Longevity Papers

The actin cytoskeleton is a fundamental and highly conserved structure that functions in diverse cellular processes, yet its direct contribution to organismal aging remains unclear. Here, we systematically interrogated how genetic and pharmacologic perturbations of actin structure and function influence lifespan and various hallmarks of aging in Caenorhabditis elegans. Whole-animal and tissue-specific knockdown of actin and key actin-binding proteins (ABPs) - arx-2 (Arp2/3), unc-60 (cofilin), and lev-11 (tropomyosin) - led to premature disruption of filament organization, reduced lifespan, and tissue-specific physiological defects. Bulk and single-nucleus RNA-sequencing revealed that ABP knockdowns elicited a strongly aged transcriptome. Actin dysfunction broadly exacerbated many age-associated phenotypes, including mitochondrial dysfunction, lipid dysregulation, loss of proteostasis, impaired autophagy, and intestinal barrier failure. Pharmacological destabilization with Latrunculin A mirrored genetic knockdowns, while mild stabilization with Jasplakinolide modestly extended lifespan, emphasizing that optimal and finely-tuned actin function is critical for healthy aging. Finally, analysis of human genome-wide association data revealed that common ACTB polymorphisms correlate with differences in age-related decline in gait speed, suggesting evolutionary conservation of a role for actin in healthy aging. Taken together, our results provide a comprehensive and publicly accessible resource that maps, for the first time, how actin integrity intersects with diverse aging pathways across tissues and scales. This descriptive framework is intended to enable future mechanistic discovery by offering a deep, unbiased dataset that can be integrated with emerging studies to define how actin dynamics contribute to aging.

C-reactive protein (CRP) and growth differentiation factor 15 (GDF15) are important markers of inflammation associated with brain health. Compared to plasma, DNA methylation (DNAm) measures of CRP and GDF15 may provide stable epigenetic measures of chronic exposure to inflammation and could therefore be robustly predictive of inflammation-related brain aging and neurodegeneration. We leveraged a subsample of Baltimore Longitudinal Study of Aging (BLSA) participants with DNAm/plasma data and longitudinal neuroimaging/cognition data (n = 430-1100). We used a proteome-wide analysis to characterize the biology of DNAm CRP and GDF15, and latent growth curve models to explore the associations with longitudinal trajectories of 19 brain region volumes and five cognitive domains. Finally, we related DNAm/plasma CRP and GDF15 to dementia risk in two external cohorts. DNAm CRP and GDF15 showed a proteomic signature consistent with systemic immune activation. We identified several brain regions with significant associations between elevated DNAm CRP And GDF15 and (a) lower brain volume level (at age 75) and (b) greater rate of atrophy. Compared to plasma CRP, DNAm CRP was more strongly associated with brain volume, cognitive trajectories, and dementia risk. DNAm and plasma GDF15 were similarly associated with several total lobar, total lobar white matter, and AD-relevant region trajectories and dementia risk, but DNAm measures outperformed plasma measures in relation to cognitive trajectories. Epigenetic signatures of CRP and GDF15 reflect immune and inflammation-related pathway activation. These signatures, especially DNAm CRP, were associated with accelerated brain atrophy, cognitive decline, as well as long-term dementia risk.

Aging and unhealthy eating habits independently and synergistically disrupt central nervous system (CNS) homeostasis, increasing susceptibility to neurological and behavioral disorders. Mitochondria plays a critical role in maintaining neuronal survival and activity, representing a central player in the pathogenesis of neurodegenerative diseases. Here, we used zebrafish as a model to investigate how aging and a high-fat diet (HFD) affect brain bioenergetics and behavior. Young (4-6 months) and aged (17-22 months) male zebrafish were fed either a standard diet or an HFD based on boiled chicken egg yolk for 14 days. Brain mitochondria was evaluated using high-resolution respirometry, transmission electron microscopy (TEM), and qRT-PCR. HFD impaired the metabolic health of both young and aged animals, promoting weight gain, increased abdominal length, and elevated fasting glucose levels. Aging intensified the HFD detrimental effects on behavior: aged HFD-fed zebrafish displayed increased anxiety-like behavior in the novel tank test, and impaired cognitive performance in the T-maze test. Notably, HFD had no significant effect on aggressive behavior regardless of age. Mitochondrial responses to HFD differed by age: while cerebral bioenergetic function declined in young fish, aged animals showed an opposite trend. TEM analysis revealed increased accumulation of fragmented mitochondria in HFD group, indicating potential mitochondrial dysfunction. RT-qPCR showed upregulation of genes involved in the electron transport chain, especially in aged zebrafish. In conclusion, our findings demonstrate an age-dependent vulnerability to the effects of HFD on both neurobehavioral and mitochondrial parameters.

Metformin, a first-line treatment for type 2 diabetes, attenuates hallmarks of aging and protects against age-related diseases, including osteoarthritis (OA). Here, we assessed the effects of imeglimin, a novel antidiabetic agent related to metformin, on the development and progression of knee OA.

Childhood trauma has been associated with accelerated biological aging, such as early pubertal development and cellular aging. Less is known about the impact of childhood trauma on brain aging, particularly across mental disorders. This cross-sectional study tested the hypothesis that childhood trauma severity is linked to accelerated brain aging using a large discovery MRI dataset. Another independent dataset was included to replicate findings.

Aging is characterized by a progressive decline in physiological integrity, often accompanied by chronic inflammation and immune dysregulation. Immunoglobulin G (IgG), a key effector of humoral immunity, undergoes substantial structural and functional remodeling with age, particularly through changes in its glycosylation profile. These modifications shift IgG toward a proinflammatory state, linking it to inflammaging and multiple age-related diseases. This review synthesizes recent advances in understanding how IgG contributes to immune aging, with a specific focus on its glycosylation-dependent functions, tissue accumulation, and bidirectional crosstalk with the gut microbiota. We also highlight the potential of IgG as a biomarker and therapeutic target in aging-related interventions. We discuss the dual functional architecture of IgG and how age-related glycan shifts-namely, increased agalactosylation, afucosylation, and bisecting N-acetylglucosamine (GlcNAc)-enhance binding to activating Fcγ receptors, amplifying proinflammatory signaling. Experimental studies demonstrate that IgG accumulation in adipose tissue contributes to metabolic dysfunction via Neonatal Fc Receptor (FcRn)-dependent pathways. Additionally, sex hormones modulate IgG glycosylation patterns, partially explaining sex-specific differences in immune aging. The concept of "glycan clocks" has emerged as a tool to assess biological age and intervention responsiveness. Moreover, the gut microbiota plays a critical role in shaping the IgG repertoire, and aging disrupts this IgG-microbiota axis, resulting in altered mucosal immunity and systemic inflammation. Interventions targeting this axis-including microbiota modulation and glycoengineering-offer promising translational avenues for immune rejuvenation. Finally, we review emerging therapeutic strategies that leverage the gut-immune interface to mitigate aging-associated cardiovascular and metabolic diseases. IgG is not merely a biomarker but an active participant in the aging process, functioning at the intersection of immune regulation, microbial symbiosis, and systemic inflammation. Its age-associated transformation reflects broader changes in host immunity and highlights new opportunities for precision interventions in immunosenescence.

The corpus callosum (CC), the brain's largest white matter commissure, undergoes significant age-related atrophy that varies across subregions. However, how network-specific callosal connections age and relate to cognitive performance remains poorly understood. We analyzed diffusion-weighted imaging data from 718 healthy adults (ages 36-100 years) from the Human Connectome Project-Aging dataset. Using a tract-to-region approach, we quantified CC tract density within seven canonical functional networks. Cubic polynomial models examined network-specific aging trajectories, while correlation and moderation analyses investigated relationships with cognitive and motor performance across age groups. Network-specific CC tract densities showed distinct aging patterns. Somatomotor and Default Mode networks exhibited highest baseline tract density but steepest age-related declines (β = -0.068 and -0.025, respectively, p < 0.001), while Visual and Limbic networks showed relative preservation. CC tract density showed small-to-medium associations with executive function, memory, and motor performance (r = -0.32 to 0.33). Critically, age moderated these brain-behavior relationships: associations were minimal in younger adults but became progressively stronger in older adults across cognitive domains. The CC follows network-specific aging trajectories, with high-order association networks showing accelerated decline while primary sensory networks remain preserved. Strengthening brain-behavior associations with advancing age suggest callosal integrity becomes increasingly critical for maintaining cognitive performance in later life.

Human dental pulp stem cells (hDPSCs) senescence impairs their proliferation and osteogenic differentiation, critical for dental stem cell therapy. This study evaluated the effects of Resveratrol on the senescence of hDPSCs to explore new therapeutic strategies. Metabolomic analysis identified age-related metabolic differences in dental pulp tissues, with enriched pathways linked to Resveratrol. In vitro, Resveratrol improved proliferation, delayed senescence, promoted osteogenic differentiation, and enhanced mitochondrial autophagy, function, and biogenesis in senescent hDPSCs, reducing mitochondrial damage and oxidative stress. Mechanistically, silencing PINK1 or PGC-1α reversed Resveratrol-mediated promotion of proliferation, osteogenesis, and senescence suppression. Blocking SIRT1 abrogated its effects on mitochondrial quality control. These findings highlight Resveratrol's potential to mitigate hDPSCs senescence via SIRT1-dependent mitochondrial regulation, offering insights for age-related dental regenerative therapies.

Loss of Fibronectin (FN) from the skeletal muscle stem cell (MuSC) niche represents a root cause of regenerative failure in aging. While FN has pleiotropic functions during healthy skeletal muscle regeneration, it remains unclear how aging affects its spatiotemporal specificity for MuSCs. Here, we demonstrate that activated MuSCs secrete an autoregulatory FN splice variant containing the EDB extra domain (EDB(+) FN), which is not expressed by accessory cells in the niche. EDB(+) FN splicing in MuSCs depends on serine/arginine-rich splicing factor 1 (Srsf1) whose promoter is controlled by Smad3. EDB(+) FN knockdown or downregulation in aging affects MuSC proliferation through aberrant integrin signaling and impairs skeletal muscle regeneration. During a defined regeneration interval in aged mice, Smad3 activation using transforming growth factor-beta 1 (TGFβ1) improves MuSC function and skeletal muscle repair by stimulating EDB(+) FN secretion. Altogether, we identify and characterize the TGFβ1-Smad3-Srsf1-EDB(+) FN pathway as a therapeutic target for age-associated regenerative failure.

Chronological aging, exposure to ultraviolet radiation, and various environmental insults deteriorate structure and function of skin. Lack of proper skincare further augments skin aging and related disorders. The objective of current study was to investigate phytochemical composition and bioactivity of Aloe Kanti (Aloe K), an Aloe vera-based topical herbal skincare gel formulation. Chemical characterization of Aloe K was performed using UHPLC, GC-FID, UPLC/MS-QToF, and HPTLC analytical platforms. To decipher the molecular mechanisms of Aloe K, HaCaT, HDFa, and B16F10 cells were used as in vitro model. Additionally, photoaged (UVB-exposed) N2, TP12, and CF1553 strains of Caenorhabditis elegans were used as in vivo models. In HaCaT cell, Aloe K treatment significantly increased levels of GSH, catalase, SOD; and decreased release of IL-6, IL-8 cytokines. A decrease in activity of TNF-α, NF-κB, IL-1β, IFN-γ was also observed in the reporter cells. Compared to control, Aloe K treatment enhance migration of keratinocytes by 24.4 %, displayed a 43.6 % inhibition of AGEs formation, and enhanced collagen production in HDFa cells by 27.8 %. Further, in melanocytes, Aloe K significantly decreased enzyme activity of Tyrosinase and TRP2; and melanin biosynthesis. Additionally, Aloe K treatment decreased molecular markers of aging (SA-β-gal, ΔΨm) in HDFa cells. Anti-oxidant and anti-aging properties of Aloe K was also reflected in photoaged C. elegans. Aloe K treatment also modulated genes involved in cell proliferation, collagen production, and aging. Collectively, Aloe Kanti assimilates several molecular responses to act against signs of skin aging and could impart enhanced skin health.

Presynaptic inhibition of Ia afferents, particularly via primary afferent depolarization (PAD), plays a crucial role in modulating transmission from Ia afferents to α-motoneurons according to task demands. In young adults, PAD is enhanced during eccentric contractions and at longer muscle lengths, supporting adaptable motor control. However, aging is associated with reduced muscle spindle sensitivity, which may impair the regulation of presynaptic inhibition via PAD. This study investigated whether aging alters the modulation of PAD according to contraction type and muscle length. Nineteen older adults (69 ± 4 years) and 16 young adults (23 ± 2 years) participated in three experimental sessions. The maximal H-reflex (H

KCP has been demonstrated to be involved in cardiac remodeling and cardiac aging. This study aims to investigate whether KCP plays a regulatory role in doxorubicin (DOX)-induced cardiac injury by modulating immune and inflammatory responses.

Microglia, the resident immune cell of the central nervous system (CNS), contribute to a range of physiological processes across the lifespan. Microglia exhibit notable sex differences in morphology, reactivity, and transcriptomic profiles. Steroid hormones in early life are believed to elicit sex differences in many cells, including microglia, in the CNS. However, few studies have examined how neonatal hormone environment impacts microglial morphology and function across the lifespan. Therefore, here we used steroid hormones to manipulate the early hormone environment to assess the appearance and persistence of sex differences in a rat model of healthy aging. Rat pups were dosed with steroid hormones on postnatal day (P)0 and 1: females received testosterone to "masculinize" them and males received flutamide, an androgen antagonist, to "feminize" them. Brain tissue was then collected at three distinct developmental timepoints: adolescence (P30), adulthood (P150), and aging (P700) for immunohistochemistry and ex vivo microglial stimulation. Transcriptomic changes in hippocampal tissue of aged animals were also assessed using 3'UTR biased transcriptome sequencing (Tag-seq). We report that testosterone treatment in females leads to lifelong alterations in body size and vaginal morphology and results in microglia that display a more "masculinized" phenotype compared to controls. Flutamide had more moderate effects on microglia morphology in males, contributing to a more "feminized" phenotype in the hippocampus in adult and aged males. Testosterone treatment also resulted in greater transcriptomic changes in the aged hippocampus compared to flutamide treatment, especially in genes related to mitochondrial function and inflammation. These results indicate that (1) early hormone environment is critical for the induction of sex differences in microglial morphology and (2) sex differences in microglial morphology reverse during aging, and this reversal is also recapitulated with early hormone treatment.

Immunosenescence, a major hallmark of systemic aging, refers to the progressive functional decline of the immune system. This decline not only compromises host defense and immunological memory but also fuels chronic inflammation and tissue degeneration (collectively known as inflammaging). While single-cell RNA sequencing (scRNA-seq) has revealed transcriptomic alterations in immune aging, analyses restricted to transcript abundance fail to capture deeper regulatory layers, such as transcript isoform diversity and the remodeling of immune receptor repertoires. To address this, we present the human peripheral immune single-cell multi-omics atlas that integrates gene expression, transcript isoforms diversity, and immune receptor repertoires. By combining single-cell full-length transcriptome sequencing (scCycloneSEQ), short-read scRNA-seq, and single-cell immune receptor sequencing (scTCR/BCR-seq), we systematically profiled peripheral blood mononuclear cells (PBMCs) from healthy young and elderly donors. Our analyses uncovered extensive age-related remodeling of immune cell composition, functional states, and TCR/BCR diversity. Notably, we identified in CD4 effector memory T cells exhibited widespread differential isoform usage (DIU), 3\'UTR length variation, and a marked reshaping of cytotoxic T lymphocyte (CTL) clonotypes--all closely associated with aging-related inflammation and cellular senescence. This multi-omics atlas delineates key molecular features of immunosenescence and provides a high-resolution resource for deciphering the regulatory architecture underlying immune aging.

Chaperone-mediated autophagy (CMA) represents a critical lysosomal degradation pathway in the context of intervertebral disc degeneration (IVDD) associated with senescence. This study revealed a novel mechanism of CMA regulation involving targeted degradation of acyl-CoA synthetase long-chain family member 4 (ACSL4), which can delay nucleus pulposus cell (NPC) senescence and inhibit IVDD progression. Mechanistic investigations demonstrated that the acetyltransferase KAT2B can facilitate the acetylation of ACSL4 at lysine residues K500, K571, and K692. This post-translational modification served as a molecular switch, significantly enhancing the affinity between ACSL4 and the CMA recognition chaperone HSPA8, thereby promoting the efficient targeting and degradation of ACSL4 via the CMA pathway. Besides, engineered exosomes are harnessed to deliver the key CMA receptor LAMP2A in an in vivo model, effectively delaying cellular senescence and significantly attenuating IVDD progression. Overall, these findings establish the crucial protective role of CMA in preventing IVDD through the degradation of ACSL4, providing novel insights for developing therapeutic strategies targeting CMA activation to alleviate disc degeneration and associated chronic pain.

The triterpenoids in Rosa roxburghii fruit (RRF) show various pharmacological activities such as antioxidant, anti-ageing, and anti-atherosclerotic. However, the therapeutic potential of these triterpenoids is limited by poor aqueous solubility, low bioavailability, and rapid systemic clearance, which can hinder their oral effectiveness. The objective of this study was to prepare an RRF nano-emulsion (RRFNE), which is conducive to enhancing the bioactivity of RRF following oral administration. The polydispersity index of RRFNE was 0.18, diameter 43.95 nm, zeta potential 36.37 mV, and triterpenoids loading 25.02 mg/g. Compared to RRF-100, the longest lifespan of RRFNE-100 was extended by 8.58%. The activities of catalase, superoxide dismutase (SOD), and glutathione peroxidase in RRFNE-100 increased by 11.33%, 16.19%, and 5.37% (p < 0.01), respectively, and malondialdehyde levels decreased by 8.98%. Additionally, RRFNE enhances the antioxidant capacity of C. elegans by activating the expression of SIR-2.1, DAF-16, and SOD-3, thus extending the nematodes' lifespan without affecting their reproductive ability.

Insulin/IGF growth factor (IGF) signaling (IIS) is a pleiotropic signaling pathway that functions across tissues to coordinate phenotypic changes in response to nutrient status. Thus, the ubiquity of the IIS pathway hinders efforts to elucidate the mechanisms driving specific IIS-related phenotypes, Previous research in the nematode worm C. elegans has demonstrated that loss of function of the IGF transmembrane receptor (IR) ortholog, DAF-2, results in a doubled lifespan and enhanced learning and memory behaviors in young and aged animals. However, these findings are the result of reducing DAF-2 receptor function rather than modulating ligand-receptor interactions. In the current study, we aimed to dissect ligand-receptor interactions that may regulate associative behaviors apart from canonical IIS lifespan phenotypes in C. elegans. To this end, we performed targeted genetic screening of Insulin-like Peptides (ILPs) previously identified as DAF-2 antagonists to test their role in learning and memory phenotypes. We discovered that only a single uncharacterized ILP, INS-17, is required for learning and memory. We also demonstrate that INS-17 is sufficient to confer extended memory ability and can promote the maintenance of learning and memory with age. Additionally, we observe that ins-17 regulates learning and memory ability independent of lifespan, uncoupling IIS-mutant phenotypes. We find that regulation of the ins-17 genetic locus explains its unique requirement among ILP for learning and memory behaviors. Finally, we found that INS-17 may act to signal a state of nutrient deprivation that is required to properly process stimulus valence to promote advantageous behaviors. Our findings deepen the understanding of how IIS can regulate specific phenotypic outputs in response to changes in internal metabolic states.

High-intensity interval training (HIIT) is capable of reversing many aging-related metabolic differences in the proteome, but studies using proteomics to investigate the mechanism of the effects of HIIT on hepatic metabolic function in aged rats have not been reported. In this study, we investigated the effects of 8 months of HIIT on mitochondrial oxidative function, oxidative stress, and inflammation in the liver of aged rats, and further explored the possible mechanisms of the metabolic effects of HIIT in aged rats by proteomics. The results of the study revealed that HIIT improved liver morphology, enhanced mitochondrial oxidative function, decreased inflammation and apoptosis levels, increased intrahepatic antioxidant function and inhibited ferroptosis in aged rats. Proteomics showed that HIIT altered changes in glycine, serine and threonine metabolic pathways in the liver, and further use of targeted amino acid metabolomics revealed that HIIT markedly increased glycine and serine content in aged livers. In vitro cells demonstrated that exogenous glycine supplementation significantly enhanced the intracellular antioxidant capacity of oxidatively stressed hepatocytes, while decreasing the level of inflammatory factor expression and significantly inhibiting the occurrence of ferroptosis. Our findings suggest that the improvement of metabolic function in aged liver tissue by HIIT may be associated with elevated glycine content, and that glycine within aged livers elevated by HIIT may mediate the maintenance of metabolic homeostasis within liver tissue.

Age related changes in circulating exosomes are implicated in cerebrovascular aging and the pathogenesis of Alzheimers disease (AD). Neurovascular dysfunction and blood brain barrier (BBB) breakdown are recognized as early events in AD, often preceding amyloid{beta} deposition. Primary human brain micro endothelial cells (HBMECs) from a 38 year-old male were treated with exosomes from young (18 to 25 years) and old (65 to 72 years) donors. Whole transcriptomic RNA sequencing analysis identified 5,432 differentially expressed genes, which were organized into five transcriptional clusters. Two principal clusters demonstrated reciprocal patterns: 1) exosomes derived from serum of older adult donors (65 to 72 years) downregulated genes essential for mitochondrial function (e.g., oxidative phosphorylation) and protein synthesis (e.g., ribosomal biogenesis) and 2) upregulating genes linked to inflammation, junctional remodeling, and proliferative signaling. Crucially, subsequent treatment with exosomes derived from serum of young adult donors (18 to 25 years) reversed these detrimental transcriptomic profiles via restoration of the expression of mitochondrial and ribosomal machinery toward baseline and suppressed the inflammatory and maladaptive proliferative signaling induced by exosomes derived from serum of older adult donors. These findings demonstrate that exosomes derived from serum of young adult donors can counteract detrimental signals of aging at the transcriptional level, reinforcing the cellular architecture underlying BBB integrity. This supports the therapeutic potential of using exosomes derived from serum of young adult donors to reverse endothelial aging and interrupt the early neurovascular dysfunction that contributes to the progression of AD.

Spinal degenerative diseases in elderly patients often require spinal fusion, but outcomes are limited by an aging microenvironment and stem cell dysfunction or depletion. In this study, we developed a bone morphogenetic protein-2 (BMP-2)/sulfated chitosan (SCS)/calcium phosphate cement (CPC) composite scaffold to enhance spinal fusion in aged mice. BMP-2/SCS significantly improved spinal fusion success rates (83.3 %) compared to BMP-2 alone (16.7 %) and high-dose BMP-2 (50 %). The BMP-2/SCS group promoted robust new bone formation and H-type vessel development, facilitating vascular-bone coupling in the fusion region. Mechanistically, SCS suppressed BMP-2-induced osteoclast overactivation and reduced MMP-9 secretion, leading to vertebral skeletal stem cell (vSSC) rejuvenation. Rejuvenated vSSCs primarily differentiated into the osteogenic bone/cartilage lineage while stromal lineage differentiation was suppressed. In contrast, co-administration of BMP-2 and alendronate sodium abolished BMP-2-mediated increases in vSSC numbers, vSSC rejuvenation, and bone integration, highlighting the indispensable role of osteoclast activity in BMP-2-induced bone regeneration. Collectively, this study demonstrates that BMP-2/SCS scaffolds effectively reverse age-related deficiencies by creating a rejuvenated bone microenvironment, promoting vascular-bone coupling, and enhancing osteogenesis, offering a promising strategy to improve spinal fusion outcomes in elderly patients.

Vitamin C has been long recognized as an important nutrient for skeletal biology, historically attributed to its role in collagen synthesis and connective tissue integrity. Recent studies, however, reveal vitamin C as a critical epigenetic regulator of cellular differentiation. As a required cofactor for α-ketoglutarate-dependent dioxygenases, vitamin C controls the enzymatic activity of a broad array of histone and DNA demethylases, thereby modulating chromatin accessibility and driving cell-specific gene expression. This review provides a novel, integrated perspective that directly links vitamin C's epigenetic functions to osteogenesis and skeletal health, highlighting experimental evidence that redefines its role beyond collagen maturation and antioxidant defense, and elucidating its sex-dimorphic effects. Importantly, inadequate vitamin C status remains widespread across diverse socioeconomic groups even in Western countries, with low vitamin C intake associated to higher risk of osteoporosis and fractures in the elderly. Viewed through the dual lenses of epigenetic-mechanistic function and clinical relevance, vitamin C emerges as a central epigenetic determinant of skeletal health and a safe, low-cost, and scalable adjuvant to complement current bone therapies. Integrating nutrient epidemiology, clinical data and epigenetic-mechanistic insights may enable targeted interventions to enhance skeletal resilience, particularly in vulnerable populations.

Ultraviolet B (UVB) exposure induces skin photoaging through triggering oxidative stress, inflammation, apoptosis, and collagen degradation. Oleuropein (OLE), Hydroxytyrosol (HT), and Verbascoside (Verb) are polyphenols derived from olive leaves, exhibiting potent antioxidant and anti-inflammatory properties. In the present study, we investigated the protective effects of OLE, HT, and Verb combination (O/H/V) against UVB-induced photoaging using in vitro models. The results showed that O/H/V treatment reduced the expression of senescence and apoptosis-related markers, while concurrently downregulated inflammatory factors and matrix metalloproteinases via suppression of MAPK and NF-κB pathways in UVB-irradiated HDF cells. In UVB-irradiated HaCaT cells, O/H/V treatment attenuated collagen degradation and pro-inflammatory factors expression via upregulation of Nrf2 levels. Furthermore, in a HaCaT-HDFs co-culture system, treatment of UVB-irradiated HaCaT cells with the O/H/V combination led to a significant reduction in pro-inflammatory factors and collagen degradation-related genes in HDFs. Together, these findings indicate that the O/H/V combination exerts protection against UVB-induced photoaging through multiple mechanisms, including inhibition of MAPK/NF-κB pathway and enhancement of Nrf2 expression.

Adipocyte deposition is believed to be a primary characteristic of age-related thymic involution, but the underlying cellular and molecular mechanisms remain unknown. We show here that thymic mesenchymal stromal cells (tMSCs) have a higher tendency to differentiate into adipocytes and melanocortin-2 receptor accessory protein (MRAP) is a potential driver of tMSCs adipogenesis. Furthermore, we discover that thymosin-α1 promotes MRAP expression in tMSCs through FoxO1 signaling pathway. Additionally, the proportion of tMSCs increase in older mice compared to young mice. Importantly, MRAP is also necessary for human thymic MSCs to differentiate into adipocytes when exposed to thymosin-α1. Single-cell RNA-seq analysis of human thymus revealed an accumulation of tMSCs and adipocytes during aging, indicating a strong potential for adipogenic differentiation in age-related thymic involution. Thus, we have revealed MRAP as a key factor in promoting thymic MSCs adipogenesis triggered by thymosin-α1 and FoxO1 pathway, which may serve as potential target to hinder adiposity in age-related thymic involution.

Micronutrient intake can modulate aging biology. α‑Klotho, a circulating anti-aging protein, exerts protective effects against age-related decline and disease. However, links between specific micronutrients and serum α‑Klotho remain poorly explored. In this cross-sectional study, we analyzed 898 participants aged 18-84 years from rural communities in Changping, Beijing, China, to assess associations between energy-adjusted micronutrient intakes (per 100 kcal) and serum α-Klotho (modeled as log-transformed). Using a single 24-hour recall, intakes of 15 micronutrients were quantified, including total vitamin A, thiamine, riboflavin, vitamin C, vitamin E, phosphorus, potassium, calcium, magnesium, zinc, sodium, iron, selenium, copper, and manganese. Multivariable linear regression showed no significant associations between any micronutrients and serum α-Klotho in the overall population (all P > 0.05). In contrast, restrictive cubic spline analysis identified an inverted U-shaped association between iron intake and serum α-Klotho (P for nonlinear = 0.002), with a turning point at 1.863 mg/100 kcal. Below this threshold, iron intake was positively associated with α-Klotho (β: 0.045; P = 0.011), whereas above it the association was negative (β: -0.018; P = 0.035). The nonlinear pattern was evident in women and in participants aged < 60 years (P for nonlinear = 0.024 and 0.007, respectively), with similar turning points (1.908 and 1.906 mg/100 kcal, respectively). Inadequate iron intake was more prevalent in these subgroups than overall (60.8% and 62% vs. 50.8%). Dietary iron intake exhibits a sex- and age-specific inverted U-shaped relationship with serum α‑Klotho in Chinese adults. Maintaining moderate iron intake may be associated with higher α‑Klotho concentrations, particularly in women and in younger individuals aged < 60 years. Prospective and intervention studies are warranted to confirm these findings.

Deep learning foundation models excel at disease prediction from medical images, yet their potential to bridge tissue morphology with the genetic architecture of disease remains underexplored. Here, we present REECAP (Representation learning for Eye Embedding Contrastive Age Phenotypes), a framework that fine-tunes the RETFound retinal foundation model using a contrastive objective guided by chronological age. Applied to 87,478 fundus images from 52,742 UK Biobank participants, REECAP aligns image representations along the aging axis, yielding multivariate ageing phenotypes for genome-wide association studies (GWAS). GWAS of REECAP embeddings identifies 178 loci, including 27 that colocalize with risk loci of age-related eye diseases, 14 of which remained undetected by conventional disease-label GWAS. By enabling conditional image synthesis, REECAP further links genetic variation to interpretable anatomical changes. Benchmarking against alternative embedding models, we show that REECAP enhances both locus discovery and disease relevance of genetic associations, suggesting that aging-informed tissue embeddings represent a powerful intermediate phenotype to discover and interpret disease loci.

Sarcopenia, a prevalent age-related degenerative disorder, poses significant challenges in geriatric care. Chinese leek demonstrates therapeutic potential against sarcopenia progression, with emerging evidence suggesting its extracellular vesicles (EVs) may mediate these effects. Notably, plant-derived EVs have garnered increasing attention due to their low immunogenicity and capacity for cross-kingdom molecular delivery. This study investigates Chinese leek-derived EVs (CL-EVs) as novel regulators of muscle homeostasis through multi-omics approaches. CL-EVs were isolated via differential ultracentrifugation and characterized using nanoparticle tracking analysis, TEM, and proteomic profiling. Using a dexamethasone (DEX)-induced C2C12 myotube atrophy model, we demonstrated CL-EVs' cellular internalization and dose-dependent restoration of myotube diameter. CL-EVs significantly alleviated DEX-induced mitochondrial impairment in C2C12 cells, evidenced by restored ATP production, reduced ROS levels, and stabilized mitochondrial membrane potential (MMP). Multi-omics analysis revealed CL-EVs activate the AMPK/SIRT1/PGC-1α axis, confirmed by Western blotting. Proteomic analysis identified selenium-associated proteins in CL-EVs. Expanding on selenocompounds' known anti-proteolytic effects through Akt modulation, we demonstrate CL-EVs attenuate myotube atrophy through dual mechanisms: inactivation of Akt/FoxO3a/Atrogin-1/MuRF1 proteolytic signaling and activation of mitochondrial biogenesis/mitophagy pathways, collectively improving muscle homeostasis. To investigate gut-muscle axis interactions, 16 S rDNA sequencing and untargeted metabolomic profiling were performed on fecal samples. CL-EVs treatment attenuated DEX-induced gut microbiota dysbiosis and correlated metabolic abnormalities in sarcopenic mice. This study establishes CL-EVs as novel regulators of muscle homeostasis through dual modulation of AMPK/SIRT1/PGC-1α activation and Akt/FoxO3a/Atrogin-1/MuRF1 inhibition. This innovative "multi-target & gut-muscle axis" paradigm provides a groundbreaking strategy for sarcopenia therapeutics.

Neurological diseases, including Alzheimer's disease, depression, and Parkinson's disease, pose a growing public health challenge. Dietary patterns, particularly the Mediterranean diet (MD), have been proposed as modifiable factors for prevention. The aim of this systematic review and meta-analysis was to evaluate the association between adherence to the MD and the risk or progression of neurological conditions.

Diabetic kidney disease (DKD) progression involves intricate interactions among senescence, oxidative stress, inflammation, and fibrosis. This study systematically investigates the regulatory role and molecular mechanisms of NUAK1 in DKD pathogenesis. Bioinformatics analysis of Gene Expression Omnibus data sets identified NUAK1 as a differentially expressed gene, validated in human kidney proximal tubule epithelial (HK-2) cells, high-fat diet and streptozotocin-induced DKD mice, d-galactose-induced senescent mice, and human peripheral blood mononuclear cells. Functional studies demonstrated that NUAK1 inhibition via siRNA knockdown, pharmacological inhibitors, or kidney tubule-targeted adeno-associated virus serotype carrying shRNA against NUAK1 delivery attenuated reactive oxygen species-tumor protein 53 (ROS/P53) axis-mediated renal tubular senescence, oxidative stress, inflammation, and fibrosis in vitro and in vivo. Mechanistically, chromatin immunoprecipitation quantitative PCR revealed that transcription factor ETS1 directly binds to the NUAK1 promoter, driving its transcriptional activation in DKD. Furthermore, molecular docking and dynamics simulations identified Asiatic acid (AA) as a potent NUAK1 inhibitor, with a stable binding affinity. AA suppressed NUAK1 expression and downstream pathological processes, ameliorating renal injury in DKD models. These findings elucidate the role and regulatory mechanisms of NUAK1 in modulating ROS/P53 axis-driven tubular senescence and oxidative stress, providing a theoretical basis for structure optimization in drug development targeting NUAK1.

Testosterone insufficiency disrupts spermatogenesis and expedites male aging. Autophagy facilitates testosterone synthesis. However, a molecular reduction mechanism of autophagy-related protein 4 homolog B (ATG4B) has not been established. Herein, we reveal that peroxiredoxin 1 (PRDX1) is clinically associated with male fertility disorders. Adult mutant mice with Leydig cell (LC)-specific deletion of the Prdx1 gene exhibit premature testicular aging and infertility. A series of in vivo and in vitro experiments, in combination with multi-omics analyses, demonstrate that PRDX1 inactivation impairs lipophagy and testosterone synthesis in LCs. Mechanistically, Cys52 and Cys173 in PRDX1 specifically target the redox-site Cys78 in ATG4B to preserve the delipidating activity of Cys74 in ATG4B, thereby promoting autophagic flux. Furthermore, PRDX1 dysfunction exacerbates testicular and systematic aging in aged mice, which can be alleviated by a 2-cysteine mimic, ebselen. Collectively, our findings demonstrate that PRDX1 promotes lipophagy and testosterone synthesis by regulating ATG4B. Our findings also propose the potential application of ebselen in the prevention and treatment of aging-related disorders, including late-onset hypogonadism.

To observe the effect of mild moxibustion on microRNA-34a (miR-34a)/silent information regulator 1 (sirt1)/tumor protein p53 (p53) signaling pathway in the thoracic aorta and kidney of senescent rats, so as to investigate the mechanism of mild moxibustion in attenuating vascular and renal aging.

This review explores the remarkable metabolic adaptations of species that thrive in extreme environments, providing insights into their resilience, flexibility and disease resistance. Species such as hibernating brown bears, migratory birds, cavefish, Greenland sharks and naked mole rats exhibit unique metabolic traits that challenge conventional paradigms of metabolic regulation. These adaptations, including resistance to hypoxia and metabolic ageing, offer potential solutions to human metabolic disorders, including obesity, type 2 diabetes and CVD. Insights from comparative physiology, particularly the mechanisms by which animals cope with food scarcity, extreme temperatures and hypoxia, could help identify novel therapeutic targets for advancing human health. For example, hibernation can serve as a model for understanding metabolic diseases, providing insights into reversible insulin resistance and energy homeostasis. This review also highlights the impact of environmental stressors, including climate change, on these species, which may jeopardise their survival despite their resilience. Accelerating anthropogenic environmental change threatens even the most resilient animal species. We call for a holistic approach to conservation and environmental protection to preserve these species and the valuable lessons they offer for managing our metabolic health.

Skin aging is linked to the overactivity of matrix metalloproteinases (MMPs) and elastase, making their inhibition a promising approach for antiaging. This study aimed to discover novel antiaging peptides from Chlorella proteins using high-throughput virtual screening.

Cognitive aging is characterized by widespread decline, yet certain fundamental processes show remarkable resilience. This study demonstrates that older adults (OAs;

Although social position plays a pivotal role in cognitive aging, most dementia prevention strategies and risk prediction models continue to emphasize biomedical and genetic factors (particularly APOE status). This disconnect raises critical questions about how social environments may shape the effect of genetic risk on dementia. We examined how APOE alleles interact with social adversity to determine dementia risk.

Commensal microbiota plays crucial roles in maintaining tissue homeostasis, yet its impact on cellular ageing and inflammaging across diverse cell types remains poorly understood. Here we present a comprehensive single-cell epigenomic and transcriptomic atlas of various tissues from mice aged under specific pathogen-free (SPF) or germ-free conditions, revealing context-dependent effects of microbiota on cellular ageing. Microbiota conferred beneficial effects in young mice but accelerated various ageing features in old, such as age-related AP-1 pathway upregulation, senescence and transcriptomic alterations, likely due to age-associated dysbiosis. Strikingly, inflammatory signatures persisted across cell types in aged germ-free mouse tissues, establishing sterile inflammation as an intrinsic feature of ageing. Age-associated B cells expanded equally under germ-free conditions and (SPF) conditions, raising the possibility that they function as intrinsic, microbiota-independent drivers of inflammageing and potential therapeutic targets. The atlas provides a resource for distinguishing intrinsic ageing features from those modulated by the microbiota, illuminating mechanisms of cellular ageing and potential anti-ageing interventions.

Healthy aging alone can lead to cognitive decline, decreased brain size, protein aggregation, accumulation of senescent cells and neuroinflammation. Furthermore, age is the primary risk factor for several neurodegenerative disorders such as Parkinson's and Alzheimer's disease. Age-related neuroinflammation, as known as inflammaging, is thought to restrict brain plasticity. Perineuronal nets (PNNs), specialized extracellular matrix structures surrounding fast-spiking parvalbumin (PV) interneurons, regulate plasticity and protect neurons from oxidative stress. Given the known impact of inflammaging on neural circuits, this study examines age-associated changes in PNN homeostasis, glial activation, and neuroinflammation in two brain regions relevant to age-related neurodegenerative diseases.

Existing proteomic aging clocks have been derived from the overall population, with little consideration of extended models tailored to individuals with different glycemic status. We aimed to quantify glycemic status-dependent proteomic signatures of aging and developed proteomic aging scores (ProAS) for health risk prediction. A total of 2923 plasma proteins were measured using Olink in 46,047 UK Biobank participants, including 37,353 with normoglycemia, 5977 with prediabetes, and 2717 with diabetes. Using a three-step screening approach, we identified 11, 23, and 21 representative protein biomarkers associated with all-cause mortality among individuals with normoglycemia, prediabetes, and diabetes, respectively. Three proteins (GDF15, EDA2R, and WFDC2) were shared across all groups, with GDF15 emerging as the top-ranked important protein in normoglycemia and prediabetes and WFDC2 in diabetes. The protein-based ProAS according to glycemic status showed significant associations with diverse health outcomes. Adding the ProAS in the models improved the predictive accuracy of mortality and incident diseases beyond conventional risk factors, but the performance progressively diminished as glycemic status deteriorated. In addition, 72, 51, and 36 out of 102 modifiable factors spanning seven categories were identified as determinants for ProRS in normoglycemia, prediabetes, and diabetes, respectively. Our findings extend the current proteomic clocks by revealing glycemic status-specific aging patterns and their ability to predict age-related outcomes, potentially refining risk stratification and targeted interventions for healthy aging.

The physical coupling between the nucleus and the cytoskeleton is essential for the mechanobiological adaptation of cells to mechanical cues presented by the surrounding extracellular matrix (ECM). Although aging is known to influence both cellular and ECM mechanical properties, it remains poorly understood how cellular senescence, a hallmark of aging, affects cellular mechano-adaptation. Here, we use substrate stiffness as a mechano-modulatory cue across three distinct models of senescence and demonstrate that senescent fibroblasts are limited in their capacity to integrate mechanical signals of increasing stiffness. The senescent nucleus undergoes progressive actin-mediated deformation and flattening as substrate stiffness increases, until a mechanical threshold is reached that provokes a decoupling of the nucleus from the cytoskeleton. This mechanical disengagement of the nucleus on stiff substrates is accompanied by a loss of cytoskeletal organization, abnormal focal adhesion (FA) maturation, and nuclear softening. We further suggest that the loss of nuclear compression is linked to changes in the nuclear localization of the key mechanosensitive transcriptional regulator Yes-associated protein (YAP). Our findings reveal a fundamental biophysical limitation in the mechano-adaptive response of senescent cells to high-stiffness environments, conditions typically associated with advanced tissue maturation and pathological scarring, which may underlie altered nuclear mechanotransduction and contribute to their specific role in both physiological and pathological contexts.

Ovarian aging is a fundamental process in female reproductive biology with broad implications for overall health and aging. As global populations age, understanding its mechanisms and systemic effects has gained urgent clinical relevance. The ovary, beyond its reproductive role, is increasingly recognized as a regulator of systemic aging due to the widespread presence of estrogen receptors. Declining ovarian function accelerates not only reproductive senescence but also contributes to age-related disorders including osteoporosis, neurodegenerative diseases, and cardiovascular conditions. However, research on ovarian aging remains fragmented, lacking integrative analysis. This review synthesizes recent advances in the cellular and molecular mechanisms underpinning ovarian aging, such as genomic instability, metabolic and oxidative stress, and microenvironmental alterations. It further discusses how ovarian decline influences systemic aging pathways and disease susceptibility and evaluates emerging therapeutic strategies such as antioxidant interventions, stem cell therapy, and ovarian tissue transplantation. By providing a comprehensive overview of ovarian aging from mechanisms to interventions, this review aims to bridge existing knowledge gaps and inspire future research toward improving women's healthspan and quality of life.

Aging constitutes the largest risk factor for melanoma progression. While a contribution of factors secreted from senescent skin fibroblasts to the progression of melanoma has been proposed, the nature of such factors and subsequent underlying mechanisms remains elusive. Here we show that the chemokine GCP-2 is excessively released by senescent fibroblasts in vitro and the skin of old melanoma patients. GCP-2 regulates, via phosphorylation of the transcription factor CREB at serine 133, defense-, cell cycle control-, and glycolysis-enhancing genes in melanoma cell lines. GCP-2 promotes oncogenic properties in vitro and in vivo in murine melanoma models. Inhibition of CREB phosphorylation in melanoma cells represses glycolytic target genes and induces a switch from glycolysis to oxidative phosphorylation that translates into a significant decline in tumor size in vivo in murine melanoma models. This study identifies a senescent fibroblast to chemokine to CREB to metabolic axis that drives melanoma progression. Targeting this axis may hold promise for novel therapeutic approaches in difficult-to-treat melanoma in older adults.

In young animals, oligodendrocyte progenitor cells (OPCs) undergo robust differentiation, progressing through stages to become pre-myelinating oligodendrocytes (Pre-OL) and ultimately myelinating oligodendrocytes (OLs). However, OPCs from aged animals have reduced differentiation ability. This disrupts myelin maintenance in the central nervous system (CNS), leading to a lack of remyelination following demyelinating injury and impaired adaptive myelination as a mechanism of learning. To uncover novel factors essential for restoring resilience in aged OPCs, we employed a data-driven approach involving the development of a computational pipeline, gSWITCH (accessible at: https://altoslabs.shinyapps.io/gSWITCH/), that allows for capture of precise dynamic gene expression patterns to pinpoint potential \'switch\' genes during lineage progression. Using gSWITCH to identify potential switch genes crucial for OPCs, we conducted a comparative analysis of gene expression in OPCs isolated from young and aged animals. This revealed a group of transcription factors with decreased expression in aged OPCs. Further analysis of transcription factor binding site enrichment in OPC switches highlighted Bcl11a, a zinc finger transcription factor that could potentially serve as a master regulator of many switch genes. Ectopic overexpression of Bcl11a in aged OPCs did not enhance their proliferation; however, it significantly enhanced their differentiation into OLs. Overexpression of Bcl11a in aged mice, followed by demyelination injury in spinal cord white matter, significantly increased the differentiation of OPCs into OLs within the injury region compared to control aged mice. Furthermore, we found that Bcl11a is absent in invertebrates and has undergone pervasive purifying selection throughout vertebrate evolution, constraining its amino-acid sequence by eliminating deleterious mutations. Our study shows that reversing the age-related decline of this evolutionarily conserved factor in aged OPCs restores their impaired capacity for differentiation.

As the world's population ages, strategies to promote healthy longevity are critical. SIRT5, belonging to the sirtuin family, plays a key role in regulating cellular metabolism and mitochondrial homeostasis by removing post-translational modifications such as succinylation, malonylation, and glutarylisation from lysine residues of proteins. Herein, we discuss the multifunctionality of SIRT5, its impact on heart function, and its involvement as a target in geroscience for the pathogenesis of cardiovascular diseases, including heart failure, diabetic cardiomyopathy, cardiac hypertrophy, and ischemia-reperfusion injury. Research indicates that SIRT5 modulates metabolic pathways, oxidative stress response, and apoptosis, making it a potential therapeutic target for extending the health span and lifespan. However, its role is complex and context-dependent, exhibiting protective and harmful effects in various pathological conditions.

Cellular senescence (CS) as an irreversible cell cycle arrest occurs in different tissues and organs. Among the others, CS is one of the most common risk factors for neurodegenerative diseases. The current study aimed to highlight the protective effects of Edaravone (EDN) as a free radical scavenger on D-galactose-induced cell senescence in PC12 cells. CS was induced following 48 h exposure to D-galactose (DG), and the protective effects of EDN at various concentrations (0.1, 1 and 10 µM) were studied. Cell proliferation, oxidative stress biomarkers such as total antioxidant capacity and lipid peroxidation rate, total protein level and protein carbonylation rate, pro-inflammatory cytokines (TNF-α) release, apoptotic cell death biomarkers including caspase 3/7 activities and the expression of p53, p21 and p16 as related genes to CS were analyzed. Experimentally induced CS resulted in a significant (p < 0.05) decrease in cell proliferation, elevation of lipid peroxidation and protein carbonylation rates, increase of TNF-α release, elevation of the number of apoptotic cells and DNA damage, along with 3.4 to 13-fold upregulation of CS-related gene expression. The most practical and effective concentration of EDN to protect PC12 cells from DG-induced injuries was found to be 1 µM. These findings in PC12 cells suggest that EDN with its antioxidant and anti-inflammatory properties could be an effective anti-aging compound to protect cells from various types of DNA-damaging factors.

Social isolation and poor nutrition are recognized risk factors for cognitive decline in older adults. However, the relationship between solitary eating, brain structure, and dietary patterns remains unclear. This study investigated the relationship between solitary eating, brain structure, and diet in healthy older Japanese adults. A total of 727 cognitively normal participants (mean age 70.32 years) underwent MRI and dietary assessments. Results showed that individuals who frequently eat alone have reduced brain volumes in regions critical for cognitive function, particularly the medial temporal lobe and hippocampus. These individuals also demonstrated less healthy dietary patterns, characterized by higher sugar and alcohol consumption, with lower intake of proteins, vitamins, and minerals. Analysis revealed that the difference in hippocampal volume between solitary and social eaters diminished when accounting for dietary factors, suggesting that nutritional factors primarily drive this relationship. However, the difference in medial temporal lobe volume remained significant after dietary adjustment, indicating that other factors, such as reduced social interaction, may affect this region. These findings emphasize the importance of social eating for maintaining brain health in older adults, suggesting that both social and nutritional aspects of eating are crucial. This research provides insights for developing healthy aging strategies that address both social and nutritional dimensions of eating behavior.

Normal cognitive aging is accompanied by molecular changes in the brain and periphery, but the specific proteomic and peptide-level alterations remain poorly defined. This study aimed to characterize age-related protein and peptide modifications by analyzing matched cerebrospinal fluid (CSF) and plasma samples from cognitively normal individuals.

Aging is a key driver of cardiac dysfunction, promoting structural remodeling, metabolic alterations, and loss of cellular resilience. In aged hearts, extracellular matrix remodeling and collagen accumulation reduce ventricular compliance, impairing both diastolic function and stress adaptability. Cardiomyocytes exhibit diminished regenerative capacity and dysregulated stress responses, with mitochondrial dysfunction emerging as a central contributor to energy imbalance, oxidative stress, and fibrosis. Traditional single-omics approaches are insufficient to capture the complexity of these interconnected changes. To address this, we employed an integrative multi-omics strategy-combining spatial transcriptomics, proteomics, and metabo-lipidomics with electron microscopy-to investigate cardiac aging in mice at three life stages: adult (12 months), middle-aged (24 months), and elderly (30 months). Electron microscopy revealed enlarged, structurally compromised mitochondria. Spatial transcriptomics showed reduced expression of cardioprotective genes (MANF, CISH, and BNP) and increased expression of profibrotic markers like CTGF. Proteomics revealed widespread mitochondrial dysregulation and impaired ATP production. Metabolic and lipidomic profiling identified reduced antioxidant metabolites and accumulation of lipotoxic species, such as ceramides and diacylglycerols. This multiscale analysis highlights key molecular and metabolic alterations driving cardiac aging, identifying potential therapeutic targets to mitigate age-related functional decline. Overall, our findings highlight the value of integrated, system-level approaches for uncovering the complex mechanisms that drive organ aging. Although our study was conducted in mice, validation in human models will be crucial to establish the translational relevance of these results and to guide future research with potential impact across diverse biomedical fields.

Limited identification of insulin resistance-associated loci hinders understanding of its role in cardiometabolic health, impeding therapeutic strategies. We apply three multivariate genome-wide association study approaches on homeostatic model assessment for insulin resistance, insulin resistance index, fasting insulin, and ratio of triglycerides to high-density lipoprotein cholesterol from MAGIC and UK Biobank to develop a comprehensive phenotype ('mvIR'), and identify 217 independent loci, including 24 novel loci. The mvIR is causally associated with higher risks of 17 cardiometabolic diseases and five aging phenotypes, independent of adiposity and sarcopenia. We outline 21 of 2644 druggable genes for insulin resistance by Mendelian randomization and colocalization, where six genes (AKT1, ERBB3, FCGR1A, FGFR1, LPL, NR1H3) encode targets for approved drugs with consistent directions in alleviating insulin resistance, with no significant side effects revealed by phenome-wide association study. This study uncovers novel loci and therapeutic targets to inform strategies promoting insulin resistance-centered cardiometabolic health and longevity.

Mitochondrial dysfunction and defective mitophagy are defining features of numerous neurodegenerative and metabolic disorders, yet existing tools provide limited ability to quantify mitophagy dynamics in real time within living, post-mitotic cells. Here we present MitoFlare, a mitochondria-targeted, reversible mtROS-responsive fluorogenic probe that enables continuous, non-genetic visualization of mitochondrial oxidative activation and turnover. MitoFlare incorporates dual TEMPO nitroxide quenchers into a long-wavelength rhodamine scaffold, producing >95% basal quenching and rapid, fully reversible fluorescence activation in response to mitochondrial superoxide, hydroxyl radicals, lipid-derived peroxyl species, and peroxynitrite. When combined with LysoTracker Green, MitoFlare forms a dual-probe imaging platform that resolves the entire mitophagy cascade with high spatial and temporal fidelity in intact PC12 neuronal cells. Using this platform, we established a quantitative framework comprising three mechanistically distinct metrics: (i) a proximity index that reports early mitochondrial engagement with lysosomes, (ii) Mander\'s M1 coefficient that captures mid-stage mitochondria-lysosome fusion and mitophagosome formation, and (iii) a quenching/swelling index that resolves terminal lysosomal degradation. Nutrient deprivation induced a complete, temporally ordered mitophagy program, including mtROS priming, Parkin-OPTN-associated fusion, and efficient acidification-dependent cargo degradation. In contrast, inhibition of v-ATPase with bafilomycin A1 arrested mitophagy at the fusion stage, resulting in persistent redox-active mitochondrial cargo that failed to undergo lysosomal digestion. Importantly, MitoFlare\'s reversible redox chemistry uniquely revealed accumulation of undegraded, oxidatively active mitochondrial remnants within non-acidified vesicles-pathological intermediates that are undetectable using irreversible ROS dyes or genetically encoded reporters. These findings demonstrate that mitophagy proceeds through discrete, redox-regulated and lysosome-dependent phases that can be quantitatively mapped in real time. By enabling synchronized measurement of oxidative activation, organelle trafficking, fusion, and degradation, the MitoFlare-LysoTracker system establishes a new benchmark for dynamic mitophagy analysis in physiologically relevant models. This platform provides a powerful foundation for mechanistic interrogation of mitochondrial quality control and for accelerating the discovery of therapeutic strategies aimed at restoring mitophagic fidelity in neurodegenerative, cardiovascular, and metabolic diseases.

Genomic stability is critical for cellular function, however, in the central nervous system highly metabolically active differentiated neurons are challenged to maintain their genome over the organismal lifespan without replication. DNA damage in neurons increases with chronological age and accelerates in neurodegenerative disorders, resulting in cellular and systemic dysregulation. Distinct DNA damage response strategies have evolved with a host of polymerases. The Y-family translesion synthesis (TLS) polymerases are well known for bypassing and repairing damaged DNA in dividing cells. However, their expression, dynamics, and role if any, in enduring postmitotic differentiated neurons of the brain are completely unknown. We show through systematic longitudinal studies for the first time that DNA polymerase kappa (POLK), a member of the Y-family polymerases, is highly expressed in neurons. With chronological age, there is a progressive and significant reduction of nuclear POLK with a concomitant accumulation in the cytoplasm that is predictive of brain tissue age. The reduction of nuclear POLK in old brains is congruent with an increase in DNA damage markers. The nuclear POLK colocalizes with damaged sites and DNA repair proteins. The cytoplasmic POLK accumulates with stress granules and endo/lysosomal markers. Nuclear POLK expression is significantly higher in GABAergic interneurons compared to excitatory pyramidal neurons and lowest in non-neurons, possibly reflective of the inherent biological differences such as firing rates and neuronal activity. Interneurons associated with microglia have significantly higher levels of cytoplasmic POLK in old age. Finally, we show that neuronal activity itself can lead to an increase in nuclear POLK levels and a reduction of the cytoplasmic fraction. Our findings open a new avenue in understanding how different classes of postmitotic neurons deploy TLS polymerase(s) to maintain their genomic integrity over time, which will help design strategies for longevity, healthspan, and prevention of neurodegeneration.

This study aimed to determine the molecular mechanisms by which the DEP domain-containing mTOR-interacting protein (DEPTOR) regulates the senescence of nucleus pulposus (NP) cells (NPCs), alleviating intervertebral disk degeneration (IDD). This study investigated how DEPTOR regulates the mechanistic target of rapamycin complex 1 (mTORC1)/S6 kinase beta-1 (S6K1)/autophagy-related gene 1 (ATG1) pathway to regulate senescence-associated secretory phenotype (SASP) and cellular autophagy in NPCs. Isobaric tags for relative and absolute quantitation was used to measure the differences in protein expression between degenerated and normal intervertebral disk tissues. Western blotting and immunofluorescence were used to quantify DEPTOR levels in NP tissues. DEPTOR was overexpressed in vitro, and changes in autophagy and SASP were monitored to determine its effects on NPCs. Moreover, lentiviral overexpression of S6K1 (LV-S6K1) and siRNA-mediated knockdown of ATG1 (ATG1-ShRNA) in both in vitro and in vivo models were used to verify whether DEPTOR stimulates autophagy in NPCs via ATG1 and inhibits SASP through S6K1. The results demonstrated that degenerated intervertebral disks had lower DEPTOR levels. Matrix metalloproteinases, inflammatory cytokines, chemokines, and aging-related proteins were downregulated when DEPTOR was overexpressed in NPCs. Furthermore, autophagic activity was stimulated, SASP secretion was inhibited, and extracellular matrix synthesis was increased. ATG1 knockdown decreased the capacity of DEPTOR to promote cellular autophagy and inhibit SASP, whereas S6K1 overexpression diminished DEPTOR-mediated SASP inhibition. DEPTOR attenuates IDD by inhibiting SASP secretion via the mTORC1/S6K1 pathway and promoting autophagy in NPCs via the mTORC1/ATG1 pathway.

Inflammation and cellular senescence are two interconnected biological processes critical for several chronic diseases. Pro-inflammatory factors promote the accumulation of reactive oxygen species, which synergistically accelerate the deterioration process. This creates a feedback loop that exacerbates telomere attrition and mitochondrial dysfunction, hallmarks of cellular senescence. Conventional therapies have been shown to influence oxidative stress and consequently cellular senescence, while the impact of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) is poorly investigated. Our aim was to explore biomarkers of cellular senescence in a population of psoriatic arthritis (PsA) patients treated with different b/tsDMARDs; we evaluated telomere length (TL), mtDNA copy numbers and oxidative damage at the beginning of therapy and after 12 months. We enrolled 50 PsA patients starting a b/tsDMARDs treatment and monitored the response to treatment for 12 months, based on the Disease Activity Index for PsA score, to identify subgroups of patients: responders and non-responders. We collected a blood sample for each patient at the beginning of therapy and after 12 months. In addition, we collected blood samples of 34 age- and sex-matched controls (CTRLs). We evaluated the cellular senescence biomarkers by qPCR. PsA patients at T0 showed a lower TL and fewer mtDNA copy numbers with respect to CTRLs (P < 0.001). Moreover, oxidative telomeric and mitochondrial damage seems to correlate positively with BMI (P < 0.05). We performed a combined ROC curve analysis to evaluate their ability to discriminate the two groups, showing an AUC of 0.828 with 59.2% sensitivity and 93.7% specificity. After 12 months of treatment monitoring, we classified 36 patients as responder and observed a TL significantly longer compared to T0 (P < 0.001), reaching comparable values to those of the CTRLs group. After patients' stratification based on the class of drugs, the result is confirmed in patients treated with TNFαi and IL17Ai. Our study provides novel insights for the molecular mechanism underlying PsA pathogenesis, highlighting the potential use of TL and mtDNA copy numbers as biomarkers for assessing cellular senescence in PsA. Moreover, our results also suggested that b/tsDMARDs may decelerate cellular senescence in PsA by preserving telomere length.

Aging compromises intestinal integrity, yet the chromatin changes driving this decline remain unclear. Polycomb-mediated repression is essential for silencing developmental genes, but this regulatory mechanism becomes dysregulated with age. Although shifts in Polycomb regulation within intestinal stem cells have been linked to gut aging, the Polycomb landscape of differentiated cell types remains unexplored. Differentiated cells comprise the majority of the gut epithelium and directly impact both tissue and whole organismal aging. Using single-cell chromatin profiling of the

Dietary habits play a pivotal role in promoting successful aging ( SA), representing a key modifiable factor that can influence the trajectory of aging. Despite growing interest in the impact of diet on SA, evidence linking common dietary components to SA among Chinese older adults remains limited. The present study aimed to investigate the associations between SA and six commonly consumed food items in Chinese diets: fruits, vegetables, garlic, nuts, mushrooms, and tea.

Vocal fold fibroblasts play an important role in the production of the extracellular matrix in the vocal folds. Myofibroblasts increase in the aging vocal fold lamina propria with increased alpha-smooth muscle actin. In addition to alpha-smooth muscle actin, various sarcomeric genes are expressed in myofibroblasts. However, there have been no studies on sarcomeric genes with myofibroblast differentiation in aging vocal folds. The purpose of this study was to analyze the changes and functions of sarcomeric genes related to myofibroblast differentiation in aging vocal folds using next-generation sequencing (NGS). Young (6-month-old, 22 rats) and old (22-month-old, 22 rats) male Sprague-Dawley rats were used for this study. NGS was performed on the harvested lamina propria of the vocal folds in each group. NGS data were analyzed using functional annotation, gene ontology, network pathways, and network analysis methods. After identifying the increased expression of sarcomeric genes in aging vocal folds, we evaluated the expression of sarcomeric genes in the normal human vocal fold lamina propria removed after surgery for various vocal fold lesions. The functions of sarcomeric genes in fibroblast senescence, proliferation, differentiation, contraction, and stiffness were investigated. Among the four sarcomeric genes identified through network cluster analysis of the NGS results, the expression levels of myosin light chain kinase 2 (Mylk2) and myomesin 2 (Myom2) were significantly higher in the lamina propria of old rats than in young rats. The increase in Mylk2 and Myom2 expression was associated with cellular senescence but not with the proliferative ability of fibroblasts. However, the expression of Mylk2 and Myom2 increased with myofibroblast differentiation. Inhibition of Mylk2 and Myom2 affects cellular contraction, leading to reduced stiffness. Our results suggest that Mylk2 and Myom2 are novel biomarkers of vocal fold myofibroblasts and are involved in the regulation of vocal fold stiffness in aging rats and humans.

Chronic diseases are highly prevalent among older adults and may be associated with their ability to achieve successful aging, which encompasses five key components: absence of major chronic diseases, freedom from disability, high cognitive function, no depressive symptoms, and active social participation. However, many disease conditions are excluded from conventional definitions of successful aging. This study aims to quantify the predictive effects of multiple chronic diseases on overall successful aging and its five core components, thus providing new evidence to refine aging frameworks. Data were obtained from the China Health and Retirement Longitudinal Study (CHARLS) covering the years 2011, 2013, and 2015. Six common chronic diseases not traditionally included in the successful aging definition were selected: hypertension, dyslipidemia, arthritis, kidney disease, liver disease, and digestive disease. Six machine learning models were applied to construct prediction frameworks of successful aging and chronic diseases. The SHapley Additive Explanations (SHAP) and ALE (Accumulated Local Effects) analyses were used to quantify the impact of each chronic disease on the prediction of successful aging, providing both global and individual-level interpretability. Logistic regression was conducted to examine the associations between key diseases identified by SHAP and the five components of successful aging. A total of 4,385 participants were included initially in this study, and a total of 1,104 participants were selected after propensity score matching for subsequent analysis. After hyperparameter tuning with Optuna, the XGBoost model was chosen for model interpretation and prediction (F1 = 0.781, F2 = 0.891, AUC = 0.707, AUPRC = 0.724). SHAP analysis indicated that hypertension, kidney disease, and arthritis were the most influential predictors of successful aging. Additionally, SHAP results highlighted that sleep duration was also among the most important features. Subsequent logistic regression further revealed that, beyond their associations with the disease component, kidney disease and arthritis were significantly linked to depressive symptoms and cognitive function, while hypertension was strongly associated with physical functioning. Our findings highlight that several chronic diseases not traditionally included in successful aging criteria are significantly associated with aging outcomes. Extending the disease spectrum within the definitions of successful aging may enhance individual-level assessment and provide insights for future research on targeted health interventions for the older adults. Furthermore, these findings may help raise awareness of health factors associated with successful aging.

With the global aging population, frailty in older adults has emerged as a critical focus in health and aging research. As a dynamic and multifactorial process, the transition to frailty is shaped by not only biological factors but also a range of social, psychological, and environmental influences. Identifying the key factors that drive the progression of frailty is essential for developing preventive interventions for at-risk individuals and for implementing more effective health practices and healthcare strategies for older adults.

Autophagy, from Greek

Down syndrome, caused by an extra copy of Chromosome 21, causes lifelong problems. One of the most common phenotypes among people with Down syndrome is premature aging, including early tissue decline, neurodegeneration, and shortened life span. Yet the reasons for premature systemic aging are a mystery and difficult to study in humans. Here we show that chromosome amplification in wild yeast also produces premature aging and shortens life span. Chromosome duplication disrupts nutrient-induced cell-cycle arrest, entry into quiescence, and cellular health during chronological aging, across genetic background and independent of which chromosome is amplified. Using a genomic screen, we discovered that these defects are due in part to aneuploidy-induced dysfunction in Ribosome Quality Control (RQC). We show that aneuploids entering quiescence display aberrant ribosome profiles, accumulate RQC intermediates, and harbor an increased load of protein aggregates compared to euploid cells. Although they maintain proteasome activity, aneuploids also show signs of ubiquitin dysregulation and sequestration into foci. Remarkably, inducing ribosome stalling in euploids produces similar aging phenotypes, while up-regulating limiting RQC subunits or poly-ubiquitin alleviates many of the aneuploid defects. We propose that the increased translational load caused by having too many mRNAs accelerates a decline in translational fidelity, contributing to premature aging.

Cognitive impairment is a frequent outcome of chronic viral infections linked to premature aging, including HIV. The mechanisms underlying this decline remain poorly understood. Here, we identify pro-inflammatory glycan degradation, characterized by loss of sialic acid and galactose, alterations that are hallmarks of premature aging, as key contributors to HIV-associated cognitive impairment (HIV-CI). In two independent cohorts of people living with HIV, these degradative changes were enriched in individuals with cognitive impairment, particularly females, and correlated with worse cognitive performance. In both a humanized mouse model of HIV and Eco-HIV, a complementary model that allows behavioral testing, pharmacological inhibition of glycan degradation with sialidase inhibitors prevented virally induced inflammation, immune activation, accelerated aging, and memory deficits. These findings implicate glycan degradation as a contributor to inflammation and cognitive impairment in HIV and highlight glycan-preserving therapies as a promising strategy to mitigate inflammation, premature aging, and cognitive decline during viral infections.

Stroke, caused by interrupted brain blood supply, predominantly affects the elderly. Epidemiological data indicate that over 70% of ischemic strokes occur in individuals aged 65 and above, and older patients are more likely to experience worse functional recovery and higher mortality rates. Most models use young animals, limiting clinical relevance for aged patients. Studying aged animals is more clinically applicable, especially since older patients often experience severe strokes. We selected a permanent middle cerebral artery occlusion (pMCAO) model to reflect strokes where reperfusion therapy is not achieved. A significant proportion of stroke patients (particularly older individuals) do not receive or benefit from thrombolysis/thrombectomy, leaving them with permanent arterial occlusion. In our aged mice model, pMCAO provides a stringent test of neuroprotective efficacy under conditions of sustained ischemia, which can illuminate melatonin's potential benefits in severe, unmanaged stroke. Melatonin, a potent antioxidant, has been shown to reduce infarction volume and improve neurobehavioral and electrophysiological recovery in ischemic stroke models. In this study, our objective was to assess the neuroprotective and neuroplasticity effects of melatonin as reflected by dendritic spine density and arborization in middle-aged mice (12-13 months old), a relevant model for aging-related stroke pathology. In this study, "middle-aged" refers to 12-13-month-old ICR mice, equivalent to approximately 40-50 human years. Twelve-month old male ICR mice subjected to pMCAO were treated with melatonin (5 mg/kg) or a vehicle before undergoing surgery. Neurobehavioral performance was assessed 24 h post-surgery, and brain tissues were collected for Golgi-Cox staining to assess stroke-induced neuronal dendritic damage and neuroplasticity. Melatonin treatment notably decreased infarct volume and neuronal degeneration, while enhancing neuron survival, increasing dendritic spine density, and promoting functional neuroplasticity in ischemic regions and promoting better neurobehavioral recovery compared to the vehicle controls (P < 0.05). In addition to evaluating infarct volume and synaptic plasticity, we assessed lipofuscin accumulation as a histological marker of neuronal aging and oxidative stress. Melatonin treatment reduced lipofuscin deposits, suggesting a potential role in attenuating age-related neurodegeneration. The administration of melatonin also resulted in a significant increase in dendritic spine density (P < 0.05) within the second- and third-order basilar dendrites of pyramidal neurons in layers II-III and III-IV of the penumbra, as well as in layer V-VI of both the ipsilateral (ischemic) and contralateral (nonischemic) cortex, when compared to vehicle controls (P < 0.05). In addition, melatonin treatment enhanced dendritic arborization in pyramidal neurons within layers II-III and III-IV of the ipsilateral cortex (P < 0.05). Furthermore, melatonin upregulation brain-derived neurotrophic factor (BDNF), growth-associated protein 43 (GAP-43) and synaptosomal-associated protein 25 (SNAP-25) expression post-insults. In this study, melatonin showed significant neuroprotective effects after ischemic stroke and enhanced neuroplasticity in middle-aged mice, suggesting its potential application in aging-related stroke therapy.

Aging profoundly impacts bone homeostasis and regeneration, yet the cellular and molecular mechanisms underlying periosteal aging remain poorly understood. Using single-cell RNA sequencing, we profiled the periosteum of 3-, 9-, and 18-month-old mice, which revealed age-related shifts in progenitor, neutrophil, and macrophage subpopulations. Aging reduced mesenchymal cell populations and impaired osteogenic potential, may contribute to periosteal homeostasis. Periosteal progenitor subsets exhibited distinct aging trajectories: Dpt⁺ fibrous-layer cells undergoing early senescence, while Postn⁺ progenitors showed osteogenic decline. Aging also shifted immune profiles, increasing inflammatory Cd38

Intestinal function and white adipose tissue (WAT) function deteriorate with age, but whether and how their deterioration is intertwined remains unknown. Increased gut permeability, microbiota dysbiosis, and aberrant immune microenvironment are the hallmarks of intestinal dysfunctions in aging. Here, we show that subcutaneous WAT dysfunction triggered aging-like intestinal dysfunctions in mouse models. Removal of inguinal subcutaneous WAT (iWAT) increased intestinal permeability and inflammation and altered gut microbiota composition as well as susceptibility to pathogen infection in mouse models. These intestinal dysfunctions were accompanied by a reduction of immunoglobulin A-producing (IgA-producing) cells and IgA biosynthesis in the lamina propria of the small intestine. Retinoic acid (RA) is a key cargo within iWAT-derived extracellular vesicles (iWAT-EVs), which, at least in part, elicits IgA class-switching and production in the small intestine and maintains microbiota homeostasis. RA content in iWAT-EVs and intestinal IgA biosynthesis are reduced during aging in mice. Replenishment of "young" iWAT-EVs rejuvenates intestinal IgA production machinery and shifts microbiota composition of aged mice to a "youth" status, which alleviates leaky gut via RA. In conclusion, our findings suggest that iWAT-EVs with RA orchestrate IgA-mediated gut microbiota homeostasis by acting on intestinal B cells, thereby maintaining intestinal health during aging.

Cognitive flexibility-the ability to adaptively shift between different mental processes-is essential for human functioning. This meta-analysis examines age-related changes in neural correlates of cognitive flexibility using two common assessments: the Wisconsin Card Sorting Test (rule-discovery) and Task-Switching Paradigm (rule-retrieval). We synthesized findings from 85 articles comprising 118 experiments with 2246 participants across young, middle-age, and older adult groups. Activation Likelihood Estimation analyses revealed an age-related decrease in neural involvement, particularly in posterior regions, with an anterior shift in older adults. Younger adults exhibited bilateral activation patterns while older adults showed left-dominant activity, indicating neural circuit redistribution. Rule-retrieval tasks consistently engaged left-lateralized frontoparietal regions across all age groups, with middle-age adults additionally recruiting the right cerebellum and medial frontal gyrus. For rule-discovery tasks, age-related changes were observed in bilateral frontoparietal regions, with older adults showing unique activation in the left inferior frontal gyrus. These findings highlight differential aging trajectories for rule-retrieval versus rule-discovery processes, reflecting changes in neural mechanisms with aging. Furthermore, middle-age adults recruited additional regions related to conflict monitoring, whereas older adults relied more on planning-related areas, suggesting strategy differences. Our study provides critical insights into the neural underpinnings of cognitive flexibility and its age-related changes, emphasizing the need for research on mechanisms and task-specific age trajectories.

Evidence suggests the development of age-related dementia is strongly associated with numerous modifiable risk factors, particularly lifestyle behaviours such as diet, sleep, and physical activity. Yet, when exploring the dietary predictors of cognitive function, many scoring systems apply linear scales to eating patterns in a way that prioritizes simplicity over predictive accuracy. The present study employed a cross-validated elastic net regression algorithm on a large dataset of self-reported dietary data (n=28,968 individuals, mean age 56.3, age range 16-100) to identify the greatest nutritional predictors of participants' performance on a validated online cognitive function test. Bias-free Regression Analysis in Nutrition (BRAiN) scores were computed, and their predictive power was found to outperform a well-recognized cognition-focused scoring system (Mediterranean-DASH Intervention for Neurodegenerative Delay, MIND) in held-out data. Non-linear relationships between intake level and cognition were noted for most foods, with greater consumption of animal and vegetable proteins, vegetables, nuts and seeds, and wholegrains, being positively associated with cognitive function, while the regular consumption of both refined fats and refined carbohydrates was negatively associated with cognitive function. Shifts in dietary patterns by age suggested that some relationships between diet and cognitive function in nutritional epidemiology may be confounded by age-related dietary trends. Our data-driven model can be easily adjusted over time to reflect potential shifts in dietary practices at the population level and inform relevant health authorities in the timely design of effective nutritional recommendations and guidelines to prevent or slow down the onset of age-related cognitive decline.

DNA damage and repair are central to the onset of cancer, aging, and aging-related diseases. Rare genetic defects in the nucleotide excision repair pathway, such as those causing the cancer-prone disorder xeroderma pigmentosum (XP) or the progeroid condition Cockayne syndrome, highlight the dramatic consequences of unrepaired DNA lesions. In this issue of the JCI, two related papers from Ogi and coworkers - Fassihi et al. and Nakazawa et al. - describe a new XP clinical entity, XP-J, linked to a pathogenic variant in the p52 subunit of the transcription-repair complex TFIIH. The studies' characterization of XP-J and the p52ΔC variant opened unexpected possibilities to ameliorate the molecular defect in another subunit of TFIIH that causes a different, more severe repair syndrome: trichothiodystrophy. This commentary provides a broader historical, medical, and molecular context for the intricate genotype-phenotype relationship between compromised repair and its clinical consequences and discusses next steps for the advances reported.

α-Klotho is a multifunctional protein implicated in vascular aging. Declining Klotho levels are associated with arterial stiffness, endothelial dysfunction, and vascular calcification. We investigated the associations between circulating klotho, aortoiliac calcification, endothelial progenitor cells, and 10-year survival.

Ageing is a risk factor for cardiovascular and neurodegenerative diseases. The myogenic response in resistance arteries is responsible for basal (myogenic) tone and blood flow autoregulation. G-protein-coupled receptors and G

Associative memory deteriorates with age. One possible reason for this associative memory deficit in older adults is a decline in inhibitory function. However, it remains unclear what role of inhibitory function plays in age-related associative memory deficits, and whether and how acute training of inhibitory function could ameliorate the detrimental effects of inhibitory deficits on associative memory in older adults. In Experiment 1, 80 participants (40 younger and 40 older adults) studied scene-word pairs while attempting to inhibit interfering words during encoding, with two conditions: gist and non-gist interferences. In Experiment 2, 66 older adults were randomly assigned to either acute inhibitory training or a control group, and eye-tracking technology was used to capture the benefits of acute inhibitory training. Results showed that older adults were more disturbed by gist than non-gist interferences because of hyper-binding, and that inhibitory function mediated the relationship between age and associative memory accuracy. Notably, although acute inhibitory training did not significantly improve associative memory accuracy in the training group compared to the control group, structural equation model showed that older adults in the acute training group showed shorter fixation durations and lower frequencies in the interference region of interest, leading to better associative memory. These results indicate that inhibitory function plays a mediating role in age-related associative memory decline, as well as its plasticity in this association. It provides a potential pathway to improve associative memory in older adults.