Longevity Papers

Biological aging is a key determinant of liver disease and mortality, but there is little evidence on noninvasive index for assessment of liver biological aging. We developed the Liver Aging Index (LAI) in the China Kadoorie Biobank (CKB, N = 21,629) using Cox-Gompertz proportional hazards model. The LAI incorporated three clinical factors (body mass index, systolic and diastolic blood pressure), eight plasma biomarkers (glucose, total cholesterol, triglycerides, high- and low-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase), and two imaging biomarkers (fat attenuation parameter and liver stiffness measurement). External validation was conducted in the National Health and Nutrition Examination Survey (NHANES; N = 3412) and the VCTE-Prognosis cohort (N = 12,170, 16 global centers). Across all cohorts, the LAI demonstrated strong discrimination for all-cause mortality (AUROC: 0.764 in NHANES; 0.759 in VCTE-Prognosis), outperforming chronological age (p < 0.05). Liver aging acceleration (LAA), defined as the difference between LAI and chronological age, was associated with substantially elevated risks: each 1-SD increase in LAA conferred a 22%-85% higher risk of all-cause mortality and a 34%-170% higher risk of liver-related event or mortality. Using genetic instruments identified in CKB, we found genetic predisposition to accelerated liver aging was associated with higher risks of cirrhosis and liver cancer (HR = 3.94 [3.20-4.86] and 7.82 [2.05-29.80]), further validated in Biobank Japan. Integrating genetics and proteomics revealed novel pathophysiological involvement of amyloid-beta clearance pathway and amyloid precursor protein in liver aging. These findings demonstrate the feasibility of a noninvasive, liver-specific biological aging index and provide new insights into mechanisms underlying liver aging.

Direct vascular aging assessment is not always feasible in routine diabetes care. We aimed to derive a control-based arterial age reference using estimated pulse wave velocity, develop a biomarker-enhanced model for predicting arterial age gap, and evaluate its ability to identify accelerated arterial aging in young-to-middle-aged adults with type 2 diabetes mellitus. This study included 300 participants (150 T2DM, 150 age- and sex-matched controls). Arterial age was derived from a control-group ePWV-age regression. Age gap was defined as estimated arterial age minus chronological age. Candidate predictors were evaluated using multivariable linear regression, and the final model was internally validated by 10-fold cross-validation. Compared with controls, participants with T2DM had higher ePWV, older estimated arterial age, larger age gap, lower adropin, and higher oxLDL (all p < 0.001). Accelerated arterial aging was more frequent in T2DM than controls (76.0% vs. 20.0%). The final model integrating HbA1c, adropin, and oxLDL explained 42% of the variance in age gap (adjusted R²=0.418), showed good discrimination for accelerated arterial aging (AUC 0.889; 95% CI 0.828-0.910), and retained acceptable internal calibration (slope 0.943). A biomarker-enhanced arterial age model integrating HbA1c, adropin, and oxLDL provided an interpretable framework for identifying accelerated arterial aging in young-to-middle-aged adults with T2DM. Although promising for translational implementation, external validation and direct pulse wave velocity benchmarking are required before clinical application. The model also enabled a three-level arterial aging classification and web-based implementation for research use, supporting its potential as a practical risk-communication tool prototype.

Retirement is a life-course transition that reshapes daily routines, social engagement, and exposure to stressors that influence later-life health. However, little is known about how frailty, an integrative indicator of biological aging, changes around retirement or whether patterns differ by education. This study examined frailty trajectories among Korean adults using seven waves of the Korean Longitudinal Study of Ageing. Distributed fixed-effects models estimated within-person changes before and after retirement, with frailty measured with a 41-item index across physical, cognitive, and psychosocial domains. Frailty remained stable prior to retirement but increased significantly during the first 2 years afterward, with elevated levels persisting. Increases were larger and sustained among individuals with lower education, whereas higher-educated retirees experienced smaller and temporary changes. Findings suggest that retirement marks a pivotal period in the accumulation of health deficits and that education serves as a protective factor, highlighting the need for policies supporting equitable post-retirement resources.

The common cause theory of age-related hearing loss and age-related disorders of cognition suggests that there are shared underlying physiological variables that may be modified with intervention. This study examined the interrelationships among physical function (PF), systolic blood pressure (SBP), hearing, and cognition in 150 adults aged 50-80 years old, utilizing a Bayesian generalized structural equation modeling approach. The findings suggest that every 10-point increase in PF results in a decrease of hearing threshold by 1.35 dB HL (95% CrI: -0.232, -0.038) independent of SBP, while every 10-year increase in age increases SBP by 7.5 mm Hg (95% CrI: 0.417, 1.098) and increases hearing threshold by 8.78 dB HL (95% CrI: 0.608, 1.152). This indicates a more active lifestyle is associated with better hearing and that while SBP increases with age, it does not mediate the relationship between PF and hearing. Sex differences were observed in hearing outcomes, with males exhibiting poorer hearing. Additionally, there was only a minimal effect of PF on cognition, and this modest improvement was not explained by systolic blood pressure in our analytical sample. These results underscore the complexity of the pathways linking cardiovascular health, sensory function, and cognitive aging. The lack of mediation by SBP highlights the importance of targeting PF directly, rather than relying solely on blood pressure management for preserving auditory and cognitive health.

Chronic inflammation and aging skew hematopoiesis toward myelopoiesis at the expense of lymphoid output. We screened type 2 and anti-inflammatory cytokines to identify extrinsic signals capable of restoring lymphoid lineage commitment in hematopoietic stem and progenitor cells (HSPCs). Interleukin 4 (IL-4) specifically inhibited inflammation-induced myelopoiesis and shifted multipotent progenitor (MPP) differentiation toward the lymphoid lineage. IL-4 activated a signal transducer and activator of transcription 6 (STAT6)-dependent transcriptional program in MPPs, increasing the expression of lymphoid-specific genes. Mechanistically, the receptor tyrosine kinase FMS-like tyrosine kinase 3 (FLT3), which is highly expressed in MPPs, interacted with IL-4Rα to facilitate STAT6 activation. In vivo, IL-4 reversed inflammation-induced hematopoietic imbalance and accelerated lymphoid recovery. In aged mice, IL-4 administration shifted the MPP composition toward a lymphoid bias and restored B and T lymphocyte output. Long-term IL-4 treatment in aged mice improved immune, metabolic, physical, and cognitive functions; these rejuvenating effects were recapitulated by transplantation of IL-4-treated HSPCs. Promoting IL-4 signaling in MPPs may enable correction of hematopoietic dysregulation in inflammatory and aging-related conditions.

DNA damage triggering senescence-associated secretory phenotype (SASP) is a key pathway of Intervertebral Disc Degeneration (IVDD). Current therapeutic strategies for IVDD face significant challenges in effectively alleviating DNA damage-mediated senescence of nucleus pulposus cells (NPCs) and IVDD repair. Here, we propose a strategy for the continuous regulation of DNA repair: starting with the scavenging of the key upstream trigger, ROS, proceeding to the repair of the DNA damage, and culminating in the promotion of DNA replication and extracellular matrix synthesis. Through single-cell sequencing of clinical samples and in vitro modeling, we elucidated how oxidative stress drives DNA damage, leading to SASP and inflammatory microenvironment within the intervertebral disc. Subsequently, we developed a continuous DNA repairing system. In this system, bimetallic-curcumin nanozymes (AuCu-Cur) scavenge ROS in NPCs and repair damaged DNA via the increased DNA glycosylase NEIL3. Additionally, the combined human umbilical cord-derived vesicles (hUCMSC-EVs) significantly enhance the bioavailability of the AuCu-Cur, promoting DNA replication, and promoting tissue repair via p-JNK pathway. In a rat tail needle puncture model, this system markedly alleviated IVDD. This study presents a promising approach to reverse the DNA damage-induced cellular senescence and IVDD, providing a repair strategy for addressing diseases associated with DNA damage and cellular senescence.

The extracellular matrix (ECM) provides both architectural integrity and signaling cues to tissues, largely through its fibrous components-collagen and elastin. Collagen fibrils consist of a core of various collagen types associated with several non-collagenous binding partners and confer tensile strength to tissues, while elastic fibers, composed of cross-linked elastin on a fibrillin-rich scaffold, ensure elasticity and resilience. Far from being mere degradative enzymes, proteases are key regulators of both the assembly and turnover of these networks. Metalloproteinases of the BMP1/tolloid-like, meprin and ADAMTS families orchestrate procollagen maturation, while lysyl oxidases and related enzymes drive covalent cross-linking of collagen and elastin fibers, also under proteolytic control. Matrix metalloproteinases (MMPs) and cysteine cathepsins further modulate collagen structure and degradation, generating bioactive fragments used as clinical biomarkers. In parallel, ADAMTS and ADAMTS-like proteases orchestrate fibrillin microfibril organization, fibulin interactions, and the topography of elastogenesis. Elastolytic proteases-including cathepsins K, S, and V, as well as MMP2, MMP7, MMP9, and MMP12-mediate physiological remodeling but also fuel pathological states when dysregulated, releasing elastin-derived peptides that act as potent signaling matrikines. Genetic or acquired defects in these proteolytic pathways underlie diverse connective tissue diseases such as osteogenesis imperfecta, Ehlers-Danlos, and acromelic dysplasias, as well as fibrosis, emphysema, and vascular aging. This review integrates recent structural, biochemical, and pathological insights into how proteases coordinate collagen and elastin dynamics, highlighting novel therapeutic strategies-including substrate- and exosite-selective inhibitors-to restore ECM homeostasis while minimizing off-target effects.

Nearly all cellular processes are pH dependent. The acidic pH inside the lysosome (vacuole in yeast) is essential for cellular content degradation, signaling, and autophagy. Defects in lysosome/vacuole acidification are a conserved hallmark of aging and age-related diseases. Traditionally, the lysosome/vacuole is thought to import free protons (H⁺) from the surrounding neutral cytosol. Here, we uncovered a conserved lysosome/vacuole acidification mechanism from yeast to human involving lysosomal/vacuolar uptake of H

Ambient temperature is a primordial determinant of longevity across the animal kingdom, yet the molecular transducers that couple thermal cues to aging rates remain elusive. Here, we interrogate the transcriptomic and metabolomic landscapes of Drosophila melanogaster to decode the mechanisms of temperature-dependent lifespan extension. We find that thermal stress drives a profound remodeling of the transcriptome that surprisingly outpaces metabolic adaptation. Through this multi-omics integration, we identify the Turandot (tot) gene family as a significant factor in the thermal longevity response. Intriguingly, tot genes are not merely passive responders to temperature; rather, they actively regulate lifespan. We demonstrate that RNAi-mediated knockdown of tot expression is sufficient to extend longevity across a range of temperatures, uncoupling the survival benefit from the thermal environment. Furthermore, this extension exhibits distinct sexual dimorphism, suggesting a sex-specific strategy in stress-response allocation. These findings establish the Turandot family as a novel, genetically separable regulator of aging, challenging the view that temperature-mediated longevity is solely a passive thermodynamic consequence.

During aging, the progressive decline in neuronal function contributes to cognitive impairment and predisposes individuals to neurodegenerative disorders. This phenomenon has become increasingly prominent in modern society. Recent studies have found that post-translational modifications (PTMs) of proteins play a crucial role in the aging process, influencing the physiological functions and pathological changes in brain cells. This article reviews the variety and complexity of PTMs across brain cell types during aging, analyzes changes in specific modification types and sites, and reveals their impacts on neurophysiological and pathological states. This review also examines the current state of translational research, noting that most of the drugs under investigation lack specificity, and their potential toxic side effects remain undetermined. In light of these concerns, this review proposes therapeutic strategies to guide innovative interventions for aging-related diseases, aiming to facilitate further research and clinical applications in this field.

Human spaceflight exposes crew members to a combination of environmental stressors - including microgravity, galactic cosmic radiation, circadian disruption, and prolonged confinement - that together induce multisystem physiological changes resembling terrestrial aging. In this narrative review, we examine how short- and medium-term spaceflight affects all twelve recognized hallmarks of aging. Integrated multi-omics analyses in astronauts and rodent models identified mitochondrial dysfunction as a central node of spaceflight biology, with oxidative damage propagating genomic instability, cellular senescence, and chronic inflammation. At the chromosomal level, telomere dynamics were characterized by a paradoxical elongation-shortening cycle that may compress years of terrestrial attrition into months. In parallel, epigenetic clock analyses showed a ∼1.9-year biological age acceleration in astronauts after a 9-day orbital mission, with hierarchical post-flight recovery (reversible transcriptomic and epigenomic shifts versus persistent chromosomal inversions and clonal hematopoiesis mutations). This partial reversibility distinguishes the spaceflight paradigm from the largely unidirectional trajectory of chronological aging. We conclude that the relationship between spaceflight biology and terrestrial geroscience is bidirectional. Aging research on Earth provides the interpretive framework that renders astronaut molecular data biologically meaningful, and spaceflight offers geroscience a compressed, partially reversible aging-like phenotype in healthy young subjects that has no direct terrestrial counterpart. The observation that space radiation induces qualitatively distinct senescent phenotypes amenable to senolytic clearance supports a translational framework in which geroprotective strategies may simultaneously serve astronaut health and promote healthy longevity in the broader aging population.

Mitochondria are increasingly recognized as master regulators of aging, integrating bioenergetics, redox control, stem cell fate, and innate immune signaling. This review synthesizes evidence that mitochondrial dysfunction is not only a hallmark but also an upstream driver of stem cell exhaustion and inflammaging. We discuss how age-associated mitochondrial DNA (mtDNA) mutations and clonal mosaicism impair respiration and reshape metabolite availability, thereby reprogramming long-lived epigenetic states that govern quiescence, lineage commitment, and regenerative output. In parallel, erosion of mitochondrial quality control (MQC), including fission-fusion balance, mitophagy, and the mitochondrial unfolded protein response (UPRmt), permits the persistence of reactive oxygen species (ROS)-producing organelles and lowers containment of mitochondrial danger signals. A central advance is that mitochondrial damage can be decoded as inflammation: cytosolic mtDNA and other mitochondrial damage-associated molecular patterns (mtDAMPs) activate cGAS-STING and NF-κB pathways, reinforcing senescence-linked cytokine circuits and chronic inflammatory tone. We further highlight nicotinamide adenine dinucleotide (NAD⁺) depletion as a metabolic bottleneck that compromises sirtuin-dependent resilience and can enforce mitochondrial dysfunction-associated senescence (MiDAS), linking redox collapse to altered senescence phenotypes and regenerative decline. Finally, we evaluate emerging mitochondria-targeted rejuvenation strategies, NAD⁺ repletion, mitophagy enhancers, mitochondrial transplantation/engineering, and precision elimination of mutant mtDNA using mitochondria-targeted transcription activator-like effector nucleases (mitoTALENs) or zinc-finger nucleases (mitoZFNs), emphasizing tissue-specific thresholds and context dependence for effective healthspan extension.

Aging is a global issue that affects human health and increases disease risk. The traditional concept of the "age gap (AG)," defined as the difference between estimated biological age and an individual's chronological age, has been used for self-monitoring the risk of age-related diseases. However, the current AG does not account for the stratified aging patterns across different stages of chronological age, which may lead to biased or paradoxical interpretations of aging acceleration. To address these limitations, we propose Personalized-context-Aware Age Gap (PAAG), a robust metric to estimate aging acceleration, based on our new pre-training model AOE-Net (Age Order Enhanced Network). AOE-Net employs age-order enhanced contrastive learning on multi-omics data from healthy populations to learn latent representations that accurately reconstruct aging trajectories by capturing biological deviation rather than technical deviation in omics data. We demonstrate that PAAG, generated via fine-tuning AOE-Net, significantly outperforms AG of conventional first- and second-generation aging clocks in predicting clinical outcomes. This superior predictive power was validated across diverse age-related diseases and phenotypes: pan-cancer (overall survival), subclinical atherosclerosis (PESA score), and osteoporosis (bone mineral density). Crucially, PAAG serves as a context-aware metric that may improve the clinical outcome prediction of existing aging clocks. Furthermore, interpretive analysis of PAAG's molecular drivers revealed a strong functional enrichment for immune-response pathways, providing a shared mechanistic link between accelerated aging and disease. Collectively, PAAG could serve as a stable indicator of aging acceleration for clinically assessing age-related diseases, and AOE-Net provides an effective pre-training model for aging study and PAAG evaluation.

Cellular senescence and OSKM (Oct4, Sox2, Klf4, and Myc)-mediated reprogramming represent interconnected biological programs that both play important roles in regulating cellular plasticity. Recent studies have highlighted the role of p16-driven senescence in establishing a stable barrier to reprogramming by limiting epigenetic flexibility. Mechanistically, p16High senescent fibroblasts enforce this barrier through stress-induced and AP-1-driven epigenetic remodeling and NNMT-mediated metabolic SAM depletion, which restricts methylation-dependent chromatin remodeling in both p16High and neighboring p16Low cells via a paracrine mechanism. Conversely, clearance of p16High cells restores SAM levels and enhances cellular plasticity in neighboring cells, enabling the acquisition of totipotent-like states during reprogramming. Within p16High cells themselves, reprogramming can reverse some features of senescence, restoring more youthful cellular states under controlled conditions. Importantly, p16High cells remain highly resistant to full reprogramming, minimizing the risk of teratoma and tumor formation in vivo and making them promising target for rejuvenation strategies based on partial reprogramming. In this review, we examine the molecular interplay between p16High senescence and reprogramming, highlighting their dual roles as both barriers to and facilitators of cell fate transitions.

DNA topoisomerase II beta (TOP2B) is crucial for the regulation of DNA topology, transcription, and genome stability. While its function has been extensively studied in post-mitotic cells such as neurons and cardiomyocytes, its role in proliferative cells, especially in the context of cellular senescence and aging, remains inadequately understood. Emerging evidence suggests that TOP2B expression declines with age and is implicated in several age-associated disorders, yet the molecular basis of its involvement in senescence remains poorly understood. In this investigation, we have specifically disrupted the promoter region of TOP2B in HEK 293T cells using CRISPR-Cas9 genome editing. The targeted region, spanning -533 to -481, which encompasses binding motifs for NF-Y and SP1, also accounts for a major proportion of TOP2B promoter activity. Knockout of this regulatory segment resulted in a marked reduction of TOP2B expression. The knockout cells exhibited classical features of senescence, including elevated ROS levels, increased senescence-associated β-galactosidase (SA-β-Gal) activity, and upregulation of key markers such as p53, p21, and p16.To examine the paracrine effects of senescence, conditioned media from TOP2B-deficient cells were given to wild-type HEK 293T cells, which also developed senescence-like phenotypes. These findings suggest that Loss of TOP2B expression is associated with the induction of senescence-like phenotypes in dividing cells and can propagate senescent signaling to neighboring cells. This study highlights a previously underappreciated role of TOP2B in the regulation of cellular aging and opens new avenues for understanding its potential contribution to age-related pathologies in proliferative cell types.

Aging is characterized by the loss of tissue homeostasis, traditionally captured by the hallmarks of aging, yet how these hallmarks integrate to drive organismal decline remains unresolved. We propose mesenchymal drift, a process in which cells progressively lose lineage identity and adopt mesenchymal features, as a convergent framework that integrates the hallmarks of aging. Accumulating evidence suggests that mesenchymal drift can both arise from and reinforce these hallmarks, forming a feedback network that drives systemic decline. Framing aging through mesenchymal drift shifts the focus from discrete molecular defects to interconnected disruptions in cellular identity and cell state regulation, providing a more cohesive view of aging biology. Mesenchymal drift may therefore represent a measurable and targetable mechanism underlying diverse age-related pathologies. Interventions such as partial reprogramming may restrain mesenchymal drift, restore cellular identity, and simultaneously counteract multiple hallmarks, positioning it as both a convergent nexus and a tractable therapeutic axis in aging biology.

Metabolite repair, or metabolite damage control, has emerged as a fundamental pillar of intermediary metabolism alongside catalysis and regulation. Enzyme promiscuity and spontaneous chemical reactions inevitably generate abnormal metabolites that can interfere with classical metabolic processes. Dedicated metabolite repair enzymes prevent or reverse such damage, thereby preserving metabolic integrity. Defects in these systems define a growing class of inborn errors of metabolism, several of which are now clinically recognized and, in some cases, treatable. We summarize recent advances in the discovery and characterization of metabolite damage and repair systems in the tricarboxylic acid cycle, glycolysis, and other pathways, highlighting examples with established or potential links to human disease. We outline strategies for identifying additional metabolite repair defects and discuss diagnostic challenges, therapeutic perspectives, and connections between metabolite repair and aging. Understanding metabolite repair exposes the mechanisms that safeguard metabolism and opens new paths toward molecular diagnosis and targeted therapy.

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and chondrocyte senescence. Emerging evidence implicates NADPH oxidase 4 (Nox4) in OA pathogenesis. This study investigated the role of Nox4 in regulating extracellular matrix (ECM) homeostasis and chondrocyte senescence through the p38 mitogen-activated protein kinase (p38MAPK) signaling pathway. We found that Nox4 expression was significantly upregulated in OA chondrocytes and cartilage. In a post-traumatic OA mouse model (Anterior cruciate ligament transection, ACLT), Nox4 knockout attenuated cartilage damage and chondrocyte senescence, while preserving ECM proteins such as type II collagen and aggrecan. In vitro experiments further demonstrated that Nox4 overexpression accelerated chondrocyte senescence, impaired ECM synthesis, and upregulated senescence markers (p16, p21, p53). Conversely, pharmacological inhibition of Nox4 with GKT137831 or scavenging reactive oxygen species (ROS) with N-acetylcysteine (NAC) alleviated these effects, suggesting that Nox4 contributes to chondrocyte senescence potentially via ROS accumulation. Furthermore, Nox4-induced p38MAPK activation was closely associated with increased senescence and ECM degradation, and these pathological changes were reversed by the p38MAPK inhibitor SB203580. These findings highlight the Nox4-p38MAPK axis as acritical driver of OA progression and suggest that targeting this pathway may offer a promising therapeutic strategy to mitigate cartilage degradation and senescence.

Pulmonary aging is characterized by progressive structural and functional decline. Neddylation is recognized as a crucial mechanism for maintaining cellular homeostasis; however, its function in pulmonary aging has not been fully elucidated. In this study, we found that the core neddylation E2 enzyme UBE2M was downregulated in aged lung tissues. Ube2m knockdown mice exhibited premature pulmonary aging, including vascular degeneration and structural disruption. Notably, in the lungs of knockout mice, although VEGF expression-primarily secreted by epithelial cells-remained unchanged, the protein level and phosphorylation of its receptor VEGFR2 on endothelial cells were significantly reduced. Mechanistic investigation confirmed that UBE2M directly regulates VEGFR2 stability in pulmonary endothelial cells via neddylation. In a doxorubicin-induced endothelial cell senescence model, UBE2M downregulation was accompanied by impaired VEGFR2 signaling, whereas UBE2M reconstitution partially alleviated cellular senescence. In elastase-induced emphysema mouse models and in lung tissues from COPD patients, both UBE2M and VEGFR2 levels were markedly reduced, and Ube2m deficiency exacerbated lung injury. In conclusion, this study demonstrates that UBE2M delays pulmonary aging by stabilizing VEGFR2 through neddylation, suggesting its potential as a therapeutic target for age-related pulmonary diseases.

Sleep deprivation (SD) is closely linked to affective disorders, cognitive impairment, and accelerated neuroaging. Using an SD mouse model, we examined the neuroprotective effects of Ganoderic acid A (GAA), focusing on ferroptosis, pyroptosis, and their potential regulation by Cryptochrome 1 (Cry1). GAA significantly ameliorated SD-induced affective deficits, cognitive decline, and aging-like phenotypes. Mechanistically, GAA reversed SD-induced dysregulation of ferroptosis-related proteins (SLC7A11, GPX4, and ACSL4, etc.), and concurrently suppressed pyroptosis by inhibiting the NLRP3-caspase-1-GSDMD signaling cascade. Notably, GAA significantly upregulated Cry1 expression, and the protective effects of GAA were substantially diminished in Cry1-deficient mice. Furthermore, surface plasmon resonance and molecular dynamics simulations demonstrated a stable interaction between GAA and Cry1, which may underlie the GAA-induced upregulation of Cry1. Collectively, these findings suggest that Cry1 is involved in the regulation of GAA-associated protective effects against SD-induced neurobehavioral disturbances and neuroaging via suppression of ferroptosis and pyroptosis.

Sarcopenia is an age-related syndrome characterized by the progressive loss of skeletal muscle mass, strength, and function. It is associated with an increased risk of falls, disability, and mortality, as well as a significant healthcare burden. Traditional assessment of sarcopenia relies on imaging techniques and physical function tests, which have important limitations, including operational complexity, difficulty in early identification, and inability to reflect underlying molecular mechanisms. The emergence of candidate biomarkers-including muscle-specific factors, inflammation-related proteins, non-coding RNAs, and nutritional metabolites-has enabled a more precise elucidation of the pathophysiological mechanisms of the disease across multiple dimensions, such as protein homeostasis, chronic inflammation, post-transcriptional regulation, and energy metabolism. These advances provide new avenues for early identification, risk stratification, identification of disease subtypes, and the development of personalized intervention strategies. This article reviews the potential applications and current challenges of these candidate biomarkers in both clinical practice and research on sarcopenia.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert systemic metabolic and anti-inflammatory effects that may be relevant to cellular senescence, a key driver of skin aging. However, human cutaneous data are lacking.

The present study investigates how Sirtuin 1 (SIRT1) regulates the worsening of calcium oxalate (CaOx) crystal-induced mitochondrial dysfunction and fibrosis in the kidneys with age. To establish a CaOx crystal deposition model, glyoxylic acid (Gly) was injected intraperitoneally into both young and aged mice. Additionally, an in vitro model was created by stimulating human renal tubular epithelial (HK2) cells with D-galactose (D-gal) and calcium oxalate monohydrate (COM). Lipid deposition, mitochondrial function, and fibrosis levels were assessed using various techniques, including western blotting (WB), polymerase chain reaction (PCR), immunohistochemistry, immunofluorescence, and specific staining methods. The effects on lipid deposition, mitochondrial function, and fibrosis were further analyzed by manipulating the expression of SIRT1 and peroxisome proliferator-activated receptor (PPAR-α), both in vitro and in vivo. Aging exacerbates the kidney mitochondrial dysfunction and fibrosis induced by CaOx crystals, with SIRT1 playing a crucial regulatory role in this process. SIRT1 regulates lipid metabolism via PPARα, intensifying the aging-related kidney mitochondrial damage and fibrosis induced by CaOx crystals.

Transposable elements (TEs) are implicated in aging and neurodegenerative disorders, but the impact on brain TE RNA dynamics in these phenomena is not fully understood. Therefore, we quantify TE RNA changes in aging postmortem human and mouse brains and in the neurodegenerative disorders Huntington's disease (HD) and Parkinson's disease (PD). We track TE small RNAs (smRNAs) to assess the relationship to TE large RNA (laRNA) expression patterns. Human brain transcriptomes from the BrainSpan Atlas display significant shifts of TE smRNA patterns, whereas aging mouse brains lack any TE RNA changes despite a clear shift in aging-associated gene messenger RNA (mRNA) levels. The human frontal cortex displays the most pronounced sense TE smRNAs with a negative relationship between the TE smRNAs and laRNAs indicative of age-associated regulatory effects. Our analysis reveals TE smRNA dysregulation in HD, whereas PD shows a stronger impact on TE laRNAs, potentially correlating with the early average age of death for HD relative to PD. Furthermore, the TE-silencing factor

Brain maintenance may help explain why some individuals remain cognitively resilient despite aging, but its biological basis is not well understood. Here, we show that brain maintenance can be quantified from the relationship between brain structure and function. Using structural MRI and resting-state functional MRI from 1280 older adults, we built a model based on young adults to estimate the functional capacity supported by preserved brain structure, and defined brain maintenance as the difference between predicted and observed function. Brain maintenance was most evident in prefrontal, cingulate, and precuneus regions and was enriched in higher-order functional networks. Higher brain maintenance was associated with slower cognitive decline, lower amyloid-β burden, and domain-specific variation in memory, attention, and processing speed. These findings provide a biologically grounded marker of resilience in healthy and pathological aging.

Background: Regular exercise is a highly effective yet underutilized strategy to reduce cardiometabolic disease burden. Whether brief structured exercise programs confer lasting cardiometabolic benefits remains unclear. The STRRIDE-Prediabetes Reunion study examined legacy effects of exercise training on cardiorespiratory fitness, body composition, and cardiometabolic health. Methods: Seventy-three participants (71.3 {+/-} 7.2 years; 64% women; 77% White) completed Reunion assessments ~11 years after completing one of four 6-month interventions differing in exercise amount, intensity, and inclusion of diet-induced weight loss. Linear mixed effects models evaluated longitudinal trajectories; secondary analyses examined baseline-adjusted associations among short-term intervention response and Reunion outcomes. Results: Abdominal adiposity improved across all groups from baseline to Reunion, with waist circumference decreasing ~3 cm over the follow-up period. In contrast, cardiorespiratory fitness and fat-free mass declined significantly. A significant group by time interaction was observed for total fat mass (p=0.01), with continued fat mass reductions observed in women randomized to high amount exercise. After baseline adjustment, greater short-term intervention response was associated with more favorable Reunion outcomes across fitness, body composition, and cardiometabolic domains; fat-free mass showed the strongest association ({beta}=0.84, p<0.0001). Conclusions: In older adults with prediabetes, the STRRIDE-Prediabetes interventions produced several legacy health effects persisting more than a decade later. Legacy effects differed by sex and exercise dose, and short-term intervention response relative to baseline was associated with long-term outcomes, supporting targeted exercise strategies to preserve cardiometabolic health and functional independence with aging.

Age-related cognitive decline is a major public health concern, with few effective interventions available. Intermittent fasting (IF) has emerged as a promising metabolic intervention, potentially enhancing neuroprotection through increased β-hydroxybutyrate (BHB) production. This study aimed to test the hypothesis that IF attenuates cognitive decline in D-galactose (D-gal)-induced aging rats, at least partly in association with BHB elevation and modulation of PI3K/AKT/GSK-3β signaling. Forty-six male Sprague-Dawley rats (2 months old) were assigned to five groups: Control, D-gal-induced aging (D-gal), D-gal + IF, D-gal + IF + LY294002 (a PI3K inhibitor), and D-gal + IF + Solvent. IF was administered for 6 weeks in conjunction with D-gal treatment. Recognition memory and spatial learning/memory were assessed using the novel object recognition and Morris water maze tests, respectively; the open field test was used to evaluate locomotor activity and anxiety-like behavior. Biochemical assays (ELISA, Western blot), histological staining, and RNA-seq transcriptomic analysis were performed. IF improved recognition memory and spatial learning/memory, preserved hippocampal neuronal morphology, increased the proportion of morphologically normal CA1 neurons, elevated serum BHB levels, reduced neuroinflammation and tau phosphorylation, and restored brain-derived neurotrophic factor (BDNF) expression. These improvements were attenuated by LY294002 intervention, supporting the involvement of the PI3K/AKT/GSK-3β pathway. Transcriptomic analysis revealed suppression of senescence-related genes and modulation of neuroprotective pathways. IF attenuated cognitive decline in D-gal-induced aging rats in association with increased BHB levels and modulation of the PI3K/AKT/GSK-3β pathway. These findings suggest that IF may represent a promising non-pharmacological intervention for age-related cognitive dysfunction, although causal roles of ketone metabolism require further validation.

Cardiac arrest (CA) is a life-threatening medical emergency, and most victims are elderly. Despite advances in resuscitation, post-CA morbidity and mortality remain high, and this is thought to result largely from brain injury in which neuroinflammation plays a key role. Yet, how individual immune cell populations contribute to the immune response in the post-CA brain is still poorly understood. Here, using single-cell RNA-sequencing (scRNA-seq), we revealed the first immune landscape of the young and aged brain on day 3 after CA. Our data demonstrate that transitions in microglial states constituted a dominant immune change in the post-CA brain. We identified 5 CA-associated microglial states that included 3 major clusters defined by pro-inflammatory signatures, a proliferative phenotype, and high Spp1 expression. These 3 states exhibited age-dependent differences: the inflammatory subset was markedly expanded in aged mice, whereas the proliferative and Spp1⁺ clusters were more prominent in young mice. Such divergent responses likely underpin age-related disparities in neurologic outcome after CA. Notably, Spp1

Ovarian aging, marked by the gradual decline in both the number and quality of oocytes, significantly impacts women's reproductive lifespan and overall health. However, the biological mechanisms driving ovarian aging remain poorly understood and current treatment strategies are limited.

This study examined the prospective association between anemia and incident sarcopenia using two large-scale aging cohorts: the China Health and Retirement Longitudinal Study (CHARLS) and the English Longitudinal Study of Ageing (ELSA). This prospective, population-based cohort study included participants aged ≥ 45 years without sarcopenia at baseline from CHARLS (Wave 1, 2011) and ELSA (Wave 4, 2008-2009). Hazard ratios (HRs) were estimated using multivariable Cox proportional hazards models with sequential adjustment for demographic, socioeconomic, lifestyle, and health-related confounders. Subgroup analyses and sensitivity analyses were conducted to test robustness. After full adjustment, baseline anemia was significantly associated with an increased risk of incident sarcopenia in both CHARLS (n = 1,407; HR = 1.73, 95% CI: 1.07-2.79) and ELSA (n = 2,921; HR = 2.62, 95% CI: 1.50-4.56). In ELSA, a stronger association was observed among females (HR = 4.72, 95% CI: 2.25-9.93), with a marginal sex interaction (P for interaction = 0.054). No significant sex interaction was detected in CHARLS.Sensitivity analyses using sequential adjustment models confirmed consistent results (CHARLS: HR = 1.53, 95% CI: 1.17-2.01; ELSA: HR = 2.59, 95% CI: 1.30-5.18). This bicohort study suggests that baseline anemia is associated with a higher risk of developing sarcopenia in older adults from two distinct populations (Chinese and British). The strength of this association and the susceptible subgroups differed between cohorts. Further studies are needed to determine whether correcting anemia can reduce sarcopenia incidence and whether risk stratification based on anemia improves prevention strategies.

Social isolation and loneliness are recognized risk factors for adverse aging outcomes, but their effects on sarcopenia remain understudied. This study investigated the independent and combined effects of social isolation and loneliness on the risk of incident sarcopenia in two large prospective cohorts: CHARLS (

As populations age and climate variability intensifies, seasonal migration has emerged as a strategy among older adults to reduce exposure to climatic extremes and optimise living conditions. In China, millions of older adults migrate annually between cold northern and tropical southern regions, providing a natural setting to examine the health effects of seasonal migration. The Frigid-Tropical Migratory Population Health (ftMPH) cohort was established to assess the short- and long-term health effects of this migration and the underlying biological, behavioural and social pathways.

Despite its strong regenerative capacity, liver aging paradoxically increases susceptibility to fibrosis and metabolic dysfunction-associated steatotic liver disease through dysregulated inflammation, senescence-associated secretory phenotypes, and immune-metabolic crosstalk. To systematically characterize these processes, we integrated longitudinal transcriptomics, single-cell RNA sequencing, and machine-learning approaches. We identified 252 aging-associated genes and developed an Aging Gene Score (AGS) to quantify senescence burden across hepatic cell populations. Single-cell analysis revealed macrophages as key drivers of fibrosis progression, with high-AGS myeloid subsets markedly expanded in cirrhotic livers. Using combined Boruta and LASSO algorithms, we established a five-gene biomarker panel (EFEMP1, LUM, DKK3, GPRC5B, NCAM2) that accurately predicts advanced fibrosis (AUC > 0.77). Furthermore, a network pharmacology framework was applied to screen medicine-food homology (MFH) herbs, identifying Fagopyrum dibotrys (Jinqiaomai) and Astragalus membranaceus (Huangqi) as top candidates. Molecular docking demonstrated strong binding between the bioactive compound MOL000098 and the fibrosis-related target COL3A1. Functional assays showed that Jinqiaomai-containing serum alleviates oxidative stress, improves HepG2 cell viability, reduces ALT and AST levels, and suppresses macrophage lipid accumulation, accompanied by reduced expression of inflammatory and fibrosis-related markers. Collectively, our findings highlight macrophage-centered mechanisms linking liver aging and fibrosis and suggest MFH-derived compounds as promising anti-aging and anti-fibrotic dietary interventions.

Classifying ovaries solely as reproductive organs has obscured their role as systemic regulators of female physiology. This Perspective makes the case that ovarian aging is a primary determinant of healthspan and belongs at the center of geroscience.

Biological aging is heterogeneous across organ systems, yet whether CT-derived abdominal aging provides prognostic value beyond routine clinical data and whether organ decomposition adds beyond a unified estimate remains untested. We developed and evaluated organ-specific and ensemble biological age models from radiomic features across five abdominal organs in 68,675 CT scans from 32,883 subjects, evaluated on alignment with chronological age of healthy subjects (nested cross validation: MAE=3.68 years, R^2=0.90). In sequential analyses restricted to adults aged 20-60 years which is the stratum of strongest BAG-disease association, ensemble biological age gaps provided incremental prognostic value beyond demographic covariates for all-cause disease and mortality (Delta C-index=0.141, 0.051) and beyond routine blood biomarkers (Delta C-index=0.048), confirming CT-derived aging captures structural information beyond laboratory markers. Organ-specific biological age added incremental prognostic value beyond ensemble selectively for focal diseases: cardiovascular (aorta, Delta C-index=0.091) and hepato-pancreatic (pancreas, Delta C-index=0.096). These findings establish a hierarchical organization of CT-derived biological aging, positioning routine CT as a source that adds prognostic value to existing clinical biomarkers.

Diabetes and aging synergistically impair bone regeneration, primarily driven by functional deterioration of bone marrow mesenchymal stem cells (BMSCs). Here, we uncover an m6A-centered regulatory network integrating ferroptosis and glycolytic metabolism that dictates BMSCs dysfunction under diabetes-aging comorbidity. Mechanistically, diabetic stress selectively activated the ALKBH5-ferroptosis axis, driving excessive ferroptosis in young BMSCs, whereas senescent BMSCs exhibited an additional repression of METTL3-mediated glycolytic flux, rendering ferroptosis inhibition alone insufficient to restore osteogenic capacity. These intersecting molecular defects cooperatively exacerbated osteoporosis progression in diabetic aging. Guided by this mechanistic framework, we developed a combinatorial regenerative strategy integrating milk-derived exosomes (MiExos) and anaerobic exercise to simultaneously target ferroptotic stress and metabolic insufficiency. Mechanistically, MiExos selectively suppressed ferroptosis by stabilizing NRF2 signaling through inhibition of ubiquitination, without perturbing glycolytic metabolism, while anaerobic exercise robustly enhanced intraosseous glycolysis. Notably, the dual intervention markedly improved bone regeneration in diabetic-aged mice. Collectively, our findings establish milk-derived exosomes as a natural nanotherapeutic capable of precise ferroptosis modulation and demonstrate that coordinated suppression of ferroptosis and activation of glycolysis is essential for overcoming bone regenerative failure in diabetes-aging comorbidity.

The mitochondrial unfolded protein response (UPR

As the challenges posed by an aging population become increasingly apparent, the prevention and treatment of age-related diseases have become key research priorities. This study hypothesizes that Zhizi Baipi Decoction exhibits aging modulatory effects. Traditional Chinese Medicine Decoction that has been passed down for generations and remains widely used in contemporary clinical practice. Due to their short lifespan, well-defined genetic backgrounds, and ease of manipulation, model organisms such as Drosophila and C. elegans are commonly employed in aging modulatory research. This study evaluated the aging modulatory potential of Zhizi Baipi Decoction using Drosophila and C. elegans as model organisms, and used a Nuclear Magnetic Resonance-based metabolomics approach to explore the aging modulatory potential of Zhizi Baipi Decoction and its intrinsic mechanism. It was found that Zhizi Baipi Decoction could prolong the lifespan of Drosophila and C. elegans, improve locomotor activity, delay intestinal aging and so on, establishing a foundational framework for the future research and development of this traditional remedy.

Atherosclerosis is a systemic vascular process linked to cardiovascular, cognitive and renal outcomes. DNA methylation (DNAm)-based scores of atherosclerosis may capture cumulative biological processes underlying vascular aging. Here, we examined associations of DNAm scores for coronary artery calcification (DNAm-CAC) and carotid plaque (DNAm-cPlaque), derived from a large study of imaging-based subclinical atherosclerosis, with prevalent and incident outcomes in two population-based cohorts of older adults: the Health and Retirement Study (HRS; n = 3,875) and The Irish Longitudinal Study on Ageing (TILDA; n = 487). Higher DNAm scores were associated with adverse cardiometabolic profiles and socioeconomic indicators. In HRS, higher DNAm-CAC was associated with prevalent cardiovascular disease (odds ratio per SD, 1.16; 95% confidence interval (CI), 1.07-1.26), lower cognitive function ({beta} = -0.50, 95% CI -0.68 to -0.32) and lower estimated glomerular filtration rate (eGFR; -1.7 ml min-1 1.73 m-2, 95% CI -2.6 to -0.8) in unadjusted models. After adjustment for demographic and clinical risk factors, DNAm-CAC ({beta} = -0.29, 95% CI -0.46 to -0.13) and DNAm-cPlaque ({beta} = -0.24, 95% CI -0.42 to -0.06) remained associated with lower cognitive function, and DNAm-cPlaque was associated with incident cognitive impairment or dementia (hazard ratio per SD, 1.16; 95% CI, 1.01-1.32). Associations were attenuated after further adjustment for race/ethnicity and socioeconomic indicators. In TILDA, higher DNAm-cPlaque was associated with worse cognitive performance (incidence rate ratio, 1.11; 95% CI, 1.01-1.21), increased risk of incident cardiovascular disease (hazard ratio, 1.18; 95% CI, 1.00-1.42) and lower eGFR, with consistent associations observed for DNAm-CAC. These findings suggest that DNAm-based scores of atherosclerosis capture systemic vascular processes linked to multiple age-related outcomes across populations. Further work is needed to clarify the biological pathways reflected by these scores and their relation to cumulative and socially patterned vascular risk.

Age-related osteoarthritis (OA) involves metabolic dysregulation and chondrocyte senescence. This study examined the nonmetabolic role of enolase 2 (ENO2) in OA pathogenesis and its therapeutic potential.

Food insecurity is a growing public health concern, particularly among older adults, as it has been linked to adverse health outcomes, including chronic diseases, sarcopenia and functional decline. However, its direct association with all-cause and premature mortality remains underexplored.

Aging-induced decline in ovarian function and oocyte quality contributes to female infertility. However, the mechanisms underlying human umbilical cord-derived mesenchymal stem cell (HucMSC)-mediated rejuvenation of aged ovaries remain poorly understood. This study aimed to systematically investigate whether and how HucMSCs restore ovarian function and oocyte quality and elucidate the potential pathways involved.

Atherosclerosis is a chronic inflammatory vascular disease characterized by lipid deposition, endothelial dysfunction, and cellular senescence, posing a significant threat to the cardiovascular system. As demonstrated in previous studies, phlorizin has been shown to have anti-atherosclerotic effects. However, the precise molecular mechanisms by which this occurs remain to be elucidated. This study aimed to investigate the preventive effect of phlorizin on atherosclerosis and elucidate the molecular network mediated by bone morphogenetic protein 10 (BMP10). A total of 40 eight-week-old Apoe

One of the most pressing scientific challenges of the current century is the mounting loss of cognitive function and vulnerability to neurodegenerative disorders associated with brain aging. This requires a paradigm shift beyond traditional neuron-focused models to address the central importance of non-neuronal glial cells, most notably astrocytes, in promoting age-related neuroinflammation. While the pro-inflammatory secretome of senescent cells, known as the senescence-associated secretory phenotype (SASP), is well-characterized in peripheral tissues, its specific role in the central nervous system remains a critical knowledge gap. This narrative review synthesizes current evidence to propose that the SASP of glial and vascular cells acts as a contributor mechanism, where it interacts with other aging hallmarks to amplify the pathological environment rather than acting as the sole link. Moving beyond standard biochemical signaling cascades, we propose conceptually transformative frameworks to explain central SASP aggression. The glymphatic-SASP traffic jam, establishing a bio-mechanical feedback loop where waste clearance failure traps secretomes in localized hotspots; and the metabolic energy vampire paradigm, demonstrating the active competition for resources between hyper-secretory glia and energy-starved neurons, were explored. Also, the innate immune mimicry triggered by retrotransposon awakening, explaining how unleashed genetic elements actively fuel self-propagating inflammation, and the loss of glial identity dictated by epigenomic state drift and SASP mosaicism were demonstrated. Furthermore, we evaluate the classic regulatory cross-talk between the SASP and nutrient-sensing pathways like AMPK and mTOR, and discuss the therapeutic potential of selectively targeting the SASP through senomorphics and metabolic resetters. Elucidating these complex, brain-specific SASP dynamics is paramount for translating these concepts into effective interventions against age-related neurological diseases.

Endogenous double-stranded RNAs (dsRNAs) are immunogenic self-molecules that drive aberrant immune activation under pathological conditions. Here, we show that dsRNAs and their regulation by RNA-binding proteins are key determinants of the fine balance between aging and immunity in Caenorhabditis elegans and cultured human cells. We find elevated levels of dsRNAs with organismal aging and cellular senescence. We identify a moonlighting function for phenylalanyl-tRNA synthetase, FARS-1/FARSA, as a key factor necessary and sufficient for extending lifespan by downregulating dsRNAs, in particular, mitochondrial dsRNAs. FARS-1/FARSA possesses a previously unrecognized dsRNA-binding domain and mediates dsRNA downregulation with the RNA helicase, RHA-2/DHX37, independently of its canonical role in translation. Notably, increased dsRNA expression resulting from genetic inhibition of fars-1/FARSA upregulates immune response-related genes and enhances innate immunity against pathogens. Our study establishes that FARS-1/FARSA is an evolutionarily conserved dsRNA-binding protein that delays aging and promotes longevity by suppressing dsRNA accumulation.

Maintaining balance requires a complex interplay between sensory and motor processes, and this ability deteriorates with age, impairing daily life activities and contributes to increased fall risks. Importantly, while cognitive-motor interference paradigms suggest an aging-related increase in the cortical involvement in balance regulation, direct evidence remains lacking. To clarify this issue, we assessed the effect of aging on sway-based corticokinematic coherence (CKC), which is a measure of the coupling between cortical electrophysiological signals and postural sway. To that end, we recorded the center-of-pressure fluctuations and electroencephalographic cortical activity of 64 young and 67 older healthy participants performing balance tasks during which sensory information was either removed or altered. We found that older adults showed increased cortical activity that appears to relate to different aspects of closed loop postural control during challenging balance conditions, and correlates with upright stance stability. They also showed increased delays between cortical activity and postural sway, indicative of slower central processing speed. Finally, despite the older cohort displaying significantly altered vestibulo-ocular reflexes, no relationship was found with CKC strength. Overall, our results provide direct evidence that cortical involvement in balance regulation increases with aging. They suggest the feasibility of assessing afferent and efferent processing during balance maintenance, paving the way for studies identifying neurophysiological determinants of fall risks.

Aging is typically framed as a one-way, irreversible accumulation of molecular damage in cells and tissues, leading to progressive functional decline. Yet mammalian reproduction, and particularly female reproduction, reveals a striking exception to this rule. Despite residing within an aging organism and within a fast-aging ovarian tissue environment, oocytes give rise to embryos that begin life with restored developmental potential and youthful molecular organization. By reframing ovarian biology as a model for rejuvenation rather than solely as a site of reproductive decline, this Essay proposes that the ovary offers a powerful blueprint for advancing the biology of aging and longevity.

Mitochondrial DNA heteroplasmy plays a crucial role in mitochondrial function, aging, and a wide range of human diseases. Recent advances in high-throughput sequencing have enabled large-scale detection of heteroplasmic variants; however, effective cohort-level integration, comparison, and visualization of Mutant Allele Frequency (MAF) values remain challenging. Existing tools often focus on single-sample visualization or require substantial manual preprocessing, limiting their scalability and usability for large cohorts. To address these challenges, we developed Mito_Plot, an open-source computational pipeline designed for standardized quantification and intuitive visualization of Mitochondrial DNA (mtDNA) heteroplasmy across multiple samples.

Somatic mutations in hematopoietic cells can drive clonal expansion without overt malignancy, a condition defined as clonal hematopoiesis of intermediate potential (CHIP). Among CHIP driver genes, TET2 is notable for its high prevalence and strong association with cardiovascular disease (CVD) and chronic inflammation. TET2 encodes a methylcytosine dioxygenase essential for epigenetic regulation, and its loss impairs hematopoietic stem cell differentiation while altering the functions of mature myeloid and lymphoid cells. Aging-related inflammation, along with lifestyle exposures, metabolic disorders, cancer therapy, and HIV infection, affects the emergence and expansion of TET2-mutant clones. Recently, evidence increasingly links TET2-CHIP to the incidence and prognosis of diverse CVDs. Emerging studies also suggest potential therapeutic strategies for TET2-CHIP-associated cardiovascular disease. This review summarizes current understanding of TET2 biology, mechanisms of TET2-CHIP development, and its cardiovascular implications.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline driven by amyloid-β plaques, tau neurofibrillary tangles, and extensive neuronal loss. Emerging evidence highlights mitochondrial dysfunction, defective mitophagy, and disrupted proteostasis as pivotal events in disease progression. Transglutaminase TG2, a multifunctional calcium-dependent enzyme, has gained attention for its capacity to link these pathological processes. Beyond catalyzing ε-(γ-glutamyl)-lysine crosslinks that stabilize amyloid and tau aggregates, TG2 interacts with mitochondrial membranes, altering permeability and bioenergetic efficiency. In neurons, aberrant TG2 activity promotes oxidative stress, impairs mitophagy through crosslinking of PINK1 and Parkin, and exacerbates calcium dyshomeostasis via modification of VDAC and ANT1, culminating in energy failure and apoptosis. Aging-related increases in ROS and inflammatory cytokines further amplify TG2 activation, reinforcing proteostatic collapse and synaptic degeneration. Recent metabolomic studies reveal that TG2-mediated dysregulation extends to lipid and amino acid metabolism, affecting mitochondrial respiration and neuronal signaling. Therapeutically, selective TG2 inhibition restores autophagic flux, mitigates mitochondrial damage, and reduces aggregate burden in preclinical models. This integrative review underscores TG2 as a central orchestrator connecting mitochondrial dysfunction, aging, mitophagy failure, and metabolic imbalance in AD. Targeting TG2's transamidase activity while preserving its regulatory roles may offer a promising strategy for neuroprotection and disease modification.

Physical activity (PA) supports health and independence in older age, yet little is known about how lifelong attitudes toward PA relate to fitness and PA in advanced age. The present study explored if active women aged 80 + differed in functional fitness and PA based on their long-term PA attitudes and athletic identity. Furthermore, a relationship between PA and depression was examined. A total of 225 women (

People with HIV (PWH) face accelerated aging and increased health risks, with DNA methylation age (DNAmAge) as a critical senescence biomarker. Particulate matter (PM) is linked to DNAmAge acceleration (AA) in general population, but its impact in PWH remains unstudied.

Nutrition, encompassing vital macro- and micronutrients (including carbs, proteins, fats, vitamins such as D and C, and minerals like iron and calcium), is fundamental to supporting life, fostering healthy ageing, and averting disease. The information on the combined impact of dietary patterns, nutritional content, and lifestyle factors on metabolic health, disease risk, and healthy ageing is summarised in this publication. According to the discussion, both macronutrient and micronutrient surpluses and deficiencies upset metabolic homeostasis, which leads to obesity, insulin resistance, cardiovascular disease, and hepatic steatosis. Dietary habits are one of the three cornerstones of health and longevity, according to biogerontological theories of ageing. The free radical theory emphasises oxidative stress in cellular damage, and the disposable soma hypothesis emphasises the trade-off between reproduction and somatic upkeep. Clinical and epidemiological data indicate that cardiometabolic outcomes, including elevated insulin sensitivity, lipid profiles, and inflammatory markers, are strongly influenced by diet quality, dietary timing (such as time-restricted eating), and overall energy balance. The review also demonstrates how nutrients can control gene expression, signalling pathways, and epigenetic alterations in addition to serving as energy sources. Nutrient availability and disease susceptibility are largely determined by interactions between the gut microbiota, food, and human metabolism. Furthermore, individual reactions to diet are very variable due to genetic, metabolic, and environmental factors, which explains why customised nutrition plans are becoming more and more popular. The findings also show that dietary habits during childhood and adolescence have an impact on long-term disease prevention, and that combining lifestyle treatments (diet and exercise) can consistently reduce the risk of chronic illness. In order to optimise health and wellness over the course of a lifetime, the data generally supports switching from reductionist, single-nutrient dietary methods to integrated, systems-oriented strategies that take into account molecular, clinical, and sociocultural factors.

Recent years have highlighted the profound influence of the gut microbiota not only on local immunity but also on systemic host physiology. However, the translational potential of findings from preclinical animal models remains limited, in part owing to their microbiomes shaped in the absence of natural environmental cues. To address this gap, we developed a scalable, cost-effective, and reproducible preclinical model of environmental exposure (ENV), in which local soil-derived microbiota colonize laboratory mice. Sustained colonization with environmental microbes, particularly Gram-negative bacteria, was associated with a shift toward local and systemic anti-inflammatory immune responses, supporting the expansion of regulatory T cells (Tregs) and IL-10⁺ innate and adaptive populations. These changes confer protection against colitis, obesity, diabetes, and sepsis, ultimately extending both health span and lifespan. Thus, natural microbial exposure lays the foundation for future studies into microbiota‒host interactions, therapeutic resistance, and the development of more physiologically relevant models for human disease.

The cell fate regulation of skeletal stem cells (SSCs) into bone marrow adipocytes (BMAd) during physiological and pathological conditions has been a subject of study. Identification, isolation, and characterization of progenitors that give rise to BMAd, is an extensive field of research. The skewing of the cell fate of SSCs to BMAd also alters the fate of the bone accrual process due to increased bone resorption. Among the several molecular pathways that alter cell fate of SSCs is accumulation of reactive oxygen species, DNA damage, and cellular senescence. The current short review will discuss the direct and indirect effects of cellular senescence in the marrow environment, that leads to SSC differentiation to BMAd. Preclinical studies using pharmacological and genetic clearance of senescent cells and suppression of the senescence associated proinflammatory signature lays the foundation for exploring these strategies as therapeutic interventions that could mitigate BMAd and associated bone loss.

Chronic kidney disease (CKD) is associated with premature aging, which reflects in the difference between biological age and chronological age. Immunoglobulin G (IgG) N-glycosylation profiles have emerged as promising biomarkers for biological aging. From the perspective of predictive, preventive, and personalized medicine (PPPM/3PM), we assumed that the evaluation of kidney-specific biological age based on IgG N-glycosylation profiles provides a better tool for targeted prevention and personalized intervention of CKD by monitoring kidney aging.

Cellular senescence is a key mechanism of skeletal aging in both physiological and accelerated conditions, such as radiotherapy. This study aimed to identify common differentially regulated microRNAs (miRs) across these contexts. We performed miR sequencing on three models: femurs from young (5-month-old) versus old (24-month-old) mice; focally radiated versus non-radiated femurs; and osteocytes from young versus old mice. Osteocytes were included in the comparison, as they have the longest lifespan in the mineralized bone matrix and they form 90-95% of all mesenchymal bone cell types. Among the three groups, miR-135a-5p and miR-671-5p were the common (i.e., shared) miRs that were downregulated, and miR-183-5p, a miR that regulates the WNT pathway, was the only shared upregulated miR, while miR-155-5p, a miR that regulates the Senescence-Associated Secretory Phenotype (SASP), was elevated in two conditions. The WNT-pathway has been positively associated with bone health and Sclerostin, a WNT-pathway inhibitor produced and secreted by osteocytes, has been implicated in accelerated skeletal deterioration following radiation. Thus, we used a neutralizing antibody to Sclerostin (Scl-Ab), to assess genes related to the WNT pathway and senescence, which are regulated by miR-183-5p and miR-155-5p, respectively. We further performed miR sequencing in radiated bones from mice treated with Scl-Ab and identified miR-133a-3p, a key miR that inhibits bone metabolism and function, which is upregulated in accelerated skeletal aging (i.e., focal radiation) downregulated by Scl-Ab. Overall, our study identifies potential regulatory gene pathways that modulate skeletal aging in the presence and absence of a WNT activator, Scl-Ab.

Despite robust evidence and international consensus for muscle-strengthening exercise, less than one in four adults meet recommended guidelines. Sustainable implementation of strength training interventions into community practice are hindered by a range of barriers, highlighting the need for a rigorous participatory approach to plan for successful and sustainable delivery.