Longevity Papers

Lipid nanoparticle (LNP)-based mRNA vaccines have transformed cancer immunotherapy, yet their efficacy in older individuals, who represent the majority of cancer patients, remains poorly understood. Here, we uncover a critical and previously underappreciated barrier to mRNA LNP cancer vaccine performance in aged hosts: impaired systemic transgene expression. Using the SM-102 mRNA LNPs as a benchmark formulation, we show that while local immune activation and antigen presentation at the injection site and draining lymph nodes remain largely intact with age, transgene expression in peripheral organs, including the liver, lungs, and spleen, is markedly reduced. This deficit limits the magnitude and durability of CD8 and CD4 T cell responses and substantially compromises tumour control. Transcriptomic profiling further reveals that attenuated transgene expression parallels broad attenuation of antigen processing, presentation, and activation pathways in immune cells from aged animals, implicating impaired systemic mRNA translation as a central driver of the downstream immune defects and antitumour efficacy loss. Building on these insights, we identify a rationally selected LNP formulation that reestablishes distal antigen expression across age groups as an engineering strategy to revive T cell immunity, achieving full rescue of therapeutic efficacy in aged mice without additional intervention. Together, these findings establish systemic mRNA translation as a tuneable lever of vaccine performance and highlight that optimizing LNP formulations to sustain systemic transgene expression across age groups may enable next-generation, age-adaptive mRNA vaccines for cancer and other diseases of aging.

Ageing is the primary risk factor for many chronic, degenerative, and life-threatening disorders, yet the translational pipeline for geroprotective interventions remains comparatively sparse. Short‑lived, experimentally tractable models with conserved ageing pathways, particularly Caenorhabditis elegans, Drosophila melanogaster, and the African turquoise killifish (Nothobranchius furzeri), have expanded discovery beyond traditionally mammalian-centric pipelines. By leveraging advances in automation, high-content imaging, and artificial intelligence (AI), these models have shifted the field from low-throughput, reductionist assays to scalable, mechanistically informed in vivo phenotypic discovery. Here, we review recent advances in middle- to high-throughput screening (HTS) technologies across these models, review key phenotypic and molecular biomarkers, such as motility, cognition and memory, intestinal integrity, mitochondrial function, and immune response, and discuss their strengths and limitations. We further evaluate the expanding role of AI from in silico screening, automated and high-content phenotyping, to integrative multi-layer mechanistic inference. Key challenges, including data standardisation, reproducibility across laboratories, limited cross‑species pharmacokinetic comparability, AI model interpretability, and the translational gap between invertebrate hits and vertebrate or mammalian efficacy, are also discussed. By highlighting recent developments in in vivo disease models, HTS methodologies, and AI integration, this review provides a comprehensive resource for developing effective models and screening strategies to accelerate therapeutics for ageing and age-related diseases.

Ageing is accompanied by physiological and lifestyle changes that may influence gut microbial metabolism. Short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate, are microbial metabolites derived from dietary fibre fermentation and play important roles in host metabolic and immune function. This systematic review and meta-analysis examined age-related differences in faecal SCFA concentrations among apparently healthy adults. Following PRISMA guidelines, searches across five databases (MEDLINE, Embase, Cochrane Central, Scopus, and PubMed) identified 18 eligible studies comparing faecal SCFA levels between stratified age groups. Random-effects meta-analyses showed that older adults had lower faecal concentrations of acetate (standardised mean difference [SMD] -0.53, 95% CI -0.90 to -0.16; p = 0.005), propionate (SMD -0.32, 95% CI -0.53 to -0.12; p = 0.002), butyrate (SMD -0.25, 95% CI -0.44 to -0.05; p = 0.015), and total SCFAs (SMD -0.59, 95% CI -0.98 to -0.21; p = 0.003) compared with younger adults. Insufficient reporting of dietary intake and physical activity precluded reliable meta-regression analyses to determine the contribution of these lifestyle factors to between-study heterogeneity. However, meta-regression identified methodological factors, specifically immediate post-collection freezing of faecal samples, exclusion of participants using antibiotics and the geographic region of studies, as significant sources of heterogeneity. Collectively, these meta-analyses provide quantitative evidence that ageing is associated with reduced faecal SCFA concentrations, indicating a potential age-related decline in microbial fermentation capacity. Understanding whether this decline is a modifiable feature of healthy ageing warrants investigation in future longitudinal and interventional studies.

The lungs harbor diverse microbial communities that may influence pulmonary health, potentially through lung aging. While accelerated lung aging can increase susceptibility to pulmonary diseases, no studies have yet linked the lung microbiome to biological aging in disease-free individuals.

Aging is the strongest risk factor for amyotrophic lateral sclerosis (ALS), yet how normative aging programs intersect with disease mechanisms remain unclear. Here we generated a lifespan-resolved, cell type- and region-specific single-nucleus RNA-sequencing atlas of the mouse spinal cord spanning embryonic development through advanced age in WT mice and end-stage disease in the SOD1-G93A ALS model. This resource enabled systematic comparison of physiological aging trajectories with disease-associated transcriptional changes across spinal cord cell types and rostrocaudal regions. We found that SOD1-G93A transcript and protein states differed markedly across spinal regions during disease onset and progression, and these molecular patterns paralleled the relative resilience of cervical regions and the heightened vulnerability of lumbar regions to degeneration in this transgenic mouse model. Prior to disease onset, we identified reduced ubiquitin expression that primed region-specific disruption of proteostasis in the SOD1-G93A spinal cord. Despite these disease-associated changes, aging-related transcriptional programs were largely preserved across most cell types, arguing against a global acceleration of aging in ALS. Instead, microglia emerged as a key exception, exhibiting accelerated and rewired aging- and disease-associated gene expression modules regulated by MITF and NRF2. Together, these findings provide an anatomically, cellularly, and temporally resolved framework for understanding how aging programs interact with disease-specific pathways to shape regional dysfunction and neurodegeneration in ALS.

Promoting brain health is vital for well-being and reducing healthcare burdens. Brain health as measured with the Brain Age Gap (BAG) - the difference between chronological and predicted brain age- relates to many factors. However, a holistic view, integrating the range of factors an individual brain is exposed to, is missing for understanding how the exposome shapes brain health. After computing BAG as an indicator of grey matter (GM) health, we predicted it using machine learning based on 261 exposome variables (spanning biomedical, environmental, lifestyle, socio-affective, and early life domains) in UK Biobank participants. Exposome data can predict GM health with factors pertaining to cardiovascular and bone health, along with alcohol and smoking, nutrition and diabetes showing greater contribution to the prediction. In such domains, life period and duration of exposure appeared crucial. These findings call for early prevention in cardiovascular and metabolic health to promote life-long brain health.

Abnormal cell fate transition determines cell instability, which can contribute to disease development. In chronic kidney disease, many renal tubular cells exhibit senescent phenotypes. The fundamental mechanisms of this fate transition remain undetermined. Here we discover that WNT10B, a ligand of the Wnt family, accelerates CKD progression through tubular senescence and proinflammatory microenvironments. Mechanistically, WNT10B mediates metabolic reprogramming from fatty acid oxidation to glycolysis, thus promoting cell senescence and cytokine secretion. Genetic ablation of Wnt10b in male CKD mouse model effectively inhibits cell senescence, inflammation, and fibrogenesis by maintaining metabolic homeostasis. Conversely, Wnt10b transgene in tubular cells aggravates metabolic imbalance, and promotes tubular senescence and fibrogenesis. Forkhead box O6 (FOXO6), a DNA-binding transcription factor, mediates the signal transduction cascade of WNT10B. ChIP-, bulk RNA-, and single-nucleus RNA- sequencing and biological assays verify that FOXO6 transcriptionally modulates PPARA and PKM to control metabolic reprogramming and regulate senescence fate transition in tubular cells. Therefore, the study reveals that WNT10B/FOXO6 signaling controls tubular cell senescence fate, and sheds a light on potential intervention targets to protect against CKD.

Despite the well-known role as degradative organelles, lysosomes have been identified as a central signaling hub in maintaining cellular homeostasis. Lysosomal dysfunction is a well-established driver of cellular senescence and age-related pathologies. However, the precise molecular mechanisms through which lysosomes actively regulate aging remain unclear. Excitingly, latest studies show that lysosomes are not merely passive in aging but may actively govern longevity. In this review we summarize two significant discoveries about lysosome and senescence. Li et al. discovered the lysosomal surveillance response (LySR) and Zhang et al. uncovered transgenerational lysosomal signaling. These pathways substantially contribute to enhanced organismal longevity. We further discuss the transcription factor EB (TFEB) as a central regulator linking lysosomal activity to senescence and tissue homeostasis. Together, these findings reposition lysosomes as dynamic regulators that integrate stress and metabolic cues to modulate aging programs. Therefore, targeting lysosomal signaling emerges as a promising strategy for extending healthspan and mitigating age-related disorders.

Cellular senescence is defined as an irreversible growth arrest observed when cells are exposed to a variety of stressors, including DNA damage, oxidative stress, or nutrient deprivation. Although senescence is a well-established driver of aging and age-related diseases, it is a highly heterogeneous process with significant variations across organisms, tissues, and cell types. The relatively low abundance of senescent cells in healthy aged tissues poses a major challenge to the longitudinal study of senescence in specific organs, including the human lung. To overcome this limitation, we developed a positive-unlabeled learning framework to generate a comprehensive list of senescence marker genes in human lungs (termed SenSet) using the largest publicly available single-cell lung dataset, the Human Lung Cell Atlas (HLCA). We validated SenSet in a highly complex ex vivo human 3D lung tissue culture model subjected to the senescence inducers bleomycin, doxorubicin, or irradiation, and established its sensitivity and accuracy in characterizing senescence. Using SenSet, we identified and validated cell-type-specific senescence signatures in distinct lung cell populations upon aging and environmental exposure. Our study provides a comprehensive analysis of senescent cells in the healthy aging lung, presenting fundamental implications for our understanding of major lung diseases, including cancer, fibrosis, chronic obstructive pulmonary disease, or asthma.

Aging people with HIV are increasingly affected by multimorbidity and polypharmacy, which heighten the risk of drug-drug interactions (DDIs) and potentially inappropriate medications (PIMs). This study evaluated a multidisciplinary, AI-supported quality improvement intervention designed to optimize polypharmacy management in older people with HIV.

As a key tool for assessing aging, DNA methylation clocks are mostly constructed based on European and American populations and rely on the high-cost Infinium MethylationEPIC microarray. These factors limit their widespread application in the Chinese population.

Emergency department (ED) length of stay (LOS) is associated with adverse outcomes and increases with age, but the extent to which this reflects differences beyond triage acuity is unclear. Emergency department (ED) length of stay (LOS) is associated with adverse outcomes and increases with age, but the extent to which this reflects differences beyond triage acuity is unclear.We conducted a retrospective cohort study of adult ED visits at a tertiary hospital in Hungary between 2016 and 2023 (n = 188,082). Triage data have been available from 2019 onward. LOS was modelled using gamma regression, adjusting for age, triage category, sex, season, and an age-triage interaction, with sensitivity analyses incorporating additional operational covariates. Admission and ED mortality were analysed using multivariable logistic regression. ED LOS increased progressively with advancing age across all triage categories. Mean LOS rose from 5.9 h in patients <65 years to 9.7 h in those ≥85 years (+64%). Age remained independently associated with longer LOS after adjustment (rate ratio per year 1.005, 95% CI 1.004-1.006), with a significant age-triage interaction (p < 0.001). Higher-acuity triage assignments were more frequent with age, yet age-related LOS differences persisted within each triage category. ED mortality increased markedly with advancing age. These patterns were consistent across sensitivity analyses. Advancing age was associated with longer ED LOS across all triage categories, independent of triage acuity, indicating that age-related differences in emergency care trajectories extend beyond differences in initial acuity. The persistence of LOS prolongation across triage strata suggests that standard acuity-based assessment does not fully capture aging-related vulnerability. From a geroscience perspective, ED LOS may reflect as a routinely available, system-level signal of aging-related vulnerability beyond triage acuity, with direct relevance for early risk identification, geriatric care pathways, delirium prevention, and health system planning.

Aging is the leading risk factor for cognitive impairment and neurodegeneration, yet molecular changes that unfold in the brain over time, and how they drive this vulnerability, remain unclear. The naturally short-lived African turquoise killifish (Nothobranchius furzeri) offers a powerful model to understand brain aging on an accelerated timescale and test the impact of potential interventions. Here, we present a multi-omic atlas of brain aging of female and male African turquoise killifish from 2 independent genetic strains of different captive lifespans, encompassing single-nuclei RNA-seq, single nuclei ATAC-seq, and bulk ATAC-seq to capture transcriptional and regulatory changes. Interestingly, our atlas indicates that aging leads to a significant expansion of microglia numbers, regardless of sex or strain, which we independently validate using in-situ hybridization. In addition, we identify robust and conserved gene regulation changes, that are consistent with activation of glucocorticoid signalling as a hallmark (and potential driver) of vertebrate brain aging. Furthermore, pharmacological inhibition of glucocorticoid receptor activity starting at middle-age led to significant rescue of key molecular and cellular aging phenotypes. Thus, our study provides a powerful resource and framework to leverage the African turquoise killifish and rapidly uncover actionable pathways driving brain aging.

The extension of lifespan has evolved independently multiple times in mammals. Long-lived species exhibit markedly lower cancer mortality rates, indicating that they may have evolved enhanced cancer resistance to accommodate their prolonged lifespan. The FOXO protein family is considered to play key roles in modulating lifespan and cancer resistance in model organisms. However, the underlying molecular mechanisms of the FOXO protein family regulating lifespan extension and cancer resistance in long-lived species remain poorly understood. Here, evolutionary analysis of four FOXO genes across 137 mammalian species revealed all the four genes were under overall purifying selection. Nonetheless, we detected modestly elevated ω values in long-lived lineages relative to background groups, and 18 positively selected sites were identified in the four FOXO genes in long-lived mammals. To further test whether these FOXO genes have occurred functional changes, we selected FOXO3 and FOXO4 to perform functional validation. Cell experiments demonstrated that bowhead whale FOXO3 and FOXO4 significantly inhibited HeLa cell proliferation, migration, and invasion. Subcellular localization assays showed that mouse FOXO3 and FOXO4 were mostly distributed in the cytosolic cytoplasm, whereas bowhead whale FOXO3 and FOXO4 were predominantly localized in the nucleus, which may increase transcriptional activity and inhibit tumorigenesis in cetaceans. In particular, bowhead whale FOXO3 was found to upregulate the tumor suppressors PTEN and FASL while downregulating the oncogene BCL6, suggesting that this FOXO3-driven expression pattern may underlie cancer resistance in long-lived mammals. Overall, our findings provide novel insights into the molecular mechanisms underlying the cancer resistance in mammals.

Brain aging involves progressive structural, functional, and molecular changes that impair cognition and increase vulnerability to neurodegenerative diseases. While neurons have traditionally received primary research focus, recent advances in single-cell transcriptomics, spatial genomics, and functional imaging reveal that glial cells-microglia, astrocytes, and oligodendrocytes-undergo profound, heterogeneous alterations during aging that actively drive brain dysfunction. These changes include microglial transition from homeostatic surveillance to inflammatory, dystrophic states; astrocyte shift from metabolic support to atypical reactive phenotypes with impaired neurovascular coupling; and oligodendrocyte dysfunction causing progressive myelin degeneration. Critically, glial aging exhibits marked regional heterogeneity, with hippocampus and prefrontal cortex showing heightened vulnerability while cerebellum remains relatively preserved, patterns mirroring cognitive decline topography. At the molecular level, glial senescence involves interconnected mechanisms including cellular senescence with senescence-associated secretory phenotype (SASP), oxidative stress and mitochondrial dysfunction, impaired proteostasis and autophagy, epigenetic alterations favoring inflammatory gene expression, and dysregulated inflammatory signaling pathways. These changes propagate through complex glial-glial and neuron-glia interaction networks, amplifying dysfunction beyond individual cellular deficits. Importantly, glia retain plasticity enabling therapeutic intervention through diverse strategies: senolytic elimination of senescent cells, microglial phenotype modulation, remyelination enhancement, metabolic interventions, and lifestyle modifications including exercise and dietary approaches. This review synthesizes current understanding of glial heterogeneity, regional vulnerability patterns, underlying molecular mechanisms, and emerging therapeutic opportunities, providing an integrated framework for targeting glial dysfunction to promote healthy brain aging and prevent cognitive decline.

Long-lived and large-bodied organisms face an inherent challenge: The more cells they contain and the longer they live, the greater the cumulative risk of acquiring mutations that can drive cancer. Yet, paradoxically, cancer incidence does not always scale with size or lifespan-a phenomenon known as Peto's paradox. This observation implies that some species have evolved highly effective anticancer mechanisms that preserve cellular and tissue integrity over long lifespans. Whales, which combine extreme longevity with vast numbers of cells, exemplify this paradox. In this commentary, we discuss a recent study showing that a key contributor to bowhead whales' exceptional lifespan and cancer resistance is their superior genome maintenance capacity. We further discuss DNA repair as a determinant of longevity in other long-lived species and explore how these naturally occurring mechanisms could be harnessed to improve genome integrity, reduce cancer risk, and promote healthy aging in humans.

Epigenetic marks are essential for maintaining cell identity, yet how epigenetic memory is robustly preserved across cell cycles while remaining plastic during cell-state transitions remains unclear. Here, we develop a theory of epigenetic memory that incorporates chromatin compartmentalization and mark modifications, including long-range spreading, writing, and erasing. The spreading-writing-erasing model generates self-sustaining epigenetic mark patterns across multiple cell generations. The model also reveals that to induce or remove a heterochromatic compartment, the writing or erasing strength must exceed a finite threshold, which depends on the long-distance scaling of the contact probability between two chromatin loci. Intriguingly, the scaling exponent for human cells appears to be evolutionarily selected for stability and plasticity in epigenetic memory. We demonstrate that adding noise in parental histone segregation during DNA replication and accelerating cell proliferation significantly enhance reprogramming efficiency in induced pluripotent stem cells. Finally, our theory also predicts cellular senescence arising from chromatin reorganization after many cell generations.

Aging impairs vaccine responses. Dai et al. reported that defective cDC2 migration in immunized old mice, diminishing humoral and cellular immunity. Oral yeast-derived nanoparticles restore DC migration and vaccine efficacy. These findings establish impaired DC migration as a key mechanism of age-related immune decline, introducing a noninvasive strategy to correct immunosenescence.

Preeclampsia is a pregnancy-specific hypertensive disorder affecting up to 5% of pregnancies worldwide and is one of the leading causes of maternal and fetal morbidity and mortality globally. It is increasingly recognized that preeclampsia, from both clinical and pathophysiological standpoints, is a heterogeneous disease and that several mechanisms may lead to a clinical syndrome of hypertension, systemic disease, and proteinuria. Beyond its acute obstetric consequences, preeclampsia confers a significantly increased risk of future hypertension, cardiovascular disease, chronic kidney disease, and multimorbidity. Distinct underlying pathological mechanisms at the time of pregnancy may not only define clinical presentation and subtype of preeclampsia but may also make varying contributions to future cardiovascular and kidney disease. Emerging evidence implicates cellular senescence, a state of irreversible cell-cycle arrest accompanied by a proinflammatory senescence-associated secretory phenotype, as one of the mechanisms of preeclampsia that may serve as a mechanistic link between preeclampsia, accelerated cardiovascular aging, and future cardiovascular and kidney disease. This review synthesizes current evidence supporting the role of senescence in the pathophysiology of preeclampsia, demonstrated as accelerated epigenetic aging, increased senescence burden, and mesenchymal stem cell dysfunction, and discusses how persistence of senescence and propagation of senescent cells may contribute to vascular dysfunction decades after affected pregnancies. We further explore the translational implications of senolytic and senomorphic therapies as potential disease-modifying strategies in women with a history of preeclampsia.

Vascular aging, endothelial dysfunction, and cellular senescence are interconnected processes that drive cardiovascular diseases (CVDs). Several studies have confirmed that microRNAs (miRNAs) are closely associated with the development of CVDs. Among them, miR-21-5p and miR-146a-5p have emerged as critical players in CVDs: MiR-21-5p is implicated in promoting inflammation and fibrosis, while miR-146a-5p influences vascular smooth muscle cell proliferation and inflammatory responses. Targeting these miRNAs for therapeutic intervention could provide a novel strategy to mitigate the deleterious effects of vascular aging. Recent advances in RNA-based therapeutics have led to the exploration of circular RNAs (circRNAs) as stable and effective miRNA inhibitors. Due to their circular structure, circRNAs exhibit greater stability than linear miRNA inhibitors, such as anti-miRs. This study aimed to evaluate the expression of miR-21-5p and miR-146a-5p in senescent human vascular endothelial cells and vascular smooth muscle cells (VSMCs) and to assess whether synthetic circRNAs could effectively inhibit these miRNAs. In a series of experiments, human umbilical vein endothelial cells (HUVECs) and VSMCs were transfected with custom-designed circRNAs targeting these miRNAs. Here, we want to focus on VSMCs. The effects on miRNA expression, target gene regulation, and cellular functions such as proliferation and migration were analyzed. Our findings demonstrate that circRNA-mediated inhibition of miR-21-5p and miR-146a-5p significantly affects gene expression and cellular behavior in senescent vascular cells, suggesting that circRNAs may serve as more efficient and stable therapeutic agents compared to traditional anti-miRs. By addressing these objectives, this study contributes to the growing body of knowledge on circRNA-mediated miRNA inhibition and its potential implications for vascular health. The results from this study not only enhance our understanding of miR-21-5p and miR-146a-5p in vascular senescence but also provide a foundation for future therapeutic strategies.

Intervertebral disc degeneration (IDD) is a prevalent disease with an increasing incidence, and aging is a key risk factor for its progression. Therefore, this study aimed to explore the role of aging-related genes in IDD through bioinformatics analysis. Differentially expressed aging-related genes were obtained from the CellAge, GSE150408 and GSE124272 datasets, followed by biomarker screening via machine learning. Finally, the identified biomarkers were validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western Blot (WB), and immunohistochemistry (IHC) assays. A total of 33 aging-related differentially expressed genes (DEGs) were screened in IDD, and machine learning combined with ROC curve analysis identified PPM1D, PIK3C2A, and BTG3 as aging-related biomarkers for IDD; Gene Set Enrichment Analysis (GSEA) revealed that these three biomarkers were enriched in gene functions including cellular senescence, multicellular organismal aging, negative regulation of cellular senescence, and Ribosome. In addition, the multifactorial regulatory network showed that transcription factor E2F1 and hsa-miR-147 co-regulated both PPM1D and BTG3. In experiments validating biomarker expression levels, BTG3 and PIK3C2A exhibited consistent expression trends across IHC, RT-qPCR, WB assays and the two datasets. BTG3 and PIK3C2A may play more critical roles in the progression of IDD, thereby providing novel insights for the development of new therapeutic strategies for IDD patients.

The growing trend of delayed childbearing in contemporary society has made fertility preservation a significant issue, prompting the search for diverse therapeutic options. Conversely, moxibustion is gaining increasing attention as a potential non-pharmacological therapy for supporting reproductive health.

Short-chain fatty acids are believed to mediate microbiome-host interactions. Acetic acid is the most abundant systemic short-chain fatty acid, but knowledge about its physiological functions comes mainly from rodent experiments, with limited human research particularly in the aging population.

Salidroside, a phenolic compound derived from Rhodiola rosea L., has been widely utilized in cosmetics and medicine for its anti-melanogenic properties. However, its role in collagen regeneration during skin aging remains unclear. In this study, we investigated the effects of salidroside on collagen synthesis and explored its underlying mechanisms in a murine model of skin aging. Administering salidroside (20, 40, and 80 mg/kg) orally for 28 days significantly increased dermal thickness, collagen volume, and the expression of collagen I and III in male mouse skin. Bioinformatic analysis of RNA-seq data from the GSE278079 dataset revealed enhanced neutrophil infiltration in aged skin, suggesting a role for inflammatory processes in skin aging. Furthermore, salidroside up-regulated the expression of the transcription factor FOS and down-regulated matrix metalloproteinase MMP9, both in vivo and in L929 fibroblasts. These changes correlated with reduced collagen degradation and enhanced fibroblast activity. Crucially, siRNA-mediated silencing of Fos in vitro partially diminished the salidroside-induced upregulation of collagen expression, substantiating a causal regulatory role for FOS in this process. Our results demonstrate that salidroside promotes collagen regeneration and mitigates skin aging, which is closely associated with the attenuation of neutrophil-mediated inflammation, alongside the upregulation of FOS and downregulation of MMP9. These findings highlight the therapeutic potential of salidroside in combating age-related skin changes.

The accumulation of the toxic byproduct A2E in retinal pigment epithelial cells, coupled with blue-light-induced photooxidation, is a key driver of oxidative damage in early age-related macular degeneration (AMD). Zeaxanthin dipalmitate (ZD), the esterified carotenoid abundant in goji berries, has higher lipophilicity and stability. In this study, ZD was isolated from the berries using its fat-soluble nature and purified using medium-pressure liquid chromatography. Isolated ZD and synthesised A2E were structurally characterised using HPLC, NMR, and positive mode LC-ESI-TQ-MS. An acellular photo-oxidation assay revealed that ZD significantly suppressed A2E degradation under blue light with higher efficacy than vitamin E, a standard antioxidant control. This indicates ZD's potent ability to filter blue light and scavenge reactive oxygen species, mitigating A2E photooxidation and phototoxicity. These findings highlight ZD's unique structural advantages for sustained retinal protection. The findings also support further

As global life expectancy rises, age-related musculoskeletal decline poses a growing public health challenge-impairing mobility, increasing frailty, and diminishing quality of life for billions worldwide. Functional deterioration often begins in midlife, yet effective early interventions remain limited. Metformin, a widely prescribed antidiabetic drug, has shown geroprotective potential. However, its capacity to preserve musculoskeletal health during early aging remains poorly defined. Addressing this gap is critical to developing scalable, cost-effective strategies to extend healthspan. Here, we investigated the effects of midlife metformin treatment in male C57BL/6 J mice by comparing young, untreated middle-aged, and metformin-treated middle-aged groups. Metformin treatment was initiated at 30 weeks of age and continued through 53 weeks. Frailty was evaluated using composite clinical and functional indices, while musculoskeletal health was assessed through motor tests and detailed histological analyses of muscle, bone, and joint tissues. Metformin-treated middle-aged mice maintained body weight comparable to that of young adult controls, preventing excessive age-associated weight gain. Both clinical and performance-based frailty scores were significantly attenuated. Muscle strength, endurance, and mass were preserved, alongside increased muscle fiber size, enhanced capillary density, and reduced fibrotic remodeling. Bone integrity was similarly maintained, evidenced by preserved trabecular architecture, osteoblast abundance, and collagen organization. Additionally, metformin supported locomotor function by preserving gait parameters and knee joint structure, including articular cartilage thickness and chondrocyte integrity. Collectively, these findings demonstrate that metformin administration supports healthspan by attenuating frailty and preserving musculoskeletal integrity in middle-aged mice, reinforcing its potential as a scalable geroprotective intervention targeting early aging.

Tissue homeostasis emerges from mechanical feedback loops balanced by cell loss and proliferation, a balance that in postmitotic tissues must be maintained without compensatory proliferation. Yet how these tissues preserve mechanical homeostasis and how this challenges function in ageing remains unclear. To establish the relationship between cell density, mechanical homeostasis, and function, we induced age-mimicking cell loss in a postmitotic retinal pigment epithelium (RPE) in vitro. This model recapitulates key structural hallmarks of RPE ageing, including reduced cell height, shortened microvilli and cytoskeletal reorganisation. The density-reduced RPE establishes a new mechanical equilibrium characterised by tissue stiffening and increased junctional contractility. Functionally, these monolayers exhibit impaired phagocytosis of photoreceptor outer segments due to compromised apicolateral plasticity, which is mechanistically linked to the modulation of actin nucleators, Arp2/3 and formins. Altogether, our findings show that a cell loss-induced shift in mechanical homeostasis drives age-related RPE dysfunction, demonstrating that structural remodelling and mechanics alone can compromise tissue function in ageing.

Normal aging is accompanied by declines in executive function, and regular physical exercise has been proposed as a protective factor. However, the neural correlates linking long-term habitual exercise to executive efficiency in older adults remain unclear. This study combined resting-state functional magnetic resonance imaging (rs-fMRI) with behavioral assessments to examine whether long-term habitual exercise is associated with executive performance and resting-state neural organization in older adults. A total of 105 older adults (52 long-term habitual exercisers and 53 non-habitual exercisers) completed task-switching, Stroop and N-back paradigms and underwent rs-fMRI scanning. Behavioral outcomes included accuracy, reaction time, task cost and executive efficiency index. Neural measures included amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo) and degree centrality (DC). Older adults with long-term habitual exercise showed higher accuracy and faster responses across tasks, with no group differences in task cost but higher executive efficiency, compared with non-habitual exercisers. They also exhibited higher ALFF, ReHo and DC in frontoparietal, motor and striatal regions, alongside lower resting-state metrics in occipito-cerebellar networks. Mediation models indicated that ALFF in the pallidum, DC in prefrontal and cingulate cortices, and ReHo in frontoparietal regions statistically accounted for the association between exercise status and executive efficiency. Long-term habitual exercise was associated with better executive performance and distinct resting-state functional organization in older adults. Frontoparietal and striatal systems emerged as candidate intrinsic correlates of executive efficiency in physically active older adults.

The lungs are highly susceptible to chronic disease in advanced age, likely due to the uniquely compromised repair function of alveolar type II (AT2) cells, facultative progenitor cells that maintain the gas exchange surface. Using aging mouse models, single-cell sequencing, and ex vivo organoid assays, we found that homeostatic aged AT2 cells exhibited an Interferon {gamma} (IFN{gamma}) response associated with IFN{gamma}+ CD8+ T cells in tertiary lymphoid structures (TLS). Aged AT2 cells exhibit impaired regeneration in organoid assays and lost markers of an IFN{gamma} response outside the lung microenvironment, demonstrating that elevated local IFN{gamma} influences the state of AT2 cells. Neutralization of IFN{gamma} signaling and immunoproteasome knockout mice with attenuated IFN{gamma} levels partially rescued aged AT2 cell regeneration. Our findings demonstrate that local IFN{gamma} signaling in aging lungs actively represses alveolar regeneration, establishing chronic inflammatory signaling as a cause of age-related decline in the lung. Halting chronic inflammatory processes restored alveolar regeneration and may provide a means to improve lung health in old age.

Mitochondria-derived vesicles (MDVs) and mitochondrial extracellular vesicles (mitoEVs) represent 2 related extensions of mitochondrial dynamics that link organelle maintenance to communication within and between cells. MDVs are small vesicles that bud directly from mitochondria, selectively packaging components of the outer membrane, inner membrane, or matrix. They serve as a localized quality control mechanism that removes oxidized or damaged material without engaging the entire mitophagic machinery. After budding, MDVs typically enter the endolysosomal pathway, where they can fuse with late endosomes or lysosomes for cargo degradation. A subset of MDVs also targets other organelles, particularly peroxisomes, contributing to organelle crosstalk, lipid metabolism, and redox balance. By contrast, mitoEVs released into the extracellular space contain intact functional mitochondria, mitochondrial contents (proteins, DNAs/RNAs, lipids, and so on), and nonmitochondrial cargo (ie, mRNAs, noncoding RNAs, and so on), which can be transferred to recipient cells and subsequently induce either pathogenic or beneficial outcomes. Therefore, mitoEVs have been implicated in metabolic cooperation, immune regulation, tissue remodeling, and aging. Accordingly, this review summarizes recent progress on the diverse mechanisms for the biogenesis of MDVs and mitoEVs, as well as available protocols for their isolation. The roles of MDVs and mitoEVs in mediating mitochondrial quality/quantity control and multiple layers of crosstalk between intracellular organelles and different cell types in health and disease are highlighted. Last, mitoEV-mediated pathogenic effects and therapeutic potential in cardiovascular disease are also discussed.

Oocyte quality, a critical determinant of female reproductive potential, experiences a progressive decline with age, largely driven by the cumulative effects of oxidative stress and mitochondrial dysfunction. This review thoroughly synthesizes the latest evidence concerning the molecular, cellular, and environmental factors that disrupt redox homeostasis within oocytes. It particularly highlights the pivotal roles of reactive oxygen species, impaired mitochondrial metabolism, epigenetic dysregulation, and alterations in the ovarian microenvironment. We further elucidate how aging, environmental toxicants, lifestyle choices, and pathological conditions such as cystic ovaries and endometriosis exacerbate oxidative damage, thereby severely compromising meiotic competence and embryonic development. Compelling evidence from both human and animal models has shed light on the intricate mechanisms underlying ROS-induced oocyte deterioration, which will be discussed herein. Moreover, we evaluate promising emerging interventions, including antioxidant, dietary, lifestyle, and mitochondria-targeted strategies, all aimed at preserving reproductive longevity. Collectively, these insights firmly establish oxidative stress as a central and undeniable driver of oocyte aging, underscoring the urgent need for integrated biomedical and environmental strategies to safeguard female fertility.

Amyloid deposition is a hallmark of numerous age-related diseases, and understanding the chemical mechanisms that govern amyloid formation is crucial for advancing the rational development of protein aggregation inhibitors. With amyloid formation rates varying widely across proteins, here we report the quantitative aggregation mechanism of medin, the most common localized amyloid in humans, and find it to be much faster compared to well-known pathological amyloids such as amyloid-β (Aβ), tau and α-synuclein. We report the microscopic rate constants and reaction orders of medin fibril formation by monitoring the aggregation of recombinant human medin in vitro via a fluorescence-based assay, global kinetic modeling, secondary structure analysis and electron microscopy. Medin spontaneously forms amyloid fibrils at physiological pH and temperature in quiescent solution at concentrations as low as 25 nM, with the highest fibril elongation rate constant when compared to those of Aβ, tau and α-synuclein. Our results identify the microscopic basis of the widespread observation of medin aggregates upon aging, offering a mechanistic starting point for drug discovery to inhibit medin aggregation.

To examined the effects of resistance training on the atherogenic index of plasma in middle-aged and older adults with type 2 diabetes mellitus. Secondary objectives included evaluating its impact on glycemic markers (hemoglobin A1c, HOMA-IR) and a broad range of cardiovascular risk factors.

Arterial stiffness with aging predicts cardiovascular diseases (CVDs) and target organ damage. While sarcopenia has been linked to arterial stiffness, the association of myosteatosis and visceral adiposity with arterial stiffness remains underexplored. As age-related fat redistribution, including myosteatosis and visceral obesity, often precedes the overt sarcopenia, their early evaluation may be beneficial in preventing arterial stiffness. Therefore, this cross-sectional study aimed to assess whether myosteatosis and visceral obesity are associated with increased arterial stiffness.

Frailty is a clinical state arising from the progressive erosion of physiological reserves across multiple systems, resulting in heightened vulnerability to stressors and an increased risk of adverse health outcomes. Strategies to promote healthy aging may benefit from the early identification of frailty and the implementation of targeted interventions aimed at mitigating or potentially reversing this condition. Interest in frailty within the context of women's health stems from epidemiological evidence indicating that women have a higher risk of developing frailty than men. Moreover, menopause has been associated with an increased susceptibility to frailty. On this basis, the present review examines the contribution of key hormonal factors involved in the physiological changes accompanying menopause to the development of frailty in women. Specifically, it focuses on steroid-related pathways, including estrogens, androgens, and vitamin D. By integrating the available evidence, this review aims to clarify their potential roles in frailty susceptibility during midlife and beyond. There are some indications, albeit based on limited evidence, of a protective role of menopausal hormone therapy. Encouragingly, healthy dietary patterns and regular physical activity have demonstrated efficacy in mitigating frailty, reinforcing the importance of lifestyle strategies to counteract the adverse effects of menopause.

Iron deficiency (ID) is proposed to be involved in cognitive aging and dementia; however, empirical data is lacking to support this hypothesis. We examined the association between absolute and functional ID and incident dementia diagnosis.

Aberrant protein acylation by reactive acyl species (RAS), termed carbon stress, is a major driver of aging and metabolic disease. While enzymatic deacylases such as sirtuins counteract aberrant acylation, whether endogenous metabolites can directly neutralize RAS remains unclear. Here, we report that nucleophilic metabolites (taurine, spermidine, and ethanolamine) react with acyl-CoAs, preventing aberrant protein acylation and potentially extending lifespan. We demonstrate that spermidine scavenges acetyl-CoA within the catalytic pocket of p300, a histone acetyltransferase, and extends lifespan in Drosophila. Taurine supplementation in mice fed a high-fat diet promotes N-fatty acyl taurine formation, confirming in vivo scavenging of RAS. These findings identify endogenous nucleophilic metabolites as scavengers that neutralize carbon stress, with implications for combating aging and metabolic disease.

Neuronal aging pace varies markedly between individuals, but what drives this variation remains unknown. Using cell-type-specific transcriptomic clocks applied to single-nucleus RNA sequencing data from 226 adults (ages 20-90), we quantified neuronal aging residuals as a donor- dominant phenotype. Variance decomposition revealed that microglial transcriptional programs predict inter-individual variation in neuronal aging residuals, a directional asymmetry consistent with a non-cell-autonomous relationship between microglial states and neuronal aging trajectories. This asymmetry is accompanied by an age-dependent shift from homeostatic to inflammatory microglial dominance beginning in midlife, with inflammatory dominance probability rising from 26% at age 35 to 92% by age 65, replicated in an independent cohort. IFN{gamma} signaling emerges as the dominant microglial program associated with accelerated neuronal aging in late adulthood. Candidate regulators of microglial IFN{gamma} activity (HIF1A, CEBPB, and EZH2) are computationally prioritized as intervention targets warranting functional validation.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that bridges innate immunity, cellular senescence and age‑related pathology. In this review, we describe the unique secretion mechanisms, compartment‑specific signaling, and redox‑dependent conformational states that MIF has in different contexts. We detail how extracellular MIF amplifies chronic inflammation through CD74, CXCR2/4 and NF‑κB, while intracellular MIF sustains proliferation, DNA repair, and autophagy by antagonizing p53. We also highlight oxidized MIF as an emerging marker with unique relevance in age-related diseases. Through systematic comparison of evidence from cardiovascular, neurodegenerative, musculoskeletal and pulmonary disease studies, this review reveals context‑dependent protective versus deleterious outcomes of MIF signaling. The nature of MIF and its involvement in age-related diseases makes it a challenging yet intriguing therapeutic target.

As organisms age, mitochondrial metabolic activity declines, and disrupted gene expression regulation mediated by histone acetylation induces the emergence of senescent physiological phenotypes in tissues. In this study, we found that periodic exposure to red light significantly increased histone H3 Lys9 acetylation (H3K9ac) levels in the tissues and organs of aged mice. Following red light exposure, silent information regulation factor 4 (SIRT4) protein levels in keratinocytes were notably reduced, whereas glycolysis, fatty acid metabolism, and the tricarboxylic acid (TCA) cycle were significantly activated in keratinocytes. The reduction in mitochondrial SIRT4 levels enhances the acetylation of mitochondrial metabolic proteins, particularly malonyl-CoA decarboxylase (MCD), a potent inhibitor of the key rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A) in fatty acid oxidation. This process promotes mitochondrial fatty acid oxidation and TCA cycle. Additionally, the decrease in SIRT4 activates SIRT1 through feedback mechanisms, thereby alleviating its inhibition on PPAR- in senescent keratinocytes and comprehensively activating the expression of genes related to lipid metabolism. This lipid metabolism activation ultimately facilitates the accumulation of acetyl-CoA within keratinocytes, increases H3K9ac levels, and reshapes the expression patterns of senescence-related genes. Eventually, cellular aging is effectively mitigated by the synergistic regulation of metabolism, inflammation, and gene expression.

Insufficient skeletal repair is the primary threat of health span and lifespan in elders with increasingly vast global burden; yet, to date, the knowledge of resolving this crisis remains limited. In this study, we addressed the specific mechanisms underlying aging-associated poor bone repair, which are driven by the mitochondrial DNA structures mitochondrial G-quadruplex (mtG4). We found that mtG4 is spatiotemporal-wisely accumulated within Pdgfra

We present a fluorogenic cyclometalated Ir(III) probe (cIr-Q) that selectively lights up telomeric G-quadruplexes (GQs), features a large Stokes shift (∼168 nm), high photostability, rapid passive nuclear entry (≤2 min), and wash-free operation. Integrated with super-resolution microscopy, cIr-Q enables in situ quantification of higher-order telomeric architectures in living cells. NMR and biochemical assays further delineate a TERRA-initiated pathway: RNA-DNA hybridization exposes the G-rich strand to fold into GQs that facilitate t-loop formation. In a senescence model, cIr-Q reports an aging-associated decrease of GQs/t-loop signals. These results establish cIr-Q as a practical biosensing platform for live-cell readout of telomeric structural biomarkers, bridging materials design with chromosome biology without fixation or permeabilization.

A decline in specific antibody responses is a hallmark of human aging, yet the differential contributions of B and T lymphocytes and their interactions remain unclear. CXCL13 is a critical chemokine that shapes germinal center organization, but the regulation of human-specific CXCL13+ Tfh cells during aging is not known. Using human tonsil organoids, single-cell RNA sequencing, and CRISPR perturbations, we mapped age-associated changes in T follicular helper (Tfh) cells, the cell type that provides T cell 'help' to B cells in germinal centers (GCs). Tonsil organoids from older donors generated weaker influenza-specific antibody responses, which we traced to Tfh cell defects rather than B cells. Single-cell profiling revealed a selective loss of mature CXCL13+ GC-Tfh cells accompanied by accumulation of Tfh precursor states. Trajectory analysis showed that aging arrests Tfh cell maturation at the early activated precursor transition, and CRISPR perturbations identified BACH2 and SOX4 as transcriptional regulators of differentiation reduced with age. These findings reveal a human-specific mechanism of immune aging with implications for strategies to restore humoral immunity.

This study examined the associations of biological age accelerations (BAAs)-KDM-BA acceleration (via Klemera and Doubal's method) and PhenoAge acceleration (epigenetics-based), defined as residuals from regressing each biological age estimate on chronological age (CA)-with multimorbidity progression (measured by the Charlson Comorbidity Index, CCI), compared to CA. Utilizing UK Biobank data (n = 317,835; median follow-up: 13 years), Cox regression models adjusted for sex, ethnicity, lifestyle, and socioeconomic factors showed that each 1-year increase in KDM-BA acceleration raised the risk of CCI progression by 9.9% (HR [95% CI]: 1.099 [1.094-1.104]) and in PhenoAge acceleration by 4.3% (HR [95% CI]: 1.043 [1.041-1.044]). Consistent results were found in subgroup, sensitivity, and restricted cubic spline analyses, with PhenoAge acceleration achieving the highest predictive performance (C-index = 0.6755) compared to KDM-BA acceleration (0.6734) and CA (0.6701). These findings support the use of BAAs as cost-effective tools for assessing the risk of multimorbidity progression.

Background: The role of biological age acceleration (BioAgeAccel) in the dynamic progression from single cardiovascular-kidney-metabolic disease (CKMD) to multimorbidity, and subsequently to dementia and mortality remains elusive. Methods: We conducted a longitudinal study with data of 433,911 UK Biobank participants. Cardiovascular-kidney-metabolic multimorbidity (CKMM) was defined as the coexistence of two or more CKMDs, including cardiovascular disease (CVD), stroke, type 2 diabetes (T2D), and chronic kidney disease. Biological aging was measured via PhenoAge and KDM-BA. Multistate models examined the association between BioAgeAccel and disease transitions, ranging from healthy to the first occurrence of CKMD (FCKMD), then progression to CKMM, dementia, and mortality. Restricted mean survival time estimated the disease transition time or life expectancy between states. Results: BioAgeAccel was significantly associated with increased risks across all disease transitions. Specifically, during CKMM progression, the hazard ratios (HRs) of the transition from healthy to FCKMD were 1.24 [95%CI 1.23-1.25] for PhenoAgeAccel and 1.16 [1.15-1.17] for KDM-BA-Accel. For subsequent transition to CKMM, the HRs were 1.20 [1.18-1.22] and 1.19 [1.17-1.21], respectively. In dementia-related transitions, PhenoAgeAccel showed the higher risk for CKMM to dementia (HR=1.13 [1.04-1.22]) than for the transition from healthy or from FCKMD to dementia. These associations were further moderated by age, physical activity, educational, and lifestyle factors. BioAgeAccel also accelerated disease progression and reduced life expectancy; for example, during CKMM progression, BioAgeAccel shortened the time between disease transitions by about 1.09 years from healthy to FCKMD, and an additional 1.75 years to CKMM. Regarding life expectancy, individuals with CKMM experienced an average reduction of about 1.36 years under PhenoAge, while those with dementia showed a decrease of about 0.77 years. Among individuals with CVD or T2D as the initial diagnosis, the impact of BioAgeAccel on progression to CKMM or dementia was stronger. Conclusions: BioAgeAccel exerts significant promotive role in the onset of CKMD and their subsequent progression to CKMM, dementia, and mortality, helping identify high-risk individuals. Implementing biological age assessments and health lifestyle interventions in middle-aged populations serves as an effective strategy for alleviating the burden of CKMDs and dementia.

To compare two 16-week high-load, velocity-intentional resistance training programs-elastic bands (HL-VIRT-EB) vs. water-based (HL-VIRT-AQ)-combined with creatine or placebo supplementation on neuroplasticity, oxidative stress, inflammation, strength, physical function, cognition, and quality of life in older adults.

Aging is a fundamental biological process that influences cancer development in a context-dependent manner; however, how aging-related programs manifest in hepatocellular carcinoma (HCC) remains incompletely understood. Here, we systematically characterized aging-associated features in HCC by establishing a liver cancer-specific aging signature, termed HCCaging, across more than 2,000 tumor samples from 16 independent cohorts. We comprehensively evaluated its heterogeneity and associations with clinical outcomes, tumor stage, immune infiltration, and therapeutic response. The HCCaging score increased with chronological age, was higher in normal liver than tumor tissues, and elevated in early- versus late-stage tumors. In contrast, 13 previously reported aging- or senescence-related gene sets failed to show consistent patterns across these conditions in HCC. Machine learning models, including gradient boosting machines and random forests, achieved higher accuracy in distinguishing tumor from non-tumor samples using the HCCaging score compared with other 13 aging- or senescence-gene sets across eight independent HCC cohorts. Single-cell transcriptomic profiling revealed that HCCaging increased with age, particularly within epithelial compartments, reaching its highest levels in hepatocytes. Notably, although the proportion of T/NK cells declined with aging, their functional programs, including activated effector function, chemokine/chemokine receptor signaling, cytolytic activity, and pro-inflammatory pathways, were enhanced in older individuals. The HCCaging score, together with key genes ACAA1 and ESR1, were negatively correlated with T/NK cell infiltration, anti-inflammatory activity, and anti-apoptotic signatures, but positively correlated with pro-apoptotic, pro-inflammatory, chemokine, and cytolytic pathways. Furthermore, increased expression of XCL1 and XCL2 in T/NK cells with aging correlated positively with HCCaging, ACAA1, and ESR1, suggesting preserved or even enhanced antitumor potential of T/NK cells in older patients. Collectively, these findings highlight the dual role of aging in liver tumorigenesis. Hepatic aging and enhanced T/NK cell effector function may confer tumor-protective effects, whereas the concomitant decline in overall T/NK cell infiltration likely compromises immunosurveillance, thereby increasing carcinogenic susceptibility in the aging liver. This study provides new insights into the heterogeneity of hepatic aging and its complex interplay with the HCC tumor microenvironment and clinical outcomes.

Background: Accelerated biological aging (BioAgeAccel) has been implicated in type II diabetes (T2D) mellitus development; however, its dynamic changes and their links to T2D incidence, mortality and glycemic traits remain unclear. Methods: Leveraging repeated measures from the UK Biobank, we first calculated two BioAgeAccel metrics (KDMAccel and PhenoAgeAccel) and derived three burdens (slope, cumulative, and relative cumulative change). We then assessed associations of BioAgeAccel transitions and these burdens with incident T2D and mortality. Secondary analyses extended the two primary outcomes by incorporating glucose, HbA1c, and six IR surrogates, which were also evaluated as potential mediators. Results: Among 13,751 included participants, 412 (3.0%) new T2D cases and 609 (4.4%) all-cause deaths were identified within a median follow-up of 9.5 years. Dynamic transition from non-accelerated to accelerated aging was markedly related to elevated T2D risk (KDMAccel: HR=1.65 [1.24~2.20]; PhenoAgeAccel: HR=1.50 [1.12~2.00]) and all-cause mortality risk (KDMAccel: HR=1.32 [1.06~1.64]; PhenoAgeAccel: HR=2.17 [1.73~2.71]). BioAgeAccel burdens demonstrated dose-response effects, with cumulative BioAgeAccel showing the greatest influence on T2D (KDMAccel: HR=1.25 [1.03~1.51]; PhenoAgeAccel: HR=1.26 [1.06~1.49]) and all-cause mortality (KDMAccel: HR=1.25 [1.07~1.47]; PhenoAgeAccel: HR=1.51 [1.31~1.74]). Similar association patterns were observed for all the eight glycemic traits. Mediation analyses revealed that these glycemic traits on average mediated 19~32% of the KDMAccel burden-T2D effect and 16~24% of the PhenoAgeAccel burden-T2D effect. Incorporating BioAgeAccel burden into FINDRISC significantly enhanced prediction accuracy, reaching up to 10.9% improvement in some specific aging transition statuses. Conclusion: Dynamic biological aging trajectories and BioAgeAccel burdens are independently related to elevated risks of T2D and all-cause mortality, partly via glycemic dysregulation, highlighting biological aging as a potential intervention target.

Sulfide:quinone oxidoreductase (SQR) is a critical enzyme that maintains sulfur metabolism by oxidizing sulfide to supersulfides, currently defined as sulfur metabolites with six valence electrons and no charge that are covalently catenated with other sulfur atoms and excludes disulfides. While SQR is known to contribute to mitochondrial electron transport, its physiological impact on systemic energy metabolism and longevity remains largely undefined. In this study, we investigated the role of SQR in mitochondrial bioenergetics and aging using SQR-deficient Schizosaccharomyces pombe ({Delta}hmt2) and a mitochondria-selective SQR-deficient (Sqrdl{Delta}N/{Delta}N) mice model. Functional analysis demonstrated that{Delta} hmt2 grew normally in glucose but not in glycerol, indicating impaired mitochondrial respiration. It showed reduced membrane potential, ATP, and lifespan. Consistent with the yeast findings, Sqrdl{Delta}N/{Delta}N mice exhibited accumulated levels of hydrogen sulfide and persulfides, and demonstrated impaired mitochondrial energy metabolism. Furthermore, supersulfide donor supplementation selectively conferred lifespan extension in wild-type yeast, but not in SQR-deficient strain, and similarly improved mitochondrial function exclusively in wild-type mouse embryonic fibroblasts, with no benefit observed in SQR-mutant counterparts. Together, our findings demonstrate that mitochondrial SQR plays an essential role in sulfur respiration, critically supporting mitochondrial function and organismal longevity across eukaryotes.

Meningeal lymphatic vessels (mLV) play essential roles in draining cerebrospinal fluid (CSF) into peripheral blood. The mLVs are hypothesized to be supportive structures to the glymphatic system, which is thought to remove metabolic byproducts from brain parenchyma and has been most directly studied in rodent models. Previous rodent studies have indicated a correlation between mLV function and cognitive performance, but this relationship in humans remains unexplored. Age-related declines in glymphatic system efficiency in humans and cognitive performance have been observed separately. This study investigates age- and sex-related differences in CSF production via choroid plexus volumes, mLV characteristics, and glymphatic system efficiency, overall elucidating the implication of cerebral lymphatic function on cognition. We recruited 26 healthy adults from Dallas-Fort Worth and acquired magnetic resonance images. mLVs along the sagittal sinus were visualized and segmented from T2-FLAIR images. The glymphatic system was evaluated by measuring diffusivity along the perivascular space. Choroid plexus volume and brain volume were estimated from T1-MPRAGE. Neuropsychological tests were conducted to assess cognitive function. Our findings indicate that glymphatic function diminishes with age, while mLV and choroid plexus volumes increase. Males displayed greater mLV volume than females, yet no sex differences were found in glymphatic function or choroid plexus volume. Notably, mLV volume increased as glymphatic function declined, independent of age. Moreover, a glymphatic-mLV latent variable significantly predicted processing speed, underscoring the influence of cerebral lymphatics on cognition. In conclusion, this study highlights a decline in glymphatic function with age, accompanied by increased mLV volumes and altered processing speed. These lymphatic system changes may underlie or contribute to the cognitive declines observed in healthy and pathological aging.

The rising prevalence of aging-associated chronic conditions underscores the need for interventions that promote healthy aging. In this study, a low-molecular-weight polysaccharide (PSP-1-1, 2.7 kDa) was isolated from steamed Polygonatum sibiricum using bioactivity-guided purification and structurally characterized as a branched β-(1 → 4)-galactan with C-6 substitutions. Using Caenorhabditis elegans, PSP-1-1 demonstrated significant anti-aging effects and neuroprotective activities. Our results showed that PSP-1-1 (100 μg/mL) significantly delayed Aβ-induced paralysis of CL4176 worms, the value of PT

Deamidation and advanced glycation end products (AGEs) are among the major post-translational modifications (PTMs) in eye lens proteins. Due to deamidation and AGE formation, proteins may aggregate and scatter light, contributing to lens aging and cataract formation. So far, the relation between the two PTMs remains poorly understood. γS-crystallin (γSC), a major subtype of γ-crystallin, undergoes significant modifications through deamidation, especially at the surface-exposed asparagine residues, N14, N76, and N143. In this study, deamidation of γSC was mimicked by mutating asparagine residues to aspartic acid residues. The deamidation mimics were then incubated with a glycating mixture, and AGE formation in proteins was evaluated by LC-MS/MS. Results indicate that deamidation promotes the formation of both non-cross-linking (CML or CEL) and cross-linking AGEs (GOLD, MOLD, or pentosidine) in lysine residues. AGE formation in arginine residues (e.g., MG-H3) is mostly unaffected. Comparative analysis shows that N14D, N143D, and N14DN76DN143D (triple deamidated, TD) consistently accumulated more AGEs than native γSC. Oxidation with 2 mM GSSG led to increased disulfide-linked cross-linking in deamidated γSC. Upon glycation, the deamidated and oxidized γSC accumulated more AGEs than deamidated γSC; however, the specific AGE levels followed the same trend as deamidated γSC. The results suggest that deamidation promotes AGE formation in γSC, and further oxidation makes it even more susceptible to AGE modifications. The combined interdependent effects of deamidation, oxidation, and AGE modifications could therefore contribute to protein cross-linking and aggregation during lens aging and cataract formation.

Postmortem tissue is a vital resource for transcriptomic studies of human microglia, yet the influence of postmortem delay (PMD) on microglial states, particularly in aging, remains insufficiently understood. Here, we examined the impact of PMD in young and aged male mice, with a particular focus on aging-associated primed microglia. We performed bulk RNA sequencing on Dectin-1-high and -low microglia isolated after PMDs of 0, 6, or 12 h, with Dectin-1 serving as a marker of primed microglia. PMD did not obscure aging-associated signatures or reduce viability, but consistently altered gene expression profiles. Upregulated pathways included mitochondrial, heat-shock, and apoptosis regulation responses, while actin cytoskeleton regulation was downregulated. These effects differed between young and aged animals, and between primed and non-primed microglia, with attenuation in primed subsets. Reanalysis of human single-cell and single-nucleus datasets confirmed that PMD-associated signatures identified in our dataset, particularly those in aging-related Dectin-1

As the first organ to develop in utero, the human heart undergoes extensive molecular, structural and metabolic remodeling during development and must sustain its function throughout life.

Immunosenescence, the age-associated decline in immune function, is a key feature of human aging. In human lymphoid organs, however, the specific immune cell populations that acquire senescence-associated phenotypes during aging and how they influence the surrounding tissue microenvironment remain poorly understood. A spatially resolved map of these senescence-associated immune states in human lymphoid tissues could help clarify their relationship with aging and their potential contributions to the progressive decline of immune function. Here, we integrated single-cell and spatial multi-omics to systematically characterize age-related senescence in human lymph nodes (LNs). Single-cell transcriptomics of lymphoid tissues from donors aged 18 to 100 years old identified 34 immune and stromal cell types and revealed age-associated upregulation of senescence signatures in specific populations. Spatial proteomic profiling of 99 LN sections from 51 donors (18-86 years) using high-plex immunofluorescence (~20 million cells) mapped senescence markers (p16, p21, HMGB1, yH2AX) at single-cell resolution, revealing diverse senescent-like cell types ("senotypes") and a stepwise shift from extrafollicular to germinal center (GC) localization with age. Notably, we observed focal clonal-like senescence in GC B cells in older donor LNs. Spatial transcriptomics, epigenomics, and metabolic imaging of selected samples further elucidate the multi-omics signatures and underlying mechanisms of functional impairment, metabolic remodeling, and distinct regulatory programs in senescent-like GC B cells. This study presents a comprehensive spatial atlas of senescence-associated immune states in human lymph nodes, revealing cell-type-specific and spatial heterogeneity that may contribute to immunosenescence and the decline of immune function during aging.

Using 30-second voice recordings from 7,081 adults aged 40-70, we trained gender-specific models to estimate voice-predicted age (Voice Age). Voice Age correlated with chronological age comparably to established omic and physiological aging clocks, while capturing an independent dimension of biological aging. Accelerated vocal aging showed association with higher adiposity, impaired sleep physiology, and cardiometabolic risk markers, supporting voice as a scalable, non-invasive functional aging biomarker.

The lymphatic system is essential for maintaining interstitial fluid balance, supporting immune surveillance, and clearing metabolic waste, yet its role in ageing has only recently come into focus. With age, lymphatic vessels and lymphoid organs undergo structural and functional decline, leading to impaired transport, disrupted immune cell trafficking, and chronic low-grade inflammation. These changes contribute to systemic inflammaging and are increasingly implicated in cardiovascular disease, metabolic dysfunction, and neurodegenerative disorders. In the central nervous system, deterioration of the glymphatic and meningeal lymphatic systems compromises cerebrospinal fluid circulation and the clearance of amyloid-β, tau, and other metabolites, thereby accelerating cognitive decline. In this review, we examine the molecular and cellular mechanisms that underline lymphatic ageing, including junctional remodeling, extracellular matrix stiffening, altered lymphangiogenic signaling, and endothelial senescence. We critically assess the consequences of lymphatic dysfunction for systemic and brain health, highlighting unresolved controversies such as the extent to which lymphatic changes are primary drivers of pathology, the limitations of rodent models and indirect imaging readouts, and the lack of ageing-resolved single-cell maps in human tissues. Finally, we discuss therapeutic avenues ranging from antioxidant and pro-lymphangiogenic strategies to lifestyle interventions and reconstructive microsurgery. Together these insights position the lymphatic system as a central, yet underexplored, determinant of resilience in ageing and a promising target for future gerotherapeutic interventions.

Aging, a complex biological process, is intrinsically linked to the pathogenesis of numerous age-related diseases. A key factor in the aging process is the accumulation of DNA damage and the subsequent activation or failure of the DNA damage response. To mitigate this damage, DNA repair mechanisms often involve the formation of DNA gaps. This study investigates the potential role of the Box A domain of High Mobility Group Box 1 (HMGB1) in modulating age-related changes. We utilized a label-free quantitative proteomic technique to analyze the plasma proteome of three female adult and eight female perimenopausal cynomolgus macaques (Macaca fascicularis), with the perimenopausal group receiving an intravenous administration of the Box A plasmid. Proteomic analysis revealed differential expressions in proteins primarily associated with stress response, immune regulation, lipid transport, and cellular homeostasis following Box A plasmid intervention. Notably, the expression levels of key proteins, such as apolipoprotein E (APOE) and sex hormone-binding globulin (SHBG), showed a reversal effect, restoring levels closer to those observed in the younger, adult monkeys. These findings highlight the potential of the Box A of HMGB1 plasmid as a therapeutic candidate to mitigate age-related proteomic alterations, offering a novel avenue for targeted interventions in aging and associated diseases.

The spleen contains diverse macrophage subsets that remove aged erythrocytes, prevent the dissemination of circulating pathogens, and shape the adaptive immune response. The mouse spleen hosts red pulp macrophages (RPM), marginal zone macrophages (MZM), marginal zone metallophilic macrophages (MMM), and tingible body macrophages (TBM). However, their transcriptomic identity, ontogeny, and dynamics during aging are unknown. Furthermore, it is not known whether homologous populations of macrophages exist in the human spleen. We find that in mice, MZM and MMM are tissue-resident macrophages that maintain their population via local proliferation, while TBM are slowly replaced by circulating monocytes. Lineage tracing shows that MMM maintain the MZM pool, and that after MMM depletion, circulating monocytes restore MMM. We show that a decrease in MMM abundance in aging precedes changes in other cellular populations and splenic niches. In human spleen, we identify TBM and perifollicular zone macrophages (PFZM) as a single macrophage population homologous to MMM and MZM in mice. We show that in both mouse and human TBM become more abundant during aging. Our results suggest age-related changes in the splenic microenvironment drive changes in tissue-resident splenic macrophage populations with potential importance for the loss of immunologic function in older individuals.

This tribute to the late Seymour Levine, marking his 100th birth year, highlights the following discoveries in rodents that we had the privilege of sharing with him. (i) Cessation of glucocorticoid receptor (GR) expression in the suprachiasmatic nucleus (SCN) upon innervation by the optic nerve around postnatal day 12 may explain phase dissociation of the master pacemaker from glucocorticoid-driven cellular clocks under, e.g., conditions of chronic stress. (ii) Maternal care protects the infant from noxious influences, while preparing it for stress coping in future life, for better and worse, i.e., the predictive adaptive response. (iii) The feeding and tactile components of maternal care allow to distinguish the activation of central from adrenal glucocorticoid-dependent components of the pup's stress response system. This knowledge helps understand how the amygdala-mediated fear response is primed. (iv) Maternal separation for 24 h at postnatal day 3 drives cognitive aging to either senility or excellence at the expense of partially impaired cognitive performance that is characteristic of a normal aging trajectory. The findings inform how glucocorticoid action during early-life experience can amplify individual variation in stress coping and adaptation from birth to senescence.

Chronic infections can reshape immune system homeostasis, yet how persistent viral infections influence immune aging remains poorly understood. People living with HIV provide a unique model to investigate how long-term viral persistence affects immune aging despite effective antiretroviral therapy. Here, we characterize immune aging by integrating plasma proteomics with epigenetic and transcriptional profiles of circulating immune cells across large cohorts of treated individuals with HIV. We find that immune aging is markedly accelerated compared with healthy individuals and parallels established DNA methylation-based aging clocks. Accelerated immune aging is strongly associated with signatures of immunosenescence and correlates with the size of the latent HIV reservoir, suggesting a persistent imprint of viral persistence on immune aging trajectories. Notably, exposure to specific antiretroviral agents, particularly nucleoside reverse transcriptase inhibitors, is associated with reduced immune aging and suppression of age-associated immune gene programs. Together, these findings identify chronic viral persistence as a driver of systemic immune aging and indicate that antiretroviral therapy can partially modulate immune aging programs.

Gait speed is a robust marker of health in older adults and is associated with cognition, yet few studies have examined this in the oldest-old and if there are differences by cognitive domain. We examined the association between gait speed and cognition across three domains in individuals aged 90 + , considering differences by gender and device use. Then, 502 participants were included from the LifeAfter90 Study. Baseline gait speed (meters/second) was measured using the 4-meter walk test. The Spanish and English Neuropsychological Assessment Scale assessed executive function (EF), verbal episodic memory (VEM), and semantic memory (SM). We tested cross-sectional and longitudinal associations of gait speed with cognition using linear mixed-effects models adjusted for age, gender, race/ethnicity, education, device, interview mode, and practice effects. Models were stratified by gender and device. Participants' mean age was 92.9 ± 2.4 years, 62.6% female, 22.3% African American/Black, 20.9% Asian, 12.3% Hispanic/Latino, 35.9% White, and 8.6% multiracial/other. Faster gait speed was associated with better EF (β(95%CI) = 1.3 (0.9, 1.8)), VEM (0.7 (0.1, 1.2)), and SM (0.8 (0.4, 1.3)). Gender-stratified models showed better EF and SM in both sexes and better VEM in women. Device-stratified models showed better EF and SM in both groups and better VEM in nondevice users. Longitudinally, faster gait speed was associated with slower SM decline (0.1 (0.0003, 0.2)). No other longitudinal associations were significant in pooled or stratified analyses. Faster baseline gait speed was linked to better cognitive performance and slower SM decline. Findings varied by domain, gender, and device use, highlighting gait speed's utility in reflecting cognitive variability among those with exceptional longevity.

Age-related cognitive decline poses challenges to healthy ageing. Physical activity (PA), sedentary behaviour (SB) and sleep have been linked to cognition, yet much evidence is cross-sectional and fails to account for the interdependent nature of these 24-h movement behaviours. This observational study applied a compositional approach to investigate longitudinal associations between 24-h movement behaviours and cognition in cognitively healthy adults.

Increasing life expectancy has increased focus on the health-related consequences of aging, such as sarcopenia and frailty. Given the prevalence of these conditions among older individuals and the frequent resulting long-term care needs, early detection and intervention are crucial.