Longevity Papers

Aging is a well-recognized risk factor in cardiovascular diseases (CVDs), primarily due to its association with the gradual decline in cardiac function. This decline significantly influences the pathogenesis of common CVDs such as myocardial infarction and heart failure. Despite the existence of several proteomic atlases of the heart, the spatially resolved proteomic dynamics essential for understanding region-specific aging mechanisms in cardiac tissue remain incompletely characterized. In this study, we conducted a region-resolved quantitative proteomic profiling for various murine cardiac regions at three distinct stages of aging (3, 12, and 20-month-old), quantifying 6 650 proteins in the heart. Leveraging integrated bioinformatics and machine learning frameworks, we uncovered that FTL1 and SERPINA3K exhibit strong age-associated expression changes across all cardiac regions. Mechanistically, the knockdown of Ftl1 led to cardiomyocyte ferroptosis and senescence, phenotypes that were ameliorated by the ferroptosis inhibitor Ferrostatin-1. Furthermore, the depletion of Serpina3k exacerbated senescence and collagen deposition through the activation of the cGAS-STING-PERK axis, effects that can be reversed via the overexpression of Serpina3k or the knockdown of Sting. The protective effect of SERPINA3K was also demonstrated in vivo through AAV9-mediated cardiomyocyte-specific overexpression in middle-aged mice, which attenuated the cGAS-STING-PERK axis and mitigated age-related fibrosis. These results strongly demonstrated that FTL1 and SERPINA3K function as key regulators of cardiac aging. Collectively, this study provides a valuable region-resolved proteomic atlas of cardiac aging and identifies key protein regulators, thereby uncovering potential targets for cardio-protective interventions against age-related cardiovascular disorders.

Prostaglandin D2 (PGD2) is a bioactive lipid mediator implicated in ovarian physiology; however, its role in mitochondrial regulation and aging-associated reproductive dysfunction remains insufficiently defined. Here, we investigated whether PGD2 restores ovarian competence through coordinated mitochondrial and endocrine remodeling using human granulosa (KGN) cells, primary ovarian cells from aged mice, and preimplantation embryos. PGD2 significantly enhanced cellular viability and attenuated senescence-associated β-galactosidase activity. Structural and functional analyses demonstrated restoration of mitochondrial network integrity, increased mitochondrial membrane potential (ΔΨm), elevated basal respiration, spare respiratory capacity, and ATP production, together with reduced proton leak, indicating improved oxidative phosphorylation efficiency. Mechanistically, PGD2 activated a mitochondrial stress-adaptive axis characterized by upregulation of SIRT1 and PINK1 and suppression of PARP1, suggesting enhanced mitochondrial quality control and preservation of metabolic flexibility. Concomitantly, PGD2 promoted steroidogenic activation, evidenced by increased StAR and CYP11A1 expression and significantly elevated estradiol and progesterone secretion. Adaptive remodeling of gonadotropin receptor signaling was observed, with increased LHR/LHCGR and reduced FSHR and AMH expression, reflecting a shift toward an LH-responsive maturation-aligned phenotype. Importantly, these ovarian cellular improvements translated to the embryonic stage. PGD2 enhanced mitochondrial membrane potential, accelerated cleavage kinetics, and improved progression to the morula and blastocyst stages. Blastocysts exhibited transcriptional patterns consistent with maternal metabolic reprogramming, including increased StAR, CYP11a1, Sirt1, and LHCGR expression. Collectively, these findings demonstrate that PGD2 restores ovarian resilience through hierarchical mitochondrial reinforcement, endocrine activation, and adaptive receptor remodeling, thereby enhancing embryonic developmental competence. PGD2 may represent a potential therapeutic modulator for improving reproductive outcomes under aging-associated ovarian dysfunction.

Sarcopenia, a hallmark of skeletal muscle aging, is a significant public health concern that substantially compromises the quality of life in the elderly. While conventional research has predominantly focused on intrinsic pathological alterations within muscle fibers, it has often overlooked the diverse cell-cell and interorgan communications mediated by nonmuscle cells in the skeletal muscle microenvironment. This microenvironment, comprising the extracellular matrix, multiple cellular components, secreted factors, and metabolites, plays a crucial role in regulating muscle homeostasis and regeneration, serving as a key driver of skeletal muscle aging. As the microenvironment undergoes profound remodeling with advancing age, this review systematically examines novel intervention strategies targeting it. By aiming to achieve coordinated multipathway remodeling of this niche, these approaches offer a fresh theoretical foundation and novel clinical avenues for delaying or reversing sarcopenia. Future research should prioritize elucidating these microenvironmental regulatory mechanisms, refining personalized intervention protocols, and rigorously validating translational applications.

Mitochondrial dysfunction and redox imbalance are key features of aging that drive cellular senescence, metabolic decline, and tissue degeneration. 4-N-furfurylcytosine (FC), a cytosine derivative with redox-modulating properties, has been proposed to counteract age-associated oxidative damage; however, its effects in mammalian aging remain unexplored. The anti-aging potential of FC was investigated using a translational approach integrating in vitro and in vivo models. Human fibroblasts (MRC-5) and keratinocytes (HaCaT) subjected to physiological and stress-induced senescence were used to assess mitochondrial function, redox balance, and proteostasis, while aged C57BL/6J mice, long-term supplemented with FC were evaluated for systemic metabolic, molecular, and behavioral outcomes. FC enhanced cell survival and mitigated key hallmarks of senescence, including β-galactosidase activity and p16 expression. Moreover, FC reduced intracellular reactive oxygen species and oxidative damage, as evidenced by decreased levels of 8-oxodG, protein carbonyls, and lipid peroxidation. FC improved mitochondrial membrane polarization and increased ATP levels while reducing oxygen consumption, indicating an altered bioenergetic state. Proteomic profiling revealed enrichment of pathways related to mitochondrial maintenance, antioxidant defense, and proteostasis, consistent with enhanced metabolic adaptability. In aged mice, FC supplementation preserved lean body mass, improved coordination and endurance, stabilized lipid and glucose metabolism, maintained telomere integrity, increased mtDNA:nDNA ratio, and reduced systemic oxidative stress markers, indicating delayed molecular aging and preserved mitochondrial function without overt adverse effects detected in the measured readouts. 4-N-furfurylcytosine modulates redox- and mitochondria-associated aging phenotypes in cellular and mouse models, with effects consistent with remodeling of mitochondrial homeostasis and improved resilience to oxidative stress. These findings support FC as a promising candidate for further investigation as a modulator of aging-related processes.

Human longevity is a complex trait shaped by genetic background and population-specific factors. Calabria, a region in Southern Italy with a high prevalence of centenarians and relative genetic isolation, is a valuable model for investigating the genetic architecture of extreme survival. Here, we performed a genome-wide association study of longevity in 705 Calabrian individuals, comparing long-lived subjects to younger controls using a mixed-model approach that accounts for relatedness and population structure. We identified 22 suggestive risk loci, among which one reached genome-wide significance. Although most loci did not replicate in external datasets, an intronic variant regulating proteasome-related gene expression was confirmed by meta-analysis. Based on the nominal significance of gene- and pathway-based analyses, it is possible to hypothesize that the biological processes potentially affecting longevity in this cohort might include proteostasis, maintenance of genome integrity, apoptosis, and insulin- and inflammation-related pathways. Notably, established longevity loci such as APOE and FOXO3 were not associated, underscoring population-specific genetic effects. Overall, our preliminary findings suggest that longevity in the Calabrian population arises from a combination of unique genetic influences and conserved aging-related mechanisms, providing new insights into the molecular basis of human lifespan extension.

Astaxanthin (ATX), a natural antioxidant whose benefits in age-related liver and kidney damage remain unclear. We established a D-galactose-induced ageing model in rats and observed the daily behaviour of the rats. Using staining methods to detect ROS, apoptosis and histopathological changes in liver and brain tissue. Determination of antioxidant levels of IL-2, IL-6 and AGES in rats. Assessment of cognitive function using the Morris water maze and ChAT. The mRNA and protein expression levels of Nrf2, Bach1, SOD1, SOD2, HO-1 were determined by real-time PCR and Western blotting. To investigate the role of the Nrf2/Bach1-ARE pathway, we used ML385, a specific inhibitor of the Nrf2 pathway, to treat rats in the inhibitor group. Aging rats showed impaired learning and memory, along with decreased levels of neurotransmitters and antioxidant enzymes. ATX and vitamin E (VE) interventions significantly alleviated these symptoms and activated the Nrf2/Bach1-ARE pathway in liver and brain tissues of aged SD rats. Furthermore, the protective effects of ATX were attenuated by the addition of the Nrf2 inhibitor ML385. ATX reduces oxidative stress and ameliorates liver and brain damage in aged rats via activation of the Nrf2/Bach1-ARE pathway.

Chronological age incompletely captures heterogeneity in biological aging. In this prospective study of 45,819 UK Biobank participants, we developed a multimodal ocular aging index (MOAI) by integrating ophthalmic phenotypes with plasma proteomic and metabolomic profiles using machine learning. The MOAI quantifies divergence between ocular biological and chronological age. Over 13.80 years of follow-up, accelerated ocular aging was significantly associated with higher risks of incident age-related macular degeneration and cataract, even after adjustment for chronological age and established risk factors. Incorporation of the MOAI significantly improved risk reclassification beyond traditional predictors. Explainable modeling and pathway enrichment analyses identified inflammation-related proteins and pathways, including cytokine-cytokine receptor interactions and PI3K-Akt signaling, as key drivers of accelerated ocular aging. These findings establish a multimodal framework for quantifying organ-specific biological aging, link ocular aging to systemic inflammatory processes, and highlight the eye as a sensitive readout of aging biology with implications for healthspan.

Amino acids are fundamental to human physiology, yet their impact on growth, development, and aging remains elusive. Here, we introduce AmiAge, a biological age predictor constructed using a Random Forest model trained on the concentrations of 18 amino acids across individuals aged 1 to 89 years. Leveraging data from 9 studies encompassing over 11,000 in-house and more than 270,000 publicly available samples with diverse demographic and genetic backgrounds, AmiAge demonstrates robust accuracy. The deviation between AmiAge and chronological age (AmiAge Gap) correlates strongly with established aging biomarkers, disease risk, and clinical outcomes. Individuals with higher gaps exhibit increased frailty, telomere attrition, and elevated incidence of age-related diseases. To enhance clinical utility, we distilled AmiAge into an 8-amino acid model (including alanine, glutamine, glycine, histidine, leucine, phenylalanine, tyrosine, and valine). Our findings suggest that this simple, scalable amino acid clock offers a valuable complement to existing biological aging metrics, with potential applications in personalized health management and aging research.

Adult hippocampal neurogenesis declines with age, but the stress pathways that shape neural precursor cell (NPC) survival and lineage progression remain incompletely understood. Here, we tested whether ferroptosis-related vulnerability contributes to the regulation of hippocampal NPCs and their progeny. Using in vitro assays, transcriptomic analyses, and in vivo genetic and pharmacologic perturbations, we find that NPCs show features consistent with elevated susceptibility to ferroptotic stress relative to more differentiated hippocampal populations. Reducing glutathione peroxidase 4 (GPX4) or increasing ferroptotic stress impairs neurogenesis-associated cellular and behavioral phenotypes, whereas pathway modulation improves selected outcomes in aged animals. These effects were context dependent, with distinct consequences across age and behavioral paradigms. Together, the findings support a model in which ferroptosis-related susceptibility contributes to the regulation of adult hippocampal neurogenesis and cognition.

Diabetic kidney disease (DKD) has emerged as a major cause of end-stage renal disease (ESRD) worldwide, with approximately 30%-40% of diabetic patients progressing to DKD and 25% eventually requiring renal replacement therapy. Glomerular cell senescence, a central pathological driver of disease progression, persists throughout the entire course of DKD and involves activation of the complement system, transcription factor regulation, mitochondrial dysfunction, oxidative stress, and DNA damage response (DDR). Despite shared senescence mechanisms, podocytes, endothelial cells, and mesangial cells exhibit distinct senescent heterogeneity. This manuscript explores the core mechanisms regulating glomerular cell senescence and their impact on renal filtration barrier injury, inflammation, and glomerulosclerosis, with a specific focus on the senescent characteristics and interactions of different types of glomerular cells. It also discusses senescence-related diagnostic biomarkers and epigenetic clocks. Our findings highlight the critical role of cell type-specific senescence in the pathogenesis of DKD and propose potential precision therapeutic strategies targeting cellular senescence, offering promising breakthroughs for preventing or alleviating the progression of DKD.

In this study, age-related alterations in cardiac electrophysiology and the response to β

This study investigated the efficacy of hydroxytyrosol (HT), an active ingredient renowned for its antioxidant and anti-inflammatory properties derived from olive leaves and oil, in mitigating skin photoaging and elucidating its underlying mechanisms. Utilizing a comprehensive methodology that included network pharmacology, molecular docking, molecular dynamics (MD) simulations, quantitative mass spectrometry-based proteomics, in vitro assays on keratinocytes, and in vivo experiments with a nude mouse model, we assessed the effects of HT against ultraviolet (UV) radiation-induced skin damage. Our results demonstrated that HT significantly reduces oxidative stress and inflammatory responses, inhibited matrix metalloproteinases (MMPs) activity, mitigates collagen and elastin degradation, enhanced moisture retention, and suppresses apoptosis in keratinocytes. Mechanistically, HT engaged critical signaling pathways such as phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT), nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and Janus kinase (JAK)-signal transducer and activator of transcription (STAT), resulting in improved skin hydration, elasticity, collagen density, attenuation of the senescence-associated secretory phenotype (SASPs), and restoration of skin integrity in vivo. These findings provide a molecular basis for the anti-photoaging properties of HT, supporting its potential application as a novel phytotherapeutic agent for the management of UV-induced skin damage.

Aging is accompanied by a progressive decline in physiological function that contributes to chronic disease development. Biological clocks estimated from high-dimensional clinical and biological measurements may provide more granular tracking of the aging processes. Current biological clocks, however, have limited cross-ancestry generalizability and clinical applicability. Here, we developed a multi-ancestry biological clock (ClinBAG) using 22 routine blood and anthropometric biomarkers in 14,328 age- and sex-balanced individuals from the All of Us Research Program. We tested the association of ClinBAG with 434 traits and evaluated its ability to predict incident disease in 152,733 non-overlapping individuals. We also conducted genome-wide association studies in European (N=74,675), African (N=22,315), and Admixed American ancestry individuals (N=19,940). Among 190 neurological phenotypes, elevated ClinBAG was associated with cognitive decline, increased incidence of dementia (HR=1.020, p=1.6x10-5) and Parkinson's disease (HR=1.014, p=0.023), and decreased risk of migraine (HR=0.991, p=8.7x10-4). We also identified common (NPRL3) and ancestry-specific genetic loci (HBB in African-ancestry and FADS1/FADS2 in European-ancestry) for ClinBAG. Single-cell enrichment revealed that ClinBAG-associated genes are overexpressed in double-negative (DN) T cells in an age-dependent manner. This study presents a clinically applicable multi-ancestry biological age clock predicting neurological disease risk. Our findings also uncover population-specific genetic drivers, particularly involving erythropoiesis and DN T-cell-mediated neuroinflammation.

Transfer RNA (tRNA) halves (tRHs) are generated via the cleavage of tRNAs, but their roles in aging and longevity remain poorly understood. Here, we demonstrate a direct role of tRHs in aging in metazoans. Through a genetic screen using Caenorhabditis elegans, we identify DIS-3/DIS3 as a ribonuclease that catalyzes tRH generation, including 5'-tRH-Gln and 5'-tRH-Asp, from tRNAs. Among them, 5'-tRH-Gln is essential for longevity conferred by various interventions, including dietary restriction. Generation of 5'-tRH-Gln reduces translation via ribosomal protein binding and upregulates the SKN-1/NRF transcription factor responsible for lifespan extension. We further show that mammalian DIS3 contributes to tRH generation and delays cellular senescence through translation downregulation by another tRH, 5'-tRH-Cys. Overall, our data demonstrate that DIS-3/DIS3 is an evolutionarily conserved tRH-generating ribonuclease that counteracts organismal and cellular aging.

Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders. Single-cell RNA-seq after treatment revealed increased expression of TFEB targets and autophagy-related genes in B cells, in line with elevated autophagic flux. These findings suggest that targeting immune cell senescence with Spermidine may improve vaccine responsiveness in older adults and highlight immune-senescence markers as potential predictors of vaccine failure in ageing populations.

Programmed degradation of maternal proteins is essential for the oocyte-to-embryo transition (OET). While pharmacological inhibition studies have established the importance of proteasomes in ovarian reserve maintenance, oocyte maturation and fertilization, the physiological impact of intrinsic proteasome insufficiency and underlying molecular mechanisms remain poorly understood. In mice, endolysosomal vesicular assemblies (ELVAs), specialized membraneless compartments composed of proteasomes, endolysosomes and autophagosomes, facilitate protein degradation during oocyte maturation and early embryogenesis. In this study, we generated mice with oocyte-specific deletion of the proteasomal core subunit Psma7, to investigate the physiological function of the 20S proteasome and its roles in ELVAs-mediated protein degradation. PSMA7-deficiency destabilized 20S proteasomes and disrupted translocation of ELVAs, leading to pronounced accumulation of ubiquitinated proteins in oocytes and zygotes. Consequently, maternal Psma7 deletion resulted in female infertility, manifested by impaired oocyte maturation and developmental arrest at one- to two-cell stage. Furthermore, we observed reduced proteasome abundance and dysfunction of ELVAs in aged oocytes, providing a mechanistic explanation for the decline in developmental competence associated with oocyte aging. Taken together, our findings elucidate the critical function of proteasome-regulated proteostasis within ELVAs in maintaining oocyte quality during OET and reproductive aging.

The field of human adult neurogenesis has been controversial despite mounting evidence. The authors propose moving beyond debating the existence of adult neurogenesis and towards discovering strategies to harness endogenous stem cell potential for resilience against cognitive aging.

Nicotinamide adenine dinucleotide (NAD

Aging is increasingly recognized as a dynamic and potentially modifiable biological process, yet translation of mechanistic discoveries into clinically validated interventions that extend human healthspan remains limited. Because dermatologists can directly observe, sample, and quantify age-related changes in vivo, the skin provides an accessible platform for gerotherapeutic evaluation. As the largest and most environmentally exposed organ, the skin integrates intrinsic hallmarks of aging, including cellular senescence, mitochondrial dysfunction, extracellular matrix remodeling, epigenetic alterations, and chronic low-grade inflammation, with lifelong environmental stressors. These mechanisms manifest as structural, functional, and molecular phenotypes that can be monitored longitudinally using non-invasive technologies. Beyond serving as a visible indicator of organismal aging, cutaneous dysfunction may also influence systemic aging through inflammatory, immune, vascular, and neuroendocrine signaling. Here we examine how skin-based biomarkers and functional endpoints can support three translational priorities: aligning interventions with heterogeneous aging trajectories, defining functionally meaningful outcome measures, and responsibly integrating emerging diagnostic technologies. Anchoring gerotherapeutic development in dermatologic science may accelerate validation of interventions aimed at preserving resilience, physiological function, and independence across the lifespan.

Existing interventions for geriatric frailty have demonstrated limited overall efficacy, underscoring the need to identify more precise frailty trajectories and develop targeted therapeutic strategies. Although substantial research has examined frailty prevalence among Chinese older adults, few studies have explored longitudinal trajectories, and limited evidence suggests that patterns resemble those observed in other countries. This study aims to identify distinct frailty trajectories and their multidimensional predictors, thereby informing personalized interventions to slow frailty progression.

In mammals, precise regulation of primordial follicle activation is essential for maintaining the female reproductive lifespan. In this study, we demonstrated that the vitamin D receptor (VDR) is expressed in both pre-granulosa cells and oocytes within primordial follicles of mice and humans.

Physical activity may enhance cognition in older adults, yet evidence from randomized controlled trials (RCTs) on mechanistic pathways remains inconclusive.

The effect of mitochondrial-haplotype (mt-haplotype) on aging was studied using a unique rat model (OKC-HET

Caloric restriction (CR) reduces age-related risks, while diet quality is critical for healthy aging. Understanding how adults adjust diets to sustain CR and maintain nutrient adequacy can inform nutrition for healthy aging. Healthy adults (

Workaholism, also referred to as problematic overworking, has received increasing attention due to its adverse consequences for individuals, families, and organizations. This perspective paper argues that workaholism represents a largely neglected risk factor for unhealthy aging, as sustained exposure to excessive and compulsive work might be associated with an increased risk of cardiometabolic conditions, including hypertension and cardiovascular disease. We further highlight that, despite the high prevalence of work-related stressors in academia, empirical research on workaholism in university settings remains limited, underscoring the need for targeted prevention and intervention strategies. Addressing workaholism through approaches that reduce problematic overworking, promote adaptive work engagement, and support a healthier balance between professional and personal life may contribute to improved long-term health trajectories among academic staff. Finally, we propose the integration of workaholism-focused assessment and intervention components into the Semmelweis-EUniWell Workplace Health Promotion Program as a scalable framework for fostering healthy aging in academic workplaces.

Epigenetic clocks, developed using blood DNA methylation data, can be used to estimate biological ages and pace of aging. We aimed to identify potential determinants of the pace of aging, estimated using blood DNA methylation, and to investigate the association between the pace of aging and all-cause mortality in a population-based Norwegian cohort with repeated DNA methylation measurements.

Aging is a major contributor to functional decline of the heart and various cardiovascular diseases. Alterations across different cardiac cell types must be tightly orchestrated during the normative aging process that has begun to be mapped at the transcriptional level through single-cell RNA-sequencing. However, current rodent models are limited in their capacity to experimentally test large numbers of candidate differentially expressed genes (DEGs). As an attractive alternative, the African Turquoise Killifish (ATK) promises more efficient genetic studies of cardiac aging because it has the shortest lifespan among vertebrates. Despite its experimental advantages, single-cell transcriptomic studies on cardiac aging in ATK have not yet been conducted. Here, we generated scRNA-seq profiles of hearts from young and old GRZ strain ATK and demonstrated changes in cellular composition, gene expression, functional pathways, and intercellular communication during cardiac aging. This dataset not only recapitulates previously characterized cardiac aging hallmarks but also highlights the contribution of underappreciated cardiovascular cell types, such as epicardium and immune cell types, to cardiac aging.

The senescence of nucleus pulposus cells (NPCs) is a hallmark pathological feature of intervertebral disc degeneration. Senescent NPCs exhibit mitochondrial dysfunction and impaired mitophagy, thus compromising mitochondrial turnover and quality control. Current therapeutic strategies predominantly target external risk factors but do not restore mitophagy. In this study, a proline carbon dot-composited poly(L-methionine) (EG

Transcription factor (TF) modules interact to regulate key biological processes and cell-state transitions in normal physiology and disease. Understanding these modules and how they evolve over time can be accomplished by constructing gene regulatory networks (GRNs). To identify context-specific TF subnetworks, we developed ChEA-KG, which generates enriched TF regulatory subnetworks for input gene sets. ChEA-KG is based on a GRN connecting 1559 human TFs via 131 181 signed and directed edges inferred from diverse published ChIP-seq (chromatin immunoprecipitation followed by sequencing) and mRNA (messenger RNA)-sequencing experiments. We demonstrate ChEA-KG's utility by applying it to uncover master regulators of aging, mechanisms of action (MoA) for drug classes, pan-cancer subtypes, and cell types from across 14 major human tissues. Next, we extend ChEA-KG to develop the webserver application ChEA-KG Time Series (ChEA-KG-TS), which identifies TF modules from time-series mRNA-sequencing datasets. Results from this workflow are automatically summarized as reports that include enrichment analysis, regulatory subnetworks, and UMAP projections of enriched TFs. We use ChEA-KG-TS to explain transient responses in two use cases. ChEA-KG and ChEA-KG-TS are available from https://chea-kg.maayanlab.cloud/ and https://chea-kg-ts.maayanlab.cloud/.

Environmental neurotoxicants are widely used in various industries, including agriculture and public health sectors, and are known to cause harmful effects to humans through environmental and occupational exposures. Neurotoxicants are increasingly recognized as significant contributors to premature brain aging and neurodegenerative disorders. This review delineates the literature on neurotoxicant-induced comprehensive biochemical and molecular pathways leading to brain aging by consolidating the mechanistic insights with a main focus on pesticides. Exposome research combines environmental monitoring with integrative multiomics technologies such as exposomics, proteomics, and adductomics to map the real impact of neurotoxicants in neurodegenerative disorders. We discussed the intersecting molecular genetic pathways, including genomic instability, telomere attrition, epigenetic remodeling, including aberrant DNA methylation and microRNA deregulation, and biochemical pathways, including mitochondrial dysfunction, oxidative stress, impaired proteostasis, and autophagic disruption across the lifespan. These complex and often intergenerational mechanisms can be contextualized within the exposome framework to emphasize the cumulative environmental exposures that shape premature brain aging. Neurotoxicant exposure interferes with critical neuroprotective pathways, induces systemic metabolic dysregulation, neuroinflammation, and neurodegeneration, and disturbs the gut-brain axis, further amplifying neuronal vulnerability. A mechanistic understanding is important for toxicity screening and regulatory frameworks to mitigate the long-term consequences of neurotoxic insults. This review highlights the importance of eco-friendly alternatives such as integrated pest management strategies to reduce pesticide burdens on humans and environmental health for sustainable development.

Brain clocks are promising tools for evaluating brain health. However, most current methods rely on structural neuroimaging. Functionally based approaches remain scarce, especially for assessing age-related neurodegenerative diseases. This study examines whether the brain age gap (BAG), the difference between chronological and predicted brain age, reflects neurodegeneration when estimated from electroencephalographic resting-state (rsEEG) α-oscillations, a well-established marker of brain functional aging. It also explores whether α-based brain clocks reflect sociodemographic diversity and structural inequality. The BAG was computed using spectral descriptors of α-activity in the rsEEG source space of 1228 healthy participants, individuals with mild cognitive impairment (MCI), and patients with Alzheimer's disease or behavioral variant frontotemporal dementia, residing in 10 countries with varying levels of structural inequality. BAGs are increased in MCI and dementia groups, particularly in posterior cortical regions. Structural inequality emerges as the strongest predictor of BAG, surpassing cognition, education, and sex. The findings indicate that an α-oscillation-based brain clock provides a sensitive functional marker of brain aging, capable of capturing neurodegenerative processes as well as the impact of social disparities. This scalable, accessible approach to brain health shows promise for translational use and population-wide screening in underserved, resource-limited settings.

During wakefulness, neuromodulators operate largely independently to support behavior and cognition. By contrast, sleep reorganizes their activity into a coordinated brain rhythm. During sleep, the major neuromodulators-norepinephrine, acetylcholine, serotonin, and dopamine-exhibit synchronized fluctuations with a periodicity of ~50 seconds. These oscillations appear as recurrent bursts of fast (10 to 30 hertz) electroencephalography activity and are phase-coupled to cerebrospinal fluid flow. Neuromodulators are vasoactive agents and drive slow vasomotion, which provide the mechanical force that supports glymphatic clearance of metabolic waste. Disruption of neuromodulator signaling, as seen in psychiatric disorders, cardiovascular disease, aging, or with commonly prescribed drugs, impairs clearance of neurotoxic proteins, including amyloid-β and tau. Failure of this evolutionarily conserved brain rhythm may therefore represent a previously unrecognized mechanistic pathway linking diverse disorders with sleep disturbances to increased dementia risk.

Mitochondria, serving as central organelles for energy metabolism, play a critical regulatory role in stem cell self-renewal and differentiation-a function increasingly supported by accumulating evidence and closely linked to various aging-related diseases. Central to their function in stem cell pluripotency are several key mechanisms, such as the control of reactive oxygen species, mitophagy, and mitochondrial-endoplasmic reticulum communication. Mitochondrial transfer, as an emerging intercellular communication mechanism, can enhance stem cell pluripotency and function by replacing damaged mitochondria or activating mitophagy in recipient cells. However, different transfer mechanisms can induce distinct effects on recipient cells. The development of artificial mitochondrial transfer technology, compared to traditional cell transplantation, reduces immune rejection and offers new strategies for stem cell therapy. This review examines the interplay between mitochondrial function and stem cell fate determination, discusses the therapeutic potential of mitochondrial transfer in stem cell-based regenerative strategies, and establishes a theoretical framework for understanding and treating mitochondrial dysfunctions and aging-associated pathologies.

Periodontitis is a chronic inflammatory disease characterized by progressive destruction of periodontal tissues and alveolar bone, traditionally attributed to microbial dysbiosis. Emerging evidence suggests that host-intrinsic factors, including circadian rhythm disruption (CRD) and cellular senescence, may critically influence disease susceptibility and progression. CRD, resulting from misalignment between central and peripheral clocks, is known to impair stem cell function, alter telomere maintenance, and disrupt oxidative stress and metabolic homeostasis across multiple tissues. In parallel, cellular senescence exacerbates tissue damage through the senescence-associated secretory phenotype (SASP), which promotes inflammation and extracellular matrix degradation. Although direct evidence linking CRD and cellular senescence to periodontitis remains limited, mechanistic studies in related models suggest that these processes may converge to dysregulate immune responses, metabolic activity, and bone remodeling in the periodontium. Circadian disruption may impair stem cell regenerative capacity, alter immune cell rhythmicity, and enhance osteoclastogenesis, whereas senescent cells may further aggravate chronic inflammation and tissue destruction. This conceptual framework integrates circadian biology with aging-related mechanisms, highlighting potential pathways through which CRD and cellular senescence may modulate periodontitis. Understanding these interactions may inform novel preventive and therapeutic strategies, including circadian alignment, senolytic approaches, and metabolic modulation, for the early and precise management of periodontal disease.

Chronic kidney disease and biological aging share overlapping mechanisms, but conventional risk models may not adequately capture their combined impact on mortality. This study aimed to determine whether integrating DNA methylation-based biological age (epigenetic age) with renal function estimates could enhance mortality risk prediction.

The study examined systemic effects of short-term exposure to an enriched environment (EE) on the morphofunctional state of the liver, oxidative-antioxidant balance, and hormonal status in young (3 months) and mature (12 months) males of Wistar rats. In adult control rats, signs of physiological aging were detected: a significant decrease in brain mass ratio, depletion of liver glycogen stores, accumulation of fluorochromes, development of oxidative stress and hormonal imbalance. EE exposure in the regimen of 2 weeks for 10 min/day exerted a pronounced protective effect predominantly in aged animals: brain mass coefficient increased, glycogen content in hepatocytes rose, fluorochrome content in the liver decreased, superoxide dismutase activity increased, and hormonal profile normalized. Young rats showed no significant changes under EE influence, indicating sufficient intrinsic adaptive reserves at this age. The obtained data demonstrate age-dependent modulation of systemic homeostasis under cognitive-sensory stimulation via mechanisms of neuroendocrine regulation and reduction of oxidative damage, opening prospects for developing non-pharmacological strategies to slow aging and maintain functional liver reserve during maturity.

Accumulation of senescent cells (SnCs) in the ageing brain contributes to Alzheimer's disease (AD) progression by secreting a senescence-associated secretory phenotype (SASP) that exacerbates neuroinflammation and neurodegeneration. Senolytic agents that selectively eliminate SnCs have emerged as a potential therapeutic strategy; however, safer natural alternatives remain underexplored. In this study, we aimed to investigate the senolytic potential of Moringa oleifera leaf extract (MOL) in an in vitro AD-senescence model using SH-SY5Y cells exposed to amyloid-β (Aβ

In this cross-sectional cohort we analyzed data from 4260 "health enthusiasts" who purchased at least one saliva-based DNA epigenetic test between 2020 and 2025 and completed detailed lifestyle and supplement questionnaires. A proprietary 9-CpG clock with a mean absolute error of 5.4 years served as the primary biomarker of biological age. High prevalence (71%) of supplement use in this cohort increased our power to study the effects of supplements compared to earlier studies that focused on the general population. We tested the association between 84 commonly used supplements and biological age measured as Age Residual. In our cross-sectional analysis, a commercially available, delayed-release calcium-alpha-ketoglutarate (dAKG) + vitamin supplement ("Rejuvant") was associated with an average 1.8-year lower Age Residual. The difference remained significant in models adjusted for age, sex, smoking, health status and additional covariates. In contrast, participants who reported taking regular AKG showed a much smaller and statistically insignificant benefit. Among medications, there was a non-significant benefit of antihistamine use, although the analysis was sample-size limited. In a longitudinal subset, intake of coenzyme Q10 (CoQ10) and dAKG was associated with increased odds of a lower Age Residual, but the results were not significant after multivariate correction. In conclusion, this study underscores the utility of an inexpensive saliva-based epigenetic test for population-level aging research and the benefits of health enthusiast cohorts. It highlights AKG and CoQ10, among others, as promising supplements warranting further investigation. Limitations like healthy user and recruitment bias remain and will require future controlled trials to fully address.

Theanine, which accumulates in Camellia sinensis (L.) O. Kuntze, has demonstrated strong neuroprotective effects and other health benefits that have attracted attention. This paper reviews relevant literature published during the past 5 years, analyzing and summarizing studies focusing on the neuroprotective functions of theanine. By alleviating neuroinflammation, theanine exerts therapeutic effects on mental disorders caused by cumulative stress, ranging from mild sleep disturbances to depression induced by sleep deprivation. It has also demonstrated beneficial effects in delaying disease progression and promoting repair in age-related neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. This paper also reviews studies investigating the protective effects of theanine against organ dysfunction caused by nerve injury, as well as its synergistic effects with other phytochemical components in promoting neurological health. The potential mechanisms underlying the neuroprotective effects of theanine are considered from three perspectives: ferroptosis induced by oxidative stress in neuronal cells, the differentiation and development of neural stem cells (NSCs), and neural signal transduction pathways. Further investigations are needed to achieve a more rigorous and comprehensive understanding of theanine. © 2026 Society of Chemical Industry.

DNA methylation changes are reliable biomarkers of aging, but the driving mechanisms remain poorly understood. Here we present SCARLET (Stem Cells and Age-ReLated Epigenetic Trajectories), a parsimonious mathematical model that describes how methylation changes in blood arise and propagate through hematopoietic stem cell divisions. Using a large human cohort, we demonstrate that seemingly distinct age-related methylation patterns can be explained by a unifying mechanistic model. We show that SCARLET captures known drivers of epigenetic aging, with accelerated individuals showing reduced ratios of stem cell pool size to division rate (N/s). Applying SCARLET to methylation data from 11 mammalian species reveals that N/s scales with maximum lifespan, suggesting that evolutionary adjustments to stem cell dynamics, rather than epigenetic maintenance efficiency, drive the previously observed relationship between methylation rates and lifespan. Our findings provide a quantitative framework for understanding epigenetic aging and suggest that stem cell dynamics may be a key driver of aging across mammals.

Reprogramming-induced rejuvenation (RIR) reverses cellular aging by transiently engaging early reprogramming states without full dedifferentiation. This review examines current developments in the molecular mechanisms, technological advances, and tissue-specific applications of RIR. Recent mechanistic insights highlight persisting questions in timing, heterogeneity, and pathways engaged in the epigenetic response. New technological advances have expanded RIR modalities beyond traditional Yamanaka factors to include mRNA-based delivery, CRISPRa, and chemical cocktails, while high-throughput screening platforms are systematically identifying novel rejuvenation factors with improved safety profiles. Recent tissue-specific applications demonstrate functional restoration across brain, liver, intestine, cardiovascular, and epithelial systems through reversal of cellular senescence, reduction of DNA damage and epigenetic age, and enhanced regenerative capacity. However, clinical translation faces challenges including narrow therapeutic windows, incomplete mechanistic understanding, and limited biomarker standardization. We discuss how single-cell technologies, computational prediction tools, and systematic in vivo testing may advance RIR toward geroscience therapies for age-related diseases.

Atherosclerotic cardiovascular disease is the leading cause of mortality worldwide, with arterial stiffness being an important predictor of cardiovascular mortality. This study aimed to examine in the Swedish longitudinal cohort of males and females (SPAF-1958) whether aerobic capacity measured at early- (34 years) and mid-adulthood (52 years) can predict arterial stiffness assessed by pulse wave velocity later in life (63 years). Further, we determined whether this association is modified by traditional cardiovascular risk factors such as obesity, smoking, blood pressure, advanced lipoprotein profiles and high-density lipoprotein (HDL) function determined as cholesterol efflux capacity. Multiple regression analysis revealed that a higher aerobic capacity at ages 34 (B = - 0.04, P = 0.002) and 52 (B = - 0.04, P = 0.005) significantly predicted lower arterial stiffness at age 63, independent of obesity, smoking, blood pressure, HDL, and HDL-cholesterol efflux capacity. In contrast, lipoprotein profiles and HDL-mediated cholesterol efflux at age 52 were not associated with arterial stiffness at age 63 (P > 0.05). These findings suggest that maintaining aerobic capacity from early adulthood can reduce arterial stiffness and cardiovascular risk in later life, independently of traditional and contemporary cardiovascular factors. This study emphasizes the need for further research on lifestyle modifications to enhance cardiovascular health.

Intracerebral hemorrhage (ICH) is a neurological disorder characterized by a high mortality rate for which there is currently no definitive cure. Research has demonstrated that adipose-derived mesenchymal stem cells (ASCs) exhibit considerable potential in treating ICH. However, the advanced age of ICH patients and the necessary cell expansion before transplantation therapy could result in the senescence of ASCs, thereby compromising their viability and therapeutic efficacy. This study aims to investigate whether FGF21 (fibroblast growth factor 21) can rejuvenate aged ASCs by enhancing macroautophagy/autophagy flux and subsequently enhance the therapeutic efficacy of ICH. We demonstrated that the autophagy flux of aged ASCs was significantly decreased and FGF21 treatment significantly reversed the senescence phenotype and increased the viability of aged ASCs. Mechanistically, our findings suggested that FGF21 rejuvenates aged ASCs by augmenting autophagy flux, a process partly mediated by TFE3 (transcription factor E3) nuclear translocation. The FGF21-induced TFE3 nuclear translocation was partially facilitated potentially via the FGFR1-SIRT1-MTOR pathway. In addition, FGF21 enhanced the potential of senescent ASCs to differentiate into neurons. In the in vivo study, we further verified that FGF21 could enhance the therapeutic effect of ASCs on acute ICH rats. In conclusion, these results indicated that FGF21 could restore ASC viability by upregulating TFE3-mediated autophagy flux in part through the FGFR1-SIRT1-MTOR signaling pathway, enhanced the potential to improve the differentiation of ASCs into neural stem cells and enhanced the therapeutic effect of ASCs transplantation in acute ICH.

Methionine restriction (MR) extends the lifespan and healthspan of numerous eukaryotic organisms, but the molecular mechanisms at play are unclear. Here we find that the ability of MR to extend the budding yeast chronological and replicative lifespans is the consequence of reduced methionine conversion to the methyl donor S-adenosylmethionine (SAM). Mechanistically, the key antiaging event downregulated by MR is the methylation of protein phosphatase 2A (PP2A). In chronological aging cells under MR, unmethylated PP2A no longer dephosphorylates Npr2, a component of the SEACIT complex, resulting in activation of non-nitrogen-starvation (NNS)-induced autophagy. Deletion of genes encoding components of SEACIT or ATG1 (encoding a central player in the initiation of autophagy) blocked the ability of MR to extend lifespan, showing the critical role of the NNS-induced autophagy pathway in lifespan extension by MR. We identify the relevant Npr2 site dephosphorylated by PP2A as serine 362 and show that Npr2 phosphomimetic mutants are sufficient to extend chronological and replicative lifespan. Finally, we discover that MR only during the early stages of chronological aging is sufficient to prolong autophagy and extend lifespan. In addition to elucidating the molecular mechanism of MR-mediated lifespan extension, this study highlights potential therapeutic targets to achieve lifespan and healthspan extension in humans without the challenging long-term dietary changes required to achieve MR.

The field of regenerative aesthetics is advancing rapidly, shifting from traditional cosmetic techniques to therapies targeting the biological mechanisms behind tissue degeneration.

Glucagon-like peptide-1 (GLP-1) receptor agonists have attracted interest as gerotherapeutics, yet clinical-trial evidence for their effects on biological aging is lacking. We report a post hoc exploratory epigenetic age analysis of a 32-week, randomized, double-blind, placebo-controlled phase 2b trial (NCT04019197) of semaglutide in adults with human immunodeficiency virus (HIV)-associated lipohypertrophy (semaglutide n = 45; placebo n = 39). The parent trial's primary endpoint was change in visceral adipose tissue, with secondary cardiometabolic and body-composition endpoints; epigenetic aging was not pre-specified. To address this gap, we profiled peripheral-blood DNA methylation (DNAm) at baseline and week 32 to assess semaglutide versus placebo on first-, second-, and third-generation epigenetic aging measures. In adjusted analyses, semaglutide reduced epigenetic aging across multiple second- and third-generation clocks, including PhenoAge ( - 4.9 years/year, p = 0.004), PCGrimAge ( - 3.1, p = 0.007), GrimAge V2 ( - 2.3, p = 0.009), OMICmAge ( - 2.2, p = 0.009), RetroAge ( - 2.2, p = 0.030), and DunedinPACE ( - 0.09 units, 9% slower, p = 0.01). Systems-based clocks showed parallel reductions in inflammation, brain, and heart aging measures. The post hoc design, modest sample size, HIV-specific cohort, and 32-week follow-up limit generalizability. Prospective trials are needed to determine whether GLP-1 receptor agonists can be repurposed as gerotherapeutics.

Mitochondria, long regarded as the cell's "powerhouses", also serve as intracellular quality-control modules that promote the elimination of damaged or proliferatively dysregulated cells. Alongside their energetic benefits, mitochondrial apoptosis regulation may have helped shape the earliest steps toward stable multicellular organization. An agent-based modeling framework is developed to isolate and quantify the evolutionary impact of a mitochondrial death-surveillance system under nutrient stress, independently of its energetic contribution. The model tracks two cell types - normal prokaryotic cells (NPCs) and dysfunctional prokaryotic cells (DPCs) - each characterized by three dynamic state variables: damage load, proliferation drive and energy deficit. Mitochondrial surveillance is formalized as a simplified rule that detects stress and eliminates dysfunctional cells when a critical dysregulation boundary is crossed. Across 1200 stochastic simulations spanning variable nutrient regimes and inoculum sizes, mitochondrial surveillance prolonged median colony-collapse time by approximately 17%-18% across both nutrient regimes. The results indicate that a mitochondria-linked, intrinsic apoptosis-like gate can stabilize simple microbial groups independently of bioenergetic benefit, and is consistent with the view that such quality-control mechanisms provided a selective advantage toward robust multicellular organization. The framework also provides a conceptual basis for viewing mitochondrial transplantation as a means to restore intracellular fate-decision control, rather than solely to augment energy supply, in settings such as aging and cancer.

Reduction in skeletal muscle mass, strength, and function, such as sarcopenia, have been associated with cognitive impairment. In Latin America (LATAM), evidence remains scarce, a critical gap given the region rapid demographic aging. Therefore, the present study aims to evaluate the association between sarcopenia and cognitive impairment among middle-aged and older adults in LATAM countries.

Telomere length (TL) is a widely used biomarker of biological aging, and is shortened in people living with HIV (PWH) due to chronic inflammation and immune-activation. The DNA methylation-based estimator of TL (DNAmTL) has emerged as a promising alternative to classical TL measurements, but their comparative performance in PWH remains poorly characterized.

Cellular aging is characterized by the progressive accumulation of intracellular damage, declining repair capacity, and altered mechanochemical signaling, ultimately leading to cellular senescence and loss of tissue homeostasis. Despite extensive experimental and theoretical efforts, the fundamental origin of senescence and its irreversible nature remain incompletely understood. In particular, it is unclear whether senescence must be imposed as a predefined cellular state or can instead emerge dynamically from more basic damage-repair mechanisms. In this work, we propose a unified age-damage structured mathematical framework for cellular aging that integrates intracellular damage accumulation, biochemical signaling, mechanical stress, and population renewal within a thermodynamically consistent variational structure. The model combines continuum thermodynamics with age-structured population dynamics, ensuring compliance with the second law of thermodynamics and providing a rigorous basis for irreversible aging processes. A central result of the model is the emergence of a damage-driven loss of homeostasis at a critical threshold of effective load, beyond which no steady intracellular damage state exists. This transition generates irreversibility at the single-cell level and propagates to the population scale through transport in age-damage space, leading naturally to the emergence of cellular senescence without introducing ad hoc senescence rules. Mechanical stress enters the model through a quadratic contribution to the effective damage load, producing a pronounced nonlinear sensitivity and predicting abrupt acceleration of aging beyond a critical stress level. To facilitate analysis and computation, we derive a reduced ODE-PDE system that retains the essential couplings between damage accumulation, biochemical signaling, mechanical stress, and population renewal. Analytical arguments and numerical illustrations demonstrate how transient mechanical or biochemical perturbations can induce persistent senescence at the population level. Overall, the proposed framework provides a mechanistic and thermodynamically grounded explanation of irreversible senescence as an emergent phenomenon in age-structured cell populations.

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Aging drives systemic metabolic dysfunction (SMD) and increases the risk of chronic illnesses such as metabolic dysfunction-associated steatotic liver disease (MASLD) and chronic kidney disease (CKD). However, mechanisms that connect aging to multi-organ deterioration are poorly understood. In this study, we identify hepatocyte Hedgehog signaling as a central regulator of ferroptosis. Using mice with hepatocyte-specific deletion of Smoothened (Smo), a key Hedgehog pathway component, we show that loss of hepatocyte Hedgehog signaling induces ferroptotic stress, lipid peroxidation, and cellular senescence. These changes were sufficient to cause spontaneous MASLD and to trigger secondary kidney injury. Smo deletion also disrupted systemic iron balance, increased hepatocyte production of the angiotensinogen, and reduced liver perfusion. Similar responses (iron dysregulation, vascular dysfunction, and reduced Hedgehog signaling) were observed in patients with MASLD and advanced fibrosis. Inhibition of ferroptosis with ferrostatin-1 reversed hepatocyte senescence, restored hepatic blood flow, and improved both liver and kidney injury in Smo-deficient mice. Overall, these findings show that hepatocyte Hedgehog signaling preserves liver homeostasis by restraining ferroptotic stress and coordinating iron-dependent vasoactive pathways. The results reveal an unrecognized aging-related communication axis between liver and kidney and identify the Hedgehog-ferroptosis pathway as a promising therapeutic target for age-associated metabolic diseases.

Males and females share nearly identical genomes yet exhibit profound differences in disease susceptibility, progression, and treatment response across the lifespan. These sex differences arise from evolutionary conflicts in which genetic variants confer opposing fitness effects between sexes, maintained by balancing selection. This review examines how sex shapes complex trait architecture from early childhood through postreproductive life. Early childhood reveals intrinsic genetic sexual dimorphism before hormonal activation. During reproductive years, sex-specific metabolic programming manifests through divergent adipose distribution and cardiometabolic risk, while autoimmune diseases demonstrate a fourfold female bias driven by incomplete X-inactivation. Postreproductive phases reveal antagonistic pleiotropy, in which variants that are beneficial for early reproduction increase late-life disease vulnerability. Systematic exclusion of X chromosome data from ∼75% of genome-wide association studies has obscured critical therapeutic targets. Sex-stratified genomic analyses consistently uncover effect sizes and risk loci that are invisible in sex-combined models. We argue that precision medicine must incorporate sex as a fundamental axis of genomic stratification across development, rather than treating it as a covariate to be adjusted away.

Abstract Background: Biological systems exhibit dynamic patterns over multiple temporal scales -from minutes to months- that are poorly captured by conventional cross-sectional or low-frequency longitudinal studies. These patterns, including circadian and ultradian rhythms, may be critical determinants of health, resilience, and disease risk in aging. Existing longitudinal studies in older adults lack high-frequency, multimodal measurements that integrate molecular, physiological, and digital health data streams. Objectives: The TIME Study aims to: (i) Characterize temporal patterns in molecular, physiological, and digital health measures in healthy older adults; (ii) determine how these patterns vary across biological domains and relate to each other; and (iii) assess how physiological systems respond to defined perturbations (oral glucose tolerance and maximal exercise). Methods: TIME is a single-site, observational, longitudinal study enrolling up to 150 adults aged [≥] 55 years. Over an 11-week main phase, participants complete seven weekly low-frequency visits, two perturbation challenge visits, and two, two-day high-frequency sampling epochs. Biospecimens, clinical measures, cognitive and physical performance tests, and continuous digital health data are collected. Follow-up visits occur at 6 and 12 months. Expected Impact: By integrating multimodal, temporally resolved data, TIME will provide a foundational dataset for understanding the role of biological rhythms in aging and inform future precision health strategies.

Lysosomal function is essential for cardiac proteostasis and cellular health, yet its regulation during ageing remains poorly defined. We aimed to determine whether whole-organ, fluorescence imaging using an In Vivo Imaging System (IVIS) provides a novel, rapid and scalable approach for quantifying lysosomal abundance in intact ex vivo hearts prior to deeper molecular analysis.

Recent advances have shifted our understanding of the blood-brain barrier (BBB) not as a static wall, but as a dynamic and evolving system whose property is variable across the lifespan: acquisitive in early development, heterogeneous in adulthood, and increasingly fragile in aging. This BBB dynamic has called for a conceptional shift in how we understand the physiological and pathological processes related to barrier functions, including CNS drug exposure and age-related neurological disorders (e.g., stroke, vascular dementia). This Editorial offers a lifespan-based perspective of the BBB dynamics, highlighting current knowledge on how the BBB evolves from development through adulthood and into aging. Overall, recognizing the developmental and dynamic nature of the BBB is essential for safer pediatric dosing, more predictable adult therapeutics, and effective vascular strategies for preserving cognitive health.

Alternations of DNA methylation occur in aging, which is regulated by DNA methyltransferases (DNMTs). In this study, we show that even though the transcription of DNMT1, the only enzyme that maintains DNA methylation in the mammalian genome, is reported to be decreased in an age-dependent manner, the decrease of

Ageing is accompanied by progressive microvascular dysfunction, a key determinant of organ performance and longevity. The molecular drivers of this process remain incompletely defined, and the mechanisms by which exercise counters vascular ageing are unclear. This study investigated whether exercise-regulated long noncoding RNAs (lncRNAs) contribute to microvascular ageing and age-related cardiac dysfunction.

Sarcopenia, the age-related decline in muscle mass and strength, affects the functional capacity of older adults. Strength training (ST) combined with adequate protein intake is a key element in reversing and improving functional capacity. Protein, especially Whey Protein isolates (WPI), is widely used to improve muscle mass. In contrast, high-protein products, such as protein yogurt (PY), may offer similar benefits for muscle health and drive additional effects on gut health, which is altered in older adults. For this, we aim to compare WP and PY supplementation during ST on body composition, strength, and gut microbiome in untrained older adults. Seventeen untrained adults (60-70 years) were randomized to either consume WP (25 g) or PY (24.5 g) along with an 8-week supervised ST program (3 sessions/week). Initial and final assessments included body composition (BIA), strength (10RM, isokinetic torque, handgrip), gait speed, resting metabolic rate, and gut microbiome (16 S rRNA sequencing). Data were analyzed using repeated-measures ANOVA and diversity metrics. Both groups increased skeletal muscle mass (WP: +0.47 kg; PY: +0.50 kg) and improved strength and gait speed (p < 0.01), with no between-group differences. Fat mass decreased only in WP (p = 0.02), while resting metabolic rate increased in PY (p = 0.03). Microbiome analysis revealed distinct shifts: WP increased the Firmicutes/Bacteroidota ratio and enriched Subdoligranulum, whereas PY enhanced alpha diversity and increased the abundance of Coprococcus. Functional pathway predictions indicated differential enrichment in metabolic and signaling processes. High-protein yogurt and whey protein similarly improve muscle mass, strength, and functional capacity during ST, while exerting distinct effects on gut microbiome composition. Yogurt represents a cost-effective alternative to whey protein and may confer additional gut health benefits.Trial registration: Clinicaltrials.gov identifier NCT06412302. Date of registration 06/05/2024.

Skin aging is an inevitable biological process caused by cellular senescence and overexposure to harmful environmental factors such as ultraviolet (UV) radiation. Senescent fibroblasts with proliferation arrest, mitochondrial dysfunction and nicotinamide adenine dinucleotide phosphate (NADPH) depletion have been proposed as a major mechanism driving skin photoaging, but the specific therapies are currently lacking. Inspired by the self-powering potential of plant-derived photosynthetic system, we herein fabricated a novel nanophotosynthetic platform that integrated Chlorella-derived nanothylakoid units (NTUs) with hyaluronic acid (HA)-based microneedles (MNs) to specifically target senescent fibroblasts for treating skin photoaging. By equipped with photosynthesis (PS)-I/II and quinolinate phosphoribosyltransferase (QPRT), the NTU-MN photosystem remarkably increased mitochondrial biogenesis and adenosine triphosphate (ATP) generation, resumed NAD(P)H pool and increased cellular anabolism, addressing the heighted bioenergetic and biosynthetic requirement for highly turnover of fibroblasts during photoaging. Furthermore, with skin penetrating ability of MNs and camouflaging of fibroblast membranes, topical application of the nanophotosystem facilitated the intradermal release of NTUs, leading to regeneration of damaged tissues, increased collagen synthesis, decreased senescence-associated secretory phenotype (SASP), and hence alleviated photoaging of skin. Thus, we developed a "green nanoplatform" with significantly anti-aging efficacy, biocompatibility, and biosafety, opening new avenues for light-driven therapies for degenerative diseases.

Ribosomes consist of approximately 80 distinct ribosomal proteins and rRNA. The genes encoding these ribosomal components are among the most highly expressed in growing cells. Changes in ribosome composition, such as those induced by oxidative stress, may compromise ribosome function. Such ribosomes are subsequently targeted for degradation. Additionally, under stress, both protein synthesis and ribosome biogenesis are downregulated. Under starvation stress, excess ribosomes are degraded through a process called ribophagy, a selective form of macroautophagy/autophagy that utilizes the autophagy pathway. While receptors for several selective autophagy pathways are known, the evolutionarily conserved ribophagy receptor was not identified until recently. In a recent publication, the authors identify Rpl12 and its homologs as receptors that promotes ribophagy from yeast to humans. They also demonstrate that ribophagy enhances lifespan and facilitates the clearance of pathogenic bacteria.

Geroscience needs biomarkers that capture the progressive decline of integrated biological systems with age. Physical capacity, a direct manifestation of systemic integrity, is a core pillar of biological aging but is typically assessed through discrete clinical tests. Speech production, a complex motor act requiring coordinated respiratory, laryngeal, and articulatory control, shares fundamental physiological pathways with global physical function and may therefore serve as an accessible digital biomarker of aging. In a longitudinal cohort of 464 community-dwelling older adults (mean age 79.6 ± 8.7 years), we tested the hypothesis that changes in speech track specific changes in physical capacity. Participants underwent a 3-month adapted physical activity (APA) program. At baseline (T0) and post-intervention (T1), we performed a battery of ten objective physical tests (strength, power, endurance, gait, balance, flexibility, mobility, appendicular lean mass, fatigue) and recorded spontaneous speech during emotional autobiographical recall. Multi-layered acoustic, temporal, and linguistic features were automatically extracted. The longitudinal association was analyzed via Spearman correlations and univariate linear mixed-effects models. The APA intervention induced significant improvements in key physical domains, including mobility, gait speed, handgrip strength, and balance (all p < 0.01). These gains were specifically correlated with concurrent changes in speech features (|ρ| = 0.11-0.22). For instance, greater lower-limb strength correlated with reduced vocal shimmer and lexical diversity, while improved flexibility was associated with a lower spectral centroid and zero-crossing rate, indicating smoother phonation. Linear mixed models confirmed significant within-individual coupling between trajectories of physical function and speech dynamics. Emotional context systematically modulated these associations, revealing different speech-stress signatures under cognitive-affective load. This study provides novel longitudinal evidence that speech is a dynamic digital biomarker of domain-specific physical capacity, reflecting underlying functional integrity. The domain-specific speech-physical coupling suggests that speech analysis can serve as a novel, integrative tool for remote monitoring of aging trajectories and the functional efficacy of interventions targeting the age-related physiological decline.

Skeletal muscle exhibits a remarkable level of plasticity that enables it to adapt to exercise training, as well as the deleterious effects of aging. Fundamental to this malleability are epigenetic processes, which collectively enhance chromatin remodeling and subsequently alter DNA availability for gene expression. A growing body of evidence has demonstrated that acute exercise is a powerful inducer of epigenetic remodeling, capable of stimulating gene-specific alterations, which transcriptionally activate exercise-responsive genes. These epigenetic processes, including DNA methylation and various histone modifications, are highly responsive to exercise-induced signaling cascades and mitochondrially-related metabolites, together indicating that exercise can modulate the nuclear and mitochondrial epigenome as a mechanism to regulate gene expression. However, aging is characterized by a unique epigenetic signature, which likely supports the alterations in gene expression observed with age. Yet, the effects of exercise on epigenetic regulation with age remain underexplored. To investigate the intersectionality of these two phenotypes and highlight significant gaps within the literature, this review aimed to discuss the different types of epigenetic modifications that have been reported within skeletal muscle and how they are altered with acute and chronic exercise. Furthermore, we aimed to analyze mitochondrial epigenetics and their role in mediating alterations in mitochondrial-nuclear crosstalk observed with exercise and age. Elucidating age-dependent adaptations in the epigenome and the differential effects of exercise in these populations will help uncover the complexity of gene regulation with age, and importantly, reveal how exercise can regulate many of these processes to improve muscle health.

Abdominal adiposity may contribute to both general and cardiovascular ageing, yet the extent to which accelerated biological age (BA) at distinct molecular levels mediates these effects has not been fully elucidated.

Older adults who have fallen are at an increased risk of future falls. Training cognitive and physical functions simultaneously, known as dual-task (DT) training, has been shown to improve mobility and reduce fall risks. With appropriate digital tools, such as smartphones and mobile apps, it is possible to deliver DT training in unsupervised, home-based settings, thereby increasing accessibility beyond the clinical environment.