Longevity Papers

Type 1 diabetes (T1D) is associated with early-onset and increased risk of coronary artery disease (CAD), particularly myocardial infarction (MI), that is not fully explained by traditional cardiovascular risk factors. Hematopoietic aging, marked by clonal hematopoiesis of indeterminate potential (CHIP) and leukocyte telomere length (LTL) attrition, has been linked to CAD risk in the general population. We investigated whether T1D is associated with increased prevalence and earlier onset of CHIP and accelerated LTL attrition, and whether these processes contribute to CAD risk. We analyzed 416,565 UK Biobank participants (1,342 T1D cases) with harmonized CHIP calls and qPCR-derived LTL measurements. T1D was defined using ICD-10 codes, diagnosis before age 40 years, and insulin initiation within one year. CHIP was defined as variant allele fraction >=2%, with higher thresholds evaluated in sensitivity analyses. Multivariable regression compared CHIP prevalence, age-specific CHIP probability, and LTL between T1D and controls. Associations of CHIP and LTL with prevalent and incident (median follow-up approximately 13.5 years) MI and CAD were evaluated within T1D. Mendelian randomization, conjFDR, and integrated single-cell genomic analyses assessed genetic relationships. CHIP prevalence was higher in T1D than in controls (4.40% vs 3.00%; absolute risk difference 1.39%, 95% CI 0.29 to 2.49; p=3.7x10-3), with higher adjusted odds (OR 1.71, 95% CI 1.31 to 2.23; p=6.9x10-5). Age modeling indicated an approximately 7-year earlier shift in CHIP risk in T1D (3% prevalence at age 52.2 vs 59.0 years). Mean LTL did not differ significantly between T1D and controls (beta -0.040 SD; p=0.13); however, T1D disease duration was associated with shorter LTL independent of covariates (beta -0.0082 SD per year; p=0.002). Within T1D, shorter LTL was associated with higher risk of both prevalent and incident MI (OR 0.77, 95% CI 0.65 to 0.91; p=0.003; HR 0.63, 95% CI 0.44 to 0.91; p=0.012). CHIP was not significantly associated with MI or CAD in this cohort. Genetic analyses supported a bidirectional relationship between T1D and LTL, but not CHIP, and identified 47 T1D-LTL loci enriched for hematopoietic stem and progenitor cell pathways. In conclusion, T1D is associated with accelerated hematopoietic aging, reflected by earlier and more prevalent CHIP and disease duration-dependent LTL attrition. LTL attrition, but not CHIP, was associated with MI risk, implicating telomere dynamics as a contributor to excess cardiovascular risk in T1D.

Muscle and bone, key tissues that maintain the body's structure and function, are closely connected via mechanical and biochemical interactions. The vascular system plays a crucial role in musculoskeletal health, not only by providing nutrients and oxygen but also by regulating growth, regeneration, and metabolism. This review systematically examines the vascular structure and function of the musculoskeletal system, and explores the complex biochemical signaling networks involving myokines, osteokines, and vascular-derived factors. Vascular dysfunction is a key contributor to the pathogenesis of degenerative diseases like sarcopenia (SP) and osteoporosis (OP), making vascular-targeted therapies a promising approach for their treatment. Potential strategies for restoring vascular health include molecular targeting, exercise training, nutritional supplementation, cardiovascular pharmacotherapy, hormone therapies, and tissue engineering-all of which may help slow aging-related musculoskeletal degeneration. Despite significant research progress, challenges remain in the clinical translation of these interventions. Future research should focus on elucidating the molecular mechanisms of muscle-bone-vascular interactions and exploring innovative tissue engineering techniques. This review provides a comprehensive understanding of the dynamic interactions between muscle, bone, and vascular systems, highlighting the importance of vascular health in musculoskeletal disease management, and proposes novel vascular-targeted approaches for the prevention and treatment of musculoskeletal disorders.

Menopause is accompanied by accelerated losses in muscle mass and strength and declining bone density. Whether creatine monohydrate benefits postmenopausal women are uncertain.

Breast cancer incidence and mortality increase with age, but the mechanisms linking aging to metastasis remain unclear. Most preclinical studies use young animal models, limiting insight into how the aged microenvironment influences cancer. Here, we show that aging markedly increases breast cancer metastasis in multiple mouse models, and this effect is dependent on host expression of the Receptor for Advanced Glycation End-products (RAGE). Aging increased tumor RAGE ligand levels, including S100A8/9 and AGEs, and induced RAGE-dependent changes in inflammatory, EMT, angiogenic, and extracellular matrix gene programs in tumors. Circulating cytokines and S100A8/9 from aged hosts promoted tumor cell invasion, which was suppressed by RAGE or S100A8/9 inhibition. In human breast cancers, elevated AGER expression and enrichment of aging- and RAGE-associated transcriptional signatures correlated with poorer survival, especially in older patients. These findings identify RAGE as a mechanistic link between aging and metastasis and a potential therapeutic target in older patients.

Aging is accompanied by a progressive decline in intestinal barrier integrity, resulting in increased permeability to luminal microbes and microbial products and contributing to chronic low-grade inflammation ("inflammaging"). While epithelial and microbial changes have been extensively studied, the role of intestinal T cells as active regulators of barrier homeostasis during aging remains underappreciated. The gut harbors the largest population of T cells in the body, including diverse conventional and unconventional subsets that directly shape epithelial differentiation, mucus production, antimicrobial defense, and tight junction organization through cytokine-mediated signaling. In this review, we synthesize current evidence linking age-related alterations in intestinal T-cell composition and function to epithelial barrier decline. We focus on key T-cell subsets including Th1, Th17, Th22, regulatory T cells, γδ T cells, mucosal-associated invariant T (MAIT) cells, and intraepithelial lymphocytes, and discuss how aging-associated shifts in their cytokine profiles may disrupt the balance between barrier maintenance, repair, and inflammation. We further examine how T-cell dysfunctions characteristic of aging, including senescent-like and exhausted phenotypes, may exacerbate epithelial injury, microbial translocation, and systemic immune activation. Insights from age-accelerated conditions such as HIV/SIV infection and inflammatory bowel disease are used to inform emerging models of T-cell-driven barrier decline in older adults.

Mutations accumulate with age in most human tissues. While some undergo clonal expansion and contribute to disease, the mutational burden tolerated by a normal cell without functional decline remains unknown. Here, we repeatedly treat proliferating human primary fibroblasts with the point mutagen

Schinopsis balansae is a tannin-rich tree belonging to the family Anacardiaceae, native to the Gran Chaco region of Argentina, and cultivated in Egypt. This study was performed to characterize the bioactive compounds of the 80% methanol extract of S. balansae leaves using HPLC-ESI/MS-MS technique, coupled with the assessment of in vitro anti-aging enzyme inhibition assays. Further, total phenolic and flavonoid content and molecular docking studies were conducted. High performance liquid chromatography-electrospray ionization coupled with mass fragmentation (HPLC-ESI/MS-MS) was used to tentatively identify the phyto-constituents of S. balansae leaf extract. The phenolic and flavonoid contents were assessed as gallic acid equivalents (GAE) and rutin equivalents (RE). Further, the anti-skin aging potential was investigated via assessment of elastase and collagenase inhibition assays. The in silico molecular docking studies were conducted on 7EST elastase and 2TCl collagenase. The HPLC/MS analysis revealed the identification of twenty-two compounds of different chemical classes like flavonoids, phenolic acids, and tannins. The total phenolic and flavonoid contents were 399.29 ± 13.23 µg gallic acid equivalent/mg and 8.25 ± 0.63 µg rutin equivalent/mg, respectively. The extract exhibited significant collagenase (IC

Familial longevity, quantified using the Longevity Relatives Count (LRC) score indicating the proportion of ancestral long-lived family members, associates with a pronounced 13 years delayed onset of cardiometabolic disease (CMD). Understanding the molecular basis of familial longevity therefore provides critical insights into mechanisms of cardiometabolic resilience. However, the combined metabolomics and proteomics profile associated with the delayed CMD onset observed in such long-lived family members is not understood yet. Hence, we integrated plasma metabolomics and proteomics in 495 participants from the Leiden Longevity Study to identify molecular signatures associated with (a contrast in) the LRC score. Metabolomics profiling captured 429 features, including amino acid derivatives, nucleosides, and lipid mediators, while proteomics quantified 374 proteins related to cardiovascular, metabolic, and inflammatory pathways. Three within-family analysis approaches were examined and overlapping findings were interpreted. We identified ten metabolites and nine proteins that are associated with increased familial longevity, exemplified by a high LRC score. High LRC scoring individuals exhibited lower levels of amino acid derivatives (prolylhydroxyproline, 5-hydroxy-tryptophan, asymmetric dimethylarginine), nucleosides (2-methylguanosine, 7-methylguanosine, pseudouridine), N-acetylneuraminic acid and quinolinic acid, indicating optimized extracellular matrix integrity, vascular function, and reduced neuroinflammatory activity. Lipid mediators, including elevated 6-keto-PGF1a and reduced 9-HOTrE/alpha-linolenic acid ratio, reflected preserved endothelial homeostasis and attenuated inflammatory signaling. At the proteome level, strong ancestral familial longevity is associated with immune regulators (RETN, NPPB, IGSF8), extracellular matrix components (EFEMP1, EPHB4), and adhesion/signaling molecules (LRP11, ICAM3, KIT, ADGRG2), highlighting coordinated regulation of inflammation, tissue remodeling, and regenerative capacity. Multi-omics pathway analyses indicated convergence on amino acid and nucleotide metabolism, lipid signaling, extracellular matrix remodeling, and receptor-mediated communication. Collectively, these multi-omics systemic signatures define a molecular framework of ancestral familial longevity characterized by reduced inflammation, preserved tissue integrity, and enhanced metabolic and regenerative processes. Our findings provide mechanistic insight into the biology of familial longevity and potentially cardiometabolic resilience.

Despite extensive research, molecular differences in human populations and the influence of ancestry, age, geography, and diet are poorly understood. We performed comprehensive multiomics profiling (including genomics, transcriptomics, proteomics, metabolomics, lipidomics, metallomics, glycomics, and microbiomics) on samples from 322 healthy individuals of European, East Asian, and South Asian ancestry across multiple continents. We identified ethnicity-associated molecular features linked to host metabolism, autoimmune disease risk, drug metabolism, and neurodegenerative pathways. We uncovered ancestry- and geography-related molecular changes affecting metabolism, immune function, microbiome composition, and biological aging. Specific genetic variants and gene expression differences were associated with lipid metabolism and immune regulation. Geography influenced biological age: East Asians showed lower biological age in their ancestral regions, whereas individuals of European ancestry exhibited lower biological age in the US/Canada than in Europe. Diet-microbiome metabolism interactions displayed ethnicity-specific patterns, many related to health. This open access resource advances understanding of ethnicity-environment interactions and supports precision medicine.

Aging is the predominant risk factor for neurodegenerative diseases, yet the mechanisms linking biological aging to selective neuronal degeneration remain incompletely understood. Accumulating evidence indicates that aging progressively disrupts epigenetic regulation, manifested as increased epigenetic noise in DNA methylation, histone modifications, and chromatin accessibility, which undermines transcriptional precision and the stability of neuronal identity. Recent advances in single-cell and spatial epigenomics further suggest that these age-associated epigenetic alterations are not merely correlative but can actively shape neuronal vulnerability across brain regions and cell types. In this review, we synthesize emerging evidence showing how epigenetic noise contributes to selective neurodegeneration across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, and discuss emerging strategies aimed at stabilizing the aging neuronal epigenome.

Sarcopenia and the age-related decline in muscular strength and regenerative capacity contribute directly to loss of autonomy, greater risk for hospitalization and healthcare utilization. One contributing cellular phenotype associated with skeletal muscle aging is a loss in the function and number of resident muscle stem cells (MuSCs) or satellite cells. MuSC activation leads to dramatic changes in cellular architecture and metabolic reprogramming, including both mitochondrial biogenesis and increased glycolysis. Despite these changes to increase energy production, high energy demands may not be fully met during periods of MuSC activation. Here we used in vitro and in vivo approaches in mice to demonstrate the function of glutaminase for age-related changes in MuSC function. By combining fluorescence-activated cell sorting (FACS) isolation with metabolomics and stable isotope tracing, we show an age-related decline in reductive (counterclockwise) flux of glutamine through the tricarboxylic acid (TCA) cycle, a pathway by which MuSCs build cellular fatty acid stores as necessary biomass for MuSC function.

The relationship between lipid metabolism and neurodegeneration is a critical determinant of brain aging with therapeutic implications. This review focuses on how polar lipids and omega-3 polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid (DHA), contribute to membrane organization, signaling, neuroinflammation resolution, and cognitive resilience during aging. The mammalian brain, containing over 50% lipids by dry weight, is exceptionally enriched in DHA, which preferentially accumulates in cognitive-critical regions including the hippocampus and prefrontal cortex. Age-related decline in brain PUFA content is a consistent finding across species and is linked to lower synaptic density, neuronal loss, and cognitive impairment. This decline results from converging mechanisms including impaired transport across the blood-brain barrier, oxidative damage, altered lipid remodeling, and reduced inflammatory resolution. We also discuss how dietary intake, endogenous PUFA biosynthesis, sex, obesity, and hepatic metabolic dysfunction may modify brain PUFA availability. Clinical evidence suggests that omega-3 interventions may provide selective cognitive benefits, particularly for executive function and in genetically susceptible populations such as APOE4 carriers, although effects differ according to dose, formulation, and baseline status. Complex lipid sources including milk fat globule membrane may offer advantages beyond simple fatty acid supplementation by improving the delivery of bioactive polar lipids. Overall, the field is moving toward mechanism-informed and precision nutrition strategies to preserve brain health across the lifespan.

Aerobic exercise has a profound influence on host physiology and cancer risk, yet the mechanisms of how these are linked remain incompletely understood. Since adult stem cells (ASCs) respond to shifts in organismal (host) physiology and are also likely the cancer cells of origin, ASC function could act as an essential mediator of the link between aerobic exercise and cancer incidence. We therefore hypothesize that exercise-induced alterations in host physiology lead to sculpting of distal tissue microenvironments to augment the regenerative capacity of ASCs whilst simultaneously activating highly conserved cell-intrinsic and cell-extrinsic processes that suppress pro-tumorigenic phenotypes. In this Perspective, we dissect this hypothesis by first examining how exercise regulates host physiology through alterations in the systemic milieu and then focus on how these changes shape distant tissue landscapes in which ASCs reside. We then discuss the effects of exercise on ASC function and speculate on the cell-intrinsic and cell-extrinsic mechanisms that may explain the apparent paradox of exercise-induced enhanced stemness in the context of tumour suppression. A better understanding of how exercise-sensing pathways regulate ASC function to maintain or restore tissue homeostasis will have implications for cancer prevention as well as for other age-related conditions in which ASC degradation is complicit.

Osteocytes, the central regulators of bone remodelling, are essential for maintaining bone homeostasis. Embedded in a nutrient-limited matrix and burdened by cumulative stress over their exceptionally long lifespan, how osteocytes sustain long-term viability remains elusive. Tunnelling nanotubes (TNTs) are newly described intercellular bridges that enable long-range transfer of organelles and have been implicated in stress adaptation. Here, we provide the first definitive identification of TNTs between cultured osteocytes, which exhibit canonical TNT morphology together with osteocyte-specific features. Functionally, osteocytic TNTs mediate intercellular transfer of membrane-bound cargo, predominantly lysosomes. Under nutrient deprivation, TNT formation and lysosome transfer are both increased, replenishing the lysosomal pool in stressed osteocytes. Transferred lysosomes then fuse with accumulated autophagosomes, thereby restoring impaired autophagic flux and suppressing apoptosis. This cytoprotective effect requires TNT integrity and intact autophagic flux. Although mitochondrial transfer is detectable, it does not confer comparable protection. The findings identify a transcellular autophagy pathway mediated by TNT-dependent lysosome sharing, revealing a previously unrecognized cooperative survival strategy among osteocytes. This work establishes a novel conceptual framework in osteocyte biology and suggests potential therapeutic avenues for bone diseases associated with osteocyte apoptosis and impaired bone remodelling.

Osteoporosis (OP) is a systemic disease characterized by a reduction in the number of trabecular bone structures and damage to the bone microstructure. It is commonly found in people who are aging or have estrogen deficiency. Oxidative stress and chronic inflammation caused by pathological factors such as aging and estrogen deficiency are key pathogenic factors. Betulinic acid (BA), a natural pentacyclic triterpenoid compound, exhibits anti‑inflammatory and antioxidant biological effects. However, its role and potential mechanisms in the inflammatory injury of osteoblasts in OP remain unclear. In the present study, in vivo experiments were conducted using an ovariectomized (OVX) rat model of OP, with bone microstructure analyzed by micro‑CT, protein expression detected by immunohistochemistry, and serum inflammatory factors measured by ELISA. BA was revealed to alleviate bone loss in OVX rats and inhibit the expression of NOD‑like receptor pyrin domain‑containing 3 (NLRP3), Asc and caspase‑1 in the femur of OVX rats, as well as suppress the release of inflammatory factors such as interleukin‑1 β, interleukin‑6, and tumor necrosis factor‑αin the serum of rats. The inflammatory injury osteoblast model of BA intervention was also studied with hydrogen peroxide (H2O2) in vitro, with reactive oxygen species (ROS) levels assessed by fluorescence assay, osteogenic differentiation evaluated by ALP staining and alizarin red staining, and autophagy‑related proteins detected by western blotting. BA pretreatment reduced production of ROS, inhibited expression of NLRP3 and downstream pathway activation, improved alkaline phosphatase activity, mineralization ability, and osteogenic differentiation ability of MC3T3‑E1 cells. Administration of BA increased the autophagy of MC3T3‑E1 cells treated with H2O2, which was confirmed by the increased expression levels of LC3b II and Beclin‑1 and the decreased expression levels of P62. In addition, BA could enhance the phosphorylation of AMPK in MC3T3‑E1 cells treated with H2O2 and reduce the phosphorylation of mTOR, but this effect could be rescued by Compound C (an AMPK blocker). BA can protect osteoblasts from inflammatory injury by reducing the production of ROS and inhibiting the activation of NLRP3 through autophagy mediated by the AMPK/mTOR pathway.

Ultraprocessed foods (UPFs), which feature reductions in naturally occurring food components (fiber, phytochemicals) as well as the addition of fat, sugar, salt, and artificial food components (colorings, preservatives) are consumed in large quantities globally. Although a growing body of research has suggested that higher levels of UPF consumption are associated with poorer cardiometabolic outcomes, literature synthesizing the evidence that UPF consumption has negative effects on the aging brain has been scarce. This review provides a comprehensive view of the evidence connecting UPF consumption to downstream consequences for the brain in aging, including proposed mechanisms of action, evidence supporting those mechanisms from basic science studies, and clinical evidence. We then survey current challenges and opportunities in the study of brain aging effects of UPF consumption and provide recommendations for researchers and policymakers.

Aging is accompanied by a progressive decline in skeletal muscle mass and function, culminating in sarcopenia, a major contributor to frailty, disability, and mortality in older adults. While skeletal muscle aging has traditionally been attributed to cell-autonomous and local tissue mechanisms, increasing evidence suggests that systemic, cell non-autonomous processes play a central role in coordinating aging across organs. The brain, particularly the hypothalamus, has emerged as a key regulator of organismal aging, yet its contribution to skeletal muscle aging remains poorly defined. Here, we tested the hypothesis that senescence confined to the brain is sufficient to induce aging-like molecular remodeling in skeletal muscle via systemic mechanisms. To model brain senescence, young mice were subjected to fractionated whole-brain irradiation (WBI), a well-established approach that induces widespread cellular senescence and neuroinflammation in the brain while sparing peripheral tissues. Two months after WBI, transcriptomic profiling of quadriceps muscle was performed and compared with that of naturally aged mice. WBI-induced robust gene expression changes in skeletal muscle that closely mirrored those observed during chronological aging. Pathway-level analyses revealed marked downregulation of mitochondrial organization, respiratory chain assembly, and metabolic processes, alongside enrichment of remodeling- and stress-associated pathways. Upstream regulator analysis identified FOXO1, FOXO3, KLF15, and STAT3, which are key drivers of muscle catabolism and atrophy, as central mediators of the observed transcriptional program. Semantic similarity analysis further demonstrated a high concordance between WBI-induced and aging-associated biological processes. Collectively, these findings demonstrate that brain senescence is sufficient to drive sarcopenia-like transcriptomic remodeling in skeletal muscle, implicating central nervous system aging as an upstream regulator of peripheral muscle decline. This brain-muscle aging axis may contribute to frailty in individuals with accelerated brain aging and in cancer survivors exposed to cranial irradiation, highlighting brain senescence as a potential therapeutic target to mitigate systemic aging and skeletal muscle dysfunction.

References [...].

Focused ultrasound (FUS) in combination with nanobubbles enables transient, localized opening of the blood-brain barrier (BBB), facilitating targeted therapeutic delivery. However, the cerebrovascular consequences of BBB opening across the lifespan are not fully understood. Here, we compare the effects of FUS-mediated BBB opening on cerebral blood flow (CBF) and neurovascular coupling (NVC) in young and aged mice using functional ultrasound imaging (fUSI), tracer BBB permeability assays, and histology. FUS reliably opened the BBB in both age groups, confirmed by penetration of high-molecular-weight tracers. In aged animals, FUS induced a more pronounced and sustained reduction in resting CBF relative to young controls. Surprisingly, despite lower baseline perfusion, aged mice exhibited preserved or enhanced NVC responses, suggesting that vasodilatory reserve remains intact or sensitized in the aging brain. Immunohistochemistry revealed greater microglial activation after FUS in aged mice, consistent with heightened neuroinflammatory responses. These findings demonstrate an age-dependent dissociation between resting perfusion and activity-evoked vascular responses following BBB opening. Our results highlight both the vulnerabilities and compensatory adaptations of the aging cerebrovasculature, emphasizing the importance of age as a critical variable in the development of FUS-based therapeutic strategies.

Despite optimal lipid-lowering treatment, numerous older adults with atherosclerotic cardiovascular disease continue to experience progression driven by inflammation, referred to as residual inflammatory risk. Cellular senescence and the senescence-associated secretory phenotype (SASP) significantly contribute to vascular inflammaging; however, pharmacological interventions in aging populations are still inadequately investigated. This review synthesizes evidence regarding the role of SASP in atherosclerosis and critically evaluates senotherapeutic strategies, emphasizing mechanisms, preclinical efficacy, and translational potential. Senescent endothelial cells, vascular smooth muscle cells, and foam cells aggregate in plaques, secreting pro-inflammatory cytokines (IL-1α, IL-6, MCP-1) and matrix metalloproteinases that enhance plaque susceptibility. Two complementary pharmacological strategies have emerged. Senolytics (dasatinib combined with quercetin, fisetin, and lanatoside C) specifically eradicate senescent cells by inhibiting anti-apoptotic pathways (BCL-2, PI3K/AKT, and HSP90). Senomorphics (rapamycin, metformin, JAK/STAT inhibitors, NF-κB inhibitors) attenuate SASP expression through modulation of mTOR, NF-κB, and JAK/STAT pathways. Preclinical studies indicate that senolytics diminish the burden of senescent cells, reduce plaque area, and limit necrotic core expansion, while simultaneously improving plaque stability. Senomorphics provide comparable advantages with profiles appropriate for prolonged utilization. Targeting SASP constitutes a rational strategy to alleviate residual inflammatory risk. Nonetheless, significant knowledge deficiencies persist concerning patient selection, dosing protocols, drug-drug interactions with cardiovascular treatments, and long-term safety. Translation necessitates stringent clinical trials in geriatric cardiovascular patients. This review offers an extensive pharmacological framework for senotherapeutics in atherosclerosis.

As global aging intensifies, elucidating reproductive health's epigenetic aging associations is crucial. However, the impact of reproductive history on multi-generational DNA methylation (DNAm) clocks remains insufficiently characterized, representing a significant gap in understanding biological vs. chronological aging divergence. This study analyzed 1117 U.S. women aged 50 or older from NHANES 1999-2002 to examine associations between reproductive history and 12 DNA methylation (DNAm) algorithms. Multivariable linear/logistic regression models assessed associations between reproductive indicators and DNAm age acceleration, adjusting for sociodemographic/biological confounders. The β coefficients represent the change in DNAm age acceleration in years. Pregnancy frequency (per additional pregnancy) showed positive associations with PhenoAgeacc (β = 0.14, 95%CI:0.01-0.27) and GrimAge2Mortacc (β = 0.10, 0.03-0.18). Categorical analyses revealed that high pregnancy parity (≥5) significantly increased the odds of GrimAge2Mortacc (OR = 2.34, 95% CI: 1.15-4.71), while high live birth parity (≥5) was associated with increased odds of HannumAgeacc (OR = 2.57, 95% CI: 1.01-6.92). Most primary associations involving second-generation clocks remained robust after false discovery rate correction. While menarche timing showed no significant associations, later menopause and a longer reproductive lifespan were significantly associated with decelerated biological aging after multiple testing correction. These findings suggest that parity and reproductive timing are associated with biological aging trajectories through methylation mechanisms, advancing our understanding of sex-specific aging drivers.

Werner (WRN) is the only human RecQ helicase family member with DNA exonuclease activity. WRN promotes genome stability through its functions in DNA replication, repair and telomere maintenance, the deficiency of which presents clinically as Werner syndrome, causing premature aging and cancer predisposition. The main DNA double strand-break sensor Ku70/80 heterodimer (Ku) is a known partner of WRN, which stimulates its nuclease activity. However, the molecular basis of Ku-WRN interplay is currently unknown. Here, we present a high resolution cryo-EM structure of human Ku bound to DNA in complex with the N-terminal WRN exonuclease domain. This structure reveals multiple interaction sites between WRN and the Ku:DNA complex. The catalytic domain of WRN-exo engages with the DNA ends, stabilized by the vWA-like Ku80 domain interacting with the N-terminal APLF-like Ku binding motif (A-KBM) of WRN. Most surprisingly, we visualize the SAP domain of Ku70 stabilized within this complex, and we identify specific contacts mediating this interaction. These interactions are validated by assessing the impact of point mutations on either side of the Ku-WRN interfaces on exonuclease activity with purified recombinant proteins, and on live protein recruitment at biphoton laser-damaged nuclear sites. Finally, we show that disruption of WRN-Ku70 interaction results in aberrant resection of stalled replication forks. Together, we define the architecture of the Ku-WRN exonuclease domain interface and its impact on WRN exonuclease activity, recruitment and replication fork processing.

Cellular senescence is a hallmark of age-related disorders, including cancer, in which senescence contributes to tumor progression and treatment resistance. Targeting senescent cells therapeutically requires noninvasive methods to longitudinally monitor senescence burden. Here, we present an injectable nanoprobe for noninvasive detection of therapy-induced senescence in lung cancer and pulmonary fibrosis via urine testing. Using human biopsy samples, clinical transcriptomic datasets and mouse models, we identify matrix metalloproteinase-7 (MMP-7) as a specific biomarker of senescence in lung cancer and bleomycin-induced fibrosis. We develop ALBANC, a nanoprobe composed of human serum albumin linked to gold nanoclusters (AuNCs) through MMP-7-cleavable peptide linkers. MMP-7-mediated cleavage releases AuNCs that are renally excreted, enabling rapid and sensitive colorimetric urine detection via a nanoparticle growth-based assay, enabling longitudinal tracking of cisplatin-induced senescence and senolysis in mouse lung tumors and fibrosis. This approach offers a noninvasive and sensitive precision tool for monitoring senescence burden in lung cancer.

Amid rapid population aging in Japan, declining public transport use has created substantial barriers to older adults' mobility and independence. Such services address first-/last-mile gaps and enable social participation, which are key determinants of healthy aging in community settings. We examined whether Green Slow Mobility (GSM)-a low-speed electric cart used as community public transport-was followed by differences in future long-term care need.

In the course of age-related macular degeneration (AMD) the retinal pigment epithelium undergoes a number of cytopathological alterations that are generated by a dysfunction of specific metabolic pathways. In detail, these include lipid and glycogen accumulation along with dismantling of specific proteins from the plasma membrane. In the present study we analyzed whether 3-methyladenine (3-MA), a classic autophagy inhibitor, may reproduce the pathobiochemical and structural alterations occurring in AMD. Different doses of 3-MA produce a loss of cell viability with lipids and glycogen accumulation, which were quantified by ultrastructural morphometry. This was concomitant with displacement and suppression of autophagy-related proteins along with increased activity of mTOR. A dismantling of phenotype-specific proteins composing tight junctions was observed as well. All these alterations were reverted by the phytochemical autophagy stimulator curcumin which was shown to act as a powerful mTOR inhibitor with an efficacy that was like the classic mTOR inhibitor rapamycin. When these compounds activating autophagy/inhibiting mTOR were administered alone, a beneficial effect was observed even in control cells. The occurrence of 3-MA-induced retinal degeneration was found to be associated with a remarkable aggregation of p62 which is reminiscent of central neurodegenerative disorders, and it was fully prevented by curcumin similarly to rapamycin. These protective effects concern cell viability, altered glycogen and lipid accumulation, and ultrastructural alterations. The present work contributes to understanding degeneration in AMD while extending key biochemical steps to neurodegenerative disorders. The use of natural phytochemicals and light-induced by-products may be used for therapeutic purposes.

Optimal sleep has a vital role in promoting healthy ageing and enhancing longevity. Here we propose Sleep Chart to assess the relationship between self-reported sleep duration and 23 biological ageing clocks derived from in vivo imaging

Diet is a modifiable lifestyle factor that may modify biological aging. However, its relationship with biomarkers of biological aging is scarce or divergent. Thus, we aimed to investigate the association between dietary patterns and epigenetic and inflammatory age acceleration.

Organs age at different rates, yet the protective mechanisms contributing to decelerated aging in certain tissues remain unclear. Applying cross-tissue comparisons to molecular readouts of aging, here we report that the intervertebral disc (IVD) ages slowly. We link the rate of aging to the persistently hypoxic environment of the IVD, and its unique ability to degrade hypoxia-inducible factor-1α (HIF-1α) in nucleus pulposus cells through optineurin-mediated selective autophagy, thereby uncoupling hypoxia from HIF-1α accumulation and limiting cellular stress. Further, we developed a small-molecule HIF-1α-targeting autophagy-tethering compound (HATC) to pharmacologically export the protective mechanism to other tissues. In aged mice, systemic weekly administration of HATC reduced HIF-1α levels across multiple organs, ameliorated a range of age-related pathologies and significantly extended both median (~14%) and maximum lifespan (~12%). These findings define a regulatory axis in which HIF-1α degradation under hypoxia contributes to longevity, and support HATC as a geroprotective strategy to improve healthspan.

Almost a century ago, calorie restriction (CR) was identified as a robust intervention for extending lifespan and healthspan, a discovery that captured the imagination of both scientists and the public. If the powerful mechanisms engaged by CR can be uncovered and harnessed through a pill, humans might be able to live longer and healthier lives. Here, we will discuss the evolution of rapamycin, an inhibitor of the mTOR (mechanistic Target Of Rapamycin) protein kinase, from an immunosuppressant to the most reproducible pharmacological geroprotector in geroscience. This is a rapidly evolving field, with the number of basic science studies, clinical trials, and off-label use of mTOR inhibitors by the general public expanding quickly. We review findings in model organisms that have revealed potent benefits of rapamycin not only for longevity but for the function of multiple organ systems and on the hallmarks of aging. We review completed and ongoing clinical trials of rapamycin and analogs for diseases of aging in humans, and discuss the challenges and side-effects of rapamycin that may limit its translation from the laboratory to the clinic. While the jury is still out, we conclude that rapamycin-or molecules that similarly act to inhibit mTOR-may yet realize the century-old dream of extending healthspan and lifespan with a small molecule.

One of the fundamental biological processes underlying aging is the decline in physical performance. Sarcopenia, dynapenia, chronic inflammation, and other factors including the loss of motor units largely account for this decline. Master athletes-individuals who train and compete well beyond early adulthood-represent a valuable model for studying healthy aging. In the general population, physical performance follows a characteristic lifespan trajectory, increasing from childhood to a peak in early adulthood and progressively declining with aging due to a reduction in muscle mass and quality, and in multisystem physiological functions. The seminal studies by Gava and colleagues on master athletes indicate that, under ideal conditions of being disease-free or injury-free, performance loss of these athletes follows an attenuated, linear fashion from early adulthood into advanced age. While lifelong training cannot halt age-related physiological deterioration, it can attenuate the rate of functional decline in cardiovascular, neurocognitive, and musculoskeletal functions. From a sex-based perspective, males demonstrate an absolute advantage in power and strength compared to females, whereas differences in endurance performance are smaller. With age, the physical performance gap between the two sexes tends to narrow, particularly in endurance disciplines. Overall, the master athlete model supports the concept that aging-related performance decay follows predictable biological rules, while its rate remains highly modifiable through sustained physical activity. These insights have important implications for exercise prescription, preventive strategies, and healthy aging.

Transition toward senescence is a cellular response to various forms of stress. This phenomenon is evolutionarily conserved across species, from insects to humans. Senescent cells (SCs) permanently withdraw from the cell cycle and undergo physiological changes, notably the acquisition of a robust secretory activity characterized by the release of numerous molecules, including cytokines, chemokines, and metalloproteinases. Through this program, termed Senescence-Associated Secretory Phenotype, SCs communicate with and influence their microenvironment. In mammalian tissues, the number of SCs increases with age and their accumulation has been proposed to contribute to age-associated pathologies. Studies in vertebrate systems have demonstrated that new SCs can arise through paracrine signaling from preexisting SCs, a process that requires the activity of the Transforming Growth Factor β (TGF-β). We have investigated the occurrence of paracrine recruitment of SCs in the fruitfly

Elderly patients exhibit heightened susceptibility to postoperative complications following general anesthesia and surgery, yet the molecular mechanisms driving this age-dependent vulnerability remain poorly defined. We performed RNA sequencing on olfactory bulb (OB), hippocampus (HI), lung, and spleen from young (3-month, m), late middle-aged (17 m), and geriatric (27 m) male C57BL/6 mice 24 h after 2 h of exposure to isoflurane anesthesia and laparotomy (ISO/OP). Short-term ISO/OP elicited pronounced, age-dependent transcriptional remodeling across tissues. Late middle-aged mice exhibited robust activation of stress- and metabolism-associated pathways in the OB and HI, accompanied by suppression of lipid, synaptic, and structural maintenance programs. In contrast, young adults displayed limited responses, characterized by modest and adaptive synaptic remodeling in the HI. Peripheral organs showed a parallel age-dependent divergence. Late middle-aged mice exhibited amplified immune and inflammatory signaling in the lung and spleen alongside suppression of structural, regulatory, and metabolic homeostatic programs, whereas young adults demonstrated attenuated, metabolically adaptive transcriptional responses. Circulating extracellular vesicles (EVs) mirrored tissue-level shifts, indicating a systemic transition from adaptive plasticity in 3 m to stress and immune dominant signaling by 17 m. Geriatric mice displayed a distinct response pattern, characterized by activation of stress and detoxification programs in brain tissues, altered circadian gene expression in lung and spleen, and extensive remodeling of EV protein cargo enriched for inflammatory and growth factor-related signatures. Together, these findings indicate that late middle-age is associated with amplified peri-anesthetic biological reactivity across central and peripheral systems, suggesting an under-recognized window for perioperative risk stratification and preventative intervention.

Spatial transcriptomics has emerged as a transformative approach for in situ mapping of cellular heterogeneity and interactions, yet existing methods often compromise throughput, cost and tissue coverage. Here we introduce Imaging Reconstruction using Indexed Sequencing (IRISeq): an optics-free, cost-effective platform that leverages spatial interaction mapping by indexed sequencing to profile tissues at adjustable sizes and resolutions (5-50 µm). We applied IRISeq to map gene expression across more than 70 coronal sections from both adult and aged mouse brains, including wild-type and two lymphocyte-deficient models (Rag1 and Prkdc mutants) and generated more than 460,000 spatial transcriptome profiles. Our integrated analysis with 783,264 single-cell transcriptomes revealed region-specific aging signatures that are lymphocyte dependent, notably a downregulation of interferon signaling and inflammation in ventricular regions upon lymphocyte depletion, alongside mutant-specific upregulation of senescence pathways. Furthermore, lymphocyte deficiency was linked to preserved abundance of ependymal cells that line the brain's ventricles and to distinct microglial state dynamics, highlighting a key role for lymphocytes in driving inflammatory processes during brain aging. Overall, IRISeq provides a high-throughput and cost-effective solution for spatially resolved transcriptomic profiling, opening new avenues for elucidating region-specific cellular mechanisms underlying aging and identifying potential therapeutic targets to preserve brain homeostasis.

Major advances over the past few decades have highlighted the complex regulation of RNA from transcription to nuclear export and from translation to decay. Despite the emerging cellular landscape of malleable and multifunctional RNA molecules, the role of RNA dysregulation in ageing, one of the most fundamental processes of human biology, is underappreciated. Here we focus on ageing-linked dysregulation of the mRNA life cycle. We summarize how RNA metabolism steadily deviates throughout ageing and senescence: in transcription, aged cells bias shorter genes at the expense of complex transcripts; in splicing, ageing-linked alternative exon usage is common; in translation, ribosomal collisions on mRNAs decouple transcriptional output from protein production; and in decay, aberrant RNAs accumulate due to poor degradation activity. We close by discussing how ageing-linked dysregulation of RNA biology can drive cellular stress and thus serve as a therapeutic target to reverse disease.

Emerging population-based evidence has linked extreme temperatures to cognitive decline, while the potential neurological effects of temperature variability (TV) remain extensively unstudied. This national cohort study sought to investigate the association of long-term TV with cognitive function among individuals during midlife and later years in China. We conducted a 10-year longitudinal study from 2011 through 2020 by enrolling 14,729 eligible respondents aged 45 years and older across 125 cities in China. Overall cognitive performance and its two domains including episodic memory and mental status were measured using the standardized questionnaires. Year-round, warm-season, and cold-season TV metrics preceding cognitive tests were estimated for each participant using the standard deviation of daily temperatures in the survey city. Linear mixed-effects models were applied to investigate the associations between TV exposure and cognitive function. Subgroup analyses were performed stratified by sex, age, and residence. We observed consistent evidence for improved cognitive performance of global and mental status associated with multiple TV exposure metrics. Specifically, for each 1-℃ increase in year-round TV, cognitive scores were elevated by 0.136 (95% confidence interval [CI] 0.062, 0.210) points in global performance and 0.115 (95% CI 0.071, 0.159) points in mental status, respectively. The change in cognitive scores associated with seasonal TV were largely similar to those observed with year-round TV. No associations between episodic memory and TV metrics were seen in the analysis of overall population. We observed nearly linear and threshold-free exposure-response associations of TV exposure with global and dimension-specific cognitive performances. Stratified analyses indicated overall stronger TV-associated cognitive effects in females, rural residents, and younger adults aged 45-65 years. This longitudinal study shows that higher TV is associated with better cognitive function in Chinese middle-aged and older adults, especially in females, rural‑dwelling and middle-aged individuals. These results suggest that moderate temperature fluctuations may promote cognitive health in aging populations, highlighting the importance of developing public health strategies that account for environmental influences in a changing climate.

Episodic memories are consistently biased by prior knowledge in the form of schemas (e.g., where objects typically are). Rational memory reconstruction models propose that this results from the strategic recruitment of schemas at retrieval when memory traces are imprecise. We recently proposed that these models can also account for the increase in schema bias with aging: Aging reduces memory precision, thereby increasing schema usage. However, causal evidence that underlying memory imprecision increases schema bias is lacking, which is a critical gap for reconstruction theories and for our extension to aging. To examine the effect of underlying memory precision on schema bias, we manipulated memory in younger adults. In two studies (n = 423), participants searched for objects in schema-congruent and incongruent scene locations; each scene was presented either three times (3×) or once (1×). During later retrieval, participants saw the background scenes and provided scene recognition responses indexing memory availability for the episode, and provided object location recall responses indexing memory precision. We found that memory precision was lower for 1× than 3× scenes, even when memory for the episode was available (i.e., participants reported confident recollection). Critically, schema bias of object recall was higher for 1× than 3× scenes, even for recollected scenes. In Experiment 2, metacognitive assessments of memory precision mediated the effects of repetition on schema bias. Therefore, weakening underlying memory precision increased schema bias, which successfully simulates prior aging effects and supports the proposal that rational reconstruction processes drive schema bias of memory both in general and in aging.

The gut microbiome contributes to age-related cognitive decline, but signaling mechanisms remain unclear. In a recent issue of Nature, Cox et al. show that P. goldsteinii-derived fatty acids activate myeloid cells, thus inducing inflammation that disrupts vagal signaling and hippocampal memory encoding.

Aging is the primary driver of chronic disease and mortality, requiring comprehensive frameworks for quantification of aging and nomination of longevity interventions. We developed mAge (multimodal age), a biological aging framework that integrates plasma proteomics, wearables, and mortality hazard to predict biological age, intrinsic capacity, and mortality risk. By combining proteomic and wearable data in UK Biobank samples, mAge exceeds unimodal baseline age prediction to 0.87 test R2 and 2.3 years mean error, and reduces unimodal baseline mortality prediction error by 21%. We further constructed organ- and cell type-specific biological clocks that quantify aging across 49 distinct subsystems, revealing that cardiac, immune, and intracellular protein signatures benefit most from wearable integration. By mapping data to FDA-approved drug targets, we identified interventions, such as GLP-1 receptor agonists, gabapentin, and ACE inhibitors, that are associated with lower overall and subsystem-specific proteomic age and mortality risk or are associated with longer time-to-death and later age-at-death in longitudinal and deceased cohorts. mAge establishes a scalable framework for nominating and validating personalized longevity interventions, bridging continuous digital monitoring with molecular aging diagnostics.

Sarcopenia refers to the involuntary loss of skeletal muscle mass and function with aging and is associated with multiple adverse health outcomes. Disruption of normal circadian rhythms due to shift work or nocturnal lifestyle is associated with the risk of several diseases such as metabolic syndrome and cancer. However, its role in sarcopenia remains unclear. The synergy of single-cell RNA sequencing and Mendelian randomization (MR) analysis provides an opportunity to reveal the important involvement of circadian rhythms in the pathogenesis of sarcopenia. Data quality control and normalisation were performed in the single-cell dataset, GSE167186. Then, different cell types were obtained by cell annotation through marker genes. Differentially expressed genes (DEGs) were further analyzed in different cell types. The intersection of DEGs and circadian-related genes in fast skeletal muscle cell were taken. Afterwards, the genes that had causal relationship with sarcopenia were selected as biomarkers by MR analysis. Variations in signaling pathways between different cell types were further analyzed. In GSE167186, 20 different cell populations identified by UMAP cluster analysis were further annotated to 8 cell types using maker genes. Afterwards, 44 DEGs were screened between fast skeletal muscle cell and circadian-related genes. Further MR Analysis yielded three genes with significant causal association with sarcopenia, which could be used as biomarkers in this study. SMARCD3 was found to have a protective effect against sarcopenia (OR = 0.9183, 95% CI = 0.8577-0.9832, p = 0.0144); in contrast, CPED1 (OR = 1.0292, 95% CI = 1.0089-1.0500, p = 0.0047) and FNBP4 (OR = 1.1096, 95% CI = 1.0316-1.1934, p = 0.0051) were associated with an increased risk of sarcopenia. The analysis of intercellular signaling revealed that the loss of the protective factor SMARCD3 in fast skeletal muscle cell triggers a specific upregulation of EGF signaling directed at FAPs. This study highlights the contribution of circadian rhythms in the pathogenesis of sarcopenia and further defines circadian rhythm-related biomarkers in sarcopenia, as demonstrated by MR analysis and scRNA-seq analysis. This suggests circadian rhythms as a focal point for pathogenesis research and potential therapeutic targeting in sarcopenia.

Currently, no consensus exists on either terminology, definition, or the biological significance of the phenomena intratrabecular tunneling. Despite this, observations of intratrabecular tunneling are frequently reported in literature covering diseases or treatments involving parathyroid hormone or kidneys. A few attempts to quantify this phenomena have been made mainly based on bone resorption, despite the concurrent presence of bone formation. This study demonstrates that intratrabecular tunneling is a previously unrecognized physiological mode of intratrabecular bone remodeling occurring across conditions and ages. Similar to intracortical remodeling, it is induced by PTH-treatment and creates an extensive interconnected tunnel-network that hollows out the trabeculae. This study primarily utilizes iliac crest bone biopsies collected from a clinical trial where patients with hypoparathyroidism were randomized to receive daily injections with either 100μg rhPTH(1-84) or placebo as add-on to conventional therapy for 6 months. In addition, further bone biopsies were collected from a 24-month open-label extension study, including patients receiving either only conventional treatment, continued rhPTH-treatment or discontinued rhPTH-treatment. Histomorphometry demonstrated that PTH-treatment induced an 18-fold and 36-fold increase in intratrabecular porosity after 6 and 30 months of treatment, respectively. After 6-months of PTH- versus conventional treatment, a median 7.7% versus 0.0% were eroded pores, 69.1% versus 0.0% were eroded-formative pores, 12.9% versus 0.0% were formative pores and 0.9% versus 81.2% were quiescent pores. PTH-treatment withdrawal normalized the intratrabecular remodeling to levels similar to conventional therapy. The intratrabecular remodeling mainly occurred in plates and junctions of trabeculae, and not in trabecular rods. Intratrabecular remodeling parameters showed a positive correlation with PTH-induced trabecular mineralization and a negative correlation with active vitamin D-supplementary doses. Dynamics of the PTH-induced intratrabecular remodeling could be tracked using time-lapsed synchrotron radiation μCT in a rabbit model and the complexity of the trabecular strain environment was confirmed with micro-finite-element analysis.

Presbyopia is linked to age-related decline in ciliary muscle (CM) function, yet pharmacologic strategies that target CM senescence remain limited. We investigated whether metformin (MET) mitigates CM aging in guinea pigs and explored the underlying mechanism. A D-galactose-induced CM aging model was established in vivo in guinea pigs and in vitro using primary ciliary smooth muscle cells (CSMCs). The effects of MET on age-related changes in tissue architecture, senescence markers, cell-cycle progression, autophagic activity, and mitochondrial homeostasis were assessed. In parallel, the involvement of glycogen synthase kinase-3β (GSK-3β) signaling in the actions of MET was examined. MET significantly attenuated D-galactose-induced senescence in CM tissue and primary CSMCs, as reflected by improved fibrillar organization, reduced expression of the senescence markers p21, p16 and p53, and relief of G1/S-phase cell-cycle arrest. At the molecular level, MET decreased GSK-3β expression, stabilized β-catenin in the cytoplasm, facilitated its nuclear translocation, and thereby supported more physiological cell-cycle progression. In addition, MET restored autophagic activity in aged CSMCs and helped maintain intracellular and mitochondrial homeostasis. MET modulates the GSK-3β pathway to coordinate cell-cycle progression with autophagic activity, thereby delaying CM aging and preserving key cellular features that underpin accommodative function. These findings suggest that MET may represent a potential noninvasive pharmacologic approach to mitigate age-related abnormalities in ocular accommodation and warrant further translational investigation.

As the earliest aging organ in females, the ovary undergoes functional decline and structural senescence that drive reproductive system alterations. Central to this process is the primordial follicle-the non-renewable reserve of female germ cells and the sole source for oocyte development. The primordial follicle pool is established prenatally, fixed in quantity, and cannot regenerate after birth, serving as the fundamental biological reserve that determines both fertility potential and reproductive lifespan. Once depletion begins, it is irreversible, directly limiting the reproductive window and influencing ovarian endocrine function. Therefore, this review briefly summarizes the latest research progress on primordial follicle development, providing an in-depth analysis of primordial follicle dormancy and activation mechanisms as well as therapeutic approaches for associated complications. This work holds significant implications for understanding reproductive aging, preventing and treating reproductive endocrine disorders, and developing novel fertility strategies, offering valuable references for comprehending the biological mechanisms and potential applications of primordial follicles.

The gut microbiota represents a complex microbial ecosystem that contributes to host metabolic regulation, immune homeostasis, and intestinal barrier function. Across the lifespan, gut microbial communities exhibit marked taxonomic and functional variation driven by environmental exposures, dietary patterns, medication use, and age-associated immune alterations. These differences are closely linked to chronic inflammatory states and immune dysregulation that accompany aging. This review synthesizes current evidence on age-associated differences in gut microbiota composition and functional capacity, with a focus on microbial traits and metabolic pathways relevant to host-microbe interactions. Pathological aging is frequently associated with reduced microbial diversity, loss of short-chain fatty acid-producing commensal bacteria, and enrichment of opportunistic or pro-inflammatory taxa. In contrast, healthy aging and longevity are commonly associated with more stable, resilient, and metabolically adaptable microbial communities. At the functional level, recurrent alterations in short-chain fatty acid biosynthesis, bile acid transformation, and tryptophan- and choline-related metabolic pathways define conserved features across aging-associated microbial profiles. Across neurodegenerative, metabolic, and cardiovascular conditions, overlapping taxonomic and functional patterns indicate shared microbiota-associated signatures linked to inflammatory states. Advances in metagenomic sequencing, functional annotation, and microbiome-focused biotechnological approaches now enable integrated analysis of microbial structure and metabolic potential. These developments provide a robust framework for identifying reproducible microbiome-based indicators relevant to aging-associated physiological changes and for translating microbiome research into biotechnology-driven applications.

Although age-related declines in muscle mass and strength are believed to result from changes in motor unit number and size, the association of motor unit number and size with muscle mass and strength in healthy individuals remains unclear. We aim to examine the association of motor unit number estimation (MUNE) and motor unit size estimation (MUSE) of abductor pollicis brevis (APB) with muscle thickness of APB and maximal pinch-grip strength among young, middle-aged, and older adults.

Vitality capacity (VC) reflects a physiological state and is a determinant domain of intrinsic capacity but has so far remained mainly theoretical. This study validates the vitality capacity domains 'energy and metabolism' and 'neuromuscular function' and examines its link to locomotor capacity and quality of life (QoL). Exploratory factor analysis (EFA) was performed on the combined dataset from the Fatigue Resistance AMErsfoort study (FRAME, n = 1000) and the Fatigue Plot study (FATPLOT,n = 620). Confirmatory factor analyses (CFA) were subsequently performed on data from the AMersfoort COhort study on functional decline, Healthy aging and Frailty (AMCOHF,n = 367) and the BrUssels sTudy on The Early pRedictors of FraiLtY (BUTTERFLY,n = 491), to validate VC in both middle-aged and older adults. Linear hierarchical regression analysis was used to investigate the relationship between VC, locomotor capacity, and QoL. EFA indicated a one-factor model and CFA validated this with good model fit in the dataset (BUTTERFLY) (Robust CFI; 0.960, SRMR: 0.040) and (AMCOHF) (Robust CFI; 0.942, SRMR: 0.055). This model validated maximal grip strength (GSmax), 30-s chair stand test (30CST), Multidimensional Fatigue Inventory (MFI-20) and Capacity to Perceived Vitality ratio physical (CPV-physical) to measure VC. Several assessments show a significant relationship with locomotor capacity and QoL. This study indicated that VC is a coherent domain and has a relationship with locomotor capacity and QoL.

The crystalline lens of the eye is an optical structure that, together with the cornea, focuses images onto the retina. In a young and healthy eye, the lens is transparent and adjusts its shape to focus on near and distant objects (accommodation). With age, it loses this flexibility (presbyopia) and may later become opaque (cataract). Understanding the full three-dimensional geometry of the crystalline lens is essential for studying age-related lens growth and accommodation mechanism, as well as for the customized design and selection of intraocular lenses the for implantation in cataract surgery. While Optical Coherence Tomography (OCT) allows imaging of the central lens region visible through the pupil, conventional in vivo measurements cannot capture the full lens shape, particularly at the periphery, due to iris obstruction. In this study, we present a novel method to reconstruct the full three-dimensional shape of the crystalline lens by combining OCT images acquired with off-axis illumination at different angles. Using this approach, full lens reconstructions were achieved in eight subjects, and key geometrical parameters - diameter, volume, and surface area- were quantified, showing strong positive correlations with age. Comparisons with estimates derived from pupil-limited regions showed strong agreement, thereby validating these estimation methods.

Urolithin A (UA) is synthesized when the body metabolizes ellagic acid and ellagitannins. UA has been a widely recognized physiologically active compound throughout the previous decade. The gut microbiota affects metabolic regulators AMPK and sirtuins, initiates autophagy, and activates mitochondrial quality control, which is essential for infection resistance, intestinal health, and inflammation reduction.

Aging is characterized by progressive loss of physiological resilience accompanied by increased susceptibility to chronic diseases. Among the interconnected hallmarks of aging, cellular senescence has emerged as a central driver of systemic inflammation through the senescence-associated secretory phenotype (SASP). Senescent cells accumulate across multiple tissues with advancing age and secrete complex mixtures of cytokines, growth factors, and proteases that reshape tissue microenvironments and propagate inflammatory signaling locally and systemically. Increasing evidence indicates that SASP composition is highly heterogeneous and depends on cell lineage, metabolic state, and the nature of the senescence-inducing stressor. Recent discoveries further demonstrate that inflammatory signaling in senescent cells is sustained by multiple nucleic acid-sensing pathways, including both cGAS-STING-dependent DNA sensing and mitochondrial RNA-mediated activation of RIG-I-like receptors. Concurrently, senescent cells deploy immune-evasion mechanisms that limit clearance by cytotoxic lymphocytes and natural killer cells, facilitating their persistence within aging tissues. Accumulation of senescent cells therefore represents a critical mechanistic link between molecular damage and the systemic inflammatory state known as inflammaging. This review synthesizes current understanding of tissue-specific SASP programs across immune, vascular, metabolic, hepatic, and neural systems. Particular emphasis is placed on mechanisms that amplify local senescence into organism-wide inflammation, including endocrine signaling, extracellular vesicle trafficking, and sex-dependent modulation of senescence pathways.

Time-restricted feeding (TRF), which confines food intake to a defined daily window, has emerged as a promising nonpharmacological strategy to improve health by aligning behavior and physiology with the endogenous circadian clock. Preclinical research has expanded substantially, now spanning both nocturnal and diurnal species, diverse dietary regimens, varying intervention durations, and examinations of sex-specific responses. These consistently show that synchronizing feeding-fasting cycles with the natural active phase of an organism's circadian rhythm enhances rhythmic gene expression across tissues. Concomitantly, this mitigates metabolic dysfunction, reduces inflammation, and lowers disease risk, often without reducing caloric intake. While findings in animal models are robust, human outcomes have been more modest and variable, influenced by the timing and duration of feeding window, metabolic state, and sex. This review synthesizes current insights into the relationship between TRF and circadian rhythms, highlighting recent discoveries and the challenges that remain for translation to humans.

Silent mating type information regulation 1 (SIRT1), a core molecule bridging energy metabolism and ageing modulation, relies on its nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase activity and pathway crosstalk to form a key regulatory network governing ageing. This review focuses on the central regulatory role of SIRT1 in cellular senescence, integrating its multidimensional mechanisms in deoxyribonucleic acid (DNA) damage response, inflammatory microenvironment modulation, autophagic function remodeling, and maintenance of energy metabolic homeostasis. Meanwhile, we summarized the intervention strategies targeting SIRT1 (e.g., small-molecule compounds and natural extracts) and the differences in their action targets, clarifying their translational potential in the prevention and treatment of ageing-related diseases. We further highlight emerging evidence on sex-specific differences, model specificity, and evolutionary conservation that shape SIRT1's role in ageing. This review aims to provide a systematic perspective for in-depth understanding of the SIRT1-mediated ageing regulatory network, and offer a reference for basic anti-ageing research, optimization of precise intervention strategies, and screening of therapeutic targets for related diseases.

Making effective everyday decisions is vital for maintaining well-being and independence in older age, yet older adults often face challenges in decision making due to age-related changes in perceptual and cognitive processes. Age-related declines in perception and cognition are not independent, in part because decoding impoverished perceptual input places additional demands on older adults' limited cognitive resources. In this study, we test whether age-related deficits in decision-making performance can be reduced by improving the perceptual clarity of decision-making materials.

With the aging of the global population, preventing the onset of mobility limitations is considered a worldwide public health priority.

Heart failure with preserved ejection fraction (HFpEF) is a cardiometabolic syndrome strongly associated with aging, systemic inflammation and endothelial dysfunction, in which impaired endothelial nitric oxide synthase (eNOS) signaling plays a central role. This study aimed to identify circulating proteins associated with HFpEF and to explore their relationship with endothelial alterations under metabolic stress. A total of 109 HFpEF patients and 49 control subjects underwent clinical, laboratory, and echocardiographic assessment. HFpEF patients exhibited a high burden of cardiometabolic comorbidities and significantly increased NT-proBNP (2851.2 ± 1565.5 vs 156.0 ± 85.2 pg/mL) and C-reactive protein levels (2.9 ± 4.5 vs 0.31 ± 0.33 mg/dL). Echocardiography revealed elevated filling pressures (E/e' 16.5 ± 3.8 vs 7.0 ± 1.9), a higher prevalence of high-probability pulmonary hypertension, and impaired right ventricular-pulmonary artery coupling. Exploratory proteomic profiling identified galectin-3 binding protein (LGALS3BP) as increased in plasma from HFpEF patients, a finding confirmed by ELISA showing significantly higher circulating levels compared with controls (8.65 ± 0.66 vs 2.36 ± 0.26 ng/mL, p < 0.001). Pathway analysis suggested a potential association between LGALS3BP and activation of nitric oxide synthase 2 (NOS2)-related inflammatory pathways. In vitro, metabolic stress conditions increased LGALS3BP expression in murine endothelial cells, with a more pronounced response in eNOS⁻/⁻ cells. In addition, eNOS deficiency was associated with the appearance of a lower-molecular weight LGALS3BP form and with increased markers of endothelial senescence and autophagy. LGALS3BP is elevated in HFpEF and is associated with endothelial alterations linked to impaired eNOS signaling under metabolic stress. These findings suggest a potential connection between endothelial stress responses and LGALS3BP expression in HFpEF, supporting further investigation of this protein as a biomarker of endothelial dysfunction in age-related cardiometabolic disease.

Nucleocytoplasmic transport is a central but underappreciated component of the proteostasis network as it controls the trafficking and partitioning of proteins between the nucleus and cytoplasm through the nuclear pore complex (NPC). Transport of large proteins across the NPC is mediated by karyopherins, a conserved family of importins and exportins that function through a Ran GTPase-dependent cycle. Beyond their canonical transport activities, karyopherins can directly contribute to proteostasis by acting as chaperone-like factors that prevent aberrant phase separation and protein aggregation. Dysregulation of karyopherin-mediated transport emerges as a convergent contributor underlying aging and diverse age-associated diseases, including neurodegeneration, cancer, cardiovascular dysfunction, chronic inflammation, and progeroid syndromes. Here, we highlight how age-related alterations in nucleocytoplasmic transport reshape proteome organization and intracellular signaling, and discuss emerging therapeutic strategies targeting karyopherins to restore proteostasis and cellular homeostasis.

Aging is associated with oxidative-stress-induced endothelial dysfunction, characterized by reduced nitric oxide (NO) signaling. The present study evaluated the contributions of mitochondrial- and non-mitochondrial oxidative stress in age-related endothelial dysfunction. Three intradermal microdialysis fibers were placed in the forearm for local delivery of pharmacological agents (10mM Tempol, 1mM MitoTempo, Ringer's vehicle control) to the cutaneous microvasculature in fifteen older (67 ± 3 yrs; 7 M, 8 F) adults. After ~20 min baseline, local heating (42°C) induced cutaneous vasodilation, and perfusion of a NO synthase inhibitor (15mM L-NAME) allowed quantification of the NO- and non-NO contributions to the local heating response. Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) and cutaneous vascular conductance (CVC=LDF/MAP) was expressed as a percentage of maximum (%CVC

Aging has effects on the immune system that are similar in men and women, but also reshapes their immune systems in unique, sex-specific ways. These sex-specific patterns of immune aging influence disease susceptibility, vaccine effectiveness, cancer survival, and responses to pharmacological therapies, and have direct implications for preventive medicine and clinical care. However, these differences in susceptibilities and responses are rarely considered in research, clinical trials, or treatment guidelines. By integrating knowledge of sex-specific immune aging with real-world outcomes from vaccines, cancer immunotherapy, and pharmacovigilance studies, this Essay argues that accounting for both sex and age is essential to advance personalized medicine.