Longevity Papers

Lipofuscin is an autofluorescent material that accrues in brain tissues with age and in Neuronal Ceroid Lipofuscinosis (NCL), a neurodegenerative disease with pediatric onset. The distribution, composition, and organellar origin of lipofuscin have remained unclear despite its widespread presence in aged tissues and involvement in neurodegeneration. Here, we elucidate lipofuscin composition in mouse and human brain and assemble a reference neuroanatomical atlas of lipofuscin accumulation with age and NCL (Type 1; CLN1) progression across 425 fine brain regions. We identify a primary role of the lysosomal-mitochondrial axis in the formation of lipofuscin pathology via multimodal mass spectrometry, ultrastructural analyses, and assays of cellular and enzymatic metabolism. We find the protein and lipid composition of lipofuscin in the aged and CLN1 brain to be remarkably similar. Dissection of implicated molecular pathways reveals protein S-acylation and unsaturated lipid homeostasis as central processes involved in lipofuscin deposition during aging and CLN1. Notably, > 95% of lipofuscin resident proteins can be S-acylated and many are substrates of the enzyme PPT1, validating a seminal hypothesis that CLN1 lipofuscin contains these lipid-modified proteins. Further, we discover deficient de-S-acylation is correlated with lipofuscin load in healthy aging, as the specific de-S-acylation enzyme activity of PPT1 is found to decline with advancing age. Finally, we identify lipid metabolite biomarkers of lipofuscin, including long-chain polyunsaturated fatty acids, bis(monoacylglycerol)phosphate (BMP), and oxidized phosphatidylethanolamine (OxPE) lipid species. Overall, we provide a comprehensive redefinition of lipofuscin neuropathology and a resource for studying aging, lysosomal storage disorders, and neurodegeneration.

Intrinsic capacity (IC) summarizes functional health across multiple domains in healthy aging research, yet evidence on whether IC can be measured and tracked before older age remains limited. Using data from the 1958 British birth cohort at ages 50 and 62 (N = 7,804), we examined whether IC could be measured as a coherent, valid and longitudinally comparable construct from midlife to early old age. A second-order model applied to 30 indicators across sensory, cognitive, physical, psychological and vitality domains supported a five-domain IC construct, with scalar invariance across sweeps enabling comparison of scores over time. IC scores showed graded associations with self-rated health and chronic disease burden in the expected directions. Mean IC declined by 6.3 points on a 0-100 scale from age 50 to 62. These findings establish a basis for studying IC trajectories from midlife, before functional decline is usually clinically apparent.

Chagas disease (ChD) and Type 2 diabetes (T2D) originate from distinct etiological processes -infectious and metabolic, respectively- yet both share a chronic inflammatory and metabolic imbalance that profoundly impacts immune-endocrine homeostasis. Persistent Trypanosoma cruzi infection in ChD induces sustained immune activation, altered adrenal steroid balance, and tissue remodeling, whereas T2D is characterized by metabolic inflammation, oxidative stress, and insulin resistance. When these two conditions coexist, their overlapping inflammatory, metabolic, and endocrine circuits may act synergistically, amplifying metabolic toxicity, immune exhaustion, and premature immunosenescence. In addition, this comorbidity thus represents the convergence of pathogen-driven and metabolism-driven inflammation, resulting in a disrupted neuroendocrine-immune dialogue and heightened susceptibility to tissue damage, particularly in the heart. Understanding the mechanistic basis of this interplay is crucial, as it highlights shared pathogenic pathways and potential molecular targets for integrated therapeutic interventions. Altogether, recognizing ChD+T2D coexistence as a mechanistic rather than merely epidemiological association provides new insights into the links between chronic infection, metabolic dysfunction, and immune aging-offering a conceptual framework for future studies aimed at restoring immune-metabolic balance and improving disease outcomes, particularly cardiac damage.

Extending brain health span - maintaining or improving cognitive, social, and emotional well-being - is critical to aligning health span with lifespan. This study examines 3-year outcomes from 3,966 adults (ages 19-94) in the BrainHealth Project, an online initiative integrating the BrainHealth Index (BHI) with cognitive training, lifestyle modules, and coaching. The BHI, assessed biannually, provides a multidimensional measure across factors of Clarity (cognitive function), Connectedness (social and purpose-driven engagement), and Emotional Balance (mental well-being). Results demonstrate sustained improvements in overall BHI and component factors, independent of baseline scores. Higher engagement with training tools - strategy-based learning, coaching, and brain-healthy habits - was associated with the greatest gains, underscoring the role of self-agency in brain health optimization. Improvements were observed across demographic groups, suggesting benefits regardless of age, gender, or education level. Findings support the potential for scalable, technology-driven interventions to help reduce years of cognitive decline while maximizing brain performance across the lifespan. Future efforts should focus on improving demographic diversity and retention as well as integrating precision brain health into public health initiatives.Trial registration: ClinicalTrials.gov, NCT04869111 (registered April 27, 2021).

Age-related macular degeneration (AMD) is characterized by progressive retinal pigment epithelium (RPE) dysfunction driven by oxidative stress and chronic inflammation, in which NLRP3 inflammasome activation plays a critical role. Mesenchymal stem cells (MSCs) exhibit therapeutic potential, but their efficacy is limited by poor survival and reduced paracrine activity in hostile microenvironments. Here, we investigated whether three-dimensional (3D) spheroid culture enhances the protective effects of umbilical cord-derived MSCs (UC-MSCs) on RPE cells by promoting autophagy and suppressing inflammasome activation.

Dendrobium officinale Kimura et Migo (Tiepi Shihu), a yin-nourishing tonic in traditional Chinese medicine, has been historically used for health maintenance and longevity promotion.

Kidney fibrosis is a central pathological feature driving progressive functional decline in chronic kidney disease (CKD); however, the molecular and epigenetic mechanisms linking kidney fibrosis to aging remain incompletely understood. In this study, we employed a natural aging mouse model and integrated transcriptomic and DNA methylation analyses to delineate age-associated kidney degenerative features and to identify key genes involved in this process. Our results showed that aging kidneys exhibited pronounced interstitial fibrosis and tubular atrophy, accompanied by increased expression of senescence markers, senescence-associated secretory phenotype (SASP) factors, and kidney injury molecule-1 (KIM-1), indicating persistent kidney injury during aging. Reduced representation bisulfite sequencing (RRBS) revealed a global, age-dependent increase in DNA methylation levels. Integrative methylome-transcriptome analyses identified fibroblast growth factor receptor 2 (FGFR2) as a prominent target of age-associated hypermethylation. Multilevel validation using RT-qPCR, Western blotting, immunofluorescence co-localization, and pyrosequencing consistently confirmed that FGFR2 expression was significantly reduced in aging kidney tissue, particularly in kidney tubular regions. Functional studies demonstrated that pharmacological inhibition of FGFR2 in vitro accelerated cellular senescence and upregulated fibrosis-related markers, supporting a causal role for FGFR2 loss in promoting kidney aging. Furthermore, reduced FGFR2 expression was accompanied by decreased co-localization with fibroblast growth factor 23 (FGF23) in aging kidneys, suggesting potential impairment of the FGF23/FGFR2 signaling axis. Collectively, these findings suggest that epigenetic silencing of FGFR2 contributes to kidney senescence and fibrotic remodeling during kidney aging and highlight FGFR2 as a potential therapeutic target for mitigating age-related kidney decline.

The mitochondrial calcium uniporter (Mcu) mediates calcium influx into the mitochondrial matrix, playing an essential role in cellular energy metabolism and survival. Although Mcu has been studied in various physiological contexts, its role in skeletal homeostasis remains poorly understood. Here we investigate how Mcu deficiency affects osteoblast differentiation and bone formation under aging-related stress. Using an inducible whole-body Mcu-knockout mouse model, we found that Mcu deletion resulted in impaired mitochondrial calcium uptake, reduced oxidative phosphorylation, fragmented mitochondrial morphology and decreased expression of osteogenic genes, leading to defective osteogenesis. Concurrently, adipogenic markers were elevated in Mcu-deficient bone marrow cells, indicating altered mesenchymal lineage commitment. Mechanistically, Mcu-deficient cells exhibited enhanced TGF-β signaling and reduced BMP/Wnt pathway activity. In vivo, inducible whole-body Mcu-knockout mice exhibited reduced trabecular bone volume and density while maintaining normal skeletal growth. Pharmacological modulation of mitochondrial calcium influx using kaempferol enhanced osteogenic differentiation and mitochondrial respiration in wild-type, but not Mcu-deficient, cells. Consistently, analysis of publicly available human datasets revealed age- and osteoporosis-associated downregulation of MCU expression in bone tissues. These findings suggest that Mcu regulates bone formation by controlling mitochondrial calcium uptake and mesenchymal lineage allocation. Targeting mitochondrial calcium signaling may offer novel therapeutic strategies for age-related skeletal disorders.

Intervertebral disc degeneration (IDD), a leading cause of low back pain, involves progressive dysfunction of nucleus pulposus (NP) cells and extracellular matrix degradation. The pathological mechanisms underlying IDD remain complex and lack comprehensive elucidation. This study identifies the RNA-binding protein TDP43 as a central driver of IDD pathogenesis through analysis of human clinical specimens and rodent models. We demonstrate that TDP43 expression escalates proportionally with disc degeneration severity and aberrantly accumulates in the mitochondria of degenerative NP cells. This mitochondrial mislocalization triggers nuclear pore complex impairment, mitochondrial membrane potential collapse, and irreversible cellular senescence. Critically, TDP43 is secreted within mitochondrial-derived vesicles, which function as intercellular mediators that propagate pro-inflammatory cytokines and senescence phenotypes to neighboring NP cells. Both genetic and pharmacological inhibition of vesicular TDP43 effectively attenuated mitochondrial dysfunction and reduced cellular senescence and ultimately decelerated IDD progression in vivo and in vitro. Our findings establish TDP43-loaded mitochondrial-derived vesicles as novel mediators of intercellular pathology and nominate TDP43 as a therapeutic target for IDD intervention.

Exercise exerts beneficial effects on multiple physiological systems, influencing biomarkers associated with aging processes and chronic diseases. This systematic review and meta-analysis aimed to evaluate the acute, subacute, and chronic effects of exercise on s-Klotho levels in healthy individuals and patients with chronic diseases. A comprehensive search was conducted in electronic databases. Included studies were randomized and non-randomized studies assessing the effects of aerobic, resistance, or combined exercise on s-Klotho levels. Interventions were classified as acute (single session), subacute (< 12 weeks), or chronic (≥ 12 weeks). Risk of bias was assessed using RoB 2 and ROBINS-I tools, and quality of evidence was evaluated with the GRADE framework. Forty-one studies were included in the qualitative synthesis, and 30 in the meta-analysis, comprising 2,765 participants (18-85 years). Twenty-five involved healthy individuals, while 21 included patients with chronic diseases. Acute and subacute aerobic exercise increased s-Klotho levels in healthy individuals (SMD 0.69; 95%CI 0.41-0.97) and diseased populations (SMD 0.62; 95%CI 0.11-1.12). Chronic exercise (12-36 weeks) showed significant increases in healthy (SMD 0.57; 95%CI 0.33-0.82) and diseased populations (SMD 1.51; 95%CI 0.87-2.16). Resistance exercise thrice weekly demonstrated the highest effect (SMD 1.60; 95%CI 0.81-2.38). Most studies had high risk of bias, with quality of evidence ranging from very low to moderate. Exercise significantly increases s-Klotho levels, with acute and subacute aerobic sessions benefiting healthy and diseased populations, while chronic resistance exercise elicited greater responses in diseased populations. Despite promising findings, low methodological quality suggests cautious interpretation.

Senescent cells accumulate with age and contribute to tissue dysfunction and chronic inflammation. Senolytic agents that selectively eliminate senescent cells hold therapeutic promise; however, few mechanistic classes have been established. Using Cell Painting-based morphological profiling, we identified a distinct cluster of senolytic compounds comprised of both known and novel autophagy inhibitors, including AZ191, bafilomycin A1, chloroquine, daurisoline, dauricine, MCOPPB, and its derivative MS1108. These compounds selectively eliminated senescent cells by disrupting autophagic flux. Our findings reveal senescent cell dependence on autophagy as an essential survival mechanism, define the existence of a mechanistically distinct class of senolytics acting through autophagy inhibition, and demonstrate the predictive value of Cell Painting in aging-related drug discovery. Our results provide new insights into senescent cell vulnerability and expand the therapeutic landscape for aging-related pathologies by highlighting autophagy as a targetable dependency.

Cellular senescence is increasingly recognized as a key mechanism linking aging to chronic disease. Diabetic atherosclerosis (DAS), a major macrovascular complication of type 2 diabetes, often progresses despite standard metabolic and lipid-lowering therapies, highlighting the involvement of aging-related processes beyond classical metabolic and inflammatory pathways. This review synthesizes evidence to propose a conceptual framework in which stress-induced senescence is a key disease-oriented aging mechanism contributing to DAS initiation and progression. Hyperglycemia and lipotoxicity induce premature senescence in endothelial cells, vascular smooth muscle cells, and macrophages through oxidative stress, mitochondrial dysfunction, and activation of the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome. Senescent cells secrete a senescence-associated secretory phenotype (SASP), which amplifies chronic vascular inflammation, promotes plaque instability, and facilitates systemic propagation of senescence, thereby contributing to multi-organ dysfunction in the heart, brain, and kidneys. Together, these features position DAS as a representative model of stress-accelerated vascular aging. From a therapeutic perspective, we discuss emerging senescence-targeted strategies, including senolytics, senomorphics, and multi-target interventions derived from integrative medicine, with emphasis on their potential to modulate the aging tissue microenvironment and delay disease progression. By framing diabetic atherosclerosis within the context of aging biology, this review provides a disease-focused perspective on mechanisms and therapeutic opportunities underlying age-associated vascular disorders.

Proteins comprise well-ordered structural domains and intrinsically disordered regions that explore broad conformational ensembles, a pervasive feature of the human proteome that underlies key aspects of cellular physiology. In the crowded intracellular environment, stress can shift protein conformational equilibria toward aggregation-prone states, exposing hydrophobic regions that can drive aberrant protein-protein interactions, promoting aggregation. To maintain proteome integrity, cells depend on an integrated protein‑quality‑control network in which molecular chaperones, their co‑factors and dedicated degradation systems act in concert. Within this network, small heat shock proteins serve as an ATP-independent first line of defense that stabilizes non-native proteins and limits irreversible aggregation. Recent work shows that small heat shock proteins can also safeguard the liquid‑like dynamics of biomolecular condensates formed by liquid-liquid phase separation. These membraneless compartments organize cellular biochemistry but are susceptible to stress- and disease-induced arrest or aggregation. Rather than undergoing phase separation autonomously, small heat shock proteins can be recruited into pre-existing condensates such as stress granules, nuclear speckles, p62 bodies, and condensates formed by disease-associated proteins, where they help preserve condensate fluidity. Together, these findings position small heat shock proteins as modulators of condensate dynamics that link protein quality control to mesoscale cellular organization, with important implications for cell biology, aging, and human disease.

Lysosomal dysfunction is a hallmark of cellular senescence, yet the mechanisms governing lysosomal protein trafficking remain incompletely understood. Here, we show that CD-M6PR, a principal receptor for lysosomal enzyme transport, is markedly reduced in senescent fibroblasts and in aged mice and humans, and that its loss correlates with the severity of autolysosomal impairment. Mechanistically, the reduction of CD-M6PR in senescent cells mainly stems from the accelerated proteasome-mediated degradation. Utilizing structural predictions and experimental validation, we identified the E3 ubiquitin ligase ZNRF2 as a critical mediator of CD-M6PR's rapid degradation in senescent cells, facilitated by ZNRF2's elevated expression in these cells. We further link stress-induced mTORC1 activation to increased ZNRF2 expression, which in turn reduces CD-M6PR protein levels, impairs lysosomal enzyme trafficking, and compromises autolysosomal function, thereby exacerbating cellular senescence. Collectively, these data define a previously unrecognized mTORC1-ZNRF2-CD-M6PR axis and reveal a novel mechanism by which aberrant mTORC1 signaling promotes lysosomal dysfunction and senescence, with potential implications for therapeutic targeting of age-related pathologies.

Background: Leukocyte telomere length (LTL) from cord blood is a marker of biological aging and long-term systemic health. Exposure to essential and toxic metals has been shown to influence LTL in a sexually dimorphic manner. However, little is known about the interplay between early-life longitudinal biodynamic patterns of these elements and cord blood LTL, as well as potential sex differences. Methods: From an ongoing longitudinal birth cohort study in Mexico City, we used available tooth samples from 231 children (129 males and 102 females) to generate 16 elemental weekly time series of direct fetal intensities from the second trimester through four to five months after birth. We analyzed the dentine growth rings using Inductively Coupled Plasma Mass Spectrometry to generate time-resolved elemental intensities. The elements included were Li, Mg, Ca, Mn, Co, Ni, Cu, Zn, As, Sr, Mo, Cd, Sn, Ba, Pb, and Bi. LTL was measured in cord blood using qPCR. We used cross-recurrence quantification analysis and entropy-complexity-based measures to generate time-resolved features that quantify the synchronization of elemental biodynamics. A stability-selection approach using five-fold cross-validation of regularized ridge regression was used for feature selection, and covariate-adjusted linear models were used to estimate associations with LTL. Findings: The biodynamic interaction of Mg-Co and Mn-Sn was identified as the most stable feature among male and female children, respectively. In males, higher vertical entropy (i.e., a measure of higher variability) of Mg-Co temporal biodynamics was associated with shorter LTL ({beta}[95%CI]: -0.9[-0.14,-0.03]; p-value<0.01), but not in females ({beta}[95%CI]:-0.02[-0.10,0.06]; p-value=0.60); whereas higher recurrence rate (i.e., a measure of higher synchronicity) of Mn-Sn temporal biodynamics was associated with longer LTL ({beta}[95%CI]: 0.09[0.02,0.16]; p-value=0.01), in females but not in males ({beta}[95%CI], 0.03[-0.04, 0.09]; p-value=0.39). Interpretation: We demonstrate that time-varying multi-elemental synchronization of early-life elemental biodynamics, a potential marker of homeostatic balance, may be associated with cord blood-based telomere length in a sexual dimorphic manner. Keywords: Metals, Telomere Aging, Elemental Biodynamics, Machine Learning, Child Health

Ceramides have garnered considerable attention as pro-aging bioactive lipids implicated in both metabolic dysfunction and musculoskeletal decline. Among these, C18:0 and C24:1 ceramides may play a role in the pathophysiology of sarcopenia, a key manifestation of age-related deterioration. However, their specific contributions to muscle degeneration remain poorly defined.

Environmental antibiotic pollution is an underexplored contributor to gut aging and chronic intestinal diseases. We provide evidence that chronic exposure to enrofloxacin (ENR), a commonly detected veterinary antibiotic, accelerates gut aging and disease progression through a mitochondria-centered mechanism. In a population-based cross-sectional analysis, recent antibiotic use was associated with increased biological age and a higher risk of diarrhea in middle-aged and older adults, supporting a link between antibiotic exposure and impaired gut health and aging processes. Using zebrafish and intestinal epithelial cell models, we demonstrate that low-dose ENR exposure impairs intestinal function, characterized by increased permeability, reduced mucus secretion, tight junction disruption, and chronic inflammation. Multi-omics profiling revealed that ENR induced gut microbial dysbiosis, reduced metabolic diversity, and intestinal hypoxia. Mitochondrial dysfunction, particularly impaired oxidative phosphorylation, was identified as the key driver of epithelial damage. Remarkably, treatment with pyrroloquinoline quinone, a mitochondrial-targeted antioxidant, reversed ENR-induced mitochondrial injury, restored intestinal integrity, reduced inflammation, and partially normalized the microbiome. Stratified analyses in the human cohort showed that higher gut microbiota-related diet quality and antioxidant capacity mitigated antibiotic-associated aging and diarrhea risk. These findings highlight mitochondrial protection and microbiota optimization as promising therapeutic strategies.

Brain aging is accompanied by progressive disturbances in calcium signaling, mitochondrial function, redox balance, neuroimmune regulation, and barrier-fluid homeostasis, collectively increasing susceptibility to neurodegenerative diseases. Therefore, identifying physiological regulators that stabilize these interconnected processes is central to understanding brain aging. Klotho, an antiaging protein initially characterized by its systemic roles in mineral metabolism and lifespan regulation, has emerged as a key modulator of cellular and tissue homeostasis across multiple organs, including the central nervous system. In the brain, Klotho is predominantly expressed in the choroid plexus and selectively in neuronal and oligodendroglial populations, positioning it at the interface of barrier physiology and neural function. Experimental studies have indicated that Klotho contributes to cerebrospinal fluid homeostasis, synaptic plasticity, neurogenesis, myelination, and resistance to metabolic and oxidative stress. Rather than acting through disease-specific pathways, Klotho stabilizes the core physiological axes that govern neuronal resilience, including Ca

Osteoarthritis (OA) is a prevalent, chronic joint disorder characterized by cartilage degradation, synovial inflammation, and extracellular matrix (ECM) remodeling, yet disease-modifying therapies remain elusive. Emerging evidence implicates ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, and cellular senescence, characterized by growth arrest and a senescence-associated secretory phenotype (SASP), as central contributors to OA pathogenesis. Ferroptotic chondrocytes release reactive lipid species and damage-associated molecular patterns (DAMPs) that induce paracrine senescence in neighboring cells, while senescent cells amplify oxidative stress and ferroptotic susceptibility, forming a self-perpetuating feed-forward loop that accelerates tissue degeneration. Histological, molecular, and in vivo studies demonstrate iron accumulation, lipid peroxidation, glutathione peroxidase 4 (GPX4) depletion, and SASP factor secretion in human OA cartilage, synovium, and animal models, linking these processes to ECM breakdown and joint inflammation. Targeted interventions, alone or in combination, can disrupt this pathological loop, preserve chondrocyte viability, reduce SASP-mediated inflammation, and mitigate cartilage damage. Integration of biomarker-guided patient stratification, advanced imaging, and spatial transcriptomic profiling may enable precision-targeted, disease-modifying therapies. Therefore, elucidating the crosstalk between ferroptosis and senescence offers a conceptual and translational framework for shifting OA management from symptomatic relief toward preservation of joint integrity and long-term disease modification.

Consistent employment, especially secure, high-wage employment, has well-documented associations with lower risk of later-life morbidity and mortality, and accelerated biological aging may underlie these associations. Although research evaluating employment and accelerated epigenetic aging is growing, questions remain about the implications of chronic work-related exposures for accelerated aging. This study uses longitudinal data from the Health and Retirement Study (HRS) and the 2016 HRS Venous Blood Study (n = 3,000) to evaluate how work-related experiences throughout midlife are associated with accelerated epigenetic aging. Results show that a history of not working for pay and a history of poor work quality (i.e., job insecurity, insufficient work hours, low wages) among workers in midlife are associated with accelerated epigenetic aging in later life. Symptoms of depression and health behaviors partially attenuate these associations. Overall, findings suggest that chronic work-related exposures are critical yet overlooked antecedents of accelerated aging.

Myocardial infarction (MI) is the leading cause of cardiovascular-related deaths worldwide, with risk increasing sharply with age. Fibrosis and inflammation occur soon after a pathological event and reflect perturbation of tissue repair that accompanies aging in general. Yet not old, but young animals are typically used for studying MI, emphasizing the unmet need for more relevant preclinical models. We previously determined that plasma dilution, also termed neutral blood exchange (NBE) (replacing ~50% of plasma with saline containing 5% albumin) broadly promotes tissue repair and maintenance, reduces fibrosis and inflammation in old mice, and improves the health of humoral and cellular compartments of blood in old people. Here, we developed a novel preclinical model via combining two complex surgeries in aged mice: jugular vein cannulation followed by plasma dilution with open heart cardiac ischemia-reperfusion (I/R). Using this approach, we found that a single dilution of old plasma that was performed 24 h after I/R significantly and broadly improved the recovery at molecular, cellular, tissue, and functional levels in aged mice. Candidate molecular pathways (JAK/STAT and TGF-β) and target proteins associated with these beneficial effects have been suggested by the bioinformatics on comparative proteomics between sham, I/R, and I/R plus NBE groups. While future studies are needed to establish the detailed processes and safety profiles of plasma dilution as a treatment of MI, this work provides important translational and mechanistic insights into recovery from cardiac injury in aged patients.

Recent comparative analyses have identified positive associations between social organisation and longevity in mammals, but independent replication with larger datasets is needed to establish the robustness of this pattern. Here, we analysed maximum recorded lifespan, body mass, and social organisation data for 1436 mammal species using Bayesian phylogenetic comparative methods, confirming that group-living and pair-living species exhibit longer lifespans than solitary species after controlling for body mass and phylogeny. Pair-living species showed slightly longer lifespans than group-living species (though credible intervals overlapped), while body mass slopes did not differ substantially among social categories and activity period showed weak associations with lifespan. These results provide independent corroboration of recent findings linking sociality to longevity in mammals and suggest that while group-living may reduce predation risk, pathogen transmission costs in larger groups may constrain longevity benefits. Our findings, based on the largest comparative dataset analysed to date, strengthen the evidence that social organisation is a key factor shaping mammalian life-history evolution alongside body size and ecological adaptations.

All organisms employ strategies to cope with changing environmental conditions. In budding yeast, nutrient deprivation induces a reversible non-proliferative state known as quiescence, characterized by extensive remodeling of gene expression, metabolism, and cellular biophysical properties. Yeast cells survive prolonged periods of starvation-induced quiescence, provided they can respire in the early stages of glucose withdrawal, and blocking respiration causes premature aging and markedly reduced survival and cytoplasmic diffusion. We find that respiration is required to initiate a quiescence-specific adaptive program. Induction of such a program prior to glucose withdrawal bypasses the need for respiration, rescuing survival and biophysical properties to the levels of respiration-competent cells. This rescue relies on proteomic adaptation and is mediated by Ras/PKA inactivation and Msn2/4-dependent activation of the environmental stress response, leading to modulation of cytoplasmic diffusion. Together, this enables long-term survival in quiescence even in the absence of respiration, underscoring the role of the stress response and the modulation of cytoplasmic properties in quiescence and aging.

Advanced maternal age is a key factor in female infertility, primarily due to declines in ovarian reserve and oocyte quality. However, the metabolic mechanisms underlying reproductive aging remain unclear. Here, we show that uridine levels in the plasma and ovaries of aged mice are significantly reduced compared with young controls. Building on this, we find that uridine supplementation significantly improves meiotic maturation, fertilization, and early embryonic development of aged oocytes, both in vivo and in vitro. Further microtranscriptomic analyses reveal that uridine enhances oocyte quality by inhibiting ferroptosis and enhancing mitochondrial function. Moreover, by integrating Limited Proteolysis-Small Molecule Mapping, western blotting and siRNA-based functional assays, we identify that uridine binds to poly(rC)-binding protein 1, thereby suppressing ferroptosis and preserving mitochondrial function. Collectively, these findings demonstrate that uridine supplementation improves fertility in aged female mice and provide mechanistic insight into ferroptosis in oocyte aging.

Cardiovascular-kidney-metabolic (CKM) syndrome represents a new framework to address the non-communicable disease burden in ageing populations. However, evidence on the association between physical activity and the integrated CKM syndrome is scarce, particularly among older Asian adults. We aimed to investigate this association in a large sample of older Chinese adults.

Cardiovascular diseases increase with aging and are closely linked to metabolic dysfunction and kidney disease through the cardiovascular-kidney-metabolic axis, but the underlying molecular mechanisms remain unclear. Accumulating evidence suggests that vascular endothelial cells (ECs) are particularly vulnerable to aging stressors, such as DNA damage. We investigated whether EC DNA damage drives cardiovascular-kidney-metabolic dysfunction.

Hydroxytyrosol (HTyr), a phenolic compound present in olive oil, exhibits antioxidant, anti-inflammatory, and neuroprotective properties, benefiting several age-related diseases. Our previous research demonstrated that oral HTyr administration counteracts age-associated neurogenesis decline in the dentate gyrus of the hippocampus by promoting the production of stem/progenitor cells and new neurons. Since new neurons generated in the dorsal dentate gyrus support contextual memory discrimination, while those generated in the ventral region modulate anxiety, we investigated whether pure HTyr, synthesized in our laboratories, selectively stimulates neurogenesis in these regions in aging mice and evaluated its effects on contextual memory and stress response. Furthermore, we examined its influence on gut microbiota composition, given the well-established role of the microbiota-gut-brain axis in memory and stress regulation. We found that HTyr induced the production of new neurons and neuroblasts in both dentate gyrus regions, with a prevalent effect in the ventral region. Consistently, we observed that HTyr treatment did not improve the contextual memory discrimination but reduced fear sensitization and anxiety-like behavior after a traumatic experience. Furthermore, we observed a reduction of neuroinflammation in HTyr-treated dentate gyri. In parallel, treatment with HTyr preserved the stability of key microbial families linked to intestinal well-being, counteracting the unhealthy effects of stress on gut microbial structure. Our results suggest that HTyr treatment in aging mice enhances resilience to posttraumatic stress by increasing neurogenesis and modulating the microbiota-gut-brain axis. Future studies should explore its potential as a therapeutic intervention for individuals experiencing posttraumatic stress disorder symptoms.

Nicotinamide riboside (NR), an endogenous precursor to the essential coenzyme nicotinamide adenine dinucleotide (NAD+), is characterized as safe and effective at longitudinally elevating NAD+ in blood and tissues, when administered orally. Preclinical research on NR as an augmenter of NAD+ has demonstrated great promise in support of healthy aging, metabolic health, and several diseases, though clinical translation of these findings has been limited. Interest in alternative routes of administration of NR has increased in recent years and led to the development of pharmaceutical-grade NR for intravenous and injectable administration. Two separate Phase 1 pilot clinical trials were conducted evaluating NR via bolus injections. While the designs of the two studies are different, the similarities warrant combined presentation to note the similarities, particularly with regards to safety-related outcomes. Trial 1 involved 45 participants that were randomized to a 3x3 design, accounting for three interventions, placebo, NR, and NAD+ and three routes of administration, intramuscular (IM), intravenous (IV), and subcutaneous (SC), resulting in a 9-arm study (placebo IM, n=5; placebo IV, n=5; placebo SC, n=5; NR IM, n=6; NR IV, n=5; NR SC, n=4; NAD+ IM, n=4; NAD+ IV, n=5; and NAD+ SC, n=6). Participants were administered NR once daily for three days, followed by a 7-day washout period. In Trial 2 (n=39), the 2x2 study design incorporated 4-arms for phase 1, where the participants were randomized to 50 or 100 mg of NR, administered either IM or SC in-clinic for 3 consecutive days, followed by a 7-day washout (50 mg IM, n=7; IM, 100 mg IM, n=11; 50 mg SC, n=11; and 100 mg SC, n=10). Phase 2 of Trial 2 involved participants self-administering either 50 or 100 mg of NR subcutaneously. Safety assessments for both trials included vitals, blood biomarkers, participant reported outcomes regarding the experience, and adverse event monitoring. Participant retention for both studies was 100%, and the injections did not result in any attributable unexpected adverse events or experiences. The experiences described by the participants regarding the actual injection varied. In Trial 2, pain more than two minutes after the injection and muscle soreness and tightness were reported by 45.9 and 43.2% of the participants, respectively, regardless of the route of administration or dose. Vitals remained generally consistent throughout both trials, and reductions in systolic blood pressure observed in both trials should be evaluated in larger, properly powered studies. Blood chemistry biomarkers for both trials did not elicit treatment-related patterns. Both trials presented within-group reductions in hsCRP in the NR SC arms, however, given baseline imbalance and small samples size, this finding should be considered hypothesis-generating, only. Overall, in both trials, the interventions, regardless of route of administration were associated with some discomfort but were well tolerated and did not produce any concerning safety signals. It is recommended that comprehensive metabolic and inflammatory panels should continue to be employed in future studies and clinical settings to assess whether consistent patterns emerge in larger populations.

Arterial stiffness is an important biomarker of cardiovascular health, and vascular age (VA) prediction provides additional value beyond chronological age. Here we present a curated arterial stiffness dataset comprising 36,223 participants aged 30-80 years from China. To benchmark its utility for VA modelling, we evaluated the Klemera-Doubal Method (KDM) and six Artificial Intelligence (AI) models: multiple linear regression, LASSO, random forest, support vector regression, XGBoost, and a deep neural network. Results showed that the dataset enables VA prediction using both statistical and learning-based approaches. Across both male and female cohorts, KDM showed the lowest prediction error under the current benchmark setting, while several nonlinear learning-based models achieved better performance than the linear baselines. Among the learning-based methods evaluated here, SVR and XGBoost showed comparatively strong performance. This dataset provides a useful open resource for vascular aging research, cardiovascular risk assessment, and methodological benchmarking.

Autoimmune diseases rise steeply with biological aging, reflecting progressive failure of immune regulation. Inherited chromosomally integrated human herpesvirus 6 (iciHHV-6) represents a unique lifelong viral exposure in which the viral genome is embedded within host telomeres, potentially altering leukocyte telomere length (LTL), a core biomarker of immune aging. Circulating metabolites may further modify these viral-telomeric interactions. We analyzed 156,927 UK Biobank participants free of autoimmune disease at baseline. Baseline iciHHV-6 carrier status, LTL, and plasma metabolomic profiles were related to incident autoimmune disease during follow-up. Mediation and interaction models were used to test whether LTL and various metabolomic pathways mediated or modified viral effects. Over follow-up, 7.8% of participants developed autoimmune disease and 1.3% were iciHHV-6 carriers. iciHHV-6 was not directly associated with autoimmune disease despite higher baseline comorbidity. Longer LTL was independently protective overall, especially for rheumatoid arthritis, although it was positively associated with multiple sclerosis. iciHHV-6 carriers had longer LTL, yielding a small but significant indirect protective effect on autoimmune risk. LTL also modified viral effects, with stronger protection among iciHHV-6-positive individuals, suggesting telomere length buffers adverse viral-immune interactions. Metabolomic analyses showed that triglyceride-rich lipoproteins and proinflammatory lipids were associated with shorter LTL and higher autoimmune risk, whereas omega-3 fatty acids, albumin, and HDL phospholipids were protective. Lipidomic pathways mediated a substantial portion of the LTL-autoimmune association and modified viral effects. These findings identify a telomere-lipid-immunity axis linking lifelong viral integration, metabolic aging, and autoimmune susceptibility, highlighting biological aging pathways as targets for autoimmune disease prevention.

N-glycosylation, a highly diverse post-translational modification, critically regulates organismal aging. The Caenorhabditis elegans (C. elegans) model is one of the excellent aging models, which exhibits distinctive N-glycosylation features including highly fucosylated core structures, bisecting β1,4-galactose, extensive phosphocholine, and methyl modifications. However, the site-specific and structure-specific landscape of the intact N-glycoproteome in adult nematodes is still unknown. In this study, we generated the first temporal atlas of the N-glycoproteome across the three stages of young adulthood (day 1), mid-life (day 5), and early senescence (day 10) of C. elegans, which identified 369 distinct glycoforms at 196 N-glycosites on 161 glycoproteins. A mixed sparse Partial Least Squares Discriminant Analysis (sPLS-DA) model, built from dual-omics data, decoded proteins and N-glycoproteins may act synergistically during the adult age progression. Time-series analysis further elucidated four distinct glycoprotein expression patterns and their functional implications. This represents the largest temporal N-glycosylation dataset of C. elegans to our knowledge. A high-throughput identification and quantification pipeline for the intact N-glycopeptides of C. elegans has been established. This study highlights key N-glycoproteins and glycans implicated in the regulation of adult age progression and may contribute to the integrative analysis of N-glycoproteome data with other omics datasets.

Paraoxonase 2 (PON2) is an enzyme exhibiting both lactonase and esterase activities, widely distributed across various tissues and localized within cellular mitochondria. It plays a vital role in innate immunity by restricting bacterial infections and has diverse functions, including the regulation of mitochondrial reactive oxygen species levels and the management of endoplasmic reticulum stress. By alleviating oxidative stress, stabilizing mitochondria, and modulating apoptosis, PON2 emerges as a significant factor in the study of cellular senescence. This review consolidates recent findings regarding PON2's physiological roles, its mechanistic connections to senescence, and the therapeutic potential of modulating its activity. Our analysis highlights PON2's considerable promise as a target for aging-related diseases, including neurodegeneration, metabolic disorders, cardiovascular diseases, chronic inflammation, and cancer.

Biological and synthetic replacement-based ageing interventions hold substantial potential to reverse many forms of age-related damage simultaneously and extend healthy lifespan beyond what can be achieved with conventional therapeutics. In this Perspective, we discuss recent insights, unmet needs, and emerging trajectories that are catalysing research and clinical development of replacement-based treatments and synergistic strategies for multi-targeted damage removal and export at the molecular, organellar, and cellular levels. The first workshop dedicated to replacement as an ageing intervention at the Aging Research & Drug Discovery 2025 conference helped prioritise key challenges, opportunities, and future directions to address the need for preventive replacement and bioengineering technologies capable of inducing systemic and sustained rejuvenation across cells, tissues, and regulatory networks. We propose a roadmap to guide research and innovation integrating replacement and next-generation damage-removal therapeutics to modulate the ageing process in the whole body, restore biological function, and extend healthy lifespan.

T cell immunosenescence refers to the progressive functional decline of T lymphocytes with aging, characterized by the phenotypic markers, mitochondrial dysfunction, and the senescence-associated secretory phenotype (SASP), representing a pivotal aspect of overall immune aging. This review systematically elucidates the critical role of T cell immunosenescence in the pathogenesis of common inflammatory skin diseases, including psoriasis, atopic dermatitis, rosacea, and seborrheic dermatitis. Senescent T cells drive the production of a disease-specific SASP via internally dysregulated signaling networks such as NF-κB, JAK-STAT, p38 MAPK, and PI3K-Akt-mTOR pathways, thereby shaping and sustaining a chronic cutaneous inflammatory microenvironment that promotes disease chronicity and recurrence. Furthermore, this review summarizes current therapeutic strategies targeting these senescence-associated pathways and SASP components, discussing both biological agents and small molecule inhibitors. Finally, we propose future research directions focusing on the direct targeting of senescent T cells or their upstream regulatory hubs to achieve deep disease remission and overcome therapeutic resistance.

Families with exceptional longevity often experience delayed onset of age-related diseases and reduced mortality across generations-a pattern influenced by shared genetic and behavioral factors. While several studies have focused on the members of longevity-enriched families (LEF), little is known about the health trajectories of the spouses marrying into these families. Given prior evidence of substantially reduced mortality among spouses of LEF members, determining whether this advantage reflects selection, shared environments, or behavioral convergence is essential for understanding the mechanisms that underlie intergenerational health transmission.

Frailty is a prevalent geriatric syndrome characterized by diminished physiological reserves and increased vulnerability to stressors. Microvascular dysfunction and inflammaging have been proposed as key biological mechanisms underlying frailty; however, objective and practical vascular biomarkers remain limited. Nailfold capillaroscopy (NFC), a non-invasive imaging method that visualizes microcirculatory architecture, may offer novel insight into the vascular component of frailty. This study aimed to investigate the association between frailty and NFC findings in older adults.

Age-associated changes in organelle structure are often viewed as passive deterioration. Our recent work challenges this view by identifying an evolutionarily conserved, age-onset remodeling of the endoplasmic reticulum (ER) that is actively driven by ER-phagy. Across multiple cell types and organisms, the ER undergoes a reduction in volume and a shift from rough ER sheets to tubular networks. ER compositional shifts accompany these changes in morphology, with declines of the proteostasis machineries enriched within rough ER and preservation of lipid-associated enzymes tied to tubular subdomains. This remodeling occurs via autolysosomal targeting and degradation of the ER, establishing selective ER-phagy as a conserved aspect of the aging process. Notably, ER-phagy is also engaged by multiple longevity paradigms, resulting in precocious, spatial reorganization of the ER. Furthermore, ER-phagy is required for lifespan extension during mTOR impairment, indicating that ER turnover is adaptive and contributes to longevity. These findings reveal ER-phagy as a regulator of organelle architecture and age-dependent shifts in cell metabolism, thus illuminating important roles for selective autophagy in shaping organelle identity and function across the lifespan.

The concepts of brain health (ie, optimal functioning of the brain across cognitive, emotional, and behavioral domains throughout life) and cognitive resilience (ie, the ability of the brain to recover after an insult) have become increasingly important as the population ages. Previous research has called attention to vascular risk factors underlying cerebrovascular disease, as well as modifiable variables that contribute to premature aging and cognitive dysfunction. In this scientific statement, we focus on the role of nonvascular physical and psychologic variables that affect brain health across the life span. We provide a broad overview of influences such as chronic medical conditions, inflammation, environmental exposures, and socioeconomic drivers that affect the developing brain, along with factors including sleep quality, the gut microbiome, and mental health that contribute to neurodegeneration. We also review the varying strength of evidence supporting biologic mechanisms and mitigating strategies that may help optimize resilience, with the goal of providing a framework for future studies.

Antagonistic trade-offs between early-life fitness and somatic maintenance are predicted to maintain variation in longevity, yet empirical support is scarce. Shephard et al. (2026) experimentally tested whether such trade-offs are concealed under typical developmental conditions using Mexican spadefoot tadpoles (Spea multiplicata) reared on typical or atypical diets. The atypical diet revealed cryptic genetic variation in larval growth and a significant negative genetic correlation with telomere length, indicating a diet-dependent trade-off in somatic maintenance.

Skeletal muscle regeneration depends on coordinated interactions between macrophages, fibro-adipogenic progenitors (FAPs), and muscle stem cells (MuSCs). Following injury, macrophages transition from pro-inflammatory to anti-inflammatory phenotypes, regulating debris clearance, cytokine secretion, and the activity of FAPs and MuSCs. FAPs transiently support MuSC-mediated regeneration but, if not cleared appropriately, differentiate into fibroblasts or adipocytes, contributing to fibrosis and fatty infiltration. Dysregulated macrophage-FAP crosstalk drives pathological conditions, including Duchenne Muscular Dystrophy (DMD) and age-related sarcopenia, where imbalances in cytokines and growth factors exacerbate maladaptive remodeling. FAP-derived colony-stimulating factor 1 (CSF1) sustains macrophage survival while macrophage-derived signals, including tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β), regulate FAP apoptosis, proliferation, and differentiation, shaping the regenerative niche. Single-cell and spatial transcriptomic approaches have revealed extensive heterogeneity among resident and infiltrating macrophages and FAP subsets, uncovering the molecular circuits underlying intercellular communication. Therapeutic strategies targeting cytokines and growth factors show promise in restoring balanced macrophage-FAP signaling, enhancing regeneration, and limiting fibrosis and fatty infiltration. Understanding the temporal dynamics of macrophage-FAP interactions is essential for developing interventions that preserve muscle homeostasis and counteract degenerative disease.

Importance: Decline in olfactory function may be used as a predictor of cognitive decline, to enhance early detection models, improve risk stratification, and enable early intervention. Objective: To assess the longitudinal association between olfactory decline, cognitive decline, and postmortem neuropathology. Design, setting and participants: Retrospective longitudinal analysis with clinicopathological correlations of a prospective population-based cohort study using data from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) and its Brain and Body Donation Program. Participants included cognitively unimpaired individuals without parkinsonism that converted to mild cognitive impairment (MCI) and/or dementia or remained cognitively stable. Main Outcomes and Measures: longitudinal change in olfaction, neuropsychiatric symptoms, motor function and memory, conversion to MCI/dementia, postmortem neuropathology Results: Over a mean follow-up period of 7.7 (5.4) years, out of 922 participants who were cognitively unimpaired at the first cognitive conference, 643 remained cognitively unimpaired, 279 converted to MCI, and 82 developed dementia. Of these, 633 individuals had at least 2 olfactory tests. Converters showed reduced olfactory function (t=-12.6, p <0.0001), faster progression in neuropsychiatric symptom burden (t=3.42, p < 0.001), and faster decline in memory (t= -7.33, p <0.0001) prior to conversion while no significant differences were observed in motor scores between converters and non-converters. Using ROC analysis, olfactory decline, increased neuropsychiatric symptom burden, as well as motor and memory decline predicted conversion to MCI with a consistent accuracy of ~ 70% up to 5 years before conversion, while UPSIT alone had an accuracy of ~ 60%. Longitudinal decline in olfaction was associated with a higher burden of a-synuclein (t= -8.21, p <0.0005), tau tangle (t= -2.66, p < 0.01) and amyloid plaque burden (t= -2.85, p < 0.005) and a faster decline over time was associated with a higher burden of tau (t=5.66, p<0.0001). Conclusions and Relevance: A reduction in olfactory identification ability is observed up to a decade prior to conversion to MCI and is associated with underlying burden of neuropathology markers, underscoring the value of incorporating olfactory testing in cognitively unimpaired individuals to identify those at-risk of future cognitive decline.

Sirtuin 1 (SIRT1) was initially identified as an enzyme that deacetylates histones and suppresses gene activity. Since then, its roles have expanded considerably, and it is now recognized as a multifunctional protein conserved across various organisms. Despite increasing interest, it remains essential to clarify how exercise-induced changes in SIRT1 counteract multiple hallmarks of aging, as well as the full scope of SIRT1's impact on different physiological systems. This review highlights recent findings on the short- and long-term effects of exercise on SIRT1 signaling in both rodents and humans during aging. We explore the molecular pathways activated in various tissues, providing insight into the specific biological functions of SIRT1 within aging cells. Optimal levels of SIRT1 help maintain homeostasis and a biochemical environment conducive to healthspan, influencing biological processes such as mitochondrial dynamics, metabolic pathways, tissue remodeling, autophagy, inflammatory responses, and redox balance. This indicates that SIRT1, a pleiotropic molecule, orchestrates multiple responses throughout aging. SIRT1 may act as a dynamic sensor for exercise benefits and protect against aging by maintaining genomic integrity. Different exercise protocols (acute and chronic) and modalities (aerobic, resistance, and combined training) can increase mRNA levels, activity, or protein levels of SIRT1 in various vital organs (adipose tissue, hippocampus, heart, liver, bone, and skeletal muscle) of aged animals and older adults, promoting health. Taken together, these observations support the notion that SIRT1 functions as a potential exerkine, and understanding its role in exercise-induced adaptations offers new insights into non-pharmacological strategies to enhance longevity.

Adverse events across the lifespan have been linked to poorer health outcomes, but the biological mechanisms remain unclear. The aim of this study was to quantify the independent and joint associations of adversity experienced in childhood and/or adulthood with molecular, clinical and functional markers of biological ageing.

In recent years, the study of human health and longevity from the perspective of environmental geochemistry has opened up a new field within environmental science. Tungsten (W) and molybdenum (Mo), both belonging to the same group of elements, are essential trace elements for biological systems and play important roles in human health. However, whether the background levels of W and Mo in a region are statistically associated with human longevity remains a scientific question worthy of investigation. This study employs Origin, SPSS mathematical statistical methods, and Overly spatial analysis techniques to investigate this issue within the research area of Yunnan Province, China. (1) Dynamic correlation evolution: The correlation between ω(W) and the longevity index evolved from non-significant during the Fifth National Census to significantly weak positive correlations in the Sixth and Seventh National Censuses. In contrast, ω(Mo) consistently showed no significant correlation across the three census periods. The ratio ω(W/Mo) shifted from a weak negative correlation to a weak but significant positive correlation. (2) Spatial analysis: Regions with high ω(W) values (66 counties) demonstrated clear longevity advantages. The proportion of counties with longevity above the national average first increased and then slightly decreased over time. These high-ω(W) counties were stably clustered in four major geographical units: the Hengduan Mountains, southwestern Yunnan, southern Yunnan, and central Yunnan. By contrast, The longevity advantages in high ω(Mo) value areas (87 counties/districts) exhibited an "inverted U-shaped" trend, widely distributed across six major fault zones and geomorphic regions, yet sharply contracted in the most recent decade. The results suggest that changes in elemental exposure intensity, potentially driven by anthropogenic activities, may be a key factor influencing regional longevity patterns. Provides a basis for exploring the relationship between trace elements in the regional geochemical environment and human health. However, the specific processes and mechanisms underlying these patterns warrant further investigation.

Senile osteoporosis (SOP) is characterized by impaired osteogenesis of bone-marrow mesenchymal stem cells (MSCs). The underlying metabolic basis remains unclear. This study aimed to identify energy-regulating pathways sustaining MSC osteogenesis during aging. Progressive activation of lipophagy was observed during MSC osteogenic differentiation, coupling lipid-droplet degradation with mitochondrial β-oxidation and ATP generation. Loss of the lipophagy receptor SPARTIN disrupted this process, leading to lipid accumulation, reduced CPT1A/CPT2 expression, suppressed oxidative phosphorylation, and impaired osteogenesis in vitro and in vivo. Conditional deletion of Spart in MSCs reproduced an osteoporosis-like phenotype in young mice. Reactivation of lipophagy using bone-tropic AAV9-LAP restored mitochondrial metabolism and bone mass in both Spart-CKO and SOP mice. Pharmacological activation with digoxin produced similar effects but induced cardiotoxicity. A senescent-neutrophil-membrane-coated nanoplatform (SNM@NP-DIG) enabled bone-targeted digoxin delivery, rescuing bone mass while minimizing cardiac injury. Overall, SPARTIN-mediated lipophagy is a critical metabolic regulator of MSC osteogenesis and represents a promising therapeutic target for senile osteoporosis.

Senile osteoporosis is driven by bone marrow stromal cell (BMSC) senescence. Ferroptosis, an iron-dependent cell death pathway, is implicated in aging. The natural flavonoid galangin possesses anti-aging properties, yet its effects on ferroptosis and BMSC senescence are unknown. Natural aging and d-galactose-induced aging models were used, with galangin supplementation. Bone mass was assessed via micro-computed tomography and histomorphometry. Senescence markers (P21, SA-β-gal, NAD+) and ferroptosis regulators (GPX4, GSH/GSSG) were measured. BMSC senescence was induced by d-galactose or serial passaging. Effects of galangin on senescence, ferroptosis, osteogenic differentiation, and dipeptidyl peptidase-4 (DPP4) signaling were evaluated. Galangin significantly attenuated bone loss and reduced senescence markers in both aging mouse models. Ferroptosis was activated in senescent BMSC. Galangin suppressed ferroptosis, rescued senescence phenotypes, and restored osteogenic differentiation capacity. Mechanistically, galangin inhibited DPP4 nuclear translocation and disrupted its interaction with NADPH oxidase NOX1, thereby blocking reactive oxygen species-dependent ferroptosis signaling without altering total DPP4 expression. Galangin ameliorates Senile osteoporosis by specifically inhibiting DPP4 nuclear translocation and its interaction with NOX1, thereby suppressing ferroptosis, rescuing BMSC senescence, and restoring osteogenic function. This identifies galangin as a promising agent against skeletal aging.

Preterm birth is increasingly recognized as a determinant of health across the lifespan, influencing neurodevelopment, psychiatric risk, cardiovascular function, and mortality. This review synthesizes current evidence linking early-life adversity, including that associated with prematurity, to accelerated aging of to the brain-heart axis. We further describe the "fetus to fifty" model, highlighting how the early-life experiences of preterm-born infants impact adult trajectories across the lifespan.

Oocytes are produced before birth in women and their abundance and quality decrease overtime until the loss of ovarian functions at menopause. In contrast, animals such as sea urchins retain stem cells that enable a continuous, high fecundity production of quality oocytes throughout their lifespan. We hypothesize that the somatic cells required for these two different adult ovarian functions are distinct. Comparing sea urchin adult ovaries with human fetal ovaries may reveal greater conservation, since they are both in a state of active oocyte production. Here, we present the first integration of the sea urchin adult ovary with the human fetal and adult ovary single cell RNA seq datasets. Using SAMap, the resulting integration demonstrates high conservation of cell states and gene expression in both the somatic cells (such as immune and muscle cells) and the germ cells of the ovary. Whereas multiple cell states change over time in the human ovary during its transition from fetal to adult stages, the sea urchin adult ovary instead represents an intermediate state that preserved most of the cell states characteristic of both the fetal and adult human ovary. Comparing reproductive strategies and ovarian function separated by 540 million years since their last common ancestor could lead to new approaches to treat human reproductive senescence. Our results highlight the potential of the sea urchin as a powerful comparative model that lacks reproductive senescence to better understand the cellular transitions underlying the aging human ovary.

Impaired immune responses are a key feature of aging; however, there are few laboratory tests that link these responses to clinical outcomes. Interferon-gamma release assays (IGRAs) for tuberculosis screening quantify release of interferon-gamma by T-cells, and the difference between unstimulated and mitogen-stimulated T-cells is assessed for test validity. We assess this measure's relationship with all-cause mortality. We obtained the most recent negative and indeterminate outpatient IGRAs from a large health system along with demographics, frailty, lymphocyte count, and inflammatory markers. We removed individuals on hemodialysis or immunosuppressive medications. We assessed the association of mitogen-nil with mortality at 6 months, 1 year, and 5 years by Kaplan-Meier analysis and Cox regression. Among 16,104 individuals, reported mitogen-nil ranged from < 0.01 to ≥ 10 IU/mL, and median (IQR) age was 64 (57, 72). Cumulative mortality (95% CI) at 5 years was estimated at 28% (23%-33%) for values 0-1 versus 19% (18%-19%) ≥ 10. In Cox regression, relative to values ≥ 10, values from 0-1 had hazard ratios for mortality at 6 months, 1 year, and 5 years of 2.77 (1.47-5.22), 2.22 (1.41-3.50), and 1.76 (1.31-2.36). Among those with data, adding lymphocyte count did not alter associations. Lower T-cell response to mitogen stimulation in IGRAs is associated with greater mortality. This common test may provide additional information to risk-stratify patients and as a phenotype of impaired immune response.

Ageing is a complex process influenced by modifiable factors such as diet, which may accelerate or decelerate physiological decline. While chronological age increases uniformly, biological ageing varies between individuals, reflecting differences in health status and the resilience of biological systems. The Klemera-Doubal Method (KDM), a composite biomarker-based index often used as an estimate of biological age, has been associated with morbidity and mortality in large cohorts. This study examined whether dietary manipulation of protein source and macronutrient composition affects KDM estimates in older adults. We analysed data from the Nutrition for Healthy Living study, a 2 × 2 factorial dietary intervention trial involving 104 participants aged 65-75 years. Participants were randomised to one of four diets: omnivorous/high-fat (OHF), omnivorous/high-carbohydrate (OHC), semi-vegetarian/high-fat (VHF) or semi-vegetarian/high-carbohydrate (VHC). KDM-derived δAge (the difference between KDM- and chronological-age) was calculated before and after a 4-week intervention. The OHF group, most like participants' baseline diets, showed no meaningful change in δAge. Compared to OHF, participants in the OHC group showed a significant reduction in δAge. The VHF and VHC groups showed similar reductions in δAge, relative to OHF, though not all reached statistical significance. KDM-derived δAge appears responsive to dietary change within 4 weeks and may offer a useful proxy for evaluating shifts in physiological status. Caution is warranted in interpreting such changes as evidence of biological age reversal as observed shifts may reflect acute physiological responsiveness to dietary inputs rather than altered ageing trajectories. Longer-term treatment would be needed to assess changes in age-related disease risks.