Longevity Papers

Osteoarthritis (OA), a chronic and degenerative joint disease, has become increasingly prevalent due to the aging population, posing a significant societal burden. However, despite progress, effective therapeutic options for osteoarthritis remain limited. In OA, chronic inflammation mediates a hypoxic microenvironment, leading to increased cellular energy demands. Over time, this causes mitochondrial dysfunction, favoring the accumulation of ROS, thereby perpetuating inflammation. Furthermore, reduced autophagy in aging chondrocytes hinder the clearance of damaged mitochondria, exacerbating oxidative stress. Herein, we have developed a simple and environmentally friendly strategy to fabricate hydrogen-releasing nanozymes (Se-HMPB@AB@COS) that spontaneously release hydrogen gas, effectively treating osteoarthritis through antioxidant, anti-inflammatory, and mitochondrial dysfunction reversal mechanisms. During the process of hydrogen therapy, small hydrogen molecules can readily penetrate mitochondria, specifically reducing the levels of •OH thereby protecting mitochondrial function. Our research further unveils that hydrogen therapy can effectively enhance mitophagy and delay chondrocyte senescence. In vivo, Se-HMPB@AB@COS encapsulated with chondroitin sulfate significantly promotes the synthesis of collagen II, inhibits the degradation of extracellular matrix, and reduces inflammatory factors. Overall, this study innovatively synthesized a hydrogen-releasing nanozyme, demonstrating its effectiveness in inhibiting oxidative stress, inflammation, promoting mitophagy and extracellular matrix synthesis, thereby reducing cartilage and mitochondrial damage, and delaying OA progression.

To identify a common molecular mechanism of sperm epigenome reprograming by environmental factors by testing whether mechanistic target of rapamycin (mTOR)-dependent and mTOR-independent disruption of the blood-testis barrier (BTB) by environmental factors (heat stress [HS] and cadmium [Cd] exposure, respectively) accelerate epigenetic aging of sperm in a mouse model.

The activity of procyanidin C1 (PCC1) is limited by poor intestinal targeting, while traditional delivery systems typically neglect the adjuvant activity of the wall material. This study aimed to explore the potential of Polygonatum polysaccharides (PSP) as wall materials for delivery systems with synergistic effects. A novel PCC1 yolk-shell nanoparticles delivery system (PCC1-P/L NPs) were fabricated using lysine as a cross-linking agent, achieving a drug loading efficiency of 93.57 %. Molecular docking analysis revealed that PSP interacted with PCC1 and lysine through hydrogen bonds and hydrophobic interactions. We further evaluated the targeted delivery efficiency and synergistic effect of PCC1-P/L NPs. It significantly increased the PCC1 concentrations in the intestine by twofold. Furthermore, PCC1-P/L NPs exerted a synergistic anti-aging effect, extending the maximum lifespan of Drosophila by 30.8 %, which significantly exceeded the effect of PCC1 or PSP alone. Moreover, the delivery system potently suppressed the accumulation of pH 3+ and esg + cells and preserved gut integrity. This study highlights PSP as a multifunctional wall material and offers a new strategy for anti-aging.

Collagen is a prevalent protein in the animalia kingdom, especially in mammals. It is abundant in all connective tissue such as bone or ligaments and thus it is subjected to substantial mechanical forces. Crosslinks play an essential role for the structural and mechanical integrity of collagen, determining its stiffness and rigidity. Until now, studies on collagen including crosslinks have either been confined to fully atomistic simulations, which are computationally intensive and restrict the accessible time and length scales, or to coarse-grained descriptions that do not resolve the force response on a residue-level and therefore do not consider the triple helical structure and the connectivity of crosslinks. To bridge this gap, we report the development and validation of a computational model based on the Martini 3 coarse-grained force field, in which we parametrized the fibrillar collagen structure including crosslinks. We validated the model, through extensive equilibrium and non-equilibrium molecular dynamics simulations, against experimental properties and all-atom simulations. Because the type and distribution of crosslinks vary with aging, we expect that this collagen model can be employed to provide insights into age-related changes in tissue mechanics and guide the development of biomimetic materials.

Menopause affects the aging process in women through significant ovarian hormone production decline in midlife. Women who experience early menopause face an accelerated physiological aging rate, along with impaired memory and increased risks of neurodegenerative diseases. However, it remains elusive how the timing of menopause affects brain activity, which could be crucial for understanding menopause-related acceleration of aging and increased risk of dementia. Recent studies have revealed a highly structured infra-slow (< 0.1 Hz) global brain activity across species and linked it to arousal and memory functions, as well as waste clearance in Alzheimer\'s diseases (AD). In this study, we examined how this global brain activity relates to age of menopause using resting-state fMRI data from the Human Connectome Project-Aging dataset. We found that women who experienced earlier menopause (mean menopausal age 45{+/-}3.5 yr) exhibited weaker global brain activity (p = 5.0x10-4) with reduced coupling to cerebrospinal fluid (CSF) flow (p = 0.017) compared to age-matched later-menopausal women (mean menopausal age 54{+/-}1.2 yr). Differences appeared mainly in higher-order brain regions, where activation levels correlated with memory performance in earlier but not in intermediate or later menopausal women. These findings highlight brain activity changes linked to early menopause, suggesting a potential mechanism underlying memory decline and the increased risk of AD and dementias in early-onset menopausal women.

Aging is accompanied by progressive declines in metabolic and cognitive functions. Growth hormone secretagogue receptor (GHSR), a receptor for the gut hormone ghrelin, is highly expressed in neurons and plays a crucial role in metabolic regulation. We previously reported that aged global GHSR-ablated mice are lean and insulin-sensitive, and that neuronal GHSR-deleted mice (Syn1-cre;Ghsr

Osteoporosis (OP) is a progressive skeletal disorder characterized by reduced bone mass, structural deterioration, and increased fracture risk, particularly in postmenopausal women and the elderly. Oxidative stress and inflammation are key contributors to the disruption of bone remodeling in OP. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of cellular redox homeostasis, has gained attention for its role in bone metabolism. This review explores Nrf2's regulatory influence on osteoblast (OB) and osteoclast (OC) activity. In OBs, moderate Nrf2 activation protects against reactive oxygen species (ROS)-induced apoptosis, enhances differentiation, and supports bone formation. In contrast, both insufficient and excessive Nrf2 expression may impair OB function. In OCs, Nrf2 suppresses ROS-mediated pathways such as MAPK and NF-κB, thereby inhibiting differentiation and resorptive activity. Nrf2 also attenuates inflammation by downregulating pro-inflammatory mediators and inhibiting NF-κB nuclear translocation. Nrf2 knockout animal models exhibit age-related bone loss, reduced bone mineral density, impaired trabecular structure, and delayed fracture healing. These effects are exacerbated by increased oxidative stress and inflammation. Notably, sex-specific differences have been observed, with female mice showing greater susceptibility to Nrf2 deficiency, potentially due to interactions with estrogen signaling. Nrf2 also regulates osteocyte-specific gene expression, further reinforcing its role in bone maintenance and mechanotransduction. Therapeutic activation of Nrf2 using agents such as bardoxolone methyl, sulforaphane, quercetin, and curcumin shows promise in mitigating bone loss. However, precise modulation is crucial to avoid potential adverse effects. Overall, Nrf2 represents a promising target for the prevention and treatment of OP and related musculoskeletal disorders.

Intervertebral disc degeneration (IDD) is a chronic degenerative disorder marked by nucleus pulposus cells (NPCs) senescence and extracellular matrix (ECM) degradation, which is a key pathological factor leading to low back pain. Current clinical treatments are mainly limited to symptomatic relief without effectively reversing the degenerative process.

Cellular senescence is a fundamental biological process characterized by stable cell cycle arrest, genomic instability, and the acquisition of a proinflammatory secretory phenotype. While senescence is traditionally associated with aging, growing evidence reveals that chronic infections such as viral, bacterial, and protozoan parasites can serve as powerful inducers of senescence, contributing to premature aging and long-term tissue damage. This review explores the diverse mechanisms by which persistent pathogens trigger or sustain senescence in host cells. We highlight how these chronic infections manipulate host DNA repair, mitochondrial dynamics, telomere maintenance, oxidative stress, and immune function to promote senescence and immunosenescence. Emerging findings also reveal how pathogens hijack the host cellular machinery to induce senescence across various tissue types. In many cases, senescence not only enables pathogen persistence but also drives pathological outcomes such as fibrosis, neurodegeneration, cardiomyopathy, and immune exhaustion. Collectively, this emerging evidence highlights a unifying strategy among diverse pathogens: the exploitation of cellular senescence to support chronic infection and promote disease. Understanding how infectious agents drive senescence offers new insights into age-related pathologies and highlights potential therapeutic targets, such as senolytic and senomorphic agents, to mitigate the long-term impacts of chronic infections.

Sarcopenia is a major contributor to frailty and functional decline among older adults. Combining exercise with nutritional strategies such as creatine monohydrate (CRE) and β-hydroxy-β-methylbutyrate (HMB) supplementation may help to preserve strength and independence. To evaluate the effects of 6-week CRE + HMB supplementation combined with an integral physical conditioning (IPC) program on functional strength and body composition in physically active older adults. In a randomized, double-blind, placebo-controlled crossover trial, 30 older adults (20 men, 10 women; ≥ 60 years) completed two 6-week intervention periods (CRE + HMB or placebo) separated by a 3-week washout. The IPC program performed in both conditions consisted of four supervised weekly sessions combining strength, power, multicomponent circuits, high-intensity interval and moderate intensity continuous training), performed at 40-100% training heart rate (THR) and 20-90% one-repetition maximum (1RM) and structured as warm-up, main part and cooldown. Functional strength and body composition (bioelectrical impedance analysis) were assessed pre- and post-intervention, respectively. Significant time × group interactions were observed for fat mass, fat-free mass, total muscle mass, skeletal muscle mass, appendicular skeletal muscle mass, muscle mass index, skeletal muscle index and ALM/BMI (all p < 0.05). The CRE + HMB group showed reductions in fat mass and body fat percentage, with slight numerical increases in muscle parameters, whereas the placebo group exhibited opposite trends. However, within-group changes were not statistically significant. In contrast, CRE + HMB significantly improved multiple functional strength outcomes, including leg/back strength, arm flexion strength, upper-body endurance (dumbbell flexion, push-ups, isometric hold) and core endurance (crunches). Regression analyses suggested that these improvements were largely independent of changes in muscle mass, supporting a potential neuromuscular mechanism. Six weeks of CRE + HMB supplementation combined with IPC enhanced functional strength and endurance in active older adults, largely independent of changes in muscle mass. This combined approach represents a promising strategy for preserving functional capacity and promoting healthy ageing.

Telomere shortening is a key hallmark of cellular aging, and its association with various infectious diseases is well-documented. However, the role of telomere dynamics in malaria pathogenesis remains underexplored. In addition to its influence, malaria infection not only modulates signals within immune cells but also drives telomere shortening in these cells via diverse mechanisms, potentially leaving long-term imprints on human health. Acute malaria infections initiate rapid telomere degradation, promote accelerated cellular senescence, and suppress telomerase expression with possible partial recovery as the parasite clears during treatment. Conversely, prolonged exposure to Plasmodium infection, prevalent among individuals residing in highly endemic regions like Africa, is often aggravated by coexisting infections, potentially exacerbating malaria pathogenesis, accelerating telomere length shortening, and increasing susceptibility to age-related ailments. Herein, we review recent findings into the effects of malaria on telomere attrition, shedding light on possible mechanisms and key factors contributing to this process. Additionally, we present an overview of how oxidative stress and inflammatory mediators contribute to telomere length shortening in malaria. Furthermore, we discuss the potential of telomere length as a biomarker for malaria severity and treatment outcomes.

Large-leaf yellow tea protein-derived oligopeptides (TPP) contain a substantial number of antioxidant peptides that facilitate skin damage repair and may be employed to mitigate skin photoaging. However, the potential alleviating mechanism by which TPP alleviates skin photoaging damage remains insufficiently understood. This study investigated the in vitro antioxidant capacity and cell migration-promoting ability of TPP. Additionally, it utilized ultraviolet (UV)-exposed and intrinsically aged ICR mice, which exhibit signs of skin aging, to assess the effects of an 8-week oral TPP intervention. The findings indicate that TPP exhibits potent free radical scavenging properties, which mitigate oxidative damage in Raw264.7 cells and promote the migration of NIH/3 T3 cells. TPP intervention significantly ameliorates oxidative stress and skin inflammation symptoms in UV-induced skin photoaging damage by restoring the activity of endogenous antioxidant enzymes and suppressing the mRNA expression of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α., as well as inhibiting the MAPK/AP-1/MMP9 signaling pathways. This study proposes that TPP is a viable plant protein-derived nutritional supplement for the prevention of UV-induced skin photoaging damage.

Extracellular vesicles present a promising alternative to stem cells in regenerative medicine and gerontology. They offer significant advantages over cell transplantation, demonstrating potential for slowing aging and treating age-related diseases. Extracellular vesicles secreted by diverse cell types modulate inflammation, stimulate tissue regeneration, and exhibit anti-inflammatory and immunomodulatory properties. This work explores the therapeutic potential of extracellular vesicles as alternatives to cell therapy, examining their key advantages and current limitations. It specifically focuses on their roles within established aging mechanisms and their dual utility as biomarkers and therapeutic agents. Critical aspects of extracellular vesicle translation are addressed, including standardized methods for production, storage stability optimization, and engineering strategies for cargo loading and targeting. Extracellular vesicles possess unique biological properties-inherent biocompatibility, low immunogenicity, ability to cross biological barriers, and high biological activity at low doses. Preclinical studies across various age-related pathologies (neurodegeneration, cardiovascular disease, sarcopenia) consistently report efficacy in reducing inflammation, promoting tissue repair, and improving functional outcomes. These findings strongly support the capacity of extracellular vesicles to mimic many therapeutic effects of parental cells while mitigating risks like tumorigenicity or immunorejection associated with whole-cell therapies. Overcoming challenges in scalable manufacturing, quality control, regulatory standardization, and targeted delivery is essential for the clinical translation of extracellular vesicles. Despite these hurdles, their compelling preclinical evidence and inherent advantages position them as a major future direction. They are expected to play a key role in combating age-related decline and advancing regenerative medicine, becoming a cornerstone of next-generation biomedical interventions over the next decade.

Circadian rhythms are endogenous, near-24-h cycles that synchronize physiological and behavioral functions with environmental cues such as light/dark cycles and food intake. While the central pacemaker in the suprachiasmatic nucleus orchestrates these rhythms, peripheral clocks distributed across organs, including the gastrointestinal tract, exhibit autonomous oscillations that are crucial for local homeostasis. Concurrently, the gut microbiota undergoes diurnal fluctuations in composition and metabolic activity that are tightly coupled to host circadian mechanisms. Recent discoveries reveal a bidirectional relationship: host clocks influence microbial dynamics through feeding behavior, immune signaling, and epithelial renewal, whereas microbial metabolites such as short-chain fatty acids (SCFAs) and bile acids modulate circadian gene expression in peripheral tissues. Disruptions in circadian alignment, whether due to genetic mutations, lifestyle factors like shift work and irregular eating, or environmental perturbations, lead to microbial dysbiosis, metabolic dysfunction, inflammation, and heightened disease susceptibility. Conversely, altered microbiota rhythms can feed back into host systems, impairing metabolic control, immune responses, and neuroendocrine signaling. This reciprocal regulation extends to disease contexts, where circadian-microbiota misalignment contributes to obesity, type 2 diabetes, inflammatory bowel disease, and even neuropsychiatric disorders. This review synthesizes current insights into the molecular and physiological cross-talk between host circadian clocks and the gut microbiota. We discuss how temporal dynamics at the cellular, systemic, and microbial levels are integrated and how their disruption underlies pathogenesis. We further explore the potential of chronobiotics and chrononutrition, including time-restricted feeding (TRF) and bioactive dietary compounds, as emerging strategies to restore circadian-microbial synchrony and improve metabolic health. Understanding this intricate dialogue between host and microbiome may pave the way for personalized, time-based interventions to enhance healthspan and prevent disease occurrence or progression. KEY POINTS: • Circadian rhythms and microbiota form a bidirectional regulatory feedback loop. • Disruption of circadian-microbial synchrony drives metabolic and inflammatory disease. • Chrononutrition offers novel strategies to restore health via circadian-microbiota alignment.

Within the same species of eusocial insects, individuals of different castes typically display widely different life-history traits: sterile workers live for a few months, while queens can live for decades. Ageing theories emphasise the importance of metabolism and oxidative stress in explaining longevity, with mitochondrial bioenergetics standing at the crossroads of energy and reactive oxygen species production. The study of mitochondrial functioning is therefore of great relevance in determining the nature of the mechanisms that explain the contrasting longevities between insect social castes. We addressed this question in the eusocial black garden ant Lasius niger. Our findings reveal that caste differences in mitochondrial bioenergetics and the oxidative balance only partially align with oxidative stress theory predictions. Long-lived queens display lower metabolic rates and mitochondrial density, yet maintain higher cellular energy availability, as reflected by a high adenylate energy charge (AEC). This may result from enhanced mitochondrial maintenance processes and potentially a specific recourse to the purine salvage pathway, promoting ATP availability while limiting oxidative cost. Our study highlights so far unrevealed bioenergetic adaptations that might contribute to the queens' remarkable lifespan.

Aging-related neuroinflammation drives cognitive decline; however, the mechanisms by which gut microbiota-modulating bioactive compounds, such as rice bran peptide KF-8, mitigate this process remain unclear. Here, KF-8 was shown to ameliorate age-related traits in aged mice by reshaping gut microbiota, notably by stabilizing Akkermansia muciniphila (AKK), to suppress systemic inflammation and cognitive deficits. Specifically, antibiotic-treated mice receiving KF-8 exhibited neuroinflammation and declined cognition. KF-8 and AKK synergistically attenuated pro-inflammatory pathways, particularly TNF-α, in the blood and in the hippocampus. While TNF-α antibodies mirrored KF-8's benefits, TNF-α recombinant protein negated KF-8's protective effects. Combined KF-8 and AKK interventions aligned with TNF-α antibody outcomes, underscoring TNF-α's pivotal role. Our findings reveal that KF-8 enhances healthy aging by modulating gut microbiota, sustaining AKK, and suppressing TNF-α-driven neuroinflammation, thereby rescuing cognitive function in aged mice.

Aging affects the reproductive system, although its impact on GnRH neurons is mainly unexplored. Thus, we compared the transcriptome and electrophysiology of GnRH neurons obtained from female middle-aged (MA, 400-430 days) and young (Y, 70 days), diestrous mice, respectively. Transcriptomic analysis revealed reproductive senescence-related molecular changes in one-third of the MA mice. The upregulated genes (n=225) were linked to immune signalling, olfactory- and vomero-nasal receptors. The downregulated genes (n=233) were related to mRNA processing, G-protein-coupled receptors, oxidative phosphorylation, electron transport, and estrogen signalling. In addition, ion channel (Na, K, Ca), neurotransmitter (ACh, GABA, glutamate)- and various neuropeptide receptor-coding genes showed differential expression indicating functional alterations of the cells. Accordingly, whole-cell patch-clamp recordings revealed a two-fold increase in spontaneous firing frequency of MA GnRH neurons. Significant changes were also observed in characteristics of action potentials and afterhyperpolarization amplitudes. Conspicuously, miniature postsynaptic currents were absent in 72% of MA-GnRH neurons and pharmacological blockade of GABA-A and glutamate receptors didn't affect firing rate. However, administration of their ligands evoked inward currents and facilitated firing in both animal groups, although with a decreased efficacy in MA animals. MA-GnRH neurons sustained responsiveness to estradiol, G-protein inhibition and kisspeptin (KP) like those of young animals. While KP receptor antagonist, KP-234 diminished firing frequency of MA GnRH neurons, it had no effect on young GnRH cells. Collectively, these findings revealed that both the transcriptome and electrophysiological activity of GnRH neurons change at middle-age and the explored alterations are hallmarks of early phase of reproductive senescence.

The possible joint association of vitamin D and obesity in regard to the clinical biomarker-based biological aging process has not been well studied. We aimed to investigate the independent and combined associations of serum 25-hydroxyvitamin D [25(OH)D] concentrations and body mass index (BMI) with phenotypic age (PhenoAge) and Klemera-Doubal method Biological Age (KDM-BA) acceleration.

Disruption of cerebral hemodynamics may impair perivascular and glymphatic clearance, contributing to aging-related brain pathology. This study aimed to explore the interaction between large-vessel hemodynamics and glymphatic neuroimaging markers in cerebral small vessel disease (CSVD), a common age-related condition.

The United Nations Sustainable Development Goal 3 (SDG-3) aims to improve global health and well-being, requiring the implementation of a range of targeted strategies. The longevity population serves as a key indicator for assessing the health of a country or region. Understanding the spatial distribution and the underlying socio-economic and environmental determinants of longevity is crucial for improving public health. Notably, China exhibits significant disparities in the geospatial distribution of its longevity population. This study makes several novel contributions by investigating the spatial heterogeneity and socio-economic factors influencing longevity across the country and its seven major geographic subregions. Using advanced geostatistical methods, we explore how various socio-economic factors, including family size, housing stability, marital status, automobile ownership, and the number of hospitals, influence the distribution of longevity populations in China. Our findings reveal that: (1) The distribution of the longevity population in China is highly uneven, with significant spatial autocorrelation. The southeastern regions, east of the Hu Line, represent the longevity hotspots, while the northwestern regions are identified as cold spots. (2) The distribution patterns in Northeast, North, and Central China show multiple longevity hotspots and cold spots. East China has a diversified pattern with concentrated core hotspots and scattered peripheral hotspots. South China exhibits considerable north-south differences in longevity distribution, while Southwest China forms a high-concentration hotspot centered around Chongqing and Sichuan, with Yunnan and Tibet as marginal cold spots. Northwest China shows a notable hotspot in Shaanxi Province and cold spots in Qinghai and western Xinjiang. (3) Socio-economic factors significantly influence the longevity population's spatial distribution, with varying impacts across gender and geographic regions. The results underscore the complex interplay of social and economic factors in shaping longevity patterns in China. This study provides a comprehensive basis for understanding the spatial distribution of longevity in China and offers valuable insights for developing more targeted and effective public health policies.

This study investigated how the timing and duration of 30% caloric restriction (CR) affect ovarian aging in mice. Mice were assigned to one of four groups: ad libitum (AL) control, long-term CR (3-11 months; CR/CR), early short-term CR (3-7 months; CR/AL), and late short-term CR (7-11 months; AL/CR). Long-term CR reduced body mass, improved insulin sensitivity, preserved the ovarian primordial follicle reserve, and attenuated ovarian macrophage infiltration compared to AL-fed mice. Metabolic benefits from CR were quickly reversed upon returning to AL feeding. Short-term CR, whether initiated early or late, did not preserve the ovarian reserve. Some benefits were observed with an early start CR, including reduced ovarian collagen deposition at 7 months and reduced macrophage infiltration at 11 months. Our findings indicate that only long-term CR preserves the ovarian reserve. Short-term CR positive effects on other ovarian aging hallmarks depended on an early age of onset.

Introduction: The locus coeruleus (LC) undergoes age-related changes and is involved in Alzheimer\'s disease pathogenesis. Vagal nerve stimulation (VNS) may modulate LC activity and could be used therapeutically, but age-related differences in VNS responses remain unexplored. Methods: We used a single-blind, sham-controlled, crossover design in 41 participants (21 younger, 20 older adults). Participants completed a visual oddball task with pupillometry during transcutaneous auricular VNS (verum: cymba concha; sham: earlobe) with ~30-minute washout between conditions. Results: Older adults showed smaller baseline pupil diameter but larger normalized task-evoked responses than younger adults a priori. VNS produced age-specific effects: older adults demonstrated increased tonic pupil size throughout stimulation and reduced oddball-evoked responses, with stronger effects with more current. Younger adults showed no consistent VNS effects. Discussion: VNS affects LC-related physiological measures differently across age groups, with older adults showing more robust responses. These age-specific effects may reflect different baseline LC activity states.

Cardiovascular diseases remain the leading cause of mortality worldwide, with aging as a major risk factor. Endothelial cell (EC) dysfunction, driven by cellular senescence, is central to age-related cardiomyopathy. Despite its clinical significance, the molecular mechanisms underlying endothelial senescence remain incompletely defined. In this study, we observed that the expression of the endothelial-specific gene heat shock protein family A member 12B (HSPA12B) declines significantly with age. HSPA12B deficiency in mice accelerates age-related EC senescence and cardiac dysfunction, whereas HSPA12B overexpression mitigates EC senescence, highlighting its protective role against vascular aging. Mechanistically, HSPA12B deficiency impairs X-box binding protein 1 (XBP1) transcriptional activity and consequently reduces the expression of its downstream target genes suppressor/enhancer of lin-12-like (SEL1L) and HMG-CoA reductase degradation protein-1 (HRD1). This disruption compromises endoplasmic reticulum-associated degradation (ERAD) of Stimulator of interferon genes (STING), resulting in persistent activation of the cyclic GMP-AMP synthase (cGAS)-STING pathway, a critical driver of EC senescence. In contrast, increased HSPA12B expression enhances XBP1 nuclear translocation and upregulates SEL1L and HRD1, thereby attenuating age-related STING activation. Importantly, pharmacological inhibition of STING reversed the senescent phenotype caused by HSPA12B deficiency. Similarly, enhancing XBP1 activity restored SEL1L and HRD1 expression, reduced STING activation, and alleviated EC senescence. Conversely, SEL1L deficiency or HRD1 inhibition exacerbated STING activation and abolished the protective effects of HSPA12B. Collectively, these findings reveal a previously unrecognized role for HSPA12B in preserving endothelial homeostasis during aging by regulating XBP1-mediated ER-associated degradation of STING and highlight HSPA12B as a potential therapeutic target for age-related cardiovascular dysfunction.

The effects of lifestyle interventions on the blood metabolome and transcriptome are well studied, but the interplay between tissues is not well understood. In a multi-omics multi-tissue design we study how the serum proteome reflects health improvements in age-related deficits such as body composition, fat and glucose metabolism and low-grade inflammation in older adults undergoing a 13-week lifestyle intervention (GOTO trial). Significant intervention effects on the fasting blood proteome were observed in both sexes, with downregulated immune-related pathways, including the complement system, inflammation, cholesterol transport and coagulation. These findings associated with improved body composition and immune-metabolic health markers. In addition, we found that the intervention-induced changes in the transcriptome of muscle and subcutaneous adipose tissue (SAT) biopsies were correlated with changes of the corresponding circulating proteins. The most notable correlations were observed for proteins involved in inflammatory processes and corresponding gene expression in the SAT. Our findings emphasize the broad beneficial effects of moderate lifestyle interventions in older adults and how circulating proteins such as FN1, LGALS3BP and PRG4 reflect the immune-metabolic health benefits.

Alterations in metabolism, stress response, sleep, circadian rhythms, and neuroendocrine processes are key features of aging and neurodegeneration. These fundamental processes are regulated by the hypothalamus, yet how its functionally distinct subregions and cell types change during human aging and Alzheimer\'s Disease (AD) remains largely unexplored. Here, we present HypoAD, a comprehensive atlas of the human hypothalamus in aging and AD, integrating high-resolution MRI from 202 individuals with single-nucleus RNA-seq (snRNA-seq) of 614,403 nuclei from young, AD, and age-matched non-dementia controls. Our analysis reveals that hypothalamic subregions governing metabolism, stress, and circadian rhythms are particularly vulnerable, exhibiting significant changes in both volumes and gene expression during aging and AD. At the molecular level, machine learning models identified the inflammatory response and regulators of circadian rhythms as key cellular predictors of AD. These signatures were reflected in specific cell types: microglia transitioned to a pro-inflammatory state, while inhibitory neurons within sleep- and circadian-regulating hypothalamic subregions showed the most profound transcriptional alterations, including disruptions in ligand-receptor interactions and G-protein-coupled receptor signaling. Together, HypoAD provides a high-resolution volumetric map and a comprehensive transcriptomic atlas of the human hypothalamus in aging and AD, linking lifestyle and behavioral changes to their underlying volumetric and molecular pathways. Additionally, HypoAD provides a framework to investigate hypothalamic dysfunction and establishes a roadmap for targeted interventions aimed at mitigating physiological disruptions to potentially slow disease progression.

Aging is associated with increased susceptibility to bacterial infections, particularly multidrug-resistant (MDR) strains, which often result in antibiotic treatment failure and high mortality rates in the elderly. However, effective preventive and therapeutic strategies remain limited. Herein, we showed that aged mice exhibited higher susceptibility to colistin-resistant Salmonella enterica serotype Typhimurium and methicillin-resistant Staphylococcus aureus compared to young mice. Notably, pre-supplementation with melatonin, a hormone markedly reduced in the aging gut, effectively restricted MDR bacterial infections in aged mice by enhancing microbial colonization resistance. Mechanistically, melatonin-induced alterations in the gut microbiota, particularly the enrichment of butyrate-producing bacteria including Faecalibaculum, Muribaculaceae, and Ruminococcus, played a pivotal role in enhancing resistance to pathogenic bacteria. Elevated gut butyrate levels following melatonin pre-supplementation not only preserved intestinal barrier integrity and mitigated inflammaging, but also directly inhibited pathogenic bacterial growth by disrupting intracellular pH homeostasis, leading to proton motive force dissipation and metabolic disturbances. These findings underscore melatonin and its metabolite, butyrate, as promising candidates for the prevention of MDR bacterial infections in the aging population.

Calcium (Ca2+) homeostasis is fundamental to neuronal physiology, including in the regulation of membrane excitability and synaptic transmission. Disruptions in the ion transporters regulating Ca2+ influx and efflux are clearly linked to seizure disorders and age-related neurodegenerative disease. Yet, the specific contributions of variants in genes encoding these transporters to neurological disease remain to be fully understood. Drosophila melanogaster has proven to be a powerful genetic model for uncovering such mechanisms, particularly through studies of mutants that display temperature-sensitive (TS) behavioral phenotypes. In a forward genetic screen, we identified a mutant line that exhibited TS convulsions along with progressive, age-dependent neurodegeneration. We mapped the mutation to Nckx30c, specifically within the transmembrane ion-binding region of this K+-dependent Na+/Ca2+ exchanger. Characterization of this mutant, together with a second Nckx30c allele, revealed TS convulsions, impaired locomotion, a markedly shortened lifespan, neurodegeneration with age, along with structural defects at larval and adult neuromuscular junctions (NMJs). Gene expression analysis confirmed that Nckx30c levels were reduced in heads of Nckx30c loss-of-function mutants. Tissue-specific manipulation revealed that knockdown of Nckx30c in neurons recapitulated the TS convulsions, locomotor defects, and shortened lifespan phenotypes. Drosophila Nckx30c is highly conserved and shares homology with mammalian SLC24A2, a solute carrier family 24 member whose neurological role is not yet fully elucidated. Our work establishes Nckx30c as an essential regulator of neuronal health and provides an in vivo framework for investigating the contribution of SLC24A2 to neuronal Ca2+ homeostasis, seizures and age-related neurodegeneration.

Falls are one of the leading causes of non-disease death and injury in the elderly, partly due to the loss of muscle mass in a musculoskeletal disorder named sarcopenia. Studying the impact of this muscle weakness on standing balance through direct human experimentation poses ethical dilemmas, involves high costs, and fails to fully capture the internal dynamics of the muscle. To address these limitations, we employ neuromusculoskeletal modeling to explore the impact of sarcopenia on balance. In this study, we introduce a novel full-body MSK model comprising both the torso and lower limbs, with 290 muscle actuators controlling 23 degrees of freedom and supporting varying levels of sarcopenia. Using reinforcement learning coupled with curriculum learning and muscle synergy representations, we trained an agent to perform standing balance on a backward-sliding plate and compared its behavior to human experiments. Our results demonstrate that, without pre-recorded experimental data, both healthy and sarcopenic agents can reproduce ankle and hip balancing strategies consistent with experimental findings. Furthermore, we show that as the degree of sarcopenia increases, the agent adapts its balancing strategy based on the platform's acceleration. The full code is open-sourced and can be found in this repository: https://github.com/cherylwang20/StandingBalance.

The preservation of tissue architecture and morphology in formalin-fixed paraffin-embedded (FFPE) tissues enables spatial resolution at the cellular and sub-cellular levels. Laser capture microdissection (LCM) combined with liquid chromatography tandem mass spectrometry analysis permits collection of tissue areas with spatial context for proteome profiling from FFPE slides. In this study, we performed proteome profiling of non-diseased renal tubulointerstitial tissue in a cohort of young (< 40 years) and old (> 70 years) individuals with the goal of spatially correlating the histomorphology to the proteomic profile. To perform in-depth characterization of renal tubulointerstitium and to identify renal aging-associated proteins, a multiplexing strategy using tandem mass tags (TMT) was employed, resulting in the quantitation of 7,355 proteins. Our approach allowed for identification of proteins with low abundance such as fibrocystin and ninein-like protein. Notably, 162 solute carrier proteins from 47 solute carrier families were identified, which were enriched in proximal and distal tubule cells. Finally, we discovered a proteomic signature associated with renal aging, which includes metalloproteinase inhibitor 3, nicotinamide N-methyltransferase, matrix metallopeptidase 7, phenazine biosynthesis-like domain-containing protein and solute carrier family 23 member 1. Overall, our study demonstrates the power of LCM combined with proteomics to leverage archived FFPE tissue samples for investigating proteomic alterations in the renal tubulointerstitium with age at a high depth of proteome coverage.

Within each cell, metabolite-sensing factors respond to coordinate metabolic homeostasis. How metabolic homeostasis is regulated intercellularly and how this may become dysregulated with age, however, remains underexplored. Here we describe a system regulated by a metabolite sensor, CtBP2. CtBP2 is secreted via exosomes in response to reductive metabolism, which is suppressed by oxidative stress. Exosomal CtBP2 administration extends lifespan in aged mice and improves healthspan in particular by reducing frailty. Mechanistically, we identify activation of CYB5R3 and AMPK downstream of exosomal CtBP2. Consistently, serum CtBP2 levels decrease with age and are negatively associated with cardiovascular disease incidence in humans yet are elevated in individuals from families with a history of longevity. Together our findings define a CtBP2-mediated metabolic system with potential for future clinical applications.

This study aimed to investigate the association between the senescence-associated secretory phenotype (SASP) and balneotherapy (BT) in the elderly.

Diabetic kidney disease (DKD) is closely linked to aging, with gut microbiota imbalance recognized as a key factor, making it a growing research focus. Studies have shown that gut dysbiosis in DKD patients is characterized by a reduction in beneficial bacteria and an overgrowth of opportunistic pathogens, leading to gut barrier disruption, systemic low-grade inflammation, oxidative stress, and accelerated fibrosis. The decrease in short-chain fatty acids (SCFAs) impairs epigenetic regulation, driving the overexpression of fibrosis-related genes. Aging itself also alters the composition of the gut microbiota, further exacerbating metabolic disorders and inflammation, thereby creating a vicious cycle. This article aims to explore the potential roles and mechanisms of gut microbiota in the shared pathogenesis of DKD and aging, providing a theoretical foundation for the development of novel therapeutic interventions.

There is keen interest amongst the general population in preventing aging and age-related infirmities. Sirolimus is approved for preventing organ rejection in kidney transplant patients, has immune-modulating and growth-inhibitory properties, and is one of the therapies currently being used off-label for this purpose. There is a lack of formal guidance, such as a policy statement or position paper, on the appropriate dosing and administration of sirolimus for aging prevention. The American College of Clinical Pharmacology strongly recommends that clinicians prescribing sirolimus weigh the benefits and risks of sirolimus for off-label use in aging prevention, ensuring patients understand that such prescriptions lack any regulatory approval and rigorous supporting evidence. Health care providers are also encouraged to inform patients of the available clinical evidence and ongoing clinical trials in age-related conditions to build a stronger foundation of safety, efficacy, and optimal dosing for sirolimus in aging prevention.

Mitochondrial dysfunction-mediated ribosomal translation suppression is a hallmark of aging and a major driver of degenerative diseases, limiting mRNA therapy efficacy. Here, ionizable coenzyme Q10 (iCoQ10)-engineered lipid/fiber microplexes (iCLNP@SF) are developed that restore the mitochondrial-ribosomal axis to enhance mRNA translation. iCoQ10 replaces conventional ionizable lipids to form prodrugged lipid nanoparticles (iCLNP), stabilized by injectable polydopamine‑modified short fibers for in situ administration. In vitro efficacy assessments showed that iCLNP@SF synergistically enhanced mitochondrial metabolism and mRNA translation in senescent cells. Further mechanistic studies revealed that iCLNP stabilized mitochondrial membrane potential, suppressed cGAS-STING activation, and reduced eIF2α phosphorylation, thereby enhancing translation. In vivo, iCLNP@SF delivery of Gas6 mRNA increased hair follicle density by ≈50% in an androgenetic alopecia mouse model, while Runx2 mRNA delivery raised new bone formation (BV/TV) to ≈40% in defect models, both markedly outperforming conventional LNPs. Together, these findings highlight a strategy that improves mRNA therapy for degenerative diseases.

Phytochemicals represent emerging anti-aging therapeutic candidates, with Marchantia polymorpha L. (liverwort) gaining significant attention due to its broad-spectrum pharmacological properties. This plant exhibits remarkable wound-healing and regenerative capabilities, making it a promising candidate for the development of modern anti-aging drugs. In the presented study, 12-ethoxy-Marchantin A (EMA), a new macrocyclic bis-bibenzyl compound, was isolated and identified from M. polymorpha. Using a Lipopolysaccharide (LPS)-induced mouse macrophage RAW264.7 macrophage model, a Caenorhabditis elegans (C. elegans) aging model, and network pharmacology analysis, we systematically investigated the pharmacological mechanisms underlying its anti-aging effects. Our results demonstrated that EMA significantly reduced inflammatory cytokines and nitric oxide (NO) in LPS-stimulated RAW264.7 cells via the nuclear factor erythroid 2-related factor 2 (Nrf2) / heme oxygenase (HO-1) pathway. Mechanistically, EMA triggered a reactive oxygen species (ROS)-mediated mitogen-activated protein kinase (MAPK)-dependent Nrf2 antioxidant signaling cascade. EMA significantly extended the lifespan and enhanced fecundity in the N2 strain of C. elegans, while reducing lipofuscin deposition and ROS levels. Additionally, EMA enhanced oxidative and heat stress resistance in the N2 strain of C. elegans. Network pharmacology revealed that its anti-aging effects may be mediated by MAPKs/Nrf2/HO-1 pathway regulation. Collectively, these findings highlight EMA as a potent anti-aging with therapeutic potential for aging-related conditions.

The shortage of liver donors for liver transplantation is currently an urgent problem. Elderly donors have become an important source of donor livers, but they are more prone to ischemia reperfusion injury (IRI) in liver transplantation. Therefore, exploring the effects and mechanisms of aging on liver IRI will provide a new theoretical basis for improving the survival rate of liver transplant patients. We constructed a mouse model of liver ischemia for 90 min and reperfusion for 6 or 24 h, and found that compared with young liver, the recovery of liver function in aged liver after IRI was slower. Detection of macrophage pyroptosis revealed that it was an important factor for aging deferring liver function restoration. Mechanistically, we demonstrated that aging triggered mitochondrial permeability transition pore (mPTP) channel opening to promote the release of Oxidized mtDNA (Ox-mtDNA), thereby inducing macrophage pyroptosis. Moreover, the activity of mPTP channel was mainly dependent on calcium uptake by acetylated mitochondrial calcium uniporter (MCU). These results illustrated that cytoplasmic Ox-mtDNA-induced macrophage pyroptosis was a key factor for aging exacerbating liver IRI. Calcium uptake via acetylated MCU triggered mPTP channel opening, which is an important mechanism for Ox-mtDNA release from mitochondria into the cytoplasm.

Chrysin (5,7-dihydroxyflavone), a natural flavonoid present in honey, propolis, and various medicinal plants, has shown promise as a calorie restriction mimetic (CRM) through its glycolysis-inhibiting action. This inhibition promotes a metabolic shift toward oxidative phosphorylation and fatty acid oxidation, potentially activating beneficial pathways like AMPK and SIRT1. The mechanism likely involves the downregulation of Hexokinase-2, leading to suppressed glycolysis and promotion of apoptosis. In this study, we assessed aging biomarkers in erythrocytes, plasma, and serum after administering chrysin (100 mg/kg, orally) and D-galactose (300 mg/kg, subcutaneously) for four weeks to Wistar rats. In the D-galactose-induced aging rat model, the markers of oxidative damage, such as protein carbonyls, malondialdehyde, and advanced oxidation protein products, were found to be elevated. However, chrysin treatment significantly upregulated antioxidant defenses, including catalase, superoxide dismutase, ferric-reducing antioxidant power (FRAP), and glutathione (GSH). Administration of chrysin to aged rats led to a decline in both inflammatory biomarkers and insulin concentrations. These findings suggest that chrysin can alleviate oxidative stress, reduce lipid peroxidation, and influence inflammation and metabolism, highlighting its potential as an anti-aging therapeutic agent. This study underscores the potential of chrysin as a natural calorie restriction mimetic, mainly by maintaining redox balance by impacting longevity pathways and metabolic health.

Many organisms undergo ontogeny, whereby individuals change in state (e.g.~in size, morphology, or condition) as they age. Understanding the evolution of traits influencing ontogeny is challenging because their fitness effects unfold across an individuals lifetime and may differ between classes such as sexes. Here, we analyze selection on non-plastic traits (e.g., fixed resource allocation strategies) that determine the development of dynamical states throughout life (e.g., body size), with consequences for fecundity and survival in age- and class-structured populations. Using invasion analysis, we derive expressions for directional and quadratic selection that decompose into age- and class-specific components. This allows us to identify convergence stable trait values, assess whether they are uninvadable or potentially experience evolutionary branching, and pinpoint the age and class pathways through which correlational and disruptive selection act. Applying our results to a model of growth under size-mediated sexual selection, we show how developmental trade-offs and sex-specific constraints can generate disruptive selection on male growth and favour the evolution of alternative male life histories. More broadly, our results highlight how adaptation is mediated by the interaction of development and demography, and provide tools to investigate how conflicts across ages and classes influence senescence, sexual dimorphism, and the diversification of ontogenetic strategies.

NADH-cytochrome b5 reductase 3 (CYB5R3) is a flavoprotein that governs nitric oxide (NO) signaling and supports NADPH oxidase 4-derived hydrogen peroxide production via coenzyme Q reduction in endothelium. While CYB5R3 expression is decreased during aging, the downstream consequences of CYB5R3 loss are not understood. Here, we demonstrate that depletion of CYB5R3 in primary human aortic endothelial cells activates a Ca2+ influx network characterized by the upregulation of calcium release-activated calcium (CRAC) channel subunits ORAI2 and ORAI3, as well as the non-selective cation channel transient receptor potential vanilloid 2 (TRPV2). When endoplasmic-reticulum Ca2+ stores were depleted, CYB5R3-deficient cells had increased Ca2+ entry through the plasma membrane, part of which was insensitive to classical store-operated Ca2+ entry (SOCE) blockers and was mediated by TRPV2, as demonstrated by genetic knockdown and pharmacologic inhibition. Mechanistically, loss of CYB5R3 increased Ca2+-dependent NO production through elevated CRAC channel activity, which oxidatively inhibited the protein tyrosine phosphatase non-receptor type 1 (PTPN1). This prevented TRPV2 dephosphorylation, thereby maintaining Janus kinase 1 (JAK1)-dependent channel activation downstream of SOCE. It also enhanced the responsiveness of TRPV2 to physiological heat stimuli. Thus, CYB5R3 normally acts as a brake, limiting NO-dependent PTPN1 oxidation and restraining TRPV2 activity. In vivo, endothelial-specific Cyb5r3 deletion enhanced acetylcholine-induced vasorelaxation and improved exercise capacity, demonstrating a physiological function for this pathway in vascular adaptation. Together, these findings identify a CYB5R3-NO-SOCE-PTPN1-TRPV2 signaling axis that couples endothelial redox balance to Ca2+ dynamics and vascular function.

Aging, a complex biological process, entails sequential changes in organisms that elevate the risk of frailty, disease, and mortality, affecting individuals at the level of cellular, organ, and organism. This process is influenced by genetic diversity, socioeconomic status, healthcare infrastructure, lifestyle choices, and cultural practices. Gerontology delves into the factors shaping longevity, aging processes, and aging from both evolutionary and individual perspectives. Centenarians and supercentenarians serve as models for studying exceptional longevity, offering insights into the aging process and resistance to age-related diseases. This research investigates common genetic variations (SNPs) shared among 3 centenarians and 18 supercentenarians, individuals aged 110 years or older. 754,520 SNPs were found to be common among all the 21 samples. Utilizing SNPnexus, a genetic variant annotation tool, we annotated coding variants and assessed potential disease susceptibilities associated with these variants. Ensembl was used as an annotation system, we annotated 1,607,122 variants, and found 11,348 coding variants. Among them, 4980 had non-synonymous variants, and 110 variants were observed to have deleterious effects. These deleterious SNPs were linked with 79 genes among them 16 novel variants were identified in 9 genes. The population frequency comparison using the 1000 Genomes Project and gnomAD revealed that a subset of these common, non-synonymous SNPs and deleterious SNPs had minor allele frequencies (MAF) below 1% or were absent entirely, suggesting potential rare variants specific to this cohort. In addition, we also found statistically significant (p < 0.05) 148 enriched pathways, among them the top enriched pathways such as extracellular matrix (ECM) remodeling, signal transduction, disease-associated pathways, sensory processing and metabolism of proteins and RNA. These preliminary findings may help prioritize candidate variants and genes for future studies on larger cohorts with appropriate controls can help in understanding the genetic basis of exceptional longevity.

Exercise triggers molecular changes in skeletal muscles, but distinguishing immediate responses from secondary inter-organ interactions in muscle biopsies remains challenging. Here, this study differentiates human embryonic stem cells (hESCs) into induced skeletal muscle (iMusc) cells to identify hypertrophic factors and generates a novel 3D human iMusc organoid model for studying the direct effects of exercise-like contractions. Transcriptomics profiling reveals iMusc organoids rapidly induced genes associated with calcium signaling, p38/MAPK, EGF/ErbB, and NGF pathways within 1 h, mimicking exercise responses in vivo. Proteomics profiling and in vivo validation reveal rapid activation of both AMPK and mTORC1 signaling, partly through increased Lamtor1 levels, resolving a paradox in exercise biology. Human muscle biopsy analyses reveal Lamtor1 decreases with aging, and increases with exercise. In vivo and organoid experiments both confirm Lamtor1's role in mTORC1-induced strength and AMPK-induced lipid metabolism. Overall, this 3D iMusc organoid model provides insights into primary contraction-induced changes and identifies Lamtor1 as a novel therapeutic target for exercise mimicry.

Organisms must constantly respond to stress to maintain homeostasis, and the successful implementation of cellular stress responses is directly linked to lifespan regulation. In this Review we examine how three age-associated stressors-loss of proteostasis, oxidative damage and dysregulated nutrient sensing-alter protein synthesis. We describe how these stressors inflict cellular damage via their effects on translation and how translational changes can serve as both sensors and responses to the stressor. Finally, we compare stress-induced translational programmes to protein synthesis alterations that occur with age and discuss whether these changes are adaptive or deleterious to longevity and healthy ageing.

Menopause marks an important transition in women's health, with the age at menopause influencing a variety of later-life health risks. However, the impact of menopause timing on longitudinal progression of frailty among Chinese middle-aged and older women remains unclear.

The global burden of chronic kidney disease (CKD) continues to rise, posing major public health challenges, partly driven by increasing obesity rates. Obesity has been established as an independent risk factor for renal dysfunction, with a complex pathophysiology involving renal hemodynamic changes, inflammation, lipid accumulation, and metabolic disorders. Recent research has also underscored the potential role of gastrointestinal dysbiosis and specific endothelial cell characteristics. Current evidence indicates that the impact of obesity on renal function becomes more pronounced with advancing age, partly owing to the significant structural and functional alterations in kidneys associated with aging. Furthermore, the interaction between obesity and aging exerts a synergistic effect on renal function. Sex-related differences are also observed, with males generally experiencing earlier declines in renal function, while females with obesity may face more rapid changes, although this remains a debated issue. In this review, we provide a thorough summary of what is currently known about how obesity affects renal function, focusing on age- and sex-related differences and the underlying mechanisms. Bibliometric analyses are employed to summarize and visualize the evolving trends and emerging hotspots in this field. Furthermore, we discuss methods for assessing renal function, weight management strategies, and novel treatment avenues for older individuals with obesity, offering insights for the prevention or mitigation of renal dysfunction.

Telomeres are essential for maintaining genomic integrity and are associated with cellular aging and disease, yet the factors influencing their inheritance across generations remain poorly understood. Leveraging PacBio HiFi long-read sequencing and 75 parent-offspring trios (n = 225) from the Genomic Answers for Kids program, we analyzed individual telomeres across chromosomes and their inheritance. Telomere length (TL) varied between chromosome arms in a way that was consistent in parents and offsprings, with average values ranging from 5000 to 8000 base pairs. Maternal and paternal TL together were a strong predictor of child TL (R2= 0.59). Notably, using telomeric variant repeats, we developed a tool that enabled allelic tracing for 53.3% of maternally and 49.9% of paternally inherited telomeres. In the child, paternally transmitted alleles were significantly longer than age-matched maternal ones ({Delta}mean = 409 bp, p = 2.6e-05), particularly when from older parents ({Delta}mean = 698 bp, p = 8.9e-05) and at chromosome arms with shorter average TL ({Delta}mean = 752 bp, p = 1.6e-06). These findings reveal parent-of-origin effects and heritable influences on TL, providing novel insights into telomere dynamics and their potential implications in age-related disease susceptibility.

Aged hematopoietic stem cells (HSCs) expand in clusters over time, while reducing their regenerative capacity and their ability to preserve the homeostasis of the hematopoietic system. The expression of Notch ligands in the bone marrow (BM) niche is essential for hematopoiesis. However, the impact of Notch signaling for adult HSC function and its involvement in HSC aging remains controversial. Here we show that Notch activation in young HSCs is not homogeneous, and it is triggered by sinusoidal expression of the Notch ligand Jagged2 (Jag2). Sinusoidal Jag2 deletion in young mice recapitulates the decrease in Notch activity observed in aged HSCs and alters HSC divisional symmetry and fate priming, promoting myeloid-biased HSCs (My-HSCs) expansion. Mechanistically, our data reveals that upon decreasing sinusoidal Jag2 expression, HSCs themselves upregulate Jag2, which cis-inhibits Notch signaling, resulting in the expansion of My-HSCs and in reduced hematopoietic regeneration. Collectively, these findings identify the crosstalk between BM niche-driven and HSC intrinsic features in regulating HSC fate priming and regenerative potential and reveal an extrinsic Notch trans-activation to intrinsic cis-inhibition switch underlying HSC aging.

Methylation-based epigenetic clocks are among the most accurate tools for predicting chronological age. Although DNA methylation (DNAm) at genomic CpG sites is linked to various regulatory mechanisms, the biological interpretability of epigenetic clocks remains surprisingly limited. One primary mechanism by which DNAm is thought to influence gene regulation is by modulating transcription factor binding activity. In this study, we examine established epigenetic clocks to assess the regulatory potential of their predictive CpGs during the aging process. Our analysis reveals that generally most CpG sites used by epigenetic clocks do not overlap known transcription factor binding sites (TFBSs), indicating that changes in TFBS dynamics may not account for prediction accuracy of these models. On the other hand, by identifying age-associated CpGs that overlap TFBSs, we identified transcription factors that may be involved in the aging process. Specifically, the TFBSs of ZBED1, NFE2, CEBPB, FOXP1, EGR1, SP1, PAX5, and MAZ were particularly enriched for age-associated CpGs, while RBPJ, NFIC, RELA, IKZF1, STAT3, and USF2 were significantly protected against methylation changes. By focusing on TFBS-associated CpGs, combined with additional feature selection and engineering steps, we developed an alternative, TFMethyl Clock model, outperforming several existing approaches. Target genes of model-selected, age-predictive CpGs are enriched in the interleukin-1{beta} production and long-chain fatty acid metabolism pathways. In contrast, these CpGs themselves are enriched mainly at binding sites of NR2C2 TF. Furthermore, approximately three-fourths of the target genes downstream of age-predictive CpGs exhibit significant age-related changes, suggesting that our approach captures deeper insights into possible methylation-driven biological aging processes. Our findings demonstrate that incorporating regulatory loci into the design of epigenetic predictors may provide mechanistic insights into the aging process while maintaining or even improving the predictive power.

Variation in the gene for apolipoprotein E (APOE) is one of the few variables that is associated with individual differences in age-related cognitive decline in humans. Therefore, it is important to understand the conditions that affect the strength of its effect. Here we examine how the effect size of APOE variation (possession of one or more e4 alleles) on a test of general cognitive ability changes with age from 11-90 years. The data are from the Lothian Birth Cohorts of 1936 and 1921 who took the same cognitive test (the Moray House Test No. 12) at, respectively, ages 11 (N = 954), 70 (N = 1001), 76 (N = 636), 79 (N = 471), and 11 (N = 483), 79 (N = 533), 87 (N = 198), 90 (N = 120). The standardised absolute effect of APOE e4 on general cognitive ability was about zero at ages 11 (beta < 0.05) and 70 (beta ≤ 0.025) and increased linearly to beta = 0.30 (p < 0.001) at age 90. The effect sizes were minimally affected by adjusting for medical conditions (hypertension, diabetes, cardiovascular disease, stroke). However, the results were less robust to removing those participants who developed dementia; effect sizes were reduced by about a third to a half, and were largely non-significant. The results suggest that the negative effect of APOE e4 on cognitive functioning becomes greater with age; this urges more work to understand the mechanisms by which e4 status renders the older person's brain increasingly vulnerable to cognitive decline and dementia.

Sarcopenia and obesity, two prevalent metabolic disorders in aging populations, often coexist and share overlapping pathophysiological mechanisms, yet the molecular mechanisms underlying their comorbidity remain elusive. This study aimed to identify key gene expression signatures and pathways underlying their comorbidity through integrative transcriptomic and bioinformatics analyses. Gene expression datasets from sarcopenia (GSE111016, skeletal muscle) and obesity (GSE152991, adipose tissue) were downloaded from the GEO database. Differentially expressed genes (DEGs) were identified using the limma package, and 208 common differentially expressed genes (CDEGs) were selected via Venn diagram intersection. Functional enrichment analyses (GO and KEGG) were performed to explore shared biological processes and pathways. A protein-protein interaction (PPI) network was constructed using STRING and Cytoscape, and key CDEGs were identified via ten topological algorithms (e.g., MCC, Degree) in the CycloHubba plugin. Pearson correlation analysis and qPCR were used to validate gene co-expression patterns and expression levels in tissue samples. GO and KEGG analyses revealed that CDEGs were significantly enriched in mitochondrial oxidative phosphorylation, electron transport chain, and thermogenesis pathways, with overlap in neurodegenerative disease pathways. The PPI network and multi-algorithm integration identified four key CDEGs: SDHB, SDHD, ATP5F1A, and ATP5F1B, all of which are components of mitochondrial respiratory chain complexes. These genes exhibited strong positive correlations (r > 0.86, p < 10⁻¹²) in both datasets and were significantly downregulated in sarcopenia and obesity tissues, as validated by qPCR. This study confirms mitochondrial dysfunction, particularly impaired oxidative phosphorylation, as a common pathological mechanism linking sarcopenia and obesity. The key genes SDHB, SDHD, ATP5F1A, and ATP5F1B represent potential therapeutic targets for managing these comorbid metabolic disorders. Future research should explore their functional roles in energy metabolism and cross-tissue crosstalk to develop targeted interventions.

Cardiorespiratory fitness (CRF) is a powerful predictor of cardiovascular events and overall mortality, often surpassing traditional risk factors in prognostic value. However, its clinical use remains limited because current assessments rely on specialized equipment, trained personnel, and lengthy procedures that are often impractical for broad or routine application, especially in at-risk populations. Because CRF is closely tied to vascular health, surrogate measures that capture vascular features may offer a practical alternative for its estimation. Retinal Color Fundus Images (CFIs) provide a non-invasive window into systemic vascular health and have already demonstrated their utility in predicting cardiovascular risk factors and diseases, yet CFIs have yet to be explored for their potential to predict CRF. In this study, we develop RetFit, a novel CRF estimator derived from CFIs by leveraging state-of-the-art vision transformers. RetFit enables a non-invasive, easy-to-acquire CRF proxy, addressing some of the limitations inherent to standard CRF measures and linking retinal imaging to the cardiovascular system. We evaluated RetFit's clinical relevance by analyzing its associations with cardiovascular risk factors, disease outcomes, and exploring its genetic architecture, benchmarking it against a submaximal-exercise-test CRF (SETCRF) estimate. We find that RetFit is prognostic of both cardiovascular events (hazard ratios as low as 0.878, 95%CI 0.856 to 0.901, p<0.001) and overall mortality (hazard ratios as low as 0.780, 95%CI 0.754 to 0.801, p<0.001) and significantly associates with the majority of disease states and risk factors explored within our analysis. Although RetFit and SETCRF shared a moderate phenotypic correlation with each other (r=0.45), their significant genetic associations were disjoint. Interpretability analyses revealed that RetFit's predictions are driven by the retinal vasculature, with the number of arterial bifurcations showing the strongest association with RetFit ({beta}=0.287, 95%CI 0.263 to 0.311, p<0.001). These findings highlight the potential of retinal imaging as a scalable, cost-effective, and accessible alternative for CRF estimation, supporting its use in large-scale screening and risk stratification in both clinical and public health contexts.

The incidence of cardiovascular diseases rises significantly with age, making it one of the leading causes of death and disability worldwide, and cellular senescence plays a crucial role in this process. Cellular senescence constitutes a salient feature of organismal aging and stands as an independent risk factor for a range of cardiovascular diseases, encompassing hypertension, atherosclerosis, myocardial infarction, heart failure, and arrhythmia. This comprehensive review endeavors to comprehensively delineate the intricate regulatory mechanisms underlying cellular senescence and its attendant biological implications, while elucidating the profound implications of this process on the initiation and progression of cardiovascular diseases. Finally, we will delve into a spectrum of targeted interventions aimed at cellular senescence, specifically focusing on eliminating the accumulation of senescent cells during disease progression or inhibiting the inherent cellular senescence processes. Our ultimate goal is to mitigate or postpone the onset of diseases that are intricately linked to cellular senescence. A profound comprehension and rigorous investigation into the regulatory mechanisms of cellular senescence and their intricate interrelationships hold significant potential to furnish invaluable scientific evidence for the prevention and therapeutic strategies against cardiovascular diseases.

Background: Intrinsic capacity (IC) is a composite measure, computed from five domains: cognition, psychological well-being, locomotion, vitality, and sensory. IC reflects the overall physiological reserve and functional capacity of an individual, making it a key indicator of healthy ageing. The substantial interindividual variability in IC is likely influenced by genetic (polygenic) as well as socioeconomic status and lifestyle factors. However, the interaction effect of these factors is yet to be explored. Objective: This study examined (1) associations of IC with socio-economic and lifestyle factors and the polygenic scores for IC (PGS-IC) when stratified by age, and (3) the interaction effects of the PGS-IC and socio-economic or lifestyle factors on IC. Methods: Our study included 13,112 participants from the Canadian Longitudinal Study on Aging (CLSA) comprehensive cohort with complete IC variables and genetic data. Composite lifestyle scores, including the Physical Activity Scale for the Elderly (PASE), Prospective Urban Rural Epidemiological study (PURE) diet, and Mediterranean diet scores, were generated following established guidelines. Associations of IC with the socioeconomic and lifestyle factors were assessed using linear regression models adjusted for age and sex. The IC scores and the PGS-IC were developed in CLSA in our previous work, and this study tested age-stratified associations of PGS-IC with IC, and interaction effects of the PGS-IC and socioeconomic or lifestyle factors on IC using linear regression models adjusted for age, sex, and the top five genetic principal components. Statistical significance was defined as a false discovery rate (FDR) adjusted P < 0.05. Results: The mean age was 61 (standard deviation 9.6) years, and 50.8% were females. Higher IC was associated with higher education (B = 0.255, 95% CI: 0.180, 0.329), higher income (B = 0.392, CI: 0.322, 0.461), physical activity (PASE score: B = 0.001, CI: 0.0004, 0.001), and healthier diets (PURE diet score: B = 0.024, CI: 0.021, 0.027; Mediterranean diet score: B = 0.018, CI: 0.016, 0.021). IC was lower in previous (B = -0.093, CI: -0.121, -0.064) and current smokers (B = -0.407, CI: -0.459, -0.355) compared to never smokers. Likewise, short (<7h: B = -0.133, CI: -0.161, -0.105) and long (>9h: B = -0.258, CI: -0.392, -0.124) sleep durations were negatively associated with IC compared to those who had optimal sleep. The PGS-IC was positively associated with IC, particularly in younger adults. Significant interaction effects were observed with Mediterranean diet (B = -0.003, CI:-0.006 -, -0.0002) in whole sample, education in younger adults (B = -0.109, CI: -0.211 -, -0.007), and sleep (younger adults: long sleep, B = 0.198, CI:0.023, 0.373; older adults: short sleep, B = -0.095, CI: -0.153 -, -0.036). Conclusion: Novel findings confirming the interaction effects of PGS-IC with socioeconomic and lifestyle factors suggest that there is a complex interplay between genetics and the environment in shaping IC and healthy ageing. Keywords: Intrinsic capacity, Ageing, Polygenic score, CLSA, Lifestyle factors

Lifestyle improvement may help reverse prediabetes. Indicators such as Life's Essential 8 (LE8) and biological aging measures (phenotypic age, cardiovascular biological age) partially reflect metabolic status in prediabetes, but their predictive value for cardiovascular mortality and stroke in this population remains unclear.

The senescence of immune cells, including macrophages, that accompany the initiation and development of tumors has become a novel research hotspot. Recently, studies have reported the molecular characteristics of senescent macrophages (sMACs) in the tumor microenvironment (TME), including cell cycle arrest, senescence-associated secretory phenotype (SASP), and senescence-associated β-galactosidase phenotype (SA-β-gal), and these characteristics not only suggest that sMACs are functionally rich in the TME, but also have the potential to become biomarkers for the identification of sMACs. The in-depth study and analysis of sMACs dialogue and mediating the changes of signaling pathways related to tumor and immune cells will help us to better understand the balance between tumor and aging. Here, we review recent advances in sMACs, including phenotypical molecular characteristics, potential functions and intervention approaches.

Identifying the drivers of cellular senescence that contribute to the decline in tissue function related to aging- and disease is critical for developing restorative interventions. Here, we investigated how increased mechanical stress from extracellular matrix (ECM) stiffening shapes endothelial cell (EC) senescence. We developed a 3D human in vitro model that decouples mechanical stress from inflammatory or biochemical inputs, enabling the study of senescence responses to tissue stiffening alone. We found that matrix stiffening induces an EC senescence phenotype with elevated p16/p21 and an immunomodulatory senescence-associated secretory phenotype (SASP), in the absence of inflammatory signals. This mechano-induced senescence state engaged a Notch-JNK-FOS signaling axis, and pharmacologic inhibition of Notch attenuated stiffness-induced senescence. Supporting the translational relevance of this mechanism, analysis of fibrotic capsule tissue from patients with synthetic breast implants, a model of localized, mechanically driven fibrosis, revealed increased p16+Notch1+ endothelial populations. Complementary single-cell RNA sequencing data confirmed their enrichment in Notch/JNK- and SASP-related gene programs. Together, these findings define vascular senescence as a mechanosensitive process and identify tissue stiffening as an upstream aging signal. Our work offers a human-relevant platform for studying targetable stages of endothelial mechanoaging.

The human microbiome is a dynamic, polymicrobial ecosystem that plays an essential role in nutrition, immune development, barrier integrity, and host physiology, acting as a mutualistic partner under balanced conditions. However, its ecological complexity, genetic adaptability through horizontal gene transfer, and interactions with other prokaryotes as well as protozoan and metazoan parasites can transform commensals into pathobionts, resulting in weakened host's barriers, immunity declines with the progression of age, and community composition shifts toward dysbiosis. Factors such as diet, genetics, aging, immune-senescence, impaired autophagy, and environmental exposure, all influence this delicate balance, determining whether the microbiome remains protective or becomes an opportunistic source of inflammation and disease. This review focuses on the study of the intestinal microbiome in humans. Maintaining microbiome homeostasis is promoted through (a) dietary diversity, (b) limited antimicrobial use, (c) use of probiotics, (d) support for gut barrier function, and (e) healthy lifestyle improvements. These actions and considerations are critical to prevent the emergence of pathogenic states and preserving the microbiome's vital role in host health throughout life.

Long noncoding RNAs (lncRNAs) regulate gene expression and play crucial roles in development and disease, including cancer. One important but still poorly understood lncRNA is TERRA (telomeric repeat-containing RNA), transcribed from telomeres and essential for telomere maintenance, genome stability, and cellular aging. TERRA adopts two structural features,R-loops and G-quadruplexes (G4s), that drive its biological activity. Its dysregulation is linked to telomere dysfunction and is prominent in Alternative Lengthening of Telomeres (ALT) cancers, where TERRA is highly upregulated and promotes telomere recombination. Here, first-in-class small molecules targeting TERRA using RIBOTAC (Ribonuclease-Targeting Chimera) technology is developed. These compounds selectively bind TERRA's G4 structures and recruit RNase L, inducing its degradation while sparing DNA G4s and other G4 RNAs. This selectivity results from ternary complex formation with RNase L and the repetitive G4 motifs enriched in TERRA. TERRA-RIBOTACs in HeLa and U2OS cells, the latter representing an ALT cancer model, are evaluated. TERRA degradation, particularly at 7p, 13q, 15q, and 20q loci, impairs telomere function and reduces colony formation. Manipulating lncRNAs like TERRA with chemical tools opens new avenues for drug development and deepens the understanding of RNA-based regulation in cancer biology.

Osteoporosis is an age-related bone metabolic disease characterized by a persistent bone mass decrease and bone structure destruction. Osteoclasts, important cells in the bone remodelling process, are closely associated with the onset and progression of osteoporosis; however, the regulatory mechanisms involved remain unclear. In this study, TFE3 cytoplasmic translocation inhibited LAMP2A expression in osteoclasts and precursors in elderly individuals with osteoporosis and the downregulation of LAMP2A expression mediated the attenuation of chaperone-mediated autophagy (CMA). This inhibition prevented intracellular CCR5 degradation, increased the osteoclast differentiation of osteoclast precursor cells, and enhanced the bone resorption activity of mature osteoclasts, leading to bone loss and remodelling. In addition, we constructed osteoclast-targeted nanoparticles carrying CMA activators and demonstrated that enhancing osteoclast CMA activity in vivo inhibited the abnormal bone resorption activity of osteoclasts, thereby effectively increasing bone mass and alleviating osteoporosis progression. This study revealed that LAMP2A-mediated CMA activity in osteoclasts and their precursors negatively regulates osteoclast differentiation and bone resorption activities both in vivo and in vitro. The attenuation of LAMP2A-mediated CMA activity plays an important role in the development of osteoporosis, and enhancing LAMP2A-mediated CMA activity represents a potential therapeutic strategy for osteoporosis.

Enhancing physical activity and managing body weight are crucial for addressing aging-related challenges. However, research on the relationship between physical activity, Weight-Adjusted Waist Index (WWI), and all-cause mortality is limited. This study aims to explore these interactions and their impact on elderly health. Data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) for 2011-2018 included 7,034 residents aged ≥ 60 years. We utilized Cox proportional hazard models to assess the relationships between physical activity, WWI, and all-cause mortality, supplemented by subgroup analyses and interaction tests. We did a mediation analysis to assess how much of the effect of physical activity on survival status was mediated through WWI. Active individuals and those transitioning from inactive to active lifestyles exhibited significantly lower all-cause mortality risks, with reductions of 26% (HR = 0.74, CI: 0.65-0.83) and 9% (HR = 0.91, CI: 0.83-0.99), respectively. A positive correlation was found between WWI and all-cause mortality, with a threshold of 11.38 cm/√kg indicating increased risk. Although no interaction between physical activity and WWI was observed (P = 0.462), mediation analysis showed that 3.06% of the effect of physical activity on survival status was mediated through WWI. Maintaining physical activity or transitioning from a sedentary lifestyle to an active one can significantly reduce all-cause mortality in the elderly. Moreover, high WWI is associated with an increased risk of death. Importantly, WWI partially mediates the relationship between physical activity and death, shedding light on why physical activity reduces mortality and reinforcing the need for health promotion strategies tailored to the elderly population.

Age-related cognitive decline and synaptic loss are associated with alterations in hippocampal synaptic protein phosphorylation and signaling pathways. Natural compounds from marine sources, such as Capsosiphon fulvescens glycopeptides (Cf-tPep), have shown potential neuroprotective properties. This study aimed to investigate the effects of trypsinized glycopeptides from C. fulvescens on synaptic protein phosphorylation and cognitive function in aging hippocampal neurons and rats.

The aim of this study was to evaluate the effects of combining self-management strategies (SMS) for reducing sedentary behavior (SB) with multicomponent exercise (ME) compared to ME alone on SB patterns and physical function among community-dwelling older adults.

This comprehensive systematic review examined the relationship between oral health and function and the incidence of physical disability and mortality.

Older adults walk with reduced ankle and greater hip mechanical output compared to young adults. This distal-to-proximal redistribution likely contributes to the greater metabolic energy expenditure during walking in older versus young adults. Due to the inverse relationship between ankle and hip use, functional electrical stimulation (FES) of the ankle extensors may increase ankle mechanical work and indirectly decrease hip mechanical work. Although FES increases stimulated muscle metabolism, bilateral soleus stimulation may restore more youthful walking kinetics without a detectable change in whole-body metabolism because ankle extension requires less metabolic energy than hip extension. Ten young adults and 10 older adults walked on a treadmill at 1.25 m/s with and without FES bilaterally applied over the respective leg ' s soleus when the anterior-posterior ground reaction force exceeded 10% body weight. FES use altered walking mechanics and metabolic power similarly across age groups (all FES condition and age-group interactions p[≥]0.214). Across age groups, FES increased ankle mechanical power (p=0.041) and redistributed mechanical work production to occur relatively more at the ankle and less at the hip (p=0.010). The lower-limb joint redistribution ratio of older adults walking with FES was not different to that of young adults during baseline (p=0.785). Moreover, walking with FES increased metabolic power by 2% (p=0.037). FES attenuated older adult distal-to-proximal redistribution and modestly increased whole-body metabolic rate. FES applied to soleus muscles during the late stance of walking affects users similarly across the lifespan, indicating that FES interventions ought to consider a person ' s functional needs, regardless of age.

Schwann cells (SC) are crucial for physiological impulse conduction in peripheral nerves. They produce myelin, provide axonal metabolic support, and contribute to reparatory processes after nerve injury. During aging, peripheral nerves acquire myelin structural anomalies and are characterized by a lower fraction of SC and a higher fraction of senescent cells. All these changes correlate with impaired electrical conduction and consequently altered function of target tissues including skeletal muscle weakness and cardiac arrhythmia. To characterize and compare cardiac and sciatic nerve SC, as well as to explore age-related differences in SC abundance and their properties, we analyzed two TdTomato reporter mouse strains to isolate Sox10 or Plp1 expressing SC. We performed RNA-sequencing on sorted TdTomato-positive cells from the heart and sciatic nerve and validated transcriptomic findings at the protein level using immunofluorescence. Our data reveal a pro-angiogenic profile in cardiac SC when compared to sciatic SC. In addition, higher levels of neural-death associated genes and lower gene and protein expression levels of the fatty acid co-transporter Fabp4/FABP4 are detected in cardiac SC from old compared to young mice, suggesting an aging-related impairment of fatty acid transport. Finally, sciatic SC activate collagen remodeling and increased pro-inflammatory signaling including TNFα. Thus, cardiac and musculoskeletal SC have different expression profiles, and undergo different changes during aging, which may contribute to impaired nerve function in both organ systems.

β-hydroxy-β-methylbutyrate (HMB) is a bioactive metabolite formed from breakdown of leucine, which increases muscle protein synthesis and reduces muscle breakdown. Previous studies have shown an inverse association between HMB levels and frailty in older adults. This study aims to assess if body composition influences this association.

The way we perceive our body and its dimensions depends on how our brain combines multisensory information. As the human sensory system declines with age, we hypothesize that body perception may change during aging. We investigated this hypothesis by comparing body ownership (BO) and upper limb perceived dimensions (mBR) in young and older individuals (>65 years). We used computational and psychophysical methods to quantify alterations in mBR and BO, and modeled their relationship with sensorimotor and cognitive factors. Results revealed altered body perception in healthy older adults, with significant underestimation in arm dimensions and increased feeling of ownership over an incongruent virtual hand, incorporating it into their motor plans. Reduced abilities in localizing one's own body in space (i.e., proprioception) emerged as a common factor influencing both BO and mBR. These findings pave the way for stimulation strategies to maintain or restore body perception in aging.

Geroscience may be the juggernaut that coalesces the pathways of biologic knowledge to expand our understanding beyond describing differences in rates of aging to feasible interventions for improving quality of life as we age. To accomplish this, geroscience must interdigitate with long-standing immutable factors about health. As early as the 17th-century, physicians and early demographers like John Graunt, Percival Potts, Bernardino Ramazzini, and Rudolf Virchow identified the importance of differences in health trajectories and outcomes for individuals, and underlying aspects of health disparities. These differences in health status relate to numerous social determinants of health as they interact with biological risk factors and the environment. These populations and the psychosocial factors that influence health and longevity must be considered as an integral part of geroscience. Longitudinal studies that examine factors influencing the development of age-related health differences over time should be a key component of geroscience. The HANDLS study provides a useful demonstration project showing the value of studying aging in urban dwelling American adults, some of whom face significant social adversity based on race, socioeconomic status, and other factors.