Longevity Papers

Theogallin, a tea-derived polyphenol enriched in newly developed cultivars such as MK5601, has been shown to have cognitive benefits. However, its biological and mechanistic effects of theogallin remain unclear. Herein, we investigated the transcriptomic profiles of six mouse tissues after oral theogallin administration. Theogallin induced tissue-enriched transcriptional responses, particularly in the brain, where it activated memory-related and neuronal activity-related pathways through the upregulation of immediate-early genes (IEGs). These transcriptional changes closely resembled brain-derived neurotrophic factor (BDNF)-induced neuronal activation and contrasted with gene expression patterns associated with Alzheimer's disease. In aged mice, theogallin improved recognition memory and increased the expression of IEGs-associated proteins, while reducing neurodegeneration-linked markers. Theogallin also enhanced neuronal gene expression in SH-SY5Y cells, supporting a direct neuromodulatory role and further promoting neurite outgrowth. Therefore, theogallin is a functional enhancer of neuronal activation with potential therapeutic relevance for age-related cognitive decline and neurodegenerative disorders.

Aging adipose tissue is a consequence of organismal aging and an "amplifier" that drives systemic metabolic disorders. This review proposes the conceptual framework of the "aging metabolic amplifier", systematically explaining how aging adipose tissue reshapes the microenvironment of distant organs through its secretory profile, thereby linking obesity, diabetes, cardiovascular diseases, and neurodegenerative diseases. The concept of the "aging metabolic amplifier" emphasizes the important role of senescent adipocytes in systemic metabolic dysfunction, and systematically elaborates on their heterogeneous characteristics, autonomous and non-autonomous changes, as well as their mechanisms in ectopic lipid deposition, cardiovascular diseases, and cognitive decline. Currently, specific intervention strategies-such as activating the thermogenic program, eliminating senescent cells, regulating autophagy, and improving the microenvironment- have been proposed, providing potential therapeutic directions for delaying aging and related metabolic diseases.

Osteoporosis, characterized by diminished bone density and compromised microstructure, presents a significant healthcare challenge, particularly in the aging population. The primary approach in addressing osteoporosis involves the use of anti-resorptive agents as well as medications that promote bone formation. However, these therapies have limitations, prompting the exploration of novel therapeutic targets. Prolyl Endopeptidase (PREP), an endopeptidase with diverse roles in neuronal peptide metabolism and various physiological processes, has emerged as a potential player in osteoporosis, though its mechanistic involvement remains largely uncharted. This study delves into the role of PREP in osteoporosis, aiming to unravel its underlying mechanisms and therapeutic potential. Utilizing murine models and cellular experiments, we systematically investigate how PREP influences osteoblast differentiation and osteoporosis pathogenesis. Our results suggest activation of the Wnt pathway counteracts the inhibitory effects of PREP deletion on osteoblast differentiation. Additionally, we observe that PREP affects osteoclastogenesis, influencing osteoclast differentiation and bone resorption capacity. Moreover, our investigation extends to age-related osteoporosis, demonstrating PREP's potential therapeutic efficacy beyond estrogen-deficiency-induced osteoporosis. In summary, this study advances our understanding of PREP's multifaceted role in osteoporosis pathogenesis. It underscores PREP as a potential therapeutic target for osteoporosis, offering fresh perspectives on its etiology and treatment.

Aging is the primary risk factor for cognitive decline and neurodegenerative disorders, characterized by impaired circuit plasticity and disrupted gamma oscillations. Non-invasive 40 Hz audiovisual stimulation (AuViS) has emerged as a promising strategy to restore cognition in models of Alzheimer's disease and stroke. Yet, the mechanisms underlying these effects remain unclear. We found that AuViS increased gamma oscillations in the dentate gyrus of middle-aged mice. Control animals displayed scarce neurogenesis, and newborn neurons exhibited limited growth and remained functionally immature. Notably, AuViS triggered the proliferation of neural progenitor cells and shifted the balance from astrocytic towards neuronal differentiation. It also promoted neuronal maturation, leading to the development of complex dendritic trees and axons with large mossy terminals bearing filopodial extensions. These structural modifications were accompanied by increased spiking capacity and spontaneous synaptic activity, indicative of effective circuit integration. These effects were dependent on TrkB signaling, implicating neurotrophin pathways. Our findings demonstrate that AuViS reestablishes neurogenesis and promotes network remodeling in the healthy aging brain, which might aid to ameliorate neurological conditions.

Multiple brain age prediction models have been developed using diverse methodological approaches. However, it remains unclear whether these models capture a shared genetic signal. We first conducted a new brain age gap (BAG) GWAS in 60,735 subjects across 29 cohorts worldwide, and then applied genomic structural equation modelling to examine the shared genetic variance with five prior BAG GWASs using a single latent BAG factor (30 cohorts overall). All six BAG GWASs loaded onto a single factor (R2=63%, 19 SNPs). Genetically, the BAG factor was positively correlated with multiple traits, with blood pressure, smoking, longevity, autism, and sleep showing putatively causal effects. Polygenic score (PGS) associations with BAG were observed already in childhood. BAG factor PGS captured more associations with health traits than individual BAG PGSs, suggesting that the shared signal may provide a more sensitive marker of brain health than any single model alone.

The gut microbiome has emerged as a critical regulator of human aging and healthspan, with age-related dysbiosis increasingly implicated in a broad spectrum of aging-associated diseases. This review synthesizes evidence linking gut microbial alterations to infectious diseases, antimicrobial resistance, autoimmune, neurodegenerative, psychiatric, cancer, metabolic, kidney, cardiovascular, bone, and muscular diseases, highlighting shared mechanisms such as chronic inflammation, immune dysregulation, and metabolite imbalance. We further explore how enabling technologies, including functional multi-omics, synthetic biology, artificial intelligence-driven analytics, biobanking, and autologous fecal microbiota transplantation, are revolutionizing microbiome research and the design of interventions. Ethical considerations surrounding microbiome-based therapies are also addressed. To translate these scientific insights into clinical innovations, we formulate the PRIME framework: a five-phase roadmap encompassing

Alzheimer's disease (AD) incidence is rising with no effective treatments. Eleutheroside B (EB) has neuroprotective potential, but its therapeutic effects and mechanisms in AD are unclear. This study investigated EB's effects on AD pathologies and elucidated its underlying mechanisms using a transgenic Caenorhabditis elegans (C. elegans) model. We found that EB could ameliorate cognitive impairment, locomotor dysfunction, and shortened lifespan induced by amyloid-β(Aβ) and Tau aggregation in C. elegans, and reduce the relative expression levels of Aβ, Tau, and phosphorylated Tau (p-Tau) proteins. EB improved the health status and anti-aging capacity of the worms, as evidenced by prolonged healthspan, elevated pharyngeal pumping rate and body bend frequency, and increased body length and width. Notably, EB exhibited no observable toxicity even at high-dose administration. Furthermore, EB activated key stress-responsive transcription factors skn-1, daf-16, and hsf-1; it also increased the expression levels of antioxidant enzymes superoxide dismutase-3(SOD-3) and glutathione S-transferase 4(GST-4), decreased reactive oxygen species (ROS) levels, and elevated the expression of heat shock proteins Hsp-4 and Hsp-6. EB also reduced the accumulation of p62/SQST-1 protein, promoted the colocalization of lgg-1:GFP with lysosomes, and increased the relative mRNA expression of autophagy-related genes aak-2, unc-51, bec-1, vps-34, and lgg-1. After targeted knockdown of these genes, the protective effects of EB against AD-related pathologies were abolished. Our findings demonstrate that EB exhibits anti-aging properties and potential for ameliorating AD, which is likely mediated via antioxidative activities and autophagy induction.

ObjectiveThis study investigates the relationship between aging and histone deacetylases (HDACs) in mandibular condylar cartilage.MethodsMale C57BL/6 mice were divided into 4 age groups: postnatal day 21 (D21, postnatal development), 3 months (3M, young adulthood), 10 months (10M, middle aging), and 18 months (18M, late aging) to cover mandibular condylar cartilage aging stages. Mandibular condylar cartilage specimens were harvested and paraffin-embedded. Hematoxylin-eosin (H&E) and Safranin O-fast green staining were performed to assess morphological changes. Immunohistochemistry (IHC) was applied to map the spatiotemporal expression of the HDAC1-11 in condylar cartilage.ResultsHDAC1, HDAC6, HDAC7, and HDAC9 were undetected in the mandibular condylar cartilage. HDAC2, 3, 4, 8, and 10 were only expressed 21 days after birth, with HDAC2 showing the strongest expression. Notably, HDAC5 expression was higher at 18 months. HDAC11 had consistent intensity until 18 months when it decreased. Other HDACs peaked at 21 days and declined with age.ConclusionThis study established the spatiotemporal expression pattern of HDAC1-11 in the temporomandibular joint (TMJ) condyle during aging. It provides a foundation for further research on HDAC functions, offering insights into TMJ aging mechanisms.

Immunological aging (immunosenescence) drives increased susceptibility to infections and reduced vaccine efficacy in elderly populations. Current bulk transcriptomic aging clocks mask critical cellular heterogeneity, limiting the mechanistic dissection of immunological aging. Here, we present Ensemble-DeepSets, an interpretable deep learning framework that operates directly on single-cell transcriptomic data from peripheral blood mononuclear cells (PBMCs) to predict immunological age at the donor level. Benchmarking against 27 diverse senescence scoring metrics and existing transcriptomic clocks across four independent healthy cohorts demonstrates superior accuracy and robustness, particularly in out-of-training-distribution age groups. The model\'s multi-scale interpretability uncovers both conserved and cohort-specific aging-related gene signatures. Crucially, we reveal divergent contributions of T cell subsets (pro-youth) versus B cells and myeloid compartments (pro-aging), and utilize single-cell resolution to highlight heterogeneous aging-associated transcriptional states within these functionally distinct subsets. Application to Systemic Lupus Erythematosus (SLE) reveals accelerated immune aging linked to myeloid activation and altered myeloid subset compositions, illustrating clinical relevance. This framework provides a versatile tool for precise quantification and mechanistic dissection of immunosenescence, providing insights critical for biomarker discovery and therapeutic targeting in aging and immune-mediated diseases.

The phylogeny of a person's hematopoietic stem cells (HSCs) can be used to quantify physiological aging of blood using a phyloAge model based on diversity decay metrics. However, this procedure currently requires accurate HSC genome sequences, which are expensive and time-consuming to obtain. We show that metrics of diversity decay can be derived from the somatic variant frequency spectrum (VFS) using more affordable, routine bulk sequencing, because HSCs evolve without recombination at a clock-like rate. We found that VFS-based models produce phyloAge estimates similar to those derived from HSC genome phylogenies. Customized for protein-coding variation and sequencing read depth, VFS-based HSC phyloAge estimates were, on average, 168 years more than chronological ages in 157 patients with acute myeloid leukemia, consistent with excess HSC aging observed in cancer patients using single cell genome phylogenies. We also tested the hypothesis that variants in cancer driver genes may confer longevity, as they occur in a significant fraction of long-lived individuals. Indeed, HSC phyloAge estimates were significantly lower, consistent with reduced hematologic cancer risk among extremely old individuals. Thus, the new metrics and models broaden the utility of the phyloAge approach, making it feasible and efficient for clinical and research applications.

Osteoarthritis(OA) is an age-related degenerative joint disease, and the absence of clinically effective therapy places a substantial burden on global health. The crosstalk among oxidation, inflammation, and aging (oxi-inflamm-aging) disrupts chondrocytes homeostasis, serving as a critical driver in OA initiation and progression. Here, we developed a mitochondria-centered therapeutic strategy aimed at concomitantly disrupting the pathogenic oxi-inflamm-aging network. This strategy emphasized a novel chimeric peptide (MW) designed by integrating the mitochondrial protective MOTS-s and cartilage-targeting WYRGRL. To enhance therapeutic delivery and efficacy, the bifunctional chimeric peptide MW is immobilized onto GeSe nanosheets, which are then embedded within a multifunctional responsive hydrogel composed of HA-MAL, MMP13-sensitive peptide, and PF127 (HMP), forming the peptide-functionalized nanocomposite hydrogel (MW@GeSe@HMP). This engineered nanocomposite hydrogel not only exhibited efficient enzyme-mimicking mimetic properties to scavenge harmful oxygen radicals, but also enabled MMP-responsive targeted release in chondrocytes. Subsequent biological experiments revealed that MW@GeSe@HMP effectively disrupted the oxi-inflamm-aging network by modulating mitochondrial function, thereby maintaining chondrocyte homeostasis. Mechanistically, MW@GeSe@HMP protected chondrocytes via hindering cGAS/STING signaling. The nanocomposite hydrogel also significantly suppressed cartilage damage and matrix degradation, effectively alleviating OA progression in a rat OA model. In conclusion, this study developed a nanocomposite hydrogel integrating bioactive peptides and two-dimensional nanoenzyme, providing a prospective therapeutic strategy and potential target for OA treatment by regulating oxi-inflamm-aging integrative network.

Age-related declines in muscle and bone mass increase the risk of sarcopenia and osteoporosis. Both conditions contribute to morbidity and mortality in older adults and frequently coexist as osteosarcopenia. Gut microbiota play a crucial role in maintaining muscle and bone homeostasis, and dysbiosis may accelerate the onset and progression of these conditions. We therefore performed a systematic review and meta-analysis of observational studies published up to May 6, 2025. We identified 45 eligible studies including 6,751 participants. Patients with sarcopenia showed significant reductions in α-diversity indices compared with controls, including Chao1 (SMD=-0.28, 95% CI=-0.44, -0.11), observed species (SMD=-0.52, 95% CI=-0.79, -0.25), and ACE (SMD=-0.24, 95% CI=-0.48, -0.01), whereas patients with osteoporosis exhibited no significant differences. Distinct clustering of β-diversity was observed in twelve of eighteen sarcopenia studies (66.7%) and twelve of twenty-one osteoporosis studies (57.1%). This suggests that microbial community structures are altered in both conditions. Moreover, sarcopenia and osteoporosis shared consistent microbial alterations, with enrichment of the genus Eggerthella and depletion of the family Lachnospiraceae and the genus Blautia. A qualitative summary of functional pathway analyses suggests potential enrichment of purine, pyrimidine, cysteine and methionine metabolism, implying common metabolic disruptions. These findings highlight overlapping microbial signatures in sarcopenia and osteoporosis and support a role for gut dysbiosis in musculoskeletal decline. They also provide mechanistic clues that may help guide future preventive and therapeutic strategies for osteosarcopenia.

Aging impacts immune function, but the mechanisms driving age related changes in immune cell subsets remain unclear. To explore age dependent changes in immune cell populations, we analyzed human peripheral blood mononuclear cells (PBMCs) from a cohort of healthy donors aged 20 to 82 years using a 36-color spectral flow cytometry panel focused on T cells. We identified a unique population of memory CD8 T cells, which lack CXCR3 and produce a Th2 like cytokine response, accumulate with age. We discovered an age-dependent bias in naive CD8 T cells toward Th2 cytokine production, accompanied by transcriptional and epigenetic changes supporting this phenotype. Moreover, health outcome association analysis linked the accumulation of these unique CXCR3 central memory CD8 T cells to asthma, chronic liver conditions, and type 2 diabetes. Together, our results support the model that an age-dependent drift in epigenetic regulation towards a Th2 like phenotype drives a pathogenic Th2 like immune population.

The Blood-Brain Barrier (BBB) is a selective barrier that regulates the entry of molecules including nutrients, environmental toxins, and therapeutic medications into the brain. Its function continues to evolve postnatally, through aging, and disease states. Here we present a global proteomics analysis focused on the ontogeny and aging of proteins in human brain microvessels (BMVs), predominantly composed of brain endothelial cells. Our proteomic study quantified 6,223 proteins and revealed possible age-related alterations in BBB permeability due to basement membrane component changes through the early developmental stage and age-dependent changes in transporter expression. Age dependent expression changes were observed within nutrient transporters and transporters that play critical roles in drug disposition. This research 1) provides important information on the mechanisms that drive changes in the metabolic content of the brain with age and 2) enables the creation of physiologically based pharmacokinetic models for CNS drug distribution across different life stages.

Senescence of vascular endothelial cells (ECs) and smooth muscle cells is pivotal in vascular aging. While the long non-coding RNA JPX has been shown to induce smooth muscle cell senescence, its role in EC senescence remains unknown. Senolytics (dasatinib + quercetin, D + Q) can eliminate senescent cells and attenuate the senescence-associated secretory phenotype (SASP), but their mechanisms in ECs are unclear. Here, we investigated the interplay between Senolytics and JPX in human umbilical vein endothelial cells (HUVECs). Using a lipopolysaccharide (LPS)-induced senescence model, we found that Senolytics alleviated endothelial senescence while suppressing the upregulation of JPX observed in senescent HUVECs. Functional assays showed that JPX knockdown inhibited, whereas JPX overexpression aggravated, EC senescence. Mechanistically, JPX interacted with bromodomain-containing protein 4 (BRD4) and transcription factor p65 to form a JPX-BRD4-p65 complex that promoted SASP expression. In vivo, Senolytics disrupted this complex and effectively mitigated endothelial senescence. Collectively, our study identifies JPX as a key regulator of vascular endothelial senescence and reveals that Senolytics exert anti-senescent effects by antagonizing the JPX-BRD4-p65 complex, providing novel mechanistic insights and potential therapeutic targets for vascular aging-related diseases.

BackgroundHeart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases; however, mechanism-based therapies targeting cellular dysfunction remain absent. Emerging evidence suggests that mitochondrial dysfunction and impaired quality control, particularly defective mitophagy, are central to the pathogenesis of HFpEF. Urolithin A (UA), a gut microbiome-derived postbiotic metabolite, has shown promise as a mitophagy activator in preclinical models; however, its therapeutic efficacy in HFpEF remains unknown. MethodsWe used a clinically relevant two-hit HFpEF mouse model (high-fat diet (HFD) plus N{omega}-nitro-L-arginine methyl ester (L-NAME)) and co-administered UA during disease progression. The cardiac structure and function were assessed using echocardiography, histology, and transmission electron microscopy. Mitochondrial bioenergetics were evaluated using Seahorse-based respirometry. Mitophagy flux was monitored using mt-Keima assays in H9c2 cells and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Mechanistic insights were obtained using immunoblotting, integrated shotgun metagenomic and lipidomic profiling, and single-nucleus RNA sequencing (snRNA-seq). ResultsUA treatment significantly attenuated cardiac remodeling and fibrosis in HFpEF mice while improving diastolic function parameters. Transmission electron microscopy revealed restoration of the mitochondrial ultrastructure, and mitochondrial stress tests demonstrated enhanced oxidative phosphorylation capacity and glycolytic reserves. Immunoblot assays revealed that UA treatment recovered PINK1/Parkin-mediated mitophagy markers (reduced LC3-II and p62/SQSTM1). Mt-Keima assays confirmed enhanced mitophagic flux in H9c2 cells under HFpEF-like stress conditions. Integrated metagenomics and lipidomics revealed significant reductions in cardiovascular risk-associated ceramides. snRNA-seq demonstrated that HFpEF-like stress downregulated contractile, calcium-handling, and mitochondrial mitophagy gene programs. UA treatment restored the mitochondrial quality control signatures and normalized profibrotic and conduction-type cell populations. ConclusionsUrolithin A restored mitochondrial quality control through the activation of mitophagy and reversed cardiac remodeling in HFpEF. These findings establish UA as a mitochondria-targeted therapeutic candidate for HFpEF. Novelty and SignificanceO_ST_ABSWhat is known?C_ST_ABS{checkmark} Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome driven by metabolic stress and myocardial remodeling, for which effective disease-modifying therapies are lacking. {checkmark}Mitochondrial dysfunction and impaired mitophagy have been implicated in HFpEF, but their roles in cardiomyocyte state remodeling and fibrosis remain incompletely defined. {checkmark}Urolithin A, a gut microbiome-derived metabolite, enhances mitophagy in aging and metabolic tissues, but its relevance to HFpEF has not been established. What new information does this article contribute?{checkmark} Urolithin A restores mitochondrial quality control and mitophagic flux in cardiomyocytes, improving diastolic function and attenuating cardiac remodeling in a two-hit HFpEF model. {checkmark}Integrated metagenomic and lipidomic analyses identify suppression of gut microbiome-associated ceramide biosynthesis as a systemic mechanism linked to Urolithin A-mediated cardioprotection. {checkmark}Single-nucleus RNA sequencing reveals that Urolithin A reverses maladaptive cardiomyocyte transcriptional state transitions toward fibrogenic and conduction-like programs.

Surfactant proteins, particularly SP-A and SP-D, S100 family members and fibronectin belong to the group of so-called stress-related molecules and share the characteristic of being expressed at anatomical barriers such as the skin, pulmonary/respiratory epithelia, and the intestinal tract. In this context, they constitute part of the body's first line of defence, acting in concert with immune cells to counter a broad spectrum of external and internal stressors (exposomes), potentially fuelling chronic low-grade inflammation (inflammaging). The levels of the above-mentioned molecules in the blood or local tissues result altered in a range of age-associated pathologies and have been proposed as potential diagnostic/prognostic biomarkers, although they generally lack specificity for a single pathological condition. Evidence from in silico analyses further suggests that most of these molecules may be regulated by members of the microRNA-29 family, pointing towards hierarchical epigenetic mechanisms that merit detailed investigation as potential contributors to ageing-related biomarker signatures. Despite research advances, the identification of robust biomarkers capable of predicting disease onset at the individual level, an essential prerequisite for precise geromedicine, remains an elusive goal in clinical practice. Although individuals differ biologically, this does not preclude the existence of overarching principles that could be reflected in hierarchical biomarkers. Within this framework, a pragmatic strategy for immediate application may involve the systematic use of currently available longitudinal data, for example, from hospitalised patients or through dedicated software programs utilised by general practitioners.

An extracellular polysaccharide (AEPS-1) with novel structure and anti-aging potential was isolated and characterized from Streptomyces sp. YJ06. Structural analysis revealed AEPS-1 is a neutral gluco-mannopolysaccharide of low molecular weight (8513 Da) featuring a unique triple-helical conformation and a highly branched architecture. It demonstrated significant in vitro antioxidant activity, characterized by exceptional reducing power alongside moderate free radical scavenging capacity. Crucially, AEPS-1 effectively extended the chronological lifespan of Saccharomyces cerevisiae by alleviating oxidative damage, as evidenced by reduced malondialdehyde (MDA) and enhanced superoxide dismutase (SOD) activity. This study highlights AEPS-1 as a promising candidate for further development as a natural anti-aging agent.

Mitochondrial dysfunction is widely recognized as a key driver of aging and neurodegenerative diseases, with mitophagy acting as an essential cellular mechanism for the selective clearance of damaged mitochondria. While pharmacological activation of mitophagy has been reported to exert beneficial effects across multiple neurodegenerative diseases, its functional relevance in amyotrophic lateral sclerosis (ALS) remains poorly characterized. Our recent study published in

Aging is associated with progressive loss of kidney function and vascular structure, with and without chronic kidney disease. However, the mechanisms driving kidney vascular aging and potential therapeutic interventions remain poorly understood.

Mitochondrial dysfunction is one of the core drivers of aging. It is manifested by reactive oxygen species (ROS) accumulation, mitochondrial DNA (mtDNA) mutations, imbalanced energy metabolism, and abnormal biosynthesis. Mitochondrial autophagy maintains cellular homeostasis by selectively removing damaged mitochondria through mechanisms including the ubiquitin-dependent pathway (PINK1/Parkin pathway) and the ubiquitin-independent pathway (mediated by receptors such as BNIP3/FUNDC1). During aging, the decrease in mitochondrial autophagy efficiency leads to the accumulation of damaged mitochondria, forming a cycle of mitochondrial damage-ROS-aging damage and aggravating aging-related diseases such as neurodegenerative diseases and cardiovascular pathologies. The targeted regulation of mitochondrial autophagy (drug modulation and exercise intervention) can restore mitochondrial function and slow aging. However, autophagy has a double-edged sword effect; moderate activation is anti-aging, but excessive activation or dysfunction accelerates the pathological process. Therefore, targeting mitochondrial autophagy may be an effective anti-aging technique; however, future focus should be on the tissue-specific regulatory threshold and the dynamic balance mechanism to achieve precise intervention.

Lung aging is a multifactorial series of molecular alterations that leads to gradual deterioration of lung function and increased vulnerability to cancer. Tumor communicates with host organs partially through extracellular vesicles; however, the mechanistic drivers and consequences of lung aging in the context of cancer remain unclear. Here we identify cancer cell-secreted dimethylarginine dimethylaminohydrolase-1 (DDAH1) protein induces citrulline accumulation and promotes lung fibrosis and aging. Mechanistically, our single-cell sequencing and genetic knockout mice evidence that citrulline availability elevation inhibits peptidyl arginine deiminase 4-mediated transforming growth factor-β1 (TGF-β1) citrullination, thereby inducing the TGF-β1/Smad3 signaling pathway in lung fibroblasts. Notably, vacuolar protein sorting assists the packaging of DDAH1 into the late endosomes. The administration of DDAH1 inhibitor reduces fibrosis and alleviates lung aging. Conclusively, our findings reveal tumor-derived DDAH1 protein contributes to citrulline accumulation to promote lung aging, shedding light on the treatment and diagnosis of tumors by inhibiting senescent lung fibroblasts.

The physiological effects of spaceflight resemble those of ageing and prolonged inactivity, and ground-based microgravity analogs have emerged as promising models for studying frailty. The human microbiome is increasingly recognised for its role in age-associated decline, although precise mechanisms remain unclear. Here, we evaluate the gut and oral microbiomes of twenty-two participants, aged 55-65, who were enrolled in a head-down tilt bedrest (HDBR) study, the first Canadian HDBR study conducted in an older cohort. Participants were randomly assigned to an inactivity or multi-modality exercise intervention group for fourteen days of HDBR, followed by seven days of rehabilitation and additional follow-up appointments. Gut (n=343) and oral (n=344) taxonomic profiles were generated using V4/V5 16S rRNA gene sequencing from fecal and salivary samples collected throughout the study. Gut functional profiles were generated using metagenomic (n=86) and metabolomic (n=83) data. Frailty was measured using a 36-item frailty index. Inactivity-associated changes to the gut microbiome during HDBR included decreasing -diversity, decreasing Akkermansia and Lactobacillus, and increasing Bacteroides. Exercise-associated changes included increasing gut Roseburia. Interestingly, oral microbiome {beta}-diversity was more strongly associated with frailty than the gut. We conclude that inactivity-associated changes to the human microbiome could contribute to the early stages of frailty development, and that exercise can serve as an effective countermeasure against these effects. These results may inform strategies to preserve the health of both older adults facing prolonged periods of inactivity, as well as astronauts during longer space exploration missions. IMPORTANCEHealthy ageing carries significant demographic, economic, and public health implications globally, and both physical activity and human-associated microorganisms play important roles in its trajectory. Using microgravity simulation in older adults as a human frailty model, we show that short periods of inactivity could have significant effects on these microbial communities, particularly in the gut, which could further contribute to multi-system physiological decline and frailty pathogenesis. Participants who completed a daily, multi-modality exercise intervention did not exhibit these changes, which may help protect both older adults facing periods of inactivity and astronauts in the advent of longer space exploration missions. Interestingly, our results suggested that oral bacteria may be a more sensitive indicator of individual frailty levels than gut bacteria. Future research should ensure that functional aspects of human-associated microbial communities are thoroughly investigated, as these may offer deeper insight into their contributions to age-related decline.

Synaptic architecture underlies neuronal computation, with autophagy serving as a key regulator of synaptic plasticity, function and local metabolism. Yet, autophagy dynamics and regulation within intact neuronal circuits remains poorly understood. Here, we developed a pH sensitive fluorescence lifetime-based imaging method which allows to monitor autophagy dynamics at the synaptic level with a second-scale temporal resolution in the living mouse brain. This approach allowed us to uncover compartmentalized autophagic activity across soma, dendrites, and axons of layer 2/3 cortical neurons. Notably, we observe experience-dependent modulation of autophagy dynamics with pronounced mobility of autophagic vesicles in apical distal dendrites compared to basal proximal dendritic branches. We identified cell-type specific basal autophagy levels in excitatory, inhibitory, and astrocytic cells in the mouse cortex. Finally, combining this approach with disease associated genetic perturbation uncovers novel in vivo autophagy related phenotypes. Altogether, this approach highlights the spatial and functional complexity of autophagy in the intact mammalian brain and establishes a framework for investigating its role in synaptic regulation during development, plasticity, and aging.

Many age-related lung diseases encompass aberrant repair mechanisms. To develop novel treatments for these diseases, it is critical to understand how biology and repair signals are altered in aged lungs. Extracellular vesicles (EVs) carry bioactive signals reflecting their source tissue; therefore, we used EVs derived from precision-cut lung slices (PCLS) as tools to investigate differences in lung biology and repair signals that occur upon ageing and injury. We compared the physicochemical properties and biological content of four groups of EVs, obtained from uninjured and injured, young and aged PCLS. Treatment with EVs obtained from young, uninjured (YU) PCLS decreased apoptotic cells in both young and aged spatially injured (AIR)-PCLS. YU EVs also increased the percentage of alveolar progenitor cells in aged AIR-PCLS, indicating that aged lungs retain the capacity to mount a repair response, if provided with the right biological cues. Small RNA sequencing revealed the miRNA content of each EV group is altered, depending on the physiological conditions of their source tissue. Bioinformatic analysis of the target genes regulated by differentially expressed miRNAs identified enrichment of genes required for lung development and repair. These findings pave the way for future therapeutic strategies to repair or regenerate aged lungs.

Sarcopenia is currently classified as an unmet medical need with an increasing incidence because of population aging. Excessive reactive oxygen species (ROS) production plays a critical role in the pathogenesis of muscle atrophy, a key feature of sarcopenia, whereas edaravone has been identified as a potent ROS scavenger in screening assays using C2C12 myocytes. In this study, we established an injured muscle-targeted drug delivery system (imDDS), which mimics the secreted protein acidic and rich in cysteine (SPARC)-mediated albumin uptake pathway, to deliver edaravone to damaged muscle tissue. SPARC on the cell surface facilitated the cellular uptake of human serum albumin (HSA) by forming disulfide bonds with the surface or intramolecular thiol groups of HSA. Endogenous albumin labeled with Evans blue accumulated in the injured muscle tissue of mice with sarcopenia, suggesting the potential of albumin to target damaged muscle tissue. Thiol-rich, edaravone-loaded HSA nanoparticles were internalized into hydrogen peroxide-injured myocytes in a SPARC-dependent manner, and edaravone was released into the cytosol in response to the acidic endosomal environment, resulting in a significant reduction of intracellular ROS levels. The nanoparticles also preferentially accumulated in SPARC-positive cells within the damaged muscle tissue of mice with sarcopenia and attenuated oxidative stress, thereby significantly restoring skeletal muscle mass and endurance. These findings suggest that edaravone-based, SPARC-guided biomimetic delivery represents a promising therapeutic strategy for sarcopenia and other muscle-related disorders.

Vascular senescence is a fundamental driver of age-related cardiovascular diseases, yet the epigenetic mechanisms controlling this process remain poorly understood. This study investigated the role and underlying mechanisms of lysine acetyltransferase 8 (KAT8), a key histone acetyltransferase, in maintaining endothelial cell homeostasis and preventing vascular senescence. We found that KAT8 expression is consistently downregulated in human aged vessels, senescent rats and mice, and in cellular models of aging. Using CRISPR/Cas9-based loss-of-function and gain-of-function approaches in endothelial cells, C57BL/6J mice, and ApoE

The relationships between 24-h time-use composition (i.e., sleep, sedentary behavior, light physical activity, and moderate-to-vigorous physical activity [MVPA]) and brain morphology in older adulthood remain poorly understood. We examined associations between 24-h time-use composition and brain age using compositional data analysis, predicting that 24-h time use would be associated with brain age and that a greater amount of time engaged in MVPA would drive associations with younger brain age.

Ex vivo organ slice cultures are attractive models to address specific biomedical research questions because they retain complex and dynamic three dimensional architecture. In addition, they require only a few animals as tissue donors thus greatly decreasing the number needed for live animal studies. The model has been most successful using tissues from very young mice, but has generally not been considered for aging research because of the challenge of maintaining viability of tissues collected from older mice. The brain is a high impact organ in aging and age-related disease research, so it was of interest to investigate the viability and related molecular and cellular characteristics of brain slice cultures (BSCs) derived from old mice. Coronal sections of 200 m thickness were collected from the middle third of the brain of 21 month old C57BL/6JN mice, cultured in a standard media concoction for seven days, exposed to chemical stressors glucose, hydrogen peroxide, lipopolysaccharide, or sodium hypochlorite for 24 to 48 hours, and then rinsed and cultured for another seven days. Results in non-treated BSCs showed cellular viability of greater than 80 percent with specific aging pathways relatively unaffected. Chemical stressors selectively targeted pathways of aging including DNA damage, autophagy, and inflammation. These preliminary observations suggest that BSCs derived from geriatric mice have potential for research into brain aging and age-related neurodegenerative conditions, and could serve as a prototype for developing organ slice cultures for other organs collected from old mice.

Neuromuscular transmission plays a crucial role in muscle function, with differences in neurotransmitter release potentially influenced by sex and aging. While hormonal effects on neurotransmission have been studied, their impact on acetylcholine (ACh) release at the neuromuscular junction remains largely unexplored. Understanding these differences could provide insights into age-related muscle function decline and sex-specific variations in neuromuscular disorders. This study aims to investigate sex- and age-related differences in spontaneous ACh release at the neuromuscular junction in mammals, focusing on variations in electromyographic (EMG) activity. Experiments were conducted on young (2 months) and old (15 months) Swiss male and female mice. EMG recordings were taken from the gastrocnemius muscle, analyzing the percentage of sites with endplate noise, noise frequency, and spike frequency. Estrous cycle stages in female mice were identified to account for hormonal fluctuations. Males exhibited a higher percentage of sites with endplate noise than females. Old females had the highest frequency of endplate noise, while old males had the largest amplitude. Spike frequency was higher in females and increased with age. These results suggest sex and age differences in neuromuscular activity, potentially influenced by hormonal and autonomic regulation. In conclusion, neuromuscular transmission differs between sexes and across aging. Estrogens may modulate cholinergic receptor function, and autonomic nervous system activity likely contributes to observed differences. These findings highlight distinct aging patterns in neuromuscular function between males and females.

Mesenchymal stem cells (MSCs) undergo senescence after expansion and in vitro culture under oxidative stress, which limits their clinical application. Ginsenoside Rh2 has been confirmed to regulate mitochondrial function, but its role in modulating the senescence of MSCs has not been clearly investigated.

Neurons adapt gene expression to counter aging, yet the mechanisms by which they harness age- related genes to resist neurodegenerative disease remain elusive. We found that transcriptionalaging inversion (TAGI) in the

For most species, Aging is an inevitable biological process that poses significant challenges to global healthcare due to age-related diseases. Recent advances in peptide therapy have highlighted anti-aging peptides (AAPs) as a promising therapeutic strategy, owing to their low immunogenicity and ease of synthesis. However, the lack of computational tools for AAP identification has hindered systematic research in this field.

This study examined whether social factors, including social support, social networks, and familism, modify the longitudinal association between ACEs and epigenetic age acceleration (EAA).

The extension of the human lifespan has increased the incidence of age-related metabolic disorders, such as type 2 diabetes and sarcopenia, which markedly impair quality of life and reduce life expectancy in older adults. Aging and insulin resistance synergistically compromise the functional integrity of the adipose and skeletal muscles. During aging, the adipose tissue exhibits impaired progenitor differentiation, chronic inflammation, fibrotic remodeling, and loss of thermogenic capacity. Skeletal muscles also exhibit changes, including satellite cell decline, mitochondrial dysfunction, defective protein turnover, and progressive sarcopenia. These changes diminish tissue plasticity and endocrine function and exacerbate insulin resistance through disrupted intracellular signaling and accumulation of metabolic burden. Notably, the deterioration of adipose and muscle tissue functions is interconnected, further exacerbating systemic metabolic dysfunction. Recent studies have contributed to elucidating the physiopathological causes and mechanisms of age-dependent cellular and molecular alterations in adipose and muscle tissues. This review summarizes the current insights into the cellular and molecular mechanisms underlying age-related alterations in adipose and muscle tissues and discusses emerging therapeutic strategies, including lifestyle interventions, pharmacological agents, approaches targeting senescent cells, and inter-organ communication that aim to preserve metabolic health in aging populations.

Ovarian aging is accompanied by a decline in the quantity and quality of follicles, leading to reduced fertility. Ovarian aging encompasses natural aging due to DNA damage, telomere attrition, and mitochondrial dysfunction, as well as a pathological functional failure caused by environmental toxins, known as a premature ovarian failure. Cell therapy is currently a focal point of research, with mesenchymal stem cells (MSCs) being particularly notable due to their wide availability, ease of expansion, strong self-renewal capabilities, multipotent differentiation, and paracrine functions. MSCs have shown great potential in the field of cell therapy, including delaying ovarian aging. MSCs can delay ovarian aging through various mechanisms: antioxidation, differentiation and regeneration, promotion of cell proliferation, inhibition of cell apoptosis, and anti-inflammatory responses. Currently, MSCs transplantation has achieved significant results in animal models, improving ovarian function and enhancing fertility. However, clinical applications still face numerous challenges, such as determining the optimal cell source, transplantation route, dosage, and long-term safety, which require further research. In this review, we will elaborate on the mechanisms of ovarian aging, the modes of action of MSCs, and the mechanisms by which MSCs delay ovarian aging, aiming to provide a theoretical basis for the clinical application of MSCs and to bring breakthroughs in the treatment of diseases such as premature ovarian failure.

Nicotinamide adenine dinucleotide (NAD) has garnered significant attention in recent years due to its central role in cellular metabolism and its potential as a supplement to promote health and longevity. While numerous human studies indicate that NAD supplementation offers benefits with minimal or no side effects, some studies show no observable advantages. This discrepancy highlights the importance of identifying individuals who are most likely to benefit from NAD-based interventions. One critical factor in the efficacy of NAD supplementation relates to its declining levels in certain individuals, driven by various causes of NAD depletion. NAD is a vital substrate for numerous enzymatic processes, notably those involving poly-ADP-ribose polymerase (PARP) enzymes. PARP enzymes, especially PARP1, play a pivotal role in DNA repair by detecting and signaling DNA damage. Excessive activation of PARP, hyperparylation, is frequently observed in DNA repair disorders where DNA damage accumulates due to defective repair mechanisms. This hyperparylation has been implicated in the pathogenesis of several premature aging diseases. Such conditions often involve defective DNA repair pathways, elevated parylation levels, and associated mitochondrial dysfunction, factors that contribute to accelerated cellular aging. In model systems that mimic these disorders, as well as in emerging human studies, NAD supplementation has demonstrated promising benefits, including improved DNA repair capacity and improved mitochondrial function. These findings suggest that NAD supplementation could serve as an effective intervention for rare genetic diseases characterized by premature aging and DNA repair deficiencies. More broadly, these insights open new avenues for general aging research.

Polyphenols are emerging as promising candidates for promoting healthy aging and neuroprotection. Here, we investigated the effects of quercetin (Q), luteolin (L), and 3-O-methylquercetin (3OMQ), individually and in combination (FORM), on lifespan, healthspan, and neurobehavioral functions in Caenorhabditis elegans. Wild-type and mutant strains (including daf-2, daf-16, and skn-1) were exposed to the compounds, followed by assessments of longevity, motility, senescence biomarkers (lipofuscin and red autofluorescence), and neuroprotection against PTZ- and methylmercury-induced damage. 3OMQ and FORM significantly extended lifespan (+ 20-24%) and improved motility and stress resilience, with effects dependent on the DAF-16/FOXO and SKN-1/Nrf2 pathways, but independent of DAF-2/IGF1R signalling. Both compounds induced DAF-16 nuclear translocation and upregulated SKN-1 expression. Furthermore, they attenuated neurodegeneration and cholinesterase hyperactivity following manganese and methylmercury exposure. These findings support the potential of 3OMQ and its polyphenol combination as anti-aging and neuroprotective agents, acting through conserved longevity and oxidative stress pathways.

Longevity medicine is an emerging clinical framework aimed at extending healthspan by targeting the biological mechanisms of aging rather than treating disease in isolation. Geroscience, which investigates the molecular and cellular pathways linking aging to chronic pathology, provides the scientific foundation for this approach. Dermatology is uniquely positioned within this paradigm, as the skin represents both a visible marker of biological aging and an accessible source of biomarkers.

Giant cell arteritis (GCA) and (PMR) are inflammatory rheumatic disorders whose pathogenesis are unclear. The interleukin (IL)-6 receptor inhibitor is the first approved biologic agent for GCA and PMR, reducing relapse rates and cumulative glucocorticoid (GC) doses. Notably, IL-6, also a key pro-inflammatory factor secreted by senescent cells, contributes to tissue aging and chronic inflammation. We aim to explore the role of senescence-associated secretory phenotype (SASP) in the pathogenesis of GCA and PMR.

Facial wrinkling is a prominent sign of aging, yet individuals exhibit unique trajectories of biological aging, contributing to the variability in facial appearance. Here, we present a pioneering study exploring the association between lifestyle choices, DNA methylation, and SNP genotypes with a range of facial skin aging phenotypes. The study demonstrated that age-related facial skin phenotypes are influenced by multiple environmental stressors. Epigenome-wide association analyses identified differentially methylated cytosines mapped to 151 loci, including novel genes associated with facial wrinkles, such as EDAR (cg02925966, p = 4.96 × 10

Biomarkers of aging have the potential to transform geroscience clinical trials because of their broad applications in stratifying participants, prioritizing interventions, and monitoring responses to geroprotectors. As longevity biotechnology companies (LBCs) continue to plan and launch innovative clinical trials, standard practices in collecting data and applying biomarkers of aging will allow the field to support parallel and ongoing validation and benchmarking efforts for aging biomarkers. Moreover, defining best practices will ensure future reuse of valuable clinical data through pre-competitive alignment on shared tools. Here, we propose recommendations for such collections. We believe that wide adoption of these recommendations will allow LBCs to produce and leverage the highest quality data from their clinical trials, while also benefiting the geroscience field more broadly with minimal additional effort.

Autophagy is a major intracellular degradative process required for maintaining homeostasis in multicellular organisms. Aberrant autophagy is considered to induce internal environmental disturbance and cell death. Therefore, it is of great significance to explore the regulatory mechanism of autophagy. Here, we report a positive role of protein Pira, a SUMO protease, in inducing autophagy and autophagy-dependent cell death during Drosophila development. We found that overexpression of pira in wing imaginal discs was able to induce selective autophagy (mitophagy) and autophagic cell death, resulting in wing loss. Moreover, Pira-induced mitophagy and cell death were dependent on the accumulation of Sima, the sole Drosophila homolog of mammalian HIF-1α. Disrupting the sima expression was adequate to inhibit the Pira effects for cell survival and wing development. In addition, the biomarkers of aging were activated in wing discs upon pira overexpression, and excessive Pira shortened fly lifespan, suggesting that Pira may be associated with aging. Together, we provided evidence demonstrating that ectopic Pira can activate the Sima/HIF-1α-mediated mitophagy and cell death, thereby leading to developmental defects in Drosophila.

With the aging of global populations, understanding the role of the cerebellum in aging is crucial. However, existing studies primarily focus on structural and functional changes, leaving the topological properties of cerebellar functional networks in aging unclear. Here, we explored the aging effects on the topological organization of cerebellar functional networks and investigated the relationship between these changes and cognitive function. The results revealed that, compared with young adults, older adults exhibited declines in the global and local network efficiency, modularity, and small-world properties of the cerebellum. Additionally, reductions were observed in the betweenness centrality within the visual network (VN), the nodal efficiency (NE) within the VN and lateral somatomotor network (SMN(Lat)). Moreover, the nodal local efficiency (NLE) decreased in the default mode network and SMN(Lat) of older adults. Notably, the gamma value of the cerebellar network was positively correlated with Stroop task accuracy in the incongruent condition among older adults. Additionally, aging impaired whole-brain (including cerebellar) network efficiency but preserved modularity and small-world properties, and at the nodal level, cerebellar regions showed selective reductions in NE and NLE, alongside degree centrality reorganization. Exploratory analyses revealed gender-specific patterns in cerebellar network topology during aging, with males experiencing relatively limited declines and females showing more extensive deterioration. The findings indicated that aging is associated with disruptions in the global and regional topology of the cerebellar functional connectome, with females exhibiting more pronounced deterioration than males. The integrity of cerebellar network topology appeared crucial for maintaining cognitive control.

Tumor senescence, a double-edged sword, can suppress tumor growth but also promote immune evasion if not properly cleared. Herein, a cell membrane-coated ZIF-8@MnOx nanoplatform co-loaded with doxorubicin (DOX) and piperlongumine (PL), termed mPDZM, is developed to remodel the senescence-mediated immune response in hepatocellular carcinoma. PL synergizes with DOX to amplify intracellular oxidative stress, which promotes both the killing of tumor cells and the clearance of senescent cells. The biomimetic ZIF-8@MnOx nanoplatform potentiates the efficacy of DOX and PL by integrating targeted delivery, hypoxia relief, and redox homeostasis disruption. mPDZM remodels the immunosuppressive microenvironment by regulating SASP release, inducing immunogenic cell death, and activating the STING signaling pathway. In vivo, mPDZM exhibits preferential tumor accumulation and minimal systemic toxicity. mPDZM treatment leads to significant tumor suppression both in the senescent and non-senescent tumor models. Moreover, mPDZM effectively promotes CD8

DNA methylation variation is associated with chronological ageing. Calorie restriction (CR) prolongs lifespan and healthspan in many species. Our hypothesis is that CR has an impact on DNA methylation patterns with increased CR leading to slower epigenetic ageing. We studied the effects of graded CR in male C57BL/6J mice on liver DNA methylation. Mice were fed ad libitum (AL) in the dark-phase or restricted by 10%, 20%, 30% or 40% from 5-months old for 19-months. Livers were collected in surviving mice at 24-months old and DNA methylation measured. Comparisons were made to 8-month-old AL fed mice. DNA methylation was significantly related to graded CR in a subset of cytosine-guanine dinucleotide (CpG) sites. In a substantially similar subset of CpG sites, DNA methylation in 24-month-old mice fed 40CR moved towards the values in 8-month-old AL fed mice, resulting in an average effective epigenetic age of about 12-months, indicative of slower epigenetic ageing. DNA methylation at several CpG sites was sensitive to glucose intolerance and circulating insulin levels, consistent with the impact of this nutrient sensing pathway on ageing. We focussed on genes where multiple CpG sites were significant for DNA methylation change with CR and found many have been implicated in age-associated liver diseases. In summary, the benefits of CR include modification of epigenetic signatures in the direction of slower ageing, consistent with the life extending effects of CR. Whether this effect is causal for the life extension under CR, and the mechanism by which it occurs remain unanswered questions.

Advanced atherosclerosis (AS) poses substantial residual risk of life-threatening cardiovascular disease, even with optimized lipid-lowering therapies. Histopathological evaluation of clinically obtained specimens revealed that advanced plaques developed a distinct senescent microenvironment compared to early stage lesions, and senescent foam cells (FCs) are the culprits in creating the pathological microenvironment via initiating senescence-propagating crosstalk with multiple vascular cells. Herein, we synthesized a zeolitic imidazolate framework-8 (ZIF-8)-based nanomedicine denoted as L-pKNZ. Unlike conventional senolytic agents that primarily induce cellular apoptosis, L-pKNZ activates FC autophagy and enhances macrophage efferocytosis. This strategy established an endogenous senolytic system to relieve FC overload while simultaneously reprogramming the senescent microenvironment. Results from multiomics analysis aligned with outcomes from in vitro/in vivo experiments, all in favor of vascular rejuvenation and AS amelioration. Critically, we successfully radiolabeled L-pKNZs with the radionuclide

Lactoferrin (LF) plays a positive role in attenuating aging. In this study, LF obtained using different processing methods (freeze-dried: F and spray-dried: S) and its gastrointestinal digesta (XF and XS) were supplemented in d-gal-induced mice to explore their antiaging effects. The results showed that LF and its digesta (LFs) effectively ameliorated cognitive decline. Mechanistically, LFs prevented neuronal and synaptic injury by restoring redox balance, inhibiting the activation of microglia and astrocytes, and activating the cAMP-response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF) pathway. Additionally, LFs increased the tight junction proteins and mucin-2, regulated the gut microbiota, particularly enriching bacteria in Firmicutes and restoring the Firmicutes/Bacteroidota ratio to maintain intestinal homeostasis. Meanwhile, LFs altered phospholipids (PLs) and other metabolites involved in glycerophospholipid metabolism such as arachidonic acid. Correlation analysis showed a significant association among metabolites, microbiota, and behaviors. These results indicated that LF and especially its digesta exert antiaging effects through multitarget pathways involving neuronal protection, neuroinflammation suppression, and microbiota-gut-brain axis regulation.

Osteoporosis is characterized by reduced bone mass and structural deterioration, leading to increased fracture risk, particularly in older adults. Parathyroid hormone (PTH) is a widely used anabolic therapy for osteoporosis; however, rapid bone loss after treatment discontinuation presents a significant clinical challenge. Cellular senescence has been implicated in age-related bone fragility. However, its role in PTH-induced bone remodeling and post-treatment bone loss remains unclear. This study aimed to investigate the effects of PTH administration frequency on bone microarchitecture and cellular senescence in young and aged mice. High-frequency PTH administration improved trabecular bone volume in both age groups, but caused cortical bone thinning, increased porosity, and elevated osteoclast activity in aged mice. PTH induces senescent osteoblast-lineage-enriched cell accumulation in aged, but not young mice, accompanied by upregulation of senescence-associated markers and activation of the mechanistic Target of Rapamycin Complex 1 pathway. Co-administration of the senolytic agents dasatinib and quercetin during PTH treatment reduced senescent cell burden, improved cortical porosity, and mitigated rapid bone loss after PTH discontinuation in aged mice. These findings indicate that senescent osteoblast-lineage-enriched cells contribute to bone fragility and post-treatment bone loss in aged individuals, suggesting that targeting senescence may enhance the efficacy and sustainability of PTH therapy for osteoporosis.

To evaluate whether oxygen-ozone therapy (OOT) can modulate aging by inducing adaptive chaos in the HMGB1-Nrf2 redox-inflammatory pathway.

Discovery of new compounds that ameliorate the negative health impacts of aging promises to be of tremendous benefit across a number of age-based comorbidities. One method to prioritize a testable subset of the nearly infinite universe of potential compounds is to use computational prediction of their likely anti-aging capacity. Here, we present a survey of longevity effects for 16 compounds suggested by a previously published computational prediction set, capitalizing upon the comprehensive, multi-species approach utilized by the

Decisions over the life course, such as stopping school, retiring, or receiving care, are shaped by public policies and have profound implications for health and aging. Yet, studying the impact of these policies is hampered by a lack of standardized and harmonized policy data, making peer review and validation difficult. The Gateway to Global Aging Data addresses these barriers by collecting, harmonizing, and documenting policies over time on education, retirement, and long-term care systems, enabling linkages to longitudinal data from international aging cohorts, thus accelerating research on health and aging.

Ovarian aging can lead to early menopause, infertility, and even premature senility in female patients, seriously impairing the quality of life. Unfortunatly, it is still lack of effective protection strategies against ovarian aging. It has been emergingly recognized that mesenchymal stem cells (MSCs) play a pivotal role in the maintenance of organ and tissue homeostasis and extracellular vesicles (EVs) have been identified as significant contributors to the paracrine action of MSCs. Human umbilical cord derived MSCs (UCMSCs) are distinguished by their superior self-renewal potential, minimal immunogenicity, and plentiful supply, rendering them an excellent candidate for EV-based therapeutic transplantation. However, whether UCMSC-EVs improve ovarian aging though regulating inflammation is still uncertain.

In their cross-sectional study, Sun et al. (Aging Clin Exp Res. 2025) provide valuable evidence that the coexistence of high body fat and low muscle mass is associated with lower bone mineral density (BMD) in postmenopausal women with type 2 diabetes (T2D). While their work importantly identifies this "sarcopenic obesity" phenotype as a risk factor, our letter offers a critical appraisal to guide future research. We argue that the sole reliance on DXA-derived areal BMD is a significant limitation, as it fails to capture the deficits in bone quality (e.g., microarchitecture, material properties) that underpin the well-known paradox of increased fracture risk at normal or elevated BMD in T2D. Furthermore, the cross-sectional design and lack of biochemical data (e.g., on inflammation, adipokines, bone turnover markers) preclude any causal or mechanistic inferences about how this body composition profile affects bone.We contend that the operational definitions of sarcopenia and obesity based solely on quantity, without assessing muscle function or fat distribution, lack phenotypic precision. Moving forward, the field must adopt longitudinal designs that integrate advanced imaging (e.g., HR-pQCT) and deep metabolic phenotyping to elucidate the underlying pathways. Ultimately, this is essential for developing targeted interventions that address the intertwined pathologies of muscle, fat, and bone in this vulnerable population.

Histone post-translational modifications (PTMs) are critical regulators of chromatin structure and gene expression, with broad implications for development, metabolism, and aging. While canonical modifications such as methylation and acetylation are well characterized, the role of histone succinylation remains poorly understood. Here, we investigated histone succinylation in the context of aging and exceptional longevity. Using mass spectrometry-based proteomics, we quantified histone succinylation in B-cells from four groups: young individuals, older individuals without parental longevity (OPUS), long-lived individuals, and offspring of long-lived individuals (OPEL). We found that histone succinylation was significantly elevated in the OPEL group compared to both young and OPUS cohorts. Nuclear proteomics further revealed enrichment of succinylated proteins in OPEL samples, supporting a role for succinylation in chromatin organization. To test whether succinate availability impacts healthspan, we supplemented middle-aged mice with succinic acid. While body weight, frailty index, and cognition were unaffected, succinic acid improved motor coordination and muscle strength. Together, our findings provide preliminary evidence that enhanced histone succinylation may serve as a protective epigenetic mechanism in individuals predisposed to exceptional longevity, and that succinate supplementation can selectively improve aspects of physical performance during aging.

Geroscience research benefits from interdisciplinary approaches, team science, and collaborations, which collectively facilitate the discovery of aging mechanisms and their translation into tangible, clinical interventions. Since its inception in 2019, the Midwest Aging Consortium (MAC) has provided an engaging platform for aging researchers in the United States' Midwest to connect, collaborate, and exchange ideas. The Sixth Annual Research Symposium of the MAC held at the Mayo Clinic in Rochester, Minnesota in April 2025 highlighted the continued impact of the MAC in bringing together aging researchers, including many trainees and early career investigators, into a collaborative environment. This record-setting event featured interdisciplinary research on key aging mechanisms, including lipid metabolism, mitochondrial dysfunction, stress response, cellular senescence, and immune adaptations across organ systems. New therapeutic concepts and clinical trial approaches were presented. Cutting-edge methodologies including single-cell and spatial transcriptomics, metabolomics, and organoid cultures, to dissect aging process in tissue-specific and systemic contexts also were presented. Overall, the MAC symposium underscored the translational potential of geroscience and reinforced the MAC's mission to accelerate aging research through regional collaborations and innovation.

Microgravity provides a unique environment for elucidating the fundamental mechanisms of human aging. In the Microgravity Associated Genetics (MESSAGE) Science Mission, Turkiye\'s first human space biology experiment, we performed an integrative analysis of telomere dynamics, transcriptomic remodeling, and microRNA regulation in peripheral blood mononuclear cells (PBMCs) collected before launch (L-7day), after suborbital ascent (L+3hrs), and during days 4-10 aboard the International Space Station (ISS). Spaceflight induced a striking early elongation of telomeres, accompanied by transcriptional activation of DNA repair, oxidative stress mitigation, mitochondrial homeostasis, and immune regulatory pathways. Concurrently, microgravity triggered robust suppression of longevity-associated microRNAs, including members of the miR-17-92, miR29, and miR34 families, suggesting coordinated epigenetic reprogramming of genome stability and stress responses. Notably, the adaptor protein gene AP2A1, recently implicated in cellular rejuvenation and mechanotransductive aging processes, emerged as a consistently microgravity-responsive hub, linking cytoskeletal signaling to telomere maintenance and DNA repair networks. Together, these findings reveal that short-duration spaceflight initiates a multi-layered molecular longevity program in human immune cells, characterized by telomere extension, stabilization of genome maintenance pathways, and suppression of aging-associated miRNA regulators. This systems-level view provides foundational insight into how human biology adapts to short-term microgravity exposure and identifies AP2A1-centered networks as promising targets for enhancing astronaut health and performance and ultimately understanding terrestrial aging.

Apolipoprotein A-II amyloidosis (AApoA-II) is the most common form of age-related amyloidosis in mice, typically arising sporadically in aged animals or in senescence-accelerated strains carrying the APOA2C variant. Here, we report that plasminogen activator inhibitor-1 deficient (PAI-1-/-) mice develop systemic AApoA-II amyloidosis with complete penetrance at an intermediate age. Congo red-positive deposits were consistently observed after 12 months in multiple organs, including kidney, spleen, liver, heart, tongue, and intestine, whereas wild-type controls displayed significantly lower amyloid burden and penetrance. Injection of amyloid enhancing factor further accelerated disease onset. Mass spectrometry of purified fibrils and immunofluorescence identified APOA2 as the causative protein. Functional assessment revealed a strong correlation between renal amyloid burden and albuminuria, establishing urinary albumin as a reliable biomarker of disease evolution for preclinical studies. This model provides a robust and reproducible system for investigating age-related amyloidosis and for pre-clinical evaluation of anti-amyloid therapies. Although the role of PAI-1 deficiency in other forms of amyloidosis remains to be demonstrated, our findings raise concern that chronic PAI-1 inhibition, currently pursued in clinical programs, may inadvertently facilitate amyloid deposition by altering extracellular matrix remodeling. PAI-1-/- mice thus represent both a valuable tool for amyloidosis research and a cautionary signal regarding therapeutic strategies targeting PAI-1.

Liver cancer incidences increase dramatically beyond 55 years of age, suggesting that age-associated changes contribute critically to tumor initiation. However, the mechanisms linking liver aging and cancer initiation are not well defined. This study investigates the role of CD44, a marker of liver tumor-initiating cells (TIC), in age-associated liver pathophysiology. Aged livers showed accumulation of CD44-expressing hepatocytes exhibiting enrichment of immune modulatory genes and activation of the immunosuppressive IL6/JAK/STAT3 pathway. Indeed, in adoptive transfer assays, antigen-exposed CD8+ T cells mounted a lower IFNgamma response in aged livers than in young livers, indicating an immunosuppressive aged milieu. Concordantly, spatial analyses showed that the proximal neighbourhoods of Cd44-expressing hepatocytes are enriched in T cells exhibiting reduced cytokine and chemokine gene expression. Finally, hepatocyte-specific knock out of Cd44 mitigated the IL6/JAK/STAT3 gene signature in aged livers. Overall, these findings suggest that CD44 expression in aged hepatocytes promotes activation of the immunosuppressive IL6/JAK/STAT3 pathway and this is associated with impaired T cell effector function.

Dual physical and cognitive decline, or physio-cognitive decline syndrome (PCDS), significantly increases disability, dementia, and mortality risks in older adults. To elucidate the neurobiological mechanisms underlying PCDS, we used an innovative, cerebellum-centered, data-driven approach to establish structural covariance networks (SCNs) and identify specific cerebellar SCNs associated with simultaneous physical and cognitive impairments. This analysis was based on MRI data from 1193 adults aged ≥50 and older (mean age ± SD: 62.8 ± 8.7 years) in the I-Lan Longitudinal Aging Study. Through non-negative matrix factorization analysis, we identified seven cerebellar SCNs, among which SCN-2, predominantly located in the posterior lobe (63% in lobule VI, 10% in Crus I), showed significant association with dual-domain impairment (ρ = 0.083 for physical domain and ρ = 0.154 for cognitive domain, p < 0.007 by Bonferroni-correction). Voxel-wise mediation analyses, adjusted for age, sex, education, and intracranial volume, revealed that specific cerebral regions, including bilateral thalamus, left frontal orbital cortex, left amygdala/hippocampus, right hippocampus, right occipital fusiform gyrus, and right temporal pole, significantly mediated the relationship between SCN-2 and dual impairments. Our findings establish SCN-2 and its mediated cerebral regions as potential biomarkers for understanding and treating PCDS, suggesting that preserving cerebellar SCNs integrity could be crucial for developing targeted interventions in healthy aging strategies.

Trajectory inference (TI) methods for single-cell snapshots of developmental systems have yielded numerous insights into the gene regulatory networks (GRNs) that control cell differentiation. Many TI algorithms have been proposed for recovering cell trajectories from single samples containing cells spanning a spectrum of differentiation states; however, these methods cannot leverage temporal information when a time course of such diverse samples is available. As interest grows in understanding how GRNs change as an organism ages, current TI theory and methods must be adapted to take advantage of all information in aging time courses of single-cell data. In this paper, we present our novel age-conscious method, Global StationaryOT, which exploits the temporal information in aging time courses to simultaneously reconstruct debiased cell trajectories at all ages. We demonstrate that this first-of-its-kind method achieves more accurate, biologically consistent trajectories in synthetic and real biological contexts where data sparsity produces significant noise in the outputs of current TI methods when they are applied to time course samples independently.

Planetary Health Diet promotes well-being of both individuals and the planet; however, whether adherence to this diet benefits brain health is less known. Using data from the UK Biobank, we examined the association between the Planetary Health Diet and risk of brain disorders and if decelerated biological aging mediated this relationship. During a median follow-up of 148 months in 69,370 participants (mean (s.d.) age 55.79 (7.85) years, 54.63 % women), the highest adherence to the Planetary Health Diet (in the highest quartile of the Planetary Health Diet Index) was associated with a 12 % (hazard ratio = 0.88, 95 % confidence interval = 0.77-1.00), 13 % (0.87, 0.76-1.00), 13 % (0.87, 0.76-0.98), and 19 % (0.81, 0.67-0.97) lower risk of stroke, depression, anxiety, and multimorbidity, respectively. The association of the Planetary Health Diet with Parkinson's disease (p-value = 0.0161) and anxiety (p-value = 0.0053) showed significant nonlinearity, whereas it had a linear association with other brain disorders. Decelerated biological aging mediated 2.36-13.03 % of the relationship between the Planetary Health Diet and brain disorder risk. Our findings support the Planetary Health Diet and biological aging deceleration for the prevention and control of brain disorders.

Neuronal activity is the result of the orchestrated actions of multitudes of synapses, acting and evolving not as individuals, but as populations. We therefore collected, for millions of synapses, a functionally relevant proxy for their strengths. Namely, we measured postsynaptic protein content by deploying a fluorescent PSD95 variant. Then we summarized, by statistical moments, the shapes of the distributions of protein contents, over local synaptic populations. In this way we explored the hypothesis that such collective properties inform on brain architectures. Our measurements cover complete parasagittal sections of the mouse brain, in animals one week to 18 months old. We identified a hierarchical organization of regions along the anterior-posterior axis, with three main clusters of divergent synaptic population shapes. One includes telencephalic regions, one is centered in the midbrain and hindbrain, and one comprises mainly the thalamus and the cerebellum. The structure emerging from our approach aligns with discoveries in studies of regional patterns of cellular gene expressions. Our results suggest that synaptic populations are dynamically regulated over the lifespan. Regions which at three months of age have thinner tails largely conserve their distribution shapes later in life, whereas heavy tails in other regions strikingly grow ever more so.

Cellular senescence is a stress responsive program that critically affects chronological and biological aging, ischemia reperfusion injury (IRI), and age related cardiovascular diseases. Of relevance, cardiac senescent cells exhibit altered characteristics that promote inflammation, remodeling, and fibrosis, ultimately contributing to the functional decline following myocardial infarction (MI). At the same time, emerging evidence suggests that senescence may also exert protective effects post-MI, limiting fibrosis. Thus, understanding the mechanisms and pathways of cardiac senescence appears critical for delineating the consequences of IRI, including identification of novel therapeutic targets for improving post-MI recovery.

Objective　Given the declining birthrate and aging society, extending healthy life expectancy by improving lifestyle habits to prevent metabolic syndrome (MetS) and maintain health-related quality of life (HR-QOL) has become a critical public health priority. Guided by the PRECEDE-PROCEED model, this study examined the relationships among lifestyle habits, MetS status, and HR-QOL.Methods　Participants included 1,393 workers (1,077 males, mean age 48.7 ± 9.2 years; 316 females, mean age 45.4 ± 8.6 years). HR-QOL was assessed using the SF-12 questionnaire, yielding the physical component summary (PCS), mental component summary (MCS), and role/social component summary scores. Relationships between HR-QOL, MetS classification, and related indicators (body mass index, abdominal circumference, blood pressure, fasting blood glucose, hemoglobin A1c (HbA1c), triglycerides (TG), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol) were analyzed. Additionally, associations between HR-QOL and lifestyle habits, such as weight gain since age 20, eating habits (eating speed, snacking, dinner within 2 h before bedtime, skipping breakfast), chewing conditions, physical activity/exercise habits (sweating-inducing exercise, daily walking, walking speed), and sleep quality were examined. Furthermore, the relationships between lifestyle habits, MetS classification, and related indices were assessed.Results　PSC and MSC scores of HR-QOL were significantly influenced by MetS classification, abdominal circumference, HbA1c, and TG levels. Lifestyle habits, including weight gain since age 20, eating habits, chewing conditions, and physical activity/exercise habits, were significantly associated with MeS classification and/or MetS-related indicators. While lifestyle habits were primarily associated with PCS and MCS, some of these associations ceased to be significant when Met classification or related indicators were included as intermediate variables.Conclusions　Our findings suggest that both MetS status and lifestyle habits are associated with HRQOL. Lifestyle habits may influence HR-QOL indirectly through their effects on MetS status. Therefore, improving lifestyle behaviors may be an effective strategy to enhance HR-QOL and promote healthy longevity.

Serum free thiols (FTs) are sensitive biomarkers of oxidative stress, closely associated with aging and chronic disease risk. Existing DTNB-based detection methods suffer from product instability, affecting analytical reliability. A more stable and high-throughput method is needed.

This study aimed to examine the effects of two distinct repetition ranges in resistance training (RT) on cognitive function and mental health outcomes in older women.

Ageing is associated with neuromuscular decline, and emerging evidence suggests that sex may influence the time course of motor unit adaptations. This study examined age- and sex-related differences in motor unit firing behaviour across young (YG), middle-aged (MA), and older adults (OLD), by integrating high-density EMG motor unit analysis with muscle morphology and daily physical activity measurements. The analysis of single motor unit activity during submaximal isometric contractions of the vastus lateralis revealed that older adults had lower firing rates and a reduced capacity to modulate discharge frequency during force-increasing contractions. In the YG and MA groups, females showed higher motor unit firing rates and variability than males, while in OLD these sex differences were no longer present. Females also demonstrated a steeper decline in firing rate modulation between MA and OLD. Reductions in muscle cross-sectional area and thickness were similar between sexes. Physical activity levels declined with age in both sexes. These findings reveal distinct, sex-specific trajectories of neuromuscular ageing, with females showing greater motor neuron function decline between MA and OLD, in the absence of sex-related differences in the rate of morphological deterioration. The attenuation of sex differences in older age suggests a convergence of neuromuscular profiles with ageing. While physical activity may contribute to the observed sex-specific patterns, other mechanisms related to hormonal shifts warrant further investigation. These insights underscore the importance of considering age and sex in the study of motor control and in the development of targeted interventions to preserve muscle function across the lifespan.

Ageing is associated with declines in mobility and balance that threaten independence and increase the risk of falls. Although these changes are often attributed to deterioration of muscular and sensory systems, growing evidence suggests that age-related alterations in cognitive control also contribute to postural instability and gait impairments. Here, we examined whether shifts in cognitive control strategy underlie impaired gait initiation in older adults by modelling how individuals update beliefs about upcoming actions. Older and younger adults performed a choice-stepping go/no-go task in which the likelihood of initiating a step was manipulated across trials. We measured anticipatory postural adjustments (APAs), the preparatory shifts in body weight that precede stepping, and modelled age-related differences in APA onset using a hierarchical Bayesian framework. Older adults initiated APAs more slowly than younger adults, particularly following repeated go trials. Computational modelling revealed reduced learning rates and heightened sensitivity to uncertainty in older adults. These findings identify altered belief updating as a cognitive mechanism shaping age-related changes in adaptive stepping behaviour.

Healthy aging is associated with structural and functional brain changes. However, cognitive abilities vary in how they change with age: whereas executive functions, like working memory, show age-related decline, aspects of linguistic processing remain relatively preserved. The heterogeneity of the cognitive-behavioral landscape in aging predicts differences among brain networks in whether and how they should change with age. To evaluate this prediction, we used individual-subject fMRI analyses ('precision fMRI') to examine the language-selective network and, for control purposes, the Multiple Demand (MD) network, which supports executive functions, in older adults (n=64) relative to young controls (n=483). In line with past claims, relative to young adults, the MD network of older adults shows weaker, less spatially extensive, and more topographically variable activations during an executive function task and reduced within-network functional connectivity. However, in stark contrast to the MD network, we find remarkable preservation of the language network in older adults. Their language network responds during language comprehension as strongly and selectively as in younger adults, and shows a similar degree of left-hemispheric lateralization and within-network functional connectivity. Our findings suggest that the language network remains young-like, at least on standard measures of function and connectivity, and align with behavioral preservation of language comprehension in healthy aging.

Germline mutation rates per generation are strikingly similar across animals, despite vast differences in life histories. Analogously, in at least one somatic cell type, mutation rates at the end of lifespan are comparable across mammals. These observations point to a key role for natural selection in shaping mutation rates. In this essay, we summarize the patterns identified to date and outline existing theories for how selection pressures might shape mutation rates in animal germline and soma. We argue that an understanding of what sets the mutation rate of a given cell type in a species requires better integration of genetics and development with population processes of selection and genetic drift.