA). As the cartilage’s barrier layer, the superficial zone maintains tissue homeostasis and is increasingly recognized as the initial site of age-related cartilage degeneration. Disruption of this zone exposes deeper layers to hostile microenvironments, accelerating pan-cartilaginous changes; however, its age-related progression remains incompletely defined. We systematically characterized aging-associated alterations in the rat tibial plateau superficial zone across imaging, biomechanical, and biological parameters. Using integrated radiology, nanomechanical testing, and histomorphometry, we found that radiographic parameters did not differ significantly between 6 and 12 months. In contrast, the cartilage indentation modulus declined with age, and interregional disparities narrowed as degeneration progressed. Histology showed reduced cell density, hypertrophic chondrocytes, decreased proteoglycan content, and collagen structural disorganization in the superficial zone. Molecular profiling demonstrated downregulation of COL-II and PRG4, alongside upregulation of Caspase3, MMP13, and COL-X. These findings indicate that the anteromedial tibial plateau exhibits the earliest and most pronounced age-dependent degeneration within the superficial zone, characterized by architectural, biological, and mechanical alterations that precede significant subchondral bone remodeling. This work delineates the spatiotemporal progression of superficial zone aging, providing insights for early OA diagnosis and intervention.
Aging weakens neural stem cell (NSC) function and reduces brain plasticity, but this process is shaped by more than the brain alone. Local niche cells become disrupted with age and inflammation, while skeletal muscle sends systemic signals through myokines, metabolites, and vascular interfaces. Evidence from exercise, parabiosis, and rejuvenation studies suggests that preserving muscle health may help protect NSC niches and brain regenerative capacity.
Epidemiological links between cognition and body physiology in aging are well established, but their strength and drivers remain unclear. Which physiological systems - from body composition to cardiovascular, pulmonary, renal, hepatic, immune, metabolic, and musculoskeletal - best predict cognition, and to what extent are cognition-body associations linked to brain variation across aging? We examined 19 physiological phenotypes alongside three neuroimaging modalities in over 30,000 UK Biobank participants. Machine learning models integrating body measures predicted cognition at r = 0.4, demonstrating a cognition-body covariation at 16%. Body composition and bone health emerged as the strongest predictors. Notably, 85.1% of cognition-body covariance overlapped with neuroimaging, especially white matter features. Moreover, 71.7% of cognition-age covariance was jointly shared with neuroimaging and physiology, and 96.8% was shared with either brain or body markers, or their overlap. Together, these findings clarify how body physiology and brain structure and function covary with cognitive aging.
