Longevity Papers

Skeletal muscle aging is characterized by a functional decline in muscle stem cells (MuSCs), yet the key regulatory mechanisms driving this deterioration remain poorly understood. By integrating transcriptomic profiles from aged MuSCs with data from C2C12 cells exposed to spaceflight conditions (which mimic an aging-like phenotype), we identified MORF4-related gene on chromosome 15 (MRG15) as a putative epigenetic regulator involved in age-related myogenic decline. Using a MuSC-specific inducible knockout (iKO) mouse model, we found that loss of MRG15 severely compromises myogenic differentiation and muscle regeneration. Subsequent RNA sequencing of iKO MuSCs, combined with ChIP-seq analysis of histone modifications, revealed that MRG15 modulates the chromatin landscape of myogenic genes through interaction with MyoD, thereby facilitating transcriptional activation and differentiation. Our findings establish MRG15 as a critical epigenetic regulator that cooperates with MyoD to orchestrate chromatin remodeling, thereby promoting transcriptional activation of the myogenic program. Dysregulation of MRG15 may underlie impaired muscle regeneration during aging.

High-quality reference genomes are essential for comparative and functional genomics yet remain unavailable for many emerging model organisms. Here, we report OctDeg2.0, a chromosome-level genome assembly and annotation of the degu (Octodon degus), generated using PacBio HiFi long-read sequencing and Hi-C scaffolding from a single male individual. Octodon degus is of growing interest as a natural animal model for aging and Alzheimer's disease research. The 3.4 billion base-pair assembly comprises 28 autosomes and both sex chromosomes, with markedly improved contiguity and completeness over the prior short-read assembly while maintaining high base accuracy. The new assembly provides substantially enhanced gene annotation, clearer resolution of chromatin architecture and cis-regulatory element landscapes, with much improved characterization of repetitive and structurally complex regions, including centromeres and segmental duplications. We present a streamlined and reproducible pipeline for high-resolution de novo genome assembly and gene annotation applicable to other emerging model organisms. This work establishes a robust genomic resource for studying molecular and cellular mechanisms in health and disease in Octodon degus.

Cardiovascular diseases (CVDs), including hypertension, heart failure, atherosclerosis and myocardial infarction, remain the leading cause of morbidity and mortality worldwide. Aging is a predominant risk factor for CVD. Cardiovascular aging is characterized by progressive structural changes at the cellular level and functional decline within the cardiovascular system, ultimately contributing to the onset and progression of CVD. These changes include alterations in left ventricular (LV) systolic and diastolic function, an increased incidence of sinus node dysfunction, myocardial hypertrophy, arterial stiffness, and fibrosis. Therefore, understanding the molecular mechanisms underlying cardiovascular aging and identifying interventions that can slow or mitigate its progression holds significant promise for CVD prevention and treatment. Numerous epidemiological and experimental studies have consistently demonstrated that physical activity or exercise training exerts protective effects against cardiovascular aging. However, the molecular mediators and underlying mechanisms of these benefits are not completely understood. Therefore, further investigation is warranted to elucidate these mechanisms, given their potential as novel therapeutic targets. In this review, we comprehensively synthesize molecular, preclinical, clinical, and epidemiological evidence to underscore the positive effects of exercise on cardiovascular aging. This review systematically investigates how exercise modulates the key biological hallmarks of cardiovascular aging, including deterioration of protein homeostasis (proteostasis), genomic instability, epigenetic disturbances, mitochondrial dysfunction, cellular senescence, chronic inflammation, and dysregulated neurohormonal signaling. The mechanistic insights of exercise-induced adaptations presented in this review may provide a valuable foundation for future investigations, paving the design of tailored exercise regimens aimed at mitigating the progression of cardiovascular aging.

Cellular senescence is a key mechanism of skeletal aging in both physiological and accelerated conditions, such as radiotherapy. This study aimed to identify common differentially regulated microRNAs (miRs) across these contexts. We performed miR sequencing on three models: femurs from young (5-month-old) versus old (24-month-old) mice; focally radiated versus non-radiated femurs; and osteocytes from young versus old mice. Osteocytes were included in the comparison, as they have the longest lifespan in the mineralized bone matrix and they form 90-95% of all mesenchymal bone cell types. Among the three groups, miR-135a-5p and miR-671-5p were the common (i.e., shared) miRs that were downregulated, and miR-183-5p, a miR that regulates the WNT pathway, was the only shared upregulated miR, while miR-155-5p, a miR that regulates the Senescence-Associated Secretory Phenotype (SASP), was elevated in two conditions. The WNT-pathway has been positively associated with bone health and Sclerostin, a WNT-pathway inhibitor produced and secreted by osteocytes, has been implicated in accelerated skeletal deterioration following radiation. Thus, we used a neutralizing antibody to Sclerostin (Scl-Ab), to assess genes related to the WNT pathway and senescence, which are regulated by miR-183-5p and miR-155-5p, respectively. We further performed miR sequencing in radiated bones from mice treated with Scl-Ab and identified miR-133a-3p, a key miR that inhibits bone metabolism and function, which is upregulated in accelerated skeletal aging (i.e., focal radiation) downregulated by Scl-Ab. Overall, our study identifies potential regulatory gene pathways that modulate skeletal aging in the presence and absence of a WNT activator, Scl-Ab.

Physical and cognitive interventions, alone or combined, are recognized strategies to enhance cognitive function in healthy older adults, though their relative effectiveness remains debated. This study aimed to compare and classify the impact of such interventions on cognitive performance. Following PRISMA guidelines, randomized controlled trials (RCTs) were identified through searches of PubMed, Web of Science, and Scopus, with screening and data extraction procedures guided by the Cochrane Handbook for Systematic Reviews of Interventions. The protocol was registered on PROSPERO (CRD42024565879). A network meta-analysis synthesized results from 87 studies including participants aged 65 and older. Interventions were grouped into seven groups, covering dual-task, single-task, technology-based formats, and a control group. Compared with controls, cognitive-motor dual-task training showed the strongest effects (SMD = 0.71, 95% CI 0.45, 0.97). Differences between exercise types were not statistically significant. However, dual-task approaches, whether technology-supported or not, outperformed traditional physical training (e.g., SMD = 0.33, 95% CI 0.05, 0.61). Findings suggest that dual-task interventions effectively enhance cognitive performance, with technology adding value by creating engaging and adaptive experiences. Technology particularly strengthened single-task training. Future research should examine specific executive functions and scalable technology-based methods to guide evidence-based strategies that promote healthy aging and cognitive resilience.

N⁶-methyladenosine (m⁶A) orchestrates RNA fate decisions through a dynamic interplay of writers, erasers, and readers, modulating splicing, stability, and translation. This review unveils how m⁶A fine-tunes senescence-associated pathways (p53/p21, p16-RB) with cancer-context-dependent duality-either as a tumor suppressor or promoter of progression/resistance. Leveraging single-cell and spatial omics, we dissect m⁶A's spatiotemporal heterogeneity in tumor-immune ecosystems. We consolidate diagnostic/prognostic biomarker advances and critically evaluate emerging therapeutics (small-molecule inhibitors, allosteric modulators, nanodelivery systems), addressing clinical barriers like selectivity and safety. Finally, we propose precision strategies targeting m⁶A-senescence networks for combined anti-cancer/anti-aging interventions.

Background: Brain perivascular spaces (PVS) are emerging MRI markers of microvascular function and waste metabolite clearance. While PVS enlargement has been linked to aging and vascular risk, it remains unclear whether PVS morphology reflects shared familial microvascular characteristics and how these are shaped by individual vascular, physiological, and neuropsychiatric factors. In this study, we investigated whether PVS morphometry captures these familial characteristics, further modulated by individual determinants. Methods: We analyzed 1,183 participants from the Stratifying Depression and Resilience Longitudinally (STRADL) family-based cohort, including 324 individuals with first-degree relatives. Automated MRI segmentation quantified PVS volume, count, density, and median length in the centrum semiovale and basal ganglia. Linear mixed-effects models assessed associations with age, hypertension, hair cortisol, depressive symptom scores, and hand grip strength while accounting for familial clustering. Results: In 1050 individuals (59.5% female; mean age 59.3 {+/-}10.1 years) PVS burden increased with age (PVSvolume%ROI {beta}=0.18, 95%CI[0.11, 0.26], p<0.0001), current depressive symptoms across both regions (PVS density: CSO, {beta}=0.092, [0.023, 0.16], p=0.009; BG, {beta}=0.11, [0.043, 0.18], p=0.002), and with higher hair cortisol (PVS count {beta}=0.08, [0.003, 0.15], p=0.041) and weaker grip strength (PVSvolume%ROI {beta}=-0.09, [-0.16, -0.02], p=0.013), in the centrum semiovale. Familial clustering was significant for PVS volume ({beta}=0.22, [0.096, 0.52], p=0.013) and median length ({beta}=0.28, [0.16, 0.49], p=0.0003), independent of other factors. Conclusions: PVS morphology reflects neuropsychiatric and shared familial microvascular architecture, with both inherited and individual factors contributing to PVS burden and morphometry, and supporting the use of PVS morphometry as a neuroimaging marker of cerebral microvascular health.

The global increase of the aging population poses major public health challenges, particularly due to the rising prevalence of age-related diseases. Among these, dementia stands out as a condition with the most significant health, social, and economic impact. Primary prevention in healthy aging, thus far, represents the most effective strategy to address this issue, and cognitive interventions emerge as promising tools to enhance and preserve cognitive functions over time. This study aimed to provide a systematic review and meta-analysis of cognitive interventions in healthy older adults, assessing their effectiveness both on cognitive performance (i.e., global cognitive functioning and main cognitive domains), measured by neuropsychological tests, and psychological components (e.g., psychiatric symptoms, quality of life, reported cognitive complaints). The use of a multilevel Bayesian approach allowed us to enhance the reliability of our findings by accounting for data structure and variability across studies. A total of 51 studies were included in the systematic review, and 43 in the meta-analysis. The results indicated that, compared to control groups, cognitive interventions are more effective in improving overall cognition (0.26; 95% CI [0.08, 0.44]). Evidence of effectiveness, albeit with smaller effect sizes, was also observed on specific cognitive domains. No effects emerged for psychological outcomes. Our findings underscore the relevance of cognitive interventions as an effective tool to promote cognitive health and prevent cognitive decline in the aging population. More research will be necessary to explore further the effectiveness of cognitive intervention on psychological components.

With a global annual cumulative incidence of depression at 4.5% in community-dwelling older adults, understanding non-pharmacological interventions is essential. This narrative review explores the neuroprotective mechanisms of physical activity (PA) on brain function and mental health in individuals aged 60 and older. We conducted a search across multiple databases (MEDLINE, PsycINFO, EMBASE) using keywords related to aging, cognition, and physical activity. Our analysis of relevant studies shows that PA benefits the brain through several pathways. Early findings focused on improved cerebral blood flow and glucose utilization. More recent evidence highlights that PA increases neurotrophic factors like BDNF and IGF-1, enhances mood-regulating neurotransmitters, and promotes structural adaptations in key brain regions. These findings suggest that PA is a cost-effective, multi-domain intervention. This review provides healthcare professionals with actionable evidence to incorporate PA into clinical practice for older adults.

Growing evidence connects sleep disorders with cognitive impairment in older adults, though underlying biological mechanisms remain unclear. We investigated how plasma metabolic profiles mediate the relationship between sleep patterns and global cognition.

Characterizing cellular aging is essential for understanding age-related diseases. While tissue-level studies reveal broad age-associated changes, they often reflect compositional shifts rather than cell-level reprogramming. The cellular damage hypothesis posits that aging involves the accumulation of DNA, chromatin, and other damage across molecular layers, increasing transcriptional entropy. Existing supervised methods for detecting cellular senescence yield cell type-specific senescence scores but rely on labeled data and lack generalizability. Here, we introduce a first-principles framework for quantifying transcriptional entropy in single cells as each cell's deviation from a transcriptomic manifold, capturing breakdown of transcriptional coordination. This unsupervised approach identifies aging-affected cell types and distinguishes two cellular aging mechanisms: loss of expression precision and activation of stress-response pathways in high entropy cells. Applied to Tabula Muris Senis and SenNet Multiome datasets, transcriptional entropy correlates with chromatin-based mitotic age and highlights regenerative tissue compartments as most affected by aging.

Aging leads to a progressive decline in overall bladder function resulting in lower urinary tract symptoms and increased susceptibility to infections. However, tissue-specific mechanisms of aging, specifically the contributions of the urothelium, remain elusive. Here, we introduce mouse bladder epithelium-derived organoids (mBEDOs) as a scalable platform to model urothelial aging. mBEDOs from aged mice recapitulate key features of age-associated cellular reprogramming, including oxidative stress, senescence, and DNA damage. We demonstrate the utility of mBEDOs for modeling Uropathogenic Escherichia coli (UPEC) infection, generating assembloids between mBEDOs and macrophages to model epithelial-immune interactions, and genetic perturbation. Using the mBEDO platform, we also identify urothelium-specific changes in purine, amino acid, and glycerophospholipid metabolism, which may contribute to age-associated cellular perturbations. Lastly, supplementation with depleted metabolites, nicotinamide and d-mannose, reduces DNA damage and oxidative stress and restores mitochondrial integrity in aged mBEDOs. These findings establish mBEDOs as an effective platform for investigating molecular and cellular underpinnings of urothelial aging and exploring metabolism-based interventions for age-associated bladder dysfunction.

Selenium-independent peroxiredoxin 6 (Prdx6) is a unique member of the peroxiredoxin family, which protects cells from various stressors by regulating reactive oxygen species (ROS) and maintaining survival signaling. As a multifunctional "moonlighting" protein, Prdx6 exhibits glutathione peroxidase (GPx), acidic calcium-independent phospholipase A2, and lysophosphatidylcholine acyltransferase activities, enabling it to reduce ROS. Loss of Prdx6, owing to dysregulation of its transactivator nuclear factor erythroid 2-related factor 2 or aberrant oxidative post-translational modifications from aging or oxidative stress, disrupts cellular homeostasis and triggers inflammatory or non-inflammatory cell death, including apoptosis and pyroptosis. Similar to GPx4, Prdx6 exhibits selenium-independent peroxidase activity and possesses phospholipid hydroperoxide-reducing GPx activity. A novel function of Prdx6 in facilitating selenium utilization was identified recently; that is, it enhances the expression and activity of selenoproteins, especially GPx4, and prevents ferroptosis. Conversely, Prdx6 deficiency reduces selenoprotein levels and promotes ferroptosis. Nevertheless, the molecular mechanisms through which Prdx6 modulates cell death and survival, particularly under aging and oxidative stress conditions contributing to cataractogenesis, remain unclear. In this review, we summarize the current knowledge of Prdx6 regulation and activity during oxidative stress and aging, highlighting its role in inflammatory and non-inflammatory signaling that contributes to eye lens pathology and cataract formation. Additionally, we discuss natural activators and potential therapeutic strategies targeting Prdx6 to extend eye lens health and delay or prevent cataract development. Overall, we conclude that enhancing Prdx6 activity offers a promising strategy to prevent or reverse age-related cataracts.

Cellular senescence, a stress-induced program causing stable cell-cycle arrest, is a hallmark of liver aging, fibrosis, and cancer. However, the cell-type-specific mechanisms, spatial organization, and cancer-associated alterations in the liver remain unclear. We profiled 43 normal human livers spanning ages and fibrosis stages using a single-cell multiome, Xenium spatial transcriptomics, and CODEX, complemented by fibrotic mouse models and 24 colorectal cancer liver metastases. We found CDKN1A+ senescent hepatocytes, fibroblasts, cholangiocytes, and endothelial cells associated with age, liver disease, or cancer. Senescence differed between aged and fibrotic livers, with similar patterns in mice. Spatially, CDKN1A+ hepatocytes localized periportally, while SERPINE1+ aging-associated hepatocytes formed spatial clusters, potentially mediated by Claudins and THBS1. Fibrotic regions contained CXCL12+ senescent fibroblasts interacting with CXCR4+ immune cells. Chemotherapy intensified senescence in hepatocytes by 5-fold relative to aging and led to unique CDKN2A+ populations. Across conditions, senescent cells shared AP-1 activation, pro-inflammatory cytokines, and apoptosis resistance, suggesting therapeutic opportunities.

Cellular senescence and brain atrophy are both associated with brain aging, suggesting these processes may share underlying biological mechanisms. This study investigated these mechanisms by integrating structural neuroimaging with gene and protein expression data from prefrontal cortex tissue collected from individuals who underwent neurosurgery. Cell-type-specific gene expression signatures associated with neuroimaging features and cellular senescence were identified and replicated in several independent datasets. Significant correlations between these signatures were observed in excitatory neurons and microglia, especially for volume-related features. These associations were also observed for excitatory neurons in an independent brain gene expression dataset from individuals below 5 years of age, implying a role for senescence during brain development. Together, this study provides a deep characterization of molecular signatures linking brain structure and cellular senescence across different life stages and suggests mechanisms supporting brain development may also contribute to volume reduction observed during aging.

Skeletal muscle regeneration is a complex and strictly regulated process that involves complex interactions between immune cells, muscle-resident progenitor cells, and stromal components. Macrophages play a central role in this process by coordinating immune responses, supporting regeneration, and promoting tissue remodeling through phenotypic transitions that respond to environmental cues. Under physiological conditions, these transitions ensure efficient tissue restoration. However, in pathological settings or conditions such as aging, muscular dystrophy, cancer cachexia, and metabolic disorders, macrophage function becomes dysregulated. This situation often leads to persistent inflammation, excessive fibrosis, and impaired regeneration of muscle tissue. Recent advances in single-cell and spatial transcriptomics technologies have revealed the remarkable heterogeneity of macrophage subpopulations within skeletal muscle. These findings emphasize the importance of immunometabolic programming as a key driver of macrophage plasticity. Shifts in glucose metabolism, oxidative phosphorylation, lipid utilization, and amino acid pathways critically influence the polarization of macrophages and their interactions with surrounding cells. Moreover, metabolic signals from the tissue microenvironment, circulating factors, and muscle-resident cells create a dynamic network of metabolic crosstalk that shapes macrophage behavior. This review provides a comprehensive summary of how macrophage immunometabolism regulates skeletal muscle regeneration in both acute injury and chronic disease. It highlights core metabolic pathways, macrophage-centered intercellular communication, and emerging therapeutic strategies that aim to reprogram macrophage metabolism for a regenerative benefit. In addition, key challenges and future directions for translating these insights into effective interventions for muscle wasting conditions are discussed.

Several if not all manifestations of aging can be postponed by a healthy lifestyle involving a balanced diet coupled with regular exercise and sufficient sleep. Similarly, various genetic and pharmacological longevity interventions can exert beneficial effects across species in a conserved manner, extending both lifespan and healthspan. While all these interventions-ranging from genetic perturbations to pharmacological supplementation to lifestyle changes-affect diverse biological processes, a common candidate mechanism underpinning at least some of their benefits is autophagy, a cellular recycling process essential for maintaining cellular homeostasis. In this review, we summarize how autophagy is affected by various pharmacological and lifestyle factors, with a focus on studies in which autophagy has been shown to play a causal role in promoting healthy aging. Specifically, we review the molecular mechanisms through which pharmacological agents, dietary restriction, exercise, sleep adjustments, as well as temperature modulation affect autophagy to extend lifespan and often also healthspan in model organisms and humans. Still, major gaps remain in human research due to limited assays to monitor autophagy and the scarcity of longitudinal studies linking autophagy dynamics to health outcomes. Closing this gap is a key challenge in converting discoveries from model organisms into interventions that consistently enhance healthy aging in humans. By summarizing current findings and highlighting remaining uncertainties, this review aims to provide a roadmap for translating insights on autophagy from model organisms into strategies to promote healthy aging in humans.

The prevalence of neurodegenerative diseases (NDs) continues to rise with the aging of populations worldwide, representing a pressing need for the establishment of therapeutic strategies. Maintaining proteostasis is crucial for healthy aging, as the accumulation of misfolded and aggregated proteins is a key contributor to age-related cellular dysfunction and disease. This study introduces a novel phenotypic assay using Caenorhabditis elegans to screen for small molecule enhancers of proteostasis, aiming at mitigating the proteotoxic stress associated with NDs. This new methodology- PRO-FitS- uses C. elegans motor activity as a proxy for the PROteome Fitness State upon a noxious protein-denaturating stimulus, while allowing a fast and experimenter-free readout. We demonstrate the efficacy of the assay by validating the role of pharmacological mTOR inhibition and serotonergic signaling activation in reducing heat shock-induced proteotoxic damage at the whole-organism level. PRO-FitS will allow the identification of novel compounds that alleviate protein aggregation disorders, potentially revealing new pathways and cellular targets not previously implicated in proteotoxicity.

One of the main factors contributing to aging is reactive oxygen species (ROS), which are produced by dysfunctional mitochondria. Reducing ROS generation is considered an essential treatment for senescence, but no effective treatment has been developed yet. In this study, vitisin B, a tetramer of resveratrol, was found to be an efficient reagent that reduces mitochondrial ROS generation after screening phenylpropanoids (PPs), metabolites produced to overcome ROS-mediated stress in plants. Vitisin B induced mitochondrial functional recovery by activating mitophagy and removing dysfunctional mitochondria. Mitochondrial functional recovery by vitisin B decreased mitochondrial ROS, a by-product generated from dysfunctional mitochondria. In addition, ROS reduction by vitisin B restored senescence-associated phenotypes. RNA sequencing identified WBP2 N-Terminal Like (WBP2NL) as a gene essential for vitisin B-mediated senescence rejuvenation. Knockdown of WBP2NL exhibited effects similar to those of vitisin B, reducing mitochondrial ROS generation and consequently reversing senescence-associated phenotypes. This study elucidates a novel mechanism by which vitisin B reverses senescence by lowering mitochondrial ROS generation. This discovery opens the way to new therapeutic options to control aging by modulating mitochondrial ROS production.

Sarcopenic obesity (SO), defined as the coexistence of excess fat mass and low muscle mass/function, has been linked to adverse outcomes. Epigenetic alterations are central hallmarks of aging. Evaluating how obesity, sarcopenia, and SO are related to epigenetic aging biomarkers may provide insights into cellular aging and disease risk.

Executive function (EF) is a critical component of healthy aging, and its decline represents a fundamental challenge to neurological health. This network meta-analysis (NMA) systematically compared and ranked the effects of a spectrum of non-pharmacological interventions on overall EF and its key subdomains-working memory, cognitive flexibility, and inhibition-in healthy older adults.

Eccrine sweat glands (ESGs) are critical organs for human thermoregulation, yet their function progressively declines with aging. This study aims to investigate the underlying mechanisms responsible for the age-related impairment of ESG function. Through comparative analysis between skin tissues from young and aged mice/human, we observed structural loosening of aged ESG and a significant reduction in the expression of extracellular matrix (ECM) components-type I and type II collagen. Further investigation revealed a significant upregulation of the inflammatory cytokine interleukin (IL)-1β and matrix metalloproteinases and proteases (MMP)-1 in aged tissues, which can modulate the collagen degradation, suggesting that ECM degradation may be regulated by an inflammatory microenvironment. To validate this hypothesis, we established a model of chronic inflammation by intradermally injecting IL-1β into the footpads of mice. The results demonstrated suppressed ESG function, structural loosening of ESG tissues, and a marked reduction of type I and type II collagen surrounding the ESGs. In summary, this study reveals that type I and type II collagen are distributed around ESGs, providing structural and functional support. The activation of the IL-1β-MMP-1 inflammatory pathway in aging may contribute to ESG dysfunction and structural disruption by degrading the collagen around ESGs.

The aging population is steadily increasing, representing a significant portion of the global population. Vitamin D deficiency is highly prevalent, particularly among older adults and has been implicated in the pathogenesis of various chronic diseases. In June 2024, a clinical practice guideline was published by the Endocrine Society, recommending empiric vitamin D supplementation for those over 75 years old, suggesting that it could reduce mortality in this age group. Meanwhile, for the general population aged 50-74 years, not only was empiric supplementation not suggested but neither was routine testing of vitamin D levels. This review discusses the pathophysiological changes associated with aging, the conditions commonly affecting older adults that may be positively impacted by vitamin D, and the potential negative effects of such supplementation. By examining the current knowledge in the field, we aim to provide practical insights into the effects of vitamin D in individuals older than 75 years and to explore the potential benefits of expanding supplementation to include younger older adults, specifically those aged 65-74 years.

Epigenetic aging is a hallmark of chronic diseases, arising from sustained injuries and unresolved repairs. To investigate cell-type-specific epigenetic alterations, we built a cross-species single-cell multi-omics atlas of DNA methylomes, chromatin accessibilities, and transcriptomes on healthy, injured (human) and aging (mouse) kidneys. We identified accelerated epigenetic aging dominated by tubular epithelia in diseased kidneys. The pathological state mirrors transcriptional trajectories observed in normal aging, driven by the preferential dysregulation of lineage-specific genes lacking CpG islands. Spatially, these epigenetic changes mapped to pathological niches of failed repair. Co-profiling of single-cell DNA methylation and 3D genome architecture revealed that epithelial repair states in disease undergo significant higher-order genome reorganizations, activating genes associated with renal decline. Our findings demonstrate that epithelial aging is driven by a collapse of 3D chromatin structure and local methylome integrity, which silences cell identity and promotes a non-resolving repair state.

Cardiac aging is a major driver of cardiovascular diseases and associated mortality, yet its therapeutic options are limited. While long interspersed nuclear element-1 (LINE-1) retrotransposons are known to drive cellular senescence, their role in cardiac aging is poorly defined. Here we showed that LINE-1 expression increased in the heart with age. To investigate their role in cardiac aging, we generated cardiomyocyte-specific Mov10-knockout mice, which failed to suppress LINE-1. These mice developed LINE-1 derepression, cardiac dysfunction and premature cardiac aging by 3 months of age, accompanied by cGAS-STING activation. Pharmacological inhibition of LINE-1 reverse transcription (with 3TC) or STING (with H-151) suppressed cGAS-STING activation and attenuated senescence in Mov10-knockout H9C2 cells. Notably, both inhibitors improved cardiac function and reduced cardiac inflammation and senescence phenotypes in naturally aged mice. Together, our findings establish LINE-1 as a driver of cardiac aging via cGAS-STING activation, highlighting LINE-1 and its downstream effectors as therapeutic targets for age-related cardiac dysfunction.

Aging, a complex physiological and molecular process, has undergone significant changes, of which gut microbiome composition has surfaced as an important key in the maintenance of neurological health. Recent studies have revealed the significant impact of age-related gut dysbiosis in the induction of neuroinflammation, metabolic syndrome, disruptions in gut-brain axis, and age-related neurological decline. Although significant studies have revealed the impact of the microbiome-gut-brain axis in individual neurological diseases, an aging-focused holistic synthesis has not yet been adequately developed. This review provides a critical assessment of the involvement of age-related dysbiosis of gut microbiota in the development and progression of neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and cognitive aging of the elderly, and to focus on age-related microbial patterns and mechanisms of dysbiosis related to neurological aging, including inflammation and immune system dysregulation, metabolic changes, oxidative stress, barrier dysfunction, and gut-brain communication through enteroendocrine, enteric neural, and vagal mechanisms, and to emphasize disease-specific and common microbial patterns of dysbiosis and beneficial and harmful microbial roles in aging diseases. This review assesses some of the latest promising therapies aimed at the microbiota, such as probiotics, prebiotics, dietary therapies, fecal microbiota transplantation, as well as pharmacological therapies, and critically discusses their limitations in terms of interindividual variability and their generalisation and applicability. Focusing on mechanistic, comparative, and translation aspects, this review offers a comprehensive approach to neurological aging due to gut microbiota and identifies gaps for future precision microbiome-based interventions.

Mesenchymal stem cells (MSCs) are pluripotent stem cells isolated from human tissues. Due to their strong self-renewal capacity, pluripotency, and immunomodulatory properties, MSCs have garnered significant attention in cell therapy and tissue regeneration. However, cellular senescence induced by replication or external stimuli can impair MSC proliferation and differentiation, making it crucial to develop interventions that delay or reverse the senescence process. From a traditional Chinese medicine perspective, senescence stems from spleen and stomach deficiency, kidney deficiency, and related factors; thus, medicines that tonify the kidney and promote Qi and blood circulation play vital roles in anti-senescence therapy. Chinese medicine, characterized by low toxicity and multi-target, multi-functional properties, has become prominent in anti-senescence research. This paper examines the MSC senescence process by discussing its causes, characteristics, and mechanisms, then summarizes how active ingredients in herbal medicines and natural compounds reverse MSC senescence, facilitating the discovery of additional anti-senescence Chinese medicines and their effective components.

The lateral prefrontal cortex (LPFC) plays a pivotal role in executive functions and exhibits a hierarchical rostro-caudal organization critical for higher-order cognition. Using connectome gradient mapping of resting-state fMRI data across young, middle-aged, and older adults (N = 478), we found preserved global gradient structure but significant compression of the principal gradient in older adults relative to middle-aged adults, particularly in dorsolateral (DLPFC) and frontopolar (FPC) regions. This reduced functional differentiation corresponded to lower spatial separation between LPFC subdivisions. Meta-analytic decoding linked these changes to attenuated engagement of executive functions. Crucially, in an independent cohort of older adults (N = 99), individuals with better executive function exhibited greater gradient range and variation at the global level, along with higher gradient values in the DLPFC and ventrolateral prefrontal cortex (VLPFC) and lower values in the premotor cortex at the regional level. These findings suggest that age-related disruption of LPFC gradient organization may reflect neural dedifferentiation and is closely related to executive decline. Gradient compression in the LPFC may serve as a novel biomarker of cognitive aging, offering insights into the hierarchical reorganization of brain networks in late life.

Cardiomyocyte telomere shortening is evident during heart failure pathogenesis. Conversely, mice with engineered telomerase deficiency develop myocardial dysfunction accompanied by p53 activation and mitochondrial repression. Yet, critical aspects remain to be established: whether cardiac dysfunction in mice lacking telomerase components arises from myocardial-intrinsic effects or systemic consequences of telomere shortening, which broader transcriptional programs follow cardiomyocyte telomere shortening, and what implications these carry for clinical heart failure.

Chronic diabetic wounds have become a major clinical challenge because of their difficulty in healing and high recurrence rate. This review proposes for the first time the theoretical framework of the "metabolism-senescence axis," systematically elucidating the central role of cellular senescence in the mechanisms underlying the impaired healing of diabetic wounds. Research has indicated that systemic and local metabolic disorders caused by hyperglycemia and insulin resistance directly drive the senescence process of local wound cells through multiple mechanisms, including mitochondrial dysfunction, oxidative stress, and the accumulation of advanced glycation end products. The accumulated senescent cells further exacerbate inflammation, inhibit repair cell function, and disrupt angiogenesis through the secretion of the senescence-associated secretory phenotype (SASP), thereby forming a vicious cycle. In terms of therapeutic strategies, various interventions have been developed, such as the selective clearance of senescent cells, SASP functional regulation, and metabolic reprogramming of senescent cells. Among these, natural products exhibit unique and irreplaceable advantages because of their multicomponent and multitarget characteristics: they can directly affect senescent cells and the SASP, synergistically regulate core signaling pathways, and reprogram metabolism while modulating the local microenvironment. The systematic integration of traditional compound therapies provides a rich arsenal for targeting senescence in diabetic wound treatment. Concurrently, the application of innovative delivery systems, such as smart-responsive hydrogels and microneedles, has effectively overcome the clinical translation bottlenecks posed by the inherent physicochemical properties of natural products. With the deepening integration of multidisciplinary approaches, the therapeutic paradigm for diabetic wounds is shifting from traditional empirical models to precision medicine, opening new avenues to overcome the therapeutic impasse of diabetic chronic wounds and achieve functional tissue repair.

Chronic inflammation has long been recognized as a major risk factor for and a causal contributor to cardiovascular disease (CVD). However, advances in omics technologies and deepening insights into CVD pathogenesis have expanded our understanding of the underlying mechanisms. Inflammation is now seen not as an isolated cause, but as one of several biological responses to cumulative tissue damage over time. In this Review, we propose that inflammation initially functions as a resilience mechanism, acting to resolve molecular and cellular damage driven by environmental stressors and intrinsic age-related entropy. With ageing, however, this protective response can become dysregulated and maladaptive, promoting collateral pathological changes. We illustrate this theory through two examples, atherosclerosis and age-related impairment of tissue perfusion, and support these conceptual models using proteomic data from large population studies with cardiovascular outcomes. Our findings reaffirm the central role of inflammation in CVD pathophysiology, but also indicate that the upstream biological driver of inflammation is molecular damage that is either not readily prevented or repaired by inadequate resilience mechanisms. Understanding the coordination of these responses offers new opportunities for targeted prevention and treatment of CVD.

Understanding how brain tissue properties change with age is crucial for identifying early markers of neurodegenerative disease. However, the biophysical alterations and their molecular bases remain poorly understood. Quantitative MRI (qMRI) offers non-invasive insight into brain tissue properties. In this study, we employed three qMRI metrics-quantitative susceptibility mapping (QSM), longitudinal relaxation rate (R1), and effective transverse relaxation rate (R2*)-to investigate age-related brain changes across the adult lifespan. Applying linear and nonlinear modeling, we observed distinct patterns of cross-sectional age-related biophysical alterations (early, late, and inverted-U patterns) in the human brain. Predictive modeling identified subcortical and thalamic regions as key contributors to age estimation. Integrating transcriptomic data revealed that these imaging-derived patterns spatially co-localize with gene expression signatures enriched in neurodevelopmental and neurodegenerative pathways. Our study advances current understanding by integrating multimodal qMRI age-related patterns and transcriptomics, uncovering distinct aging patterns, candidate age-sensitive imaging features that warrant further validation, and their potential molecular underpinnings.

Mitochondrial DNA release into the cytosol is a critical event in innate immune activation, often acting as a damage-associated molecular pattern (DAMP) that triggers inflammasome assembly. Here, we demonstrate that NLRP3 is involved in the release of D-loop mtDNA into the cytosol. We further show that NLRP3 interacts with NLRP10. NLRP10-mediated oxidized DNA cleavage involves a Schiff base intermediate and is inhibited by small molecules known to inhibit glycosylases. These findings support a model where NLRP10 interaction with oxidized DNA may contribute to long-term senescence secretory phenotype and modulate inflammasome activation. Our study highlights a novel mechanism by which NLRP10 can respond to mitochondrial stress signals to influence innate immunity and suggests therapeutic potential for targeting these interactions in inflammatory diseases.

Skin vascular aging is characterized by a specific loss of capillary-associated macrophages (CAMs), driven by impaired local proliferation. This depletion causes microvascular dysfunction. Restoring CAMs via colony-stimulating factor 1 stimulation improves capillary flow, identifying a promising therapeutic target for aging-related and diabetic vascular complications.

Oscillations between lipid anabolism and catabolism are essential for maintaining cellular health during metabolic fluctuations. Fasting, a conserved determinant of aging, improves disease outcomes and extends lifespan, yet the relative contributions of lipid catabolism versus its attenuation to fasting-induced longevity remain unresolved. The metabolic flexibility of C. elegans under variable nutrient availability provides a powerful system to address this question. We show that lifespan extension from fasting depends not on sustained activation of lipid catabolism, but on its silencing upon nutrient replenishment. The fasting-responsive nuclear hormone receptor NHR-49 activates β-oxidation; however, unlike classical ligand-regulated receptors, NHR-49 is regulated through ligand-independent mechanisms involving cofactor-mediated transcriptional attenuation and protein turnover. We identify casein kinase 1 alpha 1 (KIN-19) as a key regulator of metabolic plasticity and fasting-induced longevity that silences β-oxidation via primed phosphorylation of NHR-49. Thus, cooperative ligand-independent silencing of this conserved nuclear hormone receptor promotes fasting-associated longevity.

SIRT7 has been implicated in diverse physiological and pathological processes, yet its role in sexual dimorphism and the underlying molecular mechanisms remain insufficiently explored. Given that ERα-mediated estrogen signaling is a central regulator of sexual dimorphism and that ERα undergoes stringent quality control to preserve signaling sensitivity, we investigated whether SIRT7 and ERα are mechanistically connected. Here, we identify SIRT7 as a molecular inspector that safeguards the quality of estrogen receptor α (ERα) to fine-tune estrogen signaling through the regulation of ERα proteostasis. Under estrogen-deprived conditions or in the presence of misfolded ERα, SIRT7 deacetylates ERα and promotes its degradation through the E3 ubiquitin ligase STUB1, thereby maintaining a functional receptor pool and preserving estrogen responsiveness. During this process, deacetylated ERα competes with SIRT7 for STUB1 binding, an E3 ligase that is also required for SIRT7 protein turnover, thus leading to SIRT7 stabilization. As a feedback mechanism, upon estrogen (E2) stimulation, E2-bound ERα activates non-genomic MAPK signaling to trigger SIRT7 degradation via another E3 ligase UBR5, which ensures the proper receptor signaling activation. Given the central role of ERα in aging and hormone-related cancers, our findings highlight SIRT7 as a key regulator linking age-associated disorders and hormone-driven tumorigenesis.

An age-related decline in vasodilation mediated by neurovascular nitric oxide (NO) and vasoconstriction driven by the Piezo1 receptor precede the aggregation of soluble brain proteins such as amyloid-{beta} (A{beta}), which then causes further disruption of brain solute homeostasis, ultimately leading to neurodegeneration in Alzheimers disease. Preclinical studies show that restoring these vascular functions increases neurofluidic efflux and improves cognitive outcomes. Here, we tested effects of sublingual NO and/or Piezo1 receptor-targeted mechanotransductive whole-body vibrations (WBVp) in healthy adults (n = 29) on brain fluid dynamics and CNS-to-blood protein efflux using multimodal neuroimaging and blood biomarker analysis. The combined vasomechanic interventions (NO+WBVp) produced a synergistic enhancement of brain fluid transport and markedly increased the efflux of soluble brain-derived proteins (A{beta}40&42, glial fibrillary acidic protein) into the bloodstream. The effects increase with age and the magnitude of NO-induced hypotension. Importantly, the combined intervention was well-tolerated, with no severe adverse physiological responses. Results demonstrate that a simple, non-invasive vasomechanic intervention can transiently promote brain-to-blood protein clearance in humans, highlighting a potentially safe and accessible therapeutic avenue for neurodegenerative conditions characterized by impaired brain solute removal and protein aggregation.

Apostichopus japonicus is a traditional medicinal and culinary species, with existing anti-aging research primarily focusing on its bioactive peptides. In contrast, the anti-aging potential of its major polysaccharide, fucoidan (Aj-FUC), remains largely unexplored. Since the intestine is a central target in the aging process and the primary site for polysaccharide interaction, this study investigates the protective effects and underlying mechanisms of Aj-FUC against d-galactose (d-Gal)-induced intestinal senescence in mice.

Aging is a major public health challenge that urgently requires effective pharmacological interventions. We previously identified mitochondrial malate dehydrogenase 2 (MDH2) as a regulator of aging and discovered that the approved drug glibenclamide (Gli) can inhibit MDH2 and delay aging, but is limited by weak potency and hypoglycemia. Herein, we employed a rational secondary development strategy to optimize Gli and discovered compound

In the heterochronic parabiosis model it has been shown that blood from elderly animals exhibits markedly reduced rejuvenating effects compared to that of young organisms. Furthermore, human plasma from older subjects, when used as a supplement in cell culture media, is significantly less effective than plasma derived from younger individuals. This study analyzed plasma from a cohort of 229 subjects by a proteomic approach to reveal age-related changes.

In mosquitoes, reactive oxygen and nitrogen species (ROS and RNS) are immune effectors, byproducts of metabolism, and regulators of homeostasis. However, imbalances in ROS and RNS cause oxidative stress. Given that warmer temperature accelerates the aging-dependent weakening of immunity, we hypothesized that temperature and aging interactively modify the production of ROS/RNS like nitric oxide, and their effects. We tested this in Anopheles gambiae by rearing mosquitoes at 27C, 30C and 32C, and assessing phenotypes at 1, 5, 10 and 15 days of adulthood. Using NADPH diaphorase staining, we show that, in mosquitoes infected with bacteria, warmer temperature increases the activity of nitric oxide synthase (NOS; produces nitric oxide), while aging decreases NOS activity. Importantly, during late aging, warmer temperature reverses the aging-dependent decline in NOS activity. By mining an RNAseq dataset, we uncovered that warmer temperature and aging interact to increase the expression of both NOS and JNK, which are involved in immunity and oxidative stress. Additionally, warmer temperature and aging interact to downregulate expression of genes encoding antimicrobial effectors and superoxide detoxification enzymes, but upregulate expression of genes involved in hydrogen peroxide detoxification. Finally, manipulating nitric oxide production modifies the expression of immune genes in a temperature and age dependent manner. These findings suggest that heightened oxidative stress caused by warmer temperature accelerates senescence.

The 10-year Action for Health in Diabetes (Look AHEAD) clinical trial compared a multidomain intensive lifestyle intervention to a diabetes support and education program with respect to major cardiovascular disease events (primary outcome) and other diabetes- and obesity-related outcomes. Follow-up of the cohort continues to add other aging-related outcomes and conditions to identify the long-term consequences of factors related to lifestyle and medical care. In this transition to a study of aging among individuals at risk for accelerated aging due to type 2 diabetes and overweight or obesity, the investigators have retrospectively reframed the study using the perspective of geroscience. This perspective strengthens the importance of lifestyle changes as a core component for medical care for these individuals to slow biological aging.

This study investigates how healthy aging affects four core semantic memory processes: activation, inhibition, selection, and controlled retrieval. Two experimental paradigms were adapted in French to assess these mechanisms: a Lexical Decision Task (LDT) using ambiguous and monosemic words to examine automatic activation and inhibition, and a Cue-to-Target Association Task (CTTAT) to evaluate executive processes such as selection and controlled retrieval. For this purpose, 100 older (66.94±4.49) and 75 younger (26.64±5.87) adults were tested. Results from the LDT showed that both younger and older adults benefitted from semantic priming when processing dominant meanings and monosemic associates. In contrast, subordinate meanings and unrelated targets produced slower responses, suggesting the involvement of inhibitory mechanisms. These effects were consistent across age groups, indicating preserved early-stage activation and inhibition with aging. In the CTTAT, results showed that participants were more accurate when associating based on perceptual features than on overall meaning. While older adults preserved controlled retrieval abilities, they showed vulnerability selection process, especially in the presence of semantic distractors. Overall, the findings indicate that aging selectively affects semantic selection, whereas activation, early inhibition, and controlled retrieval remain largely intact. Together, these findings challenge global decline models of cognitive aging by showing selective effects on interference control. This work offers an integrated framework for assessing semantic control across the lifespan and lays the groundwork for future research on the interplay between automatic and controlled processes in semantic memory.

The intestine plays a crucial role in regulating metabolism and immunity, with functional decline occurring during injury and ageing. Stimulating the neogenesis of intestinal stem cells (ISCs) by activating the WNT/β-catenin signalling pathway represents a promising approach for intestinal tissue regeneration and injury repair. However, effective oral delivery of functional WNT signalling agonists to the gut remains challenging. Herein, we report a potent WNT/β-catenin signalling-inducing small extracellular vesicles (sEV) that can be administered orally and present remarkable therapeutic efficacy. We demonstrate that active R-spondin1 (RSPO1) protein can be loaded onto the surface of sEV via heparan sulfate proteoglycans. Notably, sEV-delivered RSPO1 (evRSPO1) effectively induces WNT/β-catenin signalling-inducing activity, enhances ISCs proliferation, and supports intestinal organoid growth in vitro. Importantly, oral administration of evRSPO1 activates the WNT/β-catenin signalling pathway in the cryptic stem cell niche, thereby accelerating tissue repair and regeneration in a radiation-induced intestinal injury model. Furthermore, evRSPO1 treatment induces ISCs proliferation and reverses the intestinal senescence phenotype in aged mice. Collectively, this study establishes evRSPO1 as a potential first-in-class, orally deliverable therapeutic that overcomes biological barriers to activate ISCs, enabling efficient intestinal tissue repair and rejuvenation.

Sarcopenia is an aging-related skeletal-muscle disorder characterized by progressive loss of muscle mass, strength, and function, and it frequently co-occurs with chronic liver disease (CLD) and other comorbidities. Conventional approaches struggle to resolve its pronounced heterogeneity, whereas multi-omics technologies now offer a systematic, molecular-level avenue to dissect its pathogenesis. By integrating ten omics studies of sarcopenia and six of CLD-associated sarcopenia, we propose a dual-layer "commonality-specificity" framework. At the level of commonality, we identify four core pathological pillars: proteostasis imbalance, mitochondrial dysfunction, chronic inflammation, and dysregulation of the gut-muscle axis. At the specificity level, focusing on the CLD context, we observe that these networks are selectively perturbed within the liver-disease microenvironment, leading us to advance the "cooperative accumulation of multiple weak signals" hypothesis to explain how multi-axis crosstalk drives muscle wasting in this setting. To date, omics findings remain largely correlational, posing challenges for clinical translation. Future investigations should integrate cutting-edge technologies-such as single-cell multi-omics, spatial transcriptomics, and computational modeling-to shift the research paradigm from static profiling to dynamic mechanistic dissection and precision intervention. This review provides both a theoretical foundation and a developmental roadmap for comprehensively understanding the mechanisms underlying sarcopenia comorbidities and for achieving precision diagnosis and treatment.

Accelerated biological aging serves as a risk factor for age-related diseases, its role in the prognosis of PD remains ambiguous. This study investigates the association between biological aging and the mortality in PD patients. Data were sourced from the UK Biobank. Independent prognostic factors for mortality in PD patients were assessed by Cox regression model, and a nomogram was developed to predict the survival of PD patients. A total of 569 PD patients were enrolled in this study. Phenotypic age (PhenoAge) and PhenoAge acceleration (PhenoAgeAccel) were found to affect the survival in PD patients. Independent risk factors for PD mortality included age, male gender, smoke, underweight, depressive mood, low-density lipoprotein, and higher genetic susceptibility. The nomogram constructed based on PhenoAge showed robust prediction performance for mortality in PD patients. PhenoAge emerges as a pivotal PD mortality predictor, enabling the identification of individuals experiencing accelerated biological aging and implementing targeted interventions.

The integrated stress response (ISR) and mitochondrial unfolded protein response (UPR

Dendritic Cells are central players of our immune system, linking innate sensing to adaptive immunity through antigen presentation and T cell priming. Beyond transcriptional and cytokine-based regulation, mitochondria are emerging as potential regulators of Dendritic Cell biology. While still in its infancy, evidence is accumulating that mitochondrial pathways affect Dendritic Cell differentiation; that mitochondrial remodeling and bioenergetic rewiring underpin Dendritic Cell maturation and activation in response to pathogenic and inflammatory stimuli and that shifts in mitochondrial and redox dynamics, reactive oxygen species production and mitochondrial DNA release coincide with Dendritic Cell activation and co-stimulatory molecule expression. Mitochondria are furthermore involved in regulating Dendritic Cell migration by influencing cellular metabolism and cytoskeletal dynamics and support the antigen processing and presentation machinery, thereby dictating the quality of the initiated T cell response. Importantly, mitochondrial checkpoints also regulate Dendritic Cell survival, balancing immune activation with timely cell death to preserve immune homeostasis. While the exact pathways of mitochondrial regulation are just beginning to be understood, disruptions in these programs can be far reaching. During aging, progressive mitochondrial dysfunction has been associated with impaired Dendritic Cell differentiation, diminished antigen presentation and impaired T cell responses. Similar defects have been observed in chronic diseases and cancer, leading us to hypothesize that genetic disorders linked to mitochondrial dysfunction also lead to defects in Dendritic Cell biology, impacting clinical symptoms such as immune dysregulation, heightened infection risk and inappropriate chronic inflammation. Therefore, in this review we have summarized the emerging roles of mitochondrial regulation in Dendritic Cell biology and discuss therapeutic opportunities to restore immune competence by targeting mitochondrial and redox pathways in settings of Dendritic Cell dysfunction. These insights aim to encourage further research into these topics and propose targeted metabolic reprogramming as a new therapeutic strategy for healthy ageing and chronic disease management.

BackgroundChronic inflammation predicts adverse cardiovascular outcomes, but mechanisms linking systemic inflammation to cardiac remodeling remain incompletely understood. We investigated associations between circulating inflammatory biomarkers and cardiac phenotypes in a population-based cohort and examined how environmental exposures and genetic susceptibility influence inflammatory responses. MethodsWe analyzed subsets of 488,079 UK Biobank participants with metabolomic and proteomic profiling, cardiac magnetic resonance (CMR) imaging, and longitudinal outcomes. Chronic inflammation was quantified using glycoprotein acetyls (GlycA) by nuclear magnetic resonance spectroscopy. Machine learning-based analysis extracted CMR phenotypes. Multivariable linear regression assessed GlycA-cardiac associations. Mediation analysis tested 80 inflammatory proteins as potential mediators. Cox models evaluated GlycA levels and major adverse cardiovascular events (MACE). An exposome-wide association study identified environmental determinants of inflammation, and gene-environment interactions were assessed using multi-ancestry polygenic risk scores. ResultsHigher GlycA levels were associated with restrictive cardiac remodeling: reduced left ventricular indexed end-diastolic volume ({beta} = -2.09) and stroke volume ({beta} = -1.12) with compensatory increased heart rate ({beta} = 1.38; all P < 10-228). Interleukin (IL) -1 receptor antagonist mediated 27% of the GlycA effect on end-diastolic volume (average causal mediated effect -0.51 [95% CI, -0.53 to -0.64]; P < 10-16). The highest GlycA quintile had 43% higher MACE risk versus the lowest (adjusted HR, 1.43 [95% CI, 1.38-1.49]). Trunk fat mass ({beta} = 0.35), current smoking ({beta} = 0.39), psychological distress, and low socioeconomic status were the strongest GlycA determinants (all P < 10-50). Cardiovascular polygenic risk scores modified associations between environmental exposures, inflammation, and MACE. ConclusionsChronic systemic inflammation is associated with restrictive cardiac remodeling and increased cardiovascular risk mediated by circulating cytokines and growth factors. Individual inflammatory responses are shaped by gene-environment interactions, highlighting the complex interplay between genetic susceptibility, environmental exposures, and their cumulative impact on cardiovascular health.

Skeletal muscle aging (sarcopenia) is associated with reduced peak oxygen consumption (VO peak) during exercise, a key determinant of physical function and overall health. However, the molecular mechanisms linking muscle aging to low VO peak remain poorly understood. We aimed to identify miRNA signatures and miRNA-gene regulatory networks associated with VO peak in older adults. Using small RNA and mRNA sequencing, we analyzed skeletal muscle from 72 SOMMA participants (70-79 years old) with low or high VO peak (n = 18/group) and from 36 participants spanning the full VO peak spectrum. Differential expression was assessed using LIMMA, with pathway and network analyses performed using Ingenuity Pathway Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA). We detected 1,408 miRNAs and 16,210 genes; among these, 14 miRNAs and 2,018 genes were differentially expressed (FDR < 0.05). The 14 miRNAs regulated 142 genes, and expression of 10 miRNAs inversely correlated with 50 genes enriched in mitochondrial, sirtuin-1, and nitric oxide signaling pathways. Regression analyses identified 21 miRNAs and 1,744 genes significantly correlated with VO peak after adjusting for age and sex. WGCNA revealed 10 co-expression modules associated with VO peak, with the cyan module showing the strongest correlation and enrichment for nitric oxide signaling genes. These findings highlight novel miRNA-mediated molecular pathways potentially contributing to low VO peak and skeletal muscle aging in older adults. Future studies will further investigate these miRNA-gene interactions to uncover therapeutic targets for preserving muscle function with age.

Type I collagen is the main structural protein of vertebrates and forms molecular trimers from the COL1A1 and COL1A2 gene products: proα1α(I) and proα2α(I), during biosynthesis. Calcium ions are required for trimers to form. The amino acid sequence of the C-propeptide of collagen, which is removed before collagen fibril formation, initially drives heterotrimerisation. Abnormal homotrimeric type I collagen is associated with age-related diseases including cancer, fibrosis, musculoskeletal and cardiovascular conditions but the circumstances under which the homotrimer may form are poorly understood. Here we used molecular dynamics simulations of the C-propeptide protein structure to show that inter- and intra-chain hydrogen bonding is affected by loss of calcium and that this leads chains to become destabilised, particularly at the interfaces of each chain. Loss of calcium resulted increased distances between the cysteine residues that form inter-chain disulphide bonds, preventing the formation of these bonds. Pulling simulations and modelling of calcium dissociation from monomers showed that calcium ions were more strongly bound to the α1(I) than the α2(I) chain. However, enhanced sampling methods implied the α2(I) chain has a higher trimer affinity than a third α1(I) chain in the presence of structural calcium. To quantify assembly thermodynamics, we computed relative binding free energies by alchemical thermodynamic integration, demonstrating that α2(I)-specific residues at the interchain interface conferred a measurable thermodynamic advantage to trimer formation in the presence of calcium. Hence although heterotrimerisation is normally favoured, in reduced calcium conditions the homotrimer can form by sequestering available calcium to the α1(I) chains. This study provides a molecular explanation for a calcium-based mechanism driving heterotrimerisation versus homotrimerisation of type I collagen.

As the world's population ages, the focus of healthcare is shifting from extending life span to promoting health span. There is an unmet need to identify sensitive and reliable markers of health span through more cost-effective and non-invasive methods, to enable early and effective intervention on modifiable aging factors. The eye offers a unique window into systemic health, providing direct visualization of the body's vascular and neural health. This review presents an overview of how various ocular structures can serve as biomarkers of health span-drawing on insights from ocular imaging, metabolomics, and proteomics, with evidence from basic science, animal models, and human clinical trials. The role of artificial intelligence (AI) in predicting biological age and the risk of age-related systemic conditions is also highlighted, with a focus on current applications and how AI is being integrated to synthesize and interpret multimodal data.

Are there individuals who resist episodic memory decline into older age? Analyzing 728,000 memory tests from 80,000 participants with at least 4 assessments, we introduce a simulation-calibrated framework to identify genuine memory stability. Across cohorts and models, [~]10% of adults [≥]70 years showed stable performance over a decade. In an MRI subgroup (n{approx}2,000), stable performers exhibited lower rates of brain atrophy across widespread regions, anchoring cognitive stability in structural brain maintenance. However, stability was often transient rather than trait-like: many individuals followed trajectories with extended plateaus of stable performance punctuated by episodes of accelerated decline. Accordingly, 54% showed at least one period of observed stability, averaging 10 years, whereas only 0.4% upheld stable performance over 24 years under the strictest definition. These findings are consistent with a complex-systems model of cognitive aging in which decline often reflects critical transitions rather than continuous erosion.

Maladaptive inflammation and cellular senescence contribute to diabetic kidney disease (DKD) pathogenesis and represent important therapeutic targets. Senolytic agents selectively remove senescent cells and reduce inflammation-associated tissue damage. In our pilot clinical trial in patients with DKD, the senolytic combination dasatinib plus quercetin (D + Q) reduced systemic inflammation, senescent cell abundance, and macrophage infiltration in fat. However, D + Q senotherapeutic effects on diabetic kidney injury, senescence, inflammation, and geroprotective factors have not been established.

Myeloid skewing is a central and therefore often cited hallmark of hematopoietic aging. Myeloid skewing refers to an elevated myeloid-to-lymphoid cell ratio in aged compared to young mice. Interestingly, whether the extent of myeloid skewing might be in itself a quantitative biological marker of aging has not been addressed yet, nor whether this parameter has also relevance for the extent of aging in humans. Aged mice with high level of myeloid skewing (>50% myeloid cells in blood) showed accelerated hematopoietic aging compared to mice with a low level of myeloid skewing (<30% of myeloid cells in blood), as well as an increased level of inflammatory cytokines and elevated levels of diseases. Hematopoietic stem cells (HSCs) from mice with high myeloid skewing showed an impaired repopulation capacity. Epigenetic clock analyses demonstrated that mice with a high level of myeloid skewing present with a biological age that is older than their chronological age. In humans, a high degree of myeloid skewing was associated with elevated levels of inflammatory markers, reduced mobility, a greater burden of comorbidities, and an increased mortality hazard ratio. The data support that, besides overall myeloid skewing being a central hallmark of aging in mice, the extent of the frequency of myeloid cells in blood might serve as a biological marker of aging and disease in both mice and humans. Key PointsThe extent of myeloid skewing in aged mice correlates to an increased hematological and epigenetic age and increased disease burden. The extent of myeloid skewing in older adults is associated with an increased hazard ratio of mortality and correlates with higher frailty and inflammatory markers.

To investigate the effect of moxibustion on delaying ovarian aging in naturally aging mice and to explore the underlying mechanisms.

Mitochondrial dysfunction is recognized as a biological hallmark of aging; however, bioenergetic capacity across the healthy human life course remains insufficiently characterized. While aging is generally associated with a systemic decline in mitochondrial function ("age-related bioenergetic decline"), recent research suggests that age-related bioenergetic differences are context dependent. Blood cells are extensively utilized as accessible samples for human bioenergetic profiling; therefore, our goal was to characterize bioenergetic capacity in platelets, peripheral blood mononuclear cells (PBMCs), monocytes, and lymphocytes of healthy adults from the San Diego Nathan Shock Center Clinical Cohort representative of the adult life course (20-80+ years of age). In our sample of 72 adults, we found that chronological age was positively associated with PBMC (maximal respiration [Max] β = 0.147, p = 0.028) and lymphocyte respiratory capacity (Max β = 0.135, p = 0.041). Notably, the pattern of age-related differences varied by sex; age showed a weak positive association with platelet respiration (Max β = 0.219, p = 0.037) in men but not in women. Similarly, age showed a strong positive association with PBMC respiration (Max β = 0.206, p = 0.018) in women but not in men. We also explored the relationship between glycolysis and respiration and found strong positive associations in platelets, PBMCs, and monocytes, but not lymphocytes. It is possible that, despite our cohort consisting of healthy, disease-free individuals, the elevated respiratory capacity in older adults may be reflective of compensatory mechanisms that require further investigation. Nonetheless, these findings underscore the importance of considering biological context, such as donor health, sex, and tissue type, in understanding age-related bioenergetic differences.

Osteoarthritis (OA) and osteoporosis (OP) are prevalent degenerative diseases in the elderly population, often coexisting and sharing a common pathogenic mechanism involving the receptor activator of nuclear factor κB ligand/receptor activator of nuclear factor κB (RANKL/RANK) signaling pathway. Denosumab (DS) has shown efficacy in treating OA and OP. This study aimed to investigate the mechanism through which DS mitigates age-related OA-OP by regulating macrophage polarization. Due to the poor targeting ability of DS to macrophages, we have prepared folate-modified liposomes (Lip-FA) loaded with DS (DS@Lip-FA) target macrophage nanoparticles. Using humanized mouse models of aging, we observed DS@Lip-FA effects on macrophage polarization and the subsequent impact on cartilage and bone tissues. Our results reveal that aging led to an increase in the pro-inflammatory M1 macrophages and a decrease in the anti-inflammatory M2 macrophages in both bone and cartilage tissues, which is correlated with elevated RANKL expression. DS@Lip-FA treatment effectively decreased the number of M1 macrophages and increased the number of M2 macrophages. This shift in macrophage polarization reduced chondrocyte apoptosis, promoted bone marrow mesenchymal stem cell (BMSC) proliferation and osteogenic differentiation, and reduced chondrocyte and BMSC senescence. These findings indicate that DS@Lip-FA exerts its therapeutic effects on age-related OA-OP by regulating macrophage polarization and suggest that DS@Lip-FA is a promising treatment for this complex condition in the elderly population.

Single-measure sleep duration has been extensively studied in association to cognitive impairment. However, this approach overlooks the potential impact of long-term sleep duration trajectories on cognitive function. The present study aims to identify distinct long-term sleep duration trajectories and prospectively assess their association with the risk of cognitive impairment in Chinese elderly individuals.

Frailty increases vulnerability to functional decline, hospitalization, and poor quality of life in older adults. Digital health interventions (DHIs), like mobile applications, wearable devices, and telehealth, show promise in promoting physical activity, self-management, and healthy aging. Thus, the purpose of this study is to thoroughly examine how well digital health treatments can stop or slow the evolution of frailty in older adults who live in the community.

Tongue-muscle associated behaviours (swallow, speech) are impaired in the elderly. In the Fischer 344 (F344) rat model of aging, hypoglossal motor neurons (MNs) and intrinsic tongue muscle weakness and atrophy are evident. Here we evaluated young (6-months) and old (24-months-old) F344 rat longitudinal muscles for neuromuscular junction (NMJ) innervation. In 140µm free floating sections, presynaptic components were labelled with synaptophysin and neurofilament. Postsynaptic acetylcholine receptors were labelled with α-Bungarotoxin. NMJs were imaged using confocal microscopy with presynaptic invasion of the postsynaptic endplate quantified. We found marked denervation of female and male tongue NMJs in old age. Our findings are consistent with the significant role that tongue dysfunction has in aged tongue muscle dysfunction and hypoglossal MN death.

Achilles tendinopathy represents a prototypical musculoskeletal disorder driven by a self-perpetuating "inflammaging" vicious cycle, where chronic inflammation and stem cell senescence mutually reinforce to precipitate tissue failure. Current therapeutics inadequately address the complex intercellular signaling fueling this loop. Herein, we present a reactive oxygen species (ROS)-responsive photothermal cascade nanoplatform (LT-NPs) that couples Licochalcone A delivery with mild near-infrared (NIR) hyperthermia (∼42 °C). Unlike conventional ablative therapies, this platform leverages mild thermal stress as a safe, generalized immunometabolic modulator. Mechanistically, we identify the mitochondrial DNA (mtDNA)-cGAS-STING axis as the pivotal "bridge" connecting mitochondrial dysfunction to immune dysregulation. The LT-NPs-NIR system dismantles this pathology via a synergistic "dual-lock" strategy: (1) mild photothermal heating induces heat shock protein 70 (HSP70) to seal mtDNA leakage; and (2) released Licochalcone A directly inhibits the downstream STING sensor. Crucially, this intervention re-engineers the dysregulated crosstalk between the immune niche and tendon stroma: by reprogramming M1 macrophages toward a reparative M2 phenotype and simultaneously rescuing tendon stem/progenitor cells (TSPCs) from senescence-associated secretory phenotype (SASP)-mediated senescence, the platform effectively uncouples the reciprocal feedback loop between inflammation and degeneration. In vivo, this orchestrated restoration of the microenvironment significantly suppresses heterotopic ossification and recovers biomechanical function. Consequently, the "mild photothermal cascade" concept establishes a versatile therapeutic paradigm, offering a scalable strategy to resolve the intricate inflammation-senescence crosstalk across a broad spectrum of age-related pathologies.

Heart failure (HF) significantly limits survival and decreases quality of life. The global incidence of HF is rising. The pathogenesis of HF is not yet fully understood, which results in the present treatment options still being imperfect. Therefore, there is a need to deepen the knowledge about HF pathogenesis and identify potential therapeutic targets. Aging increases the risk of developing HF. Recently, cellular senescence, a stable state of cell cycle arrest induced by various stressors or genomic damage, has been recognized to be involved in HF pathogenesis. Senescent cells may be involved in the development of age-related diseases. However, cellular senescence may occur in correlation with aging or be age-independent. Its impact is complex, especially since the heart is composed of different cell types, each of which may undergo senescence in diverse ways. Elimination of senescent cells also emerges as a potential treatment option. This article extensively reviews relations between cellular senescence and HF. Moreover, it describes the role of plasma proteins related to cellular senescence as potential biomarkers and prognostic factors in HF. This review also summarizes data concerning therapeutics targeting senescence in the HF context and implicates future research perspectives.

Aging is characterized by progressive physiological decline and increased vulnerability to metabolic and inflammatory disturbances. Palmijihwang-hwan (PM), a traditional East Asian herbal formula, has been used empirically for age-related complaints, but its mechanistic basis remains unclear. Here, we evaluated the effects of early-onset PM administration (starting at 2 months of age) on longevity-related phenotypes and metabolic regulation. PM significantly prolonged lifespan in Caenorhabditis elegans and improved survival in ICR mice without evident toxicity. Preventive PM administration reduced epididymal white adipose tissue (eWAT) mass and circulating insulin/adipokine levels. Lipidomic analysis showed a shift from lysophospholipids toward phospholipids, accompanied by downregulation of PLA2G7, indicating attenuation of adipose inflammation. PM also reshaped the gut microbiota, decreasing inflammation-associated taxa such as Oscillibacter valericigenes, and lowered adipose IL-6 and TNF-α expression. Collectively, these findings indicate that preventive early-onset PM administration modulates the gut microbial composition, counteracting the age-related enrichment of inflammation-related bacteria.

The metabolites produced by the gut microbiota play a role in age-related cognitive decline through the gut-brain axis. Within this axis, trimethylamine N-oxide (TMAO) permeates the intestinal epithelial barrier and enters systemic circulation, triggering inflammation in the central nervous system and ultimately leading to cognitive decline. However, it remains unclear whether exercise training's specific mechanism for delaying age-related cognitive decline is associated with TMAO regulation and inhibition of neuroinflammation. The aging rat model was established by intraperitoneal injection of D-galactose in SD rats, while simultaneous exercise training and TMAO interventions were conducted. The effects of exercise on cognitive function were evaluated using the new object recognition (NOR) test, the Morris water maze (MWM) test, and the radial arm maze (RAM) test. Additionally, the expression levels of TMAO and NLRP3 inflammasome-related proteins in aging rats were measured using enzyme-linked immunosorbent assays (ELISA) and Western blotting (WB), respectively. A D-galactose-induced senescence model was established in HT22 cells. Following TMAO/DMB intervention, SPiDER-β-galactosidase (SPiDER-β-gal)-positive cells and NLRP3 inflammasome-related proteins were analyzed. To validate the regulatory role of TXNIP in TMAO-induced senescence-inflammation phenotypes, knockdown/overexpression experiments were conducted. Trx1-C32S mutant cells were utilized to verify that TMAO enhances the disulfide bond binding affinity between TXNIP and Trx1. Exercise training effectively delayed the cognitive dysfunction induced by D-galactose in aging rats, as evidenced by a 22.6% increase in the discrimination index in the NOR test, an 11.2% prolongation of time in the target quadrant and a 50% enhancement in the number of platform crossings in the MWM test, and a 41.8% improvement in working memory in the RAM test. This neuroprotective effect is potentially mediated through the inhibition of the intestinal metabolite TMAO (with plasma TMAO levels reduced by 40.3%) and subsequent modulation of the TXNIP-NLRP3-Caspase-1-GSDMD inflammatory pathway. The cellular experiments revealed that TMAO/DMB intervention modulates cellular senescence-inflammation phenotypes, with TXNIP acting as a positive regulator of the NLRP3 pathway. TMAO enhances TXNIP-mediated inhibition of the redox system by promoting disulfide bond formation at Trx1-C32, providing cellular-level evidence for the underlying mechanism.

(1) Background: The naked mole-rat (

Long telomere length (TL) extends replicative capacity in vitro, and predisposes to clonal hematopoiesis. We characterized the cancer phenotype in 51 individuals from 24 families with mutant POT1, a negative regulator of telomerase elongation (median age 51, range 5-94). Hematologic malignancies were second in prevalence after melanoma (27%), and lymphoid subsets were more common. They clustered with history of sarcoma, thyroid cancer and chronic myeloproliferative neoplasms. UKB participants with pathogenic POT1 variants had long TL and higher lymphoid malignancy rates (45% by age 80, Hazard ratio 8.28, 95% CI, 5.29-13.0). Across cohorts, diagnoses encompassed acute lymphoblastic leukemia and Hodgkin lymphoma in children/young adults, and chronic lymphocytic leukemia/multiple myeloma in adults. They clustered in families manifesting as autosomal dominant pan-lymphoma with genetic anticipation at times. Lymphocyte TL was longer than granulocytes at baseline (age-adjusted mean +1 kb, P<0.0001), and was preserved longitudinally with aging. Ultra-long lymphocyte TL >99th percentile was more sensitive for identifying pathogenic variants (58% vs. 38% for granulocytes). Among asymptomatic POT1 variant carriers, 60% (12 of 20) had immunophenotype-detected B and/or T cell clonality with complete penetrance after age 65 (7 of 7). IGH CDR3 sequencing supported age-dependent pruning of the B cell repertoire, and cytogenetic and next-generation analyses uncovered preclinical clonal lymphoma-associated changes in nearly all POT1 variant carriers older than 60 (9 of 10). Our data identify extended cellular longevity due to long TL as an inherited risk factor for lymphoma explaining its syndromic association with solid tumors, and in some cases, myeloproliferative neoplasms.

Senescent cells (SCs) accumulate with aging and contribute to the development of age-related pathologies. These cells evade apoptosis through upregulation of senescent cell anti-apoptotic pathways (SCAPs), making their selective elimination, a strategy termed senolysis, a promising therapeutic avenue. Proteolysis-targeting chimeras (PROTACs) represent an emerging class of bifunctional molecules that exploit the ubiquitin-proteasome system to degrade specific target proteins. By concurrently binding a protein of interest and an E3 ubiquitin ligase, PROTACs catalyze the degradation of SCAP components, offering a novel pharmacological approach to clear SCs. This review summarizes the principles and recent advances in PROTAC technology, with a focus on its application as a senolytic strategy. We highlight how PROTACs can overcome limitations of conventional inhibitors, such as targeting "undruggable" SCAP proteins, and provide a comparative analysis of major PROTAC classes targeting BCL-2 family members, p53, BRD4, SA-β-gal, and other emerging senescence regulators. Furthermore, we also discuss the aging-specific biological and translational challenges, including altered proteasomal activity, pharmacokinetics, tissue microenvironment, and immune clearance, that must be addressed to advance PROTAC senolytics toward clinical use in age-related diseases.

Chronic wounds, especially diabetic foot ulcers, pose a major clinical challenge due to persistent inflammation, impaired angiogenesis, and cellular senescence. Senolytic therapies, which selectively eliminate senescent cells, have shown promise in promoting healing, but systemic toxicity limits their application. To address this, we developed an asymmetric fabric-based composite platform for localized senolytic delivery. Using single-cell RNA sequencing, we characterized senescence-associated alterations in human diabetic foot ulcer tissues and screened several senolytic candidates in skin fibroblasts and endothelial cells. Among these, navitoclax (ABT-263) emerged as the most effective senolytic. Incorporating ABT-263 into the fabric-based platform to prepare ABT-263-CGH, we confirmed its ability to reduce senescent cell burden while maintaining biocompatibility. In a diabetic mouse model, the ABT-263-CGH significantly enhanced wound healing, reduced senescence markers, and exhibited no detectable systemic toxicity. These findings highlight the potential of localized senolytic therapy using an asymmetric fabric-based wound dressing as a novel strategy for enhancing chronic wound healing, offering a promising therapeutic avenue for diabetic wound management, and paving the way for future clinical applications.

Aging is accompanied by a decline in physiological function and increased vulnerability to disease, with mitochondrial dysfunction and epigenetic alterations recognized as key hallmarks. Nicotinamide riboside (NR), a vitamin B3 precursor to NAD, and high-intensity interval training (HIIT) have both been proposed to ameliorate aging-related mitochondrial decline, but their effects on skeletal muscle epigenetic aging are not fully elucidated. Here, we assessed the impact of 5-month NR supplementation and 4-6 weeks HIIT on epigenetic age acceleration (EAA, via seven epigenetic clocks) in human skeletal muscle across three independent studies. NR supplementation was associated with reduced muscle EAA, particularly when measured with the PCHannum, MEAT, and DunedinPACE clocks, while HIIT produced opposite effects in some clocks, notably increasing pace of aging by DunedinPACE. Correlation analyses revealed that changes in skeletal muscle mitochondrial content correlated with changes in MEAT-derived EAA after NR and 6-weeks of HIIT. Together, these findings indicate that skeletal muscle epigenetic aging can be modulated by NR and HIIT interventions but in opposing directions, highlighting a potential link between mitochondria abundance and epigenetic clocks. Further studies are warranted to clarify how NR and exercise regulate epigenetic aging. These results offer new insights into development of strategies for promoting epigenetic outcomes and healthy aging.

Aging is associated with profound alterations in immune cell composition and function, yet the impact on peripheral γ/δ T-cell subsets remains incompletely understood. Here, we show that the peripheral γ/δ T-cell compartment is markedly remodeled with age in mice. Specifically, innate-like Ly-6C

Frailty is a prevalent syndrome in older adults and is associated with increased vulnerability to adverse health outcomes. Growth differentiation factor 15 (GDF-15), a cytokine involved in mitochondrial dysfunction and inflammation, has been proposed as a potential biomarker for age-related conditions. Evidence on the association between GDF-15 and frailty in older adults is limited. This study explores the relationship between plasma GDF-15 levels and frailty onset in community-dwelling older adults.

The Active Gains in Brain Using Exercise During Aging (AGUEDA) trial examined the effects of a 24 week resistance exercise (RE) intervention on executive function (EF) and other cognitive domains in cognitively normal older adults.

The 77PD quinone (77PDQ), a member of PPDQs family, can be frequently detected in environment and bioavailable to organisms. In nematodes, toxicity of 77PDQ on longevity and healthspan and underlying mechanism were determined. Exposure to 0.1-10 μg/L 77PDQ reduced lifespan and inhibited healthspan indicated by change of locomotion behavior during the aging. 77PDQ was accumulated in mitochondrion, and caused mitochondrial dysfunction. Activities of mitochondrial complex I/II and expression of component genes for complex I/II were inhibited by 77PDQ, and RNAi of component genes of gas-1 and mev-1 strengthened 77PDQ toxicity on longevity and healthspan. Additionally, expressions of hsp-6/60, mitochondrial UPR (mt UPR) marker genes, were inhibited by 10 μg/L 77PDQ, suggesting induction of suppression in mt UPR. 77PDQ toxicity on longevity and healthspan was also exacerbated by hsp-6/60 RNAi. Pharmacological treatment with cuminaldehyde inhibited 77PDQ toxicity on longevity and healthspan and in causing suppression in mt UPR. This beneficial effect of cuminaldehyde could be disrupted by gas-1, mev-1, hsp-6, and hsp-60 RNAi, which further confirmed role of these mitochondrial signals in controlling 77PDQ toxicity. Therefore, risk of 77PDQ exposure in inhibiting longevity and healthspan was suggested, which was associated with dysregulation of mitochondrial signals.

Nuclear Mouse ID Associated 1 (MIDA1), also known as Hsp40/DNAJC2 and ZRF1, plays a key role in the establishment of neural progenitors in the brain. In the cytoplasm, MIDA1 ensures proper protein folding, which, if disrupted, can lead to protein misfolding and ultimately neurodegeneration. Thus, MIDA1 is crucial for maintaining brain cell homeostasis. However, it remains unclear whether neurons and astrocytes express MIDA1 equally, whether the distribution of MIDA1 between the nucleus and cytoplasm differs, and if this difference changes with age. Therefore, we evaluated MIDA1 content and distribution in neurons and astrocytes of the CA1, CA3, and dentate gyrus (DG) in 3- and 12-month-old mice. The results indicated that, relative to the nucleus, cytoplasmic MIDA1 content is higher in neurons and astrocytes at both ages. An overall reduction of MIDA1 in the nucleus of neurons was noted with age, while the three-month-old mice displayed increased cytoplasmic MIDA1. In contrast, astrocytes exhibited similar levels of MIDA1 in the nucleus across the hippocampal regions analyzed. However, astrocytes from the CA1 and CA3 regions in the 12-month-old group showed increased cytoplasmic MIDA1 content. Lastly, a comparison of MIDA1 immunofluorescence between neurons and astrocytes revealed that astrocytes exhibit lower nuclear MIDA1 levels at both ages. Notably, at 12 months, cytoplasmic MIDA1 levels were higher in astrocytes than in neurons. Given that MIDA1 function depends on its subcellular location, our results suggest that MIDA1 undergoes more dynamic changes in the cytoplasm across different hippocampal areas, becoming more pronounced in astrocytes at 12 months. Thus, the chaperone role of MIDA1 may be particularly crucial as astrocytes and neurons age, coinciding with the appearance of age-related cognitive deficits detected in the novel object recognition test.

Sarcopenia is a major health concern characterized by progressive loss of muscle mass and function among the elderly. Its prevalence ranges from 10% to 27% in individuals over 60 and increases further in those above 80. The condition reduces mobility and strength, increasing risks of falls, fractures, and other age-related health issues. The ubiquitin-proteasome system (UPS) plays a central role in muscle protein degradation and contribute to muscle wasting. However, therapeutic strategies targeting this pathway remain poorly understood. This study aimed to identify ubiquitination-related genes as potential therapeutic targets for sarcopenia using integrative bioinformatics analysis. This study utilized bioinformatics approaches to identify potential therapeutic targets for sarcopenia. Six GEO datasets (GSE136344, GSE28422, GSE1428, GSE8479, GSE9103, and GSE38718) were analyzed. Data were pre-processed, normalized, and batch effects were removed using the R packages "affy" and "sva." Differentially expressed genes were identified using the "limma" package. Weighted gene co-expression network analysis was performed to identify disease-associated genes. Functional enrichment analyses were conducted using the "clusterProfiler" package for Gene Ontology (GO) is a standardized, structured vocabulary (ontology) for describing the functions of genes and gene products across all species and Kyoto Encyclopedia of Genes and Genomes (KEGG) is a comprehensive database resource that integrates genomic, chemical, and systems-level functional information pathways. Differentially ubiquitinated genes were identified by intersecting differentially expressed genes with ubiquitination-related genes from MSigDB. Protein-protein interaction networks were constructed using STRING, and machine learning algorithms were applied to screen for diagnostic signature genes. Drug-gene interactions were analyzed using DGIdb, and molecular docking was performed using AutoDock. A total 734 differentially expressed genes were identified, including 373 up-regulated and 361 down-regulated genes. Gene set enrichment analysis revealed significant enrichment in 3 KEGG pathways. Weighted gene co-expression network analysis identified 1016 disease-associated genes for functional enrichment. Thirteen differentially ubiquitinated genes were identified, and 6 key diagnostic signature genes (CBLB, PSMD6, RNF115, SMAD3, UCHL3, and ZBTB16) were selected through machine learning. Five genes (CBLB, RNF115, SMAD3, UCHL3, and ZBTB16) exhibited significant differences between older and younger groups, with ROC AUC values > 0.7. Drug prediction identified ASPARTIC ACID and CETYLPYRIDINIUM as potential agents targeting CBLB and SMAD3. This study identified key differentially ubiquitinated genes with potential therapeutic implications for sarcopenia. The findings highlight the importance of the UPS in muscle wasting and provide a foundation for further mechanistic and therapeutic research.

In mammals, thyroid hormones (THs) and their metabolites exert their regulatory effects on metabolism, oxygen consumption, energy generation and expenditure, and gene expression via genomic and non-genomic mechanisms by binding to different types of THs receptors. THs binding to nuclear receptors engages the genomic pathway, while binding to receptors on mitochondria or cell membrane receptors located on thyrointegrins initiates nongenomic mode of actions. In this contribution, we review the effects of THs and their metabolites on mitochondrial structure and functions, including both classical and non-canonical features, in various pathophysiological conditions, focusing on aging, stemness, and cancer. Our analysis indicates that nongenomic mode of actions of THs on mitochondria appear affected during aging and its alterations may contributed to development of cancer and other aging-associated disorders.

Cellular senescence is a stress-induced cellular state that contributes to tissue dysfunction, chronic inflammation, and a broad range of aging-associated pathologies. The accumulation of senescent cells (SnCs) disrupt normal tissue function, positioning them as drivers of pathological decline and therapeutic targets for aging intervention. Accordingly, multiple senescence-targeted strategies have been developed, including senolytics, senomorphics, senescence immunotherapy, and restoration-oriented interventions. These approaches aim to mitigate senescence-driven pathology by eliminating senescent cells, modulating their secretory activity, or restoring cellular function. Ongoing advancements will require precise stratification of senescent states, careful assessment of long-term safety, and the integration of optimized delivery systems for targeted therapeutic outcomes.

Elucidating the mechanisms of aging is impeded by its stochastic, multi-scale nature and cellular heterogeneity, challenges that are compounded by the overwhelming volume of biomedical literature and the complexity of genome-wide datasets. To overcome these barriers, we present PersonaAI, an interactive agentic-AI framework that acts as a digital co-scientist. By integrating literature-based reasoning with autonomous in silico validation, PersonaAI synthesizes over 560,000 aging-related publications via retrieval-augmented generation (RAG) to propose mechanistic hypotheses. These hypotheses are subsequently validated by autonomous agents utilizing single-cell RNA-seq data. Using a temporal cutoff strategy restricted to pre-2020 literature, we demonstrate that PersonaAI can generate hypotheses effectively validated by post-2021 discoveries, proving its capacity for inference beyond simple information retrieval. In application, the system identified senescent Cirbp+ hepatocytes as a liver-intrinsic aging program and uncovered a middle-aged, male-specific decline in adipose stem and progenitor cells, driven by vascular niche deterioration and disrupted VEGF-VEGFR signaling. These results establish PersonaAI as a scalable platform that augments human intuition with autonomous data-driven validation, providing a generalizable platform for accelerating discovery in aging biology.

The metabolite acetyl-CoA plays a central role in cellular metabolic homeostasis. As part of the secretory pathway, acetyl-CoA is imported into the endoplasmic reticulum (ER) by a membrane-bound transporter AT-1 (SLC33A1). AT-1 has been linked to peripheral neuropathy (heterozygous mutations), developmental delay with premature death (homozygous mutations) and intellectual disability with progeria (duplication). These phenotypes can be reproduced in the mouse. Here, we show that AT-1 overexpression in primary neurons impacts diverse phenotypes related to neuronal function and plasticity. At the gene level, AT-1 induces brain aging signatures, and key differences in ribosomal and synaptic processes were identified in both the transcriptome and the proteome. Changes in mitochondria-associated pathways were reflected in an increase in expression of mitochondrial master regulator PGC-1 and its target genes. Functionally, marked differences in mitochondrial membrane potential, architecture, and respiration were detected. Tracing experiments indicated altered glucose utilization in glycogen storage and nucleotide production. Shifts in redox metabolism were linked to differences in levels of NAD-dependent SIRT1 and CtBP2, with consequences for acetylated lysine modification. Depletion of lipid stores was associated with greater plasticity in fuel substrate utilization and a major shift in cellular lipid composition. These broad-scale changes in metabolism were coincident with reduced expression of synaptic proteins and reduced activity among synaptic networks, indicating that neuronal electrophysiology and network communication are coordinated at least in part through neuronal acetyl-CoA metabolism.

Progressive lung fibrosis is linked to aging-related dysfunction in fibroblasts, which remains poorly understood. To investigate the alterations in fibroblasts, particularly the molecular programs driving this profibrotic evolution in the aging lung, we isolated senescent lung fibroblasts from aged mice. We observed aberrant vimentin aggregates, which correlate with accelerated fibroblast senescence. CRISPR-based screening identified calumenin as a chaperone protein essential for vimentin proteostasis. A fibroblast-specific knockout of calumenin promotes the accumulation of vimentin aggregates and profibrotic factors migracytosis, exacerbating fibroblast senescence and lung aging. Mechanistically, calumenin collaborates with the TRiC complex to facilitate proper vimentin folding and recruits the chaperonin subunit Chaperonin Containing TCP1 Subunit 2 (CCT2) to degrade misfolded vimentin aggregates. Pathologically, external profibrotic stimuli trigger calcium transients and induce calumenin degradation, resulting in fibroblast senescence and the initiation of fibrosis. The natural product 9-85, derived from high-content screening, specifically targets and disrupts vimentin aggregates upon stimulation, alleviating aging-related lung fibrosis. Our findings reveal that calumenin coordinates vimentin quality control to shape cell structure and suppress the secretome of senescent fibroblasts, providing a promising therapeutic strategy for aging-related organ fibrosis.

Accumulation of senescent cells in the bone microenvironment, including bone marrow mesenchymal stromal cells (BM-MSCs), contributes to aging-related bone degeneration. Developmental endothelial locus-1 (DEL-1), the expression of which declines with old age is herein described as an endogenous secreted senolytic protein. DEL-1 promotes apoptosis of senescent BM-MSCs via a β3 integrin/CD73/adenosine/p38 mitogen-activated protein kinase (p38 MAPK)/B-cell lymphoma-2 (BCL-2) pathway, thereby leading to their clearance by macrophages. DEL-1-deficiency displays increased abundance of β3 integrin-rich CD73

Aging and metabolic syndrome (MetS) are intertwined risk factors for breast cancer (BC), but the core molecular nexus integrating these states is unknown. This study aimed to identify and validate a causal driver at this intersection.

Cognitive flexibility, a mental process crucial for adaptive behavior, involves multi-scale functioning across several neuronal organization levels. While the neural underpinnings of flexibility have been studied for decades, limited knowledge exists about the structure and age-related differentiation of the white matter subserving brain regions implicated in cognitive flexibility. This study investigated the population-level relationship between cognitive flexibility and properties of white matter across two periods of human adulthood, aiming to discern how these associations vary over different life stages and brain tracts among men and women. We propose a novel framework to study age effects in brain structure-function associations. First, a meta-analysis was conducted to identify neural regions associated with cognitive flexibility. Next, the white matter projections of these neural regions were traced through the Human Connectome Project tractography template to identify the white matter structure associated with cognitive flexibility. Then, a cohort analysis was performed to characterize myelin-related macromolecular features using a subset of the UK Biobank magnetic resonance imaging (MRI) data, which has a companion functional/behavioral dataset. We found that (1) the wiring of cognitive flexibility is defined by a subset of brain tracts, which present undifferentiated features early in adulthood and significantly differentiated types in later life. (2) These MRI-derived properties are correlated with individual subprocesses of cognition, which are closely related to cognitive flexibility function. (3) In late life, myelin-related homogeneity of specific white matter tracts implicated in cognitive flexibility declines with age, a phenomenon not observed in early life. Our findings support the age-related differentiation of white matter tracts implicated in cognitive flexibility as a natural substrate of adaptive cognitive function.

The conserved Ess1 prolyl isomerase (PIN1 in human) binds the carboxy-terminal domain (CTD) of RNA Pol II, and plays multiple roles in transcription regulation. Consistent with an essential role of the human PIN1 in telomere maintenance, previous screenings have identified the yeast Ess1 as a telomere length maintenance gene. Here, we provide evidence that Ess1 is involved in regulating both telomere transcription and replication. We find that depletion of Ess1 leads to a failure in transcription termination, explaining the essential role of Ess1 in maintaining a low level of telomere repeat containing RNA (TERRA). Furthermore, we show that Ess1 depletion promotes telomere shortening and accelerates senescence in telomerase-deficient cells. Notably, the depletion of Ess1 causes synthetic growth defects and telomere shortening in mre11Δ cells, and compromises rif2Δ-induced telomere elongation. Additionally, Ess1 depletion also accelerates senescence and eliminates type II telomere recombination in rad50Δ tlc1Δ cells. Lastly, Ess1 depletion decreases the accumulation of single-stranded DNA at telomere ends. These results support the model that Ess1 positively regulates both telomerase- and recombination-dependent telomere replication by promoting telomere-end resection. Taken together, this study reveals the yeast Ess1 as a new regulator of telomere transcription and replication via a distinct mechanism from the human PIN1.

The

Age-related hearing loss impairs speech understanding for socialization and music appreciation for enjoyment, both of which compromise quality of life and can lead to cognitive decline. It has previously been shown that while standard audiometric hearing thresholds can remain normal over time, speech understanding in noise is more difficult and there is the emergence of tinnitus. These specific hearing difficulties are not revealed by standard audiograms but we now know that they have been attributed to loss of high threshold auditory nerve fibers caused by the disappearance of terminal endings under inner hair cells. This loss can be measured by a reduction of evoked activity in the auditory nerve and atrophy of central auditory nerve endings in the anteroventral cochlear nucleus called endbulbs of Held. In the present study, we used age-graded cohorts of mice to compare hearing loss to the structure of auditory nerve synapses using serial section electron microscopy. We demonstrated a pathologic expansion and flattening of their synapses against spherical bushy cells in the rostral anteroventral cochlear nucleus in older mice with hearing loss. These changes portend impairments in sound processing and emphasize the importance of identifying "hidden" hearing loss for potential rehabilitation.

Immune-mediated intraocular inflammation, called uveitis, is a leading cause of global blindness, with the highest burden of visual impairment falling on older individuals. Immunosenescence, the functional changes in immune cells with aging, impacts the age-associated immune response, but how immunosenescence and the molecular regulators of the age-associated immune response affect the clinical course of uveitis remains unclear. In the murine model of experimental autoimmune uveitis (EAU), aged mice demonstrated a delayed onset and peak of intraocular inflammation compared to young mice. In contrast to the canonical monophasic inflammation that rapidly resolves in young mice, aged mice developed persistent, chronic inflammation. Transcriptomic and flow-cytometric analyses of immune cells and the receptor-ligand interactome revealed a dominant macrophage-CD4+ T cell signature. This signaling pathway was functionally altered on both ends: macrophages from aged mice had an impaired capacity to generate peripherally induced regulatory T cells (pTreg) through an IL-6 regulated pathway, while CD4+ T cells co-cultured with aged macrophages demonstrated increased proliferation. Our study establishes aging as a key regulator of the effector immune response in uveitis. Regulatory T cells, specifically pTreg, are essential for resolving inflammation in uveitis and an impaired ability to induce pTreg led to a sustained, chronic inflammatory uveitis phenotype in old mice, thereby linking immunosenescence to persistent neuroinflammation. These findings highlight potential therapeutic avenues for vision-threatening uveitis, especially in older patients.

The search for probiotic microorganisms that can be applied beyond gut health has advanced into areas that seek to promote longevity and to prevent neurodegenerative diseases. In this study, we have investigated non-Saccharomyces strains isolated from the Amazon, Cerrado, and Pantanal biomes and evaluated how they affect Caenorhabditis elegans. During our initial screening, based on increased body size and population, we selected eight yeast strains and characterized their cells. Then, we selected three of these strains for in vivo testing. Cryptococcus sp._T038 and Cryptococcus sp._T248 prolonged longevity and reduced the effects of thermal and oxidative stress in C. elegans. Hanseniaspora opuntiae_W164 and Saccharomyces boulardii_SB delayed beta-amyloid-induced paralysis in C. elegans CL4176. The antioxidant genes of the DAF-2/SKN-1 pathway were activated by Cryptococcus_T038 and _T248 and H. opuntiae_W164 in C. elegans strain LD1171 (GCS-1p::GFP) and by Cryptococcus_T038, H. opuntiae_W164, and S. boulardii_SB in C. elegans strain CF1553 (SOD-3p::GFP). These data reinforce that wild yeasts are potential functional probiotics.

Skin aging is characterized by a progressive decline in regenerative capacity, primarily driven by fibroblast senescence, oxidative stress, chronic inflammation, and the degradation of type I/III collagen, culminating in an extracellular matrix (ECM) imbalance. Current injectable fillers-such as hyaluronic acid, collagen, and PLLA-provide temporary structural support but fail to address the underlying cellular senescence or restore ECM homeostasis, highlighting the need for regenerative biomaterials. Silk fibroin (SF), a natural protein, self-assembles into a β-sheet-rich scaffold that structurally supports fibroblasts in depositing collagen and elastin, thereby improving the skin's ECM, accelerating wound healing, and promoting tissue regeneration. However, its role in modulating fibroblast senescence and ECM remodeling remains unclear. This study demonstrates that SF provides a suitable microenvironment for the adhesion and proliferation of fibroblasts, reducing the accumulation of SASP factors and facilitating the transition of fibroblasts from a senescent to a functional state. Furthermore, SF improves the skin microenvironment by reducing reactive oxygen species (ROS) and matrix metalloproteinase (MMP) expression through modulation of the ROS-MAPK-AP-1-MMP signal pathway, thereby delaying collagen degradation in aged skin. These findings reveal that SF uniquely rejuvenates fibroblasts and restores ECM homeostasis through a non-inflammatory mechanism, distinguishing it from conventional fillers that rely on inflammatory pathways for collagen induction. This work establishes SF as a next-generation injectable biomaterial with dual targeting of cellular senescence and ECM imbalance, offering a transformative strategy for regenerative dermatology and personalized anti-aging approaches.

Alzheimer's disease is a progressive neurodegenerative disorder marked by cognitive decline, accumulation of amyloid-β plaques and neurofibrillary tangles, synaptic dysfunction, and mitochondrial impairment. Despite multiple therapeutic strategies, currently available treatments only provide symptomatic relief without halting disease progression. Emerging evidence implicates mitochondrial dysfunction-including oxidative stress, impaired calcium signaling, mitophagy deficits, disrupted proteostasis, and electron transport chain abnormalities, as central to AD pathogenesis. These dysfunctions contribute to synaptic degeneration, increased reactive oxygen species, and neuronal death. This review consolidates current knowledge on the mechanistic pathways of mitochondrial impairment in AD and their downstream effects on neuronal health. We also explore the therapeutic potential of multitarget approaches, including agents targeting Aβ and tau pathology, oxidative stress mitigation, mitochondrial quality control, and synaptic restoration. By integrating evidence from recent preclinical and clinical studies, this work highlights mitochondrial homeostasis as a promising frontier for disease-modifying therapies in AD.

While aging is a well-established contributor to cardiovascular disease, the specific relation between biological aging-as assessed by PhenoAge and PhenoAge acceleration-and the risk of coronary heart disease (CHD) requires further evidence to elucidate. This study conducted a cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES), alongside both cross-sectional and prospective analyses using data from the UK Biobank, to investigate the association between biological aging and CHD risk across two large cohorts. The results indicated that each unit increase in PhenoAge and PhenoAge acceleration was significantly associated with a higher risk of CHD. Compared to individuals without accelerated aging, those experiencing accelerated aging face a significantly higher risk. These findings suggest that PhenoAge and its acceleration are significant risk factors for CHD development. Moreover, surrogate markers of biological aging may serve as valuable tools for both the primary and secondary prevention of CHD.

Age-related bone diseases, such as osteoporosis and degenerative joint disorders, pose a significant global health challenge, leading to over 9 million fractures annually, which not only diminishes quality of life but also imposes a substantial socioeconomic burden on healthcare systems. A major clinical obstacle in the aging population is the significantly reduced regenerative capacity of bone, often resulting in delayed fracture healing or nonunion fractures. Mitochondria, as the central regulators of cellular energy metabolism, are essential for determining cell fate and supporting tissue regeneration. However, age-associated mitochondrial dysfunction critically impairs these processes. While transplanting healthy mitochondria is a promising therapeutic strategy, its efficacy is severely limited by poor targeting efficiency and inherent fragility of mitochondria in circulation. Developing an efficient mitochondrial transplantation for elderly fractures is of great importance.

Atherosclerosis (AS) progression is driven by multiple interconnected pathological mechanisms. Among them, vascular senescence is both a key accelerator and consequence, interacting with other processes to promote AS development. Traditional monotherapies were limited to achieve synergistic therapeutic effects due to low oral bioavailability and insufficient multi-target efficacy. To overcome these limitations, we developed a baicalein-copper network (Cu-MON) for oral delivery of atorvastatin (ATV), forming a synergistic therapeutic system (CMA). Cu-MON significantly prolonged the gastrointestinal residence and increased the oral bioavailability of ATV without requiring additional excipients. Crucially, Cu-MON regulated senescence-associated genes, enhanced DNA repair pathways, and mitigated DNA damage, effectively counteracting vascular aging. The integrated CMA system combined enzymatic and non-enzymatic dual antioxidant systems to scavenge multiple ROS species. Furthermore, CMA reprogrammed macrophages from pro-inflammatory M1 to anti-inflammatory M2 phenotypes, modulated the PPAR-γ/LXR-α/ABCA-1 pathway to enhance cholesterol efflux, inhibited foam cell formation, and regulated hepatic and systemic cholesterol homeostasis. In ApoE

Age-related memory decline is a hallmark of brain aging and a primary risk factor for neurodegenerative disorders. Microglia play a crucial role in preserving memory function by maintaining brain homeostasis through phagocytosis, yet the specific mechanisms governing this protective function remain elusive. In the present study, we identified a population of Secreted Phosphoprotein 1 (Spp1)-positive microglia in both aged mouse and human brains. To investigate the role of microglial Spp1 in aging, we generated microglia-specific Spp1 knockout (Spp1-cKO) mice. We demonstrate that Spp1 deficiency selectively precipitates memory deficits in aged mice, without affecting memory function in young mice, indicating an age-dependent reliance on Spp1 signaling. Microglial phagocytic capacity positively correlates with Spp1 levels and is diminished by Spp1 deficiency. Mechanistically, Spp1 deficiency leads to the downregulation of the AKT/mitochondrial complex I pathway, thereby compromising microglial oxidative phosphorylation and function. Notably, microglia-specific overexpression of Spp1 partially ameliorates the age-related phenotypes induced by Spp1 deficiency. In conclusion, this study is the first to reveal the crucial role of microglial Spp1 in brain aging and to uncover its underlying mechanism, providing novel insights into age-related memory decline.

The prevalence of type 2 diabetes mellitus has increased worldwide and is higher among older individuals. Exploring the mechanisms underlying pancreatic β-cell dysfunction may help elucidate the pathogenesis of age-related diabetes.

Proteomics experiments on

While thrombolytic therapy can be effective for stroke, many patients are unable to benefit due to time restrictions. In an aging society, sarcopenia, a condition marked by reduced muscle volume, often worsens recovery after stroke. Our study explored how mitochondria, which are abundant in muscle, could aid in stroke recovery through exercise-induced migration. Using mouse models of chronic hypoperfusion and ischemia, alongside in vitro studies with rat primary cells under oxygen-glucose deprivation and CoCl2 exposure, we found that treadmill exercise protected against white matter injury, myelin loss, astroglial formation, and memory deficits observed 28 days post-hypoperfusion. In acute ischemia models, training reduced glial activation and post-stroke complications. Exercise increased mitochondrial levels in muscle and blood, facilitating their migration between tissues via platelets. In vitro, the addition of muscle-derived mitochondria enhanced the survival of neurons, astrocytes, and oligodendrocytes. Notably, platelets carrying mitochondria from treadmill-trained mice significantly improved ischemic white matter injury and mitigated post-stroke complications. This study highlights mitochondria as a critical part of the secretome, suggesting that muscle-derived mitochondria might play a role in the protective effects of remote ischemic preconditioning. Cell-cell mitochondrial migration, therefore, could offer a promising new approach to reducing post-stroke complications and vascular dementia.

Astrocytes are central to brain homeostasis, supporting neuronal metabolism, synaptic activity, and the blood-brain barrier. With aging, these glial cells undergo molecular and functional changes that weaken support functions and promote neuroinflammation, contributing to neurodegeneration. Yet the systems-level mechanisms by which astrocytes respond to aging-related stressors remain poorly defined in human models. Because aging also heightens risk for cardiovascular disease, cognitive impairment, type 2 diabetes, and systemic inflammation, clarifying shared astrocytic pathways is critical for understanding brain-body crosstalk. Using an in vitro human astrocyte model exposed to sublethal oxidative stress (10 µM H₂O₂) as a proxy for age-related cellular stress, we profiled transcriptomic changes and identified differentially expressed genes across antioxidant defenses, proteostasis, transcriptional regulation, vesicular trafficking, and inflammatory signaling. We then performed network-prioritization analyses on a curated human protein-protein interactome: one seeded with the astrocyte oxidative stress responsive genes and six with phenotype-associated gene sets (Alzheimer's disease, cardiovascular disease, cognitive impairment, type 2 diabetes, oxidative stress, and inflammation). Intersecting the top 5 % scoring genes from each run yielded a 127-gene core shared across all seven, enriched for proteostasis, DNA repair, mitochondrial regulation, and telomere and nuclear envelope maintenance. Structure-guided analyses highlighted vulnerable interfaces, including lamin A/C-lamin B1, α-actinin-filamins, 14-3-3 dimers, and aminoacyl-tRNA synthetase assemblies, where pathogenic variants are predicted to destabilize or aberrantly stabilize protein interactions. Structure-based interface predictions also highlight potential interactions between amyloid precursor protein (APP) and valosin-containing protein (VCP), and between p53 and 14-3-3ζ, potentially linking proteostasis and stress signaling. Together, these analyses identify a conserved astrocyte-centered network signature that may relate neurodegenerative and cardiovascular processes, and prioritize structurally testable candidates for biomarker and intervention hypothesis testing.

Premature ovarian insufficiency (POI) is a significant clinical disorder characterized by the loss of ovarian function before the age of 40, and its global prevalence is rising. The development of effective therapies is hindered by an incomplete understanding of its pathogenesis. Growing evidence indicates that dysregulated mitochondrial fission in granulosa cells (GCs) is a pivotal contributor to POI, although the upstream regulatory mechanisms remain elusive. This review synthesizes recent findings to propose a novel hypothesis: that aberrant lysine succinylation (Ksucc) of mitochondrial fission factor (MFF) may act as a crucial metabolic switch linking mitochondrial dynamics to ovarian aging. Specifically, hyper-succinylation of MFF at specific residues (e.g., K302) is hypothesized to induce a charge reversal, potentially promoting the excessive recruitment and oligomerization of dynamin-related protein 1 (DRP1) on the mitochondrial membrane. We hypothesize that this leads to mitochondrial fragmentation, bioenergetic deficits, and subsequent apoptosis of GCs and oocytes. This pathogenic cascade is theorized to be driven by a metabolic milieu of elevated succinyl-CoA and diminished desuccinylase activity of SIRT5 in POI. Evidence from related disease models suggests that reversing this imbalance through genetic or pharmacological modulation of SIRT5 can reduce MFF succinylation and restore mitochondrial dynamics. We explore the potential of targeting the SIRT5-MFF axis as a promising therapeutic strategy. Furthermore, detecting elevated MFF succinylation in clinical samples may be explored as a novel diagnostic biomarker for POI, though significant translational hurdles remain.

Aging changes the lipidome and mitochondrial function in a sex-dependent manner, yet their associations remain poorly understood. Twenty-four younger (7M/17F) and forty-three older (21M/22F) adults underwent blood draws and skeletal muscle biopsies for this cross-sectional investigation. Plasma lipidomic profiling was performed via liquid chromatography-tandem mass spectrometry, while peak mitochondrial O

This study aimed to investigate the effects of subchronic exposure to a 30 mT static magnetic field (SMF) on hematological parameters, spleen and tibia cellularity in 36-month-old and young rats. A total of 27 rats were divided into four groups (Young, Young SMF, Old, Old SMF) and two groups were exposed to SMF for 10 weeks. After exposure period, blood counts, neutrophil-to-lymphocyte ratio (NLR, an index of systemic inflammation), platelet-to-lymphocyte ratio (PLR, a platelet-based inflammatory marker) and cellularity of immune-related organs were analyzed. SMF exposure reduced lymphocyte counts and increased NLR in both age groups, while PLR increased only in young rats. In 36-month-old rats, SMF significantly reduced platelet counts, whereas this effect was not observed in young animals. SMF exposure also enhanced tibial and splenic cellularity in both groups but exerted opposite effects on the proportions of lymphocytes and erythrocytes depending on age. These findings suggest age-dependent immune modulation by SMF. In young animals, SMF likely promoted a proinflammatory shift, reflected by elevated NLR and PLR. In contrast, in 36-month-old rats, SMF may act as a nonspecific physiological stressor, potentially triggering the General Adaptation Syndrome (three-stage stress response), leading to corticosterone-mediated immunosuppression and cell redistribution. To our knowledge, this is the first study demonstrating age-dependent differential modulation of NLR and PLR by subchronic SMF exposure, linking proinflammatory shifts in youth with stress-related immunosuppression in aging. Overall, age appears to be a critical factor in determining the biological responses to SMF, underscoring the need for age-specific evaluation of SMF exposure.

Sepsis-induced acute lung injury (ALI) is a life-threatening condition with high mortality and limited effective treatments. Aging of alveolar type II (AT2) epithelial cells and mitochondrial dysfunction are key contributors to ALI pathogenesis. Ginsenoside Rb1, a major bioactive component of ginseng, has shown potential in modulating cellular senescence and mitochondrial health. This study aimed to evaluate the therapeutic efficacy of Rb1-loaded lung tissue-derived decellularized extracellular matrix hydrogel (dECM-gel) in alleviating sepsis-induced ALI.

Altered interactions with the extracellular matrix (ECM) represent a root cause of skeletal muscle stem cell (MuSC) dysfunction in aging and disease, underscoring the therapeutic potential of targeting adhesion receptors. Here, we describe the development of an approach for the medium-throughput screening of bioactive ECM-derived adhesion motifs using peptide arrays generated by highly parallel SPOT synthesis. Based on a library of ∼50 peptide sequences originating from ECM proteins, we identified several candidate motifs that robustly enhance the adhesion of MuSC-derived cells. We demonstrate that these peptide motifs can improve the

Sarcopenia is an age-related degenerative disease characterized by progressive loss of skeletal muscle mass and function, resulting severe clinical outcomes such as falls, disability, and increased all-cause mortality, thereby significantly reducing the quality of life in elderly population. With China's rapid demographic aging, sarcopenia is emerging as a critical public health challenge. In this review, we elaborate the pathogenesis of sarcopenia, identifying metabolic imbalance and cellular oxidative stress as major contributing factors to muscle degeneration. Also, this article indicates that life-style, physiological condition and genetic factors jointly influence the population susceptibility and progression of sarcopenia. On one hand, this article lists the non-genetic factors that accelerate the progression of sarcopenia; and on the other hand, it elaborates the role of multiple genes in maintaining muscle function, and the risk associations between genetic mutations and sarcopenia which has been revealed in studies from population cohort and animal models. Moreover, this article summarizes how epigenetic factors regulate muscle metabolism and aging, and comprehensively discusses the intervention effects and clinical limitations of treatment, nutritional support, and exercise therapy. We hope this review can provide a theoretical framework to advance both fundamental research and clinical strategies for sarcopenia prevention and management.