Longevity Papers

Aging is associated with cognitive decline and increased vulnerability to neurodegeneration driven by an array of molecular and cellular changes like impaired vascular integrity, demyelination, reduced neurogenesis, and chronic inflammation. Recent studies implicate the gut microbiome as a modulator of brain aging, but the underlying mechanisms remain elusive. Here, we show that depleting the gut microbiome by administering antibiotics to aged mice induces widespread molecular and structural rejuvenation in the brain. Our transcriptomic analyses by single-nucleus RNA sequencing revealed pronounced transcriptional shifts across multiple brain cell types. We confirmed that antibiotic treatment improves vascular density, promotes myelination, enhances neurogenesis, and reduces microglial reactivity. Functionally, microbiome-depleted mice showed improved hippocampal memory performance. Analyses of brain and plasma cytokine levels showed a decrease in several pro-inflammatory factors post-treatment and identified candidate factors, including the chemokine eotaxin-1. Inhibiting eotaxin-1 alone can reverse several aspects of brain aging. Our findings demonstrate that age-associated microbial inflammation contributes to brain aging and that its attenuation can restore youthful features at the molecular, cellular, and functional levels. Targeting the gut microbiome or its circulating mediators may therefore represent a non-invasive approach to promote brain health and cognitive resilience in aging.

Adiponectin is an adipose tissue-derived peptide hormone that exerts beneficial metabolic effects in many tissues throughout the body. It is most well-known for its ability to enhance insulin sensitivity and dampen chronic inflammation. The impact of age on adiponectin is controversial; levels of adiponectin in circulation in older individuals have been linked to both positive and negative effects. This review integrates genetic, mechanistic, and therapeutic perspectives on adiponectin in aging. Specific considerations that might explain the "adiponectin paradox" are described and discussed. We present potential future applications of adiponectin-based strategies to prevent age-related metabolic dysfunctions and lower the risk for age-related chronic conditions.

The abundance, dynamics, and context-dependent heterogeneity of DNA methylation, where a pattern considered abnormal in one cell type may be normal in another, complicate the identification of early methylation changes that drive or signal disease development. This complexity can obscure early markers of increased disease risk, making it challenging to detect and intervene in disease processes at their inception. Here, we report 31,744 CpG loci exhibiting highly consistent methylation profiles in the blood of young, healthy individuals. We assess alterations at these epigenetically stable loci in 8,886 individuals across 29 diverse cohorts, including those with hematological cancers (n = 3159), cardiovascular complications (n = 2788), and healthy controls (n = 2939). Our findings reveal methylation pattern disruption in myeloid and lymphoid malignancies, correlating with clonal burden dynamics and mutation frequency throughout leukemia treatment. In non-cancer cohorts, we observe that methylation levels at epigenetically stable loci become increasingly variable with age, a shift linked to higher cardiovascular disease risk and lower survival rates. This study highlights DNA methylation instability as a blood-based biomarker for both hematological cancer and cardiovascular disease and uncovers a mechanistic link between methylation dynamics and the expansion of maladaptive hematopoietic clones.

Age-related osteoporosis is increasingly recognized as a disease of stem cell dysfunction, hallmarked by the skewed lineage commitment of mesenchymal stem cells (MSCs) away from osteogenesis towards adipogenesis. This functional decline is closely linked to mitochondrial dysregulation. However, the upstream metabolic regulators that orchestrate this detrimental cell-fate switch, particularly the key nodes at the interface of mitochondrial function and cellular senescence, remain largely unknown, hindering the development of targeted therapies. To address this challenge, we implemented a bioinformatic pipeline analyzing transcriptomes of rat MSCs from GEO. Methodology included transcriptomic profiling and MitoCarta3.0 intersection to identify mitochondria-associated aging genes. A multi-algorithm strategy screened hub genes. Sixteen mitochondria-associated genes were dysregulated in MSC aging. Machine learning consistently identified ribose-5-phosphate isomerase A (RPIA), a key enzyme of the pentose phosphate pathway, as the critical hub. RPIA was up-regulated in aged MSCs, predicting senescence (area under the curve [AUROC] = 0.909). Validation in an independent dataset confirmed RPIA's up-regulation with comparable accuracy (AUROC = 0.917). To further validate the reliability of the results, we selected discarded bone tissue samples from patients aged 20 to 80 years who had undergone osteotomy, which we then examined histologically. The importance and effectiveness of RPIA have been confirmed through analysis of clinical tissue samples. At the same time, under high RPIA levels, the osteogenic potential of bone marrow mesenchymal stromal cells was significantly suppressed (P < 0.01). This study is the first to implicate RPIA in the pathobiology of skeletal aging. We propose RPIA as a metabolic switch driving mitochondrial dysfunction in senescent MSCs. Consequently, RPIA emerges as a novel, high-priority potential therapeutic target for osteoporosis, providing a compelling data-driven foundation for subsequent experimental investigation.

Senescent dermal fibroblasts accumulate and secrete chemically reactive lipids that are components of the senescence-associated secretory phenotype (SASP). These lipids, including 4-hydroxynonenal (HNE) and reactive oxidized phospholipids (OxPL), covalently bind to and modify proteins via Schiff base formation or Michael adduction. Our study examined lipid-induced collagen modifications and their impact on skin cells to evaluate the long-term consequences of senescent cells on the tissue microenvironment. Using mass spectrometry and biochemical analyses, we identified both high and low molecular-weight modifications to collagen types I, II and IV. Collagen modified by HNE reduced fibroblast proliferation and induced stress responses. In contrast, collagen modified by OxPL provoked inflammatory signaling. Both types of modifications influenced matrix remodeling by increasing proteinase expression while reducing collagen expression. Modified collagen also elevated levels of intracellular reactive oxygen species and lipid peroxidation. Macrophages cultured on modified collagen displayed altered cytokine profiles and Toll-like receptor signaling impairment, that depended on the specific type of lipid modification. Similarly, keratinocytes exposed to modified basal lamina collagen IV showed transient stress responses, increased cytokine expression, and reduced matrix metalloproteinase expression. Furthermore, lipid-modified collagen incorporated into organotypic skin equivalents disturbed keratinocyte differentiation and elevated markers of cellular senescence. These skin models also showed reduced epidermal thickness with HNE-modified collagen and parakeratosis on OxPL-modified matrices. In conclusion, the findings suggest that SASP lipids secreted by senescent fibroblasts alter collagen structure and the fate of residing cells. The responses are likely caused by cell-associated oxidation events upon interaction of cells with a lipid-modified matrix and can be inhibited by antioxidants in macrophages. Given collagen's long half-life in tissues, these modifications may represent a persistent mechanism by which senescent cells affect the tissue microenvironment beyond the lifespan of soluble SASP factors - thereby sustaining an aged phenotype over extended periods.

Aging is associated with colon epithelial barrier integrity and upregulation of myelopoiesis in the bone marrow (BM). Alamandine (Ala) and MrgD are novel members of the renin angiotensin system (RAS). This study tested the hypothesis that Ala restores the colon epithelial barrier integrity in aging via modulating gut-BM axis. Mice of age 2-3 (Young) or 22-24 months (Old) were treated with saline or Ala by using Osmotic pumps. The intestinal permeability was evaluated by using FITC-dextran. Lgr5+Olfm4+ intestinal stem cells (ISCs), Wnt3a and {beta}-catenin were evaluated by immunohistochemistry or western blotting. Fecal microbiome was analyzed by 16S rRNA sequencing. Monocyte-macrophages were characterized by flow cytometry. Cecal or serum bacterial metabolites were analyzed. The pro-myelopoietic potential of cecal supernatants (CS) was tested in the Young-BM cells. MrgD was expressed in ISCs, which was decreased in the Old. Increased intestinal permeability in aging was reversed by Ala. In the colon organoids, Ala increased Wnt3a levels that were antagonized by the NF449, SQ22536 or 666-15. Ala restored phospho-CREB and active {beta}-catenin levels that were decreased in the Old colon-organoids. Ala increased the richness and {beta}-diversity of the aging microbiome and decreased Bacillota/Bacteroidota. Ala decreased the CD80+ and increased CX3CR+ cells in the Old colons. Old-CS induced myelopoiesis in vitro in BM cells with higher number of monocytes and pro-inflammatory macrophages which was not observed in the CS derived from Ala-treated Old mice. Ala is a promising pharmacological agent for reversing the leaky gut of aging by restoring homeostasis in the gut-BM axis.

DNA damage lesions can result in mutations and genome rearrangements that are associated with cellular aging and diseases. The landscape of somatic mutations in individual tissue and cell types are dictated by their unique physiological states, cellular functions, mutagenic exposures, and efficiency of DNA repair. Articular chondrocytes and skin fibroblasts are two cell types of mesodermal origin with distinct exposure to internal and external sources of DNA damage. While somatic genome instability features of skin fibroblasts have been well detailed, knowledge about mechanisms underlying genome changes in chondrocytes is scarce. Here, we took a whole-genome sequencing approach to evaluate the load, sources, and patterns of genome changes in 18 primary human chondrocyte clones from donors with and without osteoarthritis (OA). Findings in chondrocyte clones largely agreed with a recent study of 100 single-cell sequenced chondrocytes. We compared genome changes in chondrocytes with clonally-expanded human skin fibroblasts sequenced in our previous studies. We demonstrated that skin fibroblasts show a higher burden of somatic mutations, with an increased rate of mutation accumulation per cell division. Motif-centered analyses of mutation catalogues identified only endogenous sources of mutations in chondrocytes, as opposed to skin fibroblasts which also showed a heavy burden of UV-induced mutations. Spontaneous deamination of meCpG and mutagenesis by exposure to small epoxides and SN2 electrophiles showed higher mutagenic activities in chondrocytes compared to skin fibroblasts. Chondrocytes showed ubiquitous prevalence of indels in homonucleotide runs of [≥]5 bases, while skin fibroblasts showed high contributions of UV-associated deletions of [≥]5bp not in repeats. Structural variants in rearrangement hotspots colocalized with human common fragile sites in skin fibroblasts, but not in chondrocytes. Together, our study comprehensively recorded genome instability features in chondrocytes and highlighted the unique mutagenesis landscapes of two mesenchymal cell types.

Emerging epidemiological evidence shows myasthenia gravis (MG) is associated with age-related biological processes, but its mechanism of causality remains unexplained. This bidirectional Mendelian randomization (MR) study aimed to clarify the causal relationships between quantifiable biomarkers of aging and MG.

In terms of anti-aging, ginseng has the effect of "lightning the body and prolonging the life" since ancient times. Although Panax ginseng Meyer (ginseng) has demonstrated anti-aging associations in experimental studies, clinical validation of its impact on telomere length and nicotinamide adenine dinucleotide (NAD+)/Nicotinamide adenine dinucleotide (NADH) ratio in healthy middle-aged individuals remains lacking.

The aryl hydrocarbon receptor (AhR) is a highly conserved, ligand-activated transcription factor in mammals involved in multiple physiological processes, including development, xenobiotic detoxification, and potentially aging, and some of the most potent activators of AhR are tryptophan metabolites. AhR manipulation across species has been shown to have conflicting results on aging phenotypes that are often tissue specific. To expand our understanding of AhR and aging, we studied AhR affects survival and reproduction in Drosophila melanogaster, whose genome contains an ortholog of AhR, spineless (ss). Our findings indicate that ss-deficient flies have a shorter lifespan than wildtype flies but interestingly exhibit reduced mortality until approximately 40 days of age. Similarly, ss-deficient flies are more stress resistant than wildtype at young ages, but this reverses in later age. Negative lifespan-shortening effects of tryptophan metabolites were mitigated in ss-deficient flies, suggesting that the effects of these metabolites are ss-reliant, similar to AhR in mammals. Overall, our preliminary work demonstrates an evolutionarily conserved role for AhR in the aging process and increases our knowledge of the role of AhR/ss on aging phenotypes.

Older individuals exhibit distinct biochemical and functional changes in their immune cells that can lead to chronic inflammation, reduced immunity to pathogens and organ dysfunction. Immune cells from older individuals acquire dysfunctional immunosenescent phenotypes that are classified as inflammatory, exhausted or senescent. Key molecular mechanisms, commonly described as hallmarks of ageing, drive the development of these phenotypes through both cell-autonomous and non-autonomous mechanisms. Importantly, the ageing immune system can drive multi-organ dysfunction and systemic ageing, suggesting that improving immune function in older individuals could have significant health benefits. Here, we review the effects of ageing on various immune cell subsets in mice and humans. We describe the molecular mechanisms that drive these functional changes and their effects on both lymphoid and non-lymphoid organs. We also discuss therapeutic approaches to improve the function of the ageing immune system to increase resilience and extend healthspan.

Increasing aging populations globally have made maintaining a healthy life expectancy for older adults a critical issue. Older adults are particularly susceptible to frailty, physical and mental vulnerability caused by age-related decline in physiological and psychological resilience. Preventing its onset is essential for extending a healthy lifespan. Declines in antioxidant capacity contributes to frailty; therefore, administration of antioxidants may help prevent or treat this condition. Silicon (Si)-based agent reacts with water to produce hydrogen, which selectively scavenges deleterious reactive oxygen species. Oral Si-based agent administration can effectively alleviate symptoms in various disease models associated with oxidative stress, including Parkinson's disease, ulcerative colitis, facial nerve palsy, and small intestinal ischemia-reperfusion injury. We investigated whether a Si-based agent could prevent or ameliorate frailty associated with aging using klotho mice, a premature aging model, and 105-week-old C57BL/6J mice. In klotho mice, the Si-based agent significantly alleviated age-related physical changes, including kyphosis and deterioration of coat conditions, and frailty-related somatic symptoms, including decreased spontaneous activity and motor function. Moreover, multicriteria frailty classification revealed fewer frail and pre-frail phenotypes in Si-based agent-treated klotho mice than in untreated mice. In aged C57BL/6J mice, the Si-based agent mitigated oxidative stress, suppressed motor performance and body weight decline, and reduced early mortality associated with age-related deterioration. Si-based agent may represent a potential strategy for combating frailty.

O-GlcNAcylation, the reversible addition of O-linked N-acetylglucosamine (O-GlcNAc) to serine and threonine residues, is a dynamic posttranslational modification that integrates nutrient and stress signals to fine-tune protein function and maintain cellular homeostasis. Although dysregulation of O-GlcNAc signaling is associated with age-related pathologies, its role in physiological aging remains unclear. Here we show that chronologically aged human vascular endothelial cells exhibit reduced O-GlcNAcylation due to altered abundance of enzymes in the hexosamine biosynthesis pathway and O-GlcNAc cycling. Conversely, the attenuation of O-GlcNAcylation achieved by genetic or pharmacological means, induced senescence via canonical p53/p21CIP1 and p16INK4a/Rb pathways and impaired key endothelial functions, such as proliferation and angiogenic capacity. Importantly, O-GlcNAcylated substrates identified across the entire proteome in endothelial cells closely aligned with these mechanistic and phenotypic findings. These substrates were enriched in regulators of processes central to senescence and vascular aging, such as genome stability, transcription, cell cycle, and methylation. Among these, we confirmed cell division cycle and apoptosis regulator 1 (CCAR1) as a bona fide O-GlcNAc substrate and demonstrate that its expression and O-GlcNAcylation decline during senescence in endothelial cells. CCAR1 depletion suppressed apoptosis and sensitized cells to oxidative stress-induced DNA damage, whereas restoration of CCAR1 levels mitigated premature and replicative senescence. Together, our findings establish O-GlcNAc signaling as a key regulatory system that integrates metabolic and stress cues to coordinate protein networks controlling genome stability, transcription and cellular stress adaptation, thereby preserving endothelial integrity and restraining senescence onset.

Peak bone mass (PBM) critically determines lifelong skeletal health. We showed that dietary supplementation with pyrroloquinoline quinone (PQQ) - a water-soluble bioactive compound that activates nuclear factor erythroid 2-related factor 2 (Nrf2) signaling - during pregnancy or post-weaning enhances PBM acquisition in wild-type mice, subsequently attenuating age-related bone loss and improving mechanical strength. Mechanistically, PQQ-activated Nrf2 binds directly to the parathyroid hormone 1 receptor (Pth1r) promoter, upregulating its transcription and augmenting PTH-induced osteogenesis. Pth1r overexpression rescues the impaired osteogenesis of Nrf2-deficient bone marrow mesenchymal stem cells (BMSCs). Teriparatide's (PTH 1-34) anabolic effects are markedly compromised in Nrf2-deficient mice and human BMSCs, underscoring Nrf2's essential role in PTH-mediated bone formation. Notably, PQQ and PTH 1-34 co-administration synergistically enhances skeletal anabolism in aged mice beyond PTH 1-34 monotherapy. These results establish the PQQ-Nrf2-Pth1r axis as a key regulator of bone mass accrual and suggest PQQ as a promising adjunct to teriparatide for osteoporosis.

Ageing entails a variety of cellular and physiological changes that increase susceptibility to disease and death. A significant contributor to ageing is cellular senescence, a state of irreversible cell cycle arrest triggered by stressors such as DNA damage, telomere shortening, and the senescence-associated secretory phenotype. It is challenging to understand the nonlinear interactions between these complex mechanisms using conventional laboratory approaches. Mathematical modelling is capable of representing this complexity. In this study we introduce a mathematical model that captures the dynamics of cellular ageing within a population of cells. The model integrates key processes including DNA damage repair, senescence, quiescence, apoptosis, and cell division. The model was used to simulate the effects of ageing and to evaluate the efficacy of several interventions, including senolytics, telomere length preservation, and stem cell therapy. Deterministic and stochastic simulations reproduce core ageing features: progressive accumulation of senescent cells, a generation distribution centred near experimentally observed Hayflick limits, and an exponential-like age distribution of non-senescent cells. This model captures the long-lasting effects of interventions such as telomere lengthening and stem-cell therapy. It offers a quantitative, extendable platform that supports hypothesis testing and helps identify which ageing interventions warrant experimental validation. Overall, it provides a predictive framework for interpreting cellular ageing and for guiding future experimental work.

Salamanders such as axolotls exhibit exceptional regenerative abilities and longevity. While many ectothermic species reproduce into old age, axolotls have been proposed to experience post-maturation fertility decline.

High-energy UV light from the UV-B and UV-C ranges induces severe cellular damage that leads to oxidative stress, cellular senescence, and apoptosis. Most studies of such UV-induced phenotypes have been performed in homogeneous cell cultures where all cells were subjected to comparable levels of damage. However, in physiological conditions, UV exposure generates heterogeneous cell populations in which damaged cells coexist with intact neighbors. How such cellular context influences UV-induced outcomes remains insufficiently understood. Here, we examined the effects of intact neighbouring cells on mammalian cells exposed to combined UV-B and UV-C radiation. We show that the presence of intact cells enhances apoptotic progression and clearance of cells treated with high doses of UV, while having little effect on the cells exposed to low and moderate doses. Transcriptomic profiling revealed that UV-treated cells grown in co-culture with intact neighbours exhibit a markedly attenuated transcriptional response to UV exposure, including reduced activation of oxidative stress and reparatory pathways, compared to UV-treated cells grown in monoculture. These effects required direct cell-cell contact and were not mediated by diffusible factors, gap junctions, or tunneling nanotubes. Instead, co-culture conditions were associated with extensive changes in ligand-receptor gene expression profiles, indicating altered intercellular communication in response to UV damage. Our findings demonstrate that UV-induced cellular outcomes are strongly shaped by the surrounding cellular environment and identify a contact-dependent, non-cell-autonomous layer of regulation that influences the resolution of UV-induced damage. These results have implications for understanding tissue-level responses to UV exposure in photodamage, photoaging, and disease contexts.

Skeletal aging associated with diverse age-related disorders is increasing due to unhealthy diets, stressful lifestyles, and rapid aging. Repair and regeneration of aging skeletons are a global issue. Despite the self-healing ability of bone and the availability of various treatment strategies, degenerative bone repair and regeneration face significant problems due to unbalanced bone remodeling and a lack of active treatment strategies. The development of smart materials has created opportunities for degenerative bone repair and regeneration. The smart materials are responsive to endogenous/exogenous stimuli with tailored structure and function, which can promote skeletal aging repair and regeneration. Thus, in this study, skeletal aging is recognized as the progressive state that begins from peak bone mass to pathophysiological state and disorder conditions. We have introduced and characterized skeletal aging from the perspectives of cell-matrix-microenvironment and macrostructure-function-mechanical properties, for which systemic smart drug delivery systems and local smart scaffolds are designed. The smart drug delivery systems undergo conformation change and phase transition upon stimuli to release drugs at time- and site-specific to promote aging bone repair. Smart scaffolds with versatility and mechanical strength can replace bone defects to provide a tissue repair and regeneration microenvironment. Endogenous disease microenvironments and/or external physical triggers stimulate scaffold activation, which release bioactive factors to accelerate bone regeneration. This manuscript discusses the manufacturing techniques of these smart materials and presents key challenges and future directions for clinical translation, emphasizing their potential for personalized treatment and targeted therapy of skeletal aging.

Aging of hematopoietic stem and progenitor cells (HSPCs) impairs regenerative capacity and predisposes to hematological diseases. Here, we constructed a comprehensive single-cell transcriptomic atlas comprising 186,123 CD34+ HSPCs spanning early prenatal development (6 post-conception weeks) to late adulthood (74 years). We identified six molecular programs (MPs) that define distinct functional states within the HSC/multipotent progenitor (MPP) compartment. Among these, MP1, associated with inflammaging, and MP5, related to RNA splicing and protein homeostasis, exhibited conserved age-associated dynamics across independent datasets, highlighting their central roles in stem cell aging. Leveraging these age-associated programs, we developed a machine learning-based stem cell aging clock from 84 donors to predict chronological age from HSC/MPP transcriptomes. Applying this aging clock to acute myeloid leukemia (AML) defines transcriptional age deviation (TAD), a measure of biological age divergence in leukemic HSC/MPPs. TAD captures disease-associated variation linked to genetic risk stratification and patient survival. Our study provides a high-resolution reference map of human HSPC aging, establishes a stem cell-specific aging clock and demonstrates its utility for uncovering aging-related dysregulation with prognostic relevance in hematological malignancies.

Brain aging is a multifactorial process associated with oxidative stress, chronic neuroinflammation, and synaptic dysfunction, ultimately leading to cognitive decline and increased susceptibility to neurodegenerative disorders. Epigallocatechin gallate (EGCG) is a potent antioxidant and anti-inflammatory agent, but its therapeutic potential is limited by poor stability and bioavailability. In this study, a dual nano delivery system was developed by loading chitosan-EGCG nanoparticles into mesenchymal stem cell-derived exosomes (Ex-Chit-EGCG NPs) and evaluated for neuroprotective efficacy in a D-galactose-induced brain aging model. Intranasal administration of Ex-Chit-EGCG NPs significantly improved cognitive and locomotor performance compared with exosomes alone, as evidenced by enhanced outcomes in Y-maze and open field tests. Biochemical analyses revealed that Ex-Chit-EGCG NPs effectively reduced lipid peroxidation, restored glutathione levels, and reactivated the LKB1/AMPK/SIRT1 signaling pathway. Molecular investigations demonstrated upregulation of Nrf2, BDNF, and SIRT1 together with suppression of NF-κB and Iba-1 expression, indicating attenuation of oxidative and inflammatory responses. Histopathological and immunohistochemical evaluations confirmed these findings, showing preservation of cortical and brain stem architecture with marked reductions in neuronal necrosis, gliosis, BAX, GFAP, and NLRP3 expression. Collectively, the results demonstrate that Ex-Chit-EGCG NPs exert superior neuroprotective effects compared with exosomes alone, highlighting the therapeutic advantage of combining EGCG with chitosan nanocarriers and exosomal delivery. This dual nanotherapeutic strategy offers a promising and non-invasive approach for mitigating brain aging and holds potential for translation into therapies targeting age-related neurodegenerative disorders.

This study investigated whether higher cardiorespiratory fitness (VO₂peak) is associated with better cerebral vascular and metabolic health-specifically cerebral blood flow (CBF), cerebrovascular reactivity (CVR), cerebral metabolic rate of oxygen (CMRO₂), and oxygen extraction fraction (OEF) across healthy older adults and patients with coronary artery disease (CAD). Thirty-seven healthy adults (65.3 ± 8.3 years old) and 35 CAD patients (66.4 ± 9.3 years old) underwent calibrated fMRI using hypercapnic and hyperoxic gas challenges (including carbogen) to quantify gray matter CBF, CVR, CMRO₂, and OEF. VO₂peak was obtained from a maximal cycle ergometer cardiopulmonary exercise test. Associations between VO₂peak and brain biomarkers were evaluated with group terms to test CAD-specific effects. Across all participants, VO₂peak was positively associated with CBF (β = 0.32, p = 0.02) and CVR (β = 0.002, p = 0.04) in gray matter, indicating an association between aerobic fitness and vascular health. Metabolic effects differed by group: in CAD patients, VO₂peak correlated positively with CMRO₂ (β = 0.08, p = 0.02), suggesting higher fitness may be associated with preserved oxidative metabolism, while in healthy controls, VO₂peak was negatively associated with OEF (β = -3.6, p = 0.02), consistent with aging-related adaptations driven by improved CBF without CMRO₂ changes. VO₂peak is positively associated with cerebral vascular function in older adults and shows group-specific metabolic benefits: in CAD, higher VO₂peak relates to preserved CMRO₂, whereas in healthy individuals it is linked primarily to enhanced perfusion and reduced extraction. These findings support aerobic exercise as a promising strategy to mitigate CAD-related brain alterations and highlight VO₂peak as a potentially modifiable target for prevention and rehabilitation.

Polygonatum kingianum is a known tonic herb of Traditional Chinese Medicine, extensively consumed in China, but the structure and activity of its polysaccharides remain to be clarified. In this study, a homogeneous fructan fraction, designated PKP-1b, was isolated and purified from this plant and structurally identified as an agavin-type fructan. In both Caenorhabditis elegans and a D-galactose-induced aging mouse model, PKP-1b exhibited significant anti-aging effects, including lifespan extension, improved motor function, reduced lipofuscin accumulation, and mitigation of neurodegenerative changes. Mechanistic investigations revealed that PKP-1b exerts its anti-aging effects by inhibiting the insulin/IGF-1 signaling (IIS) pathway, which in turn promotes nuclear translocation of the transcription factor DAF-16/FOXO, upregulates expression of the antioxidant gene sod-3, thereby enhancing overall antioxidant capacity and reducing oxidative damage. These findings elucidate the anti-aging mechanism of PKP-1b from P. kingianum and provide a theoretical foundation for its application in developing anti-aging products.

Aging is a "multidimensional engine" of biological dysfunction that can fundamentally reshape the pathology of Alzheimer's disease (AD), This review systematically elaborates on how aging synergistically promotes the core pathologies of AD: aging upregulates the activity of β-secretase 1 (BACE1)/γ-secretase, impairs the clearance function of glial cells and meningeal lymphatic drainage, and accelerates Aβ deposition; the imbalance of kinases/phosphatases, dysfunction of molecular chaperones, and aging exosome-mediated propagation of Tau "seeds" facilitate Tau pathology; hyperreactivity of microglia and the transformation of astrocytes to the A1 phenotype form a senescence-associated secretory phenotype (SASP) → neuroinflammation vicious cycle; downregulation of synaptic proteins and disintegration of the default mode network lead to cognitive decline. Recent studies have identified that the impaired transition of aging microglia to the disease-associated microglia (DAM) phenotype, peripheral-central aging signal transmission loops (the gut-brain axis, immune-brain axis, and metabolic-brain axis), as well as circadian rhythm/vascular metabolic dysregulation, have emerged as novel intervention targets. Precision strategies targeting aging mechanisms-such as senescent cell clearance, SASP inhibition, epigenetic reprogramming, and biomarker-guided early intervention-provide a new paradigm for blocking the progression of AD.

"Inflammaging", the chronic increase in inflammatory signaling with age, remains poorly understood in hematopoietic aging. Here, we identify the innate immune RNA sensor melanoma differentiation-associated protein 5 (MDA5) as an important factor of hematopoietic stem cell (HSC) aging. Aged Mda5

Nucleophagy is a crucial process by which cells selectively degrade nuclear components through autophagy mechanisms to maintain genomic stability. It occurs through two modes: macro-nucleophagy and micro-nucleophagy, relying on proteins such as Atg39 and Nvj1 to remove irreversibly damaged nuclear components (such as broken chromatin, micronuclei, and abnormal nuclear membrane components) caused by irreversible DNA damage, to degrade toxic nuclear protein aggregates, and to target abnormal nuclear structural components. The activity of nucleophagy is regulated at multiple levels. Transcription factors such as the MiT/TFE family and p53 can sense cellular stress signals to regulate the expression of autophagy genes. Epigenetic mechanisms such as DNA methylation, histone modification, and miRNA participate in the regulation by modifying genes or marking substrates, and these regulatory processes are modulated by signaling molecules and drugs such as mTOR inhibitors. The core function of nucleophagy is to eliminate irreparable damaged nuclear substances, toxic nuclear protein aggregates, and abnormal nuclear structural components, thereby preventing the accumulation of harmful substances. It also exerts a bidirectional regulatory role in pathological processes including cell differentiation, aging, cardiovascular diseases, neurodegenerative diseases, and cancer. Future research needs to further elucidate the regulatory mechanisms of nucleophagy, particularly the crosstalk between transcription factors and epigenetic modifications, as well as the complex connections between nucleophagy and other cellular processes. These studies will provide novel therapeutic targets and strategies for the development of treatments against cancer, neurodegenerative diseases, and cardiovascular diseases, and thus advance the progress of disease treatment and drug development.

Aging increases vulnerability to stress-induced neuronal dysfunction, yet the underlying mechanisms remain unclear. Here, in young mice (2 months), chronic stress elevates basal serum glucocorticoid (GC) levels and induces despair-like behavior, as well as impaired sociability. By contrast, aged mice (14.5 months) naturally exhibit elevated basal GC levels, but do not display depressive-like behavior or sociability deficits, although further analysis reveals a social memory impairment. However, exposure to subthreshold stress in aged mice further elevates basal GC levels and induces both emotional and sociability impairments. Notably, repeated mild stress reverses these stress-induced physiological and behavioral impairments in young and aged mice. Neural activity-dependent c-Fos expression mapping identifies the ventral subiculum (vSub) as a potential upstream neural hub that regulates both serum GC responses and emotional and social behaviors. Chemogenetic activation of the vSub, particularly the vSub-to-dorsal bed nucleus of the stria terminalis circuitry, reverses stress-induced increases in basal GC levels and the associated behavioral deficits. Transcriptomic analysis reveals that the vSub gene expression profile in aged mice significantly overlaps with that of young mice exposed to chronic stress, notably characterized by Fkbp5 upregulation. Targeted knockdown of Fkbp5 within the vSub mitigates stress-induced increases in GC levels and rescues behavioral deficits. Moreover, repeated short-term mild stress or low-dose GC treatment ameliorates stress-induced physiological and behavioral impairments, accompanied by downregulation of Fkbp5 in the vSub. Collectively, these results suggest that the aged brain acquires chronic stress-like signatures, heightening its vulnerability to maladaptive outcomes, and that repeated short-term mild stress can restore emotional and social function by normalizing vSub Fkbp5-dependent signaling.

Visceral adiposity, a core aspect of nutritional status, is increasingly recognized as a modifiable risk factor for extra-metabolic diseases. However, evidence regarding its sex-specific impact on pulmonary function, a key determinant of healthy aging, remains scarce. This study aimed to investigate the differential associations between the Visceral Adiposity Index (VAI) and impaired pulmonary function in middle-aged and older males and females.

Accelerated ovarian aging is associated with early infertility as well as other adverse health outcomes. Little is known about the factors that accelerate ovarian aging, but several studies indicate that exposure to phthalates accelerates ovarian aging. This is a significant human health concern because humans are ubiquitously and unavoidably exposed to phthalates. Thus, it is imperative to study the mechanisms of phthalate-induced accelerated ovarian aging so that strategies can be developed to prevent phthalate-induced ovarian aging. This review focuses on the mechanisms by which phthalates cause ovarian aging in non-human experimental models and highlights gaps in the literature.

Onset and progression of cardiovascular diseases are tightly linked to the aging process. Aging results in structural and functional changes including endothelial dysfunction and senescence, thereby impairing vascular functions. The molecules involved in these processes are far from understood.

Marfan syndrome (MFS) is a multisystemic heritable thoracic aortic disease entity characterized by progressive aortic dilatation and life-threatening cardiovascular complications. Chronic inflammation and oxidative stress are increasingly recognized in its pathophysiology, and are important drivers of telomere shortening, a hallmark of biological aging. We hypothesized that adults with MFS have shorter telomere length (TL) compared to healthy controls.

Aging is asynchronous across cells and organs, but whether plasma proteins can capture cell type-specific aging and predict disease and mortality remains unknown. We developed machine learning models to estimate the biological age of more than 40 distinct cell types spanning neuronal, immune, glial, endocrine, epithelial, and musculoskeletal origins using over 7,000 plasma proteins measured in 60,000 individuals across three cohorts, comprising the largest human plasma proteomics aging study to date. Individuals showed heterogeneous aging profiles, with 20-25% exhibiting accelerated aging in a single cell type and 1-3% across ten or more cell types. APOE genotype showed antagonistic aging effects in different cell types: APOE4 carriers exhibited older astrocytes but younger macrophages, while APOE2 carriers showed the inverse. Cellular aging signatures were uniquely associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Amyotrophic lateral sclerosis (ALS) showed the strongest association with skeletal myocyte aging (hazard ratio = 12.7 for extreme accelerated versus youthful aging). In Alzheimer's disease (AD), prevalent cases showed accelerated aging across multiple neural and peripheral cell types, with extreme astrocyte aging conferring AD risk comparable to APOE4 carrier status. Moreover, extreme astrocyte aging increased AD risk in APOE4/4 carriers threefold, while youthful astrocytes strikingly reduced risk. Beyond neurodegeneration, respiratory cell aging identified smokers at 58% higher lung cancer risk, and myeloid aging identified normoglycemic individuals at higher diabetes risk. Both specific cellular vulnerabilities and cumulative aging burden influenced survival, wherein youthful immune or neuronal profiles were protective. A polycellular aging risk score provided robust mortality risk stratification across platforms and cohorts. These findings establish a framework for quantifying biological aging at the cellular resolution using plasma proteomics, revealing heterogeneity in aging trajectories and their impact on disease susceptibility and resilience.

Adaptation to physiological stress is fundamental to health but varies widely among individuals. In humans, this heterogeneity is evident in markedly different gains in fitness in response to identical exercise training. The molecular determinants of this variable trainability remain poorly understood. Here we identify insulin-like growth factor binding protein-7 (IGFBP7), a senescence-associated secreted protein, as a circulating constraint on exercise adaptation. Plasma proteomics in older adults enrolled in a randomized exercise trial revealed that IGFBP7 levels inversely predicted fitness gains after one year of high-intensity interval training despite similar baseline fitness. In mice, genetic deletion of IGFBP7 markedly amplified training-induced gains in exercise capacity across distinct training protocols, whereas somatic overexpression abolished this advantage. In the UK Biobank, lower IGFBP7 levels were associated with reduced mortality and multiple incident age-related diseases, mirroring the breadth of ties between fitness and healthspan. Together, these findings identify circulating IGFBP7 as a molecular brake on physiological plasticity in response to exercise, linking training responsiveness, aging biology, and health outcomes.

Age-related osteoporosis arises from bone tissue with inadequate metabolic support for osteogenesis. We identified that DNA methylation-mediated suppression of glutathione synthetase (GSS) represents an upstream lesion limiting endogenous glutathione (GSH) synthesis and supply in aged bone, thereby constraining osteoblast differentiation. In turn, impaired GSH synthesis exacerbates oxidative stress levels and diminishes osteogenic capacity, and this metabolic bottleneck is independent of substrate availability: cysteine supplementation neither restored GSH synthesis flux in aged bone nor rescued its osteogenic deficits. To overcome this limitation, we developed an exosome-based GSH delivery platform using electroporation to efficiently load GSH. These exosomes are derived from CXCR4-enriched bone marrow mesenchymal stem cells (BMSCs), leveraging CXCR4-mediated homing to the bone marrow niche to enhance bone retention, stabilize GSH during loading and circulation, and elevate local GSH pools at osteogenic sites. In aged bone, this targeted system sustainably delivers GSH, alleviates oxidative stress, improves mitochondrial function, delays cellular senescence, and promotes osteogenesis. In summary, while DNA methylation acts upstream to constrain GSH synthesis in aging bone, therapeutically correcting the resultant metabolic deficit via bone-homing exosome-mediated GSH delivery restores osteogenic function and improves bone metabolism in aged individuals.

Cellular senescence, a stress-induced state of stable cell cycle arrest accompanied by a senescence-associated secretory phenotype (SASP), plays a paradoxical role in cancer biology. On the one hand, senescent cells function as a barrier to tumor initiation by activating the DNA damage response (DDR) and tumor suppressor pathways such as p53/p21 and p16

One of the defining phenotypes of a senescent cell is the senescence-associated secretory phenotype (SASP), which can propagate senescence in neighboring cells both in vitro and in vivo. Importantly, this paracrine spreading of senescence can act in a cell non-autonomous manner, influencing neighboring cell populations and contributing to immune cell recruitment. As cellular senescence has recently been linked to both age-related neurodegenerative phenotypes and local inflammation and is more clearly defined across brain cell types in a cell-type-dependent manner, an urgent question remains regarding how a cell-type-specific paracrine spreading of senescence occurs in the brain. Here, we set out to profile the cell-type-specific features of the SASP and characterize the directionality of paracrine senescence-spreading between major brain cell types. Through this analysis, we identified key SASP ligand-receptor pairs involved in this paracrine dissemination. Targeting these factors with specific inhibitors, we prevented the paracrine spreading of senescence in a brain cell-type-dependent manner. Taken together, we identified specific SASP targets for therapeutic intervention in the context of human brain cells and thereby informed the SASP-dependent reaction of immune cells and age-related tissue dysfunction across both normal aging and models of neurodegenerative disease.

Aging is a complex progress accompanied with the progressive deterioration of physiological functions and a marked elevation in mortality risk. Among prominent aging theories, the free radical theory and the mitochondrial dysfunction hypothesis have gained significant attention. Thus, targeted delivery of therapeutic drug to mitochondria might be able to alleviate the mitochondrial dysfunction induced by reactive oxygen species. This review summarizes the possible molecular mechanisms between mitochondrial dysfunction and aging progression. Especially, the recent breakthroughs of mitochondrial-targeted delivery platforms for therapeutics against aging progress. Innovative strategies, including small molecular modification, mitochondrial targeting functional peptide guided delivery and some other strategies are discussed. Their translational potential in anti-aging interventions is evaluated. We anticipate that mitochondria-targeted anti-aging therapeutics will soon enter clinical translation, offering potential solutions to address current age-related challenges.

DNA repair defects such as Nucleotide Excision Repair (NER) mutations can lead to progeroid syndromes characterized by growth retardation and accelerated aging with distinct tissue type specific pathologies. DNA damage induced dysfunction of specific cell types can impair the organism's overall function. It is unknown whether, in reverse, DNA repair in specific tissues can have non-cell-autonomous consequences on other tissues carrying DNA damage. To explore the organismal consequences of cell type specific DNA repair, we restricted NER activity to specific tissues and monitored consequences on organismal health in C. elegans. Unexpectedly, we observed that tissue specific DNA repair is sufficient to improve overall DNA damage resistance. Strikingly, the sole NER activity in neurons is sufficient to provide similar overall DNA damage resistance as whole body NER. We show that this systemic DNA damage resilience is mediated by neuronal Acetylcholine signaling that promotes the maintenance of mitochondrial activity throughout the organism.

Sarcopenia is a progressive, age-related condition characterized by the loss of skeletal muscle mass, strength, and function, which increases the risk of falls, frailty, and loss of independence. Despite growing recognition and its incorporation into geriatric assessments, there is still no approved pharmacological treatment. This review provides an updated overview of sarcopenia, encompassing diagnostic criteria, biological mechanisms, and emerging therapeutic strategies. Key molecular features include mitochondrial dysfunction, nicotinamide adenine dinucleotide (NAD⁺) decline, fiber-type alterations, and dysregulation of myokines. Recent singlecell and multi-omics studies have revealed the heterogeneity of muscle tissue and distinct cell-type-specific aging patterns. Therapeutic efforts are evolving beyond lifestyle interventions toward targeted approaches, including myostatin inhibitors, NAD⁺ boosters, senolytics, and microbiome modulators. However, clinical translation remains constrained by heterogeneity in trial design and the absence of standardized outcome measures. Future sarcopenia care will likely involve precision medicine guided by biomarkers and supported by digital monitoring tools. Progressing from molecular discovery to clinical application will be essential for preserving muscle health and function in aging populations.

Glucagon-like peptide-1 (GLP-1), an incretin secreted by intestinal L-cells in response to nutrients, regulates glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying, and reducing appetite via hypothalamic signaling. Beyond these canonical actions, emerging evidence reveals GLP-1's pleiotropic functions across multiple systems, with relevance to metabolic disorders, chronic inflammation, and aging-related pathologies. This review summarizes molecular mechanisms underlying GLP-1's protective roles, highlighting its contributions to metabolic balance, inhibition of NF-κB-mediated inflammation, and attenuation of cellular aging through mitochondrial enhancement and autophagy promotion. GLP-1 also influences immune cell function and alleviates hallmarks of senescence, thereby offering therapeutic potential beyond diabetes. We further critically assess the translational potential of GLP-1 receptor agonists (GLP-1RAs), pharmacological agents with superior pharmacokinetics versus native GLP-1, in treating conditions linked to dysregulated metabolism, persistent inflammation, and accelerated aging. Despite demonstrated efficacy in preclinical models and clinical studies, important challenges persist, including inter-individual variability, off-target risks, and uncertainties regarding long-term safety. We conclude by emphasizing the necessity of integrated strategies to target the metabolic-inflammatory-aging axis and by advocating optimization of GLP-1RA formulations, identification of predictive biomarkers, and expansion of their utility for age-associated diseases.

Aging clocks based on routine clinical indicators have emerged as a cost-effective tool for assessing biological age. This systematic review aims to summarize the characteristics and critically appraise these available aging clocks. Studies that developed aging clocks for adults (≥18 years) based on routine clinical indicators were retrieved from six databases (PubMed, EMBASE, Web of Science, CNKI, Wanfang Data, and Sinomed) up to June 18, 2024. The PROBAST+AI tool was used to assess the methodological quality, risk of bias, and applicability of included aging clocks. All the results were narratively summarized. Fifty-nine studies involving 81 aging clocks were included, of which 71 (87.7%) were developed using single-country datasets predominantly from China, the United States, Korea, and the United Kingdom. Notably, 31 aging clocks (38.3%) were developed with neither internal nor external validation. The majority of aging clocks were rated as having high concern regarding quality and high risk of bias, even including those published in high-impact journals. Only three aging clocks (3.7%) from two studies were rated as having low concern regarding quality and applicability during development, and two of these (4.0%) from one study further demonstrated low risk of bias and low concern for applicability during model evaluation. Future research should prioritize validating the promising aging clocks in target populations rather than developing new ones, adhere to the PROBAST+AI and TRIPOD+AI guidelines for methodological rigor and transparent reporting, and provide reproducible and user-friendly model codes and tools.

Glycation cross-links account for more than 40% of all known advanced glycation end products (AGEs) and are correlated with many age-related diseases. Despite much interest, cross-linking AGEs (xl-AGEs) remain poorly understood, as they have been challenging to discover, prepare, and quantify. Here, we describe a peptide platform that is ideally suited for the study of xl-AGEs, which not only facilitates direct comparisons between the prevalence of known xl-AGEs and other AGEs but also enables the discovery of previously unknown xl-AGEs. In this study, we use this platform to discover the first known Arg-Arg xl-AGEs, a pair of

Postmenopausal osteoporosis (PMOP) is a common disease linked to aging, and estrogen deficiency is considered to be the primary cause of PMOP. Inflammation and the gut microbiota (GM) have emerged as promising therapeutic targets for treating PMOP. Taraxasterol (Tara), a pentacyclic triterpenoid primarily derived from Taraxacum officinale, demonstrates broad biological functions and pharmacological properties. However, whether Tara in question exerts an anti-osteoporosis (OP) effect remains unclear. To investigate the potential anti-OP effects of Tara, an experimental OP model was developed using female C57BL/6 mice via bilateral ovariectomy (OVX). The mice of Tara groups received treatments via oral gavage once daily for 8 consecutive weeks. Bone microstructure parameters, the NLRP3 inflammasome, intestinal barrier and GM were assessed. Network pharmacology was employed to predict and validate its anti-OP-related molecular targets and pathways. The results revealed that Tara treatment significantly reduced bone loss and improved bone metabolism. ELISA revealed that Tara reduced proinflammatory cytokine levels, suppressed the NLRP3 inflammasome (caspase-1, IL-1β and IL-18) and affected adipokine content. The expression levels of Occludin and ZO-1 exhibited a significant increase in the Tara groups. Moreover, 16S rRNA sequencing demonstrated that the relative abundances of Ileibacterium, Erysipelotrichaceae and Oscillospiraceae decreased significantly, whereases the relative abundance of Parabacteroides increased after Tara administration. Network pharmacology identified 75 core anti-OP targets. The binding energy of target proteins and Tara ranged from approximately -5.0 to -9.0 kcal/mol, with EGFR showing the lowest binding energy. Overall, Tara ameliorated OVX-induced OP by suppressing the NLRP3 inflammasome and modulating the GM.

People with HIV (PWH) on combination antiretroviral therapy have an elevated risk for aging-related non-AIDS comorbidities. We assess whether HIV infection accelerates biological aging in two independent cohorts of PWH using six organ-specific and three organism-wide aging clocks derived from plasma proteomics of healthy individuals. Proteomic age acceleration significantly correlates with DNA methylation age and is linked to comorbidities and mortality. HIV infection accelerates systemic biological aging, with Mendelian randomization demonstrating causality between organ aging and inflammatory or metabolic complications. Accelerated aging in PWH is further related to the total HIV reservoir, and specific antiretroviral drugs reduce age acceleration. These data reveal important causal effects between chronic HIV infection, antiretroviral medication, biological aging and age-associated diseases, highlighting targets for improving health span in PWH.

DNA methylation is an established biomarker of human ageing, and analysing CpGs grouped by transcript as functional units may reveal new insights into the processes of ageing. In this study, we analyzed the GSE87571 dataset (714 samples from 14-94 years) to assess the relationship between transcript-level methylation profiles and chronological age in human blood. This approach led to the creation of Epitage, a curated set of 48 transcripts from 13 genes identified through machine learning as having methylation profiles that strongly correlate with age (R^2 >= 0.8). This analysis highlighted transcripts from the genes KCNS1, SPTBN4, and VTRNA1-2, which have been only rarely mentioned as age-related methylation markers in humans, suggesting them as underexplored candidates for future investigation. In addition, the list includes genes already implicated in aging or related pathways, such as ELOVL2, FHL2, KLF14, TRIM59, MIR29B2CHG, CALB1, OBSCN, PRRT1, OTUD7A, and SYNGR3. To validate models efficiently while ensuring reproducibility, we developed ugPlot, an open-source R package with a graphical user interface (GUI) that automates routine steps for training and testing hundreds of machine-learning models. The tool also streamlines dataset import and manipulation, reducing human error and generating publication-ready plots. Epitage thus provides a focused and accessible starting point for experimental and translational studies into the roles of DNA methylation and transcript regulation in human ageing.

Menopause is a hallmark process in biological aging that has been associated with later life neurodegenerative risk. We leveraged proteomics data from multiple cohorts (over 3,000 women) to identify biological changes underlying menopause and its links to brain aging. In N=80 rigorously-phenotyped pre, peri, and postmenopausal women with serum NULISAseq proteomics, spontaneous menopause was characterized by dysregulation in inflammatory, synaptic, metabolic, and Alzheimer's disease (AD) biologic processes, which tracked with hormones and not age. Pro-inflammatory protein upregulation was especially pronounced in women with vasomotor symptoms. In two cohorts of older women (N=94, N=100), menopause-related proteomic elevations associated with poorer cognitive outcomes and plasma AD biomarkers. Finally, validation analyses in age matched pre and postmenopausal women with plasma Olink proteomics (N=2,814) replicated the observed proteomic shifts and revealed menopause-related upregulation of additional inflammatory and catabolic processes. The molecular signatures of menopause may inform biomarkers or therapeutic targets for brain health in women.

Frailty, characterized by diminished physiological reserve and increased vulnerability to stressors, is a common geriatric syndrome associated with adverse health outcomes. While recent seminal studies have reported conflicting findings regarding taurine, a sulfur-containing amino acid with antioxidant properties, and its relationship with aging, these discrepancies may reflect the heterogeneity of aging trajectories among older adults that chronological age alone fails to capture. Here, we propose that frailty status may better capture this heterogeneity and reveal associations between taurine and aging that are obscured when using age alone. We examined taurine and upstream metabolites in the taurine biosynthesis pathway in 146 community-dwelling adults aged 20-97 years, focusing on older adults (≥69 years) stratified by frailty phenotype. We observed a non-monotonic relationship where taurine levels were highest in robust individuals, lowest in prefrail, and intermediate in frail groups. Analysis of the taurine biosynthesis pathway revealed distinct metabolic profiles across frailty states. Robust individuals demonstrated efficient pathway flux, while the prefrail group exhibited maximal metabolic disruption characterized by bottlenecks. Frail individuals showed persistent metabolic disruption but partial taurine restoration, suggesting compensatory mechanisms. Inflammatory marker associations varied by frailty status, with TNF-α showing a significant negative correlation with taurine specifically in prefrail individuals. These findings demonstrate that frailty status reveals distinct shifts in taurine metabolism and immunological regulation not captured by chronological age alone, providing a more biologically meaningful framework for understanding taurine biology in aging populations.

Alzheimer's disease (AD) is marked by hallmark neuropathological changes in the brain. However, its upstream genetic determinants, beyond the central nervous system (CNS), remain largely unexplored. To that extent, we integrated human genomic data with cross-tissue and single-cell analyses across up to 40 peripheral tissues and 100 brain regions. We observed limited genetic enrichment in the CNS, with brain-resident microglia emerging as the sole enriched cell type. Instead, AD risk loci were predominantly enriched in peripheral immune compartments and immune-enriched barrier tissues, such as the lung and the digestive tract, and particularly within myeloid-lineage cells. Leveraging gene expression profiles from peripheral immune cells, we recreated an age-related susceptibility curve for AD, identifying ages 55-60 as a critical window for immune activation linked to AD risk. Our findings position the peripheral immune system as a central contributor of disease susceptibility, opening new directions for early intervention beyond the brain.

Post operative delirium (POD) is an acute complication, characterized by fluctuating attention and confusion, which may develop and persist into cognitive decline. POD is most commonly observed in elderly patients, particularly those with preexisting cognitive impairments. Isoflurane, a widely used volatile anesthetic, is associated with POD. However. how exposure to isoflurane affects the integrity of the proteome is largely obscure. Utilizing the nematode C. elegans, we found that isoflurane leads to a long-lasting decline in protein homeostasis (proteostasis) of adult animals that express neurodegeneration-causing, abnormally long poly-glutamine stretches. Isoflurane-induced proteostasis impairments are dependent on the aging-regulating transcription factors DAF-16/FOXO and SKN-1/NRF, and can be alleviated by the knockdown of certain components of the mitophagy mechanism. Accordingly, induction of mitochondrial biogenesis protects worms that are challenged by protein aggregation from isoflurane-induced proteotoxicity. Our observations provide novel insights into the mechanism that links isoflurane, proteotoxicity and POD, and highlight the potential of mitophagy modulators as alleviators of POD.

Advanced age significantly increases postoperative complication risk, including neurological dysfunction. While the liver plays a critical role in surgical recovery, age-related changes in hepatic function remain inadequately studied in perioperative risk assessment. Methylation-Controlled J protein (MCJ), an endogenous negative regulator of mitochondrial function, represents a promising therapeutic target due to its role in exacerbating oxidative stress and compromising metabolic resilience in aging.

Selective androgen receptor modulators (SARMs) are a novel class of compounds engineered to confer the anabolic benefits of testosterone such as increased muscle and bone mass while minimizing undesirable androgenic effects. Their tissue-selective activity and oral availability have sparked significant interest in their potential applications for conditions like muscle wasting, osteoporosis, hypogonadism, and frailty. We outline the chemical underpinnings of SARMs, their clinical promise, and the major challenges that have limited their regulatory approval to date. Although multiple SARMs have shown efficacy in increasing lean body mass in clinical trials, few have demonstrated consistent improvements in functional outcomes such as strength or mobility. Safety concerns, particularly regarding hepatotoxicity and cardiovascular risk, remain incompletely resolved. Nevertheless, a subset of SARMs is being actively evaluated for indications directly related to aging and sarcopenia. We conclude that SARMs are likely to enter clinical practice in select niches of men and women, especially among the frail, the elderly, or individuals with excessive loss of lean body mass. However, widespread approval will depend on future trials demonstrating both efficacy and long-term safety.

Senile osteoporosis (SOP) is becoming a critical public health burden particularly in aging societies due to escalating fracture susceptibility among elderly populations. Despite advances in SOP research, the mechanistic role of immune cell alterations in senile osteoporosis remains unclear.

This study advances cross-national research on gender and cognitive aging by introducing an index to identify individuals at risk of low cognitive performance, based on standardized tests of recall and verbal fluency. It examines gender disparities across welfare regimes, highlighting social integration, measured by a comprehensive index of close and extended social ties and activities, as a key modifiable factor. Using Wave 9 of the Survey of Health, Ageing, and Retirement in Europe (SHARE), we analyzed data from adults aged 50+ across 27 countries (n = 62,760), grouped into four welfare regimes. Bivariate statistics show that women had a significantly lower prevalence of below-average cognitive performance than men in the social-democratic and post-socialist regimes. No gender disparities were observed in the conservative and familialistic regimes. With respect to social integration, gender differences were relatively low in social-democratic and conservative regimes. By contrast, gender gaps emerged in familialistic and post-socialist regimes, where women were overrepresented at the lowest level of integration and more men reached higher levels. Multivariable logistic regression models show that after adjusting for social integration, women also had a cognitive advantage in the conservative and familialistic regimes, suggesting that social integration partially explains gender disparities in cognition, particularly in contexts characterized by traditional gender roles. These findings underscore the importance of the societal context and social integration in shaping cognitive aging for both women and men, and indicate potential for promoting cognition through social integration in several countries.

All animals perform physical activity, but humans engage in a special kind of physical activity - exercise, defined as discretionary physical activity for health and fitness. However, the effects of physical activity on whole-organism metabolism and health are unresolved, partly because it is difficult to measure the three major components of metabolism: active energy expenditure (AEE), resting energy expenditure (REE) and dietary induced thermogenesis (DIT), which together equal total energy expenditure (TEE). Three competing models make different predictions about the effects of AEE on REE and TEE. Whereas the traditional 'additive' model of energy balance predicts that AEE is independent of REE, the 'stress' model hypothesizes that AEE temporarily increases REE partly because of transient effects of excess post-exercise oxygen consumption (EPOC). In contrast, the 'constrained energy' model predicts that increases in AEE cause compensatory decreases in REE to maintain a constant TEE. Here, we discuss how different analytical models, measurements, experimental designs and statistical methods affect tests of these three models' hypotheses. After accounting for spurious correlations, we find that longitudinal and cross-sectional data provide most support for the additive model. However, more and better data are needed to test these hypotheses rigorously. To conclude, we also review the evidence, mostly from humans, that increased levels of physical activity slow aging and reduce vulnerability to disease by diverting energy away from processes that improve reproductive success at the expense of long-term health and by increasing energy allocation to repair, maintenance and capacity-building.

Telomeres represent a molecular nexus where genome stability, aging, disease susceptibility, and regenerative potential converge. Advances in understanding how telomeres are replicated, protected, and repaired now inform fundamental questions about human lifespan, tissue renewal, the molecular origins of age-related decline, and cancer evolution. This volume presents an integrated collection of perspectives spanning telomere architecture, replication dynamics, telomere-driven genome instability, and telomere maintenance by telomerase and Alternative Lengthening of Telomeres (ALT), while also charting new therapeutic directions grounded in telomere biology. Drawing on molecular, structural, organismal, and clinical research, this collection showcases a field in rapid motion, reshaping our view of regeneration, aging, and disease.

Current single-cell metabolomics approaches are limited by insufficient sensitivity, robustness and metabolite coverage. We present an ion mobility-resolved mass cytometry technology that integrates high-throughput single-cell injection with ion mobility-mass spectrometry for multidimensional metabolomic profiling. Ion mobility-enabled selective ion accumulation and cell superposition-based amplification strategies substantially enhance sensitivity, robustness and overall analytical performance. Combined with our computational tool, MetCell, this technology allows high-throughput analysis while achieving exceptional profiling depth, detecting over 5,000 metabolic peaks and annotating approximately 800 metabolites per cell-representing a 3-fold to 10-fold improvement over existing methods. It offers attomole-level sensitivity and captures a broad dynamic range of metabolites within individual cells. Applied to 45,603 primary liver cells from aging mice, it enabled accurate cell-type and cell-subtype annotation and revealed distinct metabolic states and heterogeneity in hepatocytes during aging. This platform sets a new benchmark for high-throughput single-cell metabolomics, advancing our understanding of metabolic heterogeneity at single-cell resolution.

Cellular senescence is a hallmark of aging and a driver of functional decline across tissues, yet its heterogeneity and context dependence have limited systematic study. The Common Fund Cellular Senescence Network (SenNet) Program addresses this challenge by generating multimodal, multi-tissue datasets that profile senescent cells across the human lifespan and complementary mouse models. The SenNet Data Portal (https://data.sennetconsortium.org) serves as the public gateway to these resources, providing open access to harmonized single-cell, spatial, imaging, transcriptomic, and proteomic data; senescence biomarker catalogs; and standardized protocols that can be used to comprehensively identify and characterize senescent cells in mouse and human tissue. As of January 2026, the portal hosts 1,753 publicly available human and mouse datasets across 15 organs using 6 general assay types. Experts from 13 Tissue Mapping Centers (TMCs) and 12 Technology Development and Application (TDAs) components contribute tissue data, analyze data, identify senescent biomarkers, and agree on panels for cross-tissue antibody harmonization. They also register human tissue data into the Human Reference Atlas (HRA) and develop user interfaces for the multiscale and multimodal exploration of this data. Built on a scalable hybrid cloud microservices architecture by the Consortium Organization and Data Coordinating Center (CODCC), the Portal enables data submission, management, integrated analysis, spatial context mapping, and cross-species senescence mapping critical for aging research. This paper presents user needs, the Portal architecture, data processing workflows, and senescence-focused analytical tools. The paper also presents usage scenarios illustrating applications in biomarker discovery, quality benchmarking, hypothesis generation, spatial analysis, cost-efficient profiling, and cell distance distribution analysis. Current limitations and planned extensions, including expanded spatial-omics releases and improved tools for senotype characterization, are discussed. SenNet protocols, code, and user interfaces are freely available on https://docs.sennetconsortium.org/apis.

Aging is frequently accompanied by inflammaging-a chronic, low-grade inflammatory state that contributes to functional decline and disease risk. Disruption of the intestinal barrier is increasingly being recognized as a key driver of inflammaging; however, its relationship with the gut microbiota in older adults remains poorly understood. Here, we demonstrate a significant association of intestinal barrier dysfunction markers with systemic inflammatory markers using a cross-sectional study in this population. Notably, the genus

Targeting cellular senescence presents a promising approach to slow visible skin aging and promote tissue repair. However, most preclinical models fail to capture the full architecture of human skin or accommodate diverse skin types, limiting their translational relevance. To address this gap, we developed a controlled ex vivo human skin explant platform using freshly acquired tissues from donors of varying ages and Fitzpatrick skin types. This model applies standardized UVA and UVB doses to induce reproducible photodamage, enabling the assessment of both preventative and reparative effects of topical treatments. The results showed that ND-ZnO and NAC reduced levels of p16^INK4a and p53, which are key biomarkers measuring cellular senescence; ND-ZnO and exosomes lowered IL-1β expression, which is a biomarker measuring inflammation. Histological analysis confirmed these findings, with ND-ZnO-treated skins preserved epidermal structure, reduced inflammatory features, and maintained dermal collagen organization. We then conducted a four-week single-patient case study using the same ND-ZnO formulation. Visible improvements in redness, pigmentation, and texture were observed, aligned with the molecular and histological changes seen ex vivo. These findings suggested that the ex vivo platform has the potential to be used as a more inclusive, human-relavent model for evaluating and quantifying the anti-aging efficacies of topical treatments across diverse skin types and age groups.

Aging reshapes immunity through immunosenescence and inflammaging, increasing susceptibility to infection, exacerbating chronic conditions, and blunting vaccine responses. This review frames "immunofitness" as a practical goal of healthy aging and examines how adult vaccination builds immune resilience. Vaccination strengthens adaptive memory, leverages adjuvants to optimize antigen presentation, and can reprogramme innate cells (trained immunity), yielding heterologous benefits beyond target pathogens. We integrate evidence in older adults for influenza, respiratory syncytial virus, pneumococcal, COVID-19, and recombinant zoster vaccines, including reductions in respiratory events, cardiovascular outcomes, hospitalization, and mortality. We highlight emerging platforms and precision vaccinology to tailor schedules by immune age, comorbidity, and frailty. Integrating routine, age-appropriate vaccination with lifestyle measures is a feasible, high-impact strategy to promote immunofitness.

Mitochondrial function can be affected by mutations in mitochondrial DNA (mtDNA). However, detecting de novo mutations in mtDNA has been challenging due to its high copy number, particularly in germline cells, and the low accuracy of conventional next-generation sequencing technologies. Using highly accurate duplex sequencing, we study the frequency of de novo insertion and deletion (indel) mtDNA mutations across multiple age groups in somatic and germline tissues of three mammalian species-mouse, macaque, and human. We demonstrate that, similar to de novo nucleotide substitutions, indels accumulate rapidly with age in somatic tissues with high energetic demand (brain and skeletal muscle) or high proliferation (liver). However, in oocytes, indels accumulate slower with age than nucleotide substitutions (or do not accumulate at all). The increases in indel frequency with age are driven mostly by deletions. Short tandem repeats are highly enriched for indels, implicating DNA replication slippage as a major driver of indel formation in mtDNA. For some species and tissues, indels are depleted at protein-coding sequences, however, indels that are multiples of 3 bp are not overrepresented. omfOurs is the most detailed study of de novo small indels in mtDNA to date. It provides parameters for models of mtDNA evolution, informs molecular mechanisms for a multitude of human genetic diseases, and illuminates the accumulation of indel mutations with age. Such accumulation may have functional consequences, as it affects reproduction later in life and drives the decline of mitochondrial function during aging.

Aging heightens susceptibility to ischemia-reperfusion (IR) injury, complicating liver transplantation, while the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome drives IR- and aging-induced inflammation. Although the effects of melatonin (MLT) on IR or aging have been studied separately, its impact on NLRP3 inflammasome activation in age- related IR injury remains unclear. This study investigates the impact of aging on hepatic IR injury, evaluating MLT therapeutic potential. for mitigating age-related damage. Aged and young male Wistar rats underwent 60 min of ischemia followed by 6-24 h of reperfusion. MLT (1 mg/100 g body weight) was injected 30 min before ischemia, 10 min before reperfusion, and 2 h after reperfusion. Liver injury, oxidative stress and inflammatory responses, and activation of the NLRP3 inflammasome pathway were evaluated. Aged livers exhibited exacerbated IR injury, marked by elevated transaminases levels, severe histopathological damage, increased oxidative stress and heightened inflammatory responses compared to young IR-injured rats. MLT treatment significantly alleviated liver injury, reducing oxidative stress and inflammatory markers expression. Aging-associated IR injury correlated with increased NLRP3 inflammasome activation and pyroptosis, evidenced by the upregulation of apoptosis-associated speck-like protein containing a CARD (ASC-1), caspase-1 cleavage, interleukin (IL)-1β maturation and increased Il18 and Gsdmd gene expression; while MLT treatment suppressed this activation, downregulating these markers in aged IR-injured livers. These findings highlight the efficacy of MLT in mitigating IR-induced liver damage in aged rats by inhibiting the NLRP3 inflammasome activation, supporting its potential as a therapeutic strategy for age-related liver dysfunction.

Synaptic aging is a core manifestation of brain aging arising from the convergence of fundamental biological aging processes, including genomic instability, loss of proteostasis, mitochondrial dysfunction, oxidative stress, and chronic low-grade inflammation. As highly energy-dependent and protein-rich sites of neuronal communication, synapses are particularly vulnerable to age-associated molecular stress. Accumulating evidence indicates that age-related impairments in synaptic vesicle trafficking, recycling, and neurotransmitter homeostasis precede neuronal loss and represent early drivers of cognitive decline and neurodegeneration. Disruption of vesicle dynamics compromises neurotransmitter release, synaptic plasticity, and circuit stability, thereby accelerating synaptic failure. Dysregulation of key neurotransmitter systems, including acetylcholine, dopamine, glutamate, and γ-aminobutyric acid, further exacerbates synaptic dysfunction and cognitive impairment. These changes are driven by interconnected aging mechanisms, wherein impaired proteostasis promotes the accumulation of dysfunctional synaptic proteins, mitochondrial dysfunction limits ATP availability for vesicle mobilisation, and persistent neuroinflammation heightens synaptic vulnerability. Emerging evidence also implicates age-related blood-brain barrier disruption and gut-brain axis dysregulation as additional modulators of synaptic integrity via immune, metabolic, and neurochemical pathways. This review synthesises recent advances in understanding the molecular mechanisms of synaptic aging, with a focus on vesicle dynamics and neurotransmitter imbalance, and discusses therapeutic strategies aimed at enhancing synaptic resilience to promote healthy brain aging.

Chronic UVA exposure accelerates photoaging by inducing oxidative stress and mitochondrial dysfunction. Autophagy maintains dermal homeostasis, but its decline promotes aging. Afzelin, a flavonoid with antioxidant activity, has not been fully studied for its autophagy-related photoprotective effects.

We evaluate the converging evidence positioning lithium as a systemic modulator of bone and brain health through shared molecular pathways. This review examines the molecular basis, preclinical data, and clinical observations suggesting that lithium-long established as first-line therapy for bipolar disorder-may simultaneously protect against osteoporosis and neurodegeneration as two clinical conditions increasingly recognized to share biological substrates.

Polylactic acid microplastics (PLA-MPs), despite being marketed as biodegradable and eco-friendly alternatives to conventional plastics, have raised growing concerns regarding their potential adverse effects on human health. The reproductive toxicity of PLA-MPs exposure in male mammals has been confirmed in previous studies, but its specific effects on testosterone biosynthesis remain unclear. Male mice were treated with PLA-MPs at doses of low, medium, and high (0.01, 0.1, and 1 mg/d, respectively) for a duration of 28 days in this study. Our results demonstrated that PLA-MPs were enriched in mouse testes and led to a dose-dependent decrease in the serum testosterone concentration. We also observed the accumulation of senescent Leydig cells in the testis, along with inhibited autophagy and mitophagy. Moreover, we identified the critical involvement of autophagy and mitophagy in PLA-MPs-induced Leydig cell senescence. Re-establishment of autophagy and mitophagy effectively reserved the senescence of Leydig cell. Overall, our study revealed that PLA-MPs inhibit autophagy and mitophagy, thereby promoting Leydig cell senescence and subsequently reducing testosterone synthesis and secretion. These results advance our understanding of the pathogenic mechanisms underlying PLA-MPs-induced reproductive toxicity in male mammals.

Cellular senescence increases in frequency with age and is implicated in age-related pathologies, and identifying circulating biomarkers of senescence holds great diagnostic potential. Circulating senescence signatures are predictive of many age-related traits and diseases, though cell type-specific senescence signatures have not been comprehensively explored. In this study, senescence signatures from the Senescence Catalog (SenCat), including 14 human cell types such as peripheral blood mononuclear cells, renal epithelial cells, vascular smooth muscle cells, among others, are examined for their clinical relevance in circulation in two longitudinal studies: 1,275 participants of the Baltimore Longitudinal Study of Aging (BLSA) and 997 participants of the Invecchiare in Chianti (InCHIANTI) study. Notably, pooled senescence proteins outperformed non-senescence proteins in predicting many clinical parameters such as age and hypertension, and in many instances cell type senescence signatures mapped most strongly to their corresponding health domain. Importantly, the immune cell senescence signature is associated with future onset of several diseases such as diabetes. This study demonstrates that circulating cell type-specific biomarkers of senescence can reveal higher resolution health status than previously attained.

Ageing is a multidimensional and heterogeneous process that progresses asynchronously across organ systems. Advances in multi-omics technologies have led to the development of diverse ageing clocks, including epigenetic, proteomic, metabolomic, and imaging-based models, which extend beyond estimating crude biological age to more precisely capture organ-specific ageing trajectories and predict age-related diseases and mortality risk. Population-scale studies demonstrate substantial within-individual variation in organ-ageing rates, showing that accelerated ageing in specific organs and increased numbers of aged organs markedly contribute to systemic dysregulation and elevated mortality risk. Multi-organ-ageing clocks further highlight the role of organ crosstalk networks, such as cardiovascular-pulmonary-cerebral interactions, in shaping healthspan and survival. Building on these insights, we propose a conceptual artificial intelligence (AI)-driven multi-omics health platform that integrates clinical data, imaging, wearable sensors, and organ-specific ageing clocks to enable continuous monitoring of biological age and early risk detection. This platform supports stratified management, whereby individuals with mild ageing may benefit from lifestyle-based interventions, while those with accelerated or multi-organ ageing receive personalised pharmacological and clinical strategies. Together, multi-omics ageing clocks and AI-enabled analytics provide a transformative framework for understanding human ageing, shifting from single-organ assessment to network-level evaluation and precision anti-ageing interventions. These advances lay the groundwork for a scalable national health ecosystem aimed at extending healthy lifespan and reducing population-wide mortality risk.

Delayed healing of diabetic wounds (DW) represents a significant complication among diabetic patients, for which current therapeutic approaches remain suboptimal. Accumulating evidence indicates that fibroblast senescence plays a critical role in the impaired healing of diabetic wounds. Abnormal mitochondrial morphology has long been associated with cellular senescence and age-related pathologies, suggesting that mitochondrial dynamics are compromised during senescence. In this study, we explored the potential mechanisms through which adipose-derived mesenchymal stem cell-derived exosomes (ADSC-Exos) facilitate diabetic wound repair. We initially confirmed the presence of a substantial number of senescent fibroblasts in diabetic wound tissues. Subsequent investigations demonstrated that exosomes derived from adipose-derived stem cells can effectively alleviate fibroblast senescence. In-depth mechanistic analyses revealed that these exosomes suppress the expression of SMARCAL1, a chromatin remodeling protein, thereby enhancing the transcription of mitochondrial dynamin-related protein 1 (Drp1), and ultimately restoring mitochondrial dynamics and alleviating senescence in human dermal fibroblasts (HDFs). In vivo experiments further demonstrated that exosome administration significantly reduced HDFs senescence and accelerated wound healing in a diabetic mouse model. Collectively, our findings suggest that ADSC-Exos promote diabetic wound healing by mitigating HDFs senescence via the SMARCAL1-Drp1-mitochondrial dynamics pathway. This study elucidated the molecular mechanisms underlying exosome-mediated fibroblast senescence rescue and proposed a novel therapeutic strategy for diabetes-related wound management through targeted clearance of senescent cells.

Blood pressure variability (BPV), fluctuations in blood pressure across beat-to-beat, 24-h, day-to-day, and visit-to-visit timescales, has emerged as a risk marker that is independent of mean blood pressure. Frailty, a multidimensional syndrome of diminished physiological reserve, shares core biology with BPV, including vascular aging, impaired baroreflex function, autonomic dysregulation, and chronic low-grade inflammation. This narrative review synthesizes mechanistic, epidemiologic, and clinical evidence linking BPV and frailty. Mechanistically, arterial stiffness and endothelial dysfunction attenuate baroreflex buffering and transmit excess pulsatile load, while autonomic imbalance and inflammaging destabilize hemodynamics, compromise cerebral autoregulation, and promote sarcopenia and functional decline. Across cohorts of community-dwelling older adults and high-risk groups (e.g., chronic kidney disease and hemodialysis), higher short- and long-term BPV correlates with prevalent frailty and predicts incident frailty, cognitive decline, falls, cardiovascular events, renal progression, and mortality, often with effect sizes on par with traditional risk factors. Ambulatory blood pressure monitoring best captures short-term and circadian variability (including nocturnal patterns), home monitoring informs day-to-day variability, and clinic series quantify visit-to-visit variability; average real variability appears particularly informative in older hypertensive populations. Clinically, incorporating BPV into assessment may refine frailty screening and risk stratification, revealing vulnerability that is not apparent from mean blood pressure alone. Therapeutic implications include prioritizing long-acting antihypertensive regimens that stabilize BPV, optimizing adherence and lifestyle (exercise, diet, stress reduction), and addressing metabolic and inflammatory drivers, while recognizing that interventional evidence targeting BPV per se remains limited. Key gaps include heterogeneous BPV metrics and frailty definitions, limited standardization of measurement protocols, and a paucity of trials testing whether reducing BPV improves functional outcomes. Future work should not only harmonize BPV phenotyping and frailty definitions, but also investigate whether stabilizing BPV translates into tangible improvements in functional status, falls, and survival. Incorporating digital health tools, such as continuous monitoring and AI-driven analytics, may facilitate early detection of hemodynamic instability and its integration into frailty care models.

Longevity critically influences biocontrol efficacy, yet direct artificial selection for lifespan extension has rarely been documented in natural enemies. Here, we established long-lived lines of the parasitoid wasp Pachycrepoideus vindemmiae through artificial selection and investigated their phenotypic and genomic consequences. Two longevity-selected lines (LL1 and LL2) and their corresponding original control lines (OL1 and OL2) were generated. Females of LL1 showed a significantly extended lifespan by the fifth generation, whereas LL2 did not respond to selection. Notably, the longevity advantage of LL1 females persisted at generations 15 and 33 after cessation of selection. LL1 females also exhibited increased lifetime fecundity and enhanced resistance to cold and starvation, without changes in developmental duration, sex ratio, or body size. To explore the genetic basis of these traits, whole-genome resequencing was conducted on females and males from LL1 and OL1 at generation 33. Population genomic analyses revealed clear genetic differentiation between lines but not between sexes within lines. Selective sweep analyses in females identified genomic regions under selection enriched in energy metabolism and stress regulation, and integration with expression data revealed SNP variation and line-specific cold-induced expression of heat shock protein genes. Together, these results indicate that artificial selection can potentially produce a stable extension of female lifespan in P. vindemmiae, accompanied by distinct genomic signatures in the responsive line. Our findings provide insights into the genetic architecture of longevity and stress resistance in parasitoid wasps while highlighting both the opportunities and constraints of artificial selection for biological control improvement.

Mitochondrial dysfunction is a pervasive hallmark of diverse diseases. In endothelial cells (ECs), oxidative stress, bioenergetic failure, and dysregulated mitochondrial dynamics (fusion-fission, mitophagy) damage the endothelium and promote vascular pathologies such as diabetes, atherosclerosis, and aging. Mitochondrial augmentation, via direct transplantation of isolated mitochondria or cell-to-cell transfer of the organelle, has emerged as a strategy to restore mitochondrial function in metabolically compromised cells. We recently established that overexpressing nuclear respiratory factor 1 (NRF1), a driver of mitochondrial biogenesis, in mesenchymal stem cells (MSCs) increases mitochondrial content and preserves mitochondrial function under senescence-inducing stress. Here, we advance NRF1-primed MSCs as enhanced mitochondrial hubs for intercellular mitochondrial delivery to cells undergoing mitochondrial dysfunction. We hypothesized that NRF1 overexpression engages mitochondrial transfer machinery, thereby enhancing both tunneling nanotube (TNT)- and extracellular vesicle (EV)-mediated mitochondrial transfer to stressed ECs, improving EC mitochondrial fitness and health. mRNA-mediated NRF1 priming of MSCs increased expression of proteins involved in mitochondrial motility and transfer, enhanced TNT formation, and increased production of mitochondria-containing EVs. Single-cell RNA sequencing (scRNA-seq) results show that NRF1 priming shifted MSCs into distinct transcriptional states, with NRF1-enriched clusters exhibiting coordinated upregulation of cell-adhesion/cytoskeletal connectivity programs and vesicle-fusion/trafficking pathways, features consistent with enhanced structural coupling and secretory transfer capacity. NRF1 priming increased TNT-like F-actin intercellular bridges in direct co-culture and elevated mitochondria-containing EV transfer in transwell assays, demonstrating augmented mitochondrial delivery through both contact-dependent and contact-independent routes. Consequently, recipient ECs displayed reduced mitochondrial ROS, preserved membrane potential, improved oxidative phosphorylation and ATP production, rebalanced mitochondrial dynamics of fusion-fission and mitophagy. NRF1-primed MSCs further attenuated oxidative stress-induced EC senescence and apoptosis. Together, these findings identify NRF1 activation as a mechanism to reprogram MSCs into high-capacity mitochondrial donors and support NRF1-driven mitochondrial hub engineering as a strategy to strengthen mitochondrial transfer-based therapies for diseases characterized by mitochondrial dysfunction.

Skin aging is driven by the progressive exhaustion of stem cell niches, epigenetic drift, and accumulation of senescent cells, which together promote both aesthetic decline and a pro-tumorigenic microenvironment. This review focuses on the emerging methodological theme of small-molecule-mediated reprogramming as a strategy to restore skin homeostasis. We evaluated the shift from traditional regenerative medicine toward targeted chemical modulation, focusing on the use of small-molecule cocktails to induce partial reprogramming and rejuvenate aged stem cell populations without erasing cellular identity. Central to this theme is the integration of high-throughput virtual screening and AI-driven predictive modeling to identify potent modulators of Wnt, Notch, and TGF-β pathways. We further bridge the gap between preclinical innovation and clinical application by analyzing "serious clinical studies" with proven efficacy, including randomized controlled trials of stem cell-derived secretomes and clinically validated small molecules, such as tretinoin and firming peptides. By contextualizing advanced delivery systems, including microneedles and stimuli-responsive nanoparticles, within this reprogramming framework, we demonstrate how spatially controlled interventions can optimize clinical outcomes. This review provides a unified perspective on how the intersection of computational drug discovery and niche-targeted pharmacology is moving small-molecule skin rejuvenation from theoretical potential to widespread clinical translation.

Redox proteomics generates bounded biochemical measurements that are categorically mismatched to conventional linear algebraic formalisms. This work introduces Oxi-Shapes, a tropical geometric framework for the measurement-native analysis of bounded redox proteomic data. Oxi-Shapes represents cysteine oxidation as a scalar field over a discrete lattice, enabling global and site-wise analysis without rescaling, interpolation, or kinetic assumptions. At the global level, the framework yields internal redox entropy, lattice curvature, and derived energy functionals that characterise the geometric structure of the redox proteome. At the site level, Oxi-Shapes defines a bounded change space that makes explicit hard geometric constraints on admissible redox transitions and enables a normalised signed representation of site-wise change as a fraction of available redox freedom. Applied to an ageing mouse brain dataset, Oxi-Shapes reveals that a small decrease in mean oxidation arises from a profound redistribution of site-wise redox states, with thousands of residues shifting toward the reduced absorbing boundary. These results demonstrate that categorically correct algebraic representations expose structure in proteomic data that is inaccessible to mean-centric or unbounded analyses.

Background: Aging and various pathological conditions lead to pressure-overload in the left ventricle, promoting maladaptive hypertrophic remodeling and subsequent cardiac dysfunction, ultimately increasing the risk of heart failure. Galectin-3 (Gal-3) plays a central role in this process; however, its critical intracellular functions complicate direct therapeutic targeting. Notably, pathological microenvironments trigger the proteolytic cleavage of Gal-3 into distinct N- and C-terminal fragments. The specific contributions of these cleaved epitope forms to adverse cardiomyocyte mechanotransduction, and their potential as precision therapeutic targets in contrast to the full-length protein, remain unresolved. Methods: To address this gap, we combined rodent models of aging and pressure-overload (PO) induced cardiac hypertrophy with PO mechanobiology-driven in vitro assays and validation in human cardiac tissue and serum. Gal-3 epitope abundance, localization, phosphorylation, oligomerization, and downstream signaling were quantified using biochemical, imaging, and functional approaches. Results: We found that extracellular oligomers of the Gal-3 C-terminal epitope accumulated in serum and on cardiomyocyte surfaces in hypertrophic rodents and human subjects, where they correlated with adverse remodeling and cardiomyocyte loss. Treatment with Amalaki Rasayana (AR), a standardized nutraceutical-based cardioprotective Ayurvedic phytomedicine, and its bioactive component gallic acid (GA) significantly reduced circulating and surface-associated Gal-3 C-epitope oligomers and attenuated hypertrophy-associated cytotoxic signaling. Mechanistically, AR/GA enhanced Ser6 phosphorylation of Gal-3, promoting intracellular retention, while limiting pathological secretion and deleterious extracellular oligomerization. Following AR/GA treatment, the binding of preformed Gal-3 C-epitope oligomers to cardiomyocyte surfaces were further inhibited, thereby suppressing maladaptive mechanotransductive signaling. Importantly, circulating Gal-3 C-epitope oligomers, together with atrial natriuretic peptide (ANP), constituted a drug-responsive biomarker panel that accurately tracked hypertrophy regression, serving as an indicator of drug efficacy. Conclusions: In summary, Gal-3 C-epitope oligomers represent pathogenic signaling, drug-responsive therapeutic targets and circulating biomarkers of cardiac hypertrophy, with broader relevance to other Gal-3-driven neoplastic, fibrotic, and inflammatory diseases.

Mitochondria are essential for metabolic homeostasis and neuronal function, extending beyond ATP production to roles in cell signaling, inflammation, and stress responses. Mitochondrial dysfunction, marked by abnormal morphology, ATP deficiency, and oxidative stress, is a key feature of aging-related diseases and neurodegenerative disorders like Parkinson's. Given the importance of mitochondrial homeostasis to brain function, this study aimed to determine the possible vitamin D (VD3) effects on mitochondrial susceptibility to Ca2+-induced mitochondrial permeability transition pore (mPTP), bioenergetics in brain mitochondria, and redox balance. We demonstrated that VD3 protects isolated brain mitochondria. Male rats were divided into control and VD3-treated groups. Brain mitochondria were isolated for assessments of Ca2+-induced mitochondrial swelling secondary to MPTP opening, oxygen consumption (states 3 - ADP - stimulated and state 4 - in the presence of oligomycin), and the respiratory control ratio (RCR). Oxidative stress parameters (nitrite and lipid peroxidation), superoxide dismutase (SOD) activity, and reduced glutathione (GSH) levels were also evaluated. The results revealed that VD3 treatment blocked Ca2+-induced mitochondrial swelling secondary to MPTP opening. Additionally, VD3 improved mitochondrial RCR compared to controls, in the presence of complex I (malate/glutamate) and complex II (succinate) substrates, reduced mitochondrial succinate-driven H2O2 release, and enhanced SOD activity and GSH levels. These changes occurred in parallel with decreased nitrite and TBARS formation. These results suggest that vitamin D3; confers mitochondrial neuroprotection, emphasizing its prospective role in maintaining neuronal homeostasis and mitigating neurodegenerative processes.

Background: Epigenetic clocks based on DNA methylation (DNAm) provide quantitative indicators of biological aging. However, the extent to which diverse lifestyle factors influence DNAm-based aging measures remains unclear, especially in Japanese populations. We aimed to evaluate the associations between 52 lifestyle-related factors and multiple epigenetic aging indicators, including six DNAm ages (Horvath, Hannum, PhenoAge, GrimAge, GrimAge v2, and PCPhenoAge specific to Japanese Population), the Dunedin PACE, and six corresponding age acceleration indices. We recruited 287 Japanese adults between January and December 2024 and evaluated the association of these aging indices with their responses on lifestyle questionnaires using multivariable linear regression models. We entered items either individually or simultaneously while adjusting for major confounding factors. Results: DNAm ages showed strong intercorrelations, whereas age acceleration indices demonstrated weaker correlations. Several lifestyle factors such as late-night eating, processed food intake, smoking-related behaviors, high-intensity interval training, and thermal relaxation habits exhibited strong and clock-specific associations with aging indices. In simultaneous models incorporating all 52 factors, only a limited subset, with factors such as smoking exposure, high-intensity exercise, and sauna or stone spa use, were associated with aging indices. Each DNAm aging indicator demonstrated a distinct pattern of association with lifestyle exposure, indicating that epigenetic aging indices capture different physiological processes. Conclusions: These findings may improve our understanding of lifestyle-epigenetic interactions and provide evidence supporting the use of DNAm-based biological age as a tool for personalized healthcare in Japan.

Age-related differences in orthodontic tooth movement (OTM) and mechanical force-induced osteogenesis have been reported. Mitophagy plays a crucial role in bone metabolism and various age-related diseases, and BCL2-interacting protein 3 (BNIP3) is a mitophagy-related receptor. This study aimed to elucidate the role of mitophagy associated with BNIP3 on age-related changes in the orthodontic tension-driven osteogenic differentiation of periodontal ligament stem cells.

Aging contributes to hepatic steatosis by increasing de novo lipogenesis. The Forkhead box O6 (FOXO6) transcription factor links insulin signaling to lipid metabolism. Activated FOXO6 induces hyperlipidemia and decreases peroxisome proliferator-activated receptor alpha (PPARα), thereby promoting hepatic lipogenesis. In this paper, we describe the role of FOXO6 in hepatic steatosis in aged male rats and liver cells, and examine the relationship between FOXO6 and PPARα, and the functional consequences of their altered interaction. We find that FOXO6 induces lipid accumulation by inhibiting PPARα in aged male rat livers. Our data show that AKT signaling negatively regulates FOXO6-induced hepatic lipid accumulation, and that a key β-oxidation gene, PPARα, is decreased in aged livers. We further demonstrate that FOXO6 activation decreases PPARα expression and increases lipid accumulation. Furthermore, interaction between FOXO6 and PPARα promotes hepatic steatosis in aged males. Also, high glucose upregulates Foxo6, reduces β-oxidation gene expression, and increases cellular TG-mediated lipid accumulation. Transcriptional activation of FOXO6 by aging and high glucose cause lipid accumulation by downregulating PPARα and hyperglycemia-responsive genes in aged male rats and liver cell cultures. We provide evidence that age-related insulin resistance suppresses β-oxidation through interaction between FOXO6 and PPARα, thereby promoting hepatic lipid accumulation in aged male rats.

With increasing global life expectancy, the prognostic significance of kidney function in centenarians and supercentenarians should be clarified. The conventional estimated glomerular filtration rate (eGFR) threshold of < 60 mL/min/1.73 m

This study investigated the mechanistic intersection between aging, diabetes mellitus (DM), and prelamin A accumulation in vascular calcification (VC) progression in patients with peripheral arterial disease (PAD) undergoing lower limb amputation. Arterial segments were collected from amputated PAD patients with (PAD + DM, n = 10) and without DM (PAD, n = 8), as well as from non-vascular amputated patients (CTRL, n = 3). Additional in vivo and

Rhythmic auditory cueing (RAC) improves spatiotemporal gait parameters in older adults, often using isochronous rhythmic cues (i.e., with constant inter-beat-intervals). However, healthy gait contains fractal-like variability, (i.e., with persistent long-range correlations; LRC) which is disturbed when walking to isochronous cues. Embedding auditory cues with a fractal structure increases LRC in gait among young and older adults, though middle-aged adults are under researched. Walking requires greater cognitive resources with increased age, though how different cue-types interact with attentional load during RAC is under researched. This may depend on beat perception, as those with better beat perception benefit more from RAC. The aim of this study was to investigate the optimal parameters for RAC across the adult lifespan. We predicted that 1) walking to fractal cues would increase LRC in gait across the adult lifespan; 2) increasing attentional load would decrease LRC in gait, particularly for older adults. Moderating effects of beat perception on the impact of cue-type on LRC were also explored. Young, middle-aged, and older adults (n = 62) walked around an elliptical track in silence and in three cued walking conditions of increasing attentional load. Tones were presented in isochronous and fractal rhythms. Fractal cues increased LRC in gait, with qualitatively greater increase among middle-aged adults. Attentional load had no effect on LRC in gait. Isochronous cues resulted in decreased LRC in gait, particularly for those with better beat perception. The optimal parameters of RAC therefore depend on age, beat perception, and the target gait parameter.