Longevity Papers

Mitochondria-lysosome contacts (MLCs) are emerging as a dynamic membrane interface that integrates organelle communication with cellular homeostasis. Rather than acting solely as intermediates of degradative trafficking, MLCs organize local calcium transfer, lipid exchange, Rab7-dependent contact remodeling, and mitochondrial quality control. These functions place MLCs at the intersection of mitochondrial fitness, lysosomal competence, metabolic adaptation, and stress signaling. Aging provides a particularly informative setting in which to examine this interface, because mitochondrial dysfunction and lysosomal decline co-emerge and reinforce one another during cellular aging. Current evidence suggests that aging does not simply increase or decrease MLCs, but instead remodels their dynamics, molecular composition, and functional output. Such remodeling may impair mitophagy, alter calcium and lipid coupling, amplify oxidative and inflammatory stress, and contribute to age-related disease phenotypes. In this review, we summarize the structural organization and regulatory logic of MLCs, examine their mechanistic roles in organelle homeostasis, and discuss how aging reshapes this interface in physiological and pathological contexts. We also highlight key methodological challenges and therapeutic opportunities for the field.

Descendants of longevity-enriched sibships demonstrate a broad health and survival advantage throughout the life course. However, little is known about manifestations during very early life. Here we show a pattern of lower risk of adverse early-life outcomes in third-generation grandchildren (N = 5637) of Danish longevity-enriched sibships compared to the general population, including infant mortality (Hazard Ratio = 0.53, 95% CI [0.36, 0.77]) and a range of neonatal health indicators. These associations in fourth-generation great-grandchildren (N = 14,908) were attenuated and less consistent (e.g., infant mortality, Hazard Ratio = 0.90, [0.70, 1.17]). Dilatory patterns across successive generations were independent of stable advantages in select socioeconomic and behavioural indicators (e.g., parental education, income and maternal smoking), maternal and paternal lines of transmission, as well as secular trends in the background population. However, our socioeconomic and behavioral indicators were limited in both range and granularity. Our findings suggest that the familial aggregation of exceptional health and survival has early life developmental components.

Maintenance of the genome and epigenome stability is vital for animal longevity. Long noncoding RNAs, roX1 and roX2, are known to be important in the male X chromosome dosage complex in Drosophila males. However, their functions in Drosophila females have never been explored. This study demonstrates a role of roX RNAs in promoting heterochromatin formation in intestinal stem cells (ISCs) of Drosophila females under pathogen infection or aging. Increased heterochromatin formation in ISCs and progenitor enteroblasts (EBs) is associated with decreased active epigenetic modifications and global gene repression. Elevation of roX RNAs in ISCs promotes heterochromatinization and represses gene expression by recruiting heterochromatin proteins such as HP1a and Su(var)3-9. Overexpression of roX RNAs promotes ISCs hyperplasia, while their inactivation mitigates ISCs dysplasia and extends lifespan. Moreover, Xist RNA, the functional analog of roX RNAs, also promotes heterochromatin formation and ISCs hyperplasia in Drosophila, and significantly increases in aged people. Therefore, our findings reveal a role of roX RNAs in promoting heterochromatin expansion and controlling animal longevity.

Butyric acid improves cognitive dysfunction. Therefore, butyrylated starch acts as a butyrate carrier and resistant starch to produce butyric acid, potentially improving cognitive dysfunction. In the d-galactose-induced aging mice model, BNMS2 effectively improved cognitive dysfunction and outperformed sodium butyrate and high-amylose maize starch. BNMS2 ameliorated cognitive behavior and brain histopathology, decreased GFAP, IBA-1, Aβ, AChE, MDA, IL-6, IL-1β, and TNF-α levels, and increased BDNF, PSD-5, GSH-Px, and SOD levels to mitigate neuronal damage, oxidative stress, and inflammation. BNMS2 also produced abundant butyric acid, enhanced the abundance of beneficial bacteria (

Cognitive decline is a major public health concern in aging societies, and physical activity (PA) is a key modifiable factor. Some individuals concentrate their PA into one or two days per week-the "weekend warrior" pattern-but its long-term relationship with cognitive changes remains unclear. This study aimed to examined the association between the weekend warrior pattern and cognitive trajectories among middle-aged and older adults in China.

Environmental exposure to heavy metals and endocrine-disrupting chemicals (EDCs) activates the NLRP3 inflammasome, driving chronic inflammation that worsens or may underlie cardiovascular disease, neurodegeneration, and accelerated aging. This review examines the molecular mechanisms by which lead, cadmium, mercury, arsenic, bisphenol A, phthalates, and dioxins modulate NLRP3 signaling. Lead and cadmium activate NLRP3 through mitochondrial dysfunction and oxidative stress, whereas mercury and arsenic suppress inflammasome assembly by preventing apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization. EDCs engage receptor-mediated pathways: aryl hydrocarbon receptor (AhR) activation directly represses NLRP3 transcription, yet bisphenol A and phthalates override this suppression through NF-κB activation. Developmental timing critically determines outcomes such as prenatal exposures epigenetically programing persistent NLRP3 dysregulation. Sex hormones have been shown to modulate distinct inflammatory landscapes: estrogen suppresses NLRP3 via ERβ-dependent mechanisms, while testosterone amplifies inflammasome-dependent pathology. The skin serves as a primary interface for environmental chemical exposure and cutaneous NLRP3 activation. NLRP3-deficient mice exhibit 34% increased lifespan, and pharmacological inhibition with MCC950 extends lifespan in progeria models. The CANTOS trial demonstrated that targeting inflammation through IL-1β neutralization confers cardiovascular benefits in high-risk humans. These findings position NLRP3 as a central integrator through which the chemical exposome accelerates inflammaging and identify inflammasome inhibition as a therapeutic strategy for environmental disease prevention.

Biological aging (BA) may influence chronic kidney disease (CKD) development. We evaluated the association of accelerated BA-quantified using Klemera-Doubal method biological age (KDM-BA) and phenotypic age (PhenoAge)-with incident CKD, and assessed its predictive value beyond conventional risk factors (CKD Prediction Consortium [CKD-PC] model) in participants with diabetes.

Relationships between the concentration of circulating IGFBP-7 and risk of disease and mortality have been suggested by small-scale investigations. In this prospective study, we investigated these relationships among 53,003 UK Biobank participants. Higher IGFBP-7 level was significantly associated with increased risk for liver cancer, all-cause mortality, diabetes, and other diseases. Associations were robust across sex and age groups and persisted over long follow-up. IGFBP-7 polygenic risk scores also predicted cancer and mortality risk. IGFBP-7 level was strongly correlated with levels of previously identified aging-related proteins, but after adjustment for these proteins, remained associated with risk of bladder cancer, liver cancer, multiple myeloma, all-cause mortality, liver-related mortality, and diabetes. Our findings indicate IGFBP-7 as a novel biomarker of mortality and disease risk.

Endoplasmic reticulum (ER) stress contributes to the pathogenesis of neurodegenerative and age-associated diseases, motivating the search for compounds that enhance ER-stress resilience. Modulation of ER-redox pathways, including those associated with the oxidase ERO1A, can attenuate maladaptive unfolded protein response (UPR) signaling and improve cellular stress tolerance. Here we develop an integrative discovery strategy to identify natural compounds that mitigate ER-stress-associated phenotypes across cellular and organismal models. Structure-informed virtual screening guided by ERO1A biology prioritized the pyrazolopyridine alkaloid S88. In human SH-SY5Y-derived neurons, S88 improves survival and reduces tunicamycin-induced ER-stress markers. In Drosophila, S88 ameliorates neuromuscular and locomotor phenotypes in a UBQLN2-associated ALS model and improves aging-related outcomes. Biochemical assays did not detect inhibition of ERO1A or radical scavenging activity by S88, indicating that its molecular target remains to be identified. Together, these findings identify S88 as a natural-product scaffold that enhances ER-stress resilience across neuronal and in vivo models.

Lactate has been recognized as a major fuel substrate and also a lactyl-group donor for histone lysine lactylation. Hepatocytes act as lactate-consuming cells owing the high oxidative capability especially during exercise, a primary nonpharmacological intervention for alleviating metabolic dysfunction-associated steatotic liver diseases including steatohepatitis (MASLD/MASH). However, little is known regarding how lactate links the metabolic-epigenetic axis in hepatocytes. Here we show that declined estrogen-related receptor α (ESRRA) expression occur in MASLD/MASH accompanied with elevated levels of lactate and histone lactylation, particularly H3K18la. Such dysregulation can be partially rescued by chronic exercise in aged mice or exacerbated by genetic ablation of hepatocyte ESRRA. Mechanistically, exercise-induced ESRRA/PPARGC1A facilitates lactate consumption through transcriptional regulation of lactate dehydrogenase B and glucose-6-phosphatase catalytic subunit 1, rewiring lactate from a lactyl donor to gluconeogenic precursor in hepatocytes. Hepatocyte-specific ESRRA overexpression counteracts MASLD/MASH progression in mice, rectifying aberrant H3K18la accumulation and its marked gene transcripts that are involved in liver pathology. Our findings reveal that ESRRA functions as an exercise executor linking metabolism with epigenetic modification, highlighting a gluconeogenic-epigenetic regulatory axis that could be fine-tuned to mitigate risk factors of MASLD/MASH such as aging, menopause, a sedentary lifestyle and malnutrition.

The authors sought to examine the literature for evidence of shared similar cellular impacts between sepsis and aging. There is much available literature about shared immunologic dysregulation of toll-like receptor 4 (TLR4) activity in both conditions. Based on these findings, the authors propose a model of aging inspired by the recently published (2024) OO(H)NO! model of dysregulated immune and metabolic impacts of sepsis, which directionally maps out TLR4 dysregulation in sepsis.

Garlic (Allium sativum L.) and its aged extract contain many bioactive compounds that can bring health benefits to humans. Among them, S-1-propenyl-L-cysteine (S1PC) has recently drawn significant attention in the field of nutriceutical research. However, the mechanism of its molecular action has remained poorly understood. Here, we show that S1PC significantly activates liver kinase B1 (LKB1) through enhancing its tertiary complex formation with STRAD and MO25, leading to stimulating the phosphorylation of a mammalian NAD

Ultraviolet B (UVB) radiation contributes to skin aging and damage via increasing oxidative stress and mediating inflammatory process in skin. The identification of effective agents to protect UVB-mediated deterioration against skin is necessitated. This study aims to examine the protective effects and mechanisms of avenanthramide C (AVN C), a phenolic compound enriched in oat sprout extract (Avena sativa), against UVB-induced photoaging in human keratinocyte cells (HaCaT) and a 3D reconstructed human skin model (Neoderm-ED). AVN C reduced oxidative stress by promoting the nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) and upregulating antioxidant enzyme expression. AVN C also suppressed the production of inflammatory mediators, including COX-2, IL-1β, and TNF-α, through the inhibition of nuclear factor-kappa B (NF-κB) and upstream MAPK signaling. Moreover, AVN C inhibited UVB-induced matrix metalloproteinase (MMP)-1 and MMP-3 expression, thus preventing extracellular matrix degradation and wrinkle formation. In Neoderm-ED, AVN C protected against UVB-induced structural damage and inflammation by suppressing prostaglandin E

Metabolism unfolds within specific organelles in eukaryotic cells. Lysosomes are highly metabolically active organelles, and their metabolic states dynamically influence signal transduction, cellular homeostasis and organismal physiopathology. Despite the importance of lysosomal metabolism, a method for its in vivo measurement is currently lacking. Here we report a fluorescence-detected mid-infrared photothermal microscope (FILM) implemented with optical boxcar demodulation, artificial intelligence-assisted data denoising and spectral deconvolution, to map metabolic activity and composition of individual lysosomes in living cells and organisms. Using this method, we uncovered lipolysis and proteolysis heterogeneity across lysosomes within the same cell, as well as early-onset lysosomal dysfunction during organismal aging. In addition, we discovered organelle-level metabolic changes associated with diverse lysosomal storage diseases. This method holds the broad potential to profile metabolic fingerprints of individual organelles within their native context and quantitatively assess their dynamic changes under different physiological and pathological conditions, providing a high-resolution chemical cellular atlas.

Accumulation of DNA damage, particularly oxidative DNA damage, is a major molecular driver of senescence and aging. The enzyme apurinic/apyrimidinic endonuclease-1 (Apex1) is essential for base-excision repair, but its role in protecting the brain from age-related deterioration remains unclear. Here we show that conditional knockout (cKO) of Apex1 in forebrain neurons causes early and progressive cognitive impairment in mice. Apex1 cKO mice display deficits in spatial learning and memory (8-12 weeks), alongside reduced synaptic proteins, altered neuronal morphology, and impaired long-term potentiation at 48 weeks. We further show that a 30% caloric restriction (CR) regimen at 8-48 weeks markedly attenuates these premature aging features and improves cognitive outcomes in Apex1 cKO mice. These findings confirm Apex1 as a critical genomic maintenance factor in the aging brain and highlight the Apex1 cKO model as a valuable tool for studying endogenous defenses and dietary interventions against aging.

By eliciting lung necrosis, which enhances aerosol transmission, Mycobacterium tuberculosis (Mtb) sustains its long-term survival as a human pathogen. In studying the human-like necrotic granuloma lesions characteristic of Mtb-infected B6.Sst1S mice, we found that lung myeloid cells display elevated senescence markers: cell cycle arrest proteins p21 and p16, the DNA damage marker γH2A.X, senescence-associated β-galactosidase activity, and senescence-associated secretory phenotype (SASP). These markers were also elevated in Mtb-infected aged wild type (WT) mice but not in young WT mice. Global transcriptomics data revealed upregulation of pro-survival (PI3K, MAPK) and anti-apoptotic pathways in Mtb-infected B6.Sst1S macrophages. As senescent cells are terminally growth-arrested yet metabolically active cells that release tissue-damaging, immunosuppressive SASP, we treated Mtb-infected mice with a cocktail of three senolytic drugs (dasatinib, quercetin, and fisetin) designed to kill senescent cells. Adjunctive senolytic drug treatment in presence of anti-tuberculosis (TB) therapy prolonged survival and reduced Mtb lung counts in B6.Sst1S and aged WT mice to a greater degree than young WT mice and concomitantly reduced lung pathology and senescence markers. These findings indicate that (1) Mtb infection induce lung myeloid cells to enter a senescent state and that these cells may promote disease progression, and (2) senolytic drugs merit consideration for human clinical trials against TB.

Ferroptosis, an iron‑dependent form of regulated cell death driven by lipid peroxidation, has emerged as a key mechanism underlying tissue degeneration and impaired regeneration in musculoskeletal disorders. Although ferroptosis is associated with conditions such as tendinopathy, sarcopenia, osteoarthritis and osteoporosis, systematic synthesis connecting molecular mechanisms with disease‑specific contexts and translational implications remains limited. The present review summarizes the fundamental molecular mechanisms of ferroptosis, including iron metabolism dysregulation, lipid peroxidation processes and antioxidant defense systems centered on GPX4 and glutathione. Subsequently, the involvement of ferroptosis across major musculoskeletal diseases was investigated, highlighting how iron imbalance, oxidative stress and age‑related alterations collectively contribute to tissue dysfunction and degeneration. Particular emphasis is placed on aging‑associated changes in iron homeostasis and antioxidant capacity as potential amplifiers of ferroptotic vulnerability in musculoskeletal tissues. Experimental modeling strategies and pharmacological modulation approaches used to investigate ferroptosis in musculoskeletal research are further discussed and their mechanistic relevance and translational challenges are analyzed. Finally, the present review outlines emerging therapeutic perspectives and future research directions aimed at improving the understanding and potential clinical targeting of ferroptosis in musculoskeletal disorders. By providing a structured and integrative synthesis, the present review clarifies the role of ferroptosis at the intersection of iron dysregulation, redox imbalance and musculoskeletal decline.

Aging-related cognitive disorders have been increasingly linked to maladaptive stress pathways that persistently impair synaptic protein synthesis and plasticity. The integrated stress response (ISR) links various stressors to downstream translational reprogramming through the phosphorylation of eIF2α. Acute ISR activation can be protective, while chronic ISR activation may confine neurons and glial cells to hypo-plastic states, impairing learning and memory function. ISRIB is a prototype small molecule that activates eIF2B and restores translation homeostasis, providing a viable framework for "tuning" ISR output rather than indiscriminately blocking stress signaling. This review summarizes ISR biology in the aging brain, emphasizes cell-type heterogeneity, and evaluates the evidence for ISRIB across various conditions, including normal aging, Alzheimer's disease, vascular cognitive impairment, synucleinopathies, perioperative neurocognitive disorders, and related conditions with shared ISR pathology. We then discuss dosing, safety, optimization, limitations, translational biomarkers, and lessons from emerging clinical-stage eIF2B activators. Finally, we propose precision and combination strategies to tailor ISR modulation to disease stage, pathological context, and therapeutic window, aiming to provide new directions and a theoretical basis for the treatment of aging-related cognitive disorders.

Brain age models - machine-learning predictions of chronological age from brain imaging - are widely interpreted as markers of accelerated brain aging. Here we show that this interpretation cannot be supported. Because these models are trained to predict chronological age, they prioritize features that change similarly across people and actively downweight features that capture differences in individual trajectories, precisely the property an aging-rate biomarker must have. In effect, brain age models are optimized to ignore the very signal they are used to study, thereby risking converting stable between-person differences into apparent accelerated aging. Using theoretical analysis, simulations, and longitudinal MRI, we confirm both predicted failure modes: brain age models indicated "accelerated aging" in participants with low birth weight despite no longitudinal evidence, while a single hippocampal volume measurement was more sensitive than the brain age gap to tau-related neurodegeneration. Across much of the brain age literature, it is therefore not possible to determine whether reported effects reflect brain aging or stable anatomical differences, and the brain age gap should not be interpreted as a marker of brain aging or brain health. We propose alternative strategies that reorient prediction targets from shared age-related patterns to individual differences in change.

The growing population of postmenopausal women in an aging society has led to a heightened incidence of lumbar degenerative diseases (LDD). The degeneration of the vertebral endplate cartilage is considered the initial factor in LDD, but the effect of estrogen deficiency on this process remains unclear. Here we demonstrate that estrogen deficiency triggers senescence in vertebral bone marrow mesenchymal stem cells and leads to the release of extracellular vesicles (EVs), which further accelerate the senescence of endplate chondrocytes (EPCs). Mitochondrial ribosomal proteins translate key respiratory chain components and are negatively correlated with lifespan, as their downregulation extends lifespan across species. MRPL1, a mitochondrial ribosomal large subunit gene, is upregulated in EV mRNA cargo under estrogen deficiency. These EVs facilitate the delivery of MRPL1 mRNA into EPCs, enhancing MRPL1 protein translation, which in turn induces cellular senescence and supernormal mitochondrial protein turnover. MRPL1 overexpression also impairs ATP synthase activity by interacting with its catalytic subunit ATP5B, leading to senescence-related mitochondrial dysfunction in EPCs. Doxycycline administration suppresses MRPL1 expression and mitochondrial translation in EPCs, and markedly alleviates endplate degeneration associated with estrogen deficiency in a rat model, thereby introducing a novel therapeutic strategy for the management of LDD.

The cardiovascular-kidney-metabolic (CKM) syndrome is a major public health challenge driven by intertwined cardiometabolic and renal dysfunction. Diet-related inflammation and oxidative stress may accelerate biological aging, as reflected by DNA methylation age acceleration, thereby contributing to CKM progression and mortality. However, these pathways have not been comprehensively examined.

Aging is accompanied by a chronic low-grade inflammatory process, known as inflammaging, as well as immunosenescence, an age-related decline and dysregulation of immune function, and cellular senescence, a process in which cells enter a state of irreversible growth arrest while actively releasing pro-inflammatory factors. These processes alter the host immune regulation and tissue homeostasis. Aging-associated mechanisms are being explored for their role in periodontal and peri-implant diseases because of their promotion of dysregulated inflammation, impaired healing, and heightened susceptibility to tissue destruction. Rather than viewing periodontitis as a condition driven solely by microbial burden, it should be understood as a multifactorial disease shaped by complex host-microbe interactions, in which host-driven processes, particularly senescence and inflammaging, play a central role in amplifying bidirectional oral-systemic interactions.

Chronic sympathetic nerve activity (SNA) to end organs plays a crucial role in the pathophysiology of obesity-induced hypertension. Oxidative stress and neuroinflammation in the rostral ventrolateral medulla (RVLM), a key brainstem region regulating sympathetic outflow, have been implicated in the sympathetic overactivity in obesity. However, the upstream mechanisms driving RVLM neuroinflammation remain unknown. We hypothesized that obesity induces cellular senescence, a stress response characterized by irreversible cell cycle arrest, in the RVLM and contributes to sympathoexcitation. To test this, C57BL/6 J male mice were fed chow or a high-fat diet (HFD) for 16 weeks, followed by treatment with Dasatinib (5 mg/kg) and Quercetin (50 mg/kg) (D + Q) to selectively eliminate senescent cells. Blood pressure was assessed by radiotelemetry in conscious, freely moving mice. SNA was indirectly measured through heart rate variability (HRV) analysis, depressor response to hexamethonium, and serum norepinephrine levels. The RVLM was microdissected for gene expression and protein analysis of senescence markers and DNA damage. Our results showed that HFD mice had a significant increase in mean arterial pressure and SNA compared to chow-fed controls. Obesity was associated with increased DNA damage and upregulation of cellular senescence markers in the RVLM. Senolytic treatment with D + Q selectively improved cardiac autonomic balance as assessed by HRV, without altering indices of global SNA or blood pressure. Collectively, our findings identify cellular senescence in the RVLM as a novel contributor to obesity-induced sympathoexcitation, and senolytic therapy could be a potential therapeutic avenue for obesity-associated autonomic dysfunction.

Tissue repair is often hampered during aging. Worldwide, chronic wounds in elderly present a major challenge to the medical and socioeconomic infrastructure of societies. A comprehensive understanding of how the aging innate immune system impacts wound homeostasis is lacking. Here we employed the approach of immune modulation to restore disrupted wound repair in aged mice skin. We found that a short pulse of bacterial lipopolysaccharide (LPS) before wounding markedly accelerate tissue repair in aged mice, which - if non-primed - exhibit a defective epidermal wound closure. LPS priming induces rapid sealing of wounds, immune cell activity, keratinocyte responsiveness and their differentiation towards a newly reconstituted wound epithelium. Structural elements such as NETs composed of DNA and membrane protrusions derived from LPS-activated neutrophils and macrophages, respectively, reinforce physical skin barrier in aged wounds. The physical barrier established by LPS-primed innate immune cells subsequently facilitates epithelial tongue migration and adhesion of ECM-producing mesenchymal cells. Collectively, this not only prevents the invasion of pathogens into the restoring skin tissue after injury, but also averts the persistence of low-grade inflammation associated with aged wounds. These findings underscore the benefit of immune cell priming in promoting cellular interactions between innate immune cells and epithelial cells that consequently restores physical skin barrier and promote tissue repair.

Cellular senescence arises through replicative exhaustion or acute stress, yet whether these distinct triggers share a reproducible transcriptional organization has remained unresolved. Seven public human fibroblast RNA-seq datasets were integrated across both trigger types, moving from differential expression through Gene Ontology and Reactome enrichment to protein-protein interaction network embedding within a single harmonized framework. Both triggers converged on concordant repression of replication and chromatin programs alongside induction of inflammatory and extracellular matrix outputs. Cross-trigger combination identified 263 commonly repressed and 112 commonly induced GO terms, with consistently higher enrichment scores in the repressed set, and 145 versus 13 shared Reactome pathways. Conserved induction of calcium ion homeostasis and membrane potential regulation, and conserved repression of RHO GTPase-Formin signaling, extended the shared program beyond canonical SASP biology into dimensions not previously described in human fibroblasts. Interactome embedding, applied here for the first time in a cross-trigger senescence framework, identified ten genes occupying both induced and repressed neighborhoods simultaneously, a structural layer invisible to enrichment analysis alone. ELAVL1 coordinates SASP output and growth arrest post-transcriptionally, while suppressed PARP1 alongside active ATM defines a self-reinforcing damage configuration. These results provide a quantitative cross-study reference and a structured basis for senotherapeutic candidate prioritization.

With aging, somatic mutations in hematopoietic stem and progenitor cells (HSPC) can give rise to clonal hematopoiesis of indeterminate potential (CHIP), a premalignant state associated with diverse age-related diseases. Here we report the largest multi-ancestry genome-wide analysis of CHIP to date (N = 1,018,305), including individuals of African (N = 85,978), Admixed American (N = 191,371), East Asian (N = 13,532), European (N = 694,015), and South Asian (N = 13,193) ancestry. Multi-ancestry meta-analyses identified 72 genome-wide significant loci, including 44 novel associations implicating genes such as AFF1, ATF7IP, ATP8B4, BCL2, CEBPA, CYRIA, DNM2, ELF1, NKX2-3, PIK3CB, PRDM16, RPN1, TERC, and TRIM4. Notably, variants at MECOM and PHF20L1 showed opposite allelic effects between DNMT3A- and non-DNMT3A-driven CHIP, highlighting driver-specific germline influences. Implicated loci converge on pathways regulating telomere maintenance, cell-cycle control, hematopoietic transcription, DNA damage response and immune signaling. These findings support a model in which germline variation both expands the HSPC pool and biases clonal selection in a driver-dependent manner, providing a mechanistic basis for inter-individual heterogeneity in CHIP. Phenome-wide association analyses further linked CHIP to hematologic, neoplastic, and circulatory traits, with enrichment across hematopoietic and non-hematopoietic cell types. Together, this work expands the genomic and phenomic landscape of CHIP and reveals germline-somatic interactions that shape clonal evolution during aging.

Caspases are well recognized and studied as the central executioners of apoptosis, while recent studies have unraveled their diverse roles beyond cell apoptotic function.One emerging area of interest is non-apoptotic caspase activity as a potential regulator in lipid metabolism. This review explores the differential non-apoptotic role of caspases in lipid metabolic process, encompassing the influence of caspases on lipid reprogramming, lipid synthesis, degradation, transport, and signaling. We discuss the mechanisms underlying these interactions, their relevance to physiological processes, and their implications for various diseases. This reveals a hidden layer of regulation where the machinery of cell death is repurposed to control the fundamental processes of fat handling in living animal. Dysregulation of this system forms a vicious cycle that propagates cellular dysfunction, directly contributing to the pathogenesis of major human diseases in aging, including redox stress, NASH, type 2 diabetes, neurodegenerative disorders, and cancer. Consequently, the caspase-metabolism axis emerges as a compelling therapeutic frontier. However, the clinical translation of caspase modulators is challenged by the context-dependent duality of caspase functions.Future therapeutic strategies must therefore advance beyond pan-inhibition toward the precise, context-specific modulation of discrete caspase-mediated metabolic events to halt disease progression effectively.

Despite the fact that a third of stroke patients are over the age of 80, specialized stroke management in the elderly is in its infancy. The signature poor blood flow in the aged brain has been shown to synchronize with impaired neurovascular coupling and inflammation in the course of acute occlusive stroke. The striking pre-clinical findings indicate endothelial energy failure precedes cerebrovascular aging and may bridge the aging phenotype of cerebral blood flow to cerebrovascular dysfunction in the elderly. As the gatekeeper for energy supply and shuttling to different brain resident cells, the endothelial energy machinery affects a wide range of cerebral activities. The review focuses on the existing evidence linking endothelial energy failure with the detrimental events in the acute phase of ischemic stroke, including collateral failure, excitotoxicity, and fluid retention. This simplified picture aims to highlight the knowledge gaps and potential targets to correct the bioenergetic imbalance in the elderly stroke. The recent clinical studies demonstrating promising effects of mitotherapy in old stroke patients further signify the correction of energy machinery cerebral vessels, encouraging meticulous characterization of the old endothelium and bioengineering approaches for specialized drug delivery.

The aging process exhibits tissue-specific characteristics, yet its underlying mechanisms remain poorly understood. While it is widely accepted that a reduction in blood vessels in hard tissues contributes to aging, such as in osteoporosis, the vascular changes driving soft tissue aging and degeneration remain unclear. Here, by integrating single-cell transcriptomics and light-sheet imaging, we uncover a striking infiltration of type H-like blood vessels and an aging-specific Coch

As populations age, extending healthspan, or years lived in good health, is a global priority. Most evidence on healthy lifestyle and prolonged healthspan comes from middle-aged or comorbid populations, leaving it unclear whether benefits apply to healthy older adults. This study evaluates whether combined lifestyle behaviors are associated with disability-free survival in community-dwelling older adults.

Home-based physical exercise is an accessible strategy to help maintain physical functioning in adults over 50, but mobility gains may be limited without direct supervision. By improving cognitive processes involved in motor control, cognitive training may help enhance the effectiveness of home-based physical exercise in preventing age-related decline in mobility. This study compares the effects of a six-month home-based physical exercise, with or without cognitive training, on gait speed and balance.

Allostatic load refers to the physiological "wear and tear" that results from adaptation to stressors over the lifespan. In this study, we integrated lung function (LF) parameters into the calculation of the allostatic load score (ALS) to evaluate changes in its performance for predicting all-cause mortality. Data from 8,775 participants (aged 25-82 years; 52% female) who participated in the first wave of the Austrian LEAD cohort were used. "ALS without LF" was calculated using 12 parameters, including cardiovascular, metabolic, body composition, and bone mineral density measures. Z-scores of forced expiratory volume in 1 s (FEV

Mind-body exercises (MBEs), such as Tai Chi and yoga, have demonstrated beneficial effects on cognitive function and stress resilience across various populations. However, the biological mechanisms underlying these effects are not yet fully understood. Recent studies suggest that MBEs may influence neurobiological systems through epigenetic regulation, including DNA methylation, histone modifications, and non-coding RNAs. This review critically evaluates the current empirical evidence linking MBEs to epigenetic changes and explores their potential downstream effects on neural circuitry and cognitive outcomes. Special attention is given to biomarkers such as brain-derived neurotrophic factor (BDNF), glucocorticoid receptor (NR3C1), and FKBP5, which are involved in stress regulation and neuroplasticity. While preliminary findings are promising, most studies to date are cross-sectional, involve small sample sizes, or lack mechanistic validation. We propose a conceptual epigenetic-neural circuit model to guide future research into how MBEs may induce lasting neurobiological adaptations. Clarifying these mechanisms is crucial for the development of targeted, evidence-based interventions to support healthy cognitive aging and stress regulation.

This study aimed to investigate the effects of Opuntia ficus-indica flour (OFIF) consumption on fecal microbiota composition, cognitive function, and brain oxidative stress in RI elderly male rats. Animals were randomized into five groups: Adult Control (ACG) and Elderly Control (ECG), fed the AIN-93 M diet without OFIF; and three treated groups (OF5, OF10, OF15) receiving diets supplemented with 5%, 10%, or 15% OFIF, respectively. Memory performance was assessed using non-associative learning and novel object recognition tests, with recognition (DI) and discrimination (RI) indices. Brain fatty acid profile, protein carbonyls, and glutathione levels were measured, and fecal microbiota was analyzed by 16 S rRNA amplicon sequencing. The experimental groups showed reduced locomotion and number of crossings during the second exposure to the open field test. OF15 rats spent more time in the inner zone and achieved higher DI and RI scores in both short- and long-term evaluations. Regarding oxidative stress, OF15 exhibited elevated glutathione levels, while OF5 showed reduced protein carbonyls. Treated groups displayed increased brain concentrations of oleic, eicosenoic, arachidonic, and docosahexaenoic acids. Moreover, OF15 restored intestinal microbial diversity, evidenced by higher richness indices (Chao1 and Fisher) and enrichment of short-chain fatty acid-producing genera, including Faecalibaculum, Dorea, Prevotella, and Lachnospiraceae NK4A136. In conclusion, OFIF supplementation, particularly at 15%, modulated gut microbiota, improved memory performance, and enhanced antioxidant defenses in aged rats. These results highlight OFIF as a promising dietary strategy to modulate the gut-brain axis, supporting memory preservation, oxidative balance, and intestinal health during aging.

Risk assessment in clinical practice depends largely on clinical phenotypes, including age, sex, body mass index, blood pressure and comorbidities. Routine laboratory data remain underutilised despite their accessibility and low cost. Using data from the Singapore Longitudinal Ageing Studies (n = 5,409; follow-up median 11.4 years), we developed a mortality prediction model based on routine laboratory biomarkers. We derived a biological age (age quotient, or AQ) score, and investigated its role as a mediator between lifestyle risk factors and mortality. Both models and association analyses were validated in the US National Health and Nutrition Examination Survey (n = 6,593) and UK Biobank (n = 290,949) cohorts. AQ was significantly elevated in deceased individuals (P<0.0001). AQ acceleration was also observed (P<0.0001). In overall survival discrimination, AQ outperformed chronological age (C-index 0.629 [SE 0.011] vs 0.606 [SE 0.011]), indicating superior prognostic prediction. Additionally, incorporation of AQ into a baseline model containing chronological age resulted in an improvement in model fit (likelihood ratio test, P<0.0001), consistent with incremental predictive value for mortality beyond chronological age alone. Mediation analysis supports a partial mediating role for AQ in the relationship between lifestyle factors and mortality. In a 57-patient subset, higher AQ was associated with increased TET2 clonal hematopoiesis burden ({beta}{approx}0.016 per +1 AQ year), suggesting a potential link between AQ acceleration, CH risk and diseases of aging, requiring validation in larger cohorts. We identified differential associations between lifestyle factors and groups of biological age components, indicating selective effects across biological systems. These findings provide an evidence-based framework for earlier and more accurate identification of high-risk individuals, offering a practical and easy-to-implement tool to inform preventive strategies.

Because male physiology was historically viewed as the "norm" and data on females were considered difficult to interpret, little information regarding the effects of regular exercise on women's health over the lifespan was available leading into the 1990s. In 1993, we initiated research at the University of Colorado Boulder to determine the effects of endurance exercise training on healthy cardiovascular aging in women. To do so, we used a "masters athlete model" in which midlife and older female distance runners were compared with their healthy, but non-exercising peers, as well as young adult women. The masters runners (~50-70 years, mostly postmenopausal) had a maximal oxygen consumption (V̇O

Cellular senescence is a multifaceted stress response marked by stable proliferative arrest and the secretion of diverse biologically active factors, collectively known as the senescence-associated secretory phenotype (SASP). The senescent phenotype is remarkably variable and subject to various regulatory influences. We previously demonstrated that mitochondrial dysfunction induced by diverse stimuli, including the loss of sirtuin 3 (SIRT3), leads to the hyperactivation of AMPK and p53, culminating in senescence while concurrently suppressing much of the proinflammatory SASP. Here, we extend our findings by revealing that the absence of SIRT3 can suppress segments of the SASP even in the absence of p53. Intriguingly, SIRT3 deficiency renders cells resistant to stimulation by exogenous cytokines, such as interleukin-1. Fibroblasts derived from Sirt3 knockout mice exhibit a diminished SASP, including reduced levels of Pdgfa, and these mice display impaired wound healing and a more expansive granulation area. Furthermore, aged Sirt3 knockout mice show disrupted patterns of senescence relative to wild type controls, including increases in senescence markers in adipose tissue, but surprisingly also decreases in liver and heart. Collectively, these data underscore a role for SIRT3 in orchestrating cellular senescence phenotypes, shedding light on its regulatory influence beyond the p53-dependent pathway.

Autophagy is a core cellular mechanism that preserves tissue homeostasis by removing damaged proteins and organelles. In skeletal muscle, proper regulation of autophagic flux is essential for maintaining metabolic and structural integrity, whereas its disruption contributes to muscle atrophy, metabolic dysfunction, and age-related functional decline. Increasing evidence identifies polyamines, particularly spermidine (Spd), as important modulators of autophagy and cellular resilience, with beneficial effects on stress responses, metabolic regulation, and lifespan extension. Physical exercise likewise acts as a physiological inducer of autophagy, promoting muscle remodelling, mitochondrial quality control, and adaptive responses to stress. Within this framework, spermine oxidase (SMOX) has emerged as a relevant regulator of muscle homeostasis. SMOX expression is maintained in healthy muscle but declines in atrophic conditions. By converting spermine into spermidine, SMOX may help sustain autophagy-related pathways and support muscle mass under physiological conditions. This review explores the interplay between exercise, spermidine, and SMOX, highlighting autophagy as a unifying regulatory axis. We summarize current evidence on their individual and combined roles in preserving muscle function and discuss their potential relevance for promoting healthy muscle aging and counteracting sarcopenia.

Transposable elements (TEs) constitute nearly half of the human genome and profoundly influence hematopoietic stem cell (HSC) biology. In this review, we synthesize current evidence demonstrating that TEs exert dual and context-dependent roles in HSCs during steady-state hematopoiesis, stress responses, aging, and leukemogenesis. Under basal conditions, tightly controlled TE activity can be beneficial for HSC biology, through the induction of intrinsic type I interferon signaling and a fine-tuned control of gene expression. However, dysregulated TE activation upon stresses and aging can undermine HSC self-renewal, impair genomic integrity, and drive age-associated hematopoietic decline. TEs also play a dual role in leukemogenesis. Derepression of transcription factor motifs within TEs can activate oncogenic programs, while TE-derived nucleic acids can simultaneously elicit antiviral and DNA damage responses that trigger anti-tumoral p53- or interferon-dependent growth arrest or apoptosis. The balance between these pro- and anti-tumoral effects remains an open question, likely shaped by cellular context, TE subtypes, and the magnitude of TE expression. Finally, we discuss the potential to therapeutically modulate TE activity. Understanding TE dynamics in HSCs offers new opportunities for mechanistic insight and clinical innovation in myeloid malignancies.

Women's cardiovascular disease risk increases during midlife, in part, due to accelerated vascular dysfunction. Age-related vascular dysfunction includes increases in large artery stiffness, which may be mitigated by maintaining muscular strength. However, the relationship between handgrip strength and large artery stiffness through the lifespan in women is unknown.

Identifying factors associated with survival beyond age 90 is essential for understanding healthy aging trajectories. This study sought to investigate the associations between biological, socioeconomic, and lifestyle factors and survival in individuals aged ≥90 years.

Muscle atrophy, which is characterized by the loss and dysfunction of skeletal muscle proteins, is a major degenerative condition that is associated with aging and glucocorticoid therapy. Marine-derived compounds, particularly polyphenols, have recently potential in modulating muscle metabolism and regeneration. This study aimed to investigate the effects of the ethanolic extract from Padina arborescens (PAE) on myogenic differentiation and dexamethasone (DEXA)-induced muscle atrophy using C2C12 myotubes and a zebrafish model. PAE treatment significantly promoted myotube differentiation by modulating the Akt/mTOR signaling pathway and enhancing the expression level of myogenic regulatory factors (MyoD and myogenin). In DEXA-treated myotubes, PAE effectively suppressed the ubiquitin proteasome system, restored myosin heavy chain protein synthesis, and recovered myotube morphology. In vivo, PAE supplementation ameliorated the DEXA-induced locomotor dysfunction in zebrafish without causing developmental or neurotoxic abnormalities, as confirmed by the normal survival rate, body length, and heart rate. Collectively, these findings indicated that polyphenol-rich PAE exerts protective and anabolic effects by promoting myogenesis and preventing glucocorticoid-induced muscle degradation. Therefore, PAE may be used as a promising marine-derived therapeutic agent for maintaining skeletal muscle health and preventing muscle atrophy.

A 91-year-old female set the W90+ world record in the 200m sprint in 2024. We characterized her neuromuscular function, fatigability, denervation markers, and single-fiber contractile properties, and, where possible, compared these outcomes to published reference data. Knee extensor muscle architecture, force, power, fatigability, and motor unit (MU) behavior were assessed

Collagen, a central component of the extracellular matrix (ECM), precisely regulates tissue mechanical properties and biological functions through hierarchical assembly, playing a vital role in maintaining homeostasis. However, the molecular mechanism of assembly remains poorly understood, limiting insights into tissue remodeling, aging, and ECM-related diseases. Here, we employ time-resolved cryo-electron microscopy to resolve two critical hierarchical intermediates in fibrillar collagen assembly, proposing the 3D collagen assembly pathway. We identify a metastable triple-helical conformation as the fundamental assembly unit, whose structural lability propagates through the assembly cascade, rendering the process sensitive to microenvironmental perturbations. Through hierarchical assembly, metastable intermediates achieve enhanced structural stability, culminating in the formation of stable collagen that retains its integrity under physiological conditions. In contrast, structural defects in intermediates lead to aberrant assembly and disruption of ECM integrity. Functional assays reveal that intermediates lacking D-band retain biological activity. Our findings redefine the fibrillar collagen assembly as a hierarchical, time-resolved cascade driven by metastable intermediates and propose the fundamental F-Z-F rules. The metastable triple helix provides a structural basis for hierarchical assembly and suggests a potential link between abnormal fibrillar collagen assembly and aging-related matrix dysfunction, offering valuable insights into collagen assembly and its role in aging diseases.

Photobiomodulation (PBM) is a non-invasive strategy to enhance cognitive function, yet the effects of stimulation frequency remain unclear. We applied pulsed 810 nm PBM at 5 Hz or 40 Hz to the frontal cortex of adult rats, and 40 Hz PBM to aged rats. In young adults, both stimulation frequencies enhanced cognitive flexibility, and in aged rats 40 Hz PBM improved learning speed. In terms of brain changes, we studied cytochrome c oxidase (CCO) activity, c-Fos expression and protein levels. We observed a decrease in the prefrontal CCO activity in adults, and an increase in prefrontal c-Fos expression, both with 40 Hz. Regarding protein levels in young rats, 5 Hz PBM reduced pERK expression in the hippocampus and p38 in the prefrontal cortex, while regulating interleukins and cytokines in these regions. Additionally, 5 Hz upregulated Synapsin-I expression in both the prefrontal cortex and hippocampus, and increased PSD-95 levels selectively in the hippocampus, highlighting its role in synaptic plasticity and memory consolidation. Notably, 5 Hz also increased GFAP expression in both regions, and selectively upregulated NF-κB expression. 40 Hz PBM reduced pERK expression in the hippocampus and p38 in the prefrontal cortex, also modulating interleukins and cytokines in these areas. Additionally, 40 Hz increased p38 expression in the hippocampus and reduced p53 and BAX levels in the prefrontal cortex. Also, 40 Hz upregulated Synapsin-I in both regions and increased PSD-95 expression in both the prefrontal cortex and hippocampus. As observed with 5 Hz, 40 Hz also elevated GFAP expression in both regions. In aged rats, PBM reduced Iba-1 in prefrontal cortex and hippocampus, enhanced NeuN in prefrontal cortex, and decreased p38 and BCL-2 in the hippocampus. Collectively, these results demonstrate frequency-dependent modulation of neuroinflammation, synaptic plasticity, and apoptosis, while highlighting the beneficial effects of 40 Hz PBM in aged subjects, supporting PBM as a targeted approach to improve cognitive function across the lifespan.

Methionine restriction has emerged as a promising strategy for extending lifespan and enhancing cancer therapy. LAT4, an amino acid transporter encoded by SLC43A2, is frequently overexpressed in multiple cancers and critically contributes to systemic methionine accumulation. However, the structural basis of LAT4 function remains poorly understood, and no effective inhibitors have been developed to date. In this study, we present high-resolution cryo-electron microscopy structures of LAT4 and the related SLC43A3-encoded purine transporter ENBT1. The phenylalanine-bound structure of LAT4 enables the characterization of the substrate binding pocket. Comparison of the outward-facing ENBT1 and inward-facing LAT4 structures identifies key residues involved in the methionine transport process. Structural analysis of digitonin binding to the central cavity of LAT4 enabled identification of tubeimoside-1 (TBM-1) as a potent inhibitor of LAT4-mediated methionine uptake. We demonstrate that tubeimoside-1 reduces methionine uptake in B16F10 cancer cells. Furthermore, TBM-1 suppresses tumor progression in the MMTV-PyVT mouse model of breast cancer through systemic methionine restriction. Our study provides insights into the LAT4 transport mechanism and identifies tubeimoside-1 as a potent inhibitor of methionine uptake and establishes a foundation for developing LAT4-targeting therapeutics to restrict methionine uptake.

Aging is a complex biological process characterized by progressive functional decline across tissues and increased susceptibility to age-related diseases, with oxidative stress being a key contributing factor. Glycine-Histidine-Lysine (GHK), a naturally occurring tripeptide present in human plasma and urine, possesses potent antioxidant properties; however, its broader anti-aging potential remains inadequately explored. In this study, we employed the model organism Caenorhabditis elegans to systematically investigate the anti-aging effects of GHK-Cu (GHK complexed with copper) and elucidate its underlying molecular mechanisms. Our results demonstrated that GHK-Cu significantly extended lifespan of C. elegans and ameliorated mutiple aging-related phenotypes, including enhanced resistance to oxidative and thermal stress, improved motility, pharyngeal pumping, defecation rhythm, and reduced lipofuscin/lipid accumulation. Mechanistically, GHK-Cu preserved mitochondrial function by increasing mitochondrial membrane potential, alleviating age-related mitochondrial network fragmentation, shifting mitochondrial dynamics toward fusion via regulating drp-1 and fzo-1 expression, and promoting ATP biosynthesis. Meanwhile, GHK-Cu activating DAF-16 and SKN-1 pathway, and upregulating sod-3, gst-4, gcs-1, lys-7 and lys-8. This study provides the first mechanistic evidence that GHK-Cu delays aging through coordinated regulation of mitochondrial function and activation of both DAF-16 and SKN-1 pathways. Our findings identify novel molecular targets for developing anti-aging interventions and underscore the potential of GHK-Cu's as a multifaceted geroprotective compound.

Taste receptors are expressed in the oral cavity and numerous extra-oral tissues, where they share signaling mechanisms. Within this broad context, taste receptors regulate feeding behavior and metabolic homeostasis, potentially contributing to exceptional longevity. We evaluated differences in genotype and allele frequencies at the TAS1R2, TAS1R3, TAS2R38, and CD36 single-nucleotide polymorphisms (SNPs) and their associations with BMI and sex in two genetically and environmentally distinct populations: a cohort of near centenarian participants (LBZ) and a control cohort (CYME). Significant differences were observed in the genotype and allele distributions of the TAS1R3, TAS2R38, and CD36 SNPs. In the LBZ cohort, specific genotypes, such as TAS1R3 CC, TAS2R38 PAV/PAV, and CD36 AA, were most frequent, and likely contributed to favorable phenotypes, whereas they showed no effect in the more heterogeneous urban CYME population. The BMI was significantly higher in the LBZ cohort, particularly among females. The TAS1R2, TAS1R3, TAS2R38, and CD36 variants modulated BMI in a population- and sex-dependent manner. These results contribute to expanding the understanding of taste receptors as multifunctional chemosensors, with roles that extend beyond gustatory perception to influence systemic physiology, energy balance, and potentially contribute to phenotypic profiles associated with longevity.

Super Normal Vascular Aging (SUPERNOVA) describes individuals whose vascular system remains protected, despite exposure to cardiovascular risk factors. Understanding the determinants of arterial stiffness in this population may provide valuable insights into protection mechanisms.

The global aging population has led to age-related digestive dysfunction, which has become a key driver of malnutrition and declining health. Physiological degeneration in older adults severely reduces nutrient bioavailability, making conventional single nutrient supplementation ineffective. Nutrient delivery systems tailored to the physiological constraints of the elderly show great value in alleviating geriatric malnutrition. Micro/nanoencapsulation, emulsions, and gels are particularly promising platforms for elderly-targeted food innovation due to their tunable structure, controlled targeted release, and good biocompatibility. Moreover, combining delivery systems with 3D printing for personalized nutrition and dysphagia-friendly texture design has emerged as an important trend in age-appropriate food development. This review outlines the digestive physiological constraints of the elderly and the design principles of nutrient delivery systems, highlights the adaptive optimization and recent applications of major delivery technologies in geriatric foods, and discusses intervention strategies, current challenges, and future directions. It aims to provide theoretical support for the research and innovation of functional foods tailored for older adults.

Aging, stress-related disorders, and chronic disease are often examined across separate domains-stress physiology, nutrition, psychiatry, and geroscience-despite converging on shared phenotypes of functional decline and reduced resilience. Although adaptive responses to stress are well characterized, why comparable exposures yield sustained resilience in some individuals but progressive dysfunction in others remains insufficiently explained. We propose that the missing unifying constraint is not stress exposure itself, but the bioenergetic capacity to complete recovery. We reframe stress adaptation as a cyclical process comprising response, adaptation, and recovery, emphasizing that recovery is an active, ATP-dependent phase conditionally funded within a finite bioenergetic system. When mitochondrial processing capacity and redox flexibility are constrained, adaptive programs may persist beyond their functional window, contributing to mitochondrial congestion, epigenetic gridlock, and progressive loss of physiological plasticity-even in the absence of overt pathology. Within this perspective, we introduce Exposure-Related Malnutrition (ERM) as a proposed conceptual model describing a clinically interpretable and potentially reversible phenotype of unresolved bioenergetic triage. ERM is proposed to describe a state of relative undernutrition arising from chronic mismatch between energetic demand and recovery capacity, often occurring despite nominal intake and laboratory values within reference ranges. Distinct from frailty, sarcopenia, cachexia, metabolic syndrome, and classical malnutrition, ERM may reflect an upstream constraint in ATP-dependent recovery rather than structural loss, inflammatory wasting, metabolic thresholds, or inadequate intake. By integrating evolutionary allocation theory, developmental calibration, stress physiology, and mitochondrial mechanics, ERM is proposed to offer a unifying integrative framework for functional decline across aging and chronic disease. Clinically, this perspective shifts risk assessment from isolated thresholds toward coordinated biomarker patterns, trajectories, and recovery kinetics, potentially enabling recognition of vulnerability before incomplete resolution consolidates into irreversible pathology. We further outline translational implications of a recovery-centered approach, positioning mitochondrial processing capacity and intercellular bioenergetic support as modifiable determinants of long-term resilience.

The global demographic shift toward aging has precipitated a surge in age-related ocular pathologies, imposing a formidable public health challenge that demands urgent intervention. Blinding disorders such as age-related macular degeneration (AMD), cataracts, and dry eye disease exemplify this crisis, with their pathogenesis being intrinsically linked to tissue-specific aging processes in the eye. At the molecular level, core pathways including telomere attrition, oxidative stress, cellular senescence, and autophagic dysregulation orchestrate this degenerative cascade. This review systematically delineates the dynamic interplay network of these pathways during ocular aging, with particular emphasis on four pivotal mechanisms: oxidative stress-driven reactive oxygen species (ROS) accumulation, senescence-associated secretory phenotype (SASP)-mediated inflammatory cascades, autophagic flux dysfunction, and epigenetic remodeling aberrations. We further evaluate recent advancements in translational therapies, emphasizing the clinical potential of targeted gene-editing technologies, stem cell-derived regenerative approaches, and novel senolytic agents. Additionally, artificial intelligence (AI) -assisted diagnostics are explored as pivotal tools for precision medicine, particularly in early disease detection via retinal imaging and biomarker analysis. Future research priorities should focus on the integration of aging-specific biomarkers including methylation signatures, the advancement of tissue-selective drug delivery systems tailored to anterior and posterior ocular compartments. Collectively, these initiatives will propel the development of targeted interventions to address age-related visual decline, positioning precision medicine as the cornerstone of next-generation geriatric ophthalmic care.

Ultraviolet (UV) radiation is a major factor contributing to skin aging. Ferroptosis, a recently identified form of regulated cell death, remains controversial in its role in mid‑wave ultraviolet (UVB)‑induced skin photoaging. Preliminary evidence suggests that Dual‑Specificity Phosphatase 1 (DUSP1) may be associated with both skin photoaging and ferroptosis. This study aims to investigate the role of ferroptosis and the regulatory mechanism of DUSP1 in a UVB‑induced stress‑induced premature senescence (UVB‑SIPS) model of human dermal fibroblasts (HDFs). Our findings demonstrate that ferroptosis occurs in HDFs following UVB irradiation. Treatment with a low concentration (0.5 µM) of the ferroptosis inhibitor ferrostatin‑1 (Fer‑1) alleviated UVB‑induced senescence, reduced intracellular reactive oxygen species (ROS) accumulation, and promoted the expression of type I and type III collagen. We also observed a decrease in DUSP1 protein expression in HDFs after UVB exposure. Furthermore, in vitro knockdown of DUSP1 exacerbated cellular senescence, impaired proliferative capacity, intensified cell‑cycle arrest, upregulated the expression of senescence‑associated proteins (p53, p21, p16), and reduced the production of type I and type III collagen. Subsequent experiments indicated that DUSP1 knockdown may promote ferroptosis by down‑regulating the SLC7A11/GPX4 axis, thereby accelerating UVB‑induced photoaging in HDFs. These results suggest that DUSP1 might serve as a novel therapeutic target for mitigating skin photoaging.

To investigate the underlying mechanism of immune cell crosstalk in periodontal inflammatory ageing and to explore potential pharmaceutical interventions for safely reversing this process.