Longevity Papers

Aging is driven by cellular senescence and chronic inflammation, largely mediated by the senescence-associated secretory phenotype (SASP). SASP factors promote inflammaging, impair tissue homeostasis, and contribute to age-related diseases such as cardiovascular disease, neurodegeneration, and cancer. Current anti-aging strategies focus on senolytics or SASP inhibitors, yet these approaches have limitations. We discuss therapeutic plasma exchange (TPE) and selective apheresis, as interventions to mitigate SASP-driven aging. TPE removes inflammatory cytokines, metabolic waste, and senescence-associated proteins, while replenishing rejuvenating factors. Selective apheresis could enhance precision by targeting specific SASP components. By reducing systemic inflammation and restoring a youthful proteomic environment, these strategies may improve immune function, tissue regeneration, and overall healthspan. This review explores the mechanistic basis of SASP in aging and evaluates the potential of apheresis-based therapies as viable interventions to delay aging and age-related disease progression.

DNA repair, an evolutionarily conserved mechanism essential for restoring genetic homeostasis, has been implicated in aging and longevity by multiple lines of evidence. However, due to the challenges in obtaining human research materials, studies on the interplay between DNA repair and aging rely primarily on laboratory animal models, whose regulatory mechanisms may not fully mirror those in humans. Strikingly, the rate of aging varies by nearly an order of magnitude across humans, ranging from individuals with progeroid syndromes (lifespans under a decade) to the longest-lived recorded person (122 years). This extreme diversity provides a unique framework for comparative analysis of lifespan regulation in humans. By integrating advances in DNA repair studies across humans with divergent aging trajectories, this review provides novel insights into the molecular basis of DNA repair and lifespan, highlighting promising targeted therapies to promote longevity through precise modulation of DNA repair pathways.

Osteoarthritis (OA) is a common and debilitating joint disorder, with its pathogenesis significantly influenced by factors such as aging and obesity. A critical aspect of OA development is the senescence of chondrocytes, which is characterized by irreversible cell cycle arrest and the secretion of pro-inflammatory molecules, collectively known as the senescence-associated secretory phenotype (SASP). Senescent chondrocytes compromise the maintenance of the extracellular matrix (ECM) and accelerate cartilage degradation, thereby exacerbating the progression of OA. Contributing factors to chondrocyte senescence include oxidative stress, mechanical overload, and ECM stiffness, while cellular dysfunctions such as mitochondrial impairment and defective autophagy further promote cartilage deterioration. Emerging therapeutic strategies aim to target senescent chondrocytes through the use of senolytic and senomorphic agents, microRNA-based therapies, immunotherapies, and stem cell-based interventions. Although these treatments have demonstrated potential in preclinical studies, additional research is required to enhance their efficacy in the clinical management of OA.

There continues to be growing interest in the Science of Learning including identifying ways to apply findings. Presently, little is known about learning during healthy adulthood and methods to improve that learning. The main objective of the present systematic review is to identify and synthesize all recent cognitive and brain research investigating learning during healthy aging in adulthood. Searches were performed across Scopus, Web of Science, and ProQuest databases to identify published and unpublished studies conducted in healthy adults. Eligible studies reported measures of learning-related cognition, brain structure or function and their relationship with age, or effects of interventions to improve learning. Risk of bias was assessed using either the Mixed Methods Appraisal Tool or Critical Appraisal Skills Programme checklist. Search and screening were performed by three trained reviewers. Included studies were summarized using narrative synthesis and, for intervention studies, an effect direction plot. A total of 265 relevant studies were identified for inclusion. Studies were primarily lab-based cross-sectional studies conducted in Western contexts. Findings revealed an overall decline in learning-related cognitive and brain outcomes during healthy aging. However, declines were more pronounced in fluid abilities and explicit learning and memory while crystalized abilities and implicit learning and memory showed stability. Generally, higher education and socioeconomic status positively modulated age-related learning trajectories while baseline cognitive function influenced the effectiveness of interventions. Findings from the present systematic review are potentially limited by the exclusive focus on healthy aging and the small number of included studies conducted in non-Western contexts. Implications for policy, practice, and future research are discussed.

Large-scale brain networks are vulnerable to change with aging and become dysregulated. How these networks are altered at the cellular level remains unclear owing to challenges of bridging data across scales. Here, we integrate in vivo cortical similarity networks with whole brain spatial transcriptomics to characterize the aging brain in a lifespan cohort of macaques (N=64, ages 1-26 years). Deep-layer excitatory neurons and oligodendrocytes emerged as dominant correlates of cortical similarity, linking infragranular cell type composition to macroscopic network structure. Age-related declines in network strength were most pronounced in transmodal networks, including default mode and limbic, and aligned with regions enriched in inhibitory and glial cell types. Parvalbumin-enriched chandelier cells showed the strongest association with regional vulnerability, suggesting a role in network disconnection. Cell-type enrichment was conserved across species, with both human and macaque transcriptomic data aligning with the cortical functional hierarchy. These findings uncover a cellular basis for cortical network aging and highlight the value of imaging-transcriptomic integration across scales.

Life-history traits such as body size, reproduction, survival, and stress resistance are fundamental to an organism's fitness and are highly influenced by nutritional environments across life stages. In this study, we employed a full factorial experimental design to investigate the effects of isocaloric diets (diets with equal caloric content but differing macronutrient composition) on key life-history traits in an outbred Drosophila melanogaster population. Our results demonstrated significant diet-induced plasticity, with male wing length (a proxy for body size) being influenced by the developmental diet; males reared on carbohydrate-rich developmental diets had larger wings as adults. Fertility increased with protein-rich diets at both developmental and adult stages, reaffirming the critical role of dietary protein in enhancing reproductive success. Lifespan exhibited sexually dimorphic responses to diet: carbohydrate-rich developmental diets extended male lifespan, while carbohydrate-rich adult diets reduced lifespan in both sexes. Stress resistance traits, including starvation and desiccation resistance, were unaffected by developmental diets but were influenced by adult diets, with carbohydrate-rich adult diets enhancing survival under both stress conditions in males and females. Importantly, while most traits exhibited additive effects of nutrition across life stages, a marginal interaction for male starvation resistance suggests that developmental and adult diets can interact in a trait- and sex-specific manner. Moreover, associations between dietary effects on life-history traits were context-dependent, driven primarily by adult diets and varying by sex. These findings emphasize the profound role of stage-specific nutritional environments in modulating life-history traits and their correlations, offering valuable insights into how organisms may adapt to changing ecological conditions and highlighting the importance of considering both developmental and adult dietary contexts in evolutionary studies.

Brain age and epigenetic age (DNAmAge) are 'biological clocks' independently linked to health outcomes. However, the relationship between brain and epigenetic age remains unclear. We used path analysis to investigate relationships between chronological age, DNAmAge, and brain age and explored whether advanced aging in specific brain regions relates to DNAmAge. BrainAge (global and regional) was estimated from brain MRI in 149 participants (ages 20-80). From whole blood, four DNAmAges were calculated: Pheno, Hannum, Horvath, and SkinBlood. Mediation was used to test the indirect effect of DNAmAge on global BrainAge, as well as the reverse, with chronological age as the independent variable. Correlations between accelerated region-specific BrainAge and DNAmAge were also examined. DNAmPhenoAge mediated the relationship between chronological age and global BrainAge. DNAmPhenoAge was related to advanced BrainAge of regions higher on the sensorimotor-to-association axis of cortical organization (F(1104) = 17.5, R

As human life expectancy continues to rise, ageing and age-related diseases have become critical societal challenges, driving extensive research across genetics, molecular biology, biochemistry, and behavioral sciences. In this context, domestic dogs (Canis lupus familiaris) offer a unique model for ageing research due to their shared environmental exposures with humans, diverse genetic profiles, and relatively short lifespans. This review aims to identify potential biomarkers of ageing in dogs, facilitating a deeper understanding of age-related mechanisms and supporting the evaluation of interventions designed to promote healthy ageing. We present a research of peer-reviewed literature on age-related variations of various parameters across multiple biological systems, including epigenetic, telomere, immune, metabolic, and cognitive markers in dogs. Our findings highlight several robust biomarkers, such as DNA methylation-based epigenetic clocks, telomere attrition, CD4+/CD8+ T-cell ratio, hematological markers (e.g., globulin levels), and cognitive function scores. These biomarkers demonstrate strong parallels with human ageing processes, particularly concerning genomic and epigenetic alterations. However, challenges remain, including breed-specific variability, body size differences, and inconsistent evidence regarding inflammageing markers, such as pro-inflammatory cytokines. Despite these limitations, indicators of chronic inflammation (e.g., anemia of chronic disease and elevated globulins) are evident in older dogs. Future research directions include the standardization of biomarker protocols for dogs, the development of longitudinal studies to track dynamic age-related changes, and further exploration of emerging biomarkers, such as those related to microbiome composition and oxidative stress.

To examine the structural, metabolic, and functional trajectories of neuromuscular decline in aging and identify key mechanisms and early biomarkers to guide interventions preserving function and independence.

Aging is closely linked to chronic diseases, and gut microbiota plays a significant role in this process. The Dietary Index for Gut Microbiota (DI-GM), a novel tool reflecting the potential impact of diet on gut microbiota diversity, has an unclear association with biological aging. This study aimed to evaluate the association between DI-GM and phenotypic age acceleration (PAA), revealing the potential regulatory effect of diet on aging.

Though interest has grown significantly over the past decades in interventions that may slow the aging process, most evidence for these interventions still comes from experiments in non-human animals. These studies may suffer from design, quality and reporting issues. The quality and reporting of preclinical studies have not yet been studied systematically in anti-aging research. Here we analyzed the DrugAge database, assessing reporting study quality, bias and effect sizes across 667 anti-aging preclinical studies. We found significant shortcomings in reporting of crucial design features such as randomization and blinding, as well as large variation in reporting quality and effects across species. Non-mammal findings typically did not translate to mammals. Although anti-aging interventions may have different effects depending on when they are started, most studies began giving the intervention under investigation very early in the organisms lifespan. Our findings suggest there is substantial room for improvement in preclinical anti-aging research.

CRES is the defining member of a reproductive subgroup of family 2 cystatins of cysteine protease inhibitors. We previously showed that CRES and other subgroup members are part of a highly plastic amyloid-containing extracellular matrix (ECM) with host defense functions in the mouse epididymal lumen. Based on parallels between the epididymis and the brain, we hypothesized that CRES and CRES amyloids might also function within the brain including the ECM. Here we show that CRES is produced by hippocampal neurons and astrocytes in the male and female mouse and human brain. Further, approximately 50% of hippocampal astrocytes from aged mice, like the aged human donor samples, had significantly reduced levels of CRES compared to younger mice, suggesting an age-related decline in CRES could contribute to altered brain function. Immunofluorescence experiments showed CRES colocalized with the ECM markers phosphacan and wisteria floribunda agglutinin indicating that CRES is part of the ECM. CRES monomer and high molecular weight SDS-resistant forms were found in insoluble fractions of the hippocampus, cortex, cerebellum, and midbrain and bound to the protein aggregation disease (PAD) ligand, which preferentially binds amyloids but not protein monomers, suggesting a population of CRES exists in the brain as an amyloid structure. Collectively, our studies demonstrate that CRES/CRES amyloid is present in the mammalian brain and may contribute to ECM structure and function.

Vascular smooth muscle cell (VSMC) senescence is a pivotal driver of atherosclerosis (AS), but molecular links to ageing-related dysfunction are unclear. It is aimed to identify regulators of VSMC senescence and develop clinical interventions for ageing-related AS. Using single-cell RNA sequencing of human atherosclerotic carotid arteries and immunofluorescence validation, activating transcription factor 3 (ATF3) is identified as central to VSMC senescence. Mechanistic studies employ SMC-specific ATF3 knockout mice, CUT&Tag-seq, RNA/protein interaction assays, and m6A epitranscriptomic analyses. To bridge discovery to therapy, high-throughput virtual screening is performed for ATF3-targeting compounds and functionally validated hits. ATF3 deficiency in VSMCs accelerates ageing-induced AS by promoting senescence. Multi-omics showed ATF3 activates ATG7, triggering autophagy, while cytoplasmic ATG7 enhances ATF3 nuclear translocation, establishing a positive feedback loop. Ageing increases m6A methylation and decreases the stability of Atf3 mRNA. Terazosin (TZ) diminishes the interaction between YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) and Atf3 mRNA, helping to preserve Atf3 mRNA stability. TZ is a promising therapeutic strategy for delaying VSMC senescence and preventing AS. ATF3 protects against VSMC senescence and AS by orchestrating autophagy via a novel ATF3-ATG7 amplification loop. Repurposing TZ to stabilize ATF3 offers a translatable approach to combat ageing-driven cardiovascular disease.

Memory T cells are a highly heterogeneous collection of antigen-experienced cells that undergo dynamic adaptations upon antigen re-encounter and environmental signals. This heterogeneity hinders studies on memory T cell durability and age-related dysfunction. Using chronic Epstein-Barr virus (EBV) infection and barcode-enabled antigen tracing, we assess the influence of age on memory states at the level of single antigen-specific CD8

The small GTPase Cdc42 is a central regulator of cell polarity, but it is often hyperactivated in aged cells, contributing to senescence and aging in both yeast and animal cells. Yet, the mechanisms underlying its age-related upregulation remain poorly understood. Here, we examine how Cdc42 levels change over successive divisions in budding yeast, which undergoes asymmetric cell division, leading to aging predominantly in mother cells. Using microfluidics-based live-cell imaging and genetic analyses, we find that Cdc42 protein is unevenly distributed between mother and daughter cells during division. Notably, daughter cells inherit lower levels of Cdc42, which helps them rejuvenate. This asymmetry depends on Cdc42s association with endomembranes and requires the presence of farnesylated Ydj1, an Hsp40/DnaJ chaperone tethered to the endoplasmic reticulum. Furthermore, maintaining proper Cdc42 levels relies on its interaction with Ydj1. These findings reveal a chaperone-mediated mechanism that controls Cdc42 partitioning during asymmetric division, linking it to cellular aging--a process that may be conserved in other asymmetrically dividing cells.

The aging process is often accompanied by hepatic metabolic dysregulation and related complications, including lipid accumulation and fibrosis. Nutritional interventions are crucial for maintaining metabolic health. This study explored the effects of exogenous nucleotides (NTs) on liver health in aged SAMP8 mice over 9 months. Results demonstrated dietary NTs effectively improved liver pathology, increased body mass, enhanced antioxidant capacity, reduced lipid accumulation, downregulated lipid synthesis genes, and lowered fibrosis-related markers. Mechanistically, NTs downregulated purine biosynthesis, modulating lipid metabolism-related transcription factors to reduce lipid accumulation. Additionally, NTs enhanced the efficiency of glycolysis and increased ATP synthesis. Thus, NTs exhibited substantial effects in regulating energy metabolism, suppressing lipid synthesis, and combating fibrosis. However, the effects displayed a nonlinear dose-dependent relationship, and the precise impact of NT dosage on health remains challenging. This study advances our understanding of NTs' role in aging and metabolic dysregulation.

The nutritional environment in early life, referred to as the nutrition history, exerts far-reaching health effects beyond the developmental stage. Here, with Drosophila melanogaster as a model, we fed larvae on diets consisting of a variety of yeast mutants and explored the resulting histories that impacted adult lifespan. A larval diet comprised of yeast nat3 KO shortened the lifespan of male adults; and remarkably, this diet diminished the function of histone acetyltransferase Gcn5 in larvae. Concordantly, perturbation of Gcn5-mediated gene regulation in the larval whole body or neurons significantly contributed to the earlier death of adults. The nat3 KO diet is much more abundant in long-chain fatty acids and branched-chain amino acids (BCAAs) than the control yeast diet. Supplementing the control diet with a combination of oleic acid, valine, and acetic acid recapitulated the effects of the nat3 KO diet on the larval transcriptome and the lifespan of males. Our findings strongly suggest a causal link between a fatty acids- and BCAA-rich diet in developmental stages and lifespan reduction via the adverse effect on the Gcn5 function.

Hematopoietic stem cells (HSCs) are responsible for sustaining hematopoietic system throughout life, and their functional decline contributes to hematological disorders and organismal aging. Understanding the molecular mechanisms that govern HSC function is critical for developing interventions for treating and preventing aging-related diseases. Here, we show that DCAF8, a substrate recognition component of Cullin-RING E3 ubiquitin ligases, is highly expressed in HSCs and undergoes a progressive decline with age. Loss of DCAF8 in mice results in impaired function in HSCs, characterized by increased number yet decreased self-renewal capacity, which associates with cellular senescence and elevated DNA damage. Mechanistically, DCAF8 mediates the degradation of DOCK11, a guanine nucleotide exchange factor for CDC42. In the absence of DCAF8, DOCK11 accumulates, leading to elevated CDC42 activity and consequential loss of polarity of HSCs. Knocking out Dock11 mitigates the senescence, DNA damage, and self-renewal defects of Dcaf8-/- HSCs. This study highlights a critical role of DCAF8 in preventing HSC senescence via the DOCK11-CDC42 axis and suggests potential therapeutic targets for preventing functional decline in HSCs.

Identifying aging-associated biomarkers applicable for multiple tissues is challenging but crucial for assessing tissue aging. Here, we obtained and analyzed 456 transcriptomes on 17 organs from 30 C57BL/6 J mice with different ages, revealing the consistently upregulated mRNAs of

Cellular senescence represents a permanent state of cell cycle arrest, also observed in neurodegenerative disorders. As p300 has been identified as an epigenetic driver of replicative senescence, we aimed to investigate whether in vitro p300 inhibition could rescue the stress-induced premature senescence (SIPS) phenotype. We exploited 2D and 3D (brain organoids) in vitro models of SIPS using two different stressor agents. In addition, we combined the treatment with a p300 inhibitor and validated p300 role in SIPS by analyzing different senescence markers and the transcriptome in our models. Interestingly, p300 inhibition can counteract the DNA damage and SIPS phenotype, detecting a dysregulation of gene expression and protein translation associated with the senescence program. These findings highlight both the molecular mechanisms underlying senescence and p300 as a possible pharmacological target. Thus, targeting p300 and, by extension, senescent cells could represent a promising therapeutic strategy for age-related diseases such as neurodegenerative disorders.

Maintaining skeletal muscle mass and strength is crucial to prevent sarcopenia during healthy ageing. Ankyrin repeat and suppressor of cytokine signalling box protein 2 (Asb2), an E3 ligase, has been implicated in regulating muscle mass; however, its roles on muscle strength remain unclear, with mixed findings from previous studies. Overexpression of Asb2 decreases muscle mass, whereas its knockdown delays myoblast differentiation and reduces contractile proteins. Given these contradictory findings, we aimed to clarify the role of Asb2 in muscle mass and strength using a skeletal muscle-specific Asb2 knockout (Asb2 MKO) mouse model. Additionally, we investigate the long-term effects of Asb2 on aged muscle, underlying mechanisms on muscle regulation and metabolic effects of Asb2 MKO mice to better understand its role in muscle function and age-related metabolic diseases.

Aging is the greatest risk factor for most diseases. We propose that aging manifests as disease as a function of tumor-suppressive capabilities. Adequate tumor suppression results in cell death or an accumulation of damaged cells leading to inflammation and tissue dysfunction that underlies diseases such as cardiovascular disease, neurodegenerative diseases, or type 2 diabetes. Conversely, inadequate tumor suppression leads to cancer. Telomeres are central to this process because they oppose hyperproliferation that is required for cancer initiation by enforcing two potent tumor suppressor mechanisms: senescence and crisis. Although senescent cells promote age-related diseases via inflammatory signaling, crisis cells have lost the p53 and RB pathways, have more unstable genomes, and harbor shorter telomeres, all of which could increase inflammation to a greater degree than is seen in senescence. This model emphasizes the intimate relationship between aging, telomeres, tumor suppression, and inflammation and suggests that crisis cells may represent an unexplored driver of inflammation in advanced age.

Aging is marked by a gradual decline in multiple physiological functions, increasing the risk of age-related disorders. Multiple factors have been identified as contributors to aging, many of which are regulated by the hypothalamus. Growth hormone-releasing hormone (GHRH) produced in the hypothalamus is a key regulator of growth hormone (GH) secretion. With aging, both GHRH and GH levels decline, leading to muscle loss, increased fat accumulation, metabolic dysregulation, and cognitive impairments. GH replacement therapy has been explored as a potential intervention to counteract these effects; however, its long-term use is associated with significant risks, including metabolic disturbances, cardiovascular complications, and potential cancer promotion. In contrast, studies suggest that GHRH-based therapies can improve body composition, muscle strength, cognitive function, and cardiovascular health while avoiding the risks linked to direct GH administration. Additionally, preclinical findings indicate that GHRH agonists may offer cardioprotective and immunomodulatory benefits. In this review, we summarize current knowledge on the roles of GHRH and GH in aging, highlight the limitations of GH-based therapies, and discuss the potential of GHRH-based approaches in mitigating age-related decline and improving health span.

Ultraviolet (UV) radiation from the sun causes adverse skin changes such as premature aging. UVA radiation is the primary factor for photoaging due to its deep penetration into the dermis, and UV-induced mitochondrial DNA (mtDNA) alterations, including deletions, contribute to photoaging and cellular dysfunction. The most frequent mtDNA rearrangement is the common deletion (CD), characterized by the loss of nearly one-third of the genome, 4,977 base pairs. UV radiation exposure leads to the formation of the CD, however, a distinct characterization of UV-induced CD and the underlying molecular mechanisms driving its initiation remains unexplored. In this study, we showed that increasing doses of UV radiation led to an increase in the CD in human skin fibroblasts. We found that UVA induce the formation of the CD by increasing the cellular reactive oxygen species (ROS) and oxidized bases content in the mtDNA. Preconditioning cells with antioxidants prevented the accumulation of the UVA-induced CD, suggesting that this mutational mechanism is ROS-dependent. In stark contrast, UVB did not alter cellular ROS levels but increased the formation of cyclobutane pyrimidine dimers (CPD), leading to CD generation though a ROS-independent mechanism. We corroborated our findings by using a 3D human full-thickness skin equivalent model, where we detected UVA-dependent CD formation in both the epidermal and dermal layers of the skin. By analyzing bulk RNA from UVA-exposed human skin fibroblasts by RNA-Seq, we found that UVA led to the upregulation of genes encoding mitochondrial DNA replication proteins and to the downregulation of genes involved genes encoding mtDNA repair factors. Taken together, our findings provide insight into how UVA and UVB differ in their detrimental effects on mtDNA, with UVA impacting mtDNA maintenance and transcription via a ROS-dependent mechanism. Our findings also established the mtDNA CD as a novel potential biomarker for monitoring UVA-induced oxidative stress and photoaging in skin cells in vitro and in vivo.

Model organisms such as yeast, worms, flies, and mice were key to discovering genes and other factors controlling life span and directly improved our understanding of human aging. Today, genomic tools allow study of a broader range of species, including those with short or long life spans, closely related species with different aging rates, or differences in interspecies aging. Models such as killifish, bats, and ants have much to teach us about human aging. They also reveal a flexible biological toolkit that species can use when evolutionary pressures drive rebalancing of growth, reproduction, or resilience with age-related decline.

Skeletal muscle atrophy is a threatening condition related to aging and other pathologies such as diabetes and cancer. Thus, the development of groundbreaking therapeutic strategies is mandatory for better management of skeletal muscle atrophy in the elderly and diseased individuals. Nutritional interventions have gained recognition as fundamental strategies for attenuating or preventing the advancement of skeletal muscle atrophy, with particular attention focused on fatty acids as potential therapeutic agents. This review synthesizes contemporary knowledge regarding the molecular mechanisms through which isolated fatty acids (distinct from complex oils or mixtures) may exert beneficial effects against muscle atrophy focusing on proteostasis. The discussion begins with an overview of protein turnover regulation in skeletal muscle tissue, subsequently providing a comprehensive examination of the anti-atrophic properties of fatty acids at the molecular level. While preclinical studies utilizing laboratory models have demonstrated the therapeutic potential of fatty acids in modulating muscle atrophy pathways, translation to clinical applications requires further investigation to establish mechanistic understanding and reproducible efficacy in human subjects.

Senescent alveolar epithelial cells (AEC) play a pivotal role in the progression of idiopathic pulmonary fibrosis (IPF), attracting increasing attention from researchers. Central to the pathogenesis of pulmonary fibrosis (PF) is the excessive deposition of extracellular matrix (ECM). However, there remains a significant gap in understanding how the ECM microenvironment influences senescence in type II alveolar epithelial cells (AEC II). This study investigates the activation of the integrin-β

Capsiate, a non-pungent capsaicin analog found mainly in low-pungency cultivars of

Mesenchymal stem cells (MSC) undergo replicative senescence, a state of irreversible cell cycle arrest that limits their utility in regenerative medicine applications. To identify novel markers of senescence useful to enhance the quality of MSC-based therapies, we compared young and senescent human bone marrow-derived mesenchymal stem cells (hMSCs) using a non-invasive, label-free approach based on quantitative phase imaging (QPI) with the Livecyte microscope. Senescent hMSCs demonstrated substantial morphological alterations, including a threefold increase in cell area, elevated dry mass, reduced thickness, and decreased sphericity compared to their younger counterparts. Additionally, motility metrics such as instantaneous velocity and displacement were significantly reduced in senescent cells, underscoring functional impairments that could hinder their therapeutic potential in regenerative medicine. The application of QPI offers a promising tool for monitoring cellular health, identifying, and potentially eliminating, senescent cells to improve the quality and effectiveness of MSC-based therapies.

Despite the global impact of neurodegenerative diseases and ongoing research efforts, pharmacological therapies have shown limited benefits. In contrast, physical exercise, with no side effects, has emerged as a non-pharmacological alternative that can enhance brain structure and function, promoting a healthier neurological phenotype.

Accumulation of cytosolic DNA has emerged as a hallmark of aging, inducing sterile inflammation. Stimulator of interferon genes (STING) protein translates the sensing of cytosolic DNA by cyclic-GMP-AMP synthase (cGAS) into an inflammatory response. However, the molecular mechanisms whereby cytosolic DNA-induced cGAS-STING pathway leads to aging remain poorly understood. We show that STING does not follow the canonical pathway of activation in human fibroblasts passaged (aging) in culture, senescent fibroblasts, or progeria fibroblasts (from Hutchinson-Gilford progeria syndrome patients). Despite cytosolic DNA buildup, features of the canonical cGAS-STING pathway like increased cGAMP production, STING phosphorylation, and STING trafficking to perinuclear compartment are not observed in progeria/senescent/aging fibroblasts. Instead, STING localizes at endoplasmic reticulum, nuclear envelope, and chromatin. Despite the nonconventional STING behavior, aging/senescent/progeria cells activate inflammatory programs such as the senescence-associated secretory phenotype and the interferon response, in a cGAS and STING-dependent manner, revealing a noncanonical pathway in aging. Importantly, progeria/aging/senescent cells are hindered in their ability to activate the canonical cGAS-STING pathway with synthetic DNA, compared to young cells. This deficiency is rescued by activating vitamin D receptor signaling, unveiling mechanisms regulating the cGAS-STING pathway in aging. Significantly, in HGPS, inhibition of the noncanonical cGAS-STING pathway ameliorates cellular hallmarks of aging, reduces tissue degeneration, and extends the lifespan of progeria mice. Our study reveals that a new feature of aging is the progressively reduced ability to activate the canonical cGAS-STING pathway in response to cytosolic DNA, triggering instead a noncanonical pathway that drives senescence/aging phenotypes.

Plasma proteins derived from specific organs can estimate organ age and mortality, but their sensitivity to environmental factors and their robustness in forecasting onset of organ diseases and mortality remain unclear. To address this gap, we estimate the biological age of 11 organs using plasma proteomics data (2,916 proteins) from 44,498 individuals in the UK Biobank. Organ age estimates were sensitive to lifestyle factors and medications and were associated with future onset (within 17 years' follow-up) of a range of diseases, including heart failure, chronic obstructive pulmonary disease, type 2 diabetes and Alzheimer's disease. Notably, having an especially aged brain posed a risk of Alzheimer's disease (hazard ratio (HR) = 3.1) that was similar to carrying one copy of APOE4, the strongest genetic risk factor for sporadic Alzheimer's disease, whereas a youthful brain (HR = 0.26) provided protection that was similar to carrying two copies of APOE2, independent of APOE genotype. Accrual of aged organs progressively increased mortality risk (2-4 aged organs, HR = 2.3; 5-7 aged organs, HR = 4.5; 8+ aged organs, HR = 8.3), whereas youthful brains and immune systems were uniquely associated with longevity (youthful brain, HR = 0.60 for mortality risk; youthful immune system, HR = 0.58; youthful both, HR = 0.44). Altogether, these findings support the use of plasma proteins for monitoring of organ health and point to the brain and immune systems as key targets for longevity interventions.

N6-methyladenosine (m6A), as the most common RNA modification at the post-transcriptional level, plays a role in various pathophysiological processes. However, its underlying mechanism in skin aging remains enigmatic. Here, we identified that fat mass and obesity-associated protein (FTO) serves as a protective factor against skin aging. FTO expression is downregulated in aging skin tissues and senescent fibroblasts. Furthermore, the depletion or inhibition of FTO exacerbates dermal fibroblasts senescence and accelerates skin aging. Additionally, RNA-seq combined with MeRIP-seq revealed that lysine acetyltransferase 8 (KAT8) is the downstream target of FTO. FTO deficiency leads to an increase in m6A levels and a decrease in mRNA stability of KAT8 in a m6A-YTHDF2-dependent manner. Notably, our integrated analysis of m6A sequencing and acetylation proteomics links changes in heterochromatin structure with aging. Mechanistically, KAT8 depletion leads to heterochromatin loss and the subsequent aging by acetylating remodeling and spacing factor 1 (RSF1) at K1050. Overall, our finding reveals a pivotal role of FTO-mediated m6A modification in the skin aging by regulating KAT8/RSF1-involved heterochromatin formation. It provides new insights into the mechanisms and strategies for delaying aging and improving healthspan.

Background: Leukocyte telomere length (LTL) has been implicated in aging and age-related diseases, including chronic respiratory diseases (CRDs). However, the extent and mechanisms of shared genetic architecture between LTL and respiratory health indicators (such as CRDs and lung function parameters) remain incompletely understood. Methods: We first systematically characterized the genetic correlations and genetic overlaps between LTL and multiple respiratory health indicators. We then performed horizontal pleiotropy analysis by integrating SNP-level functional annotation, gene mapping, and pathway analysis to identify candidate pleiotropic loci, genes, and shared biological pathways. Finally, we assessed the causal relationships among these trait pairs using the latent causal variable (LCV) and MRlap. Results: There was extensive genetic overlap between LTL and respiratory health indicators, regardless of whether these trait pairs had significant genetic associations. We identified 27,885 candidate pleiotropic loci and 82 pleiotropic genes. Notably, five key genes, such as STN1, MPHOSPH9, MTRFR, MAX, and UCKL1, showed significant pleiotropic effects in multiple phenotype pairs and mediated different patterns of genetic associations. Pathway enrichment analysis of these pleiotropic genes highlighted the close association of specific trait pairs with RNA metabolism and telomere maintenance. Finally, vertical pleiotropy analysis revealed negative causal associations of LTL-idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease-LTL. Conclusions: Our findings reinforce the roles of telomere biology and RNA processing in the pathogenesis of chronic lung diseases and support a shared genetic basis for common molecular pathways.

Cellular senescence is a process in which the cell cycle becomes permanently arrested, thereby inhibiting cell division, proliferation and growth. Various cellular stresses, such as DNA damage, telomere shortening and oxidative stress, can trigger cellular senescence. Physiologically, cellular senescence contributes to tissue development, repair and critical biological processes such as embryogenesis, whereas, pathologically, it plays a key role in diverse disease subsets. To this end, elucidating the underlying mechanisms and molecular regulation of senescence is crucial. Here, in this Review, we explore recent key findings on cellular senescence in experimental and human disease models, focusing on its molecular mechanisms, regulation and future research directions to advance the field and facilitate therapeutic translation.

Aging is an inherent phenomenon that is highly important in the pathological development of numerous diseases. Aging is a multidimensional phenomenon characterized by the progressive impairment of various cellular structures and organelle functions. The basis of human organ senescence is cellular senescence. Currently, with the increase in human life expectancy and the increasing proportion of the elderly population, the economic burden of diseases related to aging is becoming increasingly heavy worldwide, and an in-depth study of the mechanism of cellular aging is urgently needed. Aging, a multifactor-driven biological process, is closely related to mitochondrial dysfunction, which is the core pathological basis of a variety of age-related diseases. This article systematically reviews the molecular pathways by which mitochondrial dysfunction drives aging through multidimensional mechanisms such as metabolic reprogramming, epigenetic regulation, telomere damage, autophagy imbalance, and the senescence-associated secretory phenotype. Metabolic reprogramming promotes tumor progression and exacerbates energy metabolism disorders through abnormal activation of the PI3K/Akt/mTOR signaling pathways. The sirtuin family (such as SIRT1 and SIRT3) maintains mitochondrial homeostasis by regulating PGC-1α, FOXO3 and other targets. Telomere shortening directly inhibits mitochondrial biosynthesis through the p53-PGC-1α axis, leading to oxidative stress accumulation and a decline in organ function. The dual roles of autophagy (removing damaged mitochondria or inducing apoptosis) suggests that its homeostasis is essential for delaying aging. The SASP mediates the inflammatory microenvironment through the cGAS‒STING pathway, which is not only a marker of aging but also a driving force of disease progression. Future studies need to integrate multiomics techniques to analyze the interaction network between mitochondria and other organelles, such as the endoplasmic reticulum and lysosomes, and explore precise intervention strategies targeting sirtuins, AMPK and telomerase. Combined therapies targeting metabolic reprogramming or SASP inhibition are expected to provide new ideas for delaying aging and preventing age-related diseases.

Aging in the context of obesity exacerbates the risk of morbidity and mortality related to cardiovascular disease. However, the maladaptive responses in the heart that arise from prolonged obesity and the specific influence of biological age remain somewhat elusive. This study investigated the effects of diet-induced obesity (DIO) and aging on physical performance and cardiovascular function in mice. 22- and 76-week-old male C57BL/6J mice were randomized to 8 weeks of chow or high-fat diet. Body weight was assessed weekly. Body composition was measured at the beginning and the end of the diet treatment. Muscular and cardiac function were evaluated at the end intervention. Aged mice with DIO exhibited faster and greater body weight gain and fat mass accumulation, reduced running distance, and lower aerobic capacity. Aged HFD mice also exhibited increased cardiac lipid accumulation and cardiomyocyte hypertrophy, with no major morphological changes observed in skeletal muscle. Proteomic analysis revealed differential expression of heart proteins associated with metabolic function in young mice, which was not observed in aged mice with DIO. Subsequently, aged mice with DIO developed overt heart failure with reduced ejection fraction, while cardiac function was unaffected by DIO in young mice. In conclusion, young mice with DIO were protected against diet-induced cardiac dysfunction, whereas DIO in aged mice led to heart failure and impaired physical performance. The protective effects observed in younger mice appear to be explained by proteomic-level remodeling of the heart oriented to sustain cardiac function.

Regular physical activity and endurance exercise training prevent age-related vascular endothelial dysfunction in the arm in men. However, the effects of physical activity and/or endurance exercise training in the legs, which have a greater predisposition for vascular disease, has not been completely elucidated. This study sought to examine the impact of aging, physical activity, and endurance exercise training on leg vascular function in men. Flow-mediated dilation (FMD) of the superficial femoral and popliteal arteries (SFA and PA, respectively) was assessed in a total of 39 men, comprised of 10 young sedentary (Y; 23±2 yrs), 8 older sedentary (OS; 76±8 yrs), 9 older physically active (OA; 71±8 yrs), and 12 older endurance exercise trained (OT) subjects with exceptional aerobic exercise capacity (V̇O

To investigate the temporal association between sarcopenia and hip fracture risk among middle-aged and elderly Chinese adults, given the rising prevalence of sarcopenia and increasing burden of hip fractures in aging populations. This longitudinal study analyzed data from 7775 participants aged ≥ 45 years in the China Health and Retirement Longitudinal Study (2011-2020). Sarcopenia was assessed based on muscle strength, mass, and physical performance. Hip fracture incidents were collected through follow-up interviews. Covariates included demographic characteristics, lifestyle factors (smoking, alcohol consumption), and chronic diseases (hypertension, diabetes, arthritis). Competing risk analysis and multiple logistic regression models were employed to evaluate the association between sarcopenia and hip fracture risk. At baseline, 1436 (18.5%) participants had sarcopenia. The sarcopenia group showed higher hip fracture incidence than the non-sarcopenia group ((7.17% vs. 3.75%, P < 0.001). Cumulative incidence analysis revealed progressively widening disparity in fracture incidence between groups over the 9-year follow-up. After adjusting for multiple confounders, sarcopenia remained independently associated with increased hip fracture risk (adjusted OR = 1.33, 95% CI: 1.00-1.77, P = 0.0498). Sarcopenia serves as an independent risk factor for hip fracture among middle-aged and elderly Chinese adults, emphasizing the importance of early sarcopenia identification and prevention strategies.

Understanding individual differences in cognitive reserve is key to predicting, and potentially influencing, factors that promote healthy cognitive aging. It has been suggested that individuals who are more curious engage in more stimulating activities and thereby increase their cognitive reserve. In the present study, we investigated the relationships between dimensions of trait curiosity and different proxies of cognitive reserve - education, occupation, and leisure activities - in groups of younger (N = 190) and middle-to-older aged adults (N = 292). Our results provide evidence for a relationship between trait curiosity and cognitive reserve, which was more pronounced in middle-to-older age. In the middle-to-older age group, all proxies of cognitive reserve were related to curiosity, albeit to different dimensions of the trait: higher interest-based epistemic curiosity and perceptual curiosity predicted higher education and leisure activities. In contrast, deprivation-sensitive curiosity was positively associated with occupation, but negatively associated with leisure. In the young group, only leisure activities were significantly predicted by perceptual curiosity. This study adds to the emerging literature on the role of personality in cognitive reserve and highlights the multifaceted influence of trait curiosity, which is larger in older age.

Emerging evidence highlights the critical role of cellular metabolism in immune cell activation, development, and function. Peroxisomes, key metabolic organelles, maintain metabolic homeostasis, yet their role in immune cells remains underexplored. While animal studies show age-related declines in peroxisome biogenesis, this process is unconfirmed in human aging. We investigated peroxisome biogenesis in human peripheral blood mononuclear cells (PBMCs) and found a significant decline in aged CD19+ B cells compared to CD4+ T cells, CD8+ T cells, and CD14+ monocytes. B cell aging also reduces peroxisomal matrix enzyme import, evidenced by decreased SKL-containing enzymes and mature ACOX1, alongside downregulation of PEX19 and E3 ubiquitin ligases PEX2, PEX10, and PEX12. These findings confirm an evolutionarily conserved and age-related decline in peroxisome biogenesis. Further, our work unveils cell type-specific changes in aging human PBMCs, and provides new insights into peroxisome-mediated immunometabolism and B cell aging.

Adaptive behavior depends on the brains capacity to vary its activity across multiple spatial and temporal scales. Yet, how distinct facets of this variability evolve from childhood to older adulthood remains poorly understood, limiting mechanistic models of neurocognitive aging. Here, we characterize lifespan neural variability using an integrated empirical-computational approach. We analyzed high-density EEG cohort data spanning 111 healthy individuals aged 9-75 years, recorded at rest and during passive and attended auditory oddball stimulation task. We extracted scale-dependent measures of EEG fluctuations amplitude and entropy, together with millisecond-resolved phase-synchrony networks in the 2-20 Hz range. Multi-condition partial least squares decomposition analysis revealed two independent lifespan trajectories. First, slow-frequency power, variance and complexity at longer timescales declined monotonically with age, indicating a progressive dampening of low-frequency fluctuations and large-scale coherence. Second, the temporal organization of phase-synchrony reconfigurations followed an inverted U-trend: young adults exhibited the slowest yet most diverse switching--characterized by low mean but high variance and low kurtosis of jump lengths at 2-6 Hz and the opposite pattern at 8-20 Hz--whereas children and older adults showed faster, more stereotyped dynamics. To mechanistically account for these patterns, we fitted a ten-node phase-oscillator model constrained by the human structural connectome. Only an intermediate, metastable coupling regime reproduced the empirical combination of reduced low-frequency variability and maximally heterogeneous synchrony dynamics observed in young adults, while deviations toward weaker or stronger coupling mimicked the childrens and older adults profiles. Our results demonstrate that development and aging entail changes in the switching dynamics of EEG phase synchronization, by differentially sculpting stationary and transient aspects of neural variability. This establishes time-resolved phase-synchrony metrics as sensitive, mechanistically grounded markers of neurocognitive status across the lifespan.

Shifts in the skin microbiome have shown a close link to chronological age. However, the contribution of skin microbiome in skin aging phenotypes remains unclear. To explore this, we performed phenotypic, metabolomic, metagenomic, and functional analyses on a cohort with divergent skin aging phenotypes. Genome-scale metabolic models (GEMs) integrated with metabolomic analysis revealed that Stenotrophomonas maltophilia, enriched in the younger group (categorized by AI-predicted age and skin elasticity), utilizes the glutathione cycle to maintain redox homeostasis. Cellular experiments showed its metabolites enhanced GSH synthesis and alleviated oxidative stress-induced skin aging by upregulating key genes in fibroblasts, including GCLM, PGD, SOD2, and NQO1. Additionally, GEMs highlighted its potential anti-aging roles in regulating host metabolic pathways involving betaine, lysolecithin, and porphyrin. In parallel, Acinetobacter guillouiae was found to influence host melanin metabolism by degrading dopamine (DA) and 3-methoxytyramine (3-MT), offering potential therapeutic strategies for mitigating pigmentation. Our findings highlight the dynamic interplay between skin microbiota and the host in aging, offering new insights for designing targeted anti-aging interventions.

Aging is a degenerative process, and while Rosa roxburghii Tratt has demonstrated notable anti-aging and antioxidant properties, the precise anti-aging effects of its seeds are not yet fully understood. The aim of this study was to employ a blend of in "dry" and "wet" approaches to investigate the anti-aging activity and underlying mechanisms of the polyphenol-rich extract from these seeds, Rosa roxburghii Tratt seed polyphenol extract (RRTSPE). UPLC-Q-Exactive Orbitrap/MS was employed to identify the chemical constituents of RRTSPE, resulting in the identification of 33 chemical components. Subsequent in vitro antioxidant assays demonstrated RRTSPE's moderate antioxidant capacity, and in vivo evaluations using Caenorhabditis elegans (C. elegans) confirmed its ability to extend lifespan, reduce lipofuscin accumulation, and enhance resistance to oxidative and heat stress. Network pharmacology analysis suggests that RRTSPE's anti-aging effects may involve key proteins linked to metabolic and inflammatory diseases. The predictions regarding the anti-aging effects of RRTSPE were further substantiated using mutant C. elegans strains (DR26, VC475, TJ1052, and CB1370), which confirmed the engagement of the insulin/IGF-1 signaling (IIS) pathway in RRTSPE's anti-aging effects. RRTSPE demonstrates its anti-aging effects in C. elegans through a multifaceted approach, which includes scavenging free radicals, diminishing reactive oxygen species (ROS), enhancing DAF-16 nuclear translocation, and modulating IIS pathway-related proteins like SOD-3 and HSP-16.2. It is the synergistic effect of these actions that underpins the broad-spectrum anti-aging potential of RRTSPE. Taken together, this study not only provides a scientific foundation for the utilization of Rosa roxburghii Tratt seeds as a natural anti-aging agent but also paves the way for further research and development in leveraging their potential health benefits.

Aging leads to a gradual decline in muscle function, yet the mechanisms by which different skeletal muscles respond to aging remain unclear. Here, we constructed transcriptional maps of 11 skeletal muscles with extensive transcriptional diversity from young and old mice. Age-related changes in gene expression displayed distinct tissue-specific patterns, involving muscle diseases and metabolic processes. Notably, the mitochondrial-enriched soleus muscle exhibited superior resistance to aging compared to other skeletal muscles. Further, we generated a single-nuclei transcriptomic atlas on representative skeletal muscles, analyzing 73,170 nuclei. We found the age-related changes in the cellular composition of different skeletal muscles and the emergence of new cell states in aged mice. Among different types of myonuclei, type II myonuclei showed particular sensitivity to aging, with reduced metabolic activity of IIb myonuclei with age. We also found cell-specific changes occurring across nonmuscle nuclei populations, including adipocytes, fibro-adipogenic progenitors, and immune cells, accelerating muscle aging and associated pathologies. Intercellular communication analysis revealed more intensive intercellular interactions in aged skeletal muscles, particularly between myonuclei and other cell types. Specifically, we validated the regulatory role of the EGF/EGFR axis in age-related inflammatory processes. These findings provide insight into muscle biology and aging and highlight potential therapeutic targets for age-associated muscle disorders.

This study investigates the factors that influence older adults' intentions to purchase smartwatches for health management, incorporating self-efficacy and perceived risk to examine understanding of technology adoption in the context of healthy aging. A sample of 199 older adults in Taiwan was analyzed using Partial Least Squares Structural Equation Modeling (PLS-SEM) and Importance-Performance Map Analysis (IPMA). Results indicate that performance expectancy, effort expectancy, social influence, and facilitating conditions significantly impact purchase intention, whereas the hypothesized negative impact of perceived risk on purchase intention was not supported. Self-efficacy enhances perceived usability and helps mitigate perceived risk, while IPMA results identify social influence as the most important factor influencing purchase intention. These findings highlight the potential of smartwatches to promote active aging by supporting health monitoring, independence, and quality of life. Practically, marketers should enhance usability, leverage social influence, and offer accessible support to strengthen purchase intention toward smartwatches among older adults.

Premature ovarian failure (POF) is a common female endocrine disorder in women, and there is currently no effective pharmacological treatment available. Acupuncture, an important component of traditional Chinese medicine, has demonstrated clinical efficacy in improving ovarian function in patients with POF; however, its underlying mechanisms remain unclear. This study systematically investigated the therapeutic mechanisms of acupuncture in cyclophosphamide (CTX)-induced POF through combined analysis of proteomic and metabolomic data. In a rat model of chemotherapy-induced ovarian dysfunction, 28-day acupuncture intervention significantly delayed the pathological alterations in ovarian morphology and slowed the decline of endocrine function, as evidenced by normalized serum FSH, LH, and AMH levels. Metabolomic profiling identified 1683 differential metabolites across positive/negative ion modes, with taurine-hypotaurine metabolism (KEGG map00430) emerging as a key antioxidant axis, correlating with enhanced superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities. Proteomic analysis revealed acupuncture-mediated reversal of 115 ovarian proteins, particularly PPAR signaling components (FABP5, ADIPOQ and PLIN1), which orchestrated lipid metabolic reprogramming. Combined analysis of proteomic and metabolomic data demonstrated strong Spearman correlations between metabolic regulators (taurine, d-aspartate) and ovarian reserve markers, while PPAR-associated proteins exhibited network connectivity with oxidative stress mediators. These findings establish that acupuncture delays POF through synchronized modulation of metabolic flexibility and PPARγ-driven antioxidant defense, providing a novel systems biology framework for understanding traditional medicine interventions in reproductive aging.

Endocrine-disrupting chemicals, particularly bisphenol A (BPA), are ubiquitous environmental contaminants that can profoundly affect hormonal systems and human health. The effects are variable and are contingent upon the developmental stage at which exposure occurs. This study aimed to investigate the effects of intrauterine and lactational BPA exposure on the adrenal glands of aged Mongolian gerbils (Meriones unguiculatus). In a controlled experimental set-up, pregnant gerbils were assigned to control or BPA-exposed groups, with the BPA group receiving a high dose during critical periods of development to assess the subsequent effects on adrenal gland function in their offspring at senile age. Biometric and hormonal assessments (estradiol, cortisol and testosterone) were conducted. Immunohistochemical and immunofluorescence analysis assessed steroidogenic activity related to testosterone production (StAR, CYP17, 3βHSD, 17βHSD, testosterone, 5α-reductase and CYP19), expression of hormone receptors (AR, ERα, ERβ, GRP30) and evaluation of epigenetic markers (EZH2). The results revealed that gerbils exposed to BPA exhibited increased body weight, alongside significant alterations in serum hormone profiles, including decreased cortisol and elevated estradiol levels. Furthermore, there was an upregulation of steroidogenic enzymes, indicating BPA's disruptive effects on adrenal hormone production and regulation. Notably, intracellular testosterone levels were elevated despite the typical age-related declines observed in control groups. Additionally, increased expression of androgen receptors and GPR30 was noted, underscoring BPA's complex impact on steroidogenic pathways. These findings emphasize the potential for intrauterine BPA exposure to induce enduring endocrine disturbances.

Resistance to age-related pathological changes (brain maintenance), including Alzheimer's disease, cerebrovascular disease, and neurodegeneration may promote cognitive resilience in aging. However, how lifestyle and health profiles relate to successful cognitive and brain aging remains poorly understood. In a novel, deeply phenotyped cohort of 211 cognitively unimpaired older adults (age = 71.0 ± 7.4 years, 46% female), we characterized principal components of lifestyle and health using questionnaire, fitness, and blood data. We estimated cognitive age gap (CAG) based on comprehensive neuropsychological data and brain age gap (BAG) based on brain-pathology markers, including plasma biomarkers of Alzheimer's pathology (pTau

Aging-induced degenerative changes in the liver are not inherently pathologic but pose an increased risk for liver diseases. However, the molecular mechanisms underlying aging-induced hepatic dyshomeostasis remain incompletely characterized. Here, we investigate how aging alters liver architecture, cellular communication, and hepatocyte zonation.

Cellular senescence is a conserved cellular program characterized by a permanent cell cycle arrest triggered by a variety of stressors. Originally described as a tumor-suppressive mechanism, it is now recognized to exert pleiotropic and context-dependent functions, contributing to key physiological processes such as embryogenesis and tissue repair, as well as to processes associated with aging and the development of age-related diseases. Unlike normal cells, senescent cells remain metabolically active despite their non-dividing state. They significantly impact their environment through the Senescence-Associated Secretory Phenotype (SASP), a complex mix of cytokines, growth factors, and proteases. This secretory profile can promote tissue repair and regeneration but, if persistent, contributes to chronic inflammation, fibrosis, and tissue dysfunction. Two major pathways primarily regulate senescence: the p53/p21 and p16^INK4a^/Rb axes. These respond to stress signals like DNA damage, oxidative stress, and oncogenic activation, enforcing stable cell cycle arrest to prevent uncontrolled proliferation. However, as senescent cells accumulate over time, their ongoing SASP activity disrupts tissue homeostasis, driving inflammation and age-related diseases. Recent advances in multi-omics technologies, including metabolomics, proteomics, and lipidomics, have provided deeper insights into the complex molecular changes within senescent cells, revealing new biomarkers and potential therapeutic targets. These approaches offer a comprehensive understanding of cellular senescence, but challenges remain in distinguishing the causal relationships within these data and translating findings into clinical applications. This review integrates recent multi-omics discoveries, highlighting their potential to refine our understanding of senescence and support the development of targeted interventions to extend healthspan and combat age-related pathologies.

Arterial stiffness is associated with overall and cardiovascular-specific mortality, and this association is exacerbated in women over 55 yr of age. Recent literature supports that stimulation of the angiotensin II type 2 receptor (AT2R) can protect from arterial stiffening, and that AT2R has a greater role in female cardiovascular physiology relative to males. The current study aimed to investigate the role of the AT2R in sex differences in aging-associated arterial stiffness. In female mice, the aging-related increase in arterial stiffness is temporally associated with a loss of aortic AT2R mRNA expression, but this is not observed in males. Chronic AT2R inhibition in vivo increases arterial stiffening in young female and male mice, as well as middle-aged female mice. The inhibition of AT2R is associated with an increase in aortic integrinα5 mRNA expression in young males and an increase in collagen1α1 mRNA expression in middle-aged females. Overall, these findings identify a sex-specific mechanism of aging-associated arterial stiffening in mice involving AT2R attenuation and collagen upregulation in females.

NDP52, a constituent of the selective autophagy receptors (SARs), was recognized for its involvement in facilitating substrate degradation via autophagic bridging. However, its autonomous function apart from autophagy remained largely unexplored. Here, we reported that NDP52 was down-regulated in degenerated chondrocytes. Besides, NDP52 deficiency promoted the extracellular matrix (ECM) degradation, inflammation, cell apoptosis and senescence via its autophagy-independent functions. The absence of NDP52 disrupted the flow of electron respiration chains and led to the production of intracellular mitochondrial reactive oxygen species (mtROS). Subsequent mechanistic investigations revealed that the downregulation of NDP52 upregulated the expression levels of mitochondrial complex Ⅰ by modulating MTIF3 expression, leading to reverse electron transport (RET) and mtROS production. Our research highlights the significance of NDP52 in facilitating chondrocyte degeneration and osteoarthritis, and provides insights into the distinctive mechanism by which autophagy receptors NDP52 induce intracellular mitochondrial ROS dysregulation via non-canonical pathways.