Longevity Papers

The gut microbiota plays a pivotal role in modulating host physiology and longevity through the production of microbial-derived molecules. Among these, bacterial exopolysaccharides (EPS) represent a structurally diverse group of surface polysaccharides with emerging roles in regulating host well-being. Here, we investigated the role of Lactobacillus strains with the capability to produce EPS, using Caenorhabditis elegans as a model organism. Results revealed significant lifespan extension in worms fed with EPS-producing bacteria, accompanied by improved health-span markers such as enhanced pharyngeal pumping and reduced lipofuscin accumulation. Transcriptomic profiling identified robust upregulation of the host detoxification and immune defense pathways, highlighting the flavin-containing monooxygenase gene fmo-2, as one of the major mediators of longevity and stress resistance triggered by EPS-producing lactobacilli. The effect was confirmed using fmo-2p::GFP reporter animals and was abrogated in fmo-2, hlh-30, and nhr-49 mutant backgrounds. Mechanistically, we demonstrated that EPS acts through a conserved transcriptional network that primarily relies on the activation of nhr-49/PPAR-α, with purified EPS being sufficient to activate fmo-2 expression. Our findings reveal that bacterial EPS activates host xenobiotic pathways to modulate aging, positioning it as a potential tool for microbiota-based longevity interventions. These insights show how microbial products can modulate fundamental biological processes across species, opening new strategies for age-related health interventions.

Phenotypic age (PhenoAge) is a biological aging clock that estimates an individual's biological age. However, the effect of PhenoAge acceleration (PhenoAgeAccel) on cancer is unclear. This study investigates the relationship between PhenoAgeAccel and cancer survivors. Data for this cohort study were sourced from the U.S. National Health and Nutrition Examination Survey (NHANES) spanning 1999-2018. The relationship between PhenoAgeAccel and cancer prevalence was evaluated using weighted multivariate logistic regression. Kaplan-Meier analyses and weighted multivariate-adjusted Cox analyses were conducted to examine the association between PhenoAgeAccel and all-cause as well as cancer-specific mortality in cancer survivors. Restricted cubic spline (RCS) analysis was utilized to assess nonlinear associations. Subgroup and sensitivity analyses were also performed to confirm the robustness of the findings. A total of 34,246 participants were included in our study, of which 3067 were cancer survivors (8.95% prevalence). With a median follow-up of 117 months (interquartile range: 50-155 months), there were 1161 deaths, including 351 from cancer. Weighted multivariate regression analysis revealed a significant positive association between higher PhenoAgeAccel and cancer prevalence (P for trend < 0.001). Multivariable-adjusted Cox regression analyses showed that elevated PhenoAgeAccel was significantly associated with increased all-cause and cancer-specific mortality among cancer survivors (P for trend < 0.001). RCS regression indicated no nonlinear relationship between PhenoAgeAccel and mortality outcomes (P for nonlinear relationship > 0.05). Kaplan-Meier analyses indicated a poorer prognosis with higher PhenoAgeAccel. Subgroup analyses based on tumor classification highlighted the differential prognostic impact of PhenoAgeAccel across various tumor types. Our findings reveal a significant linear correlation between PhenoAgeAccel and both all-cause and cancer-specific mortality in cancer survivors.

Cellular senescence is a largely heterogeneous state of cell stress that deleteriously accumulates with age. Many types of heterogeneity in senescence have been described; however, cellular senescence within the same cell type has only started to be documented. Here, we show primary, human lung fibroblasts from donors who are healthy or diagnosed with idiopathic pulmonary fibrosis (IPF) exhibit a subtle form of heterogeneity over time after DNA damage. Moreover, senescent IPF lung fibroblasts display a dysregulated transcriptional-protein DNA damage response (DDR). Weighted gene correlation network analysis (WGCNA) reveals unique and known targets linking senescent IPF lung fibroblast heterogeneity to genes associated with DNA damage and repair, cytokine and chemokine responses, and extracellular matrix (ECM) signaling. We combine our healthy and IPF senescent gene expression signatures to develop a novel gene set of senescence-associated genes that identify disease-relevant cells in human single-cell RNA-seq (scRNA-seq) data. Collectively, our results uncover human-relevant senescence signatures, highlight IPF-specific DDR, cytokine and chemokine, and ECM targets, and expand our understanding of how a dysregulated DDR contributes to senescent cell heterogeneity in IPF.

Osteoarthritis (OA) is a common chronic and degenerative disease, the pathophysiological features of which involve the whole joint. In recent years, adipose tissue-derived mesenchymal stem cells (ADSCs) have attracted much attention in the field of regenerative medicine. Nonetheless, with aging in vivo or exogenous stress in vitro, mesenchymal stem cells undergo cellular senescence, resulting in limited therapeutic efficacy. Curcumin is a natural polyphenolic compound that has antioxidative, anti-inflammatory and antiapoptotic properties. We aimed to investigate the function and molecular mechanisms of the effects of curcumin on ADSC senescence and to explore the therapeutic efficacy of curcumin-pretreated ADSCs in OA management.

The activation of the receptor for advanced glycation end-products (RAGE) induces a chronic, low-noise inflammation responsible for the aging process, known as inflammaging. Associated with numerous pathologies such as Alzheimer's, insulin-resistant diabetes, cardiovascular diseases, and certain cancers, RAGE has become an interesting therapeutic target in the context of aging well. To this end, we identified new benzo[b]thiophene-2-carboxamide derivatives as potential RAGE ligands. Herein, we developed an alternative approach to easily synthesize benzo[b]thiophene-2-carboxamide analogs from 5-arylidene-2,4-thiazolidinedione intermediates based on the Ullmann-Goldberg coupling conditions. In light of LCMS, NMR, X-ray, and DFT studies, a mechanism for this reaction was proposed. This novel strategy enabled us to synthesize analogs whose best molecule 3t', with an IC

Ageing is a universal process characterised by the deterioration of functional traits over an individual's lifespan. Differing degrees of age-related decline between individuals of the same chronological age suggest varying rates of ageing. Identifying factors influencing these inter-individual differences in 'biological age' is central to understanding ageing. In social mammals, social variables affect lifespan and are therefore likely to affect biological age. In Shark Bay, Western Australia, male bottlenose dolphins forge persisting intrasexual social bonds that affect their reproductive success and, therefore, their evolutionary fitness. We investigate the relationship between cumulative social bond strength, group size, and biological age of individual male dolphins in this population. Biological age is inferred using a species-specific epigenetic clock, the current gold standard for such an inference. We find a significant negative effect of cumulative social bond strength and a significant positive effect of group size. This implies that the negative effect of social bonds on epigenetic age cannot be attributed solely to group-living, but to benefits of the social bonds themselves. As established in humans, we find that the strength of social relationships affects epigenetic age, indicating that sociality may be linked to biological ageing more broadly across social mammals.

Stem cell exhaustion and cellular senescence are two hallmarks of aging. Mesenchymal stem cells (MSCs), as key players in tissue regeneration, are particularly vulnerable to senescence, which compromises both their endogenous regenerative capacity and their therapeutic efficacy in cell-based applications. Suppressing MSC senescence is therefore essential for developing effective regenerative and anti-aging strategies.

Aging is the primary risk factor for cardiovascular disease, cancer, neurodegeneration, and other chronic disorders. Therefore, targeting the hallmarks of aging has emerged as a promising strategy to extend healthspan. Liver X receptors (LXRs) are ligand-dependent nuclear receptors that are activated by specific oxysterols and cholesterol derivatives. They are traditionally known as key regulators of cholesterol homeostasis. However, recent evidence reveals that LXRs also influence autophagy, mitochondrial function, epigenetics, senescence, stem cell dynamics, and intercellular communication. This positions LXRs at the crossroads of multiple hallmarks of aging. This review synthesizes current knowledge on endogenous and synthetic LXR ligands, their transcriptional mechanisms, and their effects on the aforementioned hallmarks and age-related pathophysiology. The clinical development of pan-LXR agonists for atherosclerosis has been hindered by side effects, notably hepatic steatosis. Emerging strategies, including LXRβ-selective ligands, selective LXR modulators (SLiMs), and biased agonists such as dendrogenin A, offer ways to separate the protective vascular, metabolic, and neuroprotective effects from adverse outcomes. Additionally, we explore how LXR signaling intersects with the hallmarks of aging and how it can be leveraged to intervene in atherosclerosis, diabetes, cancer, osteoporosis, age-related macular degeneration, and neurodegenerative diseases. Positioning LXRs within the geroscience framework suggests that LXRs may serve as pharmacological hubs to delay aging and its comorbidities. Future work should prioritize isoform- and tissue-selective approaches, metabolite-inspired ligand design, and integration with the hallmarks of aging to unlock the full therapeutic potential of LXRs.

Aging is the gradual decline in physiological function essential for survival and reproduction. Unlike age-associated diseases, aging affects all individuals within a species, causing progressive impairments across multiple systems. Research shows that altering specific genes or dietary factors can extend lifespan, implicating molecular pathways in controlling senescence. Chronological age (CA) is a common measure of aging, but other hallmarks like telomere shortening better quantify functional decline. Identifying age-related hallmarks can help manipulate aging, spurring interest in aging clocks. These clocks predict biological age (BA) more precisely than CA, reflecting actual physiological health. As global life expectancy continues to rise, aging clocks hold promise for developing therapies to extend healthspan and improve life quality during aging.

Ovarian aging is considered the "pacemaker" and "biological clock" of systemic female aging, with early manifestations that are often insidious. In this study, we analyzed the shared and distinct molecular signatures between physiological and pathological ovarian aging models using proteomic approaches, with the aim of identifying early predictive markers and therapeutic targets for ovarian aging, evaluating model fidelity, and elucidating underlying molecular mechanisms.

Aging is associated with a progressive decline in physiological resilience, often linked to impaired stress responses and metabolic dysfunction. In Caenorhabditis elegans (C. elegans), caloric restriction (CR) and pharmacological interventions are widely used to dissect conserved longevity pathways. Here, we identify the N-methyl-D-aspartate receptor (NMDAR) antagonist memantine as a novel modulator of lifespan and stress tolerance in C. elegans. Memantine, but not ketamine, extends median lifespan and reproductive lifespan, suggesting that the observed effects are not shared with ketamine at the tested concentration. Transcriptomic analysis revealed significant overlap between memantine-treated animals and CR models, particularly eat-2 mutants, implicating shared metabolic and longevity-associated pathways. Functionally, memantine was found to reduce mitochondrial and oxidative stress, while enhancing β-oxidation of fatty acids, and modifying behavioral responses to food cues, delaying food-seeking behavior and increasing locomotion under starvation, without affecting lipid storage. In summary, these findings suggest that memantine promotes stress resilience and healthy aging via metabolic changes that overlap with CR-associated pathways, highlighting its potential as a longevity-modulating intervention.

Sensory loss is prevalent in older adults and is associated with changes to brain structure and function. In early life, the brain compensates for sensory loss by upregulating intact senses, such as in deafness where neural sensitivity for vision increases and visual peripheral perception improves. However, it is unclear if similar neuroplastic compensation occurs in older adults with sensory loss, which would show the aging brain's adaptability and inform sensory rehabilitation strategies. We tested for evidence of compensatory visual neuroplasticity in adults (N = 66) aged 53 to 80 with typical hearing or hearing loss, and if this neuroplasticity differed for visual stimuli that were or were not relevant to speech perception. Participants viewed speech-like or non-speech stimuli as we recorded cortical activity with the 64-channel electroencephalogram (EEG). Participants with more hearing loss tended to have longer cortical P1 and N1 latencies in the visual evoked potential. However, the later cortical P2 response latency decreased with more hearing loss in agreement with compensatory plasticity. Effects were independent of numerical age. Latency effects in hearing loss were more pronounced for the speech-like stimulus compared to the non-speech stimulus, but P2 responses for the non-speech stimulus showed greater cross-modal recruitment of the temporal cortex. Findings show for the first time that compensatory plasticity operates on later cortical P2 responses in older adults, is not explained by numerical age, and differs for speech and non-speech events. However, P1 and N1 responses in networks coding for visual speech may be sensitive to sensory decline.

Acyl coenzyme A binding protein (ACBP), also known as diazepam binding inhibitor (DBI), suppresses autophagy, stimulates food intake, and regulates body composition. This tissue hormone contributes to the development of age-related diseases such as metabolic syndrome, cardiovascular disease, cancer, and osteoarthritis. ACBP/DBI also plays a key pathogenic role in liver disorders, including hepatocellular carcinoma (HCC). Circulating levels of ACBP/DBI are elevated in patients with histologically diagnosed steatosis, liver fibrosis or HCC, and correlate with disease severity. Moreover, the incidence of liver cancers increases in individuals receiving benzodiazepines, which act on the same binding sites of the GABA-A receptor as ACBP/DBI. In mice, inhibiting ACBP/DBI, via inducible knockout, mutation of its receptor (the γ2 subunit of the GABA-A receptor) or antibody-mediated neutralization, alleviates various liver conditions, including ischemia-reperfusion injury, bile duct obstruction, hepatotoxicity of acetaminophen, CCl

Ovarian dysfunction caused by aging restricts female reproductive capacity and causes age-related health problems. Ferroptosis is an important mode of cell death during accelerated aging. Oviductus Ranae (OR), a traditional Chinese medicine, has been used to treat ovarian age-related diseases in women. However, the mechanisms through which OR mitigates ovarian aging, especially ferroptosis regulation, remain unclear. This study investigated the pharmacological effects and mechanisms of OR for ovarian aging in rats.

There is a growing contradiction between the rising demand for mechanical ventilation among the elderly and their heightened sensitivity to ventilator-induced lung injury (VILI). This discrepancy compels us to explore therapeutic targets for VILI in elderly patients. Our research revealed that aging increases the sensitivity of pulmonary endothelial cells to low-magnitude mechanical stretch. By analyzing transcriptome sequencing data from lung tissues of humans and mice at different ages, as well as published transcriptome sequencing data from senescent endothelial cells, we identified tissue kallikrein-related peptidase 8 (KLK8) as an age-dependent upregulated gene in lung tissues. Using KLK8 knockout mice, intra-pulmonary KLK8-overexpressing mice, and mouse lung vascular endothelial cells (MLVECs) with KLK8 overexpression or knockdown, we demonstrated that age-dependent KLK8 upregulation contributes to pulmonary endothelial senescence and increased susceptibility of aged mice to VILI. Mechanistically, KLK8 promotes pulmonary endothelial senescence by inactivating the fibronectin/focal adhesion kinase (FAK) pathway. Through transcriptional profiling, we identified the poly(ADP-ribose) polymerase 1/2 (PARP1/2) inhibitor olaparib as a potential agent that rescues KLK8-induced pulmonary endothelial cell senescence and alleviates VILI in aged mice. Our findings underscore the critical role of KLK8 in pulmonary endothelial senescence and provide preclinical evidence for PARP1/2 inhibitors as a therapeutic target for VILI in elderly individuals.

Female fertility sharply declines from the mid-thirties of their life, mainly due to age-related decreases in oocyte quality and quantity. Among numerous interconnected maternal factors, an increase in the incidence of aneuploidy caused by meiotic errors is a leading cause of oocyte competence decrease. Why advanced maternal age increases the likelihood of chromosome segregation errors in oocytes remains one of the outstanding questions in reproductive and developmental biology, and it is becoming more important as the age at which women have children continues to rise. A better understanding of this question is crucial for developing effective strategies for prophylaxis or therapeutic interventions for infertility. The progressive loss of cohesin, a ring-shaped protein complex with fundamental roles in chromosome cohesion and architecture, has recently been heavily implicated in the increase in oocyte aneuploidy rates during maternal aging. This review discusses the underlying mechanisms of age-related aneuploidy in oocytes. We particularly ask how chromosomal cohesin loss affects the fidelity of oocyte chromosome segregation and examine physiological factors that contribute to this deterioration.

Mitochondrial dynamics play a critical role in the development of aging-related diseases such as type 2 diabetes mellitus. To investigate how mitochondrial dynamics influence cellular behavior in pancreatic beta-cells, we developed a rule-based, multi-level simulation model of insulin secretion. The pancreatic beta cell model encompasses metabolic pathways (glycolysis and oxidative phosphorylation), compartmental processes (mitochondrial fusion and fission), and cellular processes (insulin secretion), allowing for the investigation of their interplay. The rule-based simulation model captures the high plasticity of these organelles and integrates and builds upon insights from various experimental studies and previous simulation models. Its rule-based specification facilitates the exploration of new hypotheses, the integration of new knowledge and data, and the successive extension of the model. The results of our simulation experiments underscore the importance of peripheral, sorted mitochondrial fission in maintaining mitochondrial health. Downregulation of the fission-associated anchor proteins Fis1 and MFF impacts mitochondrial structure and function differently, highlighting their distinct roles in maintaining mitochondrial health and cellular biogenesis, respectively. With respect to insulin secretion, Drp1 suppression shows that beta cells become unresponsive to glucose, whereas Fis1 downregulation only attenuates the cellular response. The simulation model and simulation results corroborate experimental findings and contribute to a deeper understanding of the mechanisms involved in mitochondrial dynamics of pancreatic beta cells and their relation to metabolic dysregulation in type 2 diabetes mellitus.

With the accelerating pace of population aging, the incidence of osteoarthritis (OA), a degenerative disease strongly associated with age, is rapidly increasing. Chondrocyte senescence is a major contributor to cartilage degeneration; however, effective therapeutic strategies targeting chondrocyte aging remain lacking. Mesenchymal stem cell (MSC)-based approaches have emerged as a promising means of combating cellular senescence, among which exosomes (Exos) play a pivotal role in mediating therapeutic effects. Compared with direct MSC transplantation, Exos offer a safer and more ethically acceptable alternative. Moreover, the functional properties of Exos can be modulated by the microenvironmental stimuli applied to MSCs, although the underlying molecular mechanisms remain largely unclear. In this study, we employed interferon-γ (IFN-γ) to precondition MSCs and generate functionally enhanced Exos (iExos). Both in vitro and in vivo experiments demonstrated that iExos exhibit superior antisenescent activity in chondrocytes and more effectively attenuate OA progression. Sequencing analysis, together with mechanistic studies, revealed that iExos exert these effects by sustaining mitochondrial AMPK-SIRT3 homeostasis in chondrocytes through Hsp70. These findings partially elucidate a key pathway by which stem cell-derived iExos combat chondrocyte senescence and may inform the design of stable, efficient, and safe MSC-based antisenescence strategies.

Synapse dysfunction is tightly linked to cognitive changes during aging. Emerging evidence suggests that microglia and the extracellular matrix (ECM) can potently regulate synapse integrity and plasticity. Yet the brain ECM, and its relationship with microglia, synapses, and cognition during aging remains virtually unexplored. In this study we combine ECM-optimized proteomic workflows with histological analyses in aging mice and discover regional differences in ECM composition and aging-induced ECM remodeling across basal ganglia nuclei. Moreover, we combine two distinct behavioral classification strategies with fixed-tissue confocal imaging and proteomic analysis and identify relationships between the hyaluronan- and proteoglycan-rich ECM and cognitive aging phenotypes. Finally, we provide evidence that aging midbrain microglia lose capacity to interact with and regulate the ECM, and that these aging-associated microglial changes are accompanied by local ECM accumulation and worse behavioral performance. Together, these observations indicate that changing microglia-ECM-synapse interactions contribute to cognitive functioning during healthy aging.

Autophagy preserves neuronal integrity by clearing damaged proteins and organelles, but its efficiency declines with aging and neurodegeneration. Depletion of the oxidized form of nicotinamide adenine dinucleotide (NAD

Metabolic dysfunction-associated steatotic liver disease [MASLD; previously known as nonalcoholic fatty liver disease (NAFLD)] is a prevalent chronic liver disorder strongly associated with aging, yet the mechanisms underlying age-related hepatic lipid dysregulation remain incompletely defined. This study investigates how aging alters hepatic phospholipid metabolism and the contribution of phosphatidylethanolamine N-methyltransferase (PEMT) to MASLD progression. Here, lipid accumulation was characterized in the livers of 2-, 6-, 12-, 18-, and 24-month-old mice, revealing age-dependent increases in hepatic triacylglycerol (TG), total cholesterol (TC), and lipid droplet formation. Lipidomic analysis revealed a marked imbalance in phospholipid composition, characterized by increased phosphatidylcholine (PC) and decreased phosphatidylethanolamine (PE), resulting in a 2.5-fold increase in the PC/PE ratio in 24-month-old mice compared with 6-month-old controls. Mechanistically, PEMT, a key enzyme regulating PC and PE metabolism, exhibited significantly increased expression (~2.4-fold at the protein level) in aged livers, suggesting a pivotal role in driving the observed phospholipid imbalance in vitro. PEMT inhibition significantly attenuated lipid droplet accumulation by ~30% and reduced intracellular TG levels by ~20% in D-galactose-induced senescent AML12 hepatocytes under lipid stress, compared with nonsilenced senescent controls. These findings suggest that aging-driven PEMT overexpression promotes phospholipid remodeling and hepatic lipid accumulation. By leveraging a natural aging mouse model, our study provides the first evidence linking PEMT activity to age-associated phospholipid dyshomeostasis, revealing a previously unknown mechanistic axis distinct from diet-induced MASLD and offering new therapeutic insights.

Gene expression is co-regulated by the rates of RNA synthesis and degradation, and recent evidence has linked their imbalance to the onset of aging. The naked mole-rat (NMR) is a small rodent with an exceptionally long lifespan and markedly delayed aging, yet little is known about its RNA synthesis and degradation characteristics compared to other rodents that age more rapidly. Here, we investigate RNA synthesis and degradation in NMR and mouse skin fibroblasts by monitoring incorporation of a uridine analog, 4-thiouridine. Cross-species analysis showed that the NMR cells have higher overall rates of RNA synthesis and degradation. It further revealed higher RNA degradation rates in aging-related pathways, notably Mtorc1 signaling, likely contributing to reducing the overall expression. Although known aging-associated genes, including Xrcc5, Nudt1, Fen1, and Aptx, were expressed at similar levels in NMR and mouse fibroblasts, the RNA turnover rates were largely altered. To uncover the underlying mechanism enabling differential control of RNA kinetics, we analyzed the transcript feature importance by machine learning and identified key features governing RNA degradation both common and unique in NMR and mouse fibroblasts. Our data highlight a potential role of RNA synthesis and degradation as hidden layers of gene regulation in NMR.

The global rise in population aging and the increasing burden of non-communicable diseases demand scalable, cost-effective strategies to support healthy aging. Conversational agent-based interventions, which deliver personalized guidance through interactive dialogue, offer a promising yet underexplored approach to promoting lifestyle behavior change among older adults. Thus, the purpose of this study is to systematically review the characteristics, acceptability, and effectiveness of conversational agent-based interventions for lifestyle behavior modification in older adults, and to identify key design and research considerations for advancing this emerging field.

The global population is aging, with one in six people projected to be 65 years or older by 2050. Since people aged 65 and older experience higher rates of morbidity and mortality after burn injury, there is an increased need to develop effective burn treatments in this age group. Heightened morbidity and risk of mortality may stem from increased gut leakiness and death of intestinal epithelial cells of aged individuals. Herein, we used our clinically relevant model of scald burn injury in young and aged mice to ascertain whether the colon, isolated colonic epithelium, and organoids grown from the colon, have deficiencies in cell growth, senescence, and apoptosis pathways. Aged, burn-injured mice displayed increased senescence marker

Aging is associated with cognitive deterioration accompanied by a reduction in hippocampal neurogenesis. Murine models have been widely used to study aging and age-related cognitive decline, as they recapitulate many of the key features of the degenerative process. Among these, the SAMP8 strain represents a well-established model of accelerated aging, characterized by early-onset and progressive cognitive impairment, Alzheimer\'s disease-like neuropathology, and an initial increase in hippocampal neurogenesis that ultimately depletes the neural stem cell pool. Notably, most studies using murine models of aging or neurodegeneration have focused on males or mixed-sex cohorts, leaving sex-specific differences in neurogenesis and cognitive decline largely unexplored. Recent evidence indicates that diterpenoid treatment ameliorates cognitive decline and enhances neurogenesis in 6-month-old male SAMP8 mice. However, whether females exhibit similar responses remains unknown. In this study, we characterized sex differences in hippocampal neurogenesis in 6-month-old SAMP8 mice and examined potential sex-dependent effects of diterpenoid therapy. Our findings reveal marked sex differences in neurogenic capacity and treatment responsiveness. While diterpenoid treatment enhanced hippocampal neurogenesis and cognitive performance in males, these effects were largely absent in females. Overall, female SAMP8 mice exhibited reduced baseline neurogenesis and a diminished response to therapy, highlighting the importance of considering biological sex in the design of therapeutic strategies for age-related cognitive decline.

Regular physical activity is essential for healthy aging, yet sustaining long-term engagement remains a challenge for many older adults. Emerging research highlights habit formation as a promising mechanism for maintaining physical activity, particularly when supported by contextual cues and digital technology.

Skin aging is a complex process influenced by intrinsic and extrinsic factors, leading to structural and functional changes such as reduced elasticity and increased wrinkles. This study aims to evaluate the potential biological functions of Magic vitamin A (MVA) in skin health management and skin aging through metabolomics analysis. We performed untargeted metabolomics analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to explore the changes in metabolites and related metabolic pathways induced by MVA in HaCaT cells. This suggests that MVA treatment substantially alters the cellular metabolic state. The boxplot analysis indicates that MVA altered the levels of several metabolites, including 18-beta-Glycyrrhetinic acid, Palmitoylethanolamide (PEA), 17-AAG, L-arginine, and Dehydroepiandrosterone (DHEA), all of which exhibit significant biological effects in anti-aging, anti-inflammatory, and antioxidant properties. Additionally, key metabolic pathways, such as Arginine and proline metabolism, Purine metabolism, and Arachidonic acid metabolism, also highlighted potential anti-aging pathways of MVA. Our findings suggest that MVA may improve skin health through multiple metabolic mechanisms, supporting its potential as an anti-aging agent.

Aging is a multifaceted biological process affecting various organ systems. Immunosenescence, a key feature of aging, markedly increases susceptibility to infections, cancers, autoimmune diseases, and also neurodegenerative disorders. Immunosenescence not only accelerates normal aging but also drives the progression of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). However, the lack of a consensus on the mechanistic hallmarks of immunosenescence presents a major barrier to the development and validation of anti-aging therapies. In this review, we propose 11 hallmarks of immunosenescence: genomic instability, telomere attrition, epigenetic dysregulation, stem cell exhaustion, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, chronic inflammation, altered intercellular communication, and microbiome dysbiosis. We also elucidate the intricate interplay between immunosenescence and both normal brain aging and neurodegenerative pathologies, highlighting the pivotal involvement of age-related immune dysregulation in the pathogenesis of neurodegenerative disorders. This mechanistic connection is particularly evident in prototypical neurodegenerative conditions such as AD and PD, where immunosenescence appears to significantly contribute to disease progression and phenotypic manifestations. Given that the ultimate goal of immune aging research is to prevent or alleviate age-related diseases, we also discuss potential hallmark-targeting anti-immunosenescence strategies to delay or even reverse normal aging and neurodegeneration.

Aging and age-related diseases share convergent pathways at the proteome level. Here, using plasma proteomics and machine learning, we developed organismal and ten organ-specific aging clocks in the UK Biobank (n = 43,616) and validated their high accuracy in cohorts from China (n = 3,977) and the USA (n = 800; cross-cohort r = 0.98 and 0.93). Accelerated organ aging predicted disease onset, progression and mortality beyond clinical and genetic risk factors, with brain aging being most strongly linked to mortality. Organ aging reflected both genetic and environmental determinants: brain aging was associated with lifestyle, the GABBR1 and ECM1 genes, and brain structure. Distinct organ-specific pathogenic pathways were identified, with the brain and artery clocks linking synaptic loss, vascular dysfunction and glial activation to cognitive decline and dementia. The brain aging clock further stratified Alzheimer's disease risk across APOE haplotypes, and a super-youthful brain appears to confer resilience to APOE4. Together, proteomic organ aging clocks provide a biologically interpretable framework for tracking aging and disease risk across diverse populations.

Studies in laboratory organisms typically minimize all environmental and genetic variation other than the intervention of interest. In aging studies, these highly controlled conditions have yielded profound insights into aging. But even within isogenic cohorts of lab animals in controlled environments, we observe substantial variation in lifespan. Here we exploited the climbing behavior of Drosophila to study variation in mortality among isogenic populations in a controlled environment. We show that fractionating large cohorts of relatively young isogenic flies by climbing behavior predicts future mortality risk and stress sensitivity. Using metabolomics to dissect this variation, we found metabolites whose abundances differ among the fractions. We also took advantage of the large number of individuals in each fraction, and the ease with which they can be collected, to explore the covariance structure of metabolites in flies that are genetically identical, but divisible into short-lived and long-lived fractions. In doing so, we identified metabolites and metabolic pathways as candidate biomarkers of intrinsic mortality risk.

Telomerase, essential for maintaining chromosomal telomere integrity and preventing cellular senescence, represents a promising therapeutic target. However, the inherent risks associated with existing treatments for telomerase deficiency-related diseases necessitate the development of safe and precise targeted delivery systems capable of reaching specific cell populations. Extracellular vesicles (EVs), nanoscale membrane-bound particles naturally secreted by cells, mediate intercellular communication by transporting bioactive molecules, including proteins and nucleic acids. We hypothesized that EVs could function as intrinsic vehicles for telomerase delivery.

Aortic distensibility refers to the ability of arteries to expand in response to pulse pressure generated by the cardiac cycle, and this often decreases with age. Genome-wide association studies have identified genetic variants associated with distensibility; however, the mechanisms leading to changes in distensibility remain unclear. In this study we examined aortic distensibility through the lens of genomics, considering both cellular composition and cell type specific gene expression, inferred from bulk gene expression data, to investigate how these factors contribute to the observed changes in distensibility associated with age and genotype. We found age-related decreases in the proportions of Pericytes and Fibroblast I cells, while the proportion of vascular smooth muscle cells type II (VSMC II) increased. Notably, most of the gene expression changes associated with age were identified in VSMC I, VSMC II and Fibroblast I cells. Furthermore, we observed that the cell type-specific expression of most genes associated with distensibility correlated with age, specifically VSMC I, VSMC II, Fibroblast I, and Pericyte cells. We also tested for genetic associations with the extent of increased distensibility with age in the UK Biobank and found two independent loci, both of which showed a marginally significant association with the increased distensibility with age. None of the identified GWAS SNPs were significantly associated with the inferred cellular proportions. Interestingly, we found two independent SNPs that had a genome-wide significant association with distensibility were also associated with cell type specific expression of nearby genes (SRR in VSMC I, VSMC II and Fibroblast I, as well as CDH13 in VSMC I) that have been implicated in aortic distensibility. Overall, our results identify cell type specific changes in gene expression that may help to explain genetic and age-related variation in this important physiological phenotype.

Epigenetic drift is a key feature of aging and is associated with age-related diseases including cancer, yet the underlying molecular mechanisms remain unclear. Here, by analyzing DNA methylation and gene expression data from healthy and cancerous human colon samples, we identify an aging and colon cancer-associated DNA methylation (DNAm) drift. We find evidence that this drift is conserved in the mouse intestinal epithelium, where we demonstrate its origin within intestinal stem cells and identify its cell-intrinsic and non-mitotic characteristics, finding that its expansion is regulated via crypt clonality and fission. Mechanistically, we find that this drift is driven by age-related inflammation and reduced Wnt signaling, which dysregulate iron metabolism and impair TET activity. Despite CpG-level heterogeneity, we find that DNAm changes are consistent at the gene level, suggesting potential functionality. Our findings shed light on the epigenetic mechanisms of aging and provide a mechanistic basis for the hypermethylation observed in cancer.

Alzheimer's disease (AD) genome-wide association studies (GWAS), typically based on clinical phenotypes, have identified numerous risk loci, yet linking these variants to brain changes and molecular processes remains challenging. We developed a DNE-xQTL framework integrating deep learning-derived dimensional neuroimaging endophenotypes (DNEs) with comprehensive brain molecular quantitative trait loci (xQTL) to dissect genetic pathways underlying AD- and aging-related brain variation. By performing GWAS on seven DNEs and applying integrative computational analyses, we biologically annotated each DNE and prioritized xQTL-supported gene targets. This approach both enhanced interpretation of established AD loci through DNE-mediated annotations and revealed underexplored regulatory pathways, organizing 190 candidate genes into evidence-based tiers. We highlight three regulatory clusters: glutamate-receptor and mitochondrial pathways implicating excitatory-neuron vulnerability, SREBP2-associated cholesterol homeostasis linked to vascular dysfunction, and primary-cilia-associated transport implicated in aging. By connecting pre-symptomatic brain alterations to molecular targets and relevant cell types, this framework may inform earlier risk stratification before clinical neurodegeneration occurs.

People with posttraumatic stress disorder (PTSD) are at increased risk for poor health, which could be explained by faster rates of biological aging. However, associations between PTSD and aging have most often been investigated using cross-sectional designs, with few longitudinal studies using more recently developed epigenetic measures of aging. To test whether changes in PTSD status were associated with changes in biological aging over roughly 12 years, we used data from 400 veterans assessed at two visits in the Post-Deployment Mental Health Study. Biological aging was assessed by DunedinPACE, with additional results shown for PC-GrimAge and PC-PhenoAge. Between two occasions spanning an average of 11.9 years, veterans who developed new onset PTSD showed significant increases in DunedinPACE ({beta} = 0.24, 95% CI [0.07, 0.41], p = .006), whereas remission in PTSD between occasions was not associated with significant decreases in the rate of aging ({beta} = -0.13, 95% CI [-0.33, 0.08], p = .207). When assessing PTSD symptoms, increases in PTSD symptoms between baseline and follow-up were associated with increases in DunedinPACE over the same period ({beta} = 0.07, 95% CI [0.01, 0.14], p = .032), and vice versa. Estimates for PC-GrimAge largely replicated those for DunedinPACE, whereas PC-PhenoAge replicated some associations. Conclusions: These results suggest that changes in PTSD are associated with longitudinal changes in biological aging. Efforts to prevent the onset of PTSD and reduce PTSD symptoms could slow aging and reduce risk for poor health.

Aging studies have entered a transformative era with the discovery and application of short peptides as regulators of senescence. These short peptides are encoded by small open reading frames in nuclear, mitochondrial, and viral genomes. Unlike non-coding RNAs, short peptides are evolutionarily conserved and play a role in ameliorating decline of cellular function. It has now been recognized involved in nearly all biological processes, including diseases and senescence, however, the mechanisms behind it are complicated and largely unexplored. This review aims to summarize the evidence that short peptides slow senescence by targeting interactions with core aging hallmarks in animals. The cross-species studies were reviewed from nematodes to mammals, in which short peptides can modulate the aging-related targets precisely, such as sarco/endoplasmic reticulum (SR/ER) calcium (Ca

The cerebellum, essential for motor coordination and increasingly recognized for its role in cognition, is typically considered more resilient to aging and largely spared from hallmark Alzheimer's disease (AD) pathology. However, transcriptomic analyses across fifteen mouse brain regions revealed that the cerebellum undergoes some of the earliest and most pronounced age-related changes. To investigate cerebellar aging, we applied single-nucleus RNA sequencing (RNA-seq), microglial bulk RNA-seq, and multiplexed error-robust fluorescence in situ hybridization (MERFISH)-based spatial transcriptomics. Microglia showed the most prominent changes, including elevated expression of a neuroprotective signature and reduced expression of a lipid-droplet-accumulating signature compared to hippocampal microglia. Spatial analyses further revealed that aged cerebellar microglia were positioned in close proximity to granule cells. Utilizing this relationship, we identified a proximity-dependent transcriptional state defined by the neuron-associated microglial signature. This signature reveals a region-specific microglial adaptation, highlighting cerebellar reorganization with age and potential resilience to AD.

Aging anxiety is a multidimensional psychosocial stressor with potential implications for women's long-term health, yet its biological embedding remains poorly understood. This study examined whether domain-specific aging anxieties are associated with accelerated epigenetic aging, using second-generation methylation-based biomarkers.

Numerous studies have manifested that cellular senescence involves in the pathogenesis of intervertebral disc degeneration (IDD). Here, we constructed a novel senescence-related genes (SRGs) signature for IDD.

As the global burden of chronic kidney disease (CKD) continues to rise, it is important to identify factors that may support preservation of kidney function with age. Circadian rhythmicity declines with age, and evidence suggests that circadian rhythms influence renal physiology, yet their role in long-term kidney health remains underexplored. We tested the hypothesis that lower circadian rhythmicity would be associated with an elevated risk of kidney function decline. About 1315 older adults participating in the Rush Memory and Aging Project, a prospective community-based cohort study of the chronic conditions of aging, were studied. The median age of participants was 81.5 years [IQR: 71.8-91.2], 76.3% were female, and 93.7% identified as Caucasian. The stability of the circadian activity rhythm was quantified from up to 10 consecutive days of wrist activity using interdaily stability (IS) metric. Lower baseline IS was associated with lower eGFR (estimate = -1.9 ml/min/1.73 m

In patients with postmenopausal osteoporosis, the accumulation of bone microdamage further increases fracture risk. Exosomes derived from the circulatory system of young individuals can reverse age-related defects during bone repair. Therefore, the present study aimed to elucidate the mechanisms underlying the protective effects of exosomes against structural degradation under fatigue-induced damage. To this end, a rat tibial fatigue injury model was established to investigate the protective effects of serum-derived exosomes (SDEs) isolated from young rats on bone after fatigue damage. SDEs were administered via intramedullary injection for 3 wk. The results demonstrated that treatment with SDEs significantly alleviated bone microdamage in ovariectomized rats. Specifically, it decreased cortical bone microcrack density and increased the mineral apposition rate significantly. In the distal trabecular bone region, treatment with SDEs increased bone volumetric bone mineral density (vBMD) and decreased trabecular spacing (Tb.Sp) significantly, with no significant changes in the structure model index. This study revealed that SDEs can rapidly repair fatigue-damaged bone microstructure, improving microstructural parameters in non-weight-bearing (distal tibial) cancellous bone (increased vBMD and decreased Tb.Sp). These findings provide a potential novel strategy for early intervention of microdamage in postmenopausal osteoporosis.

PurposeResearch demonstrates that cardiorespiratory fitness (CRF) mitigates age-related cognitive decline, but its specific effects across different stages of aging remain unclear. This study aimed to examine the association between CRF and global cognition in older adults, identifying the age ranges during which cognitive differences between older adults with higher and lower CRF levels were most pronounced.DesignCross-sectional.SettingData from the National Health and Nutrition Examination Survey 2011-2014.SampleA total of 2311 U.S. older adults aged 60 to 79 years.MeasuresCRF was estimated using a validated non-exercise regression equation, and participants were categorized into above- and below-median CRF groups. Global cognition was assessed using composite z-scores derived from 3 cognitive tests: CERAD Word Learning subtest, Animal Fluency Test, and Digit Symbol Substitution Test.AnalysisWeighted time-varying effect modeling was employed to examine age-related trends in the association between CRF and global cognition throughout late adulthood. Separate analyses were conducted for older adults with higher and lower CRF levels to explore differences in cognitive trajectories between these groups.ResultsParticipants with higher CRF demonstrated significantly better global cognition than those with lower CRF, particularly between the ages of 61 and 66. The largest difference was observed at age 62, where individuals with higher CRF had a mean composite score of 0.40 (95% CI = [0.27, 0.53]), compared to 0.03 (95% CI = [-0.10, 0.16]) for those with lower CRF.ConclusionPromoting improvements in CRF during key aging periods may serve as an effective strategy to delay age-related cognitive decline.

Intestinal stem cells (ISCs) drive the rapid regeneration of the gut epithelium. However, during aging, their regenerative capacity wanes, possibly through senescence and chronic inflammation, albeit little is known about how aging-associated dysfunction arises in the intestine. We previously identified the urokinase plasminogen activator receptor (uPAR) as a senescence-associated protein and developed CAR T cells able to efficiently target it. Harnessing them, here, we identify the accumulation of mostly epithelial uPAR-positive cells in the aging gut and uncover their detrimental impact on ISC function in aging. Thus, both therapeutic and prophylactic treatment with anti-uPAR CAR T cells improved barrier function, regenerative capacity, inflammation, mucosal immune function and microbiome composition in aged mice. Overall, these findings reveal the deleterious role of uPAR-positive cells on intestinal aging in vivo and provide proof of concept for the potential of targeted immune-based cell therapies to enhance tissue regeneration in aging organisms.

The telomerase RNA-protein enzyme is critical for most eukaryotes to complete genome copying by extending chromosome ends, thus solving the end-replication problem and postponing senescence. Despite the importance of the fission yeast

Janus kinase 2 (JAK2) has been linked to various neutrophil functions, but the intracellular mechanisms underlying its modulation are unknown. Neutrophils are essential cells for host defense. Neutrophil effector functions include migration, neutrophil extracellular trap production (NETosis), reactive oxygen species (ROS) production, and degranulation. The goal of this study was to elucidate the signaling mechanism through which JAK2 modulates neutrophil function and the effect of aging on this pathway. We hypothesized that JAK2-mediated modulation changes the molecular mechanisms associated with neutrophil function in an age-dependent manner. Neutrophils from young (3 mo) and aged (≥22 mo) male and female C57BL/6J mice were isolated, treated with a JAK2 inhibitor (AZD1480) or a pan-JAK inhibitor (baricitinib), and stimulated with PMA. Functional assays were conducted to assess migration, degranulation, NETosis, and metabolism. Mass spectrometry and Luminex assays provided proteomic and cytokine profiles. Our data showed that JAK2 promotes migration via membrane composition and actin remodeling, with age-dependent shifts in chemokine secretion. JAK2 primes ROS production by altering NADPH oxidase components, which contributes to NET production. JAK2 influences degranulation through actin remodeling. While aged neutrophils display impaired ROS-granule release, both young and aged neutrophils have distinct JAK-dependent release of granule contents. Metabolically, JAK2 enhances pentose phosphate pathway activity in young neutrophils and decreases glycogen breakdown in aged cells. These findings reveal mechanisms by which JAK2 modulates neutrophil function and suggest that organismal age plays a role in this modulation.

Aging causes progressive molecular and cellular changes that impair skeletal muscle function. DNA methylation is a key epigenetic regulator of this process, but its role in skeletal muscle, especially in Asian populations and postmortem samples, remains underexplored. We analyzed DNA methylation profiles from 103 pectoralis major muscle samples from autopsies of South Korean individuals (18-85 years) using the Infinium EPIC array. Targeted validation and age prediction modeling were performed with Next-Generation Sequencing (NGS) and Single Base Extension (SBE). We identified 20 age-associated CpG markers linked to genes involved in muscle structure, metabolism, and stress response. Machine learning models built on these CpG sites showed high prediction accuracy, with mean absolute errors of 5.537 years in sequencing and 3.797 years in extension platforms, and strong correlation with chronological age. This study introduces the skeletal muscle epigenetic clocks in an Asian population using postmortem skeletal muscle tissue. These novel prediction models, based on 20 common CpG markers using SBE and NGS platforms, provide a robust framework for forensic applications and enable population-tailored epigenetic profiling. Beyond predictive utility, the identified age-associated methylation signatures offer valuable insights into the molecular pathways of muscle aging and hold promise as biomarkers for translational research and age-related clinical interventions.

Functional iron deficiency affects a large proportion of patients with chronic diseases and is increasingly observed in older adults. Clinical evidence links iron deficiency to sarcopenia, yet the mechanistic relationship between iron status and muscle regeneration remains poorly defined. This study investigates how iron depletion alters muscle stem cell (MuSC) proliferation and skeletal muscle regeneration, focusing on HIF-2α signalling.

Human female fertility declines markedly with age, a pattern mirrored in

Skeletal muscle is a complex organ that undergoes aging through a multifactorial process leading to muscle atrophy and strength reduction. Mitochondrial dysfunctions prove to be a critical contributor to skeletal muscle aging, affecting the regenerative functions and differentiation of muscle satellite cells (MuSCs). Physical exercise is a nonpharmacological approach that positively affects mitochondrial functions, promoting increased mitochondrial biogenesis, enzyme activities, and respiration in the aging skeletal muscle. By means of morphological and morphometrical analyses at transmission electron microscopy, this in vitro study identified the fine structural modifications induced in mitochondria of MuSC-derived myoblasts by a long-term adapted physical exercise applied to old mice, and verified the persistence of the exercise-driven changes in the myoblast-derived myotubes. In myoblasts, physical exercise decreased mitochondrial volume while increasing mitochondrial elongation and cristae extension in comparison to the sedentary condition, a mitochondrial remodeling suggestive of higher functionality. In myotubes, physical exercise increased mitochondrial volume and decreased cristae extension, partially reverting the age-associated alterations. These findings demonstrate that physical exercise administered in elderly exerts positive effects on mitochondria of the progeny of resident MuSCs.

In the in vitro expansion of mesenchymal stem cells (MSCs), replicative or stress-induced senescence poses a significant challenge, leading to the loss of their cellular properties and therapeutic functions. Currently, there is a lack of efficient strategies to address this issue.

Sarcopenia, characterized by the progressive loss of skeletal muscle mass and function, remains a formidable challenge in aging populations. This review synthesizes current knowledge on its multifactorial pathogenesis, including mitochondrial dysfunction, oxidative stress, chronic inflammation, apoptosis, and satellite cell impairment. Neuromuscular alterations such as motor unit Remodeling and neuromuscular junction degeneration further exacerbate functional decline. Diagnostic approaches, ranging from DXA, CT, MRI, and ultrasound imaging to functional assessments like handgrip strength and gait speed, exhibit variability that complicates standardization. Therapeutic strategies are equally versatile. Resistance-based exercise and targeted nutritional support remain first-line, but late-phase trials of myostatin-neutralising antibodies (e.g., LY2495655, bimagrumab) and oral selective androgen-receptor modulators (SARMs; e.g., enobosarm, GSK2881078) now show dose-dependent gains in appendicular lean mass and preliminary functional benefits, signalling that combination regimens integrating lifestyle and drug therapy are imminent. Integration of these approaches with personalized medicine paradigms and AI-driven diagnostic tools holds promise for improved outcomes. This review also outlines critical research areas including mechanistic studies, diagnostic standardization, and translational gaps between preclinical models and clinical application. Addressing these challenges requires an interdisciplinary strategy that encompasses molecular, clinical, and public health perspectives to mitigate the personal and societal impacts of sarcopenia. Future efforts must focus on harmonizing diagnostic criteria, refining therapeutic regimens, and leveraging emerging technologies to develop targeted interventions that preserve muscle function and enhance quality of life in the aging population.

While human skin aging involves complex transcriptional alterations, the cell-type-specific regulatory mechanisms and therapeutic targets remain incompletely defined. The study aims to investigate aging-associated transcriptional programs and drug-responsive signatures at single-cell resolution.

The Senescence-Associated Secretory Phenotype (SASP), characterized by the upregulation of inflammatory cytokines, is triggered during senescence by anti-proliferation stresses, including replicative exhaustion, {gamma}-irradiation, Ras oncogene induction, and centrosome amplification. The elucidation of common signalling pathway(s) activated in SASP, induced by different antiproliferation stresses, remains an important question. Indeed, micronuclei activation of the cGAS/Sting pathway, which has been thought to drive SASP(Kwon, Leibowitz, and Lee, 2020), remains controversial(Flynn, Koch, and Mitchison, 2021; Sato and Hayashi, 2024; Takaki et al., 2024). In this report, analyses of various cell lines induced to undergo senescence by diverse stressors revealed that HIF-1 is specifically induced in senescence but not in quiescence. Consistent with our previous findings(Wu et al., 2023a), we have further demonstrated how centrosome amplification induces a non-canonical SASP dominated by HIF-1 activation rather than the classical NF{kappa}B signaling. Lastly, we revealed that during SASP, centrosome amplification-generated micronuclei do not activate the cGAS/Sting-mediated interferon response. Together, our findings demonstrate that HIF-1-activation in SASP is a defining feature of the SASP induced by diverse stressors, acting independently of micronuclei generation and cGAS/Sting activation.

The SARC-F is a 5-item questionnaire screening for patients at risk of sarcopenia. The electrical properties of tissues derived from bioelectrical impedance spectroscopy (BIS), including phase angle (PhA) and intracellular-extracellular water ratio (ICW/ECW) indices, are biomarkers of age-related loss of skeletal muscle quantity and quality. The purpose of the current study was to examine the association between SARC-F and muscle mass, strength, muscle-specific strength, and muscle quality as assessed by BIS and hand grip strength (HGS). Sarcopenia risk was assessed using the SARC-F questionnaire. BIS was used to obtain skeletal muscle mass (SMM) and skeletal muscle mass index (SMI), PhA, ICW/ECW index, membrane capacitance (Cm) and characteristic frequency (fc) for assessing muscle quantity and quality. HGS was evaluated, and muscle-specific strength (HGS/SMM) was calculated. The Pearson correlation coefficient was used to examine the associations between SARC-F scores and each muscle parameter. A total of 205 older adults aged 65-99 years were included in the current cross-sectional analysis. Of those, 142 were community-dwelling healthy older adults (110 women and32 men) and 63 were the older adults living in special nursing homes for the older adults (45 women and 18 men). SARC-F was significantly correlated with SMM, SMI, HGS, and HGS/SMM in both men and women (p < 0.05). SARC-F was also correlated with PhA, ICW/ECW index, Cm, and fc in both men and women (p < 0.001). The SARC-F score was associated with SMM, HGS, HGS/SMM, PhA, ICW/ECW index, Cm, and fc independently of age, sex, height, and BMI. SARC-F is a subjective yet simple assessment tool for muscle mass, strength, and quality relevant to sarcopenia.

Postmenopausal osteoporosis (PMOP) is a prevalent condition among postmenopausal women, closely linked to estrogen deficiency, aging, and oxidative stress. Cellular senescence, through mechanisms such as the senescence-associated secretory phenotype (SASP) and bone marrow stromal cells (BMSCs) differentiation imbalance, disrupts bone homeostasis in PMOP. Macrophages play a critical role in maintaining bone homeostasis. However, the extent of macrophage senescence in PMOP and the mechanisms by which it disrupts bone homeostasis have not yet been elucidated. Eldecalcitol (ED-71), a novel drug, has shown potential in osteoporosis treatment, though its effects on macrophage are not fully elucidated. In this study, using hydrogen peroxide (H₂O₂), we induced senescence in macrophages and assessed senescence-associated markers by SA-β-gal staining, Western blotting, and RT-qPCR. We then employed an indirect co-culture system to investigate the paracrine impact of these senescent macrophages on the osteogenic differentiation of BMSCs. The PMOP model was established using ovariectomy (OVX) in mice, followed by histological evaluation. Both 17β-Estradiol (E2) and ED-71 effectively reduced cellular senescence-related indicators such as p16, p53 and β-galactosidase in macrophages, suggesting E2 can alleviate macrophage senescence, and ED-71 may serve as an alternative. Co-culture systems revealed that senescent macrophages impaired BMSCs osteogenic differentiation, an effect reversed by ED-71. SIRT1 inhibition with EX-527 disrupted ED-71's anti-senescence action. Additionally, ED-71 improved bone mass and aging in OVX mice. In conclusion, ED-71 alleviates macrophage senescence via the SIRT1/PGC-1α signaling axis, thereby enhancing BMSC osteogenic potential and mitigating bone loss in OVX-induced osteoporosis.

Ovarian fibrosis is increasingly recognized as a pivotal factor contributing to ovarian aging, dysfunction and female infertility. It results from chronic or repetitive ovarian injury, such as that caused by repeated ovulation, which induces inflammation and excessive extracellular matrix (ECM) deposition, predominantly by activated fibroblasts and myofibroblasts. The key molecular pathways driving ovarian fibrosis include transforming growth factor-beta (TGF-β) /Smad signaling, Wnt/β-catenin and PI3K/Akt pathways, which orchestrate fibroblast activation, ECM remodeling and tissue stiffening. Elevated collagen types I and III, fibronectin and hyaluronan characterize the fibrotic ovarian stroma, disrupting normal folliculogenesis and steroidogenesis. Ovarian fibrosis is also implicated in reproductive pathologies such as polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI) and endometriosis, and may contribute to an increased risk of ovarian cancer, although definitive causal links require further elucidation. Current therapeutic strategies remain largely experimental, focusing on antifibrotic agents such as pirfenidone, TGF-β inhibitors and modulation of oxidative stress, alongside emerging interventions such as stem cell therapies, which are offer potential avenues for intervention in the ovary. This review synthesizes current insights into the cellular and molecular mechanisms driving ovarian fibrosis, its association with reproductive disorders, and emerging therapeutic strategies. It underscores key knowledge gaps and emphasizes the need for future research focused on fibroblast activation, inflammatory signaling and immune-ECM interactions to facilitate the development of targeted, long-term interventions aimed at preventing or reversing ovarian fibrosis and preserving female fertility.

Senescence-associated frailty and sarcopenia are global challenges. We here investigated neuronal activity and skeletal muscle biology in senescence-accelerated mouse prone 8 (SAMP8) mice with scalp acupuncture stimulation (SAPS). Excise activity was assessed using rotarod test in the three groups: SAMP8 mice receiving SAPS (SP8-Ap), SAMP8 controls (SP8-C), and senescence-accelerated mouse resistant 1 controls (SR1). SP8-Ap exhibited significantly improved exercise activity compared to SP8-C. SAPS increased brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the frontal cortex of SP8-Ap. Monocyte/macrophage infiltration was significantly reduced in the gastrocnemius of SP8-Ap mice, which was associated with reduced expression of various glycogen synthase kinase-3β (GSK3β)-mediated inflammatory genes and increased insulin-like growth factor (IGF)-1 mRNA and phosphorylated AKT. These results indicate that elevation of neurotropic factors in the frontal cortex by SAPS can improve the exercise activity and skeletal muscle status. SAPS may represent a novel therapeutic approach to improve senescence-related frailty.

Nutritional, genetic, and pharmacological interventions can extend lifespan; however, fewer have been shown to extend healthspan-the period of life free from chronic, debilitating diseases. In line with this, the molecular effectors that drive healthspan are even less understood than those responsible for lifespan extension. We recently reported that activation of Alcohol Dehydrogenase 1 (ADH-1) extends lifespan in yeast and C. elegans. In addition, adh-1 is transcriptionally activated in yeast, worms, mice, and humans in response to caloric restriction-an intervention that extends not only lifespan but also healthspan. Therefore, we investigated whether activating adh-1 could also extend healthspan. We demonstrate here that adh-1 activation has broad and robust effects on health, including resistance to age-related obesity, delayed sarcopenia, and attenuated neurodegeneration. Mechanistically, ADH-1-driven healthspan extension is associated with improved proteostasis. These findings position ADH-1 as a promising target for future research aimed at promoting healthy aging.

Biomechanical alterations contribute to the decreased regenerative capacity of hematopoietic stem cells (HSCs) upon aging. RhoA is a key regulator of mechanosignaling, but its role in mechanotransduction in stem cell aging remains unclear. Here we show that murine HSCs respond to increased nuclear envelope (NE) tension by inducing NE translocation of P-cPLA2, which cell-intrinsically activates RhoA. Aged HSCs experience physiologically higher intrinsic NE tension, but reducing RhoA activity lowers NE tension in aged HSCs. Feature image analysis of HSC nuclei reveals that chromatin remodeling is associated with RhoA inhibition, including restoration of youthful levels of the heterochromatin marker H3K9me2 and a decrease in chromatin accessibility and transcription at retrotransposons. Finally, we demonstrate that RhoA inhibition upregulates Klf4 expression and transcriptional activity, improving aged HSC regenerative capacity and lympho/myeloid skewing in vivo. Together, our data outline an intrinsic RhoA-dependent mechanosignaling axis, which can be pharmacologically targeted to restore aged stem cell function.

The global burden of pulmonary fibrosis is increasing. Recent studies have shown that some pulmonary fibrotic lesions caused by COVID-19 infection may persist for a long time. Emerging evidence suggested a critical association between gut microbiota and pulmonary fibrosis. In this study, the clinical follow-up data from post-COVID-19 patients indicated that those with higher CT image scores were older, had a significantly lower Blautia and Bifidobacterium to Streptococcus ratio (B/S index). We examined whether Bifidobacterium adolescentis could attenuate bleomycin-induced pulmonary fibrosis in mice, with particular attention in the aging mice. Aging mice exhibited more severe pulmonary fibrosis after BLM induction, while the intervention of B. adolescentis attenuated the degree of pulmonary fibrosis in aging mice to a state similar to that of young mice. B. adolescentis alleviated inflammatory responses by enhancing the gut barrier, and reduced fibrotic marker expression (TGF-β, IL-17, α-SMA, Collagen I/III) by modulating PPAR and Th17 signaling pathways. Furthermore, B. adolescentis stabilized gut microbiota and increased the abundance of Bifidobacterium, Turicibacter, and norank_f_Desulfovibrionaceae, thereby suppressed the prostaglandin E2 (PGE2) and affected collagen deposition. B. adolescentis alleviates pulmonary fibrosis through the gut-lung axis by regulating PGE2/PPAR/Th17 signaling, providing a promising therapeutic approach for pulmonary fibrosis management.

The elimination of senescent cells can enhance the osteointegration of implants in elderly patients. However, achieving specific clearance of senescent cells without adversely affecting the function of normal cells remains challenging. Here we show an implant surface modification technique to achieve specific clearance of locally senescent cells by modulating their metabolism. Our method involve modifying implants with BPTES, a glutaminase 1 (GLS1) inhibitor, through π-π stacking with dopamine. This modification effectively induces intracellular acidosis in senescent mesenchymal stem cells (MSCs) through suppression of glutaminolysis. Simultaneously, poly(γ-glutamate) (PGA), modified by a layer-by-layer method, serve as a high-density carbon source coating, continuously supporting glutamine metabolism in MSCs without ammonia production. Our results show that modified implants significantly reduce the senescence level around implants and promote osteointegration in aged rats. These findings provide promising insights into the design and application of orthopedic implants for elderly patients.

Neurons rely on glial lactate shuttling for metabolic support, which declines with aging and in neurodegenerative disease. Full disruption of lactate shuttling in peripheral nerves causes progressive axon degeneration, but we were interested to understand how partial disruption, a scenario more relevant to aging and disease, contributes to neurodegeneration risk. Pyruvate and lactate are interconverted by lactate dehydrogenases (LDHA and LDHB) in both lactate producing and consuming cells. We therefore began by investigating Ldhb knockout mice (loss of LDHA, the dominant LDH in liver and muscle, caused embryonic lethality), and discovered that they develop progressive neuromuscular junction atrophy and functional decline without axon degeneration. Because even Ldhb+/- heterozygosity significantly affects motor behavior, we also wondered about a potential link to congenital disease and pursued this by identifying rare loss-of-function LDHB variants among ALS patients. Next, to better understand how LDHB loss leads to motor decline, we selectively deleted it in defined cell types. SC-specific deletion caused robust motor defects, whereas motor neuron-specific deletion has little effect. Reasoning that neuronal LDHB deficiency could model age-associated decline in lactate metabolism, we asked whether it would interact with ALS genetic risk. Indeed, motor-neuron LDHB deficiency synergizes with relatively mild ALS risk variants, TDP43-Q331K and Sod1-D83G knock-in alleles, to produce early motor neuropathy, indicating that LDHB loss enhances disease risk. These findings establish lactate metabolism as a modifier of motor system vulnerability and highlight it as a therapeutic target in peripheral as well as central neurodegeneration.

The additive genetic variance of a quantitative trait usually is interpreted as a measure of its evolvability, i.e., its capacity for adaptive evolution. However, in populations with overlapping generations, evolvability is also affected by the parental age at reproduction because genotypes that reproduce earlier evolve faster than genotypes with later reproduction. I show here that directional selection of a phenotypic trait inevitably links it with relative age at reproduction and thus developmental timing, whether or not age at reproduction affects reproductive success. In turn, the evolved genetic covariance between the selected trait and reproductive age accelerates the evolutionary response of the trait mean, unless counteracted by strong selection for late reproduction. Hence, not only the genetic variance of the trait but also the genetic variance in age at reproduction contributes to a trait's evolvability, even if the trait was initially unrelated to age at reproduction. I further show that stable generation time requires selection of intermediate strength for later reproduction and that episodes of strong selection tend to shorten average generation time. After a proof of principle by individual-based simulations, I present a formalization of this theory in a quantitative genetic framework, leading to a relatively simple extension of the breeder's equation. Finally, I discuss empirical evidence and implications for senescence and life history evolution.

Aging is an irreversible degenerative process marked by declining physiological function. Developing therapeutics to delay aging and prolong healthy life represents a significant research focus. The dried roots of Asparagus cochinchinensis (Lour.) Merr. (Asparagi Radix, AR), a traditional Chinese medicine, possesses various pharmacological properties, including antioxidative, antitumor, and anti-inflammatory effects, and is commonly used in anti-aging formulas. Although steroidal saponins are its major active components, the specific compounds responsible for its anti-aging effects remain unidentified, and their mechanistic basis is unclear. This study evaluated the anti-aging effects of AR-derived total saponin extracts (ATSE) in Caenorhabditis elegans and elucidated underlying mechanisms. We prepared multiple ATSE batches from distinct geographical sources and assessed their bioactivity through lifespan and healthspan analyses (brood size, pharyngeal pumping), stress resistance, assays (oxidative, thermal), senescence biomarkers (lipofuscin accumulation, SOD activity, ROS levels). Mechanistic insights were obtained using transgenic strains and qRT-PCR, while ELSD-HPLC fingerprinting and spectrum-effect correlation identified active compounds. Key findings demonstrated that ATSE from Sichuan (T1) most effectively prolonged C. elegans lifespan (p < 0.01), enhanced stress resistance, increased SOD activity, and decreased ROS levels. The lifespan extension was primarily mediated through the FOXO/DAF-16 signaling pathway, while spectrum-effect analysis further identified (25S)-officinalisnin-II as the most active compound, extending C. elegans longevity under oxidative stress by 13.91%. Our research revealed AR's anti-aging mechanism and identified a key active compound, laying the foundation for quality-controlled AR therapeutics and providing new insights for the development of anti-aging drugs from traditional Chinese medicine.

Biguanides, including metformin, the world\'s most prescribed oral hypoglycemic, extend health-span and lifespan in vertebrates and invertebrates. Given the widespread use and apparent safety of metformin, it is assumed that its effects are not associated with toxicity, except when in marked excess. Here we determine that accumulation of damaging reducing equivalents is an unanticipated toxicity associated with biguanides, the defense against which requires post-transcriptional protection of de novo fatty acid biosynthesis. We demonstrate that biguanide treatment during impaired fatty acid biosynthesis drives NADPH toxicity, leading to catastrophic elevation of NADH/GSH reducing equivalents and accelerated death across metazoans. Multiple NADPH-generating interventions require fatty acid biosynthesis to prevent markedly shortened survival, indicating that this defense mechanism is broadly leveraged. We propose that fatty acid biosynthesis is a tunable rheostat which can minimize biguanide-induced reductive stress whilst maximizing its pro-longevity outcomes and serve as an exploitable vulnerability in reductive stress sensitive cancers.

This review highlights recent findings on the versatile serpin protein, pigment epithelium-derived factor (PEDF), as pertains to its roles in ageing and development, including its linked functions as an antioxidant and in stem cell support. The anti-oxidative properties of PEDF channel through several well-known pathways such as nicotinamide adenine dinucleotide phosphate oxidase. PEDF also supports stem cell survival in various tissues, leading to certain types of differentiation of such cells, for example, in bone. Mesenchymal stem cells engineered to overexpress PEDF have profound effects on neighbouring cells, which can be exploited therapeutically. PEDF can attenuate both the p53 and peroxisome proliferator-activated receptor-gamma pathways. This review provides a comprehensive, first-of-its-kind overview of the protein, listing a majority of all the relevant studies reported to date.

Growing evidence suggests that the gut microbiota is closely intertwined with life-history evolution in a wide range of species, including well-studied model organisms like Drosophila melanogaster. Although recent studies have explored the relationship between gut microbiota and female life-history, the link between gut microbiota and male life-history remains relatively unexplored. In this study, we investigated how gut microbiota changes with male age as well as the associations between gut microbiota composition and male life-history traits in D. melanogaster. Using 22 isolines from the Drosophila melanogaster Genetic Reference Panel (DGRP), we measured lifespan, early/late-life reproduction, and early/late-life physiological performance. We characterized the gut microbiota composition in young (5 days old) and old (26 days old) flies using 16S rDNA sequencing. We observed substantial variation in both male life-history traits and gut microbiota composition across isolines and age groups. Using machine learning, we show that gut microbiota composition could predict the chronological age of the organisms with high accuracy. The most important species contributing to machine learning prediction belonged to the Acetobacter and Ralstonia genera. Associations between gut microbiota and life-history traits were also notable, particularly involving different species from the Acetobacter genus. Our findings suggest that taxa such as Acetobacter may be relevant to the evolutionary ecology of host-microbe interactions in male fruit flies.

As populations age rapidly, understanding the psychological benefits of sustained employment has become increasingly important. In South Korea, where the suicide rate among older adults is one of the highest among Organisation for Economic Co-operation and Development (OECD) countries, identifying modifiable social determinants, such as employment, may inform effective prevention strategies.

Aging and stress are major risk factors for impaired neural plasticity and maladaptive behavior, and their interaction is shaped by genetic predispositions. We examined how aging and prior stress affect behavior, molecular markers of apoptosis and neuroplasticity, neuroinflammation, and the gut microbiota in rat strains selectively bred for contrasting nervous system excitability: high-threshold (HT, low-excitability) and low-threshold (LT, high-excitability). Adult (5-month-old) and middle-aged (14-month-old) males were studied with or without chronic emotional-pain stress in adulthood. Aging induced strain-specific behavioral and molecular profiles: in HT rats, reduced locomotion and increased freezing in the open field were accompanied by a lower amygdalar Bcl2/Bax ratio and higher Map2 expression, whereas LT rats presented fewer behavioral changes but increased Bax. Prior stress produced long-term, opposite effects: in HT rats it changed the gut microbiota composition, attenuated anxiety-like behavior and decreased amygdalar Bax, whereas in LT rats it increased anxiety with minor microbiota alterations. Overall, aging and stress produced distinct, strain-dependent signatures across behavior, gene expression, and microbiota composition. HT rats exhibit plasticity and microbiota remodeling consistent with resilience, whereas LT rats show limited behavioral flexibility and microbiota stability, a pattern potentially modeling vulnerability to stress-related aging. The use of contrasting excitability rat strains underscores the importance of genetic background for understanding individual variability in resilience and vulnerability to aging and stress.

Bone marrow exhibits functional decline, yet cellular heterogeneity and molecular mechanisms remain unclear due to limitations of traditional research methods. This study aims to characterize age-related changes and identify key drivers in bone marrow. Integrated multi-omics analysis was performed using scRNA-seq, proteomics, pseudo-bulk transcriptomics, weighted gene co-expression network analysis (WGCNA)-based transcription factor (TF) network modeling, and CellChat analysis. Samples included 6 young and aged bone marrow specimens. Statistical validation involved differential expression analysis, Cox regression modeling, and receiver operating characteristic (ROC) curve analysis. A novel hematopoietic subpopulation (3.19% of aged samples) was identified, activating the cellular senescence pathway (KEGG) and enhancing inflammatory crosstalk with CD8⁺ T cells via NMU signaling (|avg_log2FC|> 0.58, p < 0.001). Pseudo-bulk and proteomic analyses identified CAPN1, MAP2K1, and JUND as potential signal modules. Immunohistochemistry and Western blot confirmed their co-expression, while molecular docking revealed interaction interfaces. In two independent bulk-RNA cohorts (n = 58), a Cox model based on the CAPN1-MAP2K1-JUND module showed robust predictive value for aging, with AUCs of 0.7507 (p = 0.0154) and 0.90 (p = 0.0274). This study identifies a pivotal molecular module linking single-cell dynamics to tissue-level senescence in bone marrow, providing new insights into aging mechanisms and potential therapeutic targets.

Exposure to microgravity induces a rapid and profound loss of bone mass, particularly in weight-bearing skeletal regions, closely resembling accelerated osteoporosis on Earth. Traditionally attributed to mechanical unloading, bone loss in space is now recognized as being strongly regulated by oxidative stress. Excessive production of reactive oxygen species (ROS)-driven by mitochondrial dysfunction, cosmic radiation, altered circadian rhythms, and fluid shifts-disrupts osteoblast differentiation, enhances osteoclastogenesis, and compromises osteocyte viability. These effects are mediated through redox-sensitive signaling pathways, including RANK/RANKL/OPG, Wnt/β-catenin, and MAPK, as well as transcriptional regulators such as NF-κB, ERK, and FoxO. Moreover, oxidative stress modulates epigenetic regulators, notably microRNAs and long non-coding RNAs, tipping gene networks toward apoptosis, autophagy dysregulation, and cellular senescence in bone cells. Beyond mechanistic insights, recent studies highlight the long-term persistence of skeletal deficits after spaceflight and reveal sex- and age-related vulnerabilities, particularly in postmenopausal women due to estrogen deficiency. These findings position oxidative stress as a central driver of skeletal deterioration with clear translational relevance to age-related osteoporosis. Current and emerging countermeasures target both the mechanical and redox dimensions of bone loss. Pharmacological strategies include antioxidants, bisphosphonates, NADPH oxidase inhibitors, mitochondrial stabilizers, and autophagy modulators. Nutritional interventions emphasize antioxidant-rich diets, vitamin D and calcium supplementation, and omega-3 fatty acids. Mechanical and biophysical countermeasures-resistance training, vibration therapy, and artificial gravity-remain essential, while innovative approaches such as redox-sensitive gene therapy, siRNA-based modulation, and mitochondria-targeted antioxidants offer new therapeutic avenues. By integrating mechanistic, epigenetic, and translational perspectives, this review underscores the centrality of redox imbalance in spaceflight-induced bone loss and identifies actionable targets for prevention. Ultimately, dissecting ROS-mitochondria-cell fate signaling provides a unifying framework for protecting astronaut skeletal health and advancing therapies for terrestrial osteoporosis.

During brain aging, terminally differentiated neuroglia exhibit metabolic dysfunction and increased oxidative damage, compromising their function. These cellular and molecular alterations impair their ability to maintain myelin sheath integrity, contributing to age-related white matter degradation. Calorie restriction (CR) is a well-established intervention that can slow biological aging and may reduce age-related metabolic alterations, thereby preserving the molecular function of aging glia. Here we present a single nucleus resolution, transcriptomics dataset evaluating the molecular profile of oligodendrocytes and microglia in the brain of aging rhesus monkeys following lifelong, 30% calorie restriction. Oligodendrocytes from CR subjects exhibited increased expression of myelin-related genes and showed enrichment in glycolytic and fatty acid biosynthetic pathways. In CR subjects, a subpopulation of oligodendrocytes upregulated cell adhesion gene, NLGN1 and were in closer proximity to axons. Microglia from CR subjects upregulated amino acid and peptide metabolism pathways and showed a reduced myelin debris signature. Our findings reveal cell-type specific transcriptional reprogramming in response to long term CR and highlight potential protective mechanisms against myelin pathology in the aging primate brain.

Skeletal muscle is essential for movement, respiration, and metabolism, with mTORC1 acting as a key regulator of protein synthesis and degradation. In aging muscle, mTORC1 becomes overactivated, contributing to sarcopenia, though the mechanisms remain unclear. Here, we identify DEAF1, a FOXO-regulated transcription factor, as a key upstream driver of mTORC1 in aged muscle. Elevated

Gait performance depends on numerous aspects of brain functioning that are also relevant to key cognitive processes throughout the lifespan. The Timed Up and Go (TUG) test has been shown to be a reliable tool for assessing age-related mobility changes and risk of falls in older adults. This study aimed to predict TUG performance using motor-cognitive inter-network connectivity, cognitive performance and socio-demographics. 189 participants without cognitive impairment were included. Mobility was measured with the TUG through a wireless inertial sensor device. Functional connectivity between the somatomotor hand, cerebellar, and cognitive-related networks was assessed using pairwise correlations among 264 predefined regions assigned to large-scale functional networks. Connectivity between networks was summarized by averaging Fisher z-transformed values across all ROI pairs linking each network pair. Three linear regression models were constructed including the dependent variables TUG total time, turning time and turning peak-angular velocity (PAV) and the independent variables age, sex, years of education, memory and executive performance, and inter-network connectivity patterns. Somatomotor hand - ventral attentional and cerebellar - DMN inter-network connectivity were significant predictors of TUG total time. Memory performance, somatomotor hand - salience and -cingulo opercular inter-network connectivity were significant predictors of turning time. Age, years of education, somatomotor hand - dorsal attentional and cerebellar - cingulo opercular network activation were significant predictors of turning PAV. Findings indicate different contributions of attentional systems to gait performance in aging.

Collagen in the connective tissue plays a key role in the expression the aging phenotypes. While collagen production decreases with aging, collagenase expression increases, resulting in collagen breakdown. The purpose of this study is to investigate the change in the expression of proteins and genes related to the collagen signaling pathway, cell cycle, and aging phenotypes of cells with the collagen type 1 α (COL1A1) gene edited by the CRISPR/Cas9 system. The mutation of the COL1A1 gene was induced by the CRISPR/Cas9 system. Sanger DNA sequencing and Indel analyses, Sanger DNA sequencing analysis and Swiss protein modeling analysis were used to verify the induction of mutation. Aging phenotypes in the mutated cells were evaluated by collagen staining assay, SA-β-galactosidase staining assay, RT-PCR assay, Western blot analysis, gelatin zymography, and immunofluorescent staining assay. Sanger DNA sequencing analysis demonstrated that human fibrosarcoma cells with COL1A1 gene mutations were successfully established in this study. Swiss protein modeling analysis displayed the altered structure of COL1A1 in the edited cells. In addition, while collagen production was decreased, the SA-β-galactosidase staining level was increased in the edited cells. It was also found that the expression levels of CDC2, CDk2, and cyclin D were increased by down-regulating p53 and p21 levels through the increased expression of MDM2 in the edited cells. Moreover, the expression levels of MMP-1, MMP-2, MMP-9, AKT, and p-mTOR were reduced in the edited cells. These findings could provide a crucial clue in elucidating the close relationship between collagen production and senescence.

Cognitive function can decline irreversibly with age, potentially progressing to dementia. Intervention during the preclinical stage is considered effective, but evaluation often requires large-scale equipment and tests. A decline in inhibitory function precedes and is involved in a general decline in higher-order brain functions, making its assessment a key target for early detection. We focused on error-related negativity (ERN) to capture the neural network of inhibitory function. While larger ERN amplitudes indicate higher error detection ability and correlate with inhibitory function, the causal relationship, mutual influences, and age-related effects in older adults remain unclear. This study measured brain activity during an inhibitory task in young and older adults to examine the neural networks related to error detection and inhibitory function. We used LORETA iCoh Full Vector Field analysis to verify directional connectivity. In the elderly group, during error responses, we observed significantly stronger beta-band directionality from the ventral anterior cingulate cortex (ACC) to the left frontal pole. Between the ventral and dorsal ACC, we also found significantly stronger directionality in the theta, alpha, and beta bands. During correct responses, they showed significantly stronger alpha and beta-band directionality from the left dorsolateral prefrontal cortex (DLPFC) to the right frontal pole. Compared to the elderly, the young group exhibited significantly stronger mutual directionality between the ventral and dorsal prefrontal cortices in the alpha and beta bands. They also showed widespread, significantly strong directionality among the ACC, bilateral DLPFC, and frontal poles. These results suggest that error detection ability is important for the normal functioning of inhibitory control in older adults. Furthermore, an age-related decline in metacognitive abilities may be associated with impaired inhibitory function. The insights from this study can contribute to developing risk prediction models for cognitive decline and establishing effective preventive strategies.

A hallmark of successful aging is increased life experiences and knowledge. Yet how this additional information is incorporated into semantic memory is unclear. Network science has proven to be a useful tool for modeling semantic memory networks in younger and older adults. Previous research suggests that although vocabulary and knowledge are largely stable across adulthood, older adults may have semantic memory networks that are less efficient, less interconnected, and more segregated. However, prior work, including our own, has largely focused on semantic memory networks derived from highly salient, physical concepts (e.g., animals). Though words essential for natural conversation vary greatly in terms of their psycholinguistic characteristics. In the present study, we examine age-related differences in semantic memory networks derived from a free association task, using both abstract and concrete cues that varied in semantic diversity - the number of unique contexts in which they could appear. Across several analytic approaches, we found that including abstract words in semantic memory networks minimized age-related differences: there were no age differences in network efficiency, but older adults had more interconnected and less segregated semantic memory networks compared to younger adults. Looking at word-level characteristics of the semantic memory networks suggested that for both younger and older adults, words that were high in semantic diversity and were more abstract had stronger connections to other words and were more interconnected. These results suggest that abstract and semantically diverse words are a cornerstone in maintaining older adults' semantic memory networks.