Longevity Papers

Diabetic foot ulcers, ranked as the most severe complications of diabetes, frequently demonstrate a limited response to conventional treatment modalities. Mesenchymal stem cells (MSCs) constitute a prospective regenerative strategy for diabetic wound healing. However, MSCs expanded ex vivo exhibit vulnerability to proliferative aging, thus limiting translational utility. Growth arrest-specific 6 (GAS6) is known to play multiple roles in various cell and tissue repair processes. This research delineates GAS6's impact on MSCs senescence and associated intracellular signaling pathways, while assessing its ability to augment aged MSCs regenerative capacity in diabetic wound healing. GAS6 significantly improved the aging phenotype of MSCs, while siGAS6 led to the aging of MSCs. GAS6 regulated the degradation of Keap1 through the p62-dependent autophagy pathway, thereby promoting the nuclear entry of Nrf2 to exert an anti-aging effect. Meanwhile, it was verified that GAS6 regulated Keap1 and Nrf2 by activating the PI3K/Akt pathway, thus delaying the aging of MSCs. The angiogenic capacity of aging MSCs-derived conditioned medium (MSCs-CM) was improved by GAS6 through the upregulation of Nrf2, which was verified at both cellular and animal levels. GAS6 promoted the accumulation of p62 by activating the PI3K/Akt signaling pathway. p62 bound to Keap1, promoted the degradation of Keap1, and competitively inhibited Keap1's binding to Nrf2, thereby reducing the ubiquitination and degradation of Nrf2. Ultimately, Nrf2 accumulated in the cell and translocated to the nucleus, where it bound to antioxidant genes and exerted an effect of delaying the senescence of MSCs. Additionally, GAS6 improved the angiogenic capacity of aging MSCs-CM by upregulating Nrf2.

The accumulation of mitochondrial DNA (mtDNA) deletion mutants in post-mitotic cells is a hallmark of mammalian ageing and a key contributor to tissue decline in skeletal muscle and neurons. Although the occurrence of such deletions is well documented, the mechanisms by which they clonally expand to levels exceeding the threshold for respiratory chain dysfunction remain unresolved. A transcription-coupled replication model has recently been advanced, predicting that deletions affecting genes involved in a negative feedback mechanism gain a selective replication advantage. This model implies relatively short accumulation times for mutant takeover, a critical but experimentally inaccessible parameter since single-cell measurements are destructive. Here, we present a novel approach to infer such accumulation times from cross-sectional single-cell RNA sequencing (scRNAseq) data, exploiting the fact that mtDNA deletions are also reflected at the transcript level. To establish feasibility, we generated synthetic datasets using two stochastic models of the mitochondrial life cycle and used these as a gold standard. We then applied the Moran process, a classical stochastic model of birth-death dynamics, to calculate distributions of mutant accumulation times and to extract key parameters. The Moran model reproduced the distributions obtained from stochastic simulations with high fidelity, demonstrating robustness across different assumptions about mitochondrial regulation. By fitting the model to synthetic data, we successfully recovered the true values for key parameters like mutation probability, selection advantage, and the fraction of advantageous mutants. Our findings establish a methodological framework for estimating mtDNA mutant dynamics from single-cell transcriptomic data. This approach opens the way for application to large-scale datasets such as Tabula Muris Senis and Tabula Sapiens, offering new insights into the role of mtDNA deletions in ageing and age-related disease.

Menopause increases the risk of hypertension in women, yet the factors contributing to this important change remain unclear. Because early life stress has persistent and sex-specific consequences on health, we hypothesized that ageing reveals the latent effects of neonatal maternal separation (NMS) on cardiovascular homeostasis in female rats. Following birth, rats were either subjected to NMS (3 h/day from postnatal days 3 to 12) or raised under standard conditions (CTRL). Cardiovascular and neuroendocrine functions were evaluated at three distinct ages: young adult (12 weeks), middle-age (35 weeks) and old (64 weeks). Measurements included hormonal profile (multiplex assay), mean arterial blood pressure (MAP; tail cuff method), activity of the plasma angiotensin-converting enzymes (ACE and ACE2), and activation of the paraventricular nucleus of the hypothalamus (PVN; FosB immunolabelling). Age-related decline in 17β-oestradiol (E

Biological age, an indicator of an individual's health status, was initially measured using bulk tissue aging clocks. However, by averaging molecular signals across thousands of cells, these tools mask the cellular heterogeneity that characterizes aging. Recent single-cell aging clocks, enabled by high-resolution omics technologies, address this limitation. In this review, we provide a systematic overview of these tools, covering their computational foundations and the key biological insights they enable. These clocks have transformed "mosaic aging" from a hypothesis into a quantifiable phenomenon. They also highlight the plasticity of aging by tracking cell-type-specific age acceleration in disease and its reversal after interventions. Furthermore, they are opening new biological frontiers, including the "age reset" during embryogenesis, the role of the tissue microenvironment, and the molecular underpinnings of extreme longevity. Collectively, these findings recast aging not as passive decline but as a regulated, potentially malleable biological program. Single-cell aging clocks provide the foundational tools for developing the next generation of precision interventions aimed at extending human healthspan.

Fanconi anaemia (FA) is a DNA-repair disorder that compresses multiple hallmarks of ageing into childhood and early adulthood. Persistent genomic instability in FA precipitates oxidative stress, inflammatory remodelling, and metabolic reprogramming, which together erode epigenetic integrity and immune competence. Here we provide evidence FA-specific DNA-repair failure is linked to mitochondrial metabolism, nutrient-sensing networks, and immune dysfunction. In this context, we discuss how these interactions accelerate epigenetic drift and cancer susceptibility. We propose FA as a human "time-lapse" model to separate the sequence and interdependence of selected ageing hallmarks, such as genome instability, epigenetic deregulation, stem cell exhaustion, and immunosenescence, which together contribute to a markedly increased risk of early cancer development. We further highlight nutrigenomic mechanisms, including vitamin D-dependent chromatin remodelling and redox-sensitive cofactors, that modulate epigenetic states and immune resilience. Framing FA within the broader framework of ageing biology suggests testable biomarkers and precision-prevention strategies aimed at stabilising the epigenome, delaying carcinogenesis, and prolonging healthspan.

Polyamines - putrescine, spermidine, and spermine - are ubiquitous cationic molecules that are essential for cellular proliferation and homeostasis. Their intracellular concentrations decline with age, contributing to physiological and cognitive deterioration. Recent studies have revealed that spermidine supplementation extends lifespan and improves cognitive and cardiac function in various model organisms, suggesting that maintaining polyamine balance has anti-aging potential. Polyamine metabolism is tightly regulated through biosynthesis, degradation, and transport; however, age-associated upregulation of spermine oxidase (SMOX) and accumulation of its toxic byproduct acrolein promote oxidative damage and cellular senescence. Suppressing SMOX activity or polyamine degradation attenuates senescence markers and DNA damage, highlighting spermine catabolism as a therapeutic target. Polyamines also modulate epigenetic regulation, including DNA methylation and histone acetylation, thereby influencing gene expression and chromatin structure during aging. Moreover, polyamine-dependent hypusination of eIF5A sustains protein synthesis in senescent cells. These multifaceted actions indicate that polyamine metabolism integrates redox control, translational regulation, epigenetic maintenance and autophagy to determine cellular and organismal longevity. While animal studies demonstrate clear anti-aging effects of spermidine and spermine, human clinical evidence remains limited, with variable outcomes likely due to bioavailability and metabolic conversion. Future strategies combining dietary or probiotic polyamine enhancement, enzyme-targeted inhibitors, and personalized metabolic interventions hold promise for extending healthspan. Collectively, maintaining optimal polyamine homeostasis emerges as a key approach to counteract aging and age-related diseases.

The nervous system modulates aging by secreting signaling molecules to cell-nonautonomously regulate the physiological state of distal tissues such as the gut. However, the underlying mechanisms are not well understood. Here, using Caenorhabditis elegans as a model, we identified two distinct neuroendocrine signaling circuits through which motor neurons signal the gut in early life to shorten lifespan but in mid-late life to extend lifespan. Both circuits employ the same neurotransmitter acetylcholine (ACh), while recruiting two different gut ACh receptors ACR-6 and GAR-3 to regulate the transcription factor DAF-16 and HSF-1 in early and mid-late life, respectively. Strikingly, the gut expression of ACR-6 is restricted to early life, whereas that of GAR-3 is confined to mid-late life, providing a potential mechanism for the temporal control of the two circuits. These results identify a novel mechanism that empowers the nervous system to bidirectionally regulate longevity by differentially signaling the gut at different life stages.

Community-dwelling older adults residing in non-age-friendly external environments face a higher risk of restricted life-space mobility. Although improving the external environment may help mitigate this risk, environmental interventions are often complex, challenging to implement, and demonstrate limited effectiveness. Enhancing intrinsic capacity, however, may offer a novel approach to addressing the risk of restricted life-space mobility in older adults.

Loneliness is associated with premature mortality risk. Less is known about the mechanisms that may explain this association. Given its consequential health associations and relation to loneliness, purpose in life may be one such mechanism. In a prospective rotating split-sample design from 2008-2010 to 2012-2014 with 11 years of mortality status follow-up, we tested purpose in life as an indirect pathway between loneliness and future risk of death. Participants were from the Health and Retirement Study in the United States (N = 8351; M[SD] = 67.9 [9.19] years; range: 50-101; 60 % female; n = 1191 deceased). Purpose in life explained an estimated 88 % of the association between loneliness and mortality risk, with the majority of the mediated association appearing to reflect changes in purpose in life over time. These effects were independent of loneliness change during follow-up and initial levels of purpose in life. This indirect path was robust to sensitivity analyses, and further adjustment for conceptually similar constructs, such as depression, social isolation, and neuroticism. A supplemental model that tested purpose in life as the antecedent and loneliness as the indirect pathway indicated substantially smaller effects. Much of loneliness-mortality relation operated through purpose in life. Purpose in life appears to be a critical factor in the context of loneliness. It may prove fruitful to pay particular attention to the individual, community, and broader societal sources of purpose in life when looking to ameliorate the effect of loneliness on health.

Malnutrition and frailty are common and closely related in older adults. The aim of this study is to investigate the longitudinal associations on the nutritional risk indexes and frailty onset in Healthy Aging Longitudinal Study in Taiwan.

Dysregulation of the adaptive immune system is a key feature of aging and is associated with age-related chronic diseases and mortality. Here, we find that T cell aging, especially in the CD4 subset, is controlled by B cells. B cells contributed to the age-related reduction of naive CD4 T cells, their differentiation toward immunosenescent T cell subsets, and age-associated T cell receptor clonal restriction. Concurrently, mice lacking B cells displayed improvements in health span and life span. We uncovered a role for B cell-intrinsic insulin receptor signaling in influencing age-related B cell phenotypes that in turn induces CD4 T cell dysfunction, a process that is in part driven by major histocompatibility complex class II. These results identify B cells as critical mediators driving age-associated adaptive immune dysfunction and health-span outcomes and suggest previously unrecognized modalities to manage aging and related health decline.

The elegant work by Maejima et al. recently published in Aging Cell reveals a previously unrecognized mechanism linking age-related oxytocin (OXT) decline to epigenetic remodeling, mitochondrial dysfunction, and systemic inflammation (Maejima et al. 2025). Beyond documenting this relationship, the authors demonstrate its remarkable reversibility through nasal OXT administration. These findings provide the first molecular evidence supporting what has long been proposed: that the OXT system functions as a fundamental long-term regulator of health across the entire lifespan, from early development through aging (Moberg 2024, 2003; Uvnas-Moberg 1998). The current work now gives a tantalizing glimpse into the epigenetic mechanism behind this life course regulation.

The effect of biological aging on brain structure is widespread and apparent. However, little is understood regarding which regions exhibit similarities in vulnerability, and what biological processes drive regional patterns of senescence-associated atrophy. Here, we investigated whether associations between age and brain structure exhibit distinct patterns of regional vulnerability, and if so, whether they are related to patterns of cerebral physiology which also show age-related decline. Using both data-driven and hypothesis- driven approaches, we identified recurring patterns of accelerated and delayed decline across the lifespan. Notably, the results mapped using unsupervised clustering methods mirrored the organization of major arterial flow territories, suggesting that vascular architecture may serve as a key organizing principle in brain aging. These results provide support for future research on aging and neurodegenerative disorders that aim to link patterns of structural deterioration to physiological processes that may be useful for identifying 'at risk' individuals and developing novel therapeutics.

Chronic periodontitis is increasingly recognized as a potential upstream contributor to neurodegenerative processes through sustained systemic inflammation, microbial dysbiosis, and blood-brain barrier (BBB) alterations. This review synthesizes human and experimental evidence linking periodontal pathogens-including but not limited to Porphyromonas gingivalis as well as broader dysbiotic consortia such as Tannerella forsythia, Treponema denticola, and other keystone oral taxa-to neuroinflammatory cascades associated with cognitive decline. Mechanistic insights highlight the roles of glial activation, proinflammatory cytokines, and polymicrobial virulence-mediated neuronal stress in bridging oral and brain pathology, while age-related factors such as immunosenescence and microbiome imbalance amplify systemic vulnerability. Human biomarker and imaging studies support an association between chronic periodontal inflammation and neurovascular dysfunction, suggesting that oral disease may act as a persistent peripheral amplifier of central immune activation. Recent research has expanded into biomarker discovery and translational implementation, yet progress remains limited by population heterogeneity, methodological variability, and regulatory complexity. Promising interventions-including anti-inflammatory therapies, oral hygiene optimization, probiotic or dietary modulation, and molecular strategies such as polymicrobial-targeted approaches, gingipain inhibition, and microRNA-based modulation-are discussed within emerging multi-omics and precision-medicine frameworks. Although standardization and longitudinal validation are still required, integrative approaches combining inflammatory, microbial, and genetic profiling may enable individualized risk assessment and targeted prevention. As global populations age, addressing the oral-brain axis offers a practical and modifiable pathway to lessen the burden of neurodegenerative diseases and support healthier cognitive aging.

Age-related hearing loss is the leading sensory deficit in older adults, yet audiometric thresholds at conventional frequencies often poorly predict speech understanding. Two competing hypotheses have emerged: extended high-frequency (eHF) hearing loss beyond 8 kHz may unmask variance in speech performance, while hidden hearing loss from cochlear synaptopathy, detectable via auditory brainstem response (ABR) wave I amplitude reduction, may degrade temporal coding independent of audiometry. Here, in 526 ears from 263 tinnitus-free adults in the Swedish Tinnitus Outreach Project (STOP) cohort, we show that eHF pure-tone average (10-16 kHz) is the single most age-sensitive auditory measure, explaining 64% of age-related variance (R2 = 0.64) compared to only 16% for conventional audiometry (R2 = 0.16). Moreover, eHF thresholds robustly predict both word and phoneme recognition in speech-weighted noise (+4 dB SNR), explaining 34-36% of speech variance (R2 = 0.34-0.36)-substantially exceeding conventional pure-tone average (22-25%) and all ABR features (5-13%). In contrast, ABR Wave I amplitude, the putative marker of cochlear synaptopathy, contributes no additional explanatory power even in high-reliability recordings (ICC = 0.96). These findings challenge the translational relevance of cochlear synaptopathy to age-related speech deficits and suggest conduction delays, not synaptic loss, as the peripheral neural mechanism underlying speech comprehension decline in aging.

Sarcopenia, an aging-related disorder characterized by progressive loss of skeletal muscle mass and function, lacks well-defined mechanisms and specific therapeutics. This study investigated the therapeutic effects of yeast protein (YP) on dexamethasone (DEX)-induced muscle atrophy in C57BL/6J mice using transcriptomic and metabolomic approaches. High-dose (2 g per kg bodyweight) YP (H-YP) significantly ameliorated muscle histopathology, increased serum CAT and SOD activity, enhanced grip strength and hanging endurance, elevated muscle ATP and IGF-1 levels, and reduced MSTN expression (

Fibroblast-mediated decreased collagen synthesis is a key aspect of skin aging. Polyhydroxyalkanoate (PHA) materials have established clinical biocompatibility; however, the direct mechanisms of PHA microspheres on fibroblast-mediated skin rejuvenation remain unexplored. We aimed to investigate the impact of PHA microspheres on collagen production and its underlying molecular pathways. The microspheres demonstrated high biocompatibility, promoting human fibroblast proliferation in vitro and showing robust systemic safety in a rat model. In vivo, PHA microsphere injection significantly increased epidermal thickness and the expression of collagen I and III. Mechanistically, PHA microspheres improved mitochondrial function, as evidenced by elevated ATP production. MYBL2 was identified as a key transcriptional regulator; its knockdown attenuated fibroblast proliferation, collagen synthesis, and mitochondrial function. Importantly, PHA stimulation failed to rescue this effect, confirming that MYBL2 is required for the observed regeneration. In summary, we demonstrate that PHA microspheres drive fibroblast proliferation and collagen synthesis by upregulating MYBL2 and enhancing mitochondrial function. These findings provide a theoretical basis for the application of PHA microspheres as a collagen stimulant for skin rejuvenation.

The p163MR mouse model has been widely used to visualize and conditionally eliminate p16 expressing senescent cells in vivo and has been applied across diverse biological contexts, including tissue repair, fibrosis, cancer, therapy response, and aging. Despite the development of multiple senescence reporter and ablation systems, p163MR stands out for its broad and sustained adoption across independent laboratories. Here, we review the extensive published literature supporting the reproducibility and utility of the p163MR system and present new validation data across acute and chronic senescence-inducing conditions. We demonstrate reproducible induction of p16 associated bioluminescence during wound healing, chemotherapy, and aging, as well as partial but consistent reduction following ganciclovir treatment. We further delineate the strengths and limitations of the individual components of the 3MR construct, including HSV thymidine kinase mediated clearance, Renilla luciferase based bioluminescence, and monomeric red fluorescent protein, and discuss how factors such as cell abundance, tissue context, pigmentation, and substrate chemistry influence detection sensitivity. Together, these data confirm that the p163MR model is a functional and versatile tool for studying senescent cells in vivo when used with appropriate experimental design and interpretation, and they provide support for its continued application alongside emerging senescence models.

Nicotinamide adenine dinucleotide (NAD⁺) is a central metabolic coenzyme that regulates redox homeostasis, DNA repair, and cellular longevity. While the role of NAD⁺ metabolism in mammalian aging has been well studied, its significance in invertebrate systems remains underexplored. Here, we establish the silkworm (Bombyx mori) as a novel model for investigating NAD⁺-dependent lifespan regulation. Through phenotypic comparisons among silkworm strains, we found that longer-lived strains exhibit higher levels of NAD⁺ and elevated expression of BmNmnat1, a key enzyme in NAD⁺ biosynthesis. CRISPR/Cas9-mediated knockout and RNAi knockdown of BmNmnat1 led to embryonic lethality, increased DNA damage, disrupted cell cycle progression, and morphological aging phenotypes. Supplementation with nicotinic acid (NA) significantly reversed these aging-associated changes both in vitro and in vivo, including improved redox balance, reduced oxidative stress markers, and prolonged adult lifespan. Our results highlight the evolutionarily conserved role of BmNmnat1-mediated NAD⁺ metabolism in aging and establish the silkworm as a valuable invertebrate model for mechanistic studies and antiaging intervention screening.

Sarcopenia, the gradual loss of skeletal muscle mass, strength, and function, is a growing concern in aging populations. Early detection is vital to reduce the risk of frailty, disability, and mortality, yet traditional diagnostic methods such as imaging and physical performance tests are often costly, inconsistent, or difficult to implement in routine care. Artificial intelligence (AI), including machine learning (ML) and deep learning (DL), is emerging as a powerful tool in sarcopenia research and clinical practice. This review explores how AI is being applied to early detection, imaging-based diagnosis, prediction of functional outcomes, and personalized monitoring. Models trained on large datasets, such as NHANES, have demonstrated strong predictive performance using standard clinical variables. DL has enabled automated analysis of CT scans for muscle segmentation, reducing the need for manual interpretation. At the same time, ML systems integrated with wearable devices allow real-time tracking of physical function. Emerging approaches such as explainable AI, federated learning, and the integration of diverse data sources, including omics and microbiome profiles, are expanding opportunities for individualized care. Despite these advances, significant challenges remain, including variability in data quality, limited model transparency, algorithmic bias, and ethical concerns. Regulatory oversight and clinician engagement will be key to successful implementation. AI offers a promising path toward proactive, scalable, and personalized management of sarcopenia.

Epigenetic regulation has fundamental roles in the maintenance and differentiation of neural stem cells as well as fate determination of neural lineage. Although neural differentiation is irreversible under physiological conditions, neural dedifferentiation into NSCs was observed under a damaged condition and in an aged brain. However, molecular mechanisms triggering neural fate regulation still remain to be elucidated. In this study, we show that a neural turnover in the adult brain is induced by the lack of JMJD3 using NSC-visualized neural JMJD3 deleted mice. In the JMJD3 deleted brain, a marked expansion of the Nestin-GFP positive population in the hippocampus was observed. Moreover, neurosphere assays revealed not only that JMJD3 deleted neurospheres showed a significantly higher self-renewal potential but also that Nestin-negative neural progenitors converted into a Nestin-positive state in the absence of JMJD3. Intriguingly, a combination of upregulation of Plagl2 and inhibition of Dylk1a as well as increased expressions of HMGAs were detected in the neurospheres lacking JMJD3, suggesting that the lack of JMJD3 could enhance rejuvenation of chromatin state. These results suggest that JMJD3 could be involved in the fate regulation of NSC/NPCs and could provide novel and important insights to promote neural repair and regeneration.

Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by the abnormal aggregation of amyloid-β (Aβ). Bletilla striata polysaccharide (BSP), the primary active component of the traditional Chinese medicine Bletilla striata, exhibits various pharmacological effects including hemostatic, antioxidant, anti-inflammatory, and immunomodulatory activities. This study aimed to systematically investigate the protective effects and molecular mechanisms of BSP in Caenorhabditis elegans AD model. We found that BSP effectively alleviated the paralysis phenotype in AD worms, with optimal efficacy observed at a concentration of 100 μg/mL. Furthermore, BSP significantly extended the lifespan of both wild type and AD worms, reduced lipofuscin deposition and egg-laying capacity, improved neuromuscular function, learning ability, and stress resistance, and lowered the level of oxidative stress in vivo. Additionally, BSP treatment markedly suppressed Aβ aggregation in AD worms. Transcriptomic analysis revealed that BSP significantly regulates the autophagy pathway. In combination with genetic experiments, we further elucidated that BSP coordinates the insulin and AMPK signaling pathways to modulate autophagy, thereby reducing abnormal autophagosome accumulation and restoring autophagic homeostasis. Notably, the neuroprotective effects of BSP were completely abolished in mutants of key insulin signaling pathway genes (daf-2, age-1, akt-1, akt-2, daf-16) and the AMPK homologous gene aak-2, indicating that its efficacy is associated with the insulin/AMPK-autophagy regulatory axis. This study reveals the mechanism by which BSP ameliorates AD pathology through multi-target and multi-pathway regulation of autophagy, providing a new theoretical basis for its development as a candidate therapeutic agent for AD and further highlighting the potential medical value of Bletilla striata in combating AD.

Aging is characterized by the progressive decline of physiological integrity, and its driving factors include mitochondrial dysfunction, epigenetic changes and metabolic imbalance. Although some studies have shown that glycine (Gly) has anti-aging protection, its mechanism has not been clarified.

Primate social behaviors are known to mitigate a number of negative psychological and physiological problems. Social connectedness in wild baboons can predict longevity and health, but the relationship between social grooming and physical health in captive baboons is less known. We studied rates of social grooming in captive olive and olive/yellow hybrid baboons (Papio anubis; P. anubis/cynocephalus), the factors that influence social connectedness, and its potential impacts on health as measured with neutrophil and lymphocyte levels. These white blood cell measures are available through routine bloodwork and the neutrophil-to-lymphocyte ratio (NLR) is known to be predictive of health outcomes. Subjects were 162 adult baboons housed in groups consisting of 1 male, 3 to 12 females, and associated offspring. Four 30-min all-occurrence observations per group were used to collect behavioral data. Blood data was collected opportunistically during veterinary check-ups for 45 of the females. Despite group compositions differing significantly from those in the wild, the captive baboons exhibited some similar patterns of social grooming and social connectedness to those of wild baboons. NLR was not significantly associated with any measure of social connectedness initially assessed, but a relationship between social network size and lymphocyte levels emerged. Baboons with few social grooming partners exhibited an expected decline in lymphocyte levels with age, but baboons with many social grooming partners did not show this expected trend. It appears, therefore, that older female baboons with many social partners may be buffered against age related immune health declines and that social connectedness is potentially acting to mediate some of the detrimental effects of aging.

Non-coding RNAs, including piwi-interacting RNAs (piRNAs), are known to regulate osteogenic differentiation in bone marrow-derived mesenchymal stem cells (BMSCs); their role in mesenchymal stem cells (MSCs) from diverse origins remains unclear. In this study, we identified piR48444 as a key regulator that is downregulated during the osteogenic differentiation of stem cells from exfoliated deciduous teeth (SHED) but is upregulated in inflamed and aged BMSCs. Functionally, piR48444 inhibited, while its knockdown enhanced osteogenic differentiation across MSCs from multiple sources. Notably, piR48444-depleted MSCs exhibited superior bone defect repair capacity. PiR48444 antagomir promoted bone regeneration in LPS-induced osteolysis mice and aging mice. Mechanistically, we demonstrated that piR48444 targets METTL7A, suppressing BMP2 mRNA m

Human social connections are complex ecosystems formed of structural, functional and quality components. Weak social connections are associated with adverse age-related health outcomes, but we know little about the ageing-related processes underlying this. Using data from 7047 adults aged 50+ in the English Longitudinal Study of Ageing, we explore associations between diverse aspects of social connections and both older subjective age and accelerated physiological age using a validated physiological ageing combining cardiovascular, respiratory, haematologic and metabolic indicators. Doubly robust estimations using inverse-probability-weighted regression adjustment estimators show that living alone, low social integration and low social support are risk factors for physiological age acceleration. However, weak social connections did not have a statistically significant association with older subjective age. Analyses are robust to multiple sensitivity analyses and maintained four years later. We propose the hypothesis that accelerated physiological ageing may be a mechanism underpinning the relationship between weak social connections and age-related morbitidy and mortality.

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

Cellular senescence is a state of stable arrest and secretion linked to aging and disease. Here we identify that senescent cells dispose of large fragments of themselves through cell-to-cell adhesion, which we term senescent-cell adhesion fragments (SCAFs). Found across all senescent types examined, SCAFs lack nuclear material but contain organelles, including damaged mitochondria. Disrupting adherens junctions decreased SCAF formation but induced senescent-cell death, which was caused by an inability to shed damaged mitochondria. Dynamic analyses show that SCAFs ultimately rupture, releasing a complex proteome including damage-associated molecular patterns (DAMPs) and proteins linked to neurodegenerative disease. Functionally, SCAFs activate wound-healing and cancer-related programs, promoting migration and invasion. Altogether, these findings identify a new feature that facilitates senescent cell survival, but the consequence of which is external deposition of damaged intracellular contents, with implications for cancer and aging.

Spatiotemporal changes in the nuclear lamina and cell metabolism shape cell fate, yet their interplay is poorly understood. Here we identify lamin A/C as a key regulator of cysteine catabolic flux essential for proper cell fate and longevity. Its loss in naive mouse pluripotent stem cells leads to upregulation of the cysteine-generating and catabolizing enzymes, cystathionine γ-lyase (CTH) and cystathionine β-synthase (CBS), thereby promoting de novo cysteine synthesis. Increased cysteine flux into acetyl-CoA fosters histone H3K9 and H3K27 acetylation, triggering a transition from naive to primed pluripotency and abnormal cell fate and function. Conversely, the toxic gain-of-function mutation of Lmna, encoding lamin A/C and associated with premature ageing, reduces CTH and CBS levels. This reroutes cysteine catabolic flux and alters the balance between H3K9 acetylation and methylation, crucially impacting germ layer formation and genome stability. Notably, modulation of Cth and Cbs rescues the abnormal cell fate and function, restores the DNA damage repair capacity and alleviates the senescent phenotype caused by lamin A/C mutations, highlighting the potential of modulating cell metabolism to mitigate epigenetic diseases.

Enhancing autophagy increases lifespan and healthspan in animal models, yet the precise molecular mechanisms underlying these effects are not fully understood. Here we show that overexpression of the essential autophagic gene atg-18 extends the lifespan of C. elegans. We describe a previously unknown, pleiotropic mechanism by which atg-18 impacts lysosomes and extends lifespan through the transcription factor hlh-30, the master regulator of lysosomal biogenesis. We show that, under stress conditions, HLH-30 requires atg-18 for nuclear translocation. Furthermore, atg-18 overexpression broadly improves health and stress resilience yet paradoxically increases early-life susceptibility to lethal heat stress. In contrast, a loss-of-function of function mutation in atg-18 enhances heat-stress survival, uncovering a temporal-specific effect of atg-18. These finding suggest the existence of a novel ATG-18--HLH-30 autophagy-lysosome pathway that plays a key role in lifespan and healthspan.

Aging is characterized by a progressive decline in physiological resilience and functional capacity, often accompanied by chronic, low-grade systemic inflammation, a phenomenon termed "inflammaging". This persistent inflammatory milieu contributes significantly to musculoskeletal degeneration, impaired neuromotor coordination, and reduced mobility, collectively diminishing quality of life, particularly among older adults. Key biological drivers of inflammaging include cellular senescence, immune system dysregulation, and mitochondrial dysfunction, which are orchestrated through complex molecular signaling pathways such as NF-κB, mTOR, JAK/STAT, MAPK, and NLRP3. These pathways facilitate the development of the senescence-associated secretory phenotype (SASP), thereby perpetuating tissue damage and systemic inflammation. Mobility decline, frequently manifesting as sarcopenia, osteoarthritis (OA), and gait instability, is closely associated with these inflammatory processes. Early identification of individuals at risk for mobility decline using biomarkers and functional assessments enables timely and targeted interventions that can help extend 'mobility span'. Foundational strategies such as lifestyle modification remain critical in mitigating the effects of inflammaging however, emerging therapeutic modalities including nutraceuticals and pharmacological agents offer promising avenues for intervention. This review synthesizes current evidence on the interplay between inflammaging and mobility decline, emphasizing mechanistic insights, therapeutic approaches, and future research directions. Addressing these interconnected biological processes is essential for promoting healthy aging, preserving functional independence, and extending health span.

Lupiwighteone (Lup), a natural isoflavonoid, phytochemical, exhibits potential anti-inflammatory properties; however, its impacts on inflammation, oxidative stress, and aging processes remain insufficiently characterized. The present study systematically investigated the anti-inflammatory and anti-aging effects of Lup using lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and Caenorhabditis elegans (C. elegans), aiming to elucidate its underlying molecular mechanisms and biological significance. The study employed cell culture, animal experiments, and molecular biology techniques, combined with molecular docking, to evaluate Lup's modulatory effects on NF-κB and MAPK signaling cascades and the Nrf2 pathway. Our results indicated that Lup treatment significantly extended lifespan, reduced reactive oxygen species (ROS) levels, and slowed age-related physiological decline in the C. elegans model. Mechanistically, we found that Lup activated the MAPKs/Nrf2 pathway, enhanced antioxidant stress responses, and reduced oxidative damage, thereby delaying the aging process. Additionally, Lup treatment significantly suppressed the production and secretion of key pro-inflammatory mediators, including TNF-α, IL-6, and nitric oxide, while inhibiting NF-κB signaling activation in LPS-stimulated RAW264.7 cells. This inhibition was mediated by impeding IκBα degradation, thereby preventing NF-κB translocation to the nucleus. Collectively, these findings demonstrated that Lup exerts significant anti-aging, anti-inflammatory, and antioxidant activities through the dual regulation of oxidative stress and inflammation. These results not only strengthen the theoretical basis of plant-derived medicines in anti-inflammation and anti-aging but also provide new insights and practical guidance for the future development of natural pharmaceuticals.

During aging, stem cell persistence is favored over functionality, resulting in delayed responses to injury.

Blood-brain barrier (BBB) dysfunction is a hallmark of many diseases of the brain, including those that represent the largest healthcare burden (for example, Alzheimer disease and stroke). Despite this, rejuvenation and repair of the BBB is not a mainstream concept. During life, the BBB is subjected to perturbations and stresses from a wide range of endogenous or exogenous sources, which can promote brain health or can lead to brain pathologies. The BBB supports many functions that are critical for central nervous system homeostasis and so there are many mechanisms of dysfunction, and hence many targets for intervention. Furthermore, many mechanisms are shared among diseases and disease subtypes, resulting in the potential for common strategies for BBB repair. In this Review, we consider the BBB as a therapeutic target and discuss approaches to its repair and protection in specific disease states and during normal ageing.

Global population aging and increased chronic stress due to numerous mass disasters including those related to pandemics, climate change, war, displacement, and political unrest all challenge our collective resilience, with a growing burden of late-life neuropsychiatric and neurodegenerative disorders placing unprecedented demands on health and social systems worldwide. With these considerations in mind, understanding and promoting brain health is becoming a priority for the prevention of neuropsychiatric disorders across the lifespan. Brain health represents a dynamic balance of neural, cognitive, and emotional processes that determine resilience to neuropsychiatric illness. In later life, this balance becomes particularly critical as neurobiological and psychosocial stressors converge to shape trajectories of neuropsychiatric and neurodegenerative disorders. This review synthesizes current evidence on the determinants of brain health in aging, emphasizing resilience as a modifiable pathway linking neuropsychiatric illness risk and prevention. We integrate insights from neuroscience, lifestyle medicine, geroscience, and social determinants of health to emphasize the value of a whole-person, life-course approach. Particular attention is given to the interplay between stress physiology, interoceptive regulation, emotional resilience, and cognitive and brain reserve across the aging continuum. Emerging frameworks including brain clocks, precision biomarkers, digital phenotyping, and artificial intelligence, are considered as tools for risk stratification, early detection, and personalized intervention. By linking resilience mechanisms to measurable biological indices, we argue for the integration of neurobiological, psychological, behavioral, and sociocultural domains to inform next-generation strategies in neuropsychopharmacology, prevention science, and the promotion of healthy brain aging.

Sirt7 is a member of the sirtuin family of proteins, which are NAD+-dependent deacetylases and ADP-ribosyltransferases. It is involved in a wide range of cellular processes. To study the specific role of Sirt7 in haematopoiesis during aging, the gene was specifically inactivated in hematopoietic stem cells (HSC). Vav1 promoter mediated expression of CRE recombinase in floxed Sirt7 mice resulted in specific inactivation of Sirt7 in the haematopoietic stem and progenitor cells. Young mice exhibited a normal peripheral blood count and no detectable haematological aberrancies. Peripheral blood of 19-month-old Sirt7 knockout mice revealed a diminished abundance of lymphocytes, but elevated count of monocytes compared to control mice. The number of erythrocytes, platelets and haemoglobin concentration remained unchanged. In the bone marrow of aged mice, a reduced abundance of myeloid undifferentiated cells could be observed. The development of hepatomegaly due to Sirt7 gene inactivation could indicate a myeloproliferative influence. Taken together, our data demonstrate that Sirt7 functions as a critical suppressor on haematopoietic stem cells differentiation in aged mice.

The frailty phenotype has limitations in capturing the biological heterogeneity of the condition. Our study identified subtypes of frailty based on proteomics and examined their associations with several adverse outcomes.

Osteoarthritis (OA) is a progressive joint disorder characterized by inflammation and metabolic imbalance. Schisandrin A (Sch-A), a bioactive compound from Schisandra sphenanthera, is known for its anti-inflammatory and protective properties. This study investigated the effects of Sch-A on chondrocyte senescence and metabolism using IL-1β-stimulated CHON-001 cells as an in vitro OA model. Sch-A showed no cytotoxicity up to 100 μM and alleviated IL-1β-induced chondrocyte injury. It restored anabolic metabolism, suppressed catabolic activity, and reduced inflammatory and fibrotic responses. Bioinformatics indicated links between Sch-A, cellular senescence, and the PI3K/Akt pathway. Functional assays confirmed that Sch-A suppressed senescence-associated secretory phenotype (SASP) factors, senescence markers, SA-β-galactosidase activity, and PI3K/Akt activation, while PI3K inhibition enhanced its anti-senescent effects. These findings suggest that Sch-A mitigates chondrocyte senescence and metabolic dysregulation by modulating PI3K/Akt signaling, supporting its therapeutic potential for OA.

Aging is a dominant risk factor for chronic diseases characterized by the functional decline of tissues and organs. During aging, the hematopoietic system declines in regenerative capacity-seemingly attributable to increases in DNA damage, replicative stress, and autophagic flux-resulting in skewing towards a myeloid lineage and away from a lymphoid lineage. Here, we characterized the transcriptomic and cellular landscape of the aged C57Bl/6J mouse hematopoietic system using a combination of bulk RNAseq and single cell RNAseq (scRNAseq). We show that aging leads to global transcriptional alterations in bulk peripheral blood mononuclear cells (PBMCs), lineage marker-depleted bone marrow cells (Lin-BM), and in hematopoietic stem and progenitor cells (HSPCs), immunophenotypically lineage marker negative (Lin-) Sca1+ cKit+ (LSK+). These changes indicate widespread activation of inflammatory processes, namely in PBMCs and Lin-BM cells. Interestingly, there is also a downregulation of cell cycle genes in HSPCs during aging. ScRNAseq across 39 hematopoietic cell types revealed age-related skewing in cell composition. Aged PBMCs showed significant decreases in CD4 and CD8 naïve cells concomitant with increases in CD4/8 memory and CD8 exhausted T cell populations. Lin-BM cells showed significant myeloid skewing in common myeloid progenitor (CMP) cells, as well as in the HSC population. We also identified a unique HSC population marked by increased Vwf, Wwtr1, and Clca3a1 expression that does not exist in young HSCs, thus likely marking true aged HSCs. Collectively, this work should serve as a useful resource for understanding and therapeutically targeting the aged hematopoietic system.

Recombinant human bone morphogenetic protein 2 (rhBMP-2) is a well-established osteoinductive agent used in clinical practice. In this study, rhBMP-2 is found to exacerbate the imbalance between osteogenesis and adipogenesis in senescent bone marrow stromal cells (BMSCs), resulting in excess adipocytes (eADs) accumulation and a diminished osteogenic response. However, the role of eADs in age-related bone repair deficits remains unclear. Our findings indicate that eADs within the aged microenvironment contribute to impaired bone regeneration by promoting BMSC senescence and suppressing osteogenic differentiation. To address this issue, we investigated the feasibility of regulating the abnormal differentiation of senescent BMSCs to enhance aged bone regeneration. Based on this, a novel energy-supplying hydrogel system (PEGSN-PGA/rhBMP-2/Rapa, PBR) suitable for the aged regenerative microenvironment and with excellent bone integration performance is designed for local minimally invasive treatment of aged bone defects. This system effectively regulates the abnormal differentiation of senescent BMSCs, maintains the cell cycle process, and retains the regenerative potential for bone repair in the senescent microenvironment. This study presents a novel strategy for the treatment of rhBMP-2-mediated bone degenerative diseases and offers a pioneering perspective on the interplay among adipogenesis, cellular senescence, and bone regeneration during the aging process.

Aging and insulin resistance are intertwined factors in the development of metabolic diseases such as type 2 diabetes and cardiovascular disorders. Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has shown promising cardioprotective effects in preclinical and clinical studies of metabolic diseases. Yet, its action on insulin-resistant aged subjects is not clearly defined. This study aimed to investigate the effects of liraglutide on intracellular zinc levels, including its modulation of oxidative stress, mitochondrial function, and Endoplasmic Reticulum (ER) stress in a novel insulin-resistant senescent model. Insulin resistance and senescence were confirmed by reduced glucose uptake and increased β-Galactosidase Staining and increased p-H2A.X (Ser139) levels after 24 h of co-incubation with bovine serum albumin (BSA) conjugated palmitic acid (PA; 50 µM) and 278 mM D-galactose (D-Gal) in human AC16 cells. Our findings showed upregulated expression of ER and mitochondrial proteostasis markers in the early minutes of liraglutide treatment. In addition, chronic but not acute liraglutide treatment significantly increased intracellular zinc levels, accompanied by improved mitochondrial membrane potential and reduced reactive oxygen species in the insulin-resistant senescent model. Casein kinase 2 inhibition completely abolished liraglutide-induced zinc elevation and mitochondrial improvements in the chronic context, highlighting the role of casein kinase 2 in the subcellular signaling of liraglutide. These findings indicate that liraglutide alters intracellular zinc and modulates endoplasmic reticulum-mitochondria communication, giving insight into its therapeutic potential in metabolic cardiomyopathies linked to insulin resistance and aging.

Heme oxygenase-1 (HO-1, encoded by Hmox1) is a cytoprotective enzyme with well-established roles in defending against oxidative stress. Global Hmox1 deficiency in mice accelerates hematopoietic stem cell (HSC) exhaustion and aging, effects previously attributed primarily to loss of HO-1 activity within the bone marrow (BM) niche. However, the cell-intrinsic contribution of HO-1 to HSC regulation has remained unclear. Here, we show that global Hmox1 deficiency results in accumulation of an expanded but largely quiescent HSC pool characterized by compromised genome maintenance, altered apoptotic signaling, and defective cell-cycle checkpoint control. We further demonstrate that HO-1 protein is expressed in HSCs and exhibits a predominantly nuclear, non-canonical localization. Using Hoxb5-CreERT2-mediated conditional deletion of Hmox1 in HSCs, we uncover an intrinsic requirement for HO-1 in controlling early hematopoietic differentiation. HSC-specific loss of HO-1 skews stem cell output toward short-term progenitors and increases colony-forming capacity. Transcriptomic profiling of Hmox1fl/fl;Hoxb5-CreERT2 HSCs revealed broad dysregulation of pathways involved in translation and RNA metabolism, together with aberrant expression of key transcription factors controlling hematopoietic differentiation. Collectively, these findings identify a non-canonical, cell-intrinsic role for HO-1 in regulating HSC homeostasis, differentiation, and aging.

Ageing and age-related diseases are the result of complex biological processes that progressively cause deterioration of cellular and tissue function. Among the key hallmarks of ageing are epigenetic alterations and genomic instability, both of which are closely interconnected and significantly contribute to the ageing process. The epigenome, encompassing both DNA and histone modifications, regulates gene expression and maintains genomic integrity throughout life. With age, these regulatory systems become dysregulated, leading to genome-wide changes in chromatin structure, histone modifications and the reactivation of transposable elements (TEs). TEs, typically silenced in heterochromatic regions, become active in aged cells, contributing to genomic instability, mutagenesis, inflammation and metabolic disruption. Despite their significant implications, the role of TEs in the ageing process remains underexplored, and the interplay between epigenomic remodelling and TE activity remains poorly understood. In this review, we explore the molecular mechanisms underlying epigenetic alterations and TE reactivation during ageing, the impact of these changes on genomic stability and the potential therapeutic interventions targeting this interplay. By deciphering the role of epigenetic modifications and TE derepression in the ageing process, we aim to highlight novel avenues for anti-ageing and pro-longevity strategies.

Advances in human microbiome research have highlighted its influence on host health. This study aimed to characterize the oral microbiome (OM) and gut microbiome (GM) and to examine their relationships with systemic fatty acid and cytokine profiles across different age groups in healthy adults.

Longer life expectancy makes physical exercise crucial for active aging. However, adherence to traditional exercise among community-dwelling older adults is generally low. Virtual reality (VR) and mixed reality (MR) Tai Chi exergames, as novel health promotion tools, show significant potential, particularly for older adults exercising in a home setting.

Ageing is associated with attenuated type-2 bitter-taste receptor (TAS2R) signalling and contributes to metabolic, inflammatory and barrier decline, but its system-wide impact along the gut remains undefined. We combined transcription analysis, physiology, metabolomics and microbiota profiling to test whether a brief grape-seed proanthocyanidin extract (GSPE) intervention can counter age-related dysfunction by long-term modulation of intestinal

The use of peripheral blood mononuclear cells (PBMCs) in cardiovascular research is increasingly common. However, little is known regarding potential age-related changes in mitochondrial bioenergetics and oxidative stress in PBMCs, or whether such changes relate to endothelial function. We assessed mitochondrial bioenergetics and antioxidant buffering capacity (AoxBC) capacity in PBMCs from young (n=18; 21±2 yrs) and older (n=17, 66±4 yrs) adults. High-resolution respirometry and fluorometry measured mitochondrial respiration rate (

This study examined the association between childhood adversity and cognitive aging trajectories among Chinese older adults, exploring the mediating role of depressive symptoms.

Epigenetic remodeling is a hallmark of aging, yet which epigenetic layers are most affected during aging-and the extent to which they are interrelated-is not well understood. Here, we perform a comprehensive analysis of epigenetic aging encompassing 6 histone marks and DNA methylation measured across 12 tissues from > 1000 humans and mice. We identify a synchronized pattern of age-related changes across these epigenetic layers, with all changes converging upon a common set of genes. Notably, an epigenetic clock based on these genes can accurately predict age using data from any layer (Spearman ρ: 0.70 in humans, 0.81 in mice). Applying this "pan-epigenetic" clock, we observe that histone modification and DNA methylation profiles agree in the prediction of which individuals are aging more rapidly or slowly. These results demonstrate that epigenetic modifications are subject to coordinated remodeling over the lifespan, offering a unified view of epigenetic aging.

Astrocytes play key roles in maintaining brain homeostasis, metabolism, and neurovascular integrity, yet their diversity and age-related modulation remain insufficiently understood, particularly across primate lineages. While rodent studies have generated extensive knowledge, notable species differences highlight the need for comparative analyses in non-human primates. The gray mouse lemur (Microcebus murinus), a small primate widely used in aging research, offers a valuable but underexplored model for studying astroglial aging. In this study, we characterized astrocyte distribution, morphology, and reactivity in 17 mouse lemurs aged 1.0 to 11.5 years using GFAP and vimentin immunohistochemistry. We identified marked regional and morphological heterogeneity, with dense astrocytic labeling in white matter, hippocampus, and sparse but diverse cortical populations. Distinct astrocyte subtypes (including fibrous, protoplasmic, projection, pial and subpial interlaminar, radial glia-like cells, tanycytes) were documented. Varicosity-bearing processes were common across multiple astroglial subtypes and may indicate altered physiological states. Quantitative analyses revealed pronounced age-related increases in astrocytic reactivity, particularly in white matter and interlaminar astrocytes. Cortical and hippocampal changes were comparatively modest. These findings indicate region-specific astrocytic vulnerability during aging and support the translational value of the mouse lemur for investigating glial aging in primates.

Skeletal muscle and vascular health are closely interconnected, yet the mechanisms underlying their crosstalk remain poorly understood. This study investigates the role of mitochondria transfer from myocytes to endothelial cells. Using in vitro 2D and 3D coculture systems, combined with protein-level and functional analyses, we show that mitochondria are transferred via extracellular vesicles in a Rab7-dependent and cellular connection-independent manner. Connexin 43 (CX43) inhibition downregulating Growth-Associated Protein 43 (GAP43) but enhances mitochondria transfer, accompanied by increasing Rab7. Transferred mitochondria promote endothelial cells proliferation, migration, ATP production, and angiogenesis, which could be the key processes in preserving vascular integrity and muscle function. Our study indicated that the aging-associated decline in CX43 and mitochondrial quality exacerbates muscle atrophy by facilitating the transfer of dysfunctional mitochondria. These findings uncover a novel mechanism of muscle-vessel communication and highlight mitochondria transfer as a potential therapeutic target for aging-related muscular and vascular deterioration. New and Noteworthy. Mitochondria transfer is a way for cell communication. However, mitochondria transfer between myocyte and endothelial cell remains unknown. Here, we demonstrates that mitochondria transfer occurs between myocytes and endothelial cells. Interestingly, inhibition of CX43 leads to a decrease in GAP43 expression, while simultaneously upregulating Rab7 and enhancing mitochondria transfer from myocytes to endothelial cells. Furthermore, we reveal that Rab7-induced mechanism mediates the transfer of both functional and impaired mitochondria from myocytes to endothelial cells.

Diabetic foot ulcers (DFUs) are a severe complication of diabetes mellitus, characterized by impaired wound healing due to complex pathophysiological mechanisms. Cellular senescence, particularly the senescence-associated secretory phenotype (SASP), contributes to delayed healing by inducing persistent inflammation and dysfunction in dermal fibroblasts, macrophages, and adipose tissue cells. Here we review the molecular pathways leading to senescence in these cell types, including p53/p21 activation and apoptosis resistance, and how their SASP perpetuates chronic inflammation and impairs tissue regeneration. We also discuss emerging therapeutic approaches targeting senescent cells with senolytic and senomorphic agents to improve healing outcomes. These insights suggest that modulating cellular senescence may offer promising avenues for treating diabetic wounds, warranting further investigation into senescence-targeted therapies in clinical settings.

Macular degeneration (MD) causes central vision loss and leads to long-term reorganization of visual functions. Central vision loss in MD severely reduces access to high spatial frequencies (HSF) that convey fine visual details, while low spatial frequencies (LSF) remain relatively accessible through peripheral vision and may support compensatory processing. This study investigated whether repeated training in categorizing filtered scenes improves peripheral scene recognition by enhancing spatial frequency processing. Ten MD patients and ten age- and gender-matched controls performed a scene categorization task (indoor vs. outdoor) using LSF or HSF images. Both groups completed a 12-session training protocol: patients performed the task at their preferred retinal location (PRL), and controls fixated with their fovea and viewed stimuli through an individualized artificial scotoma matched to their paired patient. Before training, MD patients showed a marked deficit for HSF scenes compared to controls, and a milder deficit for LSF scenes. After training, patients exhibited a significant improvement in categorizing LSF scenes, and an improvement specifically limited to HSF outdoor scenes, suggesting enhanced use of preserved peripheral information and partial compensation for the HSF deficit. Older controls also showed reduced performance for HSF scenes in peripheral vision, and similarly benefited from training. These results highlight the potential of perceptual training to enhance peripheral visual processing in MD patients, particularly by leveraging coarse visual cues. They support the idea that such protocols may be beneficial not only for visual rehabilitation in MD but also for preserving visual-cognitive functions in normal aging.

The early-onset transcriptional phenotype of senescence has been revealed in spermatogenic dysfunctional testes of patients at childbearing age. However, limited studies have reported the biomarker and function of testicular senescence-associated genes (SAGs) in the spermatogenic dysfunction of young men. In this study, two single-cell RNA sequencing (scRNA-seq) datasets, three bulk microarray datasets, and testicular tissue from older mice, older male, patients at childbearing age with full spermatogenesis or spermatogenic dysfunction were employed to recognize the aging-related biomarker for early-onset alterations of testicular SAGs. We found RPS14, an upregulated testicular SAGs in testes of older men, was an important biomarker for early-onset alterations of testicular SAG in young spermatogenic dysfunctional testes. RPS14 was significantly upregulated in young patients' testes with spermatogenic dysfunction. Importantly, RPS14 showed significant correlation with Johnsen scores and follicle-stimulating hormone levels, and had potential predictive value in sperm retrieval surgery. Besides, RPS14 was found to be deeply involved in the testicular immune microenvironment and significantly correlated with testicular mast cells. The scRNA-seq analyses and immunofluorescence illustrated the partially similar expression pattern and distribution of RPS14 in testes of both older males and young males with spermatogenic dysfunction. Moreover, the ribosome pathway might be the core mechanism through which this gene regulates the function of testicular cells. RPS14 was shown to be an aging-related biomarker which might be involved in the pathogenesis of spermatogenic dysfunction of young patients. The findings might offer a potential diagnostic marker as well as a therapeutic target for young patients diagnosed with male infertility.

Somatic mutations accumulate throughout life and can serve as endogenous markers to trace cellular lineage relationships. In hematopoietic stem cells (HSCs), aging is associated with functional decline and clonal skewing, yet how somatic mutational histories shape clonal architecture at single-cell resolution remains incompletely understood. Here, we leverage single-cell RNA sequencing from murine and human long-term HSCs to identify expressed somatic single-nucleotide variants and reconstruct mutation-based genealogies. To address technical noise inherent to single-cell transcriptomes, we implement a stringent joint variant filtering strategy that exploits daughter cell relationships and probabilistic modeling to distinguish true somatic events from artifacts. Using these high-confidence variants, we infer phylogenetic and clonal relationships among individual HSCs and uncover striking age-dependent differences in lineage structure. Whereas young HSCs show little evidence of hierarchical clonal organization, aged HSCs frequently exhibit structured genealogies consistent with clonal expansion. Integration of mutational, transcriptional, and signature-based analyses further reveals that genetically distinct clones in aged samples are transcriptionally divergent and enriched for pathways linked to aging and DNA damage responses. Together, our findings demonstrate that somatic mutations recovered from single-cell transcriptomes can resolve HSC clonal evolution and reveal age-associated alterations in stem cell dynamics.

Exercise induces extensive, cell type specific transcriptional remodeling in skeletal muscle to support metabolic flexibility and adaptation. However, the regulatory mechanisms underlying these transcriptional programs, and the extent to which they differ between sexes, remain poorly defined. We previously reported that lifelong, muscle-specific overexpression of human Transcription Factor E-B (cTFEB;HSACre transgenic mice) recapitulates many adaptive features of endurance training in both sexes, leading to profound geroprotective effects during aging even in the absence of exercise. Here, we profile transcriptional adaptations to voluntary wheel running (VWR) and TFEB-overexpression at single-nucleus resolution in young male and female mouse tibialis anterior muscle. This represents, to our knowledge, the first integrated analysis of exercise and TFEB signaling using sex as a biological variable. Using robust bioinformatic and single-nuclei RNA-sequencing approaches, we profiled six muscle-resident cell populations and uncover previously unrecognized, sex-dependent signaling nodes governing exercise-associated metabolic plasticity. TFEB activation and endurance training by VWR elicit strongly correlated transcriptional programs enriched for lipid metabolism, mitochondrial remodeling, and immune modulation, establishing TFEB-overexpression as a partial exercise mimetic. In general, female muscle exhibited enhanced extracellular matrix and lipid-associated responses to endurance training and TFEB overexpression, whereas males preferentially engaged in angiogenic and oxidative networks, revealing distinct sex-specific, sex-dimorphic, or sex-agnostic regulatory routes to metabolic flexibility. Integration with independent multi-omics datasets from endurance -trained rats (MoTrPAC) confirms the conservation of TFEB-exercise transcriptional convergence in skeletal muscle across species and potentially muscle types. Together, these findings define TFEB as a regulator of exercise transcriptional programs and reveal sex-specific molecular frameworks that drive metabolic adaptation in skeletal muscle. Furthermore, the resulting sex-resolved, single-nucleus transcriptional atlas provides a unique resource for the field, enabling comparative, mechanistic, and hypothesis-driven exploration of exercise-responsive skeletal muscle regulatory networks across sexes.

White matter degeneration in aging drives cognitive and motor decline. Oligodendrocytes (OLs) and their precursors are central to this process. Their intrinsic aging, marked by differentiation failure, metabolic and mitochondrial deficits, and transcriptional epigenetic dysregulation, causes myelin thinning and axonal support loss. Degeneration is amplified by dysfunctional crosstalk: microglia clear debris poorly and turn inflammatory; astrocytes disrupt lipid balance and secrete inflammatory signals; vascular defects impair metabolic supply; and T cell infiltration injures OLs. We review therapies targeting OL lineage, glial networks, vascular health, and lifestyle. Positioning OLs as integrative hubs of white matter integrity offers new strategies to maintain brain function during aging.

The nuclear envelope (NE) undergoes dynamic remodeling during both physiological and pathological processes. Nuclei in cells from patients with accelerated aging diseases and from elder individuals are often lobular and convoluted. Despite extensive study, the steps of phenotype acquisition and the co-factors required are not yet fully understood. Here, we focused on progerin, a mutant form of lamin A that causes Hutchinson Gilford Progeria Syndrome (HGPS). Using an inducible cell-based system, we characterized two distinct stages of NE remodeling. Correlative light and electron microscopy of interphase-arrested cells showed that prior to cell division, progerin primarily affects the inner nuclear membrane (INM), inducing focal expansion, invagination, and the formation of multi-membranous structures, while the outer nuclear membrane remains largely unaffected. These focal regions of progerin accumulation are enriched for specific INM proteins and the nucleoporin NUP153 but largely exclude nuclear pore complexes. Live and fixed image analysis demonstrated that, upon cell division and NE reassembly, progerin-expressing cells develop pronounced nuclear lobulations characteristic of HGPS. Appreciation of this stepwise development of phenotype lends insight into cellular manifestations of aging in mitotic versus post-mitotic cell types and provides a system in which to study factors that contribute to these distinct stages in the disruption of nuclear morphology. Depletion of NUP153 reduced NE foci formation in interphase-arrested cells expressing GFP-progerin, suggesting NUP153 promotes or stabilizes INM invagination. Aberrant nuclear architecture is just one cellular feature that changes during normal and accelerated aging but its etiology provides a critical framework for understanding accompanying consequences on chromatin packaging, DNA damage, and the ER stress response.

Plasminogen activator inhibitor 1 (PAI-1) is an inhibitor of fibrinolysis, thereby promoting blood clot stabilization. PAI-1 contributes to thrombosis, diet-induced obesity, and age-associated diseases, such as diabetes, cancer, and Alzheimer disease. Circulating PAI-1 level increases with age, contributing to the increased thrombotic risk in age-related diseases. In contrast, partial PAI-1 deficiency protects patients from cardiovascular morbidity and extends life span. Decreasing circulating PAI-1 levels has both experimental and therapeutic value. RNA gene therapy can regulate the levels of target proteins, including those not amenable to traditional small-molecule or antibody-based therapies. Here, we developed a therapeutic approach to induce long-lasting PAI-1 knockdown in vivo with small interfering RNA (siRNA)-lipid nanoparticles (siPAI-1). One dose of siPAI-1 resulted in 90% knockdown of plasma PAI-1 and lasted 10 days after administration with no overt toxicity. siPAI-1 decreased thrombus weight after complete ligation of the inferior vena cava (IVC) in young and aged mice and increased survival in aged mice 4 days post-IVC ligation. Hepatic PAI-1 mRNA expression in diet-induced obese mice was >10 times higher than in healthy mice and was exponentially correlated with body weight. One dose of siPAI-1 in obese mice resulted in 70% knockdown of circulating PAI-1. Furthermore, siPAI-1 normalized the supraphysiologic concentration of PAI-1 in aged mice and prolonged life span in a fast-aging mouse model. Thus, siRNA-mediated PAI-1 knockdown represents a long-term antithrombotic approach and effective strategy to limit pathologic impact of PAI-1 in aging and age-related diseases.

Replicative senescence in immune cells undermines vaccine efficacy, with telomere attrition recognized as a key factor to cellular senescence. Studies have shown that the extracellular vesicles (EVs) of bone marrow-derived dendritic cells (BMDCs), which contain the telomeric compounds, can promote telomerase-independent T-cell telomere extension via telomere transfer. Based on this mechanism, we designed a long-term memory T-cell vaccine (LMT/OT-II), which is composed of EVs from BMDCs carrying the ovalbumin peptide OT-II. This vaccine not only enhances antigen presentation but also extends T-cell telomere length, enhancing T-cell vitality and restoring youthful characteristics. To further enhance the antitumor effects, we incorporated the immune adjuvant Poly(I:C) to activate T cells. In both young and aged mouse models, the LMT/OT-II + Poly(I:C) effectively suppressed the growth of B16-OVA melanoma and significantly prolonged the survival of the mouse models. We further developed the LMT/Adpgk + Poly(I:C) vaccine based on mouse colon cancer cell (MC38) neoantigen peptide, which also showed promising results in mice. Through telomere transfer to restore T-cell function and enhance immune memory, our study provides a novel and universal strategy for developing more effective and durable T-cell vaccines, particularly for diseases associated with immunosenescence.

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

Sulfur mustard (SM) exposure induces respiratory complications, known as "mustard lung (ML)" through oxidative stress and chronic inflammation. This study investigated premature cellular senescence as a marker of systemic aging in SM-exposed veterans with serious pulmonary conditions, focusing on oxidative stress, DNA damage, telomere shortening, and OGG1/p16 gene expression, as well as the role of pro-inflammatory dietary patterns measured by the Dietary Inflammatory Index (DII). The study included SM-exposed veterans and healthy controls. Veterans were clinically categorized based on severity and resemblance to chronic bronchitis (CB), bronchial obliterans (BO), or asthma. Leukocyte telomere length (LTL) was assessed using MMqPCR, oxidative DNA damage (8-oxo-dG) via ELISA, and OGG1/p16 gene expression by q-PCR. DII was calculated from dietary intake data. Compared to controls, SM-exposed veterans exhibited shorter telomeres, higher p16 expression, elevated 8-oxo-dG levels, and upregulated OGG1 expression, reflecting accelerated aging and oxidative DNA damage. Asthma, BO, and CB-like subgroups shared similar trends, with variations in oxidative damage and telomere shortening. The ML group had higher DII scores correlated with shorter telomeres and increased p16 expression. These findings suggest that SM exposure, coupled with pro-inflammatory dietary patterns, accelerates cellular aging through oxidative damage and inflammation. Markers such as telomere shortening, OGG1, and p16 expression signify SM-induced damage, while 8-oxo-dG levels can indicate disease severity. In addition, variations in 8-oxo-dG levels and telomere shortening can assist in distinguishing between corresponding asthma, BO, and CB. Ultimately, this study underscores the importance of targeted interventions, including dietary modifications, to mitigate the long-term effects of SM exposure and improve outcomes for affected individuals.

Osteoarthritis (OA) is a degenerative joint disorder strongly associated with senescence, involving pathological processes such as reactive oxygen species (ROS) accumulation and ferroptosis. Basic calcium phosphate (BCP) crystals are frequently found in the joints of OA patients, yet their role in OA pathogenesis remains poorly understood. Here, we aimed to investigate the role of synthetic BCP crystals in promoting OA progression and to elucidate the molecular mechanisms underlying senescence. In this study, a rat OA model was established by intra-articular injections of BCP crystals into the knee joint, and the effect of BCP crystals improving the ferroptosis phenotype of OA cartilage was investigated. Furthermore, the expression of senescence-related biomarkers and mitochondrial functions in BCP-treated chondrocytes was observed. Moreover, the role of synthetic BCP crystals in promoting ferroptosis process in chondrocytes was investigated, as well as their mechanism of action in OA, which was related to chondrocyte senescence. The in vivo findings demonstrated that BCP crystals accelerated cartilage senescence, worsened cartilage degradation, promoted osteophyte formation, and induced ferroptosis in the joint synovium. In vitro, BCP crystals intensified ferroptosis and oxidative stress in rat chondrocytes, increased ROS production, and further promoted mitochondrial dysfunction and chondrocyte senescence. Mechanistically, BCP crystals aggravated senescence-related pathological changes by inhibiting of the GPX4-NRF2 pathway and inducing ferroptosis, thereby promoting OA progression. Our findings demonstrate BCP crystals promote chondrocyte senescence by enhancing mitochondrial dysfunction and ferroptosis. This effect was mediated through downregulation of GPX4-NRF2 signaling, which provided a theoretical basis for exploring the pathogenesis and treatment of OA.

EUK-134 is a manganese-salen complex, derived from the parent molecule EUK-8, and is widely used in anti-aging skincare formulations because of its potent antioxidant activity, resulting from the catalytic decomposition of reactive oxygen species (ROS). Despite this popularity, the fundamental kinetic properties (

Endothelial senescence contributes to the development and progression of atherosclerosis. Poliumoside (Pol), a natural compound with diverse bioactivities, has been shown to attenuate oxidative stress and inflammation, major triggers of senescence. As the role of Pol in Human Umbilical Vein Endothelial Cells (HUVECs) senescence remains elusive, this study aimed to determine whether Pol protects against atherosclerosis by modulating senescence in HUVECs and to elucidate the underlying mechanisms. In the present study, compared with ApoE