Longevity Papers

Proteomics represents a powerful but underutilized approach for characterizing eye aging. Here, leveraging data from three large-scale, cross-national cohorts of over 55,000 transethnic participants, we demonstrate the ability of high-throughput proteomics combined with deep learning (DL) phenotyping to track eye aging and disease in both discovery and external validation settings. Proteomic aging driven by machine learning modeling closely aligns with signals of eye aging and DL aging phenotypes. We identifiy and validate premature proteomic aging in individuals with major age-related eye diseases (AREDs), including cataract, diabetic retinopathy, age-related macular degeneration, and glaucoma, and propose evidence supporting proteomic aging acceleration as a robust biomarker for predicting these conditions beyond chronological age, with adaptability across sexes and ethnicities. We also develop a streamlined, cost-effective proteomic aging clock that preserves predictive performance while reducing assay complexity. By integrating advanced tomographic and angiographic imaging, we derive structural and functional biomarkers through DL-driven pipelines and link accelerated proteomic aging to both neuroretinal degeneration and microvascular rarefaction in the Guangzhou Diabetic Eye Study (GDES) and the High-definition Oculo-Phenomic Evaluation (HOPE) study, highlighting coupled neural-vascular decline in eye aging. Our findings position proteomic aging combined with AI as a scalable tool for tracking eye health and disease, and provides new insights into shared aging pathways underlying multiple ocular pathologies.

Iron is a double-edged sword in aging, and age-related iron accumulation acts as a critical amplifier, rather than a sole driver, of ageing; disrupted iron homeostasis with progressive iron accumulation drives oxidative stress, mitochondrial damage and inflammaging. Ferroptosis and cellular senescence, two critical aging-related processes, share upstream drivers like oxidative stress and lipid peroxidation. This study proposed the novel ferro-aging paradigm, a cascade pathway where age-related iron overload initiates iron-catalyzed reactive oxygen species production and lipid peroxidation, ultimately inducing cellular senescence and ferroptosis to exacerbate, rather than independently cause, tissue dysfunction and age-related diseases. Iron accumulation in senescent cells stems from dysregulated iron uptake, storage, efflux, impaired ferritinophagy, and critical mitochondrial dysfunction. Senescent cells acquire ferroptosis resistance, leading to persistent tissue accumulation and chronic inflammation. Ferroptosis and senescence interact dynamically and form a positive feedback loop, with lipid peroxidation as the core executor. Ferro-aging participates in multiple age-related diseases of the nervous, cardiovascular, metabolic and skeletal systems. Targeting iron homeostasis, lipid peroxidation, senescent cells, and mitochondrial function provides promising anti-aging interventions. This review clarifies the connotation and mechanism of ferro-aging, and reveals its potential as a unified target for delaying aging and treating age-related diseases.

The ageing population and the increasing prevalence of age-related diseases underscore the urgent need for targeted therapeutic strategies. Accumulating evidence indicates that quinolinic acid (QA), a neuroinflammatory neurotoxin, contributes to the pathogenesis of neurodegenerative disorders. In this study, using Caenorhabditis elegans as a model organism, we demonstrate that chronic QA exposure acts as a robust driver of accelerated aging, significantly reducing overall healthspan. This pro-aging effect is accompanied by the premature onset of decreased locomotor function, enhanced lipofuscin accumulation, and decreased thermotolerance. Beyond these systemic aging phenotypes, QA induced pronounced cognitive deficits, including impaired short- and long-term associative memory and structural damage to dopaminergic neurons. Using this QA-induced injury model, we investigated the therapeutic potential of the clinical compound dimethyl fumarate (DMF), a derivative of a tricarboxylic acid cycle intermediate, and revealed that DMF's protective effects are partially dependent on the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In summary, our results demonstrate the therapeutic efficacy of DMF as a highly effective geroprotector and neuroprotector against QA-induced toxicity and define the Nrf2 pathway as a crucial mediator of the cognitive benefits of DMF, thus establishing its therapeutic repurposing potential for age-related neurodegenerative diseases.

Diabetic retinopathy (DR) and retinal aging, though arising from distinct causes, share converging mechanisms-including oxidative stress, chronic inflammation, mitochondrial dysfunction, and AGE accumulation-that compromise retinal integrity. These overlaps suggest common gene expression patterns, and highlight the contribution of disease-associated or accelerated aging processes to diabetes-induced retinal injury. We systematically retrieved DR- and aging-related human genes from public genetic databases, identified their overlap, and focused on those involved in key metabolic pathways (AGEs, oxidative stress, lipid metabolism, and autophagy). Genes were then cross-validated across multiple databases and filtered by ocular expression to ensure relevance to retinal pathology. Our findings show that although DR and retinal aging arise from distinct etiologies, they converge on four principal metabolic pathways-oxidative stress, AGE accumulation, lipid dysregulation, and impaired autophagy-that collectively drive similar vascular, neuronal, and inflammatory injury within the retina. Shared genes with high ocular expression reinforce the biological relevance of these pathways, while multi-pathway hub genes appear to function as central regulators that integrate redox imbalance, metabolic disruption, and proteostatic failure. These results provide a unified molecular perspective of retinal degeneration and support the potential development of therapeutic approaches designed to simultaneously target age- and diabetes-associated retinal pathology. This review suggests that DR and retinal aging, although initiated by distinct triggers, converge on shared metabolic pathways-oxidative stress, AGE accumulation, lipid dysregulation, and autophagy impairment-mediated by genes expressed in ocular tissues. Within these intersecting pathways, shared hub genes emerge as central control nodes that may amplify molecular dysfunction and represent potential therapeutic entry points. By mapping these molecular intersections, this study may provide a unified mechanistic perspective of retinal degeneration and support the development of dual-purpose strategies aimed at preventing or mitigating both DR and aging-related retinal decline. These findings highlight potential translational opportunities for targeting shared metabolic networks; however, they should be interpreted as hypothesis-generating and require further experimental and clinical validation to establish causal relationships and therapeutic relevance.

With the advent of large-scale neuroimaging datasets, expansive lifespan studies are making novel discoveries about foundational principles of human brain development and aging. In one of the largest lifespan magnetoencephalography (MEG) studies of its kind (N = 388, age 6-84 years), we document age-related coupling between local rhythmic neural activity and cortical thickness using cutting-edge analyses of whole-brain structure-function coupling. This work establishes normative linear and non-linear age-related changes that fluctuate in spectrally specific patterns and that follow a hierarchical cortical gradient from sensory to association networks. Moreover, these results demonstrate that canonical spectral bands tend to display strong lifespan coupling to structure in sensorimotor networks and diminished, more variable coupling in association networks with age. This reinforces accounts of less phylogenetic conservation of association networks due to their relative evolutionary novelty, with sensorimotor networks being more strictly conserved. The addition of spectral signatures to this account also reveals that dominant, spectrally specific oscillations (i.e., delta, theta, alpha, beta, gamma) emanating from local neural assemblies follow a hierarchical structure. Taken together, this landmark study provides a dynamic view of how age-related reorganization of large-scale networks unfolds across the human lifespan through structure-function coupling in a spectrally specific and hierarchically organized manner.

Mitochondrial dysfunction, characterized by reduced mitophagy, excessive mitochondrial elongation, and elevated reactive oxygen species production, is a hallmark of cellular senescence. However, the molecular mechanisms linking impairment of redox balance to mitophagy suppression during senescence remain poorly understood. In this study, we identified TIA-1, an RNA-binding protein, as a positive regulator of FUNDC1 expression, a key receptor for ubiquitin-independent mitophagy. Sodium butyrate and ultraviolet-B irradiation triggered oxidative stress-associated senescence in HaCaT cells, leading to reduced TIA-1 expression, decreased FUNDC1 levels, impaired mitophagy flux, excessive mitochondrial elongation, and upregulation of senescence markers. Conversely, ectopic expression of TIA-1 restored FUNDC1 levels, enhanced mitophagy, improved mitochondrial function, and reduced senescence marker expression. Ribonucleoprotein immunoprecipitation assays confirmed that TIA-1 directly interacts with FUNDC1 mRNA, and subsequent analyses indicated that TIA-1 enhances FUNDC1 expression primarily through translational control. Together, these findings establish TIA-1 as a pivotal regulator of mitochondrial homeostasis during cellular stress, acting through FUNDC1 to sustain mitophagy and limit senescence. Targeting TIA-1 may offer new strategies to mitigate mitochondrial dysfunction and restore redox balance in aging and age-related diseases.

This study aims to investigate the mechanism by which extract of Dendrobium officinale leaves (EDL) extends the lifespan of Caenorhabditis elegans. Untargeted metabolomics and network pharmacology analyses revealed that EDL primarily contains active components such as fatty acids, flavonoids, and polyphenols, which are predicted to potentially modulate pathways including MAPK, AMPK, mTOR, and longevity-related signaling pathways. Experimental results showed that 2 mg/mL EDL significantly extended the mean lifespan of nematodes by 11.4%, enhanced pharyngeal pumping rate and muscular endurance, but reduced brood size. EDL treatment also significantly decreased lipid droplet accumulation, cell apoptosis, and lipofuscin levels. Transcriptomic analysis indicated that EDL regulated the expression of multiple genes related to energy metabolism, particularly activating longevity-regulating pathways and the AMPK signaling pathway. RT-qPCR results demonstrated that EDL significantly increased the mRNA level of sod-3 in C.elegans. In conclusion, EDL may upregulate the expression of the sod-3 gene via the DAF-16/SOD-3 axis, thereby extending lifespan in C. elegans, providing a scientific basis for the high-value utilization of Dendrobium officinale leaves.

In Indonesia, adults living in rural areas have a longer life expectancy than their urban counterparts. Beyond observed longevity, attention has focused on lifespan and healthspan expectations as predictors of health outcomes. This study examines expected lifespan and expected healthspan and their associated factors among rural and urban populations in Java, Indonesia. The cross-sectional Healthy Longevity (HELO) survey collected data from the general population using in-person interviews and an online platform. Multinomial logistic regression analyses identified sociodemographic characteristics, knowledge and perceptions, personality traits, health behaviours, social support, and health status associated with expected lifespan and expected healthspan. A total of 1,199 individuals (602 rural; 597 urban) completed the survey (63.5% of rural and 66.8% of urban were female). Median age was 49 years [34 - 64] in rural areas and 50 years [35 - 63] in urban areas. Among those aged 40 - 64 years, 68.7% of rural versus 63.9% of urban individuals expected to live to 80 - 99 years. Expected healthspan was shorter among urban individuals, with 42.5% versus 38.9% expecting healthspan to end at 60 - 79 years. Higher chronological age, perceiving same-age individuals as long-lived, and stronger expectancy and value of healthy longevity were associated with higher expected lifespan and healthspan in both areas. Balanced diet and weight monitoring showed similar association in both groups. Exercise, sleep, and doctor check-ups were associated only with rural individuals. Higher conscientiousness, neuroticism, and extraversion were associated with lower expectations in rural individuals, whereas higher agreeableness and conscientiousness showed similar associations in urban individuals.

Saccharides and responsive signaling pathways are important regulators of physiological and pathological processes. Saccharides can exert these functions via dedicated intracellular transporters and through binding to cellular sensors, such as saccharide-binding receptors. Glucose homeostasis and saccharide signaling are emerging as important regulators of neurodegeneration. Here, we utilized a Drosophila model of Huntington's disease to examine the role of Glut1 (homologous to multiple human glucose transporters) and saccharide-binding receptors. We find that Glut1 knockdown increases the amount of huntingtin-polyQ protein aggregates during aging, whereas Glut1 upregulation has converse effects. RNAi screening identifies several saccharide-binding receptors that either increase or decrease the levels of huntingtin-polyQ protein aggregates. In particular, pathogenic polyglutamine aggregates are reduced by knockdown of the lectin domain-containing G-protein coupled receptor Cirl (Calcium-independent receptor for α-latrotoxin), orthologous to human ADGRL1 and ADGRL2. These findings indicate that glucose transporters and saccharide-binding receptors regulate proteostasis and neurodegeneration during aging.

Lysine63 polyubiquitination is a prevalent post-translational modification in the central nervous system. Deficiency of CYLD, a lysine63-specific deubiquitinase, is linked to synaptic dysfunction and neurodegenerative disorders. However, our understanding of how CYLD contributes to the manifestation of neuronal deficits, particularly in the context of ageing, remains limited. Here, we report that CYLD-1 is essential for physiological lifespan in the nematode Caenorhabditis elegans. Neuronal CYLD-1 supports cholinergic neurotransmission and GABAergic synapse integrity, ensuring intact locomotory capacity, as well as learning and memory competence. Specifically, the deubiquitinase activity of CYLD-1 is necessary for upholding cholinergic neurotransmission and lifespan. We further show that CYLD-1 regulates autolysosomal and lysosomal network organisation in neurons and peripheral tissues in vivo. Our work unveils a crucial role of CYLD-1 in optimizing neural activity and behavioural outcomes, to improve organismal fitness and survival.

The gut microbiome undergoes dynamic, sex-dependent changes across the lifespan. However, comprehensive studies examining the combined effects of age and sex are limited. This study investigated both compositional and functional alterations in the gut microbiome of young (4 months, n = 14) and aged (20 months, n = 20) C57BL/6 J mice of both sexes using 16S rRNA gene (V3-V5) sequencing. Microbial community structure and predicted functional profiles were analyzed via QIIME2 and PICRUSt2, with pathway annotation based on MetaCyc. Compared to aged mice, young mice exhibited higher alpha diversity, with the highest increase observed in young females. This sex-specific difference was lost in aged mice. Aging was also associated with an increased Firmicutes-to-Bacteroidetes ratio, and distinct shifts in key taxa, including increased Lactobacillus and Roseburia and reduced Bacteroides and Lachnospiraceae. Functional prediction revealed substantial age-related metabolic shifts, especially in females showing alteration in 45 pathways including upregulation of branched-chain amino acid (BCAA) metabolism, uric acid metabolism, and lipopolysaccharide biosynthesis. To directly link alterations in microbial BCAA metabolism with host metabolic outcomes, fecal abundance of the bacterial BCAA aminotransferase gene (ilvE) was quantified and found to be significantly increased in aged mice. Concurrently, aged mice exhibited higher plasma levels of BCAA, insulin, and random glucose, indicating age-associated metabolic dysregulation. Fecal ilvE abundance associated positively with plasma BCAA levels, and negatively with blood glucose in aged mice, suggesting a link between microbial BCAA metabolism and host glucose homeostasis. Our findings demonstrate that gut microbiome composition and function are influenced by both age and sex. We also showed that these alterations in microbial BCAA metabolism are associated with host metabolic parameters during aging. Our findings underscore the importance of incorporating both age and sex as biological variables in microbiome research and may inform development of age- and sex-specific microbiome-targeted interventions.

Whether new neurons contribute to human cognition in old age remains debated. Recently in Cell Stem Cell, Tosoni et al.

Hyperuricemia is a common metabolic disease and an important risk factor for low testosterone levels in men. The functional homeostasis of stem Leydig cells (SLCs) is crucial for maintaining testosterone levels. However, the potential molecular mechanism of how high uric acid (UA) levels affect SLC function remains to be elucidated. Here, we reveal that at the single-cell RNA sequencing level, SLCs exhibit senescence under high UA conditions. Mechanistically, UA binds to CCDC90B, leading to its significant accumulation within cells. This exacerbates the influx of calcium ions into mitochondria, resulting in mitochondrial quality control (MQC) imbalance. In addition, at the level of organoids and transgenic mice, we observe SLC senescence is alleviated and considerable testosterone recovery after AAV8-CCDC90B treatment. In summary, these results indicate that SLC senescence under high UA is regulated in a MQC-dependent manner, with CCDC90B being a key regulatory target. Meanwhile, AAV-mediated gene therapy may offer a promising therapeutic approach for patients with low testosterone levels.

The decline of glomerular filtration is a hallmark of aging. Methylglyoxal (MG) is a uremic toxin known to induce aging-like changes; however, whether its mechanism of action is similar remains unclear. We compare the underlying mechanisms of MG and aging using Drosophila nephrocytes as a model. In addition to lower body weight, reduced locomotion, and shorter lifespans, MG caused filtration defects and induced cellular senescence in nephrocytes similar to the effects of aging, with a corresponding upregulation of the LXR/RXR signaling pathway. Mechanistically, we found that MG and aging both increased reactive oxygen species (ROS). Antioxidant treatments and inhibition of the LXR/RXR pathway both improved the filtration function. In addition, MG and aging both reduced the level of Jub, which is a protein essential for the integrity of the slit diaphragm structure. Overexpressing jub enhanced slit diaphragm structure and prevented MG-induced functional decline. Together, the findings reveal parallel features between MG and aging, and show that inhibiting LXR/RXR signaling, reducing ROS, or strengthening the slit diaphragm structure can preserve the filtration function of Drosophila nephrocytes.

Plant-based diets may influence age-related eye diseases (AREDs), but whether ocular benefits depend on diet quality remains unclear. We examined associations of a healthy plant-based diet index (PDI-H) and an unhealthy plant-based diet index (PDI-U) with age-related macular degeneration (AMD), cataract, glaucoma, diabetic retinopathy (DR), and retinal vein occlusion (RVO) using the UK Biobank prospective cohort and an independent Tianjin hospital-based cross-sectional sample. Cox regression, logistic regression, propensity score matching, restricted cubic splines, subgroup analyses, multi-omics profiling, and machine learning were applied. Higher PDI-H was associated with lower risks of AMD, cataract, glaucoma, and DR, whereas higher PDI-U was associated with increased risks of AMD, cataract, and DR. Associations with RVO were weak or absent. Findings from Tianjin were directionally consistent with UK Biobank results and should be interpreted as supportive cross-sectional evidence. Proteomic and metabolomic analyses linked plant-based diet quality to inflammation, lipid metabolism, glycaemic regulation, and hormonal signalling. Predictive models incorporating dietary indices showed good discrimination for AMD and cataract, with modest but consistent AUC improvements after adding PDI-H and PDI-U to traditional risk factors. These findings suggest that plant-based diet quality, rather than plant-based eating alone, may be a modifiable determinant of major AREDs.

Oxidative stress, reflecting the balance between pro-oxidant and antioxidant influences from diet and lifestyle, has been implicated in cognitive decline. Sleep duration is another modifiable lifestyle factor associated with cognitive health, but its joint relationship with oxidative balance remains insufficiently understood.

CD38, an NADase implicated in aging and metabolic stress, promotes cardiac dysfunction via NAD⁺ depletion. Whether circulating CD38 is associated with incident heart failure (HF), whether this association differs by sex, and how it relates to kidney-function context remain unclear.

Midlife in females typically involves a significant neuroendocrine transition that may have effects on brain connectivity that are relevant to both normal and pathological aging. One potential contributing factor to the individual differences in cognition and risk for pathological aging is the brain's response to decreased levels of estradiol. We assessed the relationship between estradiol level and task-modulated effective connectivity between brain regions during an episodic memory task in females during midlife. We utilized data from the Human Connectome Project - Aging 2.0 release. One hundred and fifty female participants between 40 and 55 years of age were included in our analysis of the relationship between estradiol and connectivity. Pre-, peri-, and postmenopausal participants were included to capture a range of estradiol levels present during midlife. We assessed connectivity during the fMRI FaceName task utilizing Conn Toolbox on a connection level as a pairwise comparison between regions. Five connections associated with estradiol were significant during the recall portion of the FaceName task at a p<.05 FDR corrected level after controlling for age. Significant connections among the superior frontal gyrus left and brain stem and the middle temporal gyrus anterior division right and superior temporal gyrus posterior division right were identified. Negative associations between these regions were also present. There was no significant relationship between estradiol and FaceName task performance. Our results indicated that task-modulated effective connectivity was related to estradiol level during midlife in females between brain regions known to be important for memory functioning during the recall portion of an episodic memory task. These findings may have long term implications for memory function in females during the aging process due to the low levels of estradiol present post-menopause.

Dietary strategies that limit protein glycation can help slow aging and prevent age‑related diseases by reducing the accumulation of advanced glycation end products (AGEs). This study evaluated the antioxidant, antiglycation, and prebiotic potential of postbiotics produced by lactic acid bacteria using Iris albicans extract and its major isoflavonoids as carbon sources. Antioxidant activity (DPPH, ABTS, FRAP), prebiotic potential (A

Sustained independence during aging reduces morbidity and mortality. Optimal physical activity (PA) is essential for independent living in older adults by preventing sarcopenia, the loss of muscle mass, strength and physical performance - the road to frailty. The aim of this narrative review is to establish a theoretical foundation for the development of PA programs in older adults. PA and exercise interventions are considered due to the established dose-response relationship with performance capacity, whereby the 'dose' refers to the combination of exercise frequency, intensity, time and type. Initially, improvements may be observed with minimal PA, but further improvements in functional capacity require increased exercise dose to reach optimal levels. In older adults, and even more so in frail individuals, increasing the dose beyond the individualized optimal level can result in adverse effects. The exercise dose should therefore be carefully adjusted, specifically in older adults with frailty. Multidimensional and/or clinical assessments are applied to identify older adults in a state of pre-frailty or frailty. While such assessments are necessary, they are insufficient for controlling the exercises dose. Rating of perceived exertion and delayed onset of muscle soreness in association with objective testing of physical capabilities, are recognized as appropriate, albeit subjective, assessments of the optimal exercise dose and sufficient recovery time between exercise sessions for older and frail adults. Regular monitoring of objective and subjective markers of exercise response will assist older and frail adults in tailoring their exercise programs to ensure positive outcomes.

Light-induced tissue damage involves photosensitization. This process forms the basis of photodynamic therapy but also underlies photoaging and skin cancer development during excessive sun exposure. This review bridges these interlinked, yet rarely connected fields. We propose a unified classification distinguishing photosensitizers, photocatalysts, photoinitiators, and photocatalytic initiators based on absorber fate and downstream radical chain propagation. This framework resolves longstanding ambiguities and carries direct mechanistic consequences. Our central thesis is that subcellular localization determines the biological outcome far more than quantum yields. Membrane-bound photosensitizers permeabilize organelles orders of magnitude more efficiently than their broadly distributed counterparts, provided direct photosensitizer-lipid contact favors truncated lipid generation through Type I electron-transfer reactions rather than singlet oxygen oxidation. Organelle-specific targeting exploits this principle. Mitochondrial photodamage triggers regulated cell death through cardiolipin oxidation and cytochrome c release. Lysosomal targeting induces cathepsin release and autophagy dysfunction, often proving more effective for long-term cell killing. Dual-organelle strategies activate apoptosis, ferroptosis, and pyroptosis synergistically. These same mechanisms operate during sun exposure. Lipofuscin mediates radical chain amplification, creating a feed-forward cycle of visible light sensitivity in aging skin. Pheomelanin acts as a Type I photosensitizer generating superoxide and hydrogen peroxide under visible light, while eumelanin dissipates photon energy as heat. The amplification inherent in photoinitiated processes explains why modest light doses overwhelm antioxidant defenses, tipping redox homeostasis from eustress to distress. We translate these insights into mechanistically rational photoprotection strategies addressing visible light beyond conventional UV filters and into design principles for next-generation therapeutic photosensitizers.

The gut microbiome affects arterial stiffness in experimental murine models; however, evidence in human longitudinal studies is lacking. In this study, we investigated longitudinal between-person (average) and within-person (change) associations of microbiome features with arterial stiffness. We assessed the fecal microbiome using whole genome metagenomic sequencing, and arterial stiffness using carotid-femoral pulse wave velocity (cfPWV). Our analytic sample consisted of 349 adults from the Baltimore Longitudinal Study of Aging, who contributed 915 visits between 2013-2019. Using linear mixed models, we found higher microbiome evenness and butyrate-producing bacteria were associated with lower cfPWV on average (between-person), but changes in diversity were not associated with changes in cfPWV (within-person). Several potentially pathogenic bacteria were positively associated with cfPWV, both between- and within-person. Butyrate-production pathways were inversely associated with cfPWV between-person and borderline within-person. Trimethylamine-production genes were positively associated with cfPWV between-person and borderline within-person. In addition, changes in other functional pathways including peptidoglycan biosynthesis and L-arginine biosynthesis were associated with changes in cfPWV. In conclusion, cfPWV was associated with both between-person and within-person differences in gut microbiome features, with strength and consistency depending on the feature. These results can inform which microbiome features to target in interventions to improve arterial stiffness.

A decline in specific antibody responses is a hallmark of human aging, yet the differential contributions of B and T lymphocytes remain unclear. CXCL13 is a chemokine that shapes germinal center (GC) organization, but the regulation of human-specific CXCL13

ObjectivesSocial participation is a key pathway to promoting active and healthy aging. While existing studies have examined the relationship between social participation and cognitive health, relatively little is known about how different patterns of participation are associated with cognitive outcomes.MethodsDrawing on the perspective of personal-family balance, this study utilizes data from the 2018 and 2020 waves of the China Health and Retirement Longitudinal Study (CHARLS). Based on older adults' engagement in personal life domains (personal recreation, learning & socializing, economic activities, and volunteer work) and family life domains (caring for parents and grandchildren), we conducted latent class analysis to categorize social participation patterns into four types: personal-centered, family-centered, balanced, and low-participation. We then examine the associations of these patterns with cognitive decline among older adults.Results(1) Compared with the low-participation type, the personal-centered, family-centered, and balanced types are all significantly associated with a reduced risk of cognitive decline; (2) None of the three participation patterns shows a significant association with cognitive decline among older people in urban areas, whereas the personal-centered and balanced patterns are significantly associated with lower risk of cognitive decline among older people in rural areas; (3) The personal-centered pattern significantly reduces the risk of cognitive decline among the middle and oldest groups, with a stronger protective association observed in the latter. In contrast, the balanced pattern of social participation significantly reduces the risk of cognitive decline among the youngest group, but shows a positive association with cognitive decline among the oldest group.DiscussionThese findings highlight that optimizing the structure of social participation, promoting engagement among rural older adults, and adopting age-responsive approaches across different stages of later life are essential strategies for improving cognitive health.

Cardiometabolic multimorbidity (CMM) burdens aging populations. Obesity drives CMM via insulin resistance and inflammation, but their nonlinear and combined effects remain unclear. We elucidated how these factors contribute to CMM incidence.

Cerebral glucose metabolism and cortical morphology are known to undergo significant changes across the lifespan, yet their network-level coordination remains poorly understood. This study aimed to investigate whether individual-level metabolic connectivity (MC) reflects underlying inter-areal morphometric similarity, and to determine how this metabolic-morphometric coupling evolves across the adult lifespan.

While cross-sectional studies suggest that physical activity (PA) is associated with a lower risk of sarcopenia, the long-term PA patterns remain poorly characterized. We aimed to examine whether PA patterns across mid- to late adulthood are associated with sarcopenia in older age.

Sarcopenic obesity (SO) the coexistence of reduced muscle mass and excess adiposity represents a distinct geriatric syndrome rather than a coincidental overlap of two conditions. SO is driven by inflammation, insulin resistance, and myosteatosis, leading to accelerated functional decline, cardiometabolic risk, and higher mortality. Current diagnostic tools relying on BMI or isolated sarcopenia markers fail to capture this entity, delaying intervention. Recognition of SO requires integrated screening methods, novel risk indices, and dual-target therapies balancing fat loss with muscle preservation. Establishing SO as a clinical syndrome is essential for advancing risk stratification, optimizing management, and informing policy.

Cellular senescence plays a crucial role in brain aging and the decline of cognitive abilities. Although senolytic treatments, particularly the combination of dasatinib and quercetin (D+Q), show potential for improving cognition, the specific mechanisms involved are not well understood. In this study, we present strong evidence that senolytics enhance cognitive function by modulating cholesterol biosynthesis in astrocytes. Using a murine model of accelerated aging (via D-galactose exposure), we show that administering D + Q results in significant improvements in cognitive performance and a decrease in cellular senescence. A comprehensive multi-omics analysis subsequently demonstrated that senolytics are especially effective at downregulating cholesterol biosynthesis in the hippocampus. Notably, this effect was localized to astrocytes, where senolytics significantly reduced intracellular lipid accumulation and subsequent neuroinflammation. Critically, pharmacological activation of cholesterol synthesis and genetic overexpression of Hsd17b7, a key enzyme in the cholesterol synthesis pathway, in astrocytes reversed the anti-senescence benefits of senolytics in vitro, establishing a causal link between cholesterol pathway inhibition and the therapeutic effects. Overall, our work identifies the suppression of astrocytic cholesterol biosynthesis as a fundamental mechanism of senolytic action, repositioning these compounds as modulators of brain lipid metabolism and highlighting a promising therapeutic axis for combating age-related cognitive decline.

The antagonistic pleiotropy theory of aging predicts genetic trade-offs between early-life and late-life fitness. However, empirical evidence for such trade-offs in vertebrates remains scarce, particularly from causal genetic experiments. Here, combining genetic perturbation with longitudinal phenotyping in the turquoise killifish (Nothobranchius furzeri), we identify vestigial-like 3 (vgll3), previously linked by GWAS to age at maturity in humans and male Atlantic salmon, as a gene with antagonistically pleiotropic effects. Selective disruption of vgll3 isoforms accelerates male growth and maturation in a dose-dependent manner. Transcriptomic and cellular analyses indicated increased cell division, corroborated in vivo by elevated germline and intestinal stem-cell proliferation. However, early-life maturation incurs a late-life cost, linked to altered DNA damage response. Older mutant males develop melanoma-like tumors, validated via transplantation into immunodeficient rag2 models, and exhibit a shortened lifespan. Thus, we identify vgll3 as a key regulator of life-history variation with antagonistic effects across ages, balancing early-life fitness against late-life mortality.

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

Cerebrovascular disease (CeVD) is a major health concern in aging populations, and early identification is crucial for improving outcomes. Conventional diagnostic approaches are hospital-centered and limited in capturing disease risks from behavioral changes at home. We propose a framework to identify potential CeVD prodromal individuals and estimate diagnostic risk using behavioral and environmental data collected from contactless sensors in real-world homes. We used 13,362 samples (14-day windows) from 1224 older adults (598 healthy, 28 prodromal, 598 diagnosed) in South Korea. In-home behavioral and environmental factors, along with demographics and comorbidities, were used to develop models for three tasks. The framework achieved an area under the precision-recall curve of 0.85 for prodromal identification (Task 1), an area under the receiver operating characteristic curve of 0.91 for classifying diagnosed patients (Task 2), and a sensitivity of 95.12%, specificity of 96.97%, and accuracy of 96.53% for predicting imminent diagnostic risk within the prodromal group (Task 3). Model interpretation identified key digital behavioral markers, including frequent continuous activity and shorter inactive time during bedtime preparation hours (Task 1) and evening hours (Task 3). Our approach offers the potential to facilitate early detection of CeVD at home and requires further validation before clinical application.

Aging is associated with chronic low-grade inflammation in the hypothalamus, hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, and disruption of circadian rhythms of glucocorticoid secretion. Using the immunoblotting method, we found that a course of ethylmethylhydroxypyridine succinate (100 mg/kg, daily intraperitoneal injections for 14 days) reduced the level of inflammatory cytokines (IL-1β, TNFα) in the hypothalamus of aged (18-month-old) rats and upregulated the expression of anti-inflammatory cytokines (TGF-β1 and IL-10), growth factors (VEGF and BDNF), markers of mitochondriogenesis (PGC-1α, NDUFV2, SDHA, cyt c1, and COX2) and synaptogenesis (SYP), succinate receptor SUCNR1, and insulin receptor INSRβ. These molecular changes were associated with reduced circulating corticosterone levels, as determined by ELISA. Our findings demonstrate the normalizing effect of succinate/SUCNR1 signaling on the circadian activity of the HPA axis during aging.

There is currently no theory which mechanistically links parasite virulence and host senescence. One driver of senescence is energy metabolism. We expect parasites to contribute to senescence because infection increases energy allocation to the immune system, which elevates oxidative stress and damages macromolecules. Additionally, parasites deplete their host's energy, which can increase the host's rate of mortality. While these within-host processes can contribute to mortality, they also determine the risk of parasite infection through epidemiological dynamics. To understand quantitatively the impact of these interactions on infection dynamics and on the evolution of within-host parasite growth (virulence), we developed a multiscale model that describes within-host and among-host dynamics. We found that infection prevalence is maximised at intermediate levels of resource acquisition only when energy depletion contributes to senescence. Furthermore, for a single resource level, there are two evolutionary equilibria for the parasites' growth rate. This is the first time the molecular mechanisms determining senescence have been considered in the context of parasite infection, allowing us to link virulence and senescence. Our mechanistic framework provides an alternative to the virulence-transmission trade-off and reconciles conflicting empirical findings on the impact of resources on epidemiological dynamics and virulence.

Aging is recognized as the most significant risk factor for neurodegenerative diseases. Emerging evidence indicates that inflammation contributes to the progression of aging-related neurodegeneration. As a transmembrane immune receptor, triggering receptor expressed on myeloid cells 1 (TREM1) plays a crucial role in the regulation of inflammatory responses. Previously, our research group and others showed that the levels of a soluble form of TREM1 (sTREM1) were increased in the plasma or cerebrospinal fluid (CSF) of patients with Alzheimer's disease, the most common type of neurodegenerative disease among the elderly. Moreover, the elevated levels of CSF sTREM1 were closely associated with a more rapid rate of hippocampal degeneration in cognitively impaired older adults. However, the precise mechanisms by which sTREM1 contributes to aging-related neurodegeneration remain largely unclear. In this study, by utilizing senescence accelerated mouse prone 8 mice, an animal model of accelerated aging, we confirmed that serum sTREM1 levels were significantly increased during the aging process. Importantly, we demonstrated that roundabout guidance receptor 2 (ROBO2) functioned as a receptor for sTREM1 in hippocampal neurons, and its expression was also upregulated with aging. Additionally, we revealed for the first time that knockdown of neuronal ROBO2 mitigated aging-related hippocampal synaptic degeneration and cognitive impairments. Furthermore, we provided the first evidence that sTREM1 reduced the expression of synaptic proteins via the ROBO2/extracellular signal-regulated kinase pathway. These findings elucidated the mechanisms through which sTREM1 contributed to aging-related neurodegeneration and suggested that the inhibition of sTREM1-mediated signaling might represent a novel therapeutic strategy for the treatment of neurodegeneration and cognitive decline induced by aging.

Aging is the first risk factor associated with cancer, predominantly due to cumulative somatic mutations and a profound decline in antitumor immunity. The aging process remodels immune function across hematopoietic, adaptive, and innate compartments through interconnected processes, including hematopoietic stem cell dysfunction, loss of metabolic fitness, altered B and T cell phenotypes, myeloid skewing, and a complex interplay between cellular senescence and inflammaging. These changes collectively establish an immunosuppressive landscape that weakens natural tumor surveillance and constrains responses to cancer immunotherapies. Given the shift toward an aging global population and the disproportionate cancer burden in older individuals, we emphasize the clinical relevance of patient-stratification strategies. We further discuss emerging approaches aimed at rejuvenating immune function to improve immunotherapy outcomes in older patients.

Excessive artificial light at night (ALAN) disrupts circadian rhythms and may accelerate ocular aging; however, personal objective dosimetry data linking evening light exposure to specific age-related eye diseases (AREDs) remain sparse. The objective of the study is to determine whether personal high-intensity light exposure during the evening transition window (20:00-23:30) is associated with the risk of incident age-related macular degeneration (AMD), cataracts, and glaucoma. This prospective cohort study utilized data from the UK Biobank. Participants (n = 82,826) were monitored for 7 days via wrist-worn accelerometers equipped with high-resolution light sensors between 2013 and 2015. Individuals with baseline eye diseases were excluded. Average light intensity (lux) during the evening transition period (20:00-23:30) was categorized by percentiles (top 10% threshold ≈1000 lx). Incident AMD, cataract, and glaucoma were identified through linked hospital inpatient records and death registries using ICD-9 and ICD-10 codes. Among 82,826 participants, 6058 incident ARED cases occurred during a median follow-up of 7.85 years. Evening light exposure exceeding 1000 lx (top 10%) was significantly associated with increased hazards of incident AMD (HR, 1.31; 95% CI, 1.06-1.62), cataract (HR, 1.18; 95% CI, 1.08-1.30), and primary open-angle glaucoma (POAG) (HR, 1.47; 95% CI, 1.07-2.03). Significant time-response relationships were observed, with per-hour exposure to > 2250 lx further elevating the risk of overall AREDs (HR, 1.10; 95% CI, 1.04-1.16) and POAG (HR, 1.18; 95% CI, 1.04-1.35). High-intensity artificial light in the evening is an independent, modifiable risk factor for major ocular aging pathologies.

Sports/exercise engagement across the lifetime has been proposed to contribute to cognitive reserve and promote healthy brain aging. Few studies have examined whether past sports experiences are associated with current cognitive and social functions and resting-state brain activity in lifespan. The present study aimed to address that gap. Ninety healthy participants aged 20-83 years were categorized into four groups based on their self-reported sports experience: single sports (N = 25), team sports (N = 11), combined single and team sports (N = 20), and no experience (N = 34). We assessed cognitive function, social adaptation, and quality of life. Resting-state functional magnetic resonance imaging data were analyzed using amplitude of low-frequency fluctuations and seed-based functional connectivity to investigate local spontaneous activity and network-level integration. Participants with sports experience demonstrated enhanced performance in several cognitive tasks and higher social adaptation scores than those without experience. Neuroimaging analyses revealed increased amplitude of low-frequency fluctuations in the right middle frontal gyrus in the team-sport group. Furthermore, exploratory functional connectivity analysis showed reduced coupling between the right middle frontal gyrus and posterior sensory-visual regions, including the postcentral gyrus, lateral occipital cortex, and occipital fusiform gyrus. These findings suggest that lifetime sports engagement may be associated with differences in cognitive and psychosocial functioning, together with a tentative pattern of resting-state brain variation. Although the observed connectivity pattern may be broadly consistent with accounts of functional specialization or neural efficiency, the principal ALFF finding did not survive correction for multiple comparisons. Accordingly, the neuroimaging results should be regarded as preliminary and hypothesis-generating rather than confirmatory, while still providing a concrete basis for future hypothesis-driven investigation.

Aging is marked by progressive physiological decline driven by chronic inflammation, mitochondrial dysfunction, and impaired metabolic and musculoskeletal resilience. As the global population ages, dietary supplements have gained attention as potential tools to support healthy longevity. This review summarizes current evidence on nutritional compounds that target aging-related pathways, focusing on interventions that influence mitochondrial health, cognitive performance, immune function, metabolic regulation, and maintenance of muscle mass in older adults. Thirty-two human studies were identified through PubMed, Scopus, and Web of Science.

Cellular senescence-an age-associated state characterized by irreversible cell cycle arrest and proinflammatory signaling-contributes to vascular dysfunction and cardiovascular disease. However, the molecular mechanisms linking senescence to vascular impairment remain incompletely defined. Progranulin (PGRN) is a multifunctional protein involved in inflammation, lysosomal function, and cellular homeostasis, but its role in vascular aging is not well understood. We assessed PGRN expression in human and mouse arteries and in senescent vascular smooth muscle cells (VSMCs). Vascular function was examined in PGRN-deficient (

Aging is the greatest risk factor for many of society's most prevalent diseases, including diabetes, cancer, cardiovascular disease, and neurodegenerative disorders. A common thread underlying these conditions is the disruption of cellular and metabolic homeostasis. All hallmarks of aging converge on mechanisms that disrupt how cells communicate, interact, and coordinate their functions. Emerging studies have implicated diminished NAD+ levels as a contributor to several hallmarks of aging, underscoring their regulatory role in age-dependent decline. While it remains unclear whether aging drives metabolic decline or if metabolic dysregulation accelerates aging-or both-a growing body of evidence suggests that NAD+ metabolism may be a key link between disrupted communication and metabolic dysfunction. This review integrates current insights into how NAD+ metabolism and signaling influence cellular and organismal aging, emphasizing the nutritional factors that modulate these processes. Together, these perspectives position NAD+ as a unifying framework linking nutrition, metabolic resilience, and the mechanisms of healthy aging and disease.

Glucagon-like peptide-1 receptor agonists, including long-acting semaglutide, are transformative anti-obesity therapies. However, emerging evidence indicates that weight loss may come at the expense of skeletal muscle mass, a tissue essential for mobility, metabolic regulation, and overall health. Here, we show that inhibition of the gerozyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme that increases with injury and aging, improves muscle repair and strength recovery in the presence of semaglutide. In a high fat diet-induced mouse model of obesity, semaglutide alone caused significant loss of muscle mass, while preserving contractile function. Following injury, obese mice exhibited pathological calcifications previously reported for the heritable myopathy, Duchenne Muscular Dystrophy. Semaglutide had both beneficial and deleterious effects, reducing calcific remodeling, but causing reduced regenerated myofiber sizes. This impaired regenerative myofiber growth in semaglutide-treated mice was surmounted by cotreatment with a 15-PGDH inhibitor (PGDHi), which stimulated muscle stem cell function and myofiber growth, leading to enhanced strength. Importantly, PGDHi synergizes with semaglutide to boost postinjury muscle quality and muscle force without compromising weight loss.

To characterize age-associated alterations in intestinal barrier homeostasis by integrating host transcriptomic profiles and mucosa-associated microbial sequence signals recovered from human colonic biopsy RNA-seq datasets.

Falls are a leading cause of injury and growing healthcare costs, particularly in aging populations. However, early-stage balance impairments often remain undetected until severe problems arise. Quantitative assessment of human balance therefore remains a critical challenge. Here, we introduce Perturbation Recovery Time, a novel state-space-based balance metric in spired by nonlinear dynamic system theory that quantifies the duration required for gait dynamics to consistently return to a steady-state neighborhood following a perturbation. Unlike conventional approaches based on steady-state walking, this framework evaluates balance through externally induced perturbations that reveal control mechanisms not observable during unperturbed gait. Using healthy participants with experimentally induced impairments, we identified key balance-related features, including the anterior-posterior center-of-mass-center-of pressure distance, whole-body angular momentum in the frontal and sagittal planes, and vertical center-of-mass position and acceleration. These features capture the core mechanisms of balance control, including foot placement, inverted pendulum dynamics, push-off control, and trunk regulation. Perturbation Recovery Time reliably detected within-subject changes in balance associated with controlled impairments in sensory input, motor coordination, and movement consistency. These findings demonstrate that Perturbation Recovery Time provides a quantitative and sensitive measure of balance, offering a framework for early detection of balance impairments.

Genome maintenance is increasingly recognized as a shared vulnerability across aging, cancer, and neurodegeneration, yet the therapeutic implications of pathway-specific dysregulation of DNA repair remain incompletely defined.

Aging is associated with many chronic conditions that increase morbidity and mortality. These include obesity, diabetes, sarcopenia, osteoporosis, and neurodegeneration. The deubiquitinase USP19 is involved in many of these disorders suggesting that it may modulate common mechanism(s) that impact the aging process. Inactivation of USP19 is protective against muscle atrophy, obesity, and diabetes in young adult mice. Whether such protection persists in older adult mice remains unknown. In addition, the potential role of USP19 in osteoporosis remains unexplored. Here, we demonstrate that loss of USP19 is protective against loss of muscle mass and obesity in mice aged 22-24 months. Glucose tolerance was also improved in these older adult USP19 KO mice, but only in females. Bone mineral content was decreased in the USP19 KO bone, more evidently in cortical bone than in trabecular bone and only in males. This was associated with a reduced work-to-failure in the KO femurs. Osteoblasts derived from USP19 KO bone marrow cells demonstrated decreased ex-vivo mineralization compared to WT cells and the KO marrow cells showed enhanced differentiation into TRAP-positive multinucleated osteoclasts. These findings identify important potential benefits as well as risks of therapeutic targeting of USP19 for the prevention or treatment of key aging related disorders.

Senescent cells, which have irreversibly arrested cell proliferation and a senescence-associated secretory phenotype, are characterized by the production of proinflammatory cytokines and growth factors. The selective clearance of senescent cells might have beneficial effects on physiological functions or aging-related diseases. Senolytic drugs, such as ABT-263, an inhibitor of BCL-2 family proteins, selectively kill senescent cells. In the present study, we investigated the effect of IL-4 and IL-13, which contribute to type 2 immunity and fibrosis, on ABT-263-induced apoptosis in senescent cells. Doxorubicin was used to induce senescence in TIG-1 cells, a normal diploid fibroblast line commonly used to study cellular senescence. Although ABT-263 selectively induced apoptosis in senescent TIG-1 cells at lower concentrations than were required to induce apoptosis in non-senescent cells, IL-4 and IL-13 suppressed ABT-263-induced apoptosis in senescent TIG-1 cells. Pharmacological experiments using inhibitors revealed that the suppressive effects of IL-4 and IL-13 involved the IL-4Rα/JAK/STAT6 signaling pathway. We found that IL-4 and IL-13 altered the expressions of molecules involved in extracellular matrix and cell adhesion, and induced phosphorylation of the downstream FAK/Akt/GSK3β signaling pathway. In addition, senescent TIG-1 cells treated with IL-4 and IL-13 showed increased glucose consumption, and the suppressive effect of IL-4 and IL-13 was partially abolished by inhibitors of the glucose metabolic pathway. Taken together, IL-4/IL-13 signaling had a suppressive effect on ABT-263-induced apoptosis in senescent human fibroblasts. These results suggest that a combination of senolytic drugs and inhibitors targeting IL-4/IL-13 signaling might be effective for aging-related diseases.

This study quantified biomechanical modulation of walking using a multidimensional framework and examined its association with aging, with emphasis on distal ankle propulsion.

Sirtuin 1 (SIRT1), an NAD

Vascular dementia (VaD) is associated with chronic cerebral hypoperfusion, oxidative stress, mitochondrial dysfunction, and hippocampal neuronal senescence. Citronellal (CT) ameliorates cognitive impairment in 2VO-induced VaD rats. CT improved spatial learning and working memory, reduced in vivo oxidative stress, restored hippocampal dendritic spine density, upregulated hippocampal myelin basic protein (MBP), and decreased P-p53, p21, and SA-β-gal. CT also restored mitochondrial membrane potential and reduced Drp1/FIS1 expression. Mechanistically, CT suppressed TRPM2 and restored NMDAR1; TRPM2 deficiency weakened CT-mediated NMDAR1 regulation. These findings suggest that CT ameliorates VaD-related cognitive impairment by inhibiting hippocampal aging through TRPM2/NMDAR-associated oxidative stress-mitochondrial pathways.

Childhood obesity is a critical public health concern. Whether diet-induced transient obesity during development negatively impacts later-life health remains unclear, and mechanisms are poorly understood. This study investigates whether these effects persist into aging and employs integrated omics to explore underlying mechanisms. Using a high-fat diet (HFD) to induce transient developmental obesity in post-weaning rats and larval Drosophila, we examined the long-term effects on aging metabolic health in both species. Transient developmental obesity in rats was linked to accelerated aging, weight loss, worsened metabolism, colonic inflammation, and oxidative stress. Metabolomics revealed persistent gamma aminobutyric acid (GABA) dysregulation associated with intestinal ammonia levels, and gut metagenomics showed a reduction in Lactobacillales, correlating with adverse health outcomes. In Drosophila, exogenous GABA extended HF-diet lifespan. It reduced trehalose, triglycerides (TG), and oxidative stress; concurrently, it restored intestinal Lactobacillus and activated the phosphotransferase system (PTS), thereby improving metabolic homeostasis and redox status. Transient developmental obesity is associated with reduced gut Lactobacillus abundance, which may contribute to decreased GABA levels and subsequent disruption of glucose (GLU) metabolism, potentially involving the PTS pathway. These interconnected alterations may ultimately lead to systemic dysregulation of GLU and lipid metabolism and redox homeostasis in later life, compromising overall health and longevity.

Bioessential elements are essential for maintaining reproductive function, yet their homeostasis may be perturbed during aging. The dynamic regulation of these elements during aging remains insufficiently characterized. Here, a multielement single-cell inductively coupled plasma mass spectrometry (SC-ICP-MS) method was established for the quantification of seven bioessential elements, including iron (Fe), copper (Cu), calcium (Ca), zinc (Zn), magnesium (Mg), phosphorus (P) and manganese (Mn). This method was optimized using an integrated strategy to balance sensitivity, transport efficiency, and signal-to-noise ratio, and subsequently applied to quantify elemental contents in sperm collected from mice at different ages. Distinct age-dependent patterns were observed at the single-sperm level. Fe, Cu, and Ca exhibited early life maxima, whereas Zn, Mg, and P reached peak levels in midlife; Mn remained consistently low across all age groups. Interestingly, elemental heterogeneity followed a conserved inverted U-shaped trajectory, reaching a maximum at week 40. Correlation network analysis revealed a significant association between Fe and Mn at the content level, whereas elevated P content and increased heterogeneity were associated with reduced sperm concentration and impaired morphology. Functionally, Zn content was positively correlated with sperm motility, whereas elevated P content and increased heterogeneity were associated with reduced sperm concentration and impaired morphology. Ca, P, Mn, and Fe were more susceptible to dysregulation linked to compromised sperm function, whereas Mg, Zn, and Cu were associated with beneficial outcomes. These findings provide single-cell insights into age-dependent elemental homeostasis and its functional implications for male reproductive aging.

Cerebrospinal fluid (CSF) transport along meningeal pathways contributes to brain fluid homeostasis and is thought to change with aging, yet quantitative, region-resolved measurements across lifespan remain limited. We hypothesized that meningeal CSF transport dynamics exhibit region-specific age associations rather than uniform decline.