Longevity Papers

Craniomaxillofacial bone marrow mesenchymal stromal cells (BMSCs) retaining neural crest-derived neurogenic niche is driven by lineage memory and niche homeostasis. Elucidating how the neurogenic potential is maintained is critical for neurological health. Here, we explored a neural crest-like progenitor niche in BMSCs with high neurogenic and proliferative capacity by single-cell transcriptomics. In which, ANKRD1 is a pivotal regulator sustaining the neurogenic reservoir. Importantly, ANKRD1 expression in this niche declines with aging and lineage commitment, coinciding with its redistribution from a diffuse nucleoplasmic pattern to perinuclear enrichment along the nuclear lamina and loss of neural potential. Mechanistically, ANKRD1 preserves neurogenic capacity by directly binding super-enhancers of neural marker genes (SOX2, NESTIN) and maintaining open chromatin architecture. Critically, neuron-targeted ANKRD1 delivery rescues spatial memory deficits in aged mice. These findings establish ANKRD1 as a therapeutically tractable regulator that sustains neurogenic chromatin reservoirs to support neurocognitive resilience, opening avenues to counter cognitive aging.

Cellular senescence drives aging-related tissue dysfunction in part through the senescence-associated secretory phenotype (SASP), an inflammatory secretome linked to retrotransposable element (RTE) derepression. Transcriptomic and proteomic approaches have characterized the senescent program extensively, but mRNA abundance does not predict protein output well, and limited proteomic depth constrains the detection of low-abundance SASP factors and RTE-derived proteins. To bridge this gap, we used AHARibo, a metabolic labeling-based method that selectively enriches mRNAs associated with actively elongating ribosomes, to generate translatome profiles in human fibroblasts across proliferating, early senescent, and late senescent states. Comparison of total and ribosome-associated mRNA pools reveals marked translational uncoupling in early senescence: transcriptomic changes explain only 34% of translatomic variance, compared to 70% in late senescence, indicating that early senescence is substantially shaped by post-transcriptional regulation. Key senescence programs are actively regulated at the translational level: cell cycle and extracellular matrix remodeling genes are translationally suppressed and enhanced, respectively, while inflammatory SASP components are translationally depleted in early senescence - a depletion relieved in late senescence. Translationally depleted SASP genes are enriched for binding motifs of the ZFP36 family (ZFP36, ZFP36L1, ZFP36L2), implicating these RNA-binding proteins in the post-transcriptional gating of inflammatory signaling. More broadly, translational efficiency is associated with 3'UTR GC content and codon optimality, and translationally depleted mRNAs are enriched for numerous RBP and microRNA target motifs. Finally, we detect robust, locus-resolved translation of evolutionarily young LINE-1 retrotransposons, identifying full-length elements with stage-specific translational activity. Together, these findings establish translational control as a pervasive regulatory layer shaping the senescent phenotype.

Lifestyle factors play a critical role in healthy aging, yet their relationships with aging biomarkers remain insufficiently characterized, particularly in Asian populations. This study aimed to examine the cross-sectional and longitudinal associations between 15 modifiable lifestyle factors and two DNA methylation (DNAm) clocks (GrimAge acceleration [AgeDev] and DunedinPACE) in a cohort of older Asian adults.

Intestinal aging characterized by imbalance between cell senescence and mucosal self-renewal, increases susceptibility to the elderly-onset ulcerative colitis (UC), while the underlying mechanisms remain elusive. Here, we identify mRNA N4-acetylcytidine (ac

Age-related knee osteoarthritis (OA) arises from cumulative oxidative damage, chondrocyte senescence and extracellular matrix loss; yet safe and effective disease‑modifying interventions for aging‑associated OA are lacking. Pyrroloquinoline quinone (PQQ; molecular formula C

Aging is accompanied by conserved hallmarks including genomic instability, epigenetic alterations, loss of proteostasis, and mitochondrial dysfunction, but how these processes emerge and become mechanistically linked remains unclear. Here we leverage a proteome-wide, single-cell, subcellular atlas of protein expression, localization, and aggregation across yeast replicative aging to map hallmark-linked remodeling in its spatial context. We identify hundreds of previously unappreciated molecular changes that underlie major hallmarks of aging and show that hallmark phenotypes frequently manifest as compartment-specific erosion of spatial confinement, relocalization, and aggregation. 91.6% human orthologs of these hallmark-linked yeast proteins also change during human aging. Integrating these spatial phenotypes reveals many molecular connections linking different hallmarks. Temporal analysis suggests that disorganization of nucleolar ribosome biogenesis, proteostasis decline, and mitochondrial dysfunction precede other hallmarks. Together, our findings substantially deepen the molecular underpinnings of aging hallmarks and provide a framework for linking them into a hierarchical sequence of cellular failures. Keywords: aging, protein localization, protein concentration, protein aggregation, hallmarks of aging, ribosome biogenesis, aging pathways.

Testosterone production by testicular Leydig cells (LCs) in male mammals is energetically demanding and prone to mitochondrial damage. Despite these challenges, LCs exhibit remarkable longevity and minimal turnover, suggesting the existence of specialized mechanisms that maintain LC mitochondrial homeostasis under such constrains. Here we identify a mitochondrial transfer network between LCs and different testicular macrophage (tMac) subpopulations. Leydig cells release extracellular vesicles containing defective mitochondria, which are eliminated by CD206

Neurodegenerative disorders such as Alzheimer's disease (AD) and Lewy body disease (LBD) are typically diagnosed after irreversible pathology has developed. Aging, the strongest risk factor, drives molecular changes that predispose the brain to synaptic dysfunction and proteinopathy. Glycosylation and extracellular matrix (ECM) remodeling represent underexplored mechanisms linking aging to neurodegeneration, opening avenues for biomarker discovery, yet mass spectrometry-based glycoproteomics and glycomics studies remain limited. Here, we optimized an on-slide tissue digestion workflow for integrated glycome and proteome profiling from 5-mm brain regions from mice and humans using liquid chromatography data-independent acquisition-tandem mass spectrometry (LC-DIA-MS/MS). This workflow was applied to whole brains from age- and sex-stratified wild-type mice (n = 12) and to human postmortem prefrontal cortex tissue from individuals (n = 14) with brainstem- (n = 8) or limbic-predominant (n = 6) LBD, with or without AD co-pathology. DIA substantially increased protein, glycosylated protein, and ECM coverage by two- to threefold relative to traditional data-dependent acquisition (DDA), while library-free DIA searches further improved detection of low-abundance or region-specific proteins. In aged mouse brains, we observed increased levels of synapse-related proteins-including SYNPR, ZNT3, and HPCA-and enrichment of glutamatergic and postsynaptic pathways, reflecting age-associated synaptic remodeling. Glycomics revealed subtle shifts in the sulfation of chondroitin sulfate (CS) disaccharides with age. In human samples, AD-LBD brainstem tissue exhibited significantly reduced unsulfated, 4-O-sulfated, and total CS levels, along with differential expression of ECM, glycosylated, and mitochondrial proteins, and enrichment of mitochondrial pathways compared with LBD brainstem and AD-LBD limbic tissues. These findings indicate that AD co-pathology exerts a region-specific influence on the proteomic and glycomic landscape of LBD. Collectively, this study establishes a robust DIA-based on-slide digestion platform for high-resolution spatial glycomics and proteomics from minimal tissue, revealing aging- and pathology-specific molecular alterations relevant to neurodegeneration and providing a framework for biomarker discovery.

Age-related hearing loss (ARHL) is a prevalent sensory disorder with significant clinical and social burdens, yet no FDA-approved pharmacological treatments are currently available. Emerging evidence implicates declined cellular NAD

Skeletal aging is characterized by increased fragility, reduced bone mass, and deterioration of bone microstructure. Although aging-related immune dysfunction of macrophages, namely immunosenescence, is known to contribute to this process, the underlying mechanism remains poorly understood. Here, we find that the senescence of macrophages leads to a decrease in the expression of Sirtuin3 (Sirt3), which in turn leads to increased basal and lipopolysaccharides (LPS)-induced protein expression of NLRP3 and facilitates the assembly of NLRP3 inflammasome in macrophages that mediates aging-related osteoporosis. Given the phagocytic property of macrophages, we develop a genetically engineered apoptotic body-based platform for targeted delivery of Sirt3 to macrophages and verify that Sirt3-enriched apoptotic bodies (ABs-Sirt3) delay skeletal aging by promoting ubiquitination and degradation of NLRP3. Our work reveals that Sirt3 plays a key role in regulating aggravated inflammatory responses that accelerate skeletal aging during macrophage senescence and illustrates a novel nanotechnology-based therapeutic approach targeting immune senescence-induced acceleration of skeletal aging, which may provide potential therapeutic value for human patients with age-related osteoporosis.

Maternal vitamin D status is a critical factor that shapes the immune response of the offspring over the lifespan. Immune cells express vitamin D receptors and can produce local 1,25(OH)

Age-related macular degeneration (ARMD) is the primary manifestation of permanent vision loss internationally. Different factors that contribute to ARMD involve ageing, genetic predisposition, oxidative stress, immunological imbalances, aberrations in the breakdown of lipids, and persistent inflammation. Gut microbiota has emerged as the significant cause of ARMD by disrupting systemic immune and inflammatory responses and metabolic homeostasis. Age-related changes in gut microbiota (dysbiosis) cause lowered microbial diversity, enhanced gut permeability, and pro-inflammatory species, leading to macular damage. The healthy gut microbiota containing Lactobacillus casei, Lactobacillus plantarum, Lactobacillus rhamnosus, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium longum, and Faecalibacterium prausnitzii, are responsible for maintaining gut homeostasis, protecting the retina, and preventing ARMD progression. In contrast, the elevated population of pathogenic species such as Escherichia coli, Prevotella, Desulfovibrio, Enterococcus faecalis, and Streptococcus salivarius in gut dysbiosis is involved in ARMD progression. This review explores gut microbiota and their dynamics in ageing. The age-dependent gut microbiota variations and potential biological implications for the progression of ARMD are discussed. The review also discusses observations from experimental animals and explores potential microbiome-centered treatment avenues, covering probiotics, synbiotics, dietary remedies, metabolite-based treatment, and fecal microbiota transplantation for managing ARMD. Furthermore, various challenges in the management of gut microbiota-driven ARMD are also briefed with future directions. Thus, a gut microbiota-focused paradigm can offer novel choices for ARMD prevention and treatment.

Resting metabolic rate (RMR) accounts for the majority of the total energy expenditure. While RMR is known to decline with advancing age and is recognized to be lower in females compared to males, the mechanisms underlying these differences remain unclear. Changes in body composition are posited to account for age- and sex-related differences in RMR, but to what extent lacks consensus. We characterized 80 healthy adults aged 23-82 years from the San Diego Nathan Shock Center (SD-NSC) clinical cohort for body composition and RMR using dual-energy x-ray absorptiometry (DXA) and indirect calorimetry techniques, respectively. Body composition metrics-body surface area (BSA), lean tissue mass (LTM), and total body fat (TBF)-were modelled as predictive variables to assess their explanatory power against the age and sex effects on RMR. We found that the negative association between RMR and age persists even after adjusting for body composition and sex, with a predicted decrease in RMR per decade of 62.6 kcal/day (ꞵ = -62.6, P < 0.0001). While individual body composition metrics do not account for the observed sex differences in RMR, adjusting for all body composition metrics together explained the observation that females have lower RMR compared to males. Our results suggest that while differences in body composition can explain sex differences in RMR, additional factors independent of body composition contribute to age-related differences. These results provide new insights into RMR differences among healthy individuals across the human life-course, which may inform age-appropriate interventions for optimizing metabolism.

Walking is fundamental to human mobility, and slowing gait speed is a widely recognized indicator of aging-related mobility decline. Although mobility decline in older adults has been associated with aging-related neural and morphological changes in muscle, the specific neural and morphological correlates of gait speed remain incompletely characterized. Thus, our primary aim was to quantify how peripheral nerve function, muscle cross-sectional area (MCSA) and intramuscular fat (IMAT) are related to gait speed across adulthood. We studied 898 participants from the Baltimore Longitudinal Study of Aging (BLSA), aged ≥ 20 years, with complete data on gait speed, body composition, MCSA, IMAT, and peripheral nerve function. Multivariable regression explained 29 % and 40 % of the variance in usual and rapid gait speed, respectively. Peripheral nerve measures (signal amplitude and conduction velocity) showed modest associations with both usual and rapid gait speed after mutual adjustment. In contrast, age, height, body roundness index (BRI), MCSA, and IMAT were independently associated with both gait speeds. Structural equation modelling identified MCSA and IMAT as the primary mediators of age-related gait decline, while nerve function played a smaller, task-specific role. Multi-group analysis revealed that these physiological mechanisms were stable across adulthood; however, the direct effect of age on rapid gait attenuated in the oldest-old, indicating that functional decline in this cohort is fully mediated by neuromuscular and morphological factors. Together, these findings indicate that peripheral nerve function contributes to gait speed across adulthood but plays a comparatively limited role relative to muscle morphology (MCSA and IMAT), which emerge as dominant physiological contributors to age-related mobility decline.

Systemic inflammation ("inflammaging") accelerates biological aging and drives cardiovascular, metabolic, and neurodegenerative disease. Circadian rhythms regulate the amplitude and timing of immune responses, yet their mechanistic role in inflammation and longevity remains unexplored. In 62,000 adults with 7-day wearable accelerometry, interpretable machine learning model identified rhythm amplitude, stability, and moderate-to-vigorous physical activity (MVPA) as dominant predictors of accelerated aging. In a subset of 1521 participants (35% male) with available data on the systemic immune-inflammation index (SII), we further examined the associations between behavioral rhythmicity and inflammation. Low amplitude and poor rhythm stability were associated with 0.31 and 0.18 SD higher SII; low MVPA to 0.33 SD higher SII in men (all p < 0.05). Adding 15-min bout to daily MVPA or improving rhythm stability by 10-14% mitigated these effects. Sex-stratified mediation analysis revealed that inflammation accounted for 26% of the mortality risk associated with insufficient MVPA, 14% with rhythm irregularity, and 8% with low amplitude only in men. These findings position rest-activity rhythms as digital biomarkers linking daily rhythmicity to inflammation and survival and identify inflammation as a modifiable target for personalized interventions to foster healthy aging.

Skin aging has traditionally been attributed to alterations in the epidermis and dermis, including keratinocyte senescence, extracellular matrix (ECM) degradation, and fibroblast dysfunction. In contrast, the role of skin-associated adipose tissue (SAAT), particularly dermal white adipose tissue (dWAT), has been largely overlooked and considered a passive structural filler. Emerging evidence indicates that adipocyte aging is not merely a consequence of skin aging but may serve as a critical upstream driver that shapes the local microenvironment. Age-related functional decline of adipocytes, including the senescence-associated secretory phenotype (SASP), metabolic reprogramming, and altered adipokine secretion, can promote dermal ECM deterioration, perturb fibroblast function, and promote chronic low-grade inflammation. Furthermore, regional heterogeneity of dWAT across anatomical sites contributes to the spatial variability of skin aging patterns, influencing both the timing and severity of structural changes. Mechanistically, an adipocyte-immune-fibroblast tri-cellular network integrates signals from senescent adipocytes, immune cells, and fibroblasts, thereby amplifying tissue-level aging phenotypes. Current anti-aging interventions, which largely target epidermal or dermal compartments or focus on restoring tissue volume, often fail to address adipocyte dysfunction and its downstream effects. Here, we propose a conceptual framework in which adipocyte aging functions as an initiating event in skin aging, and we discuss the potential of adipocyte-targeted strategies, including senolytics, senomorphics, and functional reprogramming, to restore skin homeostasis and delay aging. This adipocyte-centered perspective reframes the pathophysiology of skin aging and highlights novel therapeutic opportunities for regenerative dermatology.

Cellular senescence, a hallmark of aging and age-related disorders, is characterized by irreversible cell cycle arrest and profound molecular alterations. Although previous transcriptomic studies have largely focused on protein-coding genes, the expression landscape of circular RNAs (circRNAs) during senescence remains poorly defined. Here, we systematically profiled circRNA expression across multiple senescence models using two human fibroblast lines (WI38 and IMR90) subjected to four distinct senescence-inducing stimuli: replicative senescence (RS), oncogene-induced senescence (OIS), doxorubicin-induced senescence (DOX), and ionizing radiation (IR). Through rigorous analysis, we identified 39,187 high-confidence circRNAs, classifying them into stimulus-specific (SS-circRNAs) and general senescence-associated circRNAs (GS-circRNAs). Among them, 24 GS-circRNAs exhibited conserved expression trends across different senescence models, and eight core circRNAs displayed consistent expression changes in both fibroblast lines, suggesting their potential as universal senescence biomarkers. Functional enrichment and co-expression network analyses revealed that SS-circRNAs participated in pathway-specific processes such as ribosome biogenesis, mitochondrial regulation, ubiquitin-mediated signaling, and RNA metabolism. Collectively, our findings provide a comprehensive atlas of circRNA dynamics across diverse senescence programs and identify candidate circRNAs that may serve as novel diagnostic or therapeutic targets for age-related diseases.

To evaluate the functional properties of the Limosilactobacillus fermentum FUA033 in fermenting pomegranate juice (FPJ), in vitro and in vivo experiments were conducted to comprehensively assess its functional potential. UPLC-MS profiling showed an increase in catechin-type compounds and a decrease in astringent phenolics. FPJ significantly prolonged the lifespan of Caenorhabditis elegans without inducing avoidance behavior. In mice, FPJ supplementation increased grip strength from 109 ± 3.35 gf to 123.7 ± 2.66 gf, improved endurance performance, enhanced glycogen storage, and increased overall antioxidant capacity. Moreover, 16S rRNA sequencing showed that FPJ reduced the firmicutes/bacteroidetes ratio and enriched beneficial genera. Correlation analysis linked these microbial changes to stronger antioxidant defenses, enhanced energy metabolism, and lower levels of fatigue-related biomarkers, suggesting a gut microbiota-mediated mechanism. Overall, pomegranate juice fermented by L. fermentum FUA033 is a promising functional beverage that may support metabolic health through the combined effects of bioactive compound enrichment and gut microbiota modulation.

Hypoxia is a physiologically relevant microenvironment in both normal and diseased tissues and has emerged as a potent modulator of cellular senescence and organismal longevity. This review synthesizes evidence that hypoxia delays senescence across diverse experimental systems and species, and highlights mechanisms by which hypoxia rewires chromatin states during senescence-associated transitions. We focus on oxygen- and α-ketoglutarate-dependent epigenetic regulators, particularly histone lysine demethylases, whose catalytic activities are limited under hypoxia. Consequently, histone methylation increases and higher-order chromatin organization is stabilized. Using oncogene-induced senescence as an experimentally tractable framework, we discuss recent findings showing that hypoxia suppresses senescence-associated histone clipping, preserves nuclear lamina integrity, and restrains large-scale heterochromatin reorganization while leaving canonical cell-cycle arrest largely intact. We further consider emerging links among DNA damage, epigenetic instability, and aging phenotypes, and propose that senescence can be viewed as a breakdown of coordinated epigenetic homeostasis. By integrating these concepts, we position hypoxia and hypoxia-mimetic interventions as promising strategies to modulate aging-associated cellular states and to explore therapeutic opportunities in age-related pathologies.

Experimental evolution studies with Drosophila melanogaster have long played a role in the effort to dissect the genetic basis of aging and longevity. While selection for postponed reproduction reliably extends lifespan, additional phenotypic consequences and the genomic bases of this adaptation remain unclear. Here, we leveraged the highly replicated Drosophila Experimental Evolution Population (DEEP) system to further investigate the relationship between longevity and other life-history traits. Derived from the same wild population, two tenfold-replicated treatments, each with populations derived from two different ancestral backgrounds: a control treatment in a 14-day generation cycle was maintained for 56 generations, and an experimental treatment in a 70-day cycle maintained for 20 generations. Experimental populations evolved to have longer lifespan, delayed development time, increased fecundity, greater stress resistance, and stronger immune defense. Pooled-population genomic data reveal highly convergent allele frequency shifts within treatments, and point to 300 candidate genes underlying differentiated phenotypes. Candidate genes are enriched for functional categories involving neural development and morphogenesis rather than canonical aging or immune defense pathways. These results recapitulate that selection for postponed reproduction drives broad physiological changes and a highly polygenic adaptive response, with an unprecedented level of experimental replication.

Mammalian ageing is defined as a gradual loss of the capacity to maintain tissue homeostasis or to repair tissues after injury or stress. Cellular senescence is induced by various cellular stressors, and there is accumulation of senescent cells in all tissues with ageing and chronic disease, which contributes to pathophysiology and organ deterioration. Long-term persistence of senescent cells and their senescence-associated secretory phenotype (SASP) impairs tissue homeostasis and regenerative capacity, leading to tissue and physiological dysfunction. Senolytics are senotherapeutic agents that systemically eliminate senescent cells, and have been shown in pre-clinical and clinical studies to improve cardiac and skeletal muscle regeneration, remodelling and physiological function. Exercise training and physical activity have also been shown to have senolytic effects. In this review, we evaluate whether targeting cell senescence using senolytics can rejuvenate the heart and skeletal muscle, reversing the ageing phenotype.

Replicative senescence in endothelial cells is characterized by an irreversible cell cycle arrest and impaired endothelial function, contributing to vascular aging and cardiovascular disease. Natural compounds are being actively studied for their potential to delay cellular senescence and protect vascular health. Among them, rice bran has demonstrated several vascular benefits that are mainly attributed to gamma-oryzanol (γ-Orz), a major bioactive component in rice bran. However, its role in regulating endothelial replicative senescence and the underlying molecular mechanisms remain unclear. This study aimed to explore the protective effects of rice bran extract (RBE) and γ-Orz on replicative senescence in porcine coronary artery endothelial cells (PCAECs). Replicative senescence was modeled in PCAECs by serial passaging from P1 to P3 with varying concentrations of RBE and γ-Orz. Senescence was evaluated by measuring senescence-associated β-galactosidase (SA-β-gal) activity, cell proliferation, oxidative stress, and the expression of cell cycle regulatory proteins. RBE and γ-Orz significantly reduced SA-β-gal activity, improved proliferation, and decreased oxidative stress in P3 cells, along with downregulation of senescence-related proteins p53, p21, and p16. Additionally, γ-Orz suppressed sodium-glucose co-transporter 2 expression, reduced NADPH oxidase overexpression, and restored eNOS levels. These findings indicate that RBE and γ-Orz delay endothelial senescence by alleviating oxidative stress, highlighting their potential to reduce cardiovascular disease risk associated with endothelial senescence.

Background: Intrinsic capacity (IC) is a key marker of healthy ageing, which captures an individuals physical and mental capacities, measured across five domains: cognitive, locomotor, psychological, vitality, and sensory. Although genetic factors are known to influence both general IC and its individual domains, existing IC indices have been developed primarily using phenotypic data, without accounting for the underlying biological architecture across domains. In this study, we developed a multi-trait polygenic score (Mt-PGS) model for IC by integrating polygenic scores derived from a broad set of phenotypes spanning the five IC domains and examined its validity. Methods: Using data from 13,085 participants of the Canadian Longitudinal Study on Aging (CLSA), we computed PGSs for 63 phenotypes related to IC domains. A supervised machine-learning model was applied to develop a mt-PGS model for IC and identify the optimal set of polygenic predictors. The validity of the mt-PGS IC score was evaluated by comparing it with a phenotype-based IC score and by examining its association with mortality. Results: Our analysis identified PGSs for 33 phenotypes with non-zero coefficients, jointly explaining 2.23% of the variance in IC. Several of the strongest contributors were most closely aligned with vitality-related phenotypes in the literature (including body mass index, grip strength, fat-free mass, diastolic blood pressure, and chronic obstructive pulmonary disease), acknowledging cross-domain relevance, and that predictors from all five IC domains were represented. The mt-PGS IC score was consistent with the phenotype-based IC score, positively correlated with the phenotype-based IC score and was inversely associated with mortality (OR = 0.04; 95% CI: 0.005 - 0.379). Conclusion: Our findings support the multisystem biological basis of IC, demonstrating that an mt-PGS model integrating diverse phenotypes is associated with the phenotype-based IC score. PGSs for the phenotypes frequently related to vitality in the literature were the strongest predictors, recognizing that several of these phenotypes may span multiple domains, and that all domains contributed to the model. If replicated across different ancestries and settings, these findings may serve as a foundation for future research for the potential integration of genetic information into IC frameworks. Keywords: Intrinsic capacity, Polygenic scores, CLSA, Machine learning, Healthy ageing

Bats have attracted considerable recent interest for their extraordinary longevity and ability to withstand infection by a range of pathogens without major harm. However, few studies have examined immune responses as a function of age, sex, or social status. We investigated sources of individual immune variation by comparing whole blood transcriptomes of wild greater spear-nosed bats, Phyllostomus hastatus, before and after ex vivo exposure to lipopolysaccharide, a membrane component of gram-negative bacteria. This species exhibits an extreme harem-polygynous mating system, which has pervasive consequences on life history traits, including male-biased mortality. We observe clear differences in immune responses, with males and older bats each mounting stronger inflammatory responses. Males also show steeper patterns of age-related variation in immune profiles, suggesting their earlier mortality is associated with accelerated immunosenescence. We did not detect largescale differences in immune responses between males of different social status, suggesting that, unlike in many primates, immune variation is not strongly influenced by social adversity. Our findings support recent calls for a more nuanced approach to understanding immune adaptations in bats that considers the diverse ways in which species and individuals differ in ecology, resource allocation, and selection.

Exercise training has attracted increasing attention as a non-pharmacological intervention approach to counteract age-related deterioration of brain and muscle function, yet objective biomarkers are needed to understand mechanisms and optimize interventions. Magnetic resonance spectroscopy (MRS) provides non-invasive, in vivo assessment of metabolic profiles altered by aging and exercise. However, MRS-based exercise research in older populations remains limited. This scoping review aims to identify brain and muscle metabolites detectable by MRS that can serve as markers of exercise training effects in aging.

The flowers of Rosa chinensis cv. 'JinBian' (RCF) has been utilized as a herbal tea for millennia to prevent aging-related diseases. RCF is enriched in flavonoids and exhibits significant antioxidant effects for anti-aging potential. However, the specific bioactive compounds and their underlying anti-aging mechanisms remain unclear.

Quantifying biological aging is crucial for understanding functional decline before the onset of morbidity. While many accelerated aging and frailty measures based on clinical data exist for humans and several for rodent models of aging, there are few options for non-human primates (NHPs). NHP clinical data has several unique features including a lack of clinically delineated normative values for features and variability in data collection over long lifespans. There are also wide discrepancies in the number of available clinical measures and number of animals across data sets. To address these challenges, we developed and validated "Aging Resilience" (AR) metrics using longitudinal, routine clinical data from two distinct non-human primate cohorts: 4,328 baboons and 281 rhesus macaques. We trained five computational models, including Linear Mixed-Effects Models, Random Forest, and Recurrent Neural Networks (RNN), to predict chronological age, subsequently deriving AR metrics that represent the velocity (Rate of Aging) and cumulative burden (Normalized Cumulative Aging) of physiological deviation. While linear models achieved high precision in predicting chronological age (test R2 up to 0.99), they correlated poorly with actual lifespan. In contrast, AR metrics derived from non-linear models (RNN and Random Forest) displayed strong predictive validity for mortality (Pearson's r > 0.8). These findings highlight a critical paradox: models that best predict chronological age do not necessarily capture the biological resilience determining healthspan. This study establishes a scalable framework for monitoring biological aging in translational models using standard veterinary records.

Aging proceeds heterogeneously across organs, making chronological age an inadequate measure of physiological decline. The concept of organ biological age (OBA) offers a refined framework to quantify organ-specific functional deterioration. However, current OBA assessments - based on epigenetic, transcriptomic, metabolomic, or imaging data-largely capture the outcomes rather than the onset of aging. Their limited sensitivity to nanoscale and microenvironmental alterations, low temporal resolution, and reliance on invasive sampling constrain clinical translation. This review examines the molecular and systemic mechanisms driving organ-specific aging and evaluates existing multi-omics and imaging approaches. We highlight quantum sensing technologies as a transformative solution. Leveraging quantum coherence and spin-based detection, quantum sensors enable non-invasive, real-time detection of weak magnetic, electric, and vibrational signals, providing unprecedented access to early and subtle changes within organ microenvironments. Integrated with artificial intelligence (AI), these sensors could support continuous, high-frequency tracking of organ aging trajectories and dynamically quantify the pace of aging. By bridging molecular energetics with organ physiology, quantum-enabled OBA assessment represents a new paradigm for precision aging medicine, shifting aging research from static observation to proactive and individualized health management. This process stands as the foremost risk factor for major human pathologies, including neurodegenerative disorders, cardiovascular diseases, and cancer, imposing unprecedented challenges on global healthcare systems.

Solid-organ transplantation in aging recipients represents a unique opportunity to study how age-related immunity in the context of non-specific immunosuppression strategies balances infection, malignancy, and rejection. We sought to characterize the association between increasing recipient age at heart transplantation with acute allograft rejection and age-related cell-specific transcriptomic changes in circulating immune cells. This single-center retrospective cohort study evaluated individuals undergoing heart transplantation between July 2013 and December 2023 at Vanderbilt University Medical Center. Eligible participants were aged [≥]18 years. A subset of individuals underwent single-cell RNA-sequencing of circulating immune cells. The primary exposure was recipient age at the time of heart transplantation. The main outcome of the clinical-epidemiological portion of this study was acute rejection, inclusive of clinically relevant acute cellular or antibody-mediated rejection, within one-year post-transplant. Secondary outcomes included cell-specific compositional and transcriptomic changes with aging in circulating immune cells. Among 799 adults, each one standard deviation increase in recipient age was associated with a ~17% lower odds of allograft rejection (adjusted OR 0.83, 95% CI 0.71-0.98). In 40 individuals who underwent single-cell RNA-sequencing of circulating immune cells, increasing recipient age was associated with increases in CD4+ and CD8+ memory T cell subsets, monocytes, and NK cells. Furthermore, genes upregulated with increasing recipient age were associated with enrichment for pathways involved in immunosenescence and chronic low-grade inflammation while downregulated genes suggested decreased protein synthesis. These findings have clinical implications for an aging transplant population and support a more personalized approach to immunosuppression.

Age-related chromatin remodeling includes shared and specific signatures across cell types, sex, and organs.

Cardiomyocyte senescence contributes to cardiac fibrosis, yet the molecular mechanisms remain unclear. Farnesylation is a post-translational modification critical for cholesterol metabolism and is mediated by the farnesyltransferase beta subunit (FNTB). However, its specific role in cardiomyocyte senescence and cardiac fibrosis remains unclear. Cardiomyocyte-specific Fntb knockout mice were generated to assess cardiac remodeling. RNA sequencing, DNA damage assays, and senescence markers identified molecular pathways. Mechanistic studies included nuclear envelope ultrastructure analysis, laminA assessments. Clinical relevance was assessed via human heart samples from hyperlipidemic patients. In cardiomyocyte-specific Fntb knockout mice, deletion of FNTB induced progressive cardiac fibrosis that preceded hypertrophy development. Pressure overload exacerbated dysfunction in knockouts, revealing fibrosis-dependent vulnerability. Mechanistically, loss of FNTB impaired laminA maturation, destabilized nuclear envelope integrity, and triggered DNA damage response activation, resulting in cardiomyocyte senescence. Senescent cardiomyocytes secreted elevated Tgf-β2 and Gdf15, driving cardiac fibroblast activation. Upstream regulation studies revealed that lipid overload suppressed Fntb transcription via Srebf2 downregulation, recapitulated in hyperlipidemic human hearts showing reduced FNTB expression. Notably, AAV9-mediated Fntb overexpression attenuated cardiac fibrosis in mice fed a high-fat diet. Collectively, our results demonstra that lipid overload suppresses FNTB expression in cardiomyocytes. This deficiency compromises nuclear integrity, triggering a senescence program and driving cardiac fibrosis. These findings uncover a novel mechanism of lipotoxic cardiomyopathy and suggest that farnesylation warrants further investigation as a potential target to fibrotic remodeling in metabolic heart diseases.

Ageing is a significant risk factor for pathophysiological alterations in the heart, but the intrinsic mechanisms by which these occur have yet to be fully elucidated. Purinergic 2×7 receptor (P2X7R) is important for the pathogenesis of numerous cardiovascular diseases; nevertheless, its function in the process of cardiac ageing remains uncertain.

Despite advances in antihypertensive therapies, uncontrolled hypertension remains a major global health challenge, particularly among older adults. Ferroptosis, an iron-dependent programmed cell death, has been implicated in age-related vascular dysfunction, but its regulatory mechanisms in hypertension are unclear. This study investigates Sestrin2, a highly conserved stress-induced protein linked to cellular senescence, in regulating ferroptosis in hypertension.

Background Older age is widely considered a risk factor for post-acute sequelae of SARS-CoV-2 infection (PASC), typically attributed to immunosenescence and inflammaging. However, whether this association reflects intrinsic biological ageing or accumulated comorbidity burden remains unclear, with implications for clinical risk stratification. Methods We conducted a retrospective cohort study using the Precision PASC Research Cohort (P2RC) from Mass General Brigham, comprising 133,792 COVID-19 patients from 12 hospitals and 20 community health centres in Massachusetts (March 2020-May 2024). PASC was ascertained using a validated computational phenotyping algorithm. We used generalised estimating equations with cluster-robust variance to model PASC risk, causal mediation analysis to decompose age effects through comorbidity burden and acute severity, and specification curve analysis across 768 analytical specifications to assess robustness. Findings After adjustment for comorbidity burden, each decade of age was associated with 6% lower odds of PASC (OR 0.94; 95% CI 0.93-0.95). Causal mediation analysis revealed that comorbidities accounted for 145% of the total age effect, indicating inconsistent mediation wherein age's direct protective effect was masked by its indirect harm through chronic disease accumulation. This protection was age-dependent: adults younger than 65 years retained robust resilience independent of comorbidities (ADE: -0.0042, p<0.001), whereas adults 65 years and older showed complete loss of this protection (ADE: +0.0020, p=0.14). Interpretation Long COVID susceptibility is driven by physiological reserve rather than chronological age until approximately age 65, beyond which age-related protective mechanisms become exhausted. Risk stratification should prioritise comorbidity burden over birth year in younger adults.

One common side effect of radiotherapy is radiation-induced skin senescence. The current study is designed to explore the possible geroprotective effect of Apigenin (Api) against skin senescence induced by an acute dose of gamma rays in male rats. Thirty-two adult male rats were assigned into four groups: Control, γ-Radiation (6 Gy), Apigenin (50 mg/kg, orally), and Rad (6 Gy) + Api (50 mg/kg) for two weeks. Exposure to an acute dose of gamma radiation caused a significant increase in the levels of MDA and a significant decrease in GSH levels in comparison to control rats. Exposure to gamma radiation significantly increased skin collagen-1, p16

Sarcopenia, characterized by the progressive age-related decline in skeletal muscle mass, strength, and function, represents a major unmet need in geriatric health. Effective and safe interventions to prevent or ameliorate muscle atrophy are urgently required.

Many risk factors for frailty have been reported, but their relative population-level contributions are not well quantified. This study quantified the population-level impact of modifiable risk factors on incident frailty among older adults using population-attributable fractions.

Membrane lipid composition influences endocytic remodeling of nutrient transporters, yet how lipid metabolism is spatially coordinated to support sustained adaptation to nutrient limitations remains unclear. Here, we investigated whether the ER-vacuole tether Mdm1 links sphingolipid homeostasis to regulation of the high-affinity methionine permease Mup1 in budding yeast. To test this, we examined Mup1 trafficking, amino acid homeostasis, and sphingolipid composition in mdm1{Delta} cells during starvation. We found that loss of Mdm1 causes persistent retention of Mup1 at the plasma membrane, accompanied by reduced intracellular methionine and broad amino acid depletion. Lipidomic analyses revealed decreased sphingoid bases and altered ceramide composition in mdm1{Delta} cells. Importantly, supplementation with the sphingolipid precursor phytosphingosine restored sphingolipid pools, rescued Mup1 endocytosis, and improved amino acid homeostasis. Consistent with a chronic amino acid restriction-like state, mdm1{Delta} cells exhibited extended chronological lifespan. Together, these findings identify Mdm1 as a spatial organizer of sphingolipid metabolism required for adaptive endocytic remodeling of Mup1, thereby linking ER-vacuole contact site function to plasma membrane proteostasis and metabolic adaptation.

Diet is an essential factor influencing biological aging, yet few exsiting dietary indices were specifically developed to target biological aging. We developed a data-driven food-based Empirical Dietary Index for Slower Epigenetic Aging (EDISEA) in the US Health and Retirement Study (HRS, n=7,398), which predicted deceleration of GrimAge, an established DNA methylation-based epigenetic clock. Participants in the highest versus lowest EDISEA quintile had 4.65-year deceleration in GrimAge (P value <0.001). We externally validated EDISEA in an independent US cohort (n=23,830), where it showed consistent associations with several epigenetic clocks and lower all-cause mortality risk. In HRS and a UK aging cohort (n=4,895), EDISEA was associated with lower risks of several aging-related diseases and functional limitations. Outcome-wide analyses in the UK Biobank (n=187,035), together with integrative proteomic, metabolic, and neuroimaging assessments, revealed biological signatures of EDISEA implicating broad vascular, inflammatory, metabolic, and brain-structural pathways through which EDISEA was associated with biological aging. EDISEA provides a scalable, biologically anchored tool to inform the development of precision nutrition strategies aimed at slowing epigenetic aging and mitigating aging-related disease burden.

Macrophage senescence drives inflammaging, a chronic, age-related inflammation. To date, the protective mechanisms against inflammaging are poorly defined. Here, we identify DNA-PK-mediated phosphorylation of murine STAT6 at serine 807 (Ser807) as a crucial post-translational modification for preventing macrophage senescence. Ser807 phosphorylation blocks STAT6 ubiquitination-mediated degradation and promotes STAT6 partnering with PU.1 to activate DNA repair genes. Macrophages lacking Ser807 phosphorylation exhibit DNA repair defects, undergo senescence, and fuel inflammaging. In vivo, the phosphor-null STAT6 mutant (STAT6(S807A)) accelerates macrophage senescence, tissue fibrosis, and systemic aging. Adoptive transfer of phosphomimetic STAT6(S807E)-expressing macrophages rescues accelerated aging. Importantly, phosphorylation of human STAT6 at the homologous residue (Ser817) is significantly reduced in the lungs of patients with chronic obstructive pulmonary disease (COPD), correlating with increased DNA damage and senescence. Thus, our findings reveal a DNA-PK-STAT6 axis enacting a non-canonical type 2 immunity via DNA repair to prevent macrophage senescence, presenting a therapeutic target for healthy aging.

Biological aging reflects complex cellular and biochemical processes that can be measured across multiple omic layers. Using routine clinical laboratory data from ~31,000 participants in the Mass General Brigham Biobank, we developed EMRAge, a biomarker of mortality risk that can be broadly recapitulated across electronic medical records. Here we show that EMRAge can be modeled using elastic net regression with DNA methylation and multi-omics to generate DNAmEMRAge and OMICmAge, respectively. Both biomarkers are strongly associated with incident and prevalent chronic diseases and mortality, performing comparably or better than current biomarkers across discovery (Massachusetts General Brigham Aging Biobank Cohort, n = 3,451) and validation cohorts (TruDiagnostic, n = 14,213; Generation Scotland, n = 18,672). Importantly, OMICmAge leverages epigenetic biomarker proxies to integrate proteomic, metabolomic and clinical domains while remaining quantifiable from DNA methylation alone. This framework establishes an accessible, scalable measure of biological aging with potential to reveal molecular interconnections that shape healthspan and disease risk.

Autophagy is an intracellular degradation process that maintains homeostasis, responds to stress, and plays key roles in preventing aging and disease. Autophagosome biogenesis, vesicle rocketing, and autolysosome tubulation are controlled by multiple actin cytoskeletal factors, but the impact of actin assembly on completion of the autophagic degradation pathway is not well understood. Here we studied autophagosomes and lysosomes in mouse fibroblasts harboring an inducible knockout (iKO) of the Arp2/3 complex, an essential actin nucleator. Arp2/3 complex ablation resulted in increased basal levels of autophagy receptors and lipidated membrane proteins from the LC3 and GABARAP families. Such phenotypes were accompanied by the steady-state presence of abnormally high numbers of autolysosomes and an inability of the Arp2/3 complex-deficient cells to complete autolysosome turnover due to lysosomal damage. When normal cells were treated with a lysosomal membrane-disrupting agent, the Arp2/3-activating protein WHAMM was recruited to lysosomes, and Arp2/3 complex activity was required for restoring intact lysosomal structure. Deletion of WHAMM in mouse or human fibroblasts decreased Arp2/3 localization to lysosomes and increased lysosomal damage. These results reveal the importance of the Arp2/3 complex and WHAMM for autophagic degradation and uncover a new role for the actin nucleation machinery in maintaining lysosomal integrity.

Exercise, a well-recognized non-pharmacological anti-aging strategy, is key for human health. Growing evidence points to exhaustive or strenuous exercise, especially when recovery is inadequate, may trigger oxidative damage and accelerate aging. This study aims to systematically the effects of exhaustive and/or strenuous exercise on aging-related molecular and physiological biomarkers using a systematic review and meta-analysis. A systematic literature search was conducted across PubMed, EBSCOhost, Cochrane, and Web of Science through August 2025 and was updated in November 2025. A three-level random-effects model was applied to pool effect sizes, and subgroup analyses along with meta-regression were conducted to investigate potential moderators and dose-response relationships. A total of 31 studies were included. Exhaustive and/or strenuous exercise significantly shortened telomere length (g =  - 0.44, 95% CI - 0.83 to - 0.03, p = 0.037), increased 8-OHdG levels (g = 0.97, 95% CI 0.03 to 0.80, p = 0.036), upregulated IL-6 (g = 0.97, 95% CI 0.04 to 1.91, p = 0.042), and reduced VO₂max (g =  - 0.23, 95% CI - 0.44 to - 0.01, p = 0.038), while HRV showed no significant change. Increases in IL-6 were more pronounced in males, individuals with developing level, and following acute long-distance endurance exercise. IL-6 exhibited a linear positive relationship with exercise dose, with the meta-regression suggesting a model-derived inflection point around ~ 4000 MET-min/week, beyond which IL-6 responses appeared to increase more steeply under exhaustive/strenuous conditions. Exhaustive and/or strenuous exercise is associated with adverse shifts in aging-related molecular and physiological biomarkers, and these effects appear dose-dependent. Future studies ought to focus on the identification of dose thresholds and clarification of regulatory factors, thereby facilitating the development of more precise, evidence-informed exercise dose frameworks in the context of aging.

Pulse wave velocity (PWV) is a marker of vascular aging and cardiovascular risk. Obstructive sleep apnea (OSA) may accelerate vascular decline, but evidence from single-night assessments is inconsistent. We examined associations of multi-night OSA severity, night-to-night variability, and snoring with arterial stiffness in a real-world setting. Adults used two in-home digital devices over a ~ 4 y period: an under-mattress sleep sensor to quantify nightly OSA severity and snoring, and a smart scale to measure aortic-leg PWV. Among 29,653 participants from 20 countries (52 ± 12 years; 84% male; BMI 27.3 ± 4.9 kg/m

Accelerated biological aging, as well as cardiovascular, kidney, and metabolic (CKM) diseases, contribute to shortened healthspan. We studied a deep-learning model, retinal BioAge, and multiple indicators of CKM syndrome in participants from UK Biobank and the US-based EyePACS dataset. Retinal BioAge was trained on 77,887 retinal images and then used to analyze separate retinal images from UK Biobank (10,976) and EyePACS (19,856). In both datasets, CKM biomarker profiles were significantly worse for the top vs. bottom quartiles of BioAgeGap (retinal BioAge-chronological age), including measures of blood pressure, kidney function, adiposity, and glycemia. The top BioAgeGap quartile also had a significantly higher prevalence of clinical CKM indicators, including hypertension, kidney disease, and diabetes (UK Biobank) or suboptimally controlled diabetes (EyePACS). Thus, analysis of retinal images for accelerated biological aging may provide opportunistic screening to help identify individuals who could benefit from formal CKM assessment, potentially contributing to earlier detection and management of CKM syndrome.

Neuroplasticity, the brain's capacity to adapt and reorganize in response to experiences and environmental changes, is fundamental to cognitive aging. As individuals age, cognitive functions such as memory, processing speed, and executive function commonly decline, driven largely by changes in neuroplasticity mechanisms like synaptic plasticity, neurogenesis, and functional reorganization. Synaptic plasticity is a well-established mechanism supporting learning and memory across the lifespan, whereas adult neurogenesis, robustly demonstrated in rodents, remains highly limited and controversial in the adult and aged human brain, with evidence largely restricted to rare post-mortem observations and injury-associated conditions. Functional reorganization allows the brain to adapt to structural changes, helping to preserve cognitive function despite age-related decline. Several factors, including oxidative stress, neuroinflammation, and hormonal shifts, exacerbate the decline in neuroplasticity, accelerating cognitive deterioration. Various interventions, including cognitive training, physical exercise, and pharmacological approaches, have demonstrated the potential to promote neuroplasticity and support cognitive health in aging populations. However, one of the major challenges is tailoring these interventions to the unique needs of individuals, as well as identifying novel therapeutic targets for intervention. To effectively address the cognitive decline associated with aging, future research should focus on developing personalized strategies and innovative techniques to enhance or modulate specific neuroplasticity-related processes under defined conditions in the aging brain. These advancements may provide better tools for delaying, mitigating, or even reversing age-related cognitive decline, improving quality of life for older individuals.

Transposable elements (TEs) in the human genome are the heritage of ancient parasitic infections. While most of human DNA comprises TEs and TE-derived elements, their repetitive nature poses technical challenges; thus, little is known about their positional identity and regulatory roles. Here, by integrating long-read and multidimensional transcriptional analyses, we investigate when, where and how TEs become part of a gene. We characterize how TE-derived isoforms change across mouse-human variation and how they are linked to gene regulatory networks controlling cell states during differentiation, organogenesis and health (aging and pathological states). Mechanistically, we identify an RNA degradation-dependent and splicing-dependent quality control mechanism that operates independently of conventional mechanisms of TE suppression, such as DNA methylation and heterochromatinization, and prevents TE-chimera expression and TE-induced cell differentiation. Overall, our findings unveil mechanisms by which viral-derived elements enhance transcriptome plasticity.

Peripheral nerve injury (PNI) significantly impairs patients' quality of life, with elderly individuals experiencing particularly severe consequences due to aging-related declines in neuronal injury response and repair capabilities. Processes of the generation and transmission of injury signals, axonal disruption, initiation of regeneration, and the elongation of regenerating axons, as well as the subsequent reinnervation by these axons, are all significantly influenced by aging. These alterations are closely associated with changes in mitochondrial function, neuronal transport systems, a persistent inflammatory milieu, and various microenvironmental non-neuronal cells. Therefore, this review synthesized the pivotal role of aging in the multifaceted regulation of the nervous system following PNI and highlighted promising molecular regulatory mechanisms in the signaling pathways. Furthermore, it identified critical areas for future research, including unresolved questions in age-associated injury responses, potential targets for pharmacological intervention, and emerging therapeutic strategies meriting consideration for research and development.

Ultraviolet (UV)-induced reactive oxygen species (ROS) production, DNA damage, and chronic inflammation lead to skin aging and cancers. Ginkgetin (GK), a biflavonoid derived from Ginkgo biloba, has known anti-inflammatory and antioxidant activities, but its anti-photoaging effect remains unclear.

Birthweight readily measurable marker of fetal growth that may influence health across the lifespan. We aimed to investigate the potential causal association between birthweight and healthy aging and to identify the mediating roles of subsequent socioeconomic, behavioral, functional, and disease-related factors to inform life-course strategies to promote healthy aging and reduce health inequities.

Ionizing radiation (IR) can induce long-term alterations in the hematopoietic and immune systems. This study aimed to investigate the potential of luteolin (with known anti-inflammatory and anti-senescence properties), a natural flavonoid, to mitigate radiation-induced hematopoietic and immune system long-term damage in a mouse model.

Lower urinary tract dysfunction (LUTD) increases with age and disproportionately affects women, yet the molecular mechanisms underlying this sex bias remain poorly defined. The aging bladder plays a central role in this decline, and our previous work identified increased cellular senescence, oxidative stress, and activation of the PERK arm of the unfolded protein response (UPR) as key features of bladder aging. In this study, conducted as part of the NIH Common Fund SenNet program to investigate cellular senescence in mice, we explored the therapeutic potential of a senolytic drug combination of Dasatinib and Quercetin (D&Q) in male and female aged (25-month-old) bladders from genetically diverse Diversity Outbred mice. We first assessed sex differences in aged bladders (>20 months of age), then evaluated whether D&Q treatment could improve bladder health by modulating ER stress. We identified significant baseline sex differences in UPR and ER-associated degradation (ERAD) proteins, with higher expression of PERK pathway ER stress components in females and more efficient ERAD and autophagy flux in males. While D&Q did not broadly alter ER stress or autophagy markers, it selectively increased ERAD markers in females. D&Q also enhanced uroplakin expression and urothelial thickness in aged females, suggesting potential benefit to urothelial integrity. These findings suggest a potential sex-specific regulatory mechanism within the UPR pathway that may contribute to the increased vulnerability of aged females to bladder dysfunction.

Stem cells maintain tissue integrity through a balance of self-renewal, differentiation, and loss of function due to aging or stress. Recent studies demonstrate that the stem cell hierarchy is not fixed. Transit-amplifying or terminally differentiated cells can dedifferentiate back into stem-like states. Such plasticity supports regeneration but, when combined with damage accumulation, may also accelerate aging and increase cancer risk. Motivated by these findings, we develop a damage-structured PDE model of a two-compartment lineage consisting of stem and terminally differentiated cells. The model incorporates dedifferentiation, together with a nonlocal δ-function kernel partitioning scheme that conserves total damage and encodes biologically motivated asymmetries. Methodologically, we emphasize reproducibility and robustness on three fronts. First, the δ-kernel partitioning prevents the unbounded drift that arises in local models while preserving conservation. Second, a conservative finite-volume discretization with upwind fluxes and verified first-order accuracy ensures stability and exact mass balance, as confirmed by manufactured-solution tests. Third, distributional metrics and systematic parameter sweeps provide reproducible ways to quantify lineage-level damage dynamics under varying dedifferentiation and repair conditions. These analyses show that threshold-dependent and repair-modulated dedifferentiation both act as protective mechanisms: the former functions as a 'detoxification loop' that recycles high-damage cells, and the latter reduces the damage burden imported during dedifferentiation. Together, they mitigate aging-inducing effects. Parameter sweeps further delineate when dedifferentiation stabilizes tissue maintenance versus when it drives aging-like dynamics. Overall, our reproducible framework integrates biological insights on stem-cell plasticity and damage segregation with rigorous mathematical modeling, providing a foundation for experimental validation and therapeutic strategies targeting stem-cell aging and cancer initiation.

Aging is accompanied by a progressive decline in protein synthesis and ribosome abundance, yet paradoxically, genetic or pharmacological attenuation of translation extends lifespan across species. Whether the age-associated decline in translation is adaptive or reflects a pathological failure of ribosome homeostasis remains unclear. Here, we show that shortened lifespan is driven by dysregulated ribosome biogenesis (RiBi) and impaired ribosome assembly. Using Caenorhabditis elegans ncl-1 loss-of-function mutants as a model of accelerated aging, we find that nucleolar enlargement coincides with decoupling of precursor and mature rRNA, ribosomal protein (RP) transcripts, and protein abundance, loss of RP stoichiometry, defective ribosomal subunit joining, and compromised proteostasis. Strikingly, lifespan can be restored downstream of the nucleolus by targeting either the RNAse P/MRP complex or the mitochondrial ribosome. These interventions rebalance mature rRNA and RP abundance, improve ribosomal assembly, and reduce protein aggregation despite persistent nucleolar enlargement and elevated pre-rRNA levels. Our findings identify accelerated age-associated ribosome dysfunction as a qualitative failure of ribosomal biogenesis, and demonstrate that restoring ribosomal homeostasis is sufficient to improve proteostasis and extend lifespan.

Aging is associated with decreased bone formation and bone mass and increased fracture risk. Wnt pathway activation by mechanical loading is a potent strategy to improve bone mass, however, load-induced bone formation is diminished with aging. Neutralizing antibody (Ab) therapies targeting Wnt pathway inhibitors Sclerostin (Scl) and Dickkopf-related protein 1 (Dkk1) have proven successful in preclinical and clinical osteoporotic conditions. We asked whether treatment combining Scl-Ab and Dkk1-Ab can increase load-induced bone formation in a preclinical model of osteoporosis. Aged (22-month) C57BL/6N female mice underwent combination Scl-Ab plus Dkk1-Ab therapy (15 mg/kg each; subcutaneously; 2x/wk; saline control) for 2 weeks, concomitant with a mechanical loading regimen previously shown to induce modest bone formation in tibias of aged mice (-2200 microstrain, 1200 cycles/day, 5 day/wk). Changes in bone morphology and formation were assessed by longitudinal microCT and dynamic histomorphometry, respectively. Molecular indices of bone formation and Wnt pathway activation were assessed by qPCR of cortical bone. Treatment with Scl-Ab plus Dkk1-Ab induced significant improvements in cancellous (BV/TV +50%) and cortical morphology (Ct.Th +25%) in non-loaded limbs of antibody-treated mice vs. vehicle control mice. Importantly, periosteal bone formation rate was 10-fold higher in loaded limbs of antibody versus vehicle treated mice, indicating a synergistic effect. Gene expression analysis showed that antibody treatment and loading synergistically upregulated Wnt1 expression, which may have contributed to the observed synergistic effect on bone formation. These results confirm the potent anabolic effect of combination Scl plus Dkk1 antibody treatment. Moreover, they show that antibody treatment and skeletal loading are more effective at increasing periosteal bone formation in aged mice than either treatment alone. These findings support the concept that combinatorial therapy using dual Scl and Dkk1 antibodies plus weight-bearing exercise may be an effective treatment for age-related osteoporosis.

Corylin is a natural flavonoid isolated from the seeds of Psoralea corylifolia L., a traditional medicinal herb historically used to treat bone-related disorders such as osteoporosis. However, its role in organismal aging and the underlying molecular mechanisms remain largely unexplored.

ABSTRACT Background: Caloric restriction (CR) improves markers of biological aging, yet long-term effects on the human metabolome remain unclear. Objective: This study examined the effects of CR (2 years) in healthy adults without obesity on circulating metabolites linked to aging and metabolic adaptations. Methods: Untargeted metabolomics was performed using fasted plasma samples collected at baseline, 12, and 24 months (BL, 12M, 24M) from CALERIE participants randomized to CR or ad libitum (AL) control. A total of 864 known metabolites were identified and grouped into nine biologically coherent super pathways to support pathway level interpretation (amino acid, peptide, carbohydrate, energy, lipid, nucleotide, cofactors and vitamins, xenobiotics, and partially characterized molecules). Principal component analysis (PCA) summarized metabolite variation, and linear mixed models assessed intervention effects on each PC in group-by-time interactions. Results: Three principal components showed significant group by time interactions: PC2 (carbohydrate), PC5 (partially characterized molecules), and PC4 (lipid). Carbohydrate (PC2) and partially characterized metabolites (PC5) decreased from baseline to 12M in both groups; from 12M to 24M, levels stabilized in CR but increased in AL for PC2, while PC5 continued to decline in CR and increased in AL. Lipid metabolites (PC4) decreased in CR and increased in AL at 12M, with the pattern reversing from 12M to 24M. Key contributors included malto saccharides and related carbohydrate intermediates for PC2, glutamine degradants and lactone sulfates for PC5, and sphingolipids for PC4. Conclusion: This study provided insights into metabolic changes during CR, particularly for carbohydrate and lipid metabolism. Carbohydrate and lipid metabolites that were reduced by CR during the weight loss phase (BL to 12M) followed by stabilization or compensatory responses during the weight maintenance phase (12M to 24M) may link CR-induced changes in metabolism to inflammation. Future research is needed to tease out CR adaptations versus diet related changes in metabolites and explore the functional significance of these metabolic changes during CR for aging and long-term metabolic health. Conclusion: CR produced distinct, time dependent shifts in carbohydrate and lipid pathways. Early reductions during weight loss followed by stabilization or compensatory responses during weight maintenance suggest dynamic metabolic remodeling that may relate to inflammation linked mechanisms. Further work is needed to distinguish CR specific adaptations from dietary influences and to clarify the functional significance of these metabolic changes for aging and long term metabolic health.

Intraperitoneal injection of D-galactose (D-gal i.p.) can accelerate aging has been used to develop models of aging previously, long-term use of D-gal has been used to induce aging in mice. Researchers are trying to determine whether short-term administration of high doses of D-gal i.p. in rats is able to induce significant signs similar to natural aging, namely increased oxidative stress and myostatin.

Despite facing the same task demands, every individual experiences different levels of perceived difficulty. This complicates the interpretation of cognitively induced brain activity due to the confounding of task demands and difficulty. Within the context of aging, differences in brain activity may reflect variations in perceived difficulty or age-related divergence in the recruitment of neural resources. The current work used titrated cognitive demands during a verbal delayed match to sample task within the fMRI. Between-group comparisons of 40 younger and 39 older healthy adults identified brain regions significantly related to behavioral performance. Brain regions were identified using the "Reserve and Resilience Framework," supporting the theories of upregulation or reorganization. The two age groups in this study did not significantly differ in their titrated cognitive capacity scores. Despite all participants performing a task they found equally challenging, moderated-mediation analysis of the fMRI data showed brain activity that differed between the two age groups. Furthermore, the relationships between brain activity and cognitive capacity differed between the age groups. Results supported upregulation, reorganization, and suppression of brain activity related to both increases and decreases in cognitive capacity. Therefore, brain activity increases and decreases appear to be balanced against each other to maintain high cognitive capacity. Furthermore, current findings show a beneficial effect of suppressed brain activity. These results support the need to expand the current cognitive reserve and resilience framework to include neural suppression as a potential mechanism of healthy cognitive aging.

Although interest in biomarkers of biological aging is growing, consensus on reliable, non-invasive indicators remains limited. Endotrophin, a bioactive fragment released during collagen type VI formation, reflects fibroblast activation and extracellular matrix remodeling and has been linked to chronic diseases, metabolic dysfunction, and inflammation. Whether circulating endotrophin also captures aging-related phenotypes and mortality risk in older adults remains unclear. We quantified serum endotrophin by the PRO-C6 assay in 1) acutely hospitalized Older patients (n = 121) at admission (T

Proteostasis is the balance of protein synthesis, protein maintenance and protein degradation. Proteostasis is disturbed in neurodegenerative disorders like Alzheimer`s disease (AD) of the aging human body. Protein synthesis by the ribosome is the most error-prone process of gene expression. If and how the error-rate of protein synthesis is regulated during human aging and contributes to AD is unknown. Here we show that ribosomal error-rate is adapted in cellular models of human aging, but not mouse aging. This adaptation involves ER-stress signaling and the Alzheimer`s disease-related proteins amyloid-beta precursor protein and presenilin 1. Our results suggest that ribosomal error-rate is a relevant parameter in human aging and disease.

Vaccines stimulate protective humoral immunity by coordinating lymphocyte activity in the germinal center (GC) response. However, the degree of protection varies across the population, with older individuals often showing lower titer antibody responses to vaccines. Previous work has correlated increased exposure to Th1 cytokines, like IL-2, with poor antibody responses in aging. Whether this is a causal relationship is unknown. Here we used Il2

The aging process is predominantly influenced by genetic and environmental factors. Environmental factors that accelerate biological aging, known as gerontogens, increase organismal vulnerability and susceptibility to disease, thereby elevating the risks of multiple aging-related disease onset and mortality. However, there is a notable deficiency in effective biomarkers for predicting aging-related phenotypes accelerated by gerontogens. Melatonin and cortisol serve as markers of the circadian system and are hormones that undergo significant alterations during the aging process. Imbalances in the melatonin-cortisol axis are closely linked to this aging process. This review summarizes the mediating effects and underlying mechanisms of melatonin-cortisol axis in gerontogen-induced aging, and discusses the feasibility of melatonin and cortisol as biomarkers for predicting aging-related phenotypes induced by gerontogens. This review evaluates the application value of melatonin and cortisol as biomarkers for the screening and risk assessment of potential gerontogens, as well as the intervention research of aging-related phenotypes induced by gerontogens.

Lifespan varies widely among individuals, yet the extent to which such variation persists when genetic and environmental differences are minimized remains unclear. Here we quantify such stochastic lifespan variation in a naturally clonal vertebrate and test whether and how this variation is linked to early-life behavioral individuality. We followed N = 33 genetically identical Amazon mollies (Poecilia formosa), separated on day 1 of their life into highly standardized environments, from birth to death. Despite genetic uniformity and environmental standardization, lifespan varies markedly, spanning 502 to 826 days. Continuous high-resolution behavioral tracking during the first four weeks of life reveals that seemingly stochastic early-life activity differences explain 32.5% of this variation. Higher activity predicts shorter lifespan during the first two weeks, but as activity levels and among-individual variation in activity decline over early development, a U-shaped relationship emerges, with both low- and high-activity individuals outliving those with intermediate activity. These findings show that signatures of lifespan emerge within days of birth, even among genetically identical individuals, highlighting developmental stochasticity and early-life contingencies as major contributors to variation in life-history outcomes.

Protein condensates that form via phase separation typically become more viscous over time and can harden in a process referred to as 'molecular aging'. Several mechanisms have been identified for this phenomenon. Of these, the ones involving enhanced {beta}-sheet or -strand interactions are of pathological relevance since they have been associated with neurodegeneration. Although there is much understanding of biopolymer phase behavior, an inclusive thermodynamic framework that unifies phase separation and {beta}-sheet-based aging is lacking. We present a time-dependent, multi-component extension of associating polymer theory that describes phase separation and aging of an intrinsically disordered protein (IDP) capable of associating through local, reversible folding. The model shows how the Second Law of Thermodynamics applies throughout, whether phase separation precedes and encourages aging or, vice versa, whether the increase in 'stickiness' during aging drives phase separation. Our calculations show how the time-dependence of the average valency of associating sites determines the aging kinetics and the development of viscoelastic properties of a biocondensate. The agreement between our calculations and the change in dynamics of condensates of 'perfect repeat' analogues of nucleoporin-98 not only validates the theory but also identifies these Nup98 variants as model systems for studying aging.

Healthy aging is accompanied by widespread changes in cortical structure and function, particularly within networks supporting multisensory integration and cognitive control. However, it remains unclear whether age-related neural alterations can be reliably decoded from individual brain activity patterns, especially under different cognitive states. This study examined whether age-related neural alterations can be decoded from time-domain functional near-infrared spectroscopy (fNIRS) signals during resting and complex audiovisual processing. fNIRS data were collected from cognitively normal younger and older adults across temporal, frontal, and parietal cortices. Nine time-domain features of oxygenated hemoglobin (HbO) were extracted and analyzed using supervised machine learning (SVM). Decoding accuracy was low at rest (peak = 0.651 with kurtosis alone) and remained poor across different classifiers. In contrast, during the audiovisual dual-task, a combination of five features-variance, peak, time-to-peak, slope, and skewness-achieved high classification accuracy (0.810), revealing robust age-related neural signatures. Spatial analysis showed that discriminative optodes were bilaterally distributed but functionally asymmetric: left temporoparietal regions were primarily involved in auditory processing and multisensory integration, whereas right frontoparietal regions supported attentional control and top-down regulation. These findings demonstrate that age-related neural dynamics are best captured under high cognitive load, highlighting time-domain fNIRS features as sensitive markers of cortical reorganization and potential indicators of healthy brain aging.

Orchestrated cellular fate remodeling is integral to tissue repair/replenishment. Extrinsic cues can trigger a switch from self-renewal priming to differentiation initiation in stem cells. However, cell fate remodeling-based therapy and/or transplanting stem cells suffer from limitations of retention and/or low efficiency. The study found reprogramming fatty acid metabolic flux facilitated cell fate remodeling. Knockdown of Ehhadh, a bi-functional fatty acid oxidase, promotes somatic cell reprogramming into iPSCs, but inhibits ESCs differentiation. Mechanically, Ehhadh knockdown disrupts the mitochondrial homeostasis, resulting in structural damage and functional impairment, via impacting on the stability of mitochondrial inner membrane transporter TIMM23. Meanwhile, Ehhadh knockdown activates AMPK/ULK1 pathway, resulting in mitophagy. The mitochondrial fission/mitophagy inhibitor, Mdivi-1, significantly attenuated Ehhadh-knockdown-induced pluripotent protein expression, but enhanced the Ehhadh-knockdown-inhibited three germ layer markers expression, providing evidence of the mechanistic causality between Ehhadh modulation and mitophagy or cell fate remodeling. In conclusion, the fatty acid oxidase Ehhadh mediates cell fate remodeling via mitophagy. The Ehhadh→mitophagy→cell fate remodeling axis provides evidence for possible strategies of manipulating stem cell fate (stemness perpetuation or differentiation execution) by modulating of fatty acid oxidation efficiency and/or targeting on mitochondrial rejuvenation and reorganization pathways, shedding light on drug development, organ replenishment, stem cell therapy, breed production.

Ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD), is characterized by sustained mucosal inflammation, disrupted epithelial barrier function, microbial dysbiosis, and impaired intestinal homeostasis. If chronic uncontrolled inflammation persists, it may lead to the development of colorectal cancer or other severe clinical complications. Emerging evidence suggests that cellular senescence promotes inflammatory cascades, aggravating UC symptoms and implicating a pathophysiological link to disease progression. Our previous studies have demonstrated that the anti-senescence compound Valnemulin (VAL) can mitigate colonic senescence and alleviate UC symptoms. In this study, subsequent integrative metagenomic and metabolomic analyses revealed that VAL's pharmacological mechanism involves restructuring the gut microbial community composition, enhancing the colonization abundance of beneficial bacteria, and thereby promoting the production of their key metabolites, which collectively contribute to UC remission. In vitro and in vivo studies demonstrated that VAL's anti-senescence effects are mediated by Neobavaisoflavone (NBIF), a functional metabolite produced by beneficial gut bacteria. NBIF effectively activates the AMP-activated protein kinase (AMPK) pathway, significantly reducing the expression levels of senescence marker proteins p16, p53, and p21. Consequently, this mechanism ameliorates the senescent phenotype in intestinal epithelial cells and contributes to the overall improvement of colonic tissue senescence in UC pathology. Concomitantly, NBIF also reduces levels of pro-inflammatory cytokines IL-1β, TNF-α, and IL-6, thereby attenuating DSS-induced pathological damage in UC. This study not only proposes a novel anti-senescence strategy for UC treatment but also elucidates the pivotal role of the gut microbiota-metabolite-AMPK axis in regulating intestinal inflammation.

Clonal hematopoiesis (CH) is an age-related phenomenon driven by the expansion of mutant hematopoietic stem cell (HSC) clones, most commonly harboring mutations in DNMT3A. While inflammation is known to promote CH, the upstream triggers of this inflammatory state remain unclear. We show that aging selectively upregulates retrotransposons in the non-hematopoietic cell compartment of the murine bone marrow, particularly in mesenchymal stromal cells. Using in vivo competitive transplant models, we demonstrate that retrotransposon-induced inflammation cell-extrinsically promotes Dnmt3a-mutant HSC expansion. This competitive advantage arises from mutant HSC resistance to inflammation-driven cell cycle perturbations. Mechanistically, we show that retrotransposon activation induces type I interferon signaling via viral mimicry, such that stromal knockdown of either Irf3 or Sting abrogates the competitive advantage of Dnmt3a-mutant HSCs. Our findings establish stromal-selective retrotransposon reactivation as a previously unrecognized, non-cell-autonomous source of inflammation that contributes to age-associated CH.

Numerous studies in C. elegans have taken advantage of gene silencing RNAi libraries and tissue-specific RNAi systems to temporally and spatially understand gene function. Tissue-specific RNAi strains were created via tissue-specific functional expression of a key gene in the RNAi system in a presumably RNAi insensitive correspondingly-mutated background. Here, we tested the level of RNAi insensitivity across different commonly used RNAi-defective mutants (rde-1 and sid-1) using lifespan analyses. Remarkably, while we found similarly important lifespan shortening in wild-type animals by silencing the polyubiquitin gene ubq-1 (UBC) at both 20{degrees}C and 25{degrees}C, we found wide and temperature-sensitive variations in RNAi sensitivity across different rde-1 and sid-1 strains from substantial sensitivity to complete insensitivity. This riveting finding warrants a re-evaluation of the tissue-specific interpretations in numerous tissue-specific RNAi studies in C. elegans. Using validated tissue-specific RNAi systems, we determined that proteasomal burden largely differs between the germline and the soma. Notably, gonadally-accumulating vitellogenin proteins substantially contributed to the total polyubiquitinated proteins observed during aging. Interestingly, we found that UBQ-1 was essential to maintain the transcription of highly expressed genes, including vitellogenins, supporting a broad and key role for polyubiquitin beyond proteostasis. Altogether, we authenticated commonly used tissue-specific RNAi systems and uncovered a new approach to improve RNAi insensitivity in RNAi-defective strains. With validated tissue-specific RNAi strains, we spatially analyzed proteasomal function and age-related polyubiquitinated protein accumulation, and revealed a converging regulatory link between UBQ-1, vitellogenin metabolism and lifespan in C. elegans.

Vascular calcification (VC) is a complex pathological process, which is closely related to chronic kidney disease, atherosclerosis, diabetes and aging. This phenomenon is mainly driven by the convergence of cellular and molecular molecular mechanisms, including osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs), persistent oxidative stress, extracellular vesicle-mediated calcification, and activation of multiple cross-signaling signaling pathways. The multifaceted evidence emphasizes the key role of VSMCs cytoskeleton remodeling in the progression of VC, and establishes a significant link between cytoskeleton dynamics and calcification initiation, which has potential predictive value under specific conditions. This article reviews the factors affecting the remodeling and stability of VSMCs cytoskeleton, focusing on their effects on VSMCs transdifferentiation and calcification. Finally, we highlighted the role of cytoskeleton in the process of cardiovascular calcification, explored strategies for mediating calcification, and proposed potential directions for future research.

Age-related changes in muscle and bone can adversely affect musculoskeletal health. Current techniques often fail to capture subtle age-related changes in bone micro-architecture and muscle tissue. Magnetic resonance imaging (MRI) is a robust tool for analyzing age-related bone deterioration, while radiomics effectively captures subtle changes in muscle tissue by extracting intricate features.

Oxidative Stress (OS) is a major feature of aging and is first brought on when the generation of Reactive Oxygen Species (ROS) surpasses the capacity of antioxidant defenses to neutralize them. Long-term exposure to ROS gradually damages vital biomolecules, resulting in the development of measurable biomarkers that indicate the degree of oxidative stress. Some forms of protein oxidation that impair enzymatic activity and interfere with cellular signaling are carbonyl compounds and advanced oxidation protein products. DNA is susceptible to OS, which can cause lesions like 8-hydroxy-2-deoxyguanosine, which indicate genomic instability and lead to cellular senescence and reduced function. Increased levels of lipid peroxidation byproducts, such as Malondialdehyde (MDA), 4-hydroxynonenal (4-NHE), and isoprostanes, indicate disturbed cellular balance and compromised membrane integrity. Additional information about the redox state can be found in antioxidant defenses. While important enzymatic antioxidants like glutathione peroxidase, catalase, and superoxide dismutase frequently show altered activity as one ages, indicating a reduced ability to counteract ROS, non-enzymatic antioxidants like glutathione, vitamins C and E, uric acid, bilirubin, and beta carotene provide extra defense but diminish with age. Combined, these biomarkers show how oxidative damage accumulates gradually and how the body's cellular defenses progressively deteriorate. By mapping their trajectories, we can better understand the biology of aging and develop targeted interventions and early detection tools to promote healthy aging. In this review, we summarized various OS biomarkers that help in the prediction of aging and age-related diseases.

The growth of mobile health has underscored the critical importance of equitable internet access in promoting healthy aging. Among older adults, particularly those in digitally underserved populations, access to mobile data is often limited due to affordability and technological barriers, leading to a phenomenon known as "data deprivation." This form of digital inequality limits the older adults' ability to participate in social, recreational, and community-based activities, which are protective against isolation and decline in later life. In South Korea, where unlimited smartphone data plans have become increasingly accessible, a unique opportunity exists to examine the real-world association of improved data accessibility on older adults' social lives and digital engagement.