Longevity Papers

Hydrogen sulfide is a gasotransmitter with biological functions, including roles in antioxidant defenses, mitochondrial bioenergetics, and cellular signaling via cysteine persulfidation. Several longevity-promoting interventions enhance endogenous hydrogen sulfide generation. However, whether enhanced hydrogen sulfide generation extends healthspan and lifespan in mammals remains unknown. Here, we investigated the in vivo effects of the non-enzymatic hydrogen sulfide generation promoted by natural diallyl sulforated compounds. Diallyl sulforated compounds extended lifespan and improved the main aspects of healthspan, including glucoregulation, locomotor function, and neurocognition in wild-type male mice across their lifespan. At the histological and molecular levels, we observed reductions in hepatic lipid-droplet size, attenuation of transcriptional and proteomic signatures associated with mTOR and immune-related pathways, and increased cysteine persulfidation in proteins. In humans, greater protein persulfidation in individuals with polypathological conditions was associated with increased muscle strength and lower triglyceride levels, supporting its physiological relevance. Our findings uncover the potential of enhanced hydrogen sulfide generation to promote healthy aging.

Ageing populations present substantial healthcare challenges, with cardiovascular disease (CVD) remaining the predominant cause of morbidity and mortality globally. Cardiac ageing is characterised by progressive cellular and molecular changes, contributing to structural and functional decline and predisposition to CVD. Component proteins (nucleoporins) of the Nuclear Pore Complex (NPC) and the nuclear lamina are both crucial for nuclear integrity and chromatin organisation, and have appeared as key players in cellular homeostasis of post-mitotic cells. Age-related changes in NPC composition and turnover, particularly in non-dividing cells, compromise nucleocytoplasmic compartmentalisation and drive genomic instability, cell death, and senescence. Emerging evidence implicates aberrant NPC components in the core hallmarks of cardiac ageing and in distinct heart diseases. Additionally, the nuclear lamina's susceptibility to damage and its interactions with NPCs might exacerbate these effects. This review presents evidence linking NPC and nuclear lamina dysfunction to features of the ageing heart and suggests that age-related NPC alterations are potential drivers of cardiomyocyte and cardiac decline with age.

Iron homeostasis which is primarily regulated through intestinal iron absorption, is usually disrupted in the elderly. But changes of intestinal iron absorption with aging have not been elucidated. This study aims to investigate the role of intestinal iron absorption in driving age-related disruption of iron homeostasis. Male C57BL/6 J mice aged 2, 12, 18, and 24 months were utilized in this study to analyze age-related changes in systemic iron status, detect the alterations in intestinal iron absorption via Ussing Chamber, and clarify its regulatory mechanisms during aging via western blot and RT-qPCR. Results showed that iron deposition occurred in the liver, heart, brain, spleen, and kidney with age. Furthermore, intestinal iron absorption elevated in aged mice, particularly in the duodenum, which was accompanied by upregulated DMT1 and FPN. As FPN is the only known iron exporter in enterocytes, the upregulation of FPN was considered as the key factor of higher iron absorption during aging. Then factors influencing FPN expression were determined. It was found that serum hepcidin and hepatic Hamp mRNA levels significantly decreased. And a reduction of over 40% in p-SMAD1/5/8 which is a transcriptional regulator of hepcidin was observed. Overall, these findings suggested that the downregulation of p-SMAD is a key factor limiting the transcription of hepcidin during aging, then increased the expression of intestinal FPN, further resulting in increased iron absorption and iron homeostasis imbalance. This study demonstrated that dysregulation of the hepcidin production during aging is a key driver of iron homeostasis disruption in the elderly, representing a target for precision intervention.

Although semantic cognition remains behaviorally stable with age, neuroimaging studies report age-related alterations in response to semantic context. We aimed to reconcile these inconsistent findings by combining behavioral and magnetoencephalography (MEG) measures and examined the neural mechanisms underlying lexical-semantic processing in healthy aging. Forty-six Finnish-speaking adults (25 female) across younger (22 - 32 years) and older (62 - 69 years) cohorts performed a semantic congruency judgment task on word pairs. Both age groups performed the task with high accuracy, with older adults responding faster than young. While advancing age was not associated with impaired task performance, MEG revealed neural reorganization in the old compared to young adults. Young participants exhibited the canonical N400 effect in the left temporal cortex 300 - 400 ms post-stimulus, followed by a Late Positive Complex (LPC), whereas older adults showed less pronounced congruency effects, and the activation distribution was shifted toward frontal and bilateral regions. Despite the absence of the canonical N400 effect in older participants, multivariate time-resolved decoding demonstrated that the congruency effect was decodable from the MEG responses in both groups from ~300 ms post-stimulus, indicating preserved sensitivity to congruency with age. Decoding performance correlated with response time, suggesting that increased neural separation between semantic concepts facilitates rapid decision-making. Critically, age groups were distinguishable based on their neural responses 300 - 800 ms post-stimulus, reflecting functional reorganization in older adults. Overall, our findings suggest that healthy aging involves adaptive reconfiguration of neural systems, supported by experience-driven strategies that preserve semantic proficiency despite broader age-related cognitive changes.

It has been suggested that two prominent frameworks in geriatrics, frailty and intrinsic capacity (IC), represent two opposite ends of the same continuum. Frailty quantifies accumulated deficits and vulnerability, and IC measures an individual's capacities and functional reserves. This study investigates the overlap between frailty and IC in a large cohort of older adults.

Biological age derived from DNA methylation (mAge) reflects aging-related physiological changes and the risk of age-related diseases. However, the association between oral microbiome and mAge remains unclear.

Mutations and polymorphisms in the Rho guanine nucleotide exchange factor 10 (ARHGEF10) locus are associated with behavioral and locomotor dysfunctions in humans, including psychiatric disorders and polyneuropathies that show age- and sex-specific prevalence. ARHGEF10 encodes a conserved guanine exchange factor that activates Rho GTPases and has proposed roles in cell migration and adhesion, but the relevant cell types and mechanisms underlying its age- and sex-dependent effects remain unclear. Drosophila darhgef10 gene is the single orthologue of vertebrate ARHGEF10 and its paralogue ARHGEF10L. Here, to gain more direct insight into possible age- and sex-dependent ARHGEF10 neuromuscular functions, we generated darhgef10 knock-out flies and quantified induced walking kinematics with high-speed imaging and coarse spontaneous behaviors--walking, micromovements, rest, and sleep--in open arenas. Mutants of both sexes exhibited abnormal walking kinematics, which worsened with age in females. Cell-type-specific knockdowns indicated that locomotor phenotypes arose primarily from neuronal, rather than glial or muscle, requirements. dArhgef10 was especially critical in glutamatergic motor neurons of aged females. dArhgef10 was also required for wakefulness and activity initiation in females but, surprisingly, not in males. Genetic rescue and isoform expression analyses suggested that sexually-dimorphic expression of long isoforms RC and/or RD underlies at least part of the sex-specific requirements of dArhgef10 in locomotor behavior control, revealing unanticipated complexity in its activity regulation. Collectively, our results suggest ARHGEF10 plays an ancient, conserved role in neurons that promotes proper wakefulness and locomotor activity in an age- and sex-dependent manner.

Global cardiovascular health promotion across the lifespan requires a comprehensive approach prioritising early life interventions. Paediatric hypertension is an increasingly recognised public health issue and an important modifiable risk factor for reducing future cardiovascular morbidity and mortality. This Review discusses the epidemiology, risk factors, diagnosis, and management of paediatric hypertension. We highlight the increasing prevalence of paediatric hypertension, its higher rates in low-income and middle-income countries (LMICs), and review its multifactorial causes globally, including genetic, environmental, and lifestyle influences. Barriers to early detection, particularly in LMICs, such as poor awareness of childhood-onset hypertension among families and health-care providers, are elucidated. Studies emphasising the short-term and long-term consequences of paediatric and youth hypertension and evidence-based diagnostic and management strategies, including non-pharmacological and pharmacological interventions, are also discussed. The management of hypertension in youth requires integrating public health strategies with clinical care to establish a robust foundation to improve lifelong health outcomes.

Epigenetic age acceleration (EAA) is a biomarker of biological aging associated with multiple diseases. Plasma metabolites are potential targets for disease prevention. Therefore, our study aims to investigate the association between plasma metabolites and EAA.

Normal aging triggers substantial topological transformation within resting-state electroencephalography (rs-EEG) networks. Given that the small-world (SW) architecture of hemispheric EEG networks may reflect an evolutionarily and developmentally optimized organization, investigating their modulations with age offers critical insights into the dynamic reorganization of functional connectivity (FC) patterns throughout adulthood. Utilizing rs-EEG data from a single-site public repository collected under eyes-closed and eyes-open conditions, we employed graph-theory methods to delineate age-related alterations in the SW architecture of hemispheric functional networks across a broad adult age range (20-70 years). In 539 cognitively intact individuals, undirected weighted FC networks were constructed using eLORETA-based lagged linear connectivity for each hemisphere and three subnetworks: default mode network (DMN), frontal network (FN), and attentional network (AN). Further quantitative analyses revealed that age-related changes in SW metrics were observed exclusively in the right hemisphere, evident during eyes-closed rest and in network reconfiguration upon eye opening (ΔSW). Right-hemispheric SW and ΔSW showed frequency- and network-specific modulation with age: in the alpha2 band, all three subnetworks exhibited increasing trends, with U-shaped trajectories in DMN and AN and a linear rise in FN. In other frequency bands, specific SW metrics displayed an inverted-U curve relationship with age (DMN: alpha1 SW, delta ΔSW; FN: gamma SW; AN: theta, alpha1, gamma SW, theta ΔSW) in later adulthood, whereas beta2 SW and gamma ΔSW in FN decreased linearly. These findings revealed a right-lateralized pattern of age-related changes in intrinsic SW architecture and provided an eyes-state-dependent baseline for evaluating hemispheric network impairments in age-related neuropsychiatric disorders.

Cardiovascular-kidney-metabolic (CKM) syndrome poses a significant and growing public health challenge. While sleep disturbances are recognized as a risk factor, the role of daytime napping in the progression of CKM syndrome remains unclear. We utilized data from the China Health and Retirement Longitudinal Study (CHARLS), a nationally representative cohort. This study included 9,810 participants for cross-sectional analysis and 4,990 participants free of advanced CKM syndrome at baseline for longitudinal analysis. Nap duration was categorized into four groups: 0, 1–29, 30–89, and ≥ 90 min. Advanced CKM syndrome (stages 3–4) was defined according to the American Heart Association criteria. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). In the longitudinal analysis, a short afternoon nap (1–29 min) was associated with a 35.3% reduction in the risk of incident advanced CKM syndrome compared to non-napping (adjusted OR = 0.647, 95% CI 0.451–0.928). This protective association was particularly significant in males (OR = 0.645, 95% CI 0.432–0.964) and individuals who were married or partnered (OR = 0.734, 95% CI 0.545–0.988). Furthermore, for older adults over 60 years of age, a moderate nap duration (30–89 min) was also linked to a lower risk (OR = 0.664, 95% CI 0.476–0.927). The cross-sectional analysis yielded consistent results. Sensitivity analyses confirmed the robustness of these findings. Short afternoon napping is associated with a reduced risk of developing advanced CKM syndrome in middle-aged and older Chinese adults, highlighting its potential as a target for primary prevention strategies aimed at mitigating CKM syndrome risk in an aging population.

Age-related meniscus injury (MI) involves inflammaging, but biomarkers and mechanisms remain unclear.

Diapause is an evolutionarily conserved strategy that enables many organisms to survive prolonged exposure to harsh environmental stressors. During this state, organisms drastically reduce their metabolic rate, halt development, and enhance stress tolerance in an energy-efficient manner. Remarkably, many diapausing organisms appear to substantially slow or suspend aging as a result of profound metabolic depression and developmental arrest. Consequently, diapause and aging appear to be programmed in opposite directions, yet both rely on many of the same master regulatory genes and epigenetic modulators. This review explores the molecular mechanisms underlying diapause-induced stress resistance and metabolic suppression, offering critical insights into how dormant biological systems preserve function and delay aging. Manipulating these shared regulatory networks has led to significant extensions in lifespan and improvements in healthspan across various model organisms. Anhydrobiotic species such as Artemia, Caenorhabditis elegans, and tardigrades can nearly suspend aging during dormancy by downregulating metabolic pathways and accumulating protective macromolecules. Notably, the African turquoise killifish, which has adapted to life in ephemeral ponds, can provide a unique platform to study both diapause and aging within a single vertebrate model. Phenotypic plasticity may offer the most compelling evolutionary explanation for resolving the paradox of how the same regulatory network can produce opposite outcomes in diapause and aging. Overall, diapause offers a powerful natural framework for uncovering anti-aging mechanisms and holds great promise for guiding the development of novel interventions to promote longevity and healthy aging.

Background: Smoking is a major preventable risk factor for all-cause mortality and disability worldwide. It leads to age-related diseases, but the effects and reversibility of smoking behaviors on different epigenetic clocks are not fully explored. Objective: To characterize the association of epigenetic age acceleration in whole blood with active and secondhand smoking (SHS), smoking intensity, and time since cessation among U.S. adults. Methods: This is a cross-sectional study in adults from the NHANES 1999-2002 survey cycles, a population-based survey representative of the U.S. adult civilian non-institutionalized population. We analyzed 2,320 adults aged [≥]50 years, including non-Hispanic White, non-Hispanic Black, Mexican American, and other populations. Those without available self-reported smoking status data were excluded. Smoking exposure was analyzed in terms of self-reported smoking status (current, former, never), intensity (packs in the last month), years since smoking cessation, and SHS (serum cotinine levels: 0.05-10 ng/ml). Epigenetic age was estimated using 12 DNA methylation age biomarkers. Survey-weighted linear models were used to estimate the association of smoking exposure with epigenetic age acceleration while adjusting for confounders and multiple comparisons. Results: We analyzed 1,043 never, 903 former, and 374 current smokers (mean age: 65.1{+/-}9.3 years, female: 49.1%). GrimAge2 was 9.1 years (95% CI: 8.0, 10.2) and 2.8 years (95% CI: 2.3, 3.3) higher in current and former smokers, respectively, than in never smokers. Smokers showed an increased pace of aging, with current smokers aging 0.15 (95% CI: 0.13, 0.17) and former smokers 0.04 (95% CI: 0.03, 0.05) additional years per chronological year, and shorter methylation-predicted telomere length (current: -132{+/-}19 bp; former: -30{+/-}15 bp). Each cigarette pack smoked in the past month was associated with increases of 0.1 years in GrimAge2 and PhenoAge, and 0.01 aged months/year in aging pace. Among former smokers, each year since smoking cessation was associated with a deceleration of -0.14 (GrimAge2) and -0.06 (PhenoAge) years, and -0.03 aged months/year in aging pace. Cotinine analyses supported dose-dependent associations of epigenetic aging with smoking and suggested a 0.8-year increase in GrimAge2 with SHS exposure. Conclusions: Smoking was associated in a dose-dependent manner with accelerated epigenetic aging in former and current smokers. However, epigenetic age acceleration declines with time since smoking cessation among former smokers.

Clonal hematopoiesis (CH), defined by the expansion of hematopoietic cells with somatic mutations in leukemogenic genes (CH of indeterminate potential (CHIP)) or with mosaic chromosomal alterations (mCAs), is associated with aging and adverse health outcomes in the general population. CHIP prevalence has been shown to be higher in People with HIV (PWH) than in controls. However, the full spectrum, prevalence, and clinical consequences of CH in PWH remain incompletely understood. Here, we provide a comprehensive assessment of CHIP and mCAs in a large sample of PWH (N~2,500) from the Swiss HIV Cohort Study. Using high-depth targeted sequencing of CHIP genes and genome-wide genotyping to call mCAs, we quantified the prevalence and clone size of both types of CH. CHIP (found in 25% of individuals) and mCAs (found in 16% of individuals) were found to be common, positively correlated with age, often co-occurring (OR=1.7, p=0.02 for autosomal mCAs), and associated with various clinical outcomes, including all-cause mortality (HR=1.3, p=0.02 for CHIP) and hematologic malignancies (HR=9.4, p=0.01 for the effect of CHIP on the risk of myeloid cancer; HR>10, p<0.001 for the effect of co-occurring CHIP and mCAs on the risk of lymphoid cancer). We also observed associations of CH with several proxies of inflammatory status (CD4:CD8 ratio, HIV viral load, late initiation of antiretroviral therapy, and toxicity of antiretroviral drugs), highlighting a potential interaction between CH and chronic immune activation.

Photoaging, caused by chronic ultraviolet (UV) exposure, leads to extracellular matrix (ECM) degradation, impaired skin function, and visible signs of aging. While collagen-based implants offer therapeutic potential, most rely on animal-derived sources, posing risks of immunogenicity and pathogen transmission. Recombinant collagens overcome these limitations but often lack the ability to form native-like fibers. Herein, we report the first injectable, self-assembled recombinant type I collagen nanofiber (SARCI) implant for reversing photoaged skin damage. The SARCI implant exhibits excellent injectability, enhanced thermal and enzymatic stability, and low immunogenicity. In vitro, it significantly promotes fibroblast proliferation, migration, and myofibroblast differentiation, while inducing chondrogenic commitment of mesenchymal stem cells. In a UV-induced photoaging mouse model, SARCI restores ECM homeostasis, improves epidermal thickness, dermal density, hydration, and transepidermal water loss, and reduces oxidative stress. Transcriptomic analysis confirms that SARCI activates ECM-receptor interaction, PI3K-Akt, and focal adhesion signaling pathways. These findings establish SARCI as a safe and effective recombinant biomaterial for regenerative dermatology and photoaging intervention.

Aging is associated with mitochondrial dysfunction and altered autophagic processes, particularly in secretory organs such as the salivary glands. In this study, we investigated metabolic changes and their interactions with mitophagy in primary salivary gland cells (PSGCs) from klotho-deficient (kl-/-) mice, a model of accelerated aging. We observed a significant reduction in both mitochondrial number and mitochondrial DNA copy number in the PSGCs of kl-/- mice compared with those of wild-type (WT) controls. In contrast, lysosomal abundance was markedly increased in PSGCs from kl-/- mice. Moreover, the expression of the autophagy marker LC3B was significantly upregulated in kl-/- PSGCs, and the expression of the mitophagy markers BNIP3 and NIX increased. Our metabolomic profiling revealed disrupted spermidine biosynthesis in the salivary glands of kl-/- mice. Interestingly, spermidine treatment in kl-/- PSGCs increased the number of mitochondria and suppressed mitophagy, as indicated by the reduced expression of BNIP3 and LC3B. Conversely, in WT PSGCs, spermidine induced the expression of autophagy and mitophagy markers, namely, BNIP3 and LC3B. These findings suggest that accelerated aging in mice impairs mitochondrial homeostasis and alters autophagy/mitophagy pathways in salivary gland cells, potentially through the dysregulation of spermidine metabolism. Our results provide insight into the molecular mechanisms of aging in salivary glands and reveal the potential role of polyamine metabolism in maintaining mitophagy during aging.

The Interplay of Genes and Environment across Multiple Studies (IGEMS) is a consortium of 21 twin studies from 5 countries (Australia, Denmark, Finland, Sweden, and United States) established to explore the nature of gene-environment interplay in cognitive, physical, and emotional health across the adult lifespan. The combined data from over 145,000 participants (aged 18 to 108 years at intake) has supported multiple research projects over the three phases of development since its inception in 2010. Phases 1 and 2 focused on launching and growing the consortium and supported important developments in data harmonization, analyses of data pooled across multiple studies, incorporation of linkages to national registries and conscription data, and integration of molecular genetic and classical twin designs. IGEMS Phase 3 focuses on developing appropriate infrastructure to maximize utilization of this large twin consortium for aging research.

Increasing lifespans make health problems in the elderly such as opioid misuse a more prominent concern. Understanding the effects that opioids may have on the aged brain can help us address age-related concerns of opioid exposure. This study aimed to assess potential interactions between aging and opioid exposure. Three-month-old (young adult) and 19-month-old (aged) C57BL/6JN mice were assigned to either a morphine (3 mg/kg, i.p.) or saline group. A conditioned placed preference (CPP) task was used to assess reward sensitivity, while rotarod and beam walk tests were used to assess sensorimotor coordination. To assess for potential age-dependent effects of morphine on gene expression, we performed RNA sequencing in the prefrontal cortex (PFC). We found that morphine induced CPP in both age groups. Our results indicate impaired motor coordination in aged mice; however, morphine did not significantly affect motor coordination in either age group, although a trend toward an increased number of slips was observed in morphine-treated aged mice. Transcriptomic analysis revealed more robust effects of morphine on gene expression in the aged brain compared to the young brain. Interestingly, we found limited overlap between morphine-regulated genes in young and old mice, suggesting that the molecular effects of morphine are age-dependent. Taken together, while we found no significant interactions between morphine (at the tested dose) and aging in the behavioral assays, morphine caused age-dependent gene expression changes. Our findings suggest that age should be considered when prescribing opioids and that age-specific therapeutics may help address opioid use disorder in the elderly.

Background Long Interspersed Nucleotide Element-1 (LINE-1, or L1) sequences occupy approximately 17% of the human genome. L1 RNA expression, required for embryogenesis, is low in middle childhood, but increases in adults, eroding heterochromatin and leading to ectopic gene misexpressions, sterile chronic inflammation, and physiological deterioration. To our knowledge, no studies have yet tested whether adults with high L1 RNA levels for their age are shorter-lived, and whether the women with higher L1 RNA levels have shorter reproductive lifespans, as would be expected if higher L1 RNA expressions accelerate both systemic and reproductive aging. Methods The RNA levels of 127 subfamilies of L1 elements in lymphoblastoid cell lines (LCLs) from 43 grandmothers and 43 grandfathers of the three-generation Utah CEPH (Centre d'Etude du Polymorphisme Humain) families were obtained from the Genetic European Variation in Disease (GEUVADIS) project. Survival and reproductive lifespan data for these subjects were obtained from the University of Utah. The sum of the RNA levels across all 127 L1 element subfamilies (a.k.a. total L1 RNA level), and the variance of RNA levels across the 127 subfamilies, were calculated for each research subject and tested for associations with longevity in both sexes and with age at last birth (ALB) for the women. Results Women in the top half of summed L1 RNA expressions, or in the top half of variance in RNA expression across the L1 subfamilies, had significantly higher mortality rates than women in the bottom half for those measures (for top half vs. bottom half total L1 RNA levels, Hazard Ratio (HR) 4.00, 95% CI 1.50-10.67, P = 0.0057; for top half vs. bottom half variance across the L1 subfamilies, HR 3.84, 95% CI 1.49-10.72, P = 0.0068). No significant associations of L1 RNA levels, or their variance, with mortality were observed in the full set of 43 men; however, restricting the analysis to the men who were 68 years or older at blood draw and survived at least four years after the blood draw (n = 31) revealed significantly higher mortality rates, within this subset of men, for those in the top half of total L1 RNA levels vs. men in the bottom half (HR 2.79, 95% CI 1.11-7.05, P = 0.03). Among the 37 women whose ALB was greater than or equal to 30 years, the approximate age when fertility begins to decline, higher total L1 RNA levels were associated, though not significantly, with a younger ALB. However, selecting for relatively healthy individuals by restricting the analyses to women who were younger than 75.5 years at blood draw and survived at least five years after the blood draw (n = 27) revealed a strong association of higher intra-individual variance in L1 RNA expression across the 127 L1 subfamilies with a younger ALB (Pearson r = -0.44, p = 0.02). Conclusions These results from a small cohort of research subjects lend support to the hypothesis that the regulation of L1 RNA expressions in adults significantly influences the rates of both systemic and reproductive aging. Expanded studies of similar design are needed to further test this hypothesis.

Intrinsic biological rhythms regulate key physiological and behavioural processes, yet the influence of sex and age on these rhythms is not fully understood. We comprehensively examined 24-hour (circadian) and >24-hour (infradian; 5-day and 10-day) rhythms in wheel-running and ingestive behaviours in single-housed young and middle-aged male and female mice. Circadian analysis revealed that middle-aged mice, particularly females, exhibited more precise daily rhythms and shifted a greater proportion of activity and feeding to the lights-on phase compared to young female mice. Middle-aged animals also ran for longer durations per day, suggesting age-related changes in activity regulation. Analysis of infradian rhythms further highlighted sex- and age-specific differences. Young female mice displayed robust 5-day rhythms in wheel-running activity, which were absent in middle-aged females. In contrast, few males (young or middle-aged) showed significant 5-day rhythms. Ten-day rhythms were most prominent in male mice, while females rarely expressed this periodicity. Physiologically, middle-aged mice lost more body weight in response to single housing, with middle-aged females being most affected. Interactions among behavioural rhythms in females also showed greater complexity, which increased with age. These findings reveal distinct sex- and age-dependent patterns in circadian and infradian rhythms as well as in physiological responses to isolation. Our work highlights the need to account for sex and age in chronobiological research, with broader implications for understanding vulnerability to age-related metabolic and behavioural disorders.

Cardiovascular dysfunction frequently accompanies aging and is often worsened by adverse lifestyle factors and genetic susceptibility. The apolipoprotein E (APOE) gene modulates susceptibility to cardiovascular disease, but how exercise and diet interact with APOE genotype remains insufficiently understood. We investigate the cardioprotective potential of exercise in humanized APOE-targeted replacement mice on control and high-fat diet, using photon-counting computed tomography (PCCT) and deep learning-based image segmentation.

Parental age at reproduction is increasingly recognized as a factor influencing offspring lifespan and other fitness-related traits, yet the underlying proximate physiological mechanisms remain poorly understood. Immune function and oxidative status are two potential mediators of age-related parental effects, as both are key hallmarks of ageing. However, very few studies have examined the relationship between parental age and offspring physiological condition in wild populations. We examined immunological and cellular mechanisms potentially responsible for parental age effects in the long-lived seabird Scopoli's shearwater (Calonectris diomedea). We measured 10 markers of immune function and oxidative status in 35 chicks from either younger or older parents at two different developmental phases: one month of age and at fledging. Chicks of younger parents exhibited higher haptoglobin levels at fledging compared to chicks of older parents. No effects of parental age were found on leukocyte profiles, humoral components of acquired immunity, antioxidant enzyme activity, or DNA damage in the offspring. Our results suggest, whilst chicks of younger parents might experience more stressful conditions, overall mechanisms supporting somatic maintenance might shield offsprings from the transgenerational transfer of molecular damage that parents accumulate with age. Our findings provide novel insights into the physiological bases of parental age effects in a long-lived species.

This study systematically investigated the structure-activity relationships of nine hydroxyproline-branched-chain amino acid dipeptides to elucidate their anti-aging potential. Quantum chemical calculations revealed that electronic properties, particularly a lower HOMO-LUMO energy gap (ΔE) and chemical hardness (η), were critical structural determinants governing the peptides' radical scavenging efficiencies against DPPH

Aging proceeds in a nonuniform spatiotemporal manner across tissues. While metabolic stress and chronic inflammation are implicated, the underlying mechanisms remain elusive. Here, we propose that imperfect wound healing-a failure of full resolution-creates and sustains pathological niches that drive progressive age-related dysfunction. Using the liver as a model system, we deconstruct this 'imperfect repair'. We posit that it is driven by a pro-fibrotic, non-resolving microenvironment sustained by complex crosstalk between functionally heterogeneous senescent cells and non-senescent scar-associated cell (SAC) populations (including macrophages, endothelial cells (ECs), and hepatic stellate cells (HSCs)). This pathological ecosystem is further shaped by the spatial context of hepatic zonation collapse, and the dysregulation of core signaling hubs, like WNT, Transforming Growth Factor (TGF)-β, and YAP and TAZ (YAP/TAZ). Viewing aging through the lens of imperfect repair provides a unifying framework linking senescence, inflammation, and fibrosis. This perspective shifts the therapeutic paradigm from targeting single senescent cells toward engineering the pathological niche itself, and redirects focus from end-stage disease, to the sub-clinical, spatial origins of tissue vulnerability.

Accelerated biological aging (BA) is linked to adverse cardiovascular events, but its role in heart failure with preserved ejection fraction (HFpEF) remains unclear. We analyzed 1,727 HFpEF patients from RED-CARPET Study (ChiCTR2000039901), assessing BA using Klemera-Doubal and PhenoAge methods. During a median 4.9-year follow-up, 321 all-cause and 180 cardiovascular deaths occurred. After full adjustment, per 1-SD increase in BA acceleration showed significantly higher risk of all-cause mortality (KDMAge HR 1.55, 95% CI 1.40-1.72; PhenoAge HR 1.24, 95% CI 1.11-1.40) and cardiovascular mortality (KDMAge HR 1.47, 95% CI 1.28-1.69; PhenoAge HR 1.21, 95% CI 1.04-1.41). BA acceleration was also significantly related to increased left ventricular mass index (LVMI), relative wall thickness, and E/e' ratio. Mediation analysis revealed that both LVMI and the E/e' ratio partially mediated the relationship between BA acceleration and mortality. These findings suggest BA acceleration may serve as a key prognostic marker in patients with HFpEF.

Adult stem cells (SCs) transition between quiescent and active states to maintain tissue integrity, and dysregulation of this balance can lead to tissue degeneration, cancer, or premature aging. Both intrinsic factors and extrinsic niche signals influence these states; however, the molecular mechanisms that integrate extrinsic cues with intrinsic programs remain poorly understood. Here, we show that the conserved repressive histone mark, H2AK119ub, serves as a molecular switch linking inhibitory fibroblast growth factor (FGF) signals with the quiescent transcriptional program in hair follicle stem cells (HFSCs). Modulation of FGF signaling is associated with changes in H2AK119ub levels, thereby toggling HFSCs between quiescence and activation states. Mechanistically, H2AK119ub directly represses a proliferation-promoting transcriptional program preserving HFSC quiescence. Loss of H2AK119ub in HFSCs shortens the quiescent phase and induces repeated rounds of HFSC activation, ultimately leading to SC exhaustion - a hallmark of aging tissue. Analysis of other mammalian SC systems and Drosophila germline SCs confirms that H2AK119ub is a broadly conserved hallmark of quiescence and is dynamic upon SC activation. These findings reveal a signaling-epigenetic axis that controls SC quiescence and underscores the importance of the conserved role of H2AK119ub in maintaining tissue homeostasis.

Atrazine (ATR), a widely employed triazine herbicide, poses multiorgan toxicity through environmental bioaccumulation. The potential link between chronic pesticide exposure and cardiovascular aging remains a critical yet underexplored public health concern. Lycopene (LYC), a natural carotenoid with antioxidative properties, demonstrates therapeutic potential against xenobiotic-induced pathologies, although its cardioprotective mechanisms against ATR require systematic elucidation. This study employed a chicken model to investigate cardiac outcomes following chronic ATR exposure with or without LYC intervention. Histopathological assessments revealed that LYC supplementation substantially mitigated the ATR-induced myocardial structural disorganization and interstitial abnormalities. Ultrastructural analysis confirmed the capacity of LYC to reverse the ATR-triggered mitochondrial architecture disruption. Mechanistic investigations identified that ATR exposure induces tricarboxylic acid (TCA) cycle disorder, leading to pathological copper ion accumulation. These metabolic disturbances were associated with elevated cellular senescence biomarkers and disrupted proteostasis. LYC administration demonstrated dual regulatory effects, effectively normalizing copper homeostasis and restoring mitochondrial metabolic flux. The findings establish that chronic ATR exposure promotes cardiac aging through TCA cycle-impaired-mediated cuproptosis, a novel pathway counteracted by LYC via modulation of copper metabolism and mitochondrial functionality. This study enhances our understanding of environmental-toxicant-induced cardiovascular pathogenesis and positions LYC as a promising therapeutic candidate for mitigating pesticide-associated cardiotoxicity.

Aging is accompanied by functional decline and increased senescence of pancreatic {beta}-cells. These changes may be influenced by islet-resident macrophages (iMACs) that remodel tissue in response to environmental cues. To explore the molecular mechanisms underlying {beta}-cell aging and senescence, we profiled small non-coding RNAs (sncRNAs) in FACS-sorted {beta}-cells and iMACs from 3-, 12-, and 22-month-old mouse islets or from senescence-associated {beta}gal (SA-{beta}gal) positive {beta}-cells of 8-month-old mice. Overall, senescent {beta}-cells displayed distinct sncRNA signatures that only partially overlapped with those of aging. However, several miRNAs previously found to be deregulated in obese or diabetic conditions were modulated in both aging and senescent {beta}-cells, including upregulation of miRNAs linked to inflammation. In vitro exposure to pro-inflammatory cytokines partially reproduced these profiles. Aging also reshaped the {beta}-cell tRNA-derived fragment (tRF) pool, enhancing global mitochondrial tRF levels. Interestingly, some changes in miRNAs and tRFs were {beta}-cell specific, whereas others occurred also in other aged metabolic tissues. iMACs also showed age-related sncRNA remodeling, including upregulation of anti-inflammatory miRNAs and mitochondrial tRFs, suggesting adaptive immune reprogramming. Together, these data reveal a profound, coordinated reshaping of the sncRNA landscape in {beta}-cells and iMACs during aging, offering new insights into molecular mechanisms driving age-related islet dysfunction.

Stroke is a major acute cerebrovascular disorder and a leading cause of disability and death, for which ageing is a key risk factor. However, individuals of the same chronological age differ markedly in cerebrovascular vulnerability. This study aimed to investigate the association between biological aging and stroke risk and prognosis using several validated aging metrics.

This study aimed to assess whether dietary nitrate supplementation with resistance training (RT) augments gait performance and functional mobility in inactive middle-aged and older adults. We hypothesized that combining nitrate-rich beetroot juice (BRJ) with RT would yield improvements in gait and functional mobility compared to RT with nitrate-depleted beetroot juice placebo (PLA) supplementation. In this 12-week, randomized, double-blind, placebo-controlled pilot trial, 28 healthy, inactive adults (56 ± 7 years) were assigned to either a BRJ (~ 12.8 mmol nitrate/day) or PLA group while completing a supervised, full-body RT program (2×/week). Pre- and post-intervention assessments included the instrumented stand and walk (iSAW), 6-min walk test (i6MWT), and timed up and go (iTUG) tests. Supplement adherence, training compliance, and volume were equivalent between groups. ANCOVA analyses controlling baseline values revealed significant between-group differences favoring the BRJ group for gait speed (adjusted means: 1.38 vs 1.27 m/s, p = .010), stride length (p < .001), and iTUG duration (p < .05). Within-group analyses confirmed that the BRJ group experienced significant improvements in gait speed (p < 0.001) and iTUG duration (p < 0.05), while the PLA group showed no functional changes, indicating that 12 weeks of RT alone was insufficient to improve functional mobility in our sample despite equivalent training responses (p > .05). In our middle-aged sample, supplementing dietary nitrate alongside RT led to clinically meaningful improvements in functional mobility during self-selected conditions, exceeding the gains from 12 weeks of twice-weekly RT alone. Preliminary descriptive analyses revealed sex-specific group-level differences that might suggest emerging trends. Although no inferential statistics were conducted, the patterns provide potential directions for future research investigating the effects of RT in middle-aged adults.

Grandparents have increasingly taken more active caregiving roles for grandchildren. Given their vulnerability to aging-associated health declines, it is essential to understand how grandparent caregiving, along with grandparent gender and family relationships, may influence aging processes. This study examined how grandparent caregiving status interacts with gender and family affectual solidarity to affect epigenetic aging, an indicator of healthspan and mortality risk.

Sarcopenia and cognitive impairment (CI) are major contributors to disability in older people, significantly reducing quality of life and imposing a substantial burden on healthcare systems. Sarcopenia accelerates cognitive decline through mechanisms such as chronic inflammation, mitochondrial dysfunction, and disruption of the muscle-brain axis. Conversely, CI impairs motor planning and daily functioning, further exacerbating muscle loss and physical deterioration. Previous studies have shown that physical exercise optimizes peripheral physiological conditions, promoting neuroplasticity in the central nervous system. Similarly, repetitive transcranial magnetic stimulation (rTMS) enhances brain plasticity, improving both cognitive and physical functions. This study aims to evaluate the combined effects of multicomponent exercise and rTMS on sarcopenia and CI in older people.

The higher incidence of ovarian aging has led to a significant decline in the female fertility rate, raising social concerns about women's health. In recent years, the rapid development of RNA cross-linked proteomics technology has identified the role of RNA-binding proteins (RBPs) in ovarian aging. Ovarian aging disrupts the hypothalamic-pituitary-ovarian axis, resulting in aberrant hormone secretion, irregular menstrual cycles, oocyte apoptosis, and abnormal embryonic development. Given this, we have compiled the role of RNA-binding proteins in ovarian aging and further explored how different ovarian RBPs promote apoptosis and serve as therapeutic targets. We aim to analyze the effects of RNA-binding proteins on ovarian function to provide more explicit ideas for delaying ovarian aging and treating ovarian diseases.

Epigenetic clocks estimate chronological and biological age from DNA methylation patterns, but conventional models typically train on hundreds of thousands of CpG sites and large training cohorts. We previously demonstrated that tissue-unique methylation sites change in a predictable manner upon aging and disease. Here, we demonstrate that clocks built from tissue-unique methylation sites enable accurate age prediction in the human colon using a compact feature set and limited training data. We trained a machine learning model on healthy colon tissue, identifying CpG sites that capture both chronological age and anatomical location (proximal vs. distal). This clock maintains high predictive performance (r = 0.978; MAE 3.9 years) while using an order of magnitude fewer sites and samples than traditional approaches. Applying the model to tissues from individuals with HIV infection, inflammatory bowel disease (IBD), and colonic polyps reveals consistent patterns of accelerated aging, while aspirin treatment is associated with partial deceleration. Our findings establish tissue-unique CpGs as a powerful basis for efficient, interpretable clocks and offer new insights into how chronic inflammation and neoplasia shape the aging landscape of the colon.

The growing epidemiological burden of multimorbidity among older adults underscores an urgent need to develop interventions that can address multiple age-related diseases (ARDs) at once. Yet, the biological mechanisms driving their co-occurrence remain poorly understood. In this study, we conducted a multivariate genome-wide association analysis to dissect the shared genetic architecture of five common ARDs: heart attack, high cholesterol, hypertension, stroke, and type 2 diabetes. We defined this shared genetic component as the multivariate age-related disease factor (mvARD) and identified 263 independent variants across 180 genomic loci associated with mvARD. These variants were significantly enriched for associations with extreme human longevity, lending empirical support for the geroscience hypothesis in humans. Integrative gene prioritization using transcriptome-wide association studies, colocalization analysis, and Mendelian randomization identified four high-confidence genes in blood-DCAF16, PHF13, MGA, and GTF2B-with putative causal roles on mvARD. Using two-sample Mendelian randomization, we also found several modifiable lifestyle factors, including body mass index and dietary intake, that causally influenced the risk for multiple ARDs. Together, our findings revealed a shared genetic basis for common ARDs that overlapped with the biology of human aging and pointed to potential molecular and behavioral targets for delaying disease onset and promoting healthy aging.

Background Intrinsic lymphatic contractility is essential for tissue fluid balance, immunity and organ function, yet no FDA-approved pharmacologic treatments specifically restore lymphatic contractility. Lymph is returned to the circulation by ion channel-driven cyclic contractions of collecting lymphatic vessels. Although voltage-gated sodium (NaV) channels drive cardiomyocyte excitability, their role in lymphatic muscle cell (LMC) physiology is not well defined. We identified NaV1.3, a NaV channel historically viewed as developmentally restricted and limited in adult tissues, as unexpectedly and selectively expressed in adult lymphatic muscle but absent from heart, vascular smooth muscle, and mature brain. We tested whether selective NaV1.3 activation restores impaired lymphatic pumping in aging and radiation injury. Methods NaV1.3 expression in LMCs was confirmed through single-cell RNA sequencing analysis and immunostaining of mouse and human lymphatic vessels. Lymphatic contractility was quantified by in vivo fluorescence lymphangiography and interstitial fluid clearance was measured with a new bioluminescence assay. NaV1.3 function was assessed in young, aged, and radiation-injured mice. NaV1.3 knockout (Scn3a-/-) mice established the requirement of NaV1.3 for basal lymphatic excitability and responsiveness to the NaV1.3-specific activator, Tf2. Results In mouse and human lymphatic vessels, NaV1.3 is expressed in adult LMCs. Although dispensable for basal lymphatic contractions, NaV1.3 acted as a pharmacologically recruitable reserve that amplified contractile output. Acute NaV1.3 activation with Tf2 increased lymphangion ejection fraction and accelerated interstitial fluid clearance. Tf2 fully restored lymphatic pumping in aged mice and partially rescued radiation-induced contractile deficits. All Tf2 responses were abolished in Scn3a-/- mice, confirming NaV1.3 dependence. Conclusions NaV1.3 is a selectively druggable ion channel in adult lymphatic muscle that can be recruited to restore lymphatic pump function across aging and injury. Targeted NaV1.3 activation provides a molecular entry point for treating diseases characterized by lymphatic pump failure, a domain with no existing pharmacologic therapies.

Hammerhead ribozymes have found extensive applications in gene expression regulation across diverse biological systems including Escherichia coli, yeast, plants, and mammalian cells. However, their implementation in parasitic nematodes remains unexplored. Strongyloides stercoralis emerges as a particularly valuable model organism for studying developmental transitions in parasitic nematodes due to its unique life cycle alternating between parasitic and free-living stages. To expand the experimental toolkit for investigating developmental, evolutionary, and behavioral processes in this species, we established a conditional gene regulation system through transgenic integration of synthetic ribozyme constructs and demonstrated efficacy in regulating both exogenous (mrfp) and endogenous (unc-22) gene expression through targeted RNA processing mechanisms. Focusing on the insulin/IGF-1 signaling pathway, a critical regulator of parasitic nematode development and longevity, we implemented ribozyme-mediated post-transcriptional control to dissect functional divergence between two isoforms of the insulin receptor homolog Ss-DAF-2. Comparative analysis revealed isoform-specific characteristics: while both isoforms maintain conserved signaling functions, isoform B exhibits specific binding affinity for human insulin and demonstrates significant transcriptional upregulation during parasitic transition phases. This ligand selectivity profile suggests that isoform B may serve as a molecular interface for host-derived insulin signaling coordination during parasitism. This study established a programmable ribozyme tool in S. stercoralis, functionally discriminated the two Ss-DAF-2 isoforms through precision RNA engineering, and identified isoform-specific ligand preferences with implications for host-parasite signaling. Our findings not only validate ribozyme-based approaches for genetic manipulation in parasitic nematodes but also lay the groundwork for future implementation of synthetic RNA switches in helminth research.

The increasing focus on longevity and cellular health has brought into the spotlight two key compounds, urolithin A (UroA) and spermidine, for their promising roles in autophagy and mitophagy. Urolithin A, a natural metabolite derived from ellagitannins, stimulates mitophagy through pathways such as PTEN induced kinase 1 (PINK1)/ Parkin RBR E3 ubiquitin protein ligase (PRKN), leading to improved mitochondrial health and enhanced muscle function. On the other hand, spermidine, a polyamine found in various food sources, induces autophagy by regulating key signaling pathways such as 5' AMP-activated protein kinase (AMPK) and sirtuin 1, thus mitigating age-related cellular decline and promoting cardiovascular and cognitive health. While both UroA and spermidine target cellular maintenance, they affect overlapping as well as distinct signaling pathways. Thus, they do not have completely identical effects, although they overlap in many ways, and offer varying benefits in terms of metabolic function, oxidative stress reduction, and longevity. This review article aims to describe the mechanisms of action of UroA and spermidine not only on the maintenance of cellular health, which is mediated by the induction and maintenance of autophagy and mitophagy, but also on their potential clinical relevance. The analysis presented here suggests that although both compounds are safe and offer substantial health benefits and are involved in both autophagy and mitophagy, the role of UroA in mitophagy places it as a targeted intervention for mitochondrial health, whereas the broader influence of spermidine on autophagy and metabolic regulation may provide more comprehensive anti-aging effects.

The Lansing effect is a transgenerational age effect by which old parents tend to produce less viable descendants. Despite its importance for the evolution of lifespan and parental effects, the transgenerational nature of age effects and the underlying mechanisms are poorly understood. In an experiment using the three-spined stickleback, we test whether the age of mothers (generation P0) at reproduction affects parental traits of the F1 offspring, and whether they subsequently influence the early development and viability of the F2 descendants. Daughters (F1 females) of old (2-year-old) and young (1-year-old) mothers showed comparable body size, spawning rate, clutch size and egg telomere length (TL). However, sons (F1 males) of old mothers had a smaller adult body size and produced sperm with shorter TL than those of younger mothers. Structural equation model analysis revealed that P0 female age influenced embryo TL and hatching success of the F2 descendants through its effect on sperm TL of F1 males. There was also an interacting effect of P0 female age and telomerase reverse transcriptase gene (tert) mRNA level in eggs of the F1 females on the hatching success of the F2 descendants. Our results provide novel evidence that maternal age can have transmissive effects on successive generations through the gamete traits of their offspring, especially sperm TL and egg tert gene transcripts. We conclude that this transmissible age effect on grandoffspring TL and viability can shape the evolution of life histories because TL is related to health, ageing and lifespan.

Background: Telomere length (TL), a biomarker of biological aging, but its association with Alzheimer's disease (AD) remains unclear. Methods: We estimated TL in whole-genome sequencing data from 35014 Alzheimer's Disease Sequencing Project participants using TelSeq, which after quality control yielded a dataset including 6973 persons of European ancestry (EA), 4188 African Americans (AA), 4005 Caribbean Hispanics (CH), and 4170 Native American Hispanics (NAH). TL was log-transformed, adjusted for age and blood cell counts, and z-scaled. Scaled TL was dichotomized into long and short groups according to the median. An AD GWAS for the interaction of TL with variants having a minor allele count >20 was performed in each ancestry group using logistic regression models including SNP and TL main effects and a SNPxTL interaction term. Results: AD risk was associated with shorter TL ({beta} = -0.18, P < 2x10-16). Longer TL was associated with dosages of APOE {epsilon}2 (P<5.08x10-8) and APOE {epsilon}4 (P=2.10x10-2). In the EA group, genome-wide significant (GWS) TLxSNP interactions were identified for variants in SEMA6A (P=1.42x10-8) and LOC105378654 (P=4.17x10-8), between IL15 and INPP4B (P=1.77x10-8) and upstream of RP11-2N5.2 (P=4.60x10-8). In the NAH group, GWS interactions were observed with an intronic variant in BSN (P=3.26x10-8) and missense variant in MST1 (P=3.26x10-8). In the total sample, interactions with variants between CTD-2160D9.1 and EEF1A1P20 (P<1.19x10-8), in TBC1D22A (P=1.06x10-8) and in PLK1 (P=3.28x10-8) were GWS. Conclusion: We identified variants that significantly impact AD risk through their interaction with TL, suggesting that TL maintenance pathways may be central to AD pathogenesis.

Aging is a complex biological process characterized by molecular changes across multiple biological scales. While these alterations have been extensively studied in humans and rodents, the molecular changes associated with aging in dogs remain underexplored despite their relevance as a model for human aging. In this study, we profiled gene expression (n = 16,273 genes) and protein abundance (n = 2041 proteins) in whole blood and blood plasma from 40 laboratory beagles across young (3-5 years old, n = 10), old (8-9 years old, n = 17), and geriatric (10-14 years old, n = 13) life stages. We identified 816 genes and 40 proteins that significantly changed in abundance during aging, converging on pathways involved in DNA repair, collagen processing, and inflammation. Notably, these canine aging signatures overlapped with human age-associated genes, including those tied to the hallmarks of aging, reinforcing the existence of conserved aging mechanisms across species.

The prevalence of cardiovascular disease increases with age, driven by processes of inflammation, oxidative stress, and mitochondrial dysfunction. Delaying the cascade caused by these risk factors will be essential to reducing cardiovascular morbidity and mortality in our aging population. Sirtuins are nicotinamide adenine dinucleotide-dependent deacetylase enzymes involved in metabolic regulation that show promise in attenuating these disease processes and increasing longevity. This review will examine the role of sirtuins at the cellular level in relation to cardiovascular health and discuss their potential as novel therapeutic targets for atherosclerosis, heart failure, and metabolic syndrome.

Social isolation can have lasting effects on physiological aging and overall health in older adults. However, few studies have examined the behavioral and psychological mechanisms that mediate the relationship between social isolation and accelerated biological aging.

Previous studies have shown that low-fat diet (LFD) is associated with various health benefits, and that lipid and fatty acid metabolism are linked to telomere shortening. However, no epidemiological studies have examined the association between LFD and telomere length (TL). Dietary information was collected using 24-hour recalls among 6,981 adults from a nationwide cross-sectional study. Diet quality was assessed using overall LFD, healthful LFD (hLFD), and unhealthful LFD (uLFD). TL was measured using quantitative PCR. Linear regression was employed to evaluate the association between LFDs and log-transformed TL, and ordinal logistic regression was performed to assess the association of LFDs with ordinal quintiles of TL in descending order. In both fully adjusted linear and ordinal regression models, higher overall LFD [Tertile 3 vs. Tertile 1: percentage change = 2.48%, 95% confidence interval (CI): 0.60%, 4.40%,

Aging is characterized by amplified inflammation, including proinflammatory macrophages and increased susceptibility to endotoxemia. Here we uncover a mechanism by which macrophages maintain their inflammatory phenotype through autocrine GDF3-SMAD2/3 signaling, which ultimately exacerbates endotoxemia. We show that inflammatory adipose tissue macrophages display an age-dependent increase in GDF3, a TGFβ-family cytokine. Lifelong systemic or myeloid-specific Gdf3 deletion leads to reduced endotoxic inflammation. Using pharmacological interventions to modulate the GDF3-SMAD2/3 axis, we demonstrate its role in regulating the inflammatory adipose tissue macrophage phenotype and endotoxemia lethality in old mice. Mechanistically, single-cell RNA sequencing and assay for transposase-accessible chromatin with sequencing analyses suggest that GDF3 induces a shift toward an inflammatory state by limiting methylation-dependent chromatin compaction. Leveraging human adipose tissue samples and 11,084 participants from the atherosclerosis risk in communities study, we validate the relevance of GDF3 to aging in humans. These findings position the GDF3-SMAD2/3 axis as a critical driver of age-associated chromatin remodeling and a promising therapeutic target for mitigating macrophage-related inflammation in aging.

Diabetic cardiomyopathy (DCM) is a major complication of diabetes and a leading contributor to heart failure, in which cardiomyocyte senescence plays an increasingly recognized role. However, the underlying mechanisms driving this process remain poorly defined. Here, we identify the (pro)renin receptor (PRR) as a critical mediator of cardiomyocyte senescence in DCM. Using a high-fat diet and streptozotocin (STZ)-induced DCM mouse model, as well as primary cardiomyocytes exposed to high glucose and palmitic acid, we demonstrate that PRR expression is significantly upregulated in diabetic hearts and closely associated with key senescence markers, including SA-β-gal, γ-H2AX, p16, and p21. PRR overexpression exacerbates these senescence phenotypes and promotes the secretion of profibrotic senescence-associated secretory phenotype factors, contributing to increased myocardial fibrosis and cardiac dysfunction. Mechanistically, PRR stabilizes the p53 protein by inhibiting tripartite motif-containing 24 (TRIM24)-mediated ubiquitination and proteasomal degradation, thereby activating the p53-p21 axis. These findings reveal a novel role of the PRR in diabetic myocardial senescence and provide potential therapeutic targets for attenuating DCM progression.

Immunosenescence, particularly the altered ratio of naïve and memory T cells, contributes to a diminished immune reserve and impaired adaptive immunity in aging and frail populations. The role of TGF-β signaling pathway-a critical hallmark of organismal senescence and T-cell exhaustion-in terminally differentiated effector memory T (Temra) cells remains elusive. We devised single-cell and bulk-cell RNA sequencing (RNA-seq) datasets to identify age-group-specific transcriptional regulatory networks in T cells and elucidate the roles of TGF-β signaling constituents associated with immunosenescence in Temra.

Frailty is an age-related geriatric syndrome with largely unknown mechanisms. We conducted a longitudinal study of aging C57BL/6JNIA mice (females; n = 40, male; n = 49), measured frailty index and derived DNA methylation data from PBMCs. We selected frailty-related differentially methylated CpGs and determined differentially methylated regions (DMRs), focusing on both age-independent and -dependent frailty, and using both mixed-sex and sex-stratified subgroups. We propose a joint set of 925 frailty-related DMRs, perform an association study with frailty outcomes, build epigenetic frailty clocks and validate in mice with interventions. Notably, age-independent frailty DMRs are enriched in nervous and endocrine pathways, distinct from signaling and lipid metabolism pathways identified from age-dependent DMRs. We observe hypermethylation in signaling pathways and hypomethylation in lipid metabolism and cytochrome P450 pathways with frailty progression. 36 DMRs show consistent associations in validation. These findings highlight distinct epigenetic signatures underlying frailty and aging, with potential sex-specific mechanisms.

Spinal cord injury (SCI) causes not only intraspinal damage but also systemic organ pathology, with aging as a key determinant of outcomes. The mechanisms by which old age aggravate SCI pathology remain unclear. The voltage-gated proton channel Hv1 plays a key role in regulating immune responses. Hv1 increases with aging and SCI, and Hv1 KO provides neuroprotection in young mice. We hypothesized that age-related Hv1 upregulation worsens spinal cord, spleen, and lung pathology and hinders locomotor recovery after SCI via immune modulation. Using aged Hv1 KO and WT male mice subjected to moderate SCI, we assessed behavioral and molecular outcomes. Transcriptomic analysis revealed that Hv1 mRNA expression was higher in the brains of aged sham mice and further upregulated in injured spinal cord tissues. Spinal cord RNA-seq showed acute innate immune and cytokine activation in both genotypes. Hv1 deletion enhanced chromatin remodeling, epigenetic and Wnt signaling, while suppressing NF-κB-driven inflammation and oxidative stress-induced apoptosis. In the spleen, Hv1 depletion enhanced immune responses while suppressing mitosis. T cell and leukocyte activation increased, whereas lung cytokine signaling decreased. Functional recovery improved with reduced tissue damage. After chronic SCI, Hv1 KO mice showed elevated circadian rhythm and T cell proliferation in the spinal cord, increased mitotic gene expression but reduced adaptive immunity in the spleen, and enhanced immune activation with decreased cilium activity in the lungs. Together, our findings reveal how Hv1 contributes to age-related intraspinal damage and peripheral immune dysfunction after SCI, highlighting a potential therapeutic target for elderly patients.

Virus-induced accelerated aging has emerged as a potential contributor to HIV-associated neurocognitive disorders (HAND), despite widespread implementation of combination antiretroviral therapy (cART). Although evidence of accelerated aging in people living with HIV (PLWH) has been reported, most investigations of acute infection rely on in vitro systems or small animal models, leaving a critical gap in understanding early neuropathological events. To address this, we analyzed formalin-fixed, paraffin-embedded (FFPE) brain tissues from rhesus macaques acutely infected with simian immunodeficiency virus (SIV). We focused on two key aging-related proteins: the cellular senescence marker p16INK4a (p16) and the NAD-dependent deacetylase sirtuin 1 (SIRT1). We hypothesized that accelerated aging phenotypes would be detectable during acute infection, manifesting as increased p16 expression and altered SIRT1 levels, correlating with neurodegeneration. Consistent with this hypothesis, we observed marked upregulation of GFAP and p16, along with evidence of neurodegeneration, across multiple brain regions - including the frontal lobe, caudate, putamen, thalamus, hippocampus, and cerebellum - by 21 days post-infection. These findings suggest that aging-related and senescence pathways are activated almost immediately following HIV infection, highlighting the potential importance of astrocyte- or CNS-specific therapeutic strategies to mitigate early neuropathology.

Aging, the decline in physiological function over time, is marked by the intracellular accumulation of damaged components. It can be attributed to trade-offs between organismal maintenance and the generation of high-quality offspring, where the parent retains damage upon reproduction and produces rejuvenated descendants. This occurs even in bacteria, such as

Age-related sarcopenia, characterized by progressive loss of skeletal muscle mass and strength, impacts metabolic health and quality of life in the elderly. Heat shock factor 1 (HSF1) is a transcription factor that orchestrates cellular responses to various stresses, while its role in sarcopenia remains unknown. Here, HSF1 mRNA expression was decreased in muscles of aged mice and humans, correlating negatively with the atrophic gene and positively with the mitochondrial gene. Aged HSF1 muscle-specific knockout mice exhibited severe muscle atrophy and reduced endurance capacity, partially due to smaller fast fibers and mitochondrial dysfunction in slow fibers, as well as impaired systemic metabolic performance. In contrast, HSF1 overexpression in skeletal muscle improved these functions. Mechanistically, via RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq), it is revealed that HSF1 transcriptionally activated Sirtuin3 (SIRT3) for the deacetylation of both PGC1α1 and PGC1α4 isoforms of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), in skeletal muscle, enhancing mitochondrial function and muscle hypertrophy in vivo and in vitro, and inducing fibronectin type III domain-containing protein 5 (FNDC5)/Irisin for tissue crosstalk. Thus, HSF1 regulates skeletal muscle functions and systemic energy homeostasis via the SIRT3-PGC1α axis, representing a potential therapeutic target for sarcopenia and metabolic disorders.

Brain aging can cause cognitive and motor disabilities which often correlate with changes in dendritic branch, axon collateral, and synapse numbers. However, from invertebrates to mammals, age-related decline is typically restricted to specific neuron types or brain parts, indicating differential vulnerability. The rules to pinpoint the susceptibility of distinct brain elements to aging remain largely unknown. Here, we combine longitudinal studies with neuroanatomical, electrophysiological, and optophysiological analyses in the Drosophila genetic model to identify aging-susceptible and aging-resilient elements in a sensorimotor circuit that underlies escape. Young and mid-aged flies escape predator-like visual stimuli with a jump followed by flight, but behavioral performance declines with age. Mapping the underlying functional decline into the brain shows that most circuit components are robust against aging and remain functional even in old flies that have lost the behavior. By contrast, behavioral decline is caused by the selective decay of synaptic transmission between one specific visual projection neuron type (LC4) and the dendrite of one identified descending neuron (GF). Structurally, presynaptic active zone marker density is reduced whereas postsynaptic marker density remains normal. Other central synapses in this circuit as well as neuromuscular synapses are robust to aging. The synaptic connection susceptible to aging is also the circuit element most vulnerable to starvation or oxidative stress. Moreover, the vulnerable circuit element is also required for habituation, and thus, underlying circuit plasticity. In conjunction with data from mammalian brains our data suggest that a trade-off for functional neural circuit plasticity might be vulnerability to aging.

Pigment epithelium-derived factor (PEDF) contributes to the beneficial effects of exercise by suppressing cellular senescence in multiple organs. Its expression declines in the skeletal muscle of aged animals, suggesting a role in age-related frailty. To investigate the association between circulating PEDF and physical performance, we analyzed its associations with skeletal muscle mass and mobility in a cohort of older women. A cross-sectional analysis was conducted in 143 community-dwelling females (mean age 77.01 ± 4.16 years). Serum PEDF and body composition were measured, and physical performance was assessed via gait speed, handgrip strength, leg extension strength, and the Five Times Sit-to-Stand test. Serum PEDF levels positively correlated with skeletal muscle mass index (SMI) and gait speed, while no significant correlation was observed between serum PEDF levels and other physical function parameters. These findings suggest that circulating PEDF is associated with skeletal muscle mass and mobility in older adults, warranting further investigation into its potential role as a myokine in humans.

High-protein (HP) diets are widely adopted in Western societies for body-weight management; yet, they exacerbate senescence-associated metabolic deterioration, posing an unresolved pathophysiological conundrum. Here, we demonstrate that long-term HP intake mediates adipocyte-specific NAD

Myosteatosis, defined as the pathological accumulation of fat within skeletal muscle, has emerged as a critical yet underrecognized feature of muscle aging and metabolic dysregulation. Despite its growing clinical relevance, the field remains constrained by fragmented definitions, heterogeneous diagnostic criteria, and limited mechanistic understanding, all of which hamper effective detection and intervention. This review synthesizes current evidence to delineate the epidemiological landscape and clinical ramifications of myosteatosis across organ systems, and to highlight emerging myokine-driven endocrine signaling, biomarker candidates, and diagnostic strategies.

An ageing-related pathology has recently been described as one that develops and/or progresses with increasing chronological age, that is associated with, or contributes to, functional decline and that is evidenced by studies in humans. The pineal gland is a photo-neuroendocrine organ whose primary function is to produce and secrete melatonin in response to light-dark cycle environmental cues. The gland may undergo ageing-related structural and morphological changes, including calcification, gliosis, cyst formation, and reduced density of β-adrenergic receptors, which are hypothesised to reduce melatonin secretion. Pineal gland senescence describes the ageing-related decline in neuroendocrine function, with reduced secretion of melatonin, which may contribute to ageing-related sleep disorders and disruption of other circadian-driven physiological functions and may have secondary effects such as contributing to cognitive and mood disorders related to sleep disturbance.

Baseline sarcopenia has been linked to cognitive decline in older adults; however, the impact of longitudinal changes in sarcopenia status on cognitive trajectories remains unclear.

Previous single-cell and single-nucleus heart atlases, often limited by small sample sizes, lack the statistical power needed for phenotype association analysis, particularly for cardiovascular diseases and cardiac aging. To address this, we integrated data from 436 samples across 12 single-cell studies, harmonized the corresponding sample metadata, and constructed a comprehensive heart atlas comprising 355,762 cells and 1,436,719 nuclei. Consensus annotation identified 10 broad cell types and 54 fine-grained subsets. Associating gene expression patterns and cell type proportions with phenotypic data, we identified NRG1-expressing endocardial cells linked to multiple cardiac diseases and found that interferon (IFN) response signatures mark aging in multiple heart cell types. Importantly, we also developed PopComm, a novel computational method for inferring ligand-receptor (LR) interactions from population-scale single-cell data and quantifying interaction strength for individual samples. Using PopComm, we revealed a close association between the IFN response state and altered cell-cell communication during cardiac aging.

The functional decline of the haematopoietic system during ageing propagates detrimental effects on the whole organism, ultimately eroding life and healthspan. Quantifying haematopoietic ageing holds great scientific and clinical relevance. Alterations in chromatin architecture are a well-established hallmark of ageing that encode rich and informative signatures of the ageing process, yet they remain largely unexplored as quantitative markers. Here, we present an interpretable deep learning approach based on convolutional neural networks, ChromAgeNet, that learns changes in the spatial features of chromatin architecture during natural aging of Hematopoietic Stem Cells (HSCs). We trained our algorithm on 3D microscope images of DAPI-stained HSC nuclei to discriminate between young and aged murine HSCs, achieving and AUROC of 0.77 {+/-} 0.03. This approach outperforms classical machine learning models trained on handcrafted chromatin features from the same dataset. We then applied explainable artificial intelligence techniques, identifying chromatin entropy, peripheral heterochromatin and chromatin condensates as predictive markers. As a proof of concept, we evaluated the potential of our model as a phenotypic screening tool for aged HSCs treated with epigenetic drugs to detect rejuvenation. Altogether, we demonstrate that changes in chromatin organization can be modeled via machine learning to predict cellular ageing in the hematopoietic compartment. Our developed framework, ChromAgeNet, serves as an interpretable algorithm to unravel the intricate relationship between chromatin changes and cellular ageing, and advance high throughput drug screening for rejuvenation therapies.

Background Hutchinson-Gilford progeria syndrome (HGPS) is a devastating premature aging disorder driven by the accumulation of progerin, leading to severe vascular pathology. While epigenetic alterations are implicated, the spatiotemporal reorganization of the higher-order chromatin and its functional impact on vascular smooth muscle cell (VSMC) transcription remain poorly defined. Results Through an integrated multi-omics approach combining in situ high-throughput chromosome conformation capture (Hi-C) and Cleavage Under Targets and Tagmentation (CUT&Tag) profiling of CTCF, SMC1A, H3K27me3, H3K27ac, and H3K36me3 with transcriptomic analyses from control and HGPS iPSC-derived VSMCs, we reveal that global topologically associating domain (TAD) architecture remains largely intact in HGPS. However, the internal chromatin states of TADs undergo dynamic, passage-specific remodeling, characterized by a progressive accumulation of broad H3K27me3-repressed domains. This is accompanied by a loss of A/B compartment segregation, as confirmed by DNA-FISH, indicating a collapse of higher-order chromatin organization in late passage. Crucially, we uncover widespread rewiring of enhancer-promoter (E-P) loops, which is linked to the dysregulation of genes critical for vascular development, extracellular matrix organization, and atherosclerosis. Conclusions Our study demonstrates that spatiotemporal redistribution of repressive histone marks and reorganization of E-P interactions within a structurally resilient TAD framework underpin widespread transcriptional dysregulation in HGPS vascular pathogenesis. This uncovers a critical dissociation between higher-order chromatin architecture and histone modification landscape, providing a mechanistic basis for the failure of vascular homeostasis in progeria.

Human brain aging involves a variety of cellular and synaptic changes, but how these changes affect brain function and signals remains poorly understood due to experimental limitations in humans, meriting the use of detailed computational models. We identified key human cellular and synaptic changes occurring with age from previous studies, including a loss of inhibitory cells, NMDA receptors, and spines. We integrated these changes into our detailed human cortical microcircuit models and simulated activity in middle age (~50 years) and older (~70 years) microcircuits, and linked the altered mechanisms to reduced spike rates and impaired signal detection. We then simulated EEG potentials arising from the microcircuit activity and found that the emergent power spectral changes due to these aging cellular mechanisms reproduced most of the resting-state EEG biomarkers seen in human aging, including reduced aperiodic offset, exponent, and periodic peak center frequency. Using machine learning, we demonstrated that the changes to the cellular and synaptic aging mechanisms can be estimated accurately from the simulated EEG aging biomarkers. Our results link cellular and synaptic mechanisms of aging with impaired cortical function and physiological biomarkers in clinically relevant brain signals.

Background Cellular defenses against retrotransposable elements (RTEs) weaken with age and RTEs have been reported to contribute to Alzheimer\'s disease (AD) pathogenesis by promoting neuroinflammation. The mechanisms implicated include DNA damage promoted by retrotransposition and interferon system activation by RTE-derived cDNA intermediates. LINE-1 (L1) retrotransposons are of particular interest because they are the only autonomously active RTEs in the human genome. Results To investigate L1 activation and retrotransposition in AD, we performed Nanopore long-read DNA sequencing on six late-onset AD (LOAD) and six age-matched control human prefrontal cortex (PFC) samples. We developed and validated a stringent RTE insertion calling pipeline and identified two high-confidence somatic insertions, one AluY and one L1HS. We estimate that ~1% of cells in the aged PFC have a somatic RTE insertion. AD samples were hypomethylated, and genome-wide analysis of differentially methylated regions (DMRs) supports a process of epigenetic drift in AD. DMR-associated gene sets primarily related to brain function and inflammation. To investigate L1 activation we used CpG methylation as a proxy for L1 expression. We observed decreased methylation at young L1 elements. While most reads overlapping the L1HS promoter were highly methylated (>80% methylated), 7% were <50% methylated, 1% were <25%, and the highly demethylated read fraction increased in AD. L1HS 5\' UTR methylation was strongly correlated with RNA expression. Conclusions CpG methylation-mediated repression of young RTEs is compromised in old age - our findings indicate that this is further exacerbated in AD. Amid these failing defenses, we report somatic retrotransposition events in the aging and demented brain.

Proteostasis and the regulation of protein folding and sorting play a critical role in maintaining cellular homeostasis. The failure of proteostasis contributes to heart failure and aging, but, despite its importance, the mechanisms and factors regulating proteostasis in cardiomyocytes remain poorly characterized.

Chronic kidney disease (CKD) is closely associated with mitochondrial dysfunction, oxidative stress, and aging-related damage. CDGSH iron-sulfur domain-containing protein 2 (CISD2) plays a central role in mitochondrial homeostasis, calcium regulation, and cellular longevity, and its reduced expression has been linked to renal aging and CKD progression. In this study, an immunoinformatics-guided strategy was employed to identify small-molecule candidates capable of modulating CISD2 activity. A multi-step virtual screening pipeline-including drug-likeness filtering, absorption, distribution, metabolism, and excretion (ADME) prediction, molecular docking, and molecular dynamics simulations-was applied to an initial library of ~ 10,000 compounds. From this process, (2R)-2-[3,4-bis(oxidanyl)phenyl]-6-oxidanyl-2,3-dihydrochromen-4-one (6J6) emerged as the top candidate. 6J6 demonstrated favorable drug-like properties, strong predicted binding affinity, and stable interactions with the CISD2 binding pocket. Comparative analyses further suggest that 6J6 may offer advantages over known CISD2-targeting compounds such as hesperetin. KEGG-based pathway analysis indicated that CISD2 upregulation could promote mitochondrial biogenesis, reduce reactive oxygen species accumulation, and suppress inflammatory signaling, all of which are relevant to CKD. Unlike our earlier hesperetin-based study focused on liver aging, this work introduces 6J6 as a computationally identified for kidney disease, broadening the therapeutic scope of CISD2 modulation. These findings position 6J6 as a putative CISD2 modulator and provide a computational framework for advancing CKD drug discovery, though experimental validation remains necessary.

Oxytocin, a hormone linked to reproduction and health, may mediate life-history trade-offs across the human life course. Yet, how oxytocin naturally varies with age remains poorly understood. Here, working with the Tsimane, forager-horticulturalists of lowland Bolivia, we collected the largest sample of oxytocin measurements to date (n = 1,242 samples, n = 405 individuals, age = 2 to 84 y, 51% female), and i) examined how oxytocin varies throughout the life course in females and males, and ii) investigated potential drivers of age- and sex-specific variation. Our sample provides rare insight into the relationship between oxytocin and age in a context where energy is limited and trade-offs between reproduction and somatic maintenance are more salient. We found that oxytocin follows a nonlinear sex-specific trajectory throughout the life course. In females, oxytocin levels were high during the reproductive years and declined in the early to midforties, a pattern largely explained by breastfeeding and, to a lesser extent, childcare and good self-rated health. In males, oxytocin was low in early adulthood but high in old age, and although higher oxytocin was linked to good self-rated health, this did not explain the rise in oxytocin in later life. These findings suggest that oxytocin is instrumental for reproduction and caregiving in females and may also be associated with health in both males and females. Together, our work highlights oxytocin's broader biological significance across the human life course, suggesting that it may play a pivotal role in coordinating age- and sex-specific trade-offs involving reproduction and health.

As a target organ in direct contact with external air, lung tissue is more susceptible to aging, and lung aging is closely related to the development of chronic lung diseases such as chronic obstructive pulmonary disease and pulmonary fibrosis. Evolutionarily speaking, the Wnt signaling pathway is highly conserved and plays an important role in embryonic development, tissue homeostasis, as well as cell proliferation, differentiation, apoptosis, and migration of a variety of cells. Alterations in Wnt signaling pathway activity can accelerate the pathological process of chronic lung diseases. In recent years, a large number of studies have focused on the regulatory role of the Wnt signaling pathway in the lung aging process and aging-related chronic lung diseases. Therefore, this paper systematically reviews the relationship between the Wnt signaling pathway and lung aging and its role in aging-related chronic lung diseases.