Longevity Papers

As the most abundant human cell and the foundation of transfusion medicine, red blood cells (RBCs) offer a unique readout of systemic health, yet they have never been characterized at population scale. We generated a proteome atlas of 13,091 blood donors with multi-omics longitudinal phenotyping, characterizing the influence of demographics and genetic variation on the reproducibility of RBC proteomes across donations. Elastic-net aging clocks captured biological aging with high accuracy and uncovered genetic regulators of {Delta}Age at FN1, C4/IKZF1, CRAT, PFAS, TRIM58. Across independent cohorts, {Delta}Age was accelerated in G6PD deficiency, sickle cell trait/disease, and iron deficiency, reversed by iron repletion, and slowed in high-frequency donors, linking molecular aging to brain iron/myelin and cognitive performance. Molecular aging signatures predicted storage, osmotic, and oxidative hemolysis, hemoglobin increments after transfusion, and long-term donor activity over 12-years. These results establish RBC proteomics as a scalable biomarker of aging, donor healthspan, and transfusion outcomes.

How cell identity is maintained is a fundamental question, and loss of cell identity is a hallmark of aging that is associated with multiple age-related diseases. In the adult Drosophila midgut, we identified a post-transcriptional regulatory layer that supervises enterocyte (EC) identity and fails upon aging. Combining single-cell RNA-seq with lineage tracing in aging ECs and classical genetics we found that aging ECs express genes that unlock the differentiated state. Upon aging, the protein Rogue (CG13928), a translational repressor, orchestrates reactivation of a stem-cell-related translational repression machinery involving p-body-associated RNA-binding proteins that cancels the differentiated state. In young ECs, this machinery is continuously suppressed by the deubiquitinase Non-stop (dUSP22) and the ubiquitin E2 dUbcH8/Kdo and the E3 enzyme CTLH, together suppress the stem-cell related RNA binding proteins safeguarding EC identity. Upon aging, the levels of dUSP22 decline, dUbcH8/Kdo and the E3 CTLH complex are cleared via Rogue, and the stem cell-related p-bodies are reactivated, self-destroying EC identity.

This study aims to explore the shared transcriptomic features of caloric restriction (CR) and endurance exercise in skeletal muscle among older adults. As age increases, muscle atrophy gradually becomes a common issue of functional decline in the elderly. Utilizing bioinformatics analysis, this research identified 101 overlapping differentially expressed genes (DEGs) involved in both CR and endurance exercise. These genes are primarily enriched in key biological pathways related to longevity, Apelin signaling, AMPK signaling, FoxO signaling, and cGMP-PKG signaling pathways. Additionally, we identified 10 key genes (such as LPL, PPARGC1A, and IGF1), 4 transcription factors (FOXC1, POU2F2, GATA2, and STAT3), and 4 microRNAs (miR-155-5p, miR-124-3p, miR-1-3p, and miR-16-5p) interacting with these genes. Drug-gene interaction analysis identified carotuximab as a compound with potential relevance for future investigation in the context of muscle aging. These findings provide new insights into the molecular mechanisms underlying muscle functional decline in the elderly and propose potential targets and drugs for intervention development.

Chronic lung diseases are a growing global health burden in aging populations, yet their underlying mechanisms remain poorly defined, and current treatment options are limited. Cellular senescence, a hallmark of aging, is increasingly recognized as a key driver of chronic lung pathology and is often accompanied by dysfunction in subcellular organelles. Among these, peroxisomes have emerged as important regulators, though their specific roles in senescence remain underexplored. To address this gap, we investigated the function of peroxisomes during replicative and oxidative stress-induced senescence in human fetal lung fibroblasts (HFL-1). We found that peroxisomal biogenesis, including the import receptor PEX5 expression, is significantly downregulated in senescent cells. Loss of PEX5 activated p38 mitogen-activated protein kinase (p38 MAPK) signaling, reduced nuclear translocation of the transcription factor EB (TFEB), and impaired autophagic flux, thereby promoting a pro-senescent cellular state. Metabolomic profiling revealed that PEX5 overexpression enhanced taurine biosynthesis by facilitating the peroxisomal localization of its key synthetic enzymes. Remarkably, exogenous taurine supplementation restored PEX5 levels in senescent fibroblasts and aged mouse lungs, mitigating senescence phenotypes and establishing a PEX5-taurine-PEX5 positive feedback loop. Together, these findings delineate a novel peroxisome-centered regulatory mechanism that integrates p38 MAPK-TFEB signaling and taurine metabolism to control cellular senescence. This work provides new insights into the interplay between organelle function and aging and highlights potential targets for therapeutic intervention in age-related lung diseases.

Population aging has intensified interest in identifying physiological determinants of biological age beyond chronological age. Muscle loss and bone deterioration are key features of age-related decline, yet their individual, joint, and sex-specific contributions to biological age acceleration remain insufficiently characterized in Asian populations.

Aging involves multiple detrimental changes in the systemic milieu, leading to functional deterioration and age-related diseases. However, the potential self-protective adaptive alterations during aging remain underexplored. Here we show that phosphoenolpyruvate (PEP), a glycolytic metabolite, acts as a protective factor against age-related chronic inflammation. Longitudinal analyses in mice and humans reveal a biphasic PEP trajectory, characterized by initial accumulation followed by progressive decline. Blocking PEP accumulation exacerbates inflammation and accelerates aging phenotypes, whereas PEP administration before its decline promotes healthy aging in mice. In aged humans, high PEP levels strongly correlate with lower inflammation and healthier traits. Mechanistically, PEP acts as an endogenous inhibitor of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway by competitively binding to cGAS. Moreover, PEP alleviates neuroinflammation and improves cognitive function in an Alzheimer's disease mouse model. Thus, our findings define PEP accumulation as an evolutionarily conserved geroprotective mechanism, positioning PEP as a promising intervention for aging and associated diseases.

Different types of dietary restriction (DR) have been practiced by humans for religious and medical purposes for millennia, but only during the past three decades has the scientific study of DR at cellular and molecular levels proliferated. Here we review the evidence testing a variety of DR paradigms in the context of aging, focusing on mammalian findings. We discuss potential DR mimetics that modulate autophagy, FGF21, AMPK, mTORC1, NAD

Age-related hearing loss (ARHL) is a prevalent neurodegenerative condition characterized by the progressive loss of spiral ganglion neurons (SGNs). Although oxidative stress is recognized as a central pathogenic driver of ARHL, the precise molecular triggers that initiate and amplify SGN damage remain elusive. Here, we investigated the role of the Transient Receptor Potential Vanilloid 2 (TRPV2) channel in ARHL. We found that TRPV2 expression was significantly upregulated in the SGNs of aged mice, which was associated with elevated oxidative stress. Pharmacological activation of TRPV2 in 6-month-old mice (a pre-senescent stage with preserved baseline hearing) accelerated the onset of high-frequency hearing damage, as evidenced by auditory brainstem response (ABR) measurements. Consistently, TRPV2 activation exacerbated oxidative damage (assessed by 4-HNE staining) and increased apoptotic cell death (detected via TUNEL) in the SGN population. In primary SGN cultures, TRPV2 overexpression aggravated oxidative stress, whereas TRPV2 knockdown in SH-SY5Y cells (a human neuroblastoma cell line) markedly mitigated the oxidative injury as reflected by reduced 4-HNE. Our findings establish that the age-related upregulation of TRPV2 sensitizes SGNs to oxidative stress, thereby promoting neuronal damage and exacerbating ARHL. This work highlights TRPV2 as a promising therapeutic target for intervening in the progression of ARHL.

Physical inactivity is a major, modifiable driver of non-communicable diseases in aging populations. We quantified the prevalence of physical inactivity among Iranian older adults and identified demographic, socioeconomic, and health-related correlates. We analyzed nationally representative 2021 STEPS data from 5,491 adults aged ≥ 60 years. Physical activity was assessed via World Health Organization Global Physical Activity Questionnaire (WHO GPAQ) and categorized as sufficient (≥ 600 MET-min/week) vs. insufficient (< 600). Sedentary time (min/day) was recorded. Complex survey design was accounted for in estimates. Associations with inactivity were examined using sex-stratified generalized linear mixed-effects models adjusting for age, education, marital and employment status, urban or rural residence, wealth tertile, obesity, depressive symptoms, and multimorbidity. Among the participants, mean sedentary time was 288 min/day and mean total activity was 1,326 MET-min/week. Overall, 69.6% (95% CI: 68.3-71.0) were inactive, higher in women (76.8%, 75.0-78.5) than men (62.4%, 60.3-64.4). Inactivity was highest in adults aged ≥ 80 years (80.9%, 77.1-84.7). Urban residence was associated with higher odds of inactivity (adjusted OR [aOR] 1.35, 95% CI: 1.13-1.61) and higher education (≥ 12 years formal education) showed lower odds (aOR 0.73, 0.61-0.88). Obesity and depressive symptoms were each related to higher odds of inactivity (aOR 1.34, 1.08-1.66 and aOR 1.30, 1.12-1.51); odds were progressively higher across multimorbidity categories (e.g., ≥ 3 conditions, aOR 1.26, 1.02-1.55 vs. none). Sex differences were evident. Compared with ages 60-69, adults aged ≥ 80 had higher odds of inactivity in women (aOR 3.20, 95% CI 1.96-5.24) than in men (aOR 1.91, 1.41-2.60). Urban residence and higher wealth were also related to higher odds in women (urban aOR 1.62, 1.25-2.11; wealth Q3 aOR 1.41, 1.14-1.75), while higher wealth was related to lower odds in men (Q3 aOR 0.76, 0.61-0.94). Physical inactivity is highly prevalent among Iranian older adults, especially women, the oldest age groups, urban residents, and those with obesity, depression, or multiple chronic conditions. Findings support gender-responsive, multicomponent strategies-including community programs, primary-care integration, and activity-supportive urban design-to reduce inactivity and advance healthy aging in Iran.

Degenerative temporomandibular joint disease (TMJ-DJD), a common condition in middle-aged and elderly populations, has seen a continuous rise in incidence with global population aging. Aging synergistically promotes TMJ degeneration through multilevel mechanisms. At the cellular level, aging manifests as epigenetic alterations, formation of the senescence-associated secretory phenotype, mitochondrial dysfunction, exacerbated oxidative stress, and declined stem cell repair capacity, collectively accelerating degradation of the chondrocyte extracellular matrix and apoptosis. At the systemic level, immunosenescence leads to a chronic low-grade inflammatory state; various endocrine changes (e.g. in sex hormones, the growth hormone/insulin-like growth factor-1 axis, and thyroid hormones) impair tissue anabolic and repair capacity. Meanwhile, declined tissue mechanosensation and hardening of the extracellular matrix further reduce the joint's adaptability to external load. Additionally, aging acts as an endogenous factor that disrupts central and peripheral circadian rhythms, indirectly promoting TMJ degeneration by impairing cartilage metabolism and inflammatory responses. In summary, aging drives the pathogenesis and progression of TMJ-DJD via multiple pathways, including cellular dysfunction, systemic homeostasis imbalance, and disruption of biological rhythms. Targeting the above mechanisms may provide novel therapeutic strategies for future clinical interventions in TMJ degenerative joint diseases.

This longitudinal study leveraged data from the China Health and Retirement Longitudinal Study (CHARLS, 2015 wave) which contains longitudinal data from 28 provinces across the country to examine the synergistic impacts of chronic nocturnal light and air pollution (PM2.5) exposure on cardiovascular diseases (CVDs) as well as how two neuropsychological disorders (depression and cognitive impairment) mediate that effect among middle-aged and older adults in China. Using multivariable-adjusted mixed-effects logistic regression models, we identified significant interaction effects between annual changes in artificial light at night (ΔALAN) and PM2.5 exposure on hypertension (OR = 1.32, 95% CI: 1.12-1.56, p = 0.013), heart disease (OR = 1.24, 95% CI: 1.05-1.47, p = 0.028), and stroke (OR = 1.18, 95% CI: 1.02-1.36, p = 0.042). Notably, depressive symptoms and cognitive impairment mediated 18.7% and 12.3% of the total CVD risk, respectively. Subgroup analyses revealed heightened vulnerability in women (OR 1.42 vs. men OR 1.03) and adults aged ≥75 years (1.8-fold greater than younger groups). Our findings underscore the necessity of dual interventions: (1) environmental policies targeting nighttime light reduction (e.g., dimmable LED streetlights) together with air quality improvement, and (2) community-based mental health programs aiming to mitigate neuropsychological mediators. These integrated strategies could substantially alleviate the CVD burden in aging populations exposed to urbanization-driven environmental stressors.

Background: White matter hyperintensities (WMH) are widely used to assess cerebral small vessel disease (SVD) but reflect late-stage injury. Diffusion MRI based biomarkers have been proposed to capture earlier SVD-related microstructural damage but their temporal progression relative to WMH and the risk factors associated with this progression have not been explored. Methods: We analyzed longitudinal neuroimaging data from 2,047 participants from a population-based cohort study (aged 49-101 years, 47% female). Using multi-output nonlinear mixed-effects models, we characterized the temporal progression of WMH and four diffusion MRI based biomarkers: fractional anisotropy of the genu of the corpus callosum (Genu-FA), peak width of skeletonized mean diffusivity (PSMD), free water (FW), and Arteriolosclerosis-score (ARTS). Models incorporated participant-specific time shifts, correlations between biomarkers, and effects of risk factors (sex, education, APOE ?4 status, and cardiometabolic conditions). Results: ARTS, Genu-FA, FW, and PSMD became abnormal in 50% of the study population 16, 12, 10, and 7 years before WMH, respectively. Global markers (ARTS, FW, PSMD, WMH) were correlated, indicating shared substrates of widespread white matter injury. Genu-FA, a vascular risk microstructural injury biomarker, was weakly coupled with WMH and had an earlier but more linear worsening across adulthood. Cardiometabolic conditions predicted earlier worsening of all biomarkers. Females showed earlier WMH, Genu-FA, and ARTS abnormalities whereas males exhibited earlier PSMD and FW abnormalities. Conclusions: Diffusion MRI based biomarkers capture microstructural injury at least a decade before appearance of WMH, revealing a prolonged phase of early SVD and highlighting their potential for SVD prevention.

Sarcopenia is an age-associated degenerative disorder of skeletal muscle, characterized by the progressive decline in muscle mass and function, which increases the risk of falls, injuries, and accidental death in older adults. Deciphering its pathogenic mechanisms is crucial for advancing early detection, precision prevention, and ultimately improving the quality of life for the elderly population. Increasing evidence suggests that epigenetic regulation plays a central role in driving sarcopenia. DNA methylation, chromatin remodeling, and noncoding RNA regulation collectively accelerate the deterioration of bone and muscle by altering gene expression involved in biosynthesis and metabolism, disrupting protein homeostasis, activating inflammatory pathways, and compromising mitochondrial integrity. This review, which synthesizes the most recent progress in epigenetic research on sarcopenia, uses structured searches of PubMed and Web of Science for studies published from 2014 to the present and emphasizes how these interconnected regulatory networks drive the initiation and progression of the disease. Importantly, we emphasize their translational potential to identify novel biomarkers, enabling early risk stratification and informing the development of targeted therapeutic strategies, thereby laying the groundwork for precision clinical intervention.

With an aging population globally, prevention of frailty and sarcopenia will become a public health priority. Growth Differentiation Factor-15 (GDF-15), a stress-responsive cytokine of the TGF-β superfamily, has emerged as a promising biomarker linking mitochondrial dysfunction, cellular senescence, and systemic inflammation to biological and phenotypic aging.

Osteoarthritis (OA) is a prevalent joint disease with a complex etiology, involving epigenetic alterations. Recent studies have suggested the potential of Oct4, Sox2 and Klf4 (OSK) in rejuvenating adult cells and facilitating tissue repair, but their specific role in OA pathophysiology and treatment remains unclear. Here we employed an adeno-associated virus (AAV) vector to achieve ectopic expression of OSK (AAV-OSK). Chondrocytes expressing OSK retained chondrocyte-specific markers with no increase in stemness-associated genes. AAV-OSK significantly preserved chondrocyte vitality in an inflammatory environment and counteracted the upregulation of osteogenic genes during OG differentiation. In OA murine models, AAV-OSK administration led to a notable improvement in cartilage integrity, a reduction in subchondral bone thickening and promoted the hyalinization of fibrocartilage. Furthermore, chondrocyte senescence and DNA methyltransferase expression were markedly diminished in the AAV-OSK group. Tet methylcytosine dioxygenase 2 was identified as a pivotal factor underlying the benefits of OSK-driven cartilage regeneration. Collectively, our study underscores that OSK expression within the knee joint modulates epigenetic alterations, mitigating OA progression and cartilage fibrosis through partial reprogramming, highlighting its therapeutic promise for comprehensive OA intervention.

Enterococcus faecium CPU2401, isolated from traditional pickles, was assessed for its probiotic potential through an integrated approach combining whole-genome sequencing and phenotypic assays. The complete genome (2,803,294 bp) comprises a chromosome (2,724,439 bp) and a plasmid (78,855 bp), with a GC content of 38.38% and 2,786 predicted genes. Genomic analysis revealed the presence of various resistance genes (e.g., optrA, efmA) and numerous genes involved in secondary metabolite synthesis, such as carbohydrate-active enzymes (CAZymes). Phenotypically, E. faecium CPU2401 exhibited high gastrointestinal tolerance, with survival rates of 55.4% at pH 4 and 86.7% in the presence of 0.1% bile salts. It also showed good antioxidant capacity, scavenging 3.83% of DPPH, 22.0% of hydroxyl, and 83.4% of superoxide anion radicals, together with notable antibacterial activity against pathogens including Salmonella Typhimurium and Staphylococcus aureus. In Caenorhabditis elegans, E. faecium CPU2401 enhanced resistance to S. Typhimurium infection and significantly extended lifespan by 22.4% compared to the control. These findings underscore the strain's promise as a probiotic candidate for functional food and health applications.

Sleep architecture and continuity deteriorate markedly with aging, yet these changes are frequently approached as isolated sleep disorders rather than as manifestations of systemic biological dysregulation. Accumulating evidence indicates that age-related sleep fragmentation reflects the progressive disruption of interconnected metabolic, inflammatory and circadian networks that are central to the biology of aging. In this context, sleep can be more accurately interpreted as a functional readout of systemic biological coherence and resilience in later life. In this integrative mechanistic review, we synthesize current evidence linking metabolic dysregulation, inflammaging and circadian desynchronization to sleep deterioration in older adults, and propose an integrative conceptual framework structured around three interdependent functional domains: Temporal (circadian organization), Energetic (metabolic flexibility and bioenergetics), and Redox-Neuroimmune (chronic low-grade inflammation and oxidative stress). These domains converge on the AMPK-mTOR-SIRT1 axis, which acts as a central mechanistic hub coordinating energy sensing, inflammatory tone and molecular clock regulation. Within this framework, sleep deterioration is conceptualized not as a primary pathological entity, but as the downstream functional expression of impaired nocturnal cellular maintenance driven by reduced AMPK activity, persistent mTOR signalling and declining SIRT1-dependent regulation. Bidirectional feedback loops are considered, whereby sleep fragmentation may further exacerbate metabolic and inflammatory dysregulation, reinforcing loss of biological coherence with aging. Importantly, we explicitly address current methodological limitations, particularly the challenges of assessing AMPK-mTOR-SIRT1 activity in humans using non-invasive approaches. Rather than offering prescriptive therapeutic recommendations, this framework is intended as a mechanistic, hypothesis-generating model to guide future research, biomarker development and translational studies focused on metabolic-circadian resilience and biological aging.

Intervertebral disc degeneration (IVDD) is a common degenerative spinal disorder and a major contributor to low back pain. Although aging is a key risk factor, the causal role of biological aging markers, such as telomere length (TL), in IVDD remains unclear. Moreover, the metabolic pathways underlying this association are largely unexplored. This study employed a 2-sample Mendelian randomization (MR) framework based on genome-wide association study summary data to investigate the causal effect of TL on IVDD risk. Genetic correlation between TL and IVDD was further evaluated using linkage disequilibrium score regression (LDSC). Additionally, we performed a network MR mediation analysis to investigate whether circulating blood metabolites mediate the relationship between TL and IVDD. Univariate MR analysis showed that TL had a significant causal effect on IVDD. (odds ratio = 0.883, 95% CI: 0.835-0.934, P = 1.15 × 10-5). LDSC revealed a significant negative genetic correlation between TL and IVDD (rg = -0.1409, SE = 0.0274, P = 2.6 × 10-7). Mediation analysis identified 16 circulating metabolites as partial mediators, with tyrosine showing the most significant mediating effect. Specifically, genetically predicted TL was negatively associated with tyrosine levels (β = -0.124, 95% CI: -0.159 to-0.089), and elevated tyrosine levels were causally associated with increased IVDD risk (β = 0.113, 95% CI: 0.055-0.172). The indirect effect mediated by tyrosine accounted for 12.78% (95% CI: 7.42%-18.14%) of the total effect of TL on IVDD. This study provides robust genetic evidence supporting a protective effect of longer TL against IVDD, and highlights tyrosine as a potential metabolic mediator in this process. These findings provide new insights about the aging-metabolism-degeneration axis in spinal health and propose telomere maintenance and amino acid metabolism as promising targets for early intervention in intervertebral disc degeneration.

Gait variability is a critical functional indicator of dynamic balance and neurocognitive decline in health. Its translation into clinical practice is, however, challenged by a lack of age-related normative trajectories and reference values under real-world ecological settings. Furthermore, the conventional metrics used to estimate gait variability (Coefficient of Variation, CV; Standard Deviation, SD) have a fundamental methodological flaw: the inherent sensitivity of conventional metrics to the statistical outliers and environmental noise in real-world walking. In this study, we mitigate this factor by applying a robust statistical framework to quantify gait variability. Analysing a large-scale cohort of community-dwelling older adults (n=2,193), we first demonstrate that free-living gait data follows a heavy-tailed distribution, necessitating the use of robust estimators like the Robust Coefficient of Variation (RCV-MAD) and Median Absolute Deviation (MAD). Leveraging these metrics, we established the normative trajectory and reference values of real-world gait variability across the ageing lifespan, revealing a distinct, age-dependent increase in spatio-temporal fluctuations, indicating a decline in rhythmicity and steadiness with age. We further demonstrated the clinical utility of these robust metrics: RCV-MAD consistently yielded larger effect sizes than conventional CV in discriminating between fallers and non-fallers across all gait parameters. Furthermore, we illustrate the potential of long-term unsupervised monitoring to capture intrinsic variability during real-world walking. Validated for consistency and reliability, this robust framework provides the necessary ecological validity to transform gait variability into a standardised, rapid clinical metric for assessing functional decline at an early timepoint.

Identifying modifiable environmental factors of chronic kidney disease (CKD) in older adults is important for developing strategies to prevent CKD. This study aimed to investigate cross-sectional and longitudinal associations of residential environmental exposure, including air pollution and walkability, with kidney function in older adults in the Netherlands. For the cross-sectional analyses, data from two cohorts of the Longitudinal Aging Study Amsterdam were used: 1992/93 (n = 1182; mean age = 72.3 ± 8.5) and 2008/09 (n = 741; mean age = 71.6 ± 7.8). Longitudinal analyses included 227 participants (mean age at baseline = 62.6 ± 5.4). Kidney function was assessed by calculating eGFR from serum creatinine measurements. PM

Retinal age gap (RAG)-the difference between retina-predicted age and chronological age-indicates biological ageing that has been linked to the risk of mortality and chronic disease. We aimed to identify risk factors associated with higher RAG in an Australian population. This cross-sectional study included 5107 participants from the Busselton Healthy Ageing Study (BHAS), a Western Australian community-based cohort. Retinal age was estimated using a validated deep-learning model applied to fundus photographs. Multivariable linear regression models were employed to examine associations between sociodemographic, lifestyle, and clinical factors and the RAG. RCS analysis was performed to investigate potential non-linear relationships and determine threshold effects between each risk factor and the RAG. A total of 4798 BHAS participants had available retinal images for RAG estimation, with a mean age of 58.0 years (SD = 5.8). Fifty-five percent were women, and around 1.5% identified as non-Caucasians. After adjusting for age, sex, and ethnicity, systolic blood pressure (SBP) (β = 0.033, 95% confidence interval [CI]: 0.025-0.042, p < 0.001), diastolic blood pressure (β = 0.052, 95% CI: 0.038-0.066, p < 0.001), body mass index (BMI) (β = 0.065, 95% CI: 0.039-0.092, p < 0.001), alcohol consumption (β = 0.146, 95% CI: 0.078-0.215, p < 0.001), and glycated haemoglobin (HbA1c) (β = 0.461, 95% CI: 0.224-0.698, p < 0.001) were significantly, positively associated with RAG. This indicates the potential clinical use of RAG to facilitate epidemiological investigation, risk stratification, healthy ageing promotion, and reducing age-related disease burden.

Sarcopenia is a major health concern in aging populations. Resistance training (RT) is widely recommended to improve muscle mass, strength, and physical function in older adults. In recent years, research on both biological mechanisms and clinical effects of RT has increased. However, these two fields have largely progressed in parallel, with limited evidence linking biological mechanisms to clinical efficacy. This narrative review integrates preclinical and clinical mechanistic evidence on RT in sarcopenia. It evaluates consistency across key biological pathways, including protein metabolism, mitochondrial function, chronic inflammation, and satellite cell regulation. Furthermore, it summarizes clinical evidence on RT in older adults and analyzes potential broader benefits. Finally, the review discusses the translational relevance of RT-related mechanisms and offers practical recommendations for prescribing RT. Current evidence suggests that improvements in mitochondrial adaptations show relatively consistent findings across preclinical and human studies. However, translation remains limited for protein metabolism regulatory mechanisms and chronic inflammation. YAP/TAZ proteins in the Hippo pathway may link mechanical signaling induced by RT to satellite cell regulation. Overall, although the preclinical mechanisms of RT in sarcopenia are relatively clear, translating them into clinical practice should be approached with caution. This review provides a practical guide to optimizing RT strategies and to guide future translational research.

Cognitive impairment and low muscle mass are prevalent conditions in later life, and each has been independently associated with adverse health outcomes. Both conditions are heterogeneous and may arise from multiple underlying etiologies. However, evidence regarding their combined association with all-cause mortality remains limited, particularly among older adults in China. Therefore, this study aimed to investigate the independent and joint associations of cognitive impairment and low muscle mass with all-cause mortality using data from a large prospective cohort.

The human striatum is a central hub for a diverse array of motor, cognitive, and affective behaviors, yet it lacks obvious cytoarchitectural boundaries that define functional territories. Here, we uncover a robust and molecularly defined mesoscale architecture in the human striatum. Using Slide-tags, a scalable single-nucleus spatial transcriptomics technology, we profiled 1.1 million cells across the full span of the anterior striatum of 19 postmortem donors, spatially mapping all striatal populations. Our data uncover a natural subdivision of the striatum into six zones, each defined by molecularly distinct populations of medium spiny neurons, and featuring spatially coordinated neuron-astrocyte signaling. Relative to MSNs in ventral zones, MSNs in dorsal zones exhibit higher expression of genes for synaptic remodeling and plasticity via ephrin and TGF-beta, while the ventral zone is defined by greater expression of semaphorin, protein chaperone, and hedgehog signaling pathways. By imputing zonal identities onto a larger single-nucleus RNA-seq cohort of 131 donors, we find that the dorsal zones exhibit greater age-related transcriptional changes, and that overall, the gene-expression differences that define spatial zonation patterns are attenuated with advancing age. This atlas provides a mesoscale molecular definition of human striatal anatomy, linking cell type identity to functional specialization and aging susceptibility.

Background: Cognitively unimpaired (CU) adults vary substantially in their risk of developing mild cognitive impairment (MCI), yet most subtyping approaches focus on downstream neurobiological or cognitive markers rather than upstream, modifiable risk factors. We aimed to identify clinically meaningful subgroups of CU adults defined by integrated comorbid, behavioral, and social risk profiles, and to evaluate heterogeneity in both incident MCI risk and cardiometabolic treatment effects. Methods: We conducted a prospective cohort study of 121,322 CU adults aged over 50 years from the All of Us Research Program. Baseline comorbidities, lifestyle behaviors, and social determinants of health were jointly modeled using the Bayesian Mixed Integrative Data Subtyping framework, which integrates binary and continuous modalities via modality-specific likelihoods and shared latent constructs. Subtype-specific risk of incident MCI was assessed using multivariable Cox proportional hazards models adjusting for demographics and baseline medication use. A double/debiased machine learning interactive regression model with inverse probability of censoring weights to mitigate bias from informative censoring was implemented to estimate the average treatment effects of antihypertensive agents, Glucagon-Like Peptide (GLP) receptor agonists, and non-GLP antidiabetic medications on time to MCI. Results: Four distinct subtypes were identified: I low-risk healthy aging, II behavioral/social vulnerability, III cardiometabolic-depressive multimorbidity, and IV mixed social-medical vulnerability profiles. Compared with Subtype I, Subtype III demonstrated the highest risk of incident MCI (HR: 3.69, 95% CI: 3.14-4.33), followed by Subtype IV and Subtype II. In treatment effect analyses, antihypertensive use was associated with a modest prolongation of MCI-free survival overall (time ratio:1.04, 95% CI: 1.03-1.06), with the largest benefit observed in Subtype III (time ratio: 1.14, 95% CI: 1.09-1.19). Non-GLP antidiabetic therapies were similarly associated with modest overall delay, with significant benefits in Subtypes I and III. GLP-class therapies were not associated with overall delay but showed a significant association in Subtype III. Conclusions: Integrative subtyping based on comorbid, behavioral, and social risk factors reveals clinically meaningful heterogeneity in both cognitive risk and treatment response. Aligning dementia prevention strategies with dominant vulnerability pathways may enhance the effectiveness and equity of population-level precision prevention. Key Words: multi-modal integrative subtyping; differential cognitive risk; treatment effect heterogeneity; All of Us Research Program

Human brain structure changes dynamically across the lifespan, closely linked to cognitive development and decline. T1-weighted and T2-weighted magnetic resonance imaging (MRI) are widely used to assess anatomical and microstructural properties. However, acquiring longitudinal multimodal MRI is resource-intensive, limiting characterization of age-related trajectories. Here, we propose LS-MAT, a generative framework for synthesizing personalized, multimodal, and age-conditioned structural MRIs to support lifespan neuroimaging research. The framework integrates: (i) a variational autoencoder with a generative adversarial network for efficient latent encoding, (ii) a latent diffusion model for high-resolution conditional synthesis, and (iii) a ControlNet for modality-guided structural consistency. We trained and evaluated the model on large-scale, publicly available datasets spanning ages 5-100 years. LS-MAT achieved strong performance in modality conversion, measured by peak signal-to-noise ratio, structural similarity index measure, and mean squared error. The generated images captured established developmental and aging trends, including ventricular enlargement, cortical thinning, and age-related trajectories of T1/T2-weighted ratio-based microstructural profiles. Compared with existing methods, our model outperformed previous approaches in both modality conversion and age-conditioned synthesis tasks. These findings highlight the potential of generative modeling to overcome data scarcity in lifespan neuroimaging and provide a powerful tool for studying structural brain changes. The pipeline not only supports longitudinal analyses but also enables the derivation of microstructural profile features and is openly available at https://github.com/hobacteria/LS-MAT.

Population ageing has widened the gap between lifespan and healthspan, with frailty and functional dependence increasingly shaping late-life outcomes. Yet trajectories in older age remain highly heterogeneous, suggesting that vulnerability is not determined by chronological age alone but by differences in adaptive capacity. This review reframes resilience as a dynamic, multilevel construct linking molecular maintenance, regulation within the immune-endocrine-autonomic "vital systems triad," and functional trajectories captured by the WHO Intrinsic Capacity framework. We synthesize evidence supporting operational resilience indicators based on recovery dynamics, physiological flexibility, and integrated biomarker profiles spanning multi-omics, autonomic and endocrine rhythms, digital measures, and functional performance. We further discuss how lifestyle, psychosocial, and emerging pharmacological strategies converge on shared resilience pathways and generate measurable molecular and physiological signatures. Finally, we propose an integrated longevity medicine framework as a translational model to incorporate resilience assessment into clinical decision-making, predictive modelling, and prevention-oriented policy. Positioning resilience as a modifiable target may help shift ageing strategies from disease-centred care toward preserving adaptive capacity, functional independence, and meaningful engagement across the life course.

Aging is one of the most important risk factors for Intervertebral disc degeneration, a major contributor to chronic low back and neck pain. Recently, we demonstrated a critical role for SIRT6, a nuclear NAD - dependent deacetylase and defatty acylase, in maintaining intervertebral disc health with aging. We therefore investigated whether pharmacological activation of SIRT6 improves disc health by examining the spinal phenotype of 24-month-old mice treated with the well-studied agonist MDL-800 for 6 months. Histological studies revealed healthy disc tissue morphology, enhanced cell viability, and lower degeneration scores in mice treated with MDL-800. Further mechanistic insights revealed that SIRT6 activation decreased H3K9ac levels, improved cell phenotype and matrix quality, and reduced the SASP burden in the disc, characterized by decreased abundance of p21, IL-6, and TGF-b. Tissue RNA-Seq, in vitro measurements of histone 3 modifications, and multi-omics ATAC-seq/RNA-seq analyses revealed that SIRT6 activation altered the epigenetic status (decreased H3K9ac, H3K36me3, and H3K79me2) and transcriptomic landscape of disc cells. Notably, MDL-800 treatment increased LC3II levels in disc cells, indicating enhanced autophagic flux. Furthermore, plasma LC-MS and nuclear magnetic resonance (NMR) analyses revealed minimal systemic metabolomic changes. ScRNA-sequencing of splenocytes and bone marrow cells and systemic cytokine profiling indicated good tolerance and the absence of systemic inflammation following MDL-800 treatment. Our study demonstrates that SIRT6 activation modulates autophagy, cell senescence, and matrix homeostasis in the disc, underscoring the feasibility of targeting SIRT6 activation as a promising pharmacological strategy to maintain disc health in the aging spine.

Two different individuals can consume an identical diet but experience different physiological outcomes. While there are many potential mechanistic reasons for this, one increasingly recognized reason is that differences in an animal's microbiome can lead to differences in the processing of dietary nutrients. Thus, though a diet might start out the same, how it is experienced by a host is dependent on their microbiome. While exciting, mechanistic studies of diet-microbiome-host effects are often limited by the lack of high throughput laboratory techniques to identify and define interactions between dietary metabolites, microbial metabolism, and host biology. We hypothesized that the model organism Caenorhabditis elegans is an advantageous animal model for rapidly identifying and genetically dissecting interactions between dietary nutrients, microbial metabolism, and host physiology. Here, we used an established model of the effects of dietary glucose on insulin resistant mutant animals (daf-2/IR mutants) to study how differences in bacterial metabolism influence the consequences of dietary sugars on animal physiology. We found that the effect of dietary sugars on daf-2 mutant physiology is dependent on how the microbiome metabolizes dietary sugars. We found dietary sugar suppresses multiple daf-2 mutant phenotypes in the presence of some bacteria but has no effect in the presence of others. To determine how bacteria mediate the effects of dietary sugars on host physiology we screened 5,000 transposon mutations in the canonical C. elegans dietary bacteria, E. coli OP50 for effects on animal insulin signaling. From this, we found that the effects of exogenous sugars on the phenotype of daf-2 mutant animals is dependent on the function of pyruvate dehydrogenase in bacteria and that the loss of bacterial pyruvate dehydrogenase genes (ex. aceE) is sufficient to mimic the effects of dietary sugars on dauer formation, longevity, and gene expression in insulin signaling deficient animals. Collectively, our findings further support the growing body of evidence that the effects of dietary nutrients on animal physiology can be influenced by the gut microbiome. In addition, these studies demonstrate the advantages of the C. elegans model system for studying 3-way diet-microbiome-host interactions that are difficult to dissect in other model systems.

A loss of muscle mass and strength with aging may reflect a generalized and progressive disease known as sarcopenia. Mounting evidence shows that sarcopenia is associated with poor health outcomes in older adults. Currently, no specific drugs are approved for the treatment of sarcopenia. In this context, exercise training has emerged as a cornerstone non-pharmacological strategy to disease management. This narrative review synthesizes evidence on the effects of exercise training on muscle strength, muscle mass, and physical performance in sarcopenic older adults published recently (from 2024 onward).

Background: Clinical evidence supports a greater impact of arterial stiffening in cardiovascular mortality in women versus men. Arterial stiffness increases across the menopausal transition, implicating a role of the loss of estrogens in arterial stiffening, but mediating mechanisms remain unclear. Methods: The role of estradiol and smooth muscle cell (SMC) estrogen receptor alpha (ER) in arterial stiffening, by aortic pulse wave velocity (PWV), was assessed in 3 models: (1) the loss of estradiol in young, female mice comparing sham surgery or bilateral ovariectomy (OVEX) {+/-} estradiol, (2) the impact of sham versus OVEX surgery in young, female SMC-ER-intact and SMC-ER-knockout (KO) littermates, and (3) arterial stiffening during natural aging by comparing young and aged, female and male SMC-ER-intact and SMC-ER-KO littermates. Mechanistic pathways were assessed using histological assessment of aortic fibrosis and elastin degradation, aortic MMP expression, and atomic force microscopy. Results: OVEX increased PWV and aortic medial fibrosis, with no impact on elastin integrity, in young female mice. Arterial stiffening and fibrosis were prevented in OVEX mice that were supplemented with estradiol. OVEX-induced arterial stiffening in SMC-ER-intact female mice was prevented in SMC-ER-KO littermates. In this model, OVEX was also associated with increased aortic medial fibrosis without changes in elastin integrity. Aging from 3 to 18 months significantly increased PWV in female and male SMC-ER-intact mice. Aging-induced stiffening was fully prevented in female and partially prevented in male SMC-ER-KO mice. SMC-ER contributes to aging-associated arterial stiffening by sex-specific mechanisms, including elastin degradation in females and phenotypic changes in SMC stiffness and probability to form cellular adhesions in males. Circulating estradiol was significantly decreased in serum from aged compared with young female mice. Conclusions: These findings support that SMC-ER contributes to arterial stiffening in female and male mice in situations where the vasculature is exposed to low levels of estradiol.

Rhododendron pachypodum flowers are traditionally consumed by ethnic minorities in Yunnan as seasonal edible flowers, yet their bioactive iridoid constituents and associated biological activities remain underexplored. This study characterized the iridoid constituents and evaluated in vivo bioactivities relevant to healthspan. Nine iridoids were isolated from the flowers, including seven previously undescribed analogues (1-7) and two known compounds (8-9). The structures of these compounds were determined based on 1D/2D NMR spectroscopic data and HRMS data, while absolute configurations were assigned by comparing experimental ECD spectra with TD-DFT-calculated spectra. The in vivo effects of compounds 5 and 8 were assessed in Caenorhabditis elegans, including lifespan, pharyngeal pumping, locomotion, and survival under oxidative and heat stress, as well as early brood size and body size. Both compounds significantly extended lifespan across multiple doses (up to 30.8% for compound 8 and 30.4% for compound 5), and the effects exceeded those of the positive control β-nicotinamide mononucleotide (NMN, 25.4%; all P < 0.001). They also improved pharyngeal pumping and locomotion and enhanced survival under oxidative stress (up to 41.1% for compound 8; P < 0.001). Compound 5 additionally increased heat-stress tolerance and stimulated early brood size, whereas compound 8 exerted stronger effects on body size. This work integrates rigorous phytochemical characterization with in vivo functional evaluation and supports further mechanistic and safety evaluations.

The reduction in number and decreased differentiation capacity of oligodendrocyte progenitor cells (OPCs) directly affect myelination in demyelinating diseases and aging, but the underlying mechanisms remain incompletely characterized. Here we observed a marked decline in the number of OPCs during aging, notably within the subpopulation highly expressing Acss2, which encodes acetyl-CoA synthetase 2 (ACSS2). Deletion of ACSS2 in the oligodendrocyte lineage resulted in a reduced OPC population, defective myelinogenesis during development, impaired myelin maintenance in adulthood and aging, and exacerbated age-related cognitive deficits. Mechanistically, ACSS2-mediated acetylation of H4K12 and H3K27 enhances the expression of Gria2, an AMPA receptor subunit critical for OPC proliferation. Furthermore, supplementation with the ACSS2 substrate acetate preserved the number of OPCs, promoted remyelination after injury and improved cognitive function in aged mice. Together, our findings highlight the essential role of ACSS2-mediated acetate utilization in maintaining the OPC population and promoting myelin production during development, demyelination and aging.

Fibrotic remodeling of tissues and tumors establishes immune-suppressive microenvironments that drive organ dysfunction and, in cancer, limit responses to immunotherapy. Cells exhibiting features of cellular senescence are conserved drivers of fibrotic remodeling and thus represent therapeutic targets, yet senescent states are heterogeneous and can exert both beneficial and pathogenic effects, complicating therapeutic intervention. Here, we show that P-selectin is selectively expressed by subsets of senescent-like cells in fibrotic tissues and fibrotic tumor microenvironments. Leveraging fucoidan-based nanoparticles that bind P-selectin, we develop senescence-modulating nanoparticles (SMNPs) to selectively target these disease-associated cell states. SMNPs exhibit potent antifibrotic and immunomodulatory activity while markedly improving therapeutic index. Mechanistically, we identify a pathogenic, immune-suppressive macrophage population as a principal functional target of SMNPs in vivo. In fibrotic tumors, niche remodeling restores immune infiltration and sensitizes tumors to immune checkpoint-based therapies. More broadly, SMNPs establish a generalizable nanotherapeutic strategy for selectively targeting pathogenic senescent cell subsets across fibrotic disease and cancer.

Chaperone-mediated autophagy (CMA) is a selective autophagy pathway that targets specific proteins containing a KFERQ-like motif for lysosomal degradation. It has been shown by us and others that CMA decreases during physiological aging in most tissues, and its impairment is associated with increased incidence of age-related pathologies, such as cardiovascular disease, neurodegenerative disorders or sarcopenia. However, its involvement in age-related macular degeneration (AMD), a prevalent progressive maculopathy that leads to bilateral central vision loss, had not been explored. In the early stages of AMD, the retinal pigment epithelium (RPE), a monolayer of cells that provides trophic support to photoreceptors, already presents major morphological and functional alterations but the cause of this cell type-specific vulnerability is unknown. In our latest work, we analyzed human donor RPE samples and found that CMA is selectively impaired in the RPE of AMD patients compared to healthy donors. These alterations lead to the accumulation of undegraded CMA substrates and untimely recycling of other proteins. Crucially, these findings are conserved in donor-derived iPSC-RPE models. We used this clinically relevant model to assess the consequences of dysfunctional CMA in AMD and found that it caused proteotoxicity, increased oxidative damage, and altered metabolism. Most importantly, using the new-generation CMA activator CA77.1, we restored proteostasis in AMD iPSC-RPE. Our findings shed light on the selective vulnerability of the RPE in AMD and provide evidence in support of CMA as a novel druggable target against AMD.

Oscillatory coupling between respiration, heart rate, and cortical function is fundamental to physiological regulation yet remains poorly characterized in humans. Diminished respiratory heart rate variability (RespHRV)- the rhythmic heart rate modulation accompanying respiration-has emerged as a transdiagnostic biomarker of mental and physical health, reduced in anxiety, depression, cardiovascular disease, and aging (Beauchaine & Thayer, 2015; Menuet & Gourine et al., 2025). However, the cortical substrates that coordinate rhythmic cardiovascular-respiratory coupling are not well understood. Our current findings highlight the involvement of the left orbitofrontal cortex (OFC) in oscillatory cardiorespiratory dynamics. In adults aged 50-70 (N = 55; mean age = 60.1 {+/-} 6.0 years; 29 female), across both a slow-paced breathing condition and a random-paced breathing condition, greater heart rate oscillatory power during 9-week breathing training sessions predicted OFC volume increases. OFC changes were most strongly linked with upper low-frequency range power during practice (0.09-0.13 Hz; p < 0.005, cluster-corrected) but were not tightly constrained by precise breathing frequency. These effects covaried with improved attentional and executive performance, including reduced pupil responses to distractors and enhanced working memory and associative memory scores. Our findings identify the orbitofrontal cortex as a key site of cortical plasticity linked to rhythmic cardiovascular-respiratory engagement. By delineating how oscillatory body-brain coupling supports cognitive control-related processes, including attentional filtering and memory updating, this work bridges mechanistic neuroscience and translational intervention science, suggesting a frequency-general pathway through which simple breathing practices may enhance neurovisceral integration and cognitive resilience in aging.

Escitalopram is one of the most widely prescribed selective serotonin reuptake inhibitors (SSRIs) for treating depression and anxiety disorders in adolescents and pregnant women. While some SSRIs have been reported to extend lifespan, the impact of escitalopram on the aging process remains unclear. Here, we demonstrated that escitalopram administration at juvenile, young, or old adult stages significantly shortens lifespan and impairs healthspan in Caenorhabditis elegans. This pro-aging phenotype was accompanied by increased lipofuscin accumulation and reduced stress resistance. Mechanistically, escitalopram induced mitochondrial dysfunction, characterized by elevated ROS production and diminished membrane potential. Genetic analyses established that these detrimental effects are mediated by the insulin/IGF-1 signaling (IIS) pathway, leading to the subsequent suppression of autophagy. Mutant worms in IIS (daf-2, daf-16, and sod-3) or autophagy-related genes (unc-51, atg-3, and atg-13) abolished the lifespan reduction. Consistently, in human BJ fibroblasts, escitalopram triggered premature cellular senescence, marked by increased SA-β-gal activity and upregulated P53/P21 expression, and impaired cell proliferation, which was mediated by impairment in fusion between autophagosome and lysosome. Collectively, our cross-species study reveals that escitalopram, contrary to some other SSRIs, accelerates aging through impairment of the evolutionarily conserved IIS/autophagy axis, suggesting its potential pro-aging toxicity with long-term use.

Background: The relationship between hip osteoarthritis (hip OA) and Alzheimer's disease (AD) presents a critical paradox within the emerging "bone-brain axis": widespread phenotypic comorbidity sharply contradicts evolutionary theories of biological antagonism. This study integrates longitudinal and multi-omic analyses to determine whether this clinical overlap masks an underlying genetic neuroprotection. Methods: We analyzed longitudinal phenotypic data from 261,767 UK Biobank participants using Cox proportional hazards and Fine-Gray competing risk models. To investigate the shared genetic architecture, we applied MiXeR modeling to genome-wide association study summary statistics. Causal relationships were evaluated using global and cell-type-stratified Mendelian randomization across eight distinct brain cell types. Shared genomic loci were identified via conjunctional/conditional false discovery rate and fine-mapping. Single-nucleus RNA-sequencing (snRNA-seq) data from the ROSMAP cohort validated the disease-associated transcriptional dynamics of prioritized target genes. Results: Observational survival analyses initially suggested an increased AD risk in patients with hip OA; however, this association was fully attenuated after adjusting for a history of depression, revealing a "phenotypic illusion" driven by the pain-depression axis. Conversely, cell-type-stratified genomic analyses uncovered a profound biological antagonism: genetic liability for hip OA confers robust neuroprotection specifically localized to the neurovascular unit (NVU), primarily driven by astrocytes and pericytes. Mechanistically, this NVU fortification is orchestrated by the MAPT locus and PI3K/AKT signaling, with snRNA-seq confirming the active transcriptional remodeling of these core effectors in the AD brain. Conclusion: We demonstrate that genetic liability to hip OA confers robust neurovascular protection against AD, a profound biological antagonism that is clinically masked by depression-mediated phenotypic comorbidity. These findings propose an evolutionary trade-off model within the bone-brain axis, underscoring the urgency of active hip OA pain management to mitigate depressive symptoms and decelerate cognitive aging, while cautioning against the uncritical repurposing of anabolic inhibitors across these interconnected systems.

Prolonged mechanical unloading leads to significant musculoskeletal degradation, posing serious health risks for bedridden patients and astronauts. By contrast, hibernating animals such as Spermophilus dauricus have evolved natural resistance to muscle atrophy and bone loss during extended periods of inactivity. These animals deploy coordinated protective mechanisms, including calpain inhibition, Wingless-related integration site (Wnt)/β-catenin signalling modulation, mitochondrial dynamics regulation, and enhanced antioxidant defences, to maintain musculoskeletal homeostasis. In this study, we systematically compare the molecular adaptations to disuse in both hibernation and unloading models. Our findings reveal both overlapping and distinct regulatory strategies that govern skeletal muscle and bone preservation under mechanical unloading. These insights offer a unique perspective for developing mechanism-based countermeasures against spaceflight-induced musculoskeletal deterioration, and may further inform strategies to combat age-related or disease-associated muscle and bone loss in terrestrial settings. This work underscores the translational potential of hibernation biology for advancing space medicine and human health.

Early detection of retinal molecular biomarkers is crucial for addressing the unmet clinical need to prevent irreversible neural tissue damage in ophthalmic and neurodegenerative diseases. Among emerging molecular sensing techniques, non-resonant Raman spectroscopy stands out as a naturally label-free and noninvasive method, offering rich biochemical information. However, in vivo detection of non-resonant Raman spectra from retinal tissue has proven to be challenging so far. Previous studies have reported conflicting results, likely due to overwhelming pigment autofluorescence. In this study, we identified the optic nerve head as the optimal retinal location for acquiring non-resonant Raman spectra in the molecular fingerprint region. Through longitudinal intra-subject measurements, we revealed dynamic changes in the molecular composition. Furthermore, a comparative study across age groups enabled the identification of molecular alterations associated with aging. These findings establish a critical foundation for utilizing non-resonant Raman spectroscopy as an early diagnostic tool for the detection of molecular biomarkers associated with ophthalmic and neurodegenerative diseases.

Aging is a complex biological process that heightens susceptibility to age-related diseases, often driven by declining mitochondrial function. Mitophagy, the selective removal of damaged mitochondria, is a key quality-control mechanism essential for maintaining cellular health, and its decline has been closely linked to aging. However, the specific role of mitophagy in cellular senescence, a hallmark of aging, remains insufficiently understood, largely due to the lack of methods to manipulate mitophagy. In this study, we employed UMI-77, a new potent mitophagy activator, to evaluate its effects on senescence in mouse mesenchymal stem cells (MSCs). Our results show that UMI-77 preserves mitochondrial integrity and effectively delays cellular senescence through mitophagy. Mechanistically, UMI-77 markedly suppressed the senescence-associated secretory phenotype (SASP). Together, our findings reveal a new anti-aging therapeutic application for UMI-77 by targeting senescence-associated chronic inflammation through mitophagy induction and SASP reduction.

This Review discusses the current state of knowledge on the contribution of the gut microbiome as a potential key actor in defining how we age. The gut microbiome is a complex ecosystem that establishes lifelong dynamic interactions with the host at multiple levels (several gut-organ axes), differently influencing ageing patterns and age-related disease onset and progression across populations. Accordingly, the definition of a 'normative' gut microbiome remains elusive, depending largely on the interaction with the external environment. In this complex scenario, the causal role of the gut microbiome in defining the ageing trajectory and its precise contribution to various organ-specific age-related diseases is still uncertain in clinical terms and could be context specific. Multiparametric and uniqueness indexes within a given population have shown a certain capacity for predicting disability and mortality. However, the gut microbiome is shaped over time by exposure to different intrinsic and environmental factors, resulting in a high degree of inter-individual variability, a key phenomenon that should be considered to develop novel personalized strategies to counteract age-related disease and frailty.

Deep neural networks (DNNs) trained on magnetic resonance images can estimate global brain age (GBA), which reflects women's neurological disease risk. GBA gap (GBAG), the difference between GBA and chronological age (CA), quantifies excessive global aging; local BAG (LBAG) has not been examined despite allowing voxelwise resolution. Using a novel DNN architecture, we estimate LBAG for 12,284 UK Biobank females with chronological ages (CAs) ranging between 46 and 82 years (y) and quantify how it relates to cognition and women's health variables (CA at menopause, reproductive span, menopausal hormone therapy (HT), contraceptive use (CU), number of births). Women with longer reproductive spans (-0.042/y ≤ β ≤ -0.037/y, p < 0.001) had older CAs at menopause onset (-0.052/y ≤ β ≤ -0.046/y, p < 0.001), more births (-0.230 ≤ β ≤ -0.190 per birth, p < 0.001) and younger brains (more negative LBAGs, younger GBAs); a 1-unit increase in each of these variables reflects an LBAG change of β y. Left temporal lobe effects of CA at menopause onset are strongest (-0.0517 ≤ β ≤ -0.0510, p < 0.001). Cognitive scores are related to LBAGs negatively and most strongly in subcortical and right-hemisphere cortex (-0.021 ≤ β ≤ -0.017 per score unit, p < 0.01). In postmenopausal women, delayed regional brain aging is predicted by longer endogenous hormone exposure indexed by later menopause onset, longer reproductive span, and more births. This research highlights the complex role of women's health factors upon brain aging and related cognitive trajectories.

Given the growing global interest in Healthy Longevity Medicine (HLM), the field lacks understanding about public knowledge and interest, which are crucial for any public health intervention relying on HLM. This study presents findings from the Healthy Longevity (HELO) survey conducted in Singapore, assessing public knowledge regarding lifespan (number of years a person is alive), healthspan (number of years a person spends in good health), and interest in HLM. This nationwide cross-sectional survey, conducted between June and August 2024, involved 3034 participants. Main domains including questions on demographics, living arrangements, medical information, health behaviours, income and financial status were tested for associations with knowledge about lifespan and healthspan, and interest in HLM clinics using binary logistic regression. While 82.3% of 46 years old [IQR, 34-59] participants correctly defined lifespan, 41.3% accurately defined healthspan and 55.5% expressed interest in HLM clinics. Younger age, male gender, Chinese ethnicity, higher education and income, full-time employment, lower body mass index, supplement use, moderate (vs. no) alcohol consumption, high exercise frequency and enrolment in (self-paid) annual health screenings were associated with better knowledge and stronger interest in HLM clinics. These findings highlight the need for targeted education to enhance understanding of healthspan and implement evidence-based preventive health programmes, supporting the clinical translation of geroscience into Precision Geromedicine through HLM clinics.

Epigenetic clocks estimate biological age from DNA methylation patterns at CpG sites, providing robust predictions of mortality and morbidity risk. "Blue zones"-regions of exceptional longevity-offer a unique opportunity to investigate how biological aging diverges from chronological age. However, standard clocks are typically trained on large, heterogeneous datasets, reflecting average population trends rather than region-specific dynamics. Using data from the Costa Rican Longevity and Healthy Aging Study (CRELES), we profiled DNA methylation from residents of the Nicoya blue zone (n = 206) and a comparison population in other parts of Costa Rica (n = 875). We propose training a SuperLearner, an ensemble machine learning approach, on the non-Nicoyan Costa Ricans to optimize predictive performance across existing clocks and flexible machine learners. Theoretically justified by its Oracle property, SuperLearner performs asymptotically as well as the best candidate predictor in the ensemble, resulting in a weighted combination of algorithms used to predict age. We then used this trained model to construct a calibrated hypothesis test comparing residual age distributions between the blue zone region and the comparison population. Comparing our approach to the five top-performing epigenetic clocks (ranked by MSE) in the Costa Rican cohort, only SuperLearner suggested age deceleration (an average of ~ 1 year) in the non-Nicoyan reference group. Before calibration, SuperLearner showed the strongest evidence for slowed biological aging among blue zone Nicoyans, estimating a three-year reduction (-3.05, 95% CI: [-3.64,-2.46]) in epigenetic age. Calibrating with non-Nicoyan Costa Ricans improved consistency between estimates in all clocks, decreasing the estimated aging advantage in Nicoyans to about two years (-1.96, 95% CI: [-2.56,-1.37]). This approach provides a robust framework for estimating longevity in distinct regions when a relevant comparison population is available.

Biological age provides a more direct reflection of physiological status than chronological age, serving as a vital measure to evaluate health risks and aging interventions. While steroid metabolomics offers rich information for exploring aging mechanisms, the complex and nonlinear interactions within metabolic networks remain challenging in modeling. Here, we propose and describe METRON as a deep learning framework to predict biological ages from steroid metabolomics. Specifically, a Metabolite Interaction Perception Module (MIPM) is proposed to capture the interactions. Subsequently, a Group-Rational Kolmogorov-Arnold Network is also integrated to capture intricate dependencies and enhance the representation capability. We demonstrate that METRON achieves promising performance as compared to other machine learning and deep learning methods. Beyond performance, METRON offers interpretability by recovering the established markers such as Dehydroepiandrosterone (DHEA) and identifying 17-hydroxyprogesterone (17-OH-P4) as the key signature linked to hypothalamic-pituitary-adrenal axis dynamics. These results support the capacity of METRON not only to estimate biological age but also to uncover underappreciated metabolic drivers behind aging.

Aging is accompanied by molecular changes across multiple biological systems that contribute to functional decline and increased disease risk, but the underlying mechanisms and inter-individual variation remain poorly understood. We investigated whether multi-omics integration can reveal coordinated molecular processes associated with accelerated PhenoAge, a clinical biomarker-based estimate of biological aging. Using UK Biobank data from ~20,000 participants, we integrated plasma proteomics and metabolomics with PhenoAge. Individuals were stratified by extreme PhenoAge acceleration (PhenoAgeAccel) to enhance biological contrast. We applied a supervised multi-omics integration framework (DIABLO) to identify correlated molecular features that distinguish accelerated from slower PhenoAge. Proteomics alone provided strong discrimination between aging groups, whereas metabolomics showed weaker performance. Integrating both modalities did not substantially improve classification accuracy but revealed four multi-omics modules: immune-inflammatory, lipid-vascular, nutrient-metabolic, and HDL-apolipoprotein pathways. The dominant signature reflected immune and inflammatory activation with metabolic support, consistent with established aging processes, while additional components highlighted lipid transport, vascular signaling, and nutrient regulation. Nearly half of DIABLO-selected proteins overlapped curated aging and senescence databases, supporting relevance to aging. Together, these results show that multi-omics integration enables the identification of coordinated proteomic-metabolomic axes associated with accelerated aging processes, enhancing biological interpretability beyond single-omics analyses.

Cellular senescence has been implicated in the pathophysiology of radiotherapy-related bone loss. Based on our previous work, clearance of senescent cells using genetic and pharmacological tools alleviates the anomalies associated with radiation-associated bone deterioration. The pro-inflammatory senescence associated secretome referred to as senescence associated secretory phenotype (SASP), is a hallmark of cellular senescence. The modulation of SASP by senomorphic drugs, potentially can suppress the pro-inflammatory secretome of senescent cells, irrespective of the underlying senescence mechanism. In this study we tested a senomorphic drug, ruxolitinib, a Janus kinase inhibitor (JAKi), during acute and chronic radiotherapy related effects on the bone. Our clinical data indicate an early increase in several pro-inflammatory SASP proteins following radiotherapy of spinal metastasis in prostate cancer patients. Longitudinal assessment of SASP-related genes confirmed this acute elevation in several SASP markers in systemic circulation following irradiation of mouse femurs. In a proof-of-concept study, following two preclinical radiotherapy regimens of cumulative doses of 30Gy (5 x 6Gy) and 60Gy (5 x 12Gy), a senomorphic approach of JAKi treatment was more effective in alleviating radiation-related bone loss compared to the senolytic cocktail of D+Q. Early and intermittent suppression of SASP using JAK inhibitors alleviated chronic bone deterioration, diminished telomere dysfunction, lowered senescence and SASP marker expression, reduced bone marrow adiposity, and mitigated radiation related lymphatic impairment. Overall, our study shows that early targeting of SASP proteins could be a potential therapeutic to prevent radiotherapy-related chronic bone loss and risk of fractures.

Given that low-grade inflammation is implicated in the pathophysiology of age-related frailty, we tested the hypothesis that individual blood biomarkers are associated with the risk of developing frailty in later life.

Environmental pollutants have long been a major threat to human health, and long-term or high-concentration exposure can trigger acute or chronic diseases. These hazards often mediate tissue dysfunction and drive disease progression by inducing cell senescence and cell death (including apoptosis, pyroptosis, and ferroptosis). In recent years, the cGAS-STING signaling axis, as the core pathway for sensing cytosolic DNA, has received extensive attention and research. Its activation can promote the expression of type I interferons and inflammatory factors, playing an important role in immune defense such as anti-infection and anti-tumor. Notably, senescence-associated DNA leakage and mitochondrial dysfunction provide persistent ligands for cGAS, thereby establishing a self-sustaining cGAS-STING-driven inflammatory loop that exacerbates aging-related pathologies. However, research on the link between pollutants and the cGAS-STING pathway is still limited. In this review, we describe in detail the mechanism of action of the cGAS-STING pathway, focusing on how various pollutants (including heavy metals, air pollutants, and industrial chemicals) interfere with the cGAS-STING pathway, leading to cell damage and disease occurrence. Finally, we also list some drugs that can alleviate the impact of pollutants on the cGAS-STING signaling axis. Overall, this review aims to provide a theoretical basis for a deeper understanding of pollutant toxicity mechanisms and for developing intervention strategies targeting the cGAS-STING pathway.

The majority of bacteria in the vertebrate gut harbor integrated bacterial viruses ("bacteriophages" or "phages"; integrated phage are termed "prophages"). To probe phage replication strategies in the mammalian gut microbiome, we investigated phage activity in a large longitudinal study of diversity outbred mice (913 animals) undergoing extreme dietary restriction with detailed phenotypic characterization across lifespan.

Losses of functional reserve across multiple physiological systems have been identified in frail patients, yet the exact aetiology of frailty remains unclear. Although strongly associated with chronological age, frailty often develops at a younger age in patients with organ failure. Frailty is prevalent in patients with kidney failure; however, individuals experience improvements in physical frailty measures following kidney transplantation. This makes younger patients with kidney failure a unique population for studying both the accelerated onset of frailty and its reversal. This research project aims to test the hypothesis that frailty secondary to organ failure and age-related frailty are associated with similar molecular and physiological measures.

Although cellular senescence in pulmonary epithelial cells is a recognized driver of chronic lung diseases, the role of dietary factors in initiating this process remains poorly defined. Here, we identify monosodium glutamate (MSG), the primary source of umami taste, as a trigger of a novel dietary-lung axis. We demonstrate that chronic intake of high amounts of MSG elevates pulmonary L-glutamic acid (Glu) levels, which activate an NMDAR-miMOMP signaling cascade in pulmonary epithelial cells, leading to cellular senescence and lung injury. This mechanism is consistent across multiple high-Glu diets, including high-fat and high-protein regimens. Furthermore, we demonstrate that high-Glu diets exacerbate pulmonary fibrosis progression by increasing the senescence burden. Our findings suggest that dietary Glu is a modifiable risk factor for chronic lung diseases and reveal that the NMDAR-miMOMP-senescence axis is a potential therapeutic target for metabolic respiratory syndromes.

Vascular senescence is a key contributor to ageing-related diseases, including atherosclerosis. Initial intervention is based on aggressive management of traditional risk factors, yet microbial metabolites remain underestimated as modifiable factors. We recently identified phenylacetate (PAA), a gut microbiota-linked metabolite, as a potent accelerator of endothelial senescence, raising the question of its causal role in atherosclerosis. Here, we show that PAA promotes vascular niche senescence and perivascular adipose tissue (PVAT) dysfunction, associated with atherosclerosis in humans and mice. Furthermore, PAA administration to atherosclerosis-prone mice was sufficient to drive atherosclerosis without altering lipid profile. Mechanistically, we found that PAA induces senescence-messaging secretome, containing IL6, from endothelial cells, which stimulates Notch1 and disrupts insulin signaling in adipocytes. Blocking the PAA-IL6-Notch1 axis as well as senolytics rescued adipocyte senescence and dysfunction. Identification of the strong link between PAA and atherosclerosis opens new avenues for microbiome-targeted preventive and therapeutic strategies in ageing.

Ischemic stroke doubles the risk of dementia. Stroke severity and location affect cognition early, but late dementia risk is not related to infarct characteristics, nor is it reduced by preventing additional strokes, and its mechanism is unknown. We identified a plasma proteomic signature of chronic stroke that was consistent with blood-brain barrier (BBB) dysfunction, including a 58% decrease in plasma levels of platelet-derived growth factor B and downregulation of its pathway compared to healthy controls. During 2 years of follow-up, the stroke-specific proteome was accentuated in stroke survivors who subsequently declined in the processing speed/executive function cognitive domain. To test BBB function, we performed dynamic contrast-enhanced MRI 6-9 months after stroke in an additional cohort and found 1.7-fold higher whole brain BBB leakage compared to controls. Finally, we compared autopsy tissue from people with infarcts and dementia at death to those with infarcts and no dementia. Those who died with dementia had dramatic loss of vascular mural cell coverage compared to those without dementia (median 0.7% vs. 27%). Thus, our proteomic, functional, and structural data implicate chronic BBB dysfunction in cognitive decline late after stroke, revealing potential proteomic and imaging biomarkers and, importantly, a novel target for intervention.

Lifestyle and environmental factors such as diet, physical activity, residential greenspace exposure, alcohol consumption, and sleep are increasingly promoted as modifiable targets for maintaining cognitive health and mitigating age-related decline. Yet, it remains unclear how well they predict cognitive functioning and, importantly, to what extent their associations with cognition are reflected in brain and bodily health. Here, we applied machine learning to multimodal data from over 10,000 UK Biobank participants to evaluate the predictive value of twelve lifestyle and environment domains, spanning physical activity, diet, smoking and alcohol consumption, sleep, sexual behavior, electronic device use, and environmental exposures, for cognitive functioning - both individually and in combination - and performed commonality analysis to quantify the extent to which these associations are captured by body and brain markers. A model integrating all lifestyle and environment domains explained 23% of the variance in cognition at an out-of-sample r=0.48, comparable to models based on body and brain measures. Physical activity, together with diet, alcohol consumption, sun exposure, and local environmental characteristics, emerged as the strongest predictors of cognitive functioning. A composite brain marker integrating three neuroimaging modalities accounted for 57.7% of the lifestyle-cognition association, while a composite body marker spanning nine physiological systems accounted for 47.8%. Jointly, lifestyle, environment, body, and brain captured nearly all age-related variation in cognition (92.6%). Collectively, these results indicate that integrating lifestyle and environmental factors enables robust prediction of cognitive functioning and that a substantial portion of this association is reflected in brain and body health.

Aging poses a growing global health burden, creating an urgent need for effective interventions. This study reveals that fenofibrate, a clinically approved drug for hyperlipidemia, exerts significant anti-aging effects by targeting fundamental aging processes. We demonstrated that fenofibrate treatment delays systemic aging in D galactose-induced aging mice, 18-month-old mice and SAMP8 mice and reverses cellular senescence. Mechanistically, fenofibrate ameliorates age-related lipid accumulation, as evidenced by lipidomic profiling and histological analyses in both cellular and animal models. Notably, we identify carnitine palmitoyl transferase 1 C (CPT1C) as a crucial mediator of fenofibrate's ability to restore mitochondrial function in senescent cells, as validated by comprehensive metabolic analyses. Fenofibrate is a specific peroxisome proliferator activated receptor α (PPARα) agonist. These effects are mediated through PPARα activation, upregulating downstream metabolic regulators CPT1C. Fenofibrate cannot reverse aging in Pparα

BACKGROUND: Abdominal aortic aneurysm (AAA) is a life-threatening condition with >80% mortality upon rupture and no effective pharmacotherapy available. Despite epidemiological evidence linking metformin use to reduced AAA progression, its mechanism remains elusive. Notably, peroxisome proliferator-activated receptor {gamma} coactivator 1 (PGC-1, encoded by Ppargc1a) is downregulated in human AAA, yet its functional role in metformin's protection is unknown. METHODS: We employed porcine pancreatic elastase (PPE)-induced murine AAA, VSMC-specific Ppargc1a knockout (Ppargc1aVSMC-KO), primary VSMC senescence models, and pharmacological inhibition (Compound C for AMPK; Ex-527 for SIRT1) to define the AMPK-SIRT1-PGC-1 axis. RESULTS: Metformin significantly inhibited AAA expansion, suppressed VSMC senescence (p53/p21{downarrow}, SA-{beta}-gal{downarrow}), and preserved contractile phenotype (SMTN{uparrow}, IL- 6/TNF-{downarrow}). Crucially, all benefits were abrogated in Ppargc1aVSMC-KO mice, which exhibited accelerated aneurysm growth, mitochondrial fragmentation, ATP depletion, and ROS accumulation. Mechanistically, metformin activated AMPK/SIRT1 to upregulate PGC-1; AMPK or SIRT1 inhibition blocked this cascade and reversed protection. CONCLUSION: Metformin restrains AAA by restoring VSMC mitochondrial homeostasis via the AMPK/SIRT1[->]PGC-1 axis, positioning PGC-1 as a nonredundant, cell-autonomous guardian against vascular degeneration. These findings provide a mechanistic foundation for repurposing metformin and developing PGC-1- targeted therapies in AAA.

Biomarkers of aging, particularly DNA methylation-based clocks, have shown promise as tools to assess whether interventions may impact the rate of biological aging. Among possible interventions physical exercise has shown protective effects against many age-associated diseases, while time-restricted feeding (TRF), has shown metabolic benefits in preclinical models. The combined effect of exercise and TRF on aging biomarkers remains largely unexplored. In this 52-week four-armed, randomized, controlled trial (clinicaltrials.gov: NCT07207044) 240 healthy adults aged 65 and over will be allocated to four groups: combined cardio and strength training (EXE), TRF, combined EXE and TRF, or control. Participants will undergo assessments at baseline, 3, 6, and 12 months, with follow-ups at 2, 5, and 10 years. The primary outcome measure is DNA-methylation age with secondary measures including RNA-sequencing, metabolomics, inflammatory marker, microbiome analysis, cognitive and physical measures. By deeply phenotyping participants the Fasting And eXercise (FAXAge ) study will provide novel insights into whether TRF, EXE, or a combination can slow or reverse biological aging in older adults.

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in ageing populations, with oxidative stress recognised as a key pathogenic driver. The dietary antioxidant and cytoprotectant, L-ergothioneine (ET), is avidly accumulated in many tissues, especially the eye. However its relationship to AMD has not been investigated. Here, we examined ET's distribution in ocular tissue and assessed circulating and intraocular ET levels in patients with neovascular AMD. Compared with ocularly-normal age-matched individuals, AMD patients exhibited significantly lower serum ET; elevated levels of ET metabolites, hercynine and ETSO, which may be generated by oxidative stress; and elevated levels of serum allantoin, a product of oxidative damage to urate in humans. Levels of ET in aqueous humour in AMD patients were marginally lower than cataractous patients who are already known to have significantly lower ET levels than healthy eyes. High ET levels were seen in human ocular tissues concentrating in regions vulnerable to oxidative injury, including the lens, retina, retinal pigment epithelium, and choroid, supporting a physiological protective role of ET in the eye. These findings identify the strong association between low ET levels and AMD, warranting further studies to determine whether ET supplementation can modify AMD risk or progression.

Bone marrow (BM) mesenchymal stem cells (BM-MSCs) have a crucial role in BM homeostasis and regenerative therapy. While lipids are known to be fundamental components of metabolism, their precise role in modulating the function and behavior of BM-MSCs remains unclear. In this review, we present a comprehensive update on the biology of BM-MSCs in response to fatty acids and cholesterol, which are the major health-related lipids. We discuss the importance of BM as a receptor and producer of lipids and summarize the mechanistic insights by which cholesterol and fatty acids, including endocannabinoids and short-chain fatty acids, regulate BM-MSC stemness, rejuvenation, and commitment. Understanding the complex and interdependent role of lipids on BM-MSCs is critical for proper BM and bone homeostasis. Future research should focus on the development of metabolic strategies to optimize health of the BM and its cells and to refine treatments for BM-related diseases or tissue regeneration.

Erzhi Pills (EZP), a traditional Chinese herbal formula, has demonstrated potential aging-modulating properties, while its mechanisms in modulating immunosenescence remain incompletely understood. Two complementary aging murine models were employed to investigate the anti-immunosenescence efficacy of EZP, providing experimental validation for its translational application in delaying age-related immune decline. Morphological and physiological parameters were monitored and thymic/splenic organ coefficients were calculated. Histopathological evaluation of thymic involution was performed via hematoxylin-eosin (H&E) staining. Flow cytometry quantified splenic T cell subsets (naïve/memory CD4

Aging is characterized by progressive physiological and psychological changes, leading to decreased cellular metabolism and increased vulnerability to age-related diseases.

The global rise in intestinal dysfunction has been linked to modifiable risk factors including high-fat diet (HFD)-induced obesity/diabetes, microplastics (MPs) and aging, yet their combined effects remain unclear. This study examined the combined effects of chronic low dose polystyrene MPs (∼25 µg/(kg·day)) with HFD or aging on intestinal barrier function in C57BL/6 J mice over 14 weeks. Juvenile mice receiving either normal chow (NCD) or HFD, along with aged NCD-fed mice, were subjected to MPs exposure. Results demonstrated that MPs exposure or HFD feeding (and aging) significantly exacerbated the pathological changes developed in colon tissues of mice relative to those of control mice, including gut permeability, oxidative stress, pro-inflammatory response and apoptosis. Moreover, combination of MPs exposure with HFD feeding (and aging) further potentiated the harmful effects on colon dysfunctions, clearly showing a synergistic deterioration effect ('double hit'). More importantly, we found that the recovery of colon damages resulting from MPs exposure and HFD feeding was disrupted after their withdrawal, leading to the worse effects on gut microbiota dysbiosis and intestinal function. Furthermore, oral administration of Akkermansia muciniphila prevented intestinal barrier dysfunction and decreased intestinal permeability from MPs exposure and HFD feeding co-exposure. Our findings in this study emphasized the important role of avoiding MPs exposure in the prevention and treatment of intestinal-related dysfunctions, and provided potential therapeutic approaches. The oral administration of gut microbiota, such as Akkermansia muciniphila, contributed to restoration of intestinal barrier function, uncovering a new landscape for treating intestinal disabilities caused by MPs exposure.

Cognitive aging reflects underlying biological aging processes and is a key driver of late-life functional outcomes. Emerging evidence indicates that cohabitation with companion animals may influence multiple systemic pathways involved in cognitive aging, yet this potentially modifiable lifestyle factor remains underrecognized. The present narrative review synthesizes current evidence on how companion animals may influence cognitive aging through multilevel pathways, including both direct biological mechanisms and proximal psychosocial mediators. The reviewed literature suggests that companion animal ownership may counteract cognitive decline through several primary biological pathways, including stress regulation and neuroendocrine buffering, cerebrovascular and metabolic health, neuroplasticity and neuroimmune modulation, and neurovascular aging and vascular cognitive impairment processes. In parallel, companion animals may exert their effects through psychosocial pathways that ultimately operate via biological systems and indirectly affect cognitive aging through intrapersonal emotion regulation, interpersonal social facilitation, behavioral activation, and cognitive stimulation. We further identify possible key moderating factors shaping these associations, including gender, attachment strength, type and number of animals, cultural context, and the presence versus absence of a companion animal. Finally, we provide a concise overview of methodological approaches for assessing cognitive aging within the context of companion animal research. Overall, this perspective highlights possible cognitive benefits that can be associated with companion animal ownership which may arise from a dynamic interplay of biological, psychological, and social processes differentially modulated by individual, relational, and contextual factors.