Longevity Papers

Phenotypic age (PhenoAge) is a biological aging clock that estimates an individual's biological age. However, the effect of PhenoAge acceleration (PhenoAgeAccel) on cancer is unclear. This study investigates the relationship between PhenoAgeAccel and cancer survivors. Data for this cohort study were sourced from the U.S. National Health and Nutrition Examination Survey (NHANES) spanning 1999-2018. The relationship between PhenoAgeAccel and cancer prevalence was evaluated using weighted multivariate logistic regression. Kaplan-Meier analyses and weighted multivariate-adjusted Cox analyses were conducted to examine the association between PhenoAgeAccel and all-cause as well as cancer-specific mortality in cancer survivors. Restricted cubic spline (RCS) analysis was utilized to assess nonlinear associations. Subgroup and sensitivity analyses were also performed to confirm the robustness of the findings. A total of 34,246 participants were included in our study, of which 3067 were cancer survivors (8.95% prevalence). With a median follow-up of 117 months (interquartile range: 50-155 months), there were 1161 deaths, including 351 from cancer. Weighted multivariate regression analysis revealed a significant positive association between higher PhenoAgeAccel and cancer prevalence (P for trend < 0.001). Multivariable-adjusted Cox regression analyses showed that elevated PhenoAgeAccel was significantly associated with increased all-cause and cancer-specific mortality among cancer survivors (P for trend < 0.001). RCS regression indicated no nonlinear relationship between PhenoAgeAccel and mortality outcomes (P for nonlinear relationship > 0.05). Kaplan-Meier analyses indicated a poorer prognosis with higher PhenoAgeAccel. Subgroup analyses based on tumor classification highlighted the differential prognostic impact of PhenoAgeAccel across various tumor types. Our findings reveal a significant linear correlation between PhenoAgeAccel and both all-cause and cancer-specific mortality in cancer survivors.

The Senescence-Associated Secretory Phenotype (SASP), characterized by the upregulation of inflammatory cytokines, is triggered during senescence by anti-proliferation stresses, including replicative exhaustion, {gamma}-irradiation, Ras oncogene induction, and centrosome amplification. The elucidation of common signalling pathway(s) activated in SASP, induced by different antiproliferation stresses, remains an important question. Indeed, micronuclei activation of the cGAS/Sting pathway, which has been thought to drive SASP(Kwon, Leibowitz, and Lee, 2020), remains controversial(Flynn, Koch, and Mitchison, 2021; Sato and Hayashi, 2024; Takaki et al., 2024). In this report, analyses of various cell lines induced to undergo senescence by diverse stressors revealed that HIF-1 is specifically induced in senescence but not in quiescence. Consistent with our previous findings(Wu et al., 2023a), we have further demonstrated how centrosome amplification induces a non-canonical SASP dominated by HIF-1 activation rather than the classical NF{kappa}B signaling. Lastly, we revealed that during SASP, centrosome amplification-generated micronuclei do not activate the cGAS/Sting-mediated interferon response. Together, our findings demonstrate that HIF-1-activation in SASP is a defining feature of the SASP induced by diverse stressors, acting independently of micronuclei generation and cGAS/Sting activation.

Plasma circulating cell-free nucleic acids (ccfNAs) have emerged as promising non-invasive biomarkers of aging. While age-associated changes have been reported, data in relation to extreme aging and longevity remain scarce. Here, we assessed ccfNA levels and integrity, and ccfDNA methylation in a cohort of 86 individuals, analyzed both overall and stratified by sex, including nonagenarians (NON: 90-98 years, n = 29), centenarians (CEN: 100-109 years, n = 28), and a middle-aged control group (CG: 38-67 years, n = 29) of nonagenarians' and centenarians' offspring, using our previously optimized multiparametric analysis workflow targeting nuclear (ccfnDNA) and mitochondrial (ccfmtDNA) DNA, ribosomal RNA (ccfrRNA), messenger RNA (ccfmRNA), and microRNAs (ccfmiRNAs). ccfnDNA levels followed non-linear trajectories, decreasing from CG to nonagenarians (28%-64.5%, significant in nonagenarian men compared to CG), then slightly increasing in centenarians. ccfmRNA and ccfmtDNA followed the opposite pattern, with significantly lower ccfmRNA levels in centenarians (44.5%), and both were strongly correlated (r = 0.59-0.83, p < 0.0001), suggesting a shared regulatory mechanism. Additionally, ccfnDNA integrity significantly decreased from CG to CEN (20.7%), while ccfmtDNA and ccfrRNA integrities, and ccfDNA methylation, did not vary. Among the seven ccfmiRNAs analyzed, miR-93-5p, miR-126-3p, and liver-specific miR-122-5p, exhibited significant age-related decreases (40.5%-70.3%), reaching their lowest levels in centenarians. Our study thereby provides novel findings regarding age- and sex- related changes in ccfNAs, highlighting both dynamic and stable characteristics linked to longevity. It identified potential ccfNA-based longevity biomarkers, and supports ccfmiRNAs as the most promising and sensitive biomarkers of longevity.

ABSTRACT Significance: Vascular aging is a major contributor to cardiovascular disease, yet the molecular mechanisms of age-associated vascular dysfunction remain incompletely defined. This study reveals a critical role for progranulin (PGRN) in regulating vascular senescence, function, and remodeling during aging. Methods: We assessed PGRN expression in human and mouse arteries and senescent vascular smooth muscle cells (VSMCs). Functional vascular studies were performed in PGRN-deficient (PGRN-/-) mice. Senescence was modulated pharmacologically using the senolytic agent navitoclax (ABT-263), and vascular phenotype was evaluated in adult (6-month-old) and aged mice (18-month-old). Results: PGRN expression increased with age in human and mouse arteries, correlating with elevated p21 expression. PGRN deficiency in adult mice induced endothelial dysfunction, increased vasoconstriction, and induced vascular inflammation and remodeling. Transcriptomic analysis of PGRN-/- VSMCs revealed a senescence-associated signature, including perturbed oxidative phosphorylation, altered epigenetic regulation, and collagen pathways. Pharmacological clearance of senescent cells improved endothelial function but increased vascular contractility in PGRN-/- mice. In aged mice, PGRN deficiency aggravated vascular dysfunction, remodeling, and renal injury without further increasing senescence markers - suggesting premature, rather than progressive, senescence in the PGRN-/- mice. Conclusion: PGRN is a novel regulator of vascular aging, coordinating senescence, inflammation, and remodeling. While endothelial senescence contributes to dysfunction, VSMCs senescence may serve an adaptive role in modulating vascular tone. Targeting PGRN or senescence pathways may offer therapeutic opportunities for age-related vascular diseases, especially in patients with PGRN mutations associated with frontotemporal dementia.

With the global population aging, optimizing bone regeneration is becoming increasingly important for enhancing the quality of life among elderly individuals. Progenitor cell-based therapies, such as mesenchymal stromal cells and induced pluripotent stem cells for bone regeneration have shown challenges due to cellular senescence and the control of the differentiation processes remain significant hurdles. In particular, elevated expression of senescence markers may play a pivotal role in limiting bone regeneration. This systematic review examines how these senescence markers influence the efficacy of progenitor cell therapies and whether targeting them could improve outcomes.

Sensory loss is prevalent in older adults and is associated with changes to brain structure and function. In early life, the brain compensates for sensory loss by upregulating intact senses, such as in deafness where neural sensitivity for vision increases and visual peripheral perception improves. However, it is unclear if similar neuroplastic compensation occurs in older adults with sensory loss, which would show the aging brain's adaptability and inform sensory rehabilitation strategies. We tested for evidence of compensatory visual neuroplasticity in adults (N = 66) aged 53 to 80 with typical hearing or hearing loss, and if this neuroplasticity differed for visual stimuli that were or were not relevant to speech perception. Participants viewed speech-like or non-speech stimuli as we recorded cortical activity with the 64-channel electroencephalogram (EEG). Participants with more hearing loss tended to have longer cortical P1 and N1 latencies in the visual evoked potential. However, the later cortical P2 response latency decreased with more hearing loss in agreement with compensatory plasticity. Effects were independent of numerical age. Latency effects in hearing loss were more pronounced for the speech-like stimulus compared to the non-speech stimulus, but P2 responses for the non-speech stimulus showed greater cross-modal recruitment of the temporal cortex. Findings show for the first time that compensatory plasticity operates on later cortical P2 responses in older adults, is not explained by numerical age, and differs for speech and non-speech events. However, P1 and N1 responses in networks coding for visual speech may be sensitive to sensory decline.

Aging is a significant cancer risk factor, yet its impact on the extracellular matrix (ECM) in tumor initiation and progression has been traditionally overlooked. While significant amounts of research focus on cellular and genetic links between aging and cancer, recent studies highlight how age-induced ECM changes create a tumor-permissive environment. Here we review this emerging research area, where age-related ECM alterations, such as age-induced increases in matrix stiffness, biochemical changes, and resultant dysregulated mechanosensitive pathways, are explored for their influence in cancer initiation and progression. Additionally, recent studies have showed how aged cells contribute to ECM alterations, further reinforcing tumor-permissive changes. This review examines both aspects of ECM aging, i.e. material-driven and cell-driven, and highlights current understandings of how ECM aging influences interactions within the tumor microenvironment in multiple cancer types, with a focus on biomechanical aspects. We also discuss emerging age-mimetic in vitro models facilitating studies of age-dependent cancer progression and therapeutic responses. Finally, we review therapeutic strategies that target aging-associated components or ECM changes to improve treatment efficacy.

Mitochondrial dynamics play a critical role in the development of aging-related diseases such as type 2 diabetes mellitus. To investigate how mitochondrial dynamics influence cellular behavior in pancreatic beta-cells, we developed a rule-based, multi-level simulation model of insulin secretion. The pancreatic beta cell model encompasses metabolic pathways (glycolysis and oxidative phosphorylation), compartmental processes (mitochondrial fusion and fission), and cellular processes (insulin secretion), allowing for the investigation of their interplay. The rule-based simulation model captures the high plasticity of these organelles and integrates and builds upon insights from various experimental studies and previous simulation models. Its rule-based specification facilitates the exploration of new hypotheses, the integration of new knowledge and data, and the successive extension of the model. The results of our simulation experiments underscore the importance of peripheral, sorted mitochondrial fission in maintaining mitochondrial health. Downregulation of the fission-associated anchor proteins Fis1 and MFF impacts mitochondrial structure and function differently, highlighting their distinct roles in maintaining mitochondrial health and cellular biogenesis, respectively. With respect to insulin secretion, Drp1 suppression shows that beta cells become unresponsive to glucose, whereas Fis1 downregulation only attenuates the cellular response. The simulation model and simulation results corroborate experimental findings and contribute to a deeper understanding of the mechanisms involved in mitochondrial dynamics of pancreatic beta cells and their relation to metabolic dysregulation in type 2 diabetes mellitus.

With the accelerating pace of population aging, the incidence of osteoarthritis (OA), a degenerative disease strongly associated with age, is rapidly increasing. Chondrocyte senescence is a major contributor to cartilage degeneration; however, effective therapeutic strategies targeting chondrocyte aging remain lacking. Mesenchymal stem cell (MSC)-based approaches have emerged as a promising means of combating cellular senescence, among which exosomes (Exos) play a pivotal role in mediating therapeutic effects. Compared with direct MSC transplantation, Exos offer a safer and more ethically acceptable alternative. Moreover, the functional properties of Exos can be modulated by the microenvironmental stimuli applied to MSCs, although the underlying molecular mechanisms remain largely unclear. In this study, we employed interferon-γ (IFN-γ) to precondition MSCs and generate functionally enhanced Exos (iExos). Both in vitro and in vivo experiments demonstrated that iExos exhibit superior antisenescent activity in chondrocytes and more effectively attenuate OA progression. Sequencing analysis, together with mechanistic studies, revealed that iExos exert these effects by sustaining mitochondrial AMPK-SIRT3 homeostasis in chondrocytes through Hsp70. These findings partially elucidate a key pathway by which stem cell-derived iExos combat chondrocyte senescence and may inform the design of stable, efficient, and safe MSC-based antisenescence strategies.

Synapse dysfunction is tightly linked to cognitive changes during aging. Emerging evidence suggests that microglia and the extracellular matrix (ECM) can potently regulate synapse integrity and plasticity. Yet the brain ECM, and its relationship with microglia, synapses, and cognition during aging remains virtually unexplored. In this study we combine ECM-optimized proteomic workflows with histological analyses in aging mice and discover regional differences in ECM composition and aging-induced ECM remodeling across basal ganglia nuclei. Moreover, we combine two distinct behavioral classification strategies with fixed-tissue confocal imaging and proteomic analysis and identify relationships between the hyaluronan- and proteoglycan-rich ECM and cognitive aging phenotypes. Finally, we provide evidence that aging midbrain microglia lose capacity to interact with and regulate the ECM, and that these aging-associated microglial changes are accompanied by local ECM accumulation and worse behavioral performance. Together, these observations indicate that changing microglia-ECM-synapse interactions contribute to cognitive functioning during healthy aging.

Autophagy preserves neuronal integrity by clearing damaged proteins and organelles, but its efficiency declines with aging and neurodegeneration. Depletion of the oxidized form of nicotinamide adenine dinucleotide (NAD

Metabolic dysfunction-associated steatotic liver disease [MASLD; previously known as nonalcoholic fatty liver disease (NAFLD)] is a prevalent chronic liver disorder strongly associated with aging, yet the mechanisms underlying age-related hepatic lipid dysregulation remain incompletely defined. This study investigates how aging alters hepatic phospholipid metabolism and the contribution of phosphatidylethanolamine N-methyltransferase (PEMT) to MASLD progression. Here, lipid accumulation was characterized in the livers of 2-, 6-, 12-, 18-, and 24-month-old mice, revealing age-dependent increases in hepatic triacylglycerol (TG), total cholesterol (TC), and lipid droplet formation. Lipidomic analysis revealed a marked imbalance in phospholipid composition, characterized by increased phosphatidylcholine (PC) and decreased phosphatidylethanolamine (PE), resulting in a 2.5-fold increase in the PC/PE ratio in 24-month-old mice compared with 6-month-old controls. Mechanistically, PEMT, a key enzyme regulating PC and PE metabolism, exhibited significantly increased expression (~2.4-fold at the protein level) in aged livers, suggesting a pivotal role in driving the observed phospholipid imbalance in vitro. PEMT inhibition significantly attenuated lipid droplet accumulation by ~30% and reduced intracellular TG levels by ~20% in D-galactose-induced senescent AML12 hepatocytes under lipid stress, compared with nonsilenced senescent controls. These findings suggest that aging-driven PEMT overexpression promotes phospholipid remodeling and hepatic lipid accumulation. By leveraging a natural aging mouse model, our study provides the first evidence linking PEMT activity to age-associated phospholipid dyshomeostasis, revealing a previously unknown mechanistic axis distinct from diet-induced MASLD and offering new therapeutic insights.

Gene expression is co-regulated by the rates of RNA synthesis and degradation, and recent evidence has linked their imbalance to the onset of aging. The naked mole-rat (NMR) is a small rodent with an exceptionally long lifespan and markedly delayed aging, yet little is known about its RNA synthesis and degradation characteristics compared to other rodents that age more rapidly. Here, we investigate RNA synthesis and degradation in NMR and mouse skin fibroblasts by monitoring incorporation of a uridine analog, 4-thiouridine. Cross-species analysis showed that the NMR cells have higher overall rates of RNA synthesis and degradation. It further revealed higher RNA degradation rates in aging-related pathways, notably Mtorc1 signaling, likely contributing to reducing the overall expression. Although known aging-associated genes, including Xrcc5, Nudt1, Fen1, and Aptx, were expressed at similar levels in NMR and mouse fibroblasts, the RNA turnover rates were largely altered. To uncover the underlying mechanism enabling differential control of RNA kinetics, we analyzed the transcript feature importance by machine learning and identified key features governing RNA degradation both common and unique in NMR and mouse fibroblasts. Our data highlight a potential role of RNA synthesis and degradation as hidden layers of gene regulation in NMR.

The liver plays a central role in regulating systemic metabolism, and its function declines with age, contributing to increased susceptibility to metabolic diseases. Metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by hepatic lipid accumulation and inflammation, is an early manifestation of liver dysfunction strongly associated with aging, insulin resistance, and high-fat diet (HFD) consumption. Ames Dwarf mice, which are growth hormone (GH)-deficient and long-lived, retain insulin sensitivity and exhibit resistance to age-related metabolic decline, making them an ideal model to study hepatic protection mechanisms. In this study, male and female Ames Dwarf and wildtype (WT) mice were fed either a standard diet or HFD for 12 weeks. WT males developed classical features of MASLD, including hepatic steatosis, hepatocyte ballooning, and elevated levels of inflammatory cytokines (IL-1β, MCP-1, IL-2, and IL-4). In contrast, Ames Dwarf mice exhibited minimal liver pathology, reduced lipid accumulation, and limited cytokine induction. Transcriptomic profiling revealed that WT mice upregulated genes involved in inflammation and proliferation, while Ames Dwarf mice showed activation of protective metabolic pathways (PPAR and AMPK) and suppression of lipogenic and fibrotic gene programs. Notably, female Ames Dwarf mice displayed the strongest resistance to HFD-induced changes, with minimal transcriptomic alterations. These findings suggest that disrupted GH signaling in Ames Dwarf mice leads to a reprogrammed hepatic response that preserves metabolic health and protects against MASLD, highlighting potential links between aging, GH signaling, and liver resilience.

Studies in laboratory organisms typically minimize all environmental and genetic variation other than the intervention of interest. In aging studies, these highly controlled conditions have yielded profound insights into aging. But even within isogenic cohorts of lab animals in controlled environments, we observe substantial variation in lifespan. Here we exploited the climbing behavior of Drosophila to study variation in mortality among isogenic populations in a controlled environment. We show that fractionating large cohorts of relatively young isogenic flies by climbing behavior predicts future mortality risk and stress sensitivity. Using metabolomics to dissect this variation, we found metabolites whose abundances differ among the fractions. We also took advantage of the large number of individuals in each fraction, and the ease with which they can be collected, to explore the covariance structure of metabolites in flies that are genetically identical, but divisible into short-lived and long-lived fractions. In doing so, we identified metabolites and metabolic pathways as candidate biomarkers of intrinsic mortality risk.

Telomerase, essential for maintaining chromosomal telomere integrity and preventing cellular senescence, represents a promising therapeutic target. However, the inherent risks associated with existing treatments for telomerase deficiency-related diseases necessitate the development of safe and precise targeted delivery systems capable of reaching specific cell populations. Extracellular vesicles (EVs), nanoscale membrane-bound particles naturally secreted by cells, mediate intercellular communication by transporting bioactive molecules, including proteins and nucleic acids. We hypothesized that EVs could function as intrinsic vehicles for telomerase delivery.

Robust 3D tissue culture models to activate aged fibroblasts for cell-based therapies and identify regulators of such activation are still missing. In our previous study, we showed that aged fibroblasts can be activated simply through applying compressive force, without the need for exogenous factors, leading to increased migration. In this study, we develop a pipeline to evaluate the role of specific pharmacological inhibitors for transcription factor inference and cell migration involved in aged fibroblast activation. By integrating RNA-seq data with bioinformatic tools (prize collecting Steiner tree method and iRegulon) we inferred 15 candidates. In addition, we used cell migration and heterochromatin content as readouts for validating these candidates. Furthermore, we identified three potential master regulators of fibroblast activation and rejuvenation: FOXO1, STAT3, and PDK1. These findings offer valuable insights for future drug discovery, disease modeling, and regenerative medicine.

Aging or injury to the joints can lead to cartilage degeneration and osteoarthritis (OA), for which there are limited effective treatments. We found that expression of 15-hydroxy prostaglandin dehydrogenase (15-PGDH) is increased in the articular cartilage of aged or injured mice. Both systemic and local inhibition of 15-PGDH with a small molecule inhibitor (PGDHi) led to regeneration of articular cartilage and reduction in OA-associated pain. Using single cell RNA-sequencing and multiplexed immunofluorescence imaging of cartilage, we identified the major chondrocyte subpopulations. Inhibition of 15-PGDH decreased hypertrophic-like chondrocytes expressing 15-PGDH and increased extracellular matrix-synthesizing articular chondrocytes. Cartilage regeneration appears to occur through gene expression changes in pre-existing chondrocytes, rather than stem or progenitor cell proliferation. 15-PGDH inhibition could be a potential disease-modifying and regenerative approach for osteoarthritis.

The relationship between the intestinal microbiota and human health during ageing is an area of increasing interest due to increasing health challenges experienced by ageing populations. This paper develops a mathematical model describing the age-related biological changes associated with alterations to the microbiota, vitamin D levels, immunosenescence and inflammageing to determine the likely impact of manipulating the intestinal microbiota with dietary components. Age-dependent parameters are incorporated into a previously developed model to determine the evolution of intestinal bacterial populations, vitamin D receptor:1,25 dihydroxyvitamin D levels, epithelial barrier integrity and immune response with increasing age. Results suggest an age-related decline in both innate and adaptive immunity, weakening of the intestinal barrier, elevation in systemic inflammation and reduced serum vitamin D, resulting in individuals over 60 years old becoming vitamin D deficient (<50 nmol/L). Numerical simulations indicate that administration of probiotics and/or vitamin D supplements upregulates the VDR complex at all ages, which helps restore epithelial barrier function, particularly in older adults in whom the intestinal barrier has been compromised. The greatest benefit is derived from co-supplementation with probiotics and age-dependent doses of vitamin D. Finally, the value of gathering additional experimental data motivated by the modelling insights is discussed.

Paramylon (PM), an insoluble β-1,3-glucan produced by Euglena gracilis, reportedly possesses immunomodulatory and metabolic regulatory effects. However, its effect on longevity remains unclear. For this study, using Caenorhabditis elegans as a model, we evaluated lifespan-extending effects of PM and elucidated its underlying molecular mechanisms. Dietary PM supplementation prolonged the C. elegans lifespan significantly without affecting either growth or fertility, indicating the effects as independent of caloric restriction. Findings indicate that PM intake strongly upregulated clec-196, an ortholog of the β-glucan receptor DECTIN-1. Also, RNA interference of clec-196 eliminated PM-induced lifespan extension, indicating clec-196 as necessary for the physiological response to PM. Moreover, PM supplementation increased expression of jnk-1 and daf-16, which were suppressed when clec-196 was knocked down, suggesting that clec-196 functions upstream of the JNK-1/DAF-16 pathway. The lifespan-extending effect of PM was completely absent in loss-of-function mutant of daf-16, underscoring its indispensable role. Furthermore, PM feeding activated the DAF-16-mediated antioxidant pathway, as evidenced by upregulation of antioxidant genes and by suppression of hydrogen peroxide accumulation. These findings suggest that PM might serve as a functional food ingredient exhibiting anti-aging potential.

Existing therapies for androgenetic alopecia (AGA) fall short of expectations due to the complex pathogenesis, deficient drug enrichment, and obvious adverse effects. Although elevated dihydrotestosterone (DHT) is responsible for the miniaturization of hair follicles (HFs), cell aging has been found to be closely associated with AGA, however not received sufficient attention before. In this study, we first explored the deleterious effects of DHT on HFs, then identified the anti-aging potential of conjugated linoleic acid (CLA) from several polyunsaturated fatty acids. We then developed CLA-loaded nanovesicles (Arg-CLAVs) capable of counteracting DHT-induced HF aging. Arg-CLAVs rejuvenated DHT-induced senescent cells by alleviating oxidative stress, reducing the production of senescence-associated secretory phenotype, and modulating the MAPK-ERK signaling pathway. Moreover, Arg-CLAVs enhanced the HF niche by facilitating angiogenesis, preserving local oxidative homeostasis, and promoting the proliferation and migration of dermal papilla cells. Given its unique properties of nanocarriers, Arg-CLAVs exhibited better skin retention and HF targeting ability compared to the normal tincture. Subsequently, minoxidil (MNX) was loaded into the nanovesicle (MNX@Arg-CLAVs) and evaluated for its hair growth-promoting efficacy in vivo. Our results demonstrated that, in both male and female AGA mice, MNX@Arg-CLAVs with reduced MNX dosage and lower organic solvent contents, exhibited stronger effects on hair regeneration promotion and anti-aging in HFs, while inducing less formulation-associated skin irritation than commercial topical MNX tincture. In sum, this study developed a novel nanoplatform with HF anti-aging activity for AGA that enables synergistic effects with existing drugs.

Aging proceeds heterogeneously across tissues, yet how biological age varies within the spatial architecture of individual organs remains poorly understood. Here, we introduce stAge, a framework that quantifies localized transcriptomic age (tAge) from spatial transcriptomics data in mouse and human samples during natural aging and in response to injury, infection, neurodegeneration, and cancer. stAge captures age differences among samples and provides a single multi-tissue model for assessing aging within and across organs. Across tissues and conditions, stAge uncovers robust spatial gradients of biological age and shows that injury and neurodegeneration induce pronounced age acceleration, with stronger responses in older organisms and partial normalization during recovery. With advancing age, tissues develop pronounced hotspots of accelerated aging and coldspots of preserved resilience. Hotspots are enriched for metabolic and immune aging signatures, whereas chromatin-related signatures are associated with coldspots. These findings show that aging is spatially structured within tissues and lay a foundation for developing spatially targeted rejuvenation strategies.

Aging research has advanced significantly over the past century, from early studies on animal models to a current emphasis on clinical and translational applications. As research literature expands exponentially, traditional narrative reviews can no longer capture the field's complexity, highlighting the need for new, unbiased synthesis tools. Here, we leverage advanced natural language processing (NLP) and machine learning (ML) techniques to analyze 461,789 abstracts related to aging published between 1925 and 2023. By integrating Latent Dirichlet Allocation (LDA), term frequency-inverse document frequency (TF-IDF) analysis, dimensionality reduction and clustering, we delineate a comprehensive thematic landscape of aging research. Our results show a clear shift: early decades focused on cellular and molecular mechanisms, while recent years emphasize clinical studies, especially neurodegenerative disorders. Notably, we identify a persistent divide between the biology of aging (BoA) and clinical research, with minimal conceptual overlap between them. Furthermore, we identify distinct clusters representing key biological processes, some of which may have previously been overlooked as cohesive research domains. Finally, we highlight both established and underexplored interconnections that could guide future research. This study outlines shifting priorities and translational gaps in aging research and offers a scalable, data-driven alternative to conventional reviews.

The global population is rapidly aging, presenting significant public health challenges, particularly with the increased risk of chronic diseases. Biological age acceleration refers to a faster-than-expected aging process, which is associated with an increased risk of age-related chronic diseases. Uric acid to high-density lipoprotein cholesterol ratio (UHR) is a novel biomarker that reflects metabolic disturbances and has been linked to various chronic conditions. Understanding the relationship between UHR and biological age acceleration, as well as its modifiable risk factors, is crucial for developing strategies aimed at promoting healthy aging and managing chronic diseases in older adults. Using data from a cohort study, the ratio of uric acid to high-density cholesterol (UHR), uric acid (UA), and high-density lipoprotein (HDL) were assessed in relation to biological age acceleration, including phenotypic age acceleration (PhAA) and Klemera-Doubal method age acceleration (KDM-AA), through multiple linear and logistic regression models, adjusted for demographic characteristics, lifestyle factors, and medical histories. Restricted cubic spline (RCS), subgroup, and interaction analyses were also conducted. Subgroups were stratified according to age (< 60 vs. ≥60 years), sex (male vs. female), race (Black vs. others), BMI (< 30 vs. ≥30), hypertension (yes/no), cardiovascular disease (yes/no), cancer (yes/no), and physical activity level (< 600, 600-3999, and ≥ 4000 min/week). The results reveal significant associations between elevated UHR, UA levels, reduced HDL cholesterol, and accelerated biological aging. RCS regression analyses revealed a complex relationship between UHR and age acceleration, with a non-linear association with PhAA and a linear relationship with KDM-AA. Subgroup analysis showed that the association between UHR and biological age acceleration remained robust across all groups. Interaction analyses revealed differential effects across subgroups, particularly among individuals with varying physical activity levels, cardiovascular disease, and hypertension status. This study demonstrates a significant positive association between UHR and markers of biological age acceleration. These findings suggest that UHR could serve as a potential biomarker for aging and chronic disease management in older adults, offering insights into strategies to reduce the burden of age-related conditions.

Aneuploid cells are known to increase with age. Previously, we demonstrated an increased number of aneuploid fibroblasts isolated from aged mice due to chromosomal instability (CIN), which is caused by oxidative stress. It is unclear whether this phenomenon also occurs in human cells, which are more resistant to oxidative stress than mouse cells. Here, we found that fibroblasts from aged individuals exhibited an increase in aneuploid cells. The frequency of chromosome missegregation and micronuclei increased in these cells, indicating CIN. A DNA fiber assay revealed the presence of replication stress, accompanied by an increase in 53BP1 nuclear bodies and ultrafine bridges. Increased levels of reactive oxygen species derived from mitochondria, along with reduced mitochondrial membrane potential, imply that these cells experienced oxidative stress due to mitochondrial functional decline. Antioxidant treatment reduced the frequency of chromosome missegregation and micronuclei, suggesting that oxidative stress causes CIN. Oxidative stress also causes replication stress, which precedes CIN. Spindle microtubules were stabilized in fibroblasts from aged individuals, which was alleviated by antioxidant treatment. Taken together, these findings suggest that aging-related CIN in human fibroblasts is caused by oxidative stress associated with mitochondrial dysfunction, which induces replication stress that in turn causes CIN through microtubule stabilization. Although human fibroblasts are more resistant to the ambient oxygen environment than mouse fibroblasts, our findings showed that they undergo oxidative stress that causes CIN with age in a manner similar to mouse fibroblasts, revealing a conserved phenomenon in mammalian cells.

Functional iron deficiency affects a large proportion of patients with chronic diseases and is increasingly observed in older adults. Clinical evidence links iron deficiency to sarcopenia, yet the mechanistic relationship between iron status and muscle regeneration remains poorly defined. This study investigates how iron depletion alters muscle stem cell (MuSC) proliferation and skeletal muscle regeneration, focusing on HIF-2α signalling.

Human female fertility declines markedly with age, a pattern mirrored in

Skeletal muscle is a complex organ that undergoes aging through a multifactorial process leading to muscle atrophy and strength reduction. Mitochondrial dysfunctions prove to be a critical contributor to skeletal muscle aging, affecting the regenerative functions and differentiation of muscle satellite cells (MuSCs). Physical exercise is a nonpharmacological approach that positively affects mitochondrial functions, promoting increased mitochondrial biogenesis, enzyme activities, and respiration in the aging skeletal muscle. By means of morphological and morphometrical analyses at transmission electron microscopy, this in vitro study identified the fine structural modifications induced in mitochondria of MuSC-derived myoblasts by a long-term adapted physical exercise applied to old mice, and verified the persistence of the exercise-driven changes in the myoblast-derived myotubes. In myoblasts, physical exercise decreased mitochondrial volume while increasing mitochondrial elongation and cristae extension in comparison to the sedentary condition, a mitochondrial remodeling suggestive of higher functionality. In myotubes, physical exercise increased mitochondrial volume and decreased cristae extension, partially reverting the age-associated alterations. These findings demonstrate that physical exercise administered in elderly exerts positive effects on mitochondria of the progeny of resident MuSCs.

In the in vitro expansion of mesenchymal stem cells (MSCs), replicative or stress-induced senescence poses a significant challenge, leading to the loss of their cellular properties and therapeutic functions. Currently, there is a lack of efficient strategies to address this issue.

Sarcopenia, characterized by the progressive loss of skeletal muscle mass and function, remains a formidable challenge in aging populations. This review synthesizes current knowledge on its multifactorial pathogenesis, including mitochondrial dysfunction, oxidative stress, chronic inflammation, apoptosis, and satellite cell impairment. Neuromuscular alterations such as motor unit Remodeling and neuromuscular junction degeneration further exacerbate functional decline. Diagnostic approaches, ranging from DXA, CT, MRI, and ultrasound imaging to functional assessments like handgrip strength and gait speed, exhibit variability that complicates standardization. Therapeutic strategies are equally versatile. Resistance-based exercise and targeted nutritional support remain first-line, but late-phase trials of myostatin-neutralising antibodies (e.g., LY2495655, bimagrumab) and oral selective androgen-receptor modulators (SARMs; e.g., enobosarm, GSK2881078) now show dose-dependent gains in appendicular lean mass and preliminary functional benefits, signalling that combination regimens integrating lifestyle and drug therapy are imminent. Integration of these approaches with personalized medicine paradigms and AI-driven diagnostic tools holds promise for improved outcomes. This review also outlines critical research areas including mechanistic studies, diagnostic standardization, and translational gaps between preclinical models and clinical application. Addressing these challenges requires an interdisciplinary strategy that encompasses molecular, clinical, and public health perspectives to mitigate the personal and societal impacts of sarcopenia. Future efforts must focus on harmonizing diagnostic criteria, refining therapeutic regimens, and leveraging emerging technologies to develop targeted interventions that preserve muscle function and enhance quality of life in the aging population.

While human skin aging involves complex transcriptional alterations, the cell-type-specific regulatory mechanisms and therapeutic targets remain incompletely defined. The study aims to investigate aging-associated transcriptional programs and drug-responsive signatures at single-cell resolution.

Somatic mutations accumulate with age and can cause cell death, but their quantitative contribution to limiting human lifespan remains unclear. We developed an incremental modeling framework that progressively incorporates factors contributing to aging into a model of population survival dynamics, which we used to estimate lifespan limits if all aging hallmarks were eliminated except somatic mutations. Our analysis reveals fundamental asymmetry across organs: post-mitotic cells such as neurons and cardiomyocytes act as critical longevity bottlenecks, with somatic mutations reducing median lifespan from a theoretical non-aging baseline of 430 years to 169 years. In contrast, proliferating tissues like liver maintain functionality for thousands of years through cellular replacement, effectively neutralizing mutation-driven decline. Multi-organ integration predicts median lifespans of 134-170 years--approximately twice current human longevity. This substantial yet incomplete reduction indicates that somatic mutations significantly drive aging but cannot alone account for observed mortality, implying comparable contributions from other hallmarks.

Mammalian maximum lifespan (MLS) varies over a hundred-fold, yet the molecular mechanisms underlying this diversity remain unclear. We present a cross-species analysis of alternative splicing (AS) across six tissues in 26 mammals, identifying hundreds of conserved AS events significantly associated with MLS, with the brain containing twice as many tissue-specific events as peripheral tissues. MLS-AS events are enriched in pathways related to mRNA processing, stress response, neuronal functions, and epigenetic regulation, and are largely distinct from genes whose expression correlates with MLS, indicating that AS captures unique lifespan-related signals. The brain exhibits certain associations divergent from peripheral tissues and reduced overlap with body mass (BM)-associated splicing; neither is observed at the gene expression level. While MLS- and age-associated AS events show limited overlap, the shared events are enriched in intrinsically disordered protein regions, suggesting a role in protein flexibility and stress adaptability. Furthermore, MLS-associated AS events display stronger RNA-binding protein (RBP) motif coordination than age-associated ones, highlighting a more genetically programmed adaptation for lifespan determination, in contrast to the more variable splicing changes seen with chronological aging. These findings suggest alternative splicing as a distinct, transcription-independent axis of lifespan regulation, offering insights into the molecular basis of longevity.

The global burden of pulmonary fibrosis is increasing. Recent studies have shown that some pulmonary fibrotic lesions caused by COVID-19 infection may persist for a long time. Emerging evidence suggested a critical association between gut microbiota and pulmonary fibrosis. In this study, the clinical follow-up data from post-COVID-19 patients indicated that those with higher CT image scores were older, had a significantly lower Blautia and Bifidobacterium to Streptococcus ratio (B/S index). We examined whether Bifidobacterium adolescentis could attenuate bleomycin-induced pulmonary fibrosis in mice, with particular attention in the aging mice. Aging mice exhibited more severe pulmonary fibrosis after BLM induction, while the intervention of B. adolescentis attenuated the degree of pulmonary fibrosis in aging mice to a state similar to that of young mice. B. adolescentis alleviated inflammatory responses by enhancing the gut barrier, and reduced fibrotic marker expression (TGF-β, IL-17, α-SMA, Collagen I/III) by modulating PPAR and Th17 signaling pathways. Furthermore, B. adolescentis stabilized gut microbiota and increased the abundance of Bifidobacterium, Turicibacter, and norank_f_Desulfovibrionaceae, thereby suppressed the prostaglandin E2 (PGE2) and affected collagen deposition. B. adolescentis alleviates pulmonary fibrosis through the gut-lung axis by regulating PGE2/PPAR/Th17 signaling, providing a promising therapeutic approach for pulmonary fibrosis management.

The elimination of senescent cells can enhance the osteointegration of implants in elderly patients. However, achieving specific clearance of senescent cells without adversely affecting the function of normal cells remains challenging. Here we show an implant surface modification technique to achieve specific clearance of locally senescent cells by modulating their metabolism. Our method involve modifying implants with BPTES, a glutaminase 1 (GLS1) inhibitor, through π-π stacking with dopamine. This modification effectively induces intracellular acidosis in senescent mesenchymal stem cells (MSCs) through suppression of glutaminolysis. Simultaneously, poly(γ-glutamate) (PGA), modified by a layer-by-layer method, serve as a high-density carbon source coating, continuously supporting glutamine metabolism in MSCs without ammonia production. Our results show that modified implants significantly reduce the senescence level around implants and promote osteointegration in aged rats. These findings provide promising insights into the design and application of orthopedic implants for elderly patients.

Neurons rely on glial lactate shuttling for metabolic support, which declines with aging and in neurodegenerative disease. Full disruption of lactate shuttling in peripheral nerves causes progressive axon degeneration, but we were interested to understand how partial disruption, a scenario more relevant to aging and disease, contributes to neurodegeneration risk. Pyruvate and lactate are interconverted by lactate dehydrogenases (LDHA and LDHB) in both lactate producing and consuming cells. We therefore began by investigating Ldhb knockout mice (loss of LDHA, the dominant LDH in liver and muscle, caused embryonic lethality), and discovered that they develop progressive neuromuscular junction atrophy and functional decline without axon degeneration. Because even Ldhb+/- heterozygosity significantly affects motor behavior, we also wondered about a potential link to congenital disease and pursued this by identifying rare loss-of-function LDHB variants among ALS patients. Next, to better understand how LDHB loss leads to motor decline, we selectively deleted it in defined cell types. SC-specific deletion caused robust motor defects, whereas motor neuron-specific deletion has little effect. Reasoning that neuronal LDHB deficiency could model age-associated decline in lactate metabolism, we asked whether it would interact with ALS genetic risk. Indeed, motor-neuron LDHB deficiency synergizes with relatively mild ALS risk variants, TDP43-Q331K and Sod1-D83G knock-in alleles, to produce early motor neuropathy, indicating that LDHB loss enhances disease risk. These findings establish lactate metabolism as a modifier of motor system vulnerability and highlight it as a therapeutic target in peripheral as well as central neurodegeneration.

The additive genetic variance of a quantitative trait usually is interpreted as a measure of its evolvability, i.e., its capacity for adaptive evolution. However, in populations with overlapping generations, evolvability is also affected by the parental age at reproduction because genotypes that reproduce earlier evolve faster than genotypes with later reproduction. I show here that directional selection of a phenotypic trait inevitably links it with relative age at reproduction and thus developmental timing, whether or not age at reproduction affects reproductive success. In turn, the evolved genetic covariance between the selected trait and reproductive age accelerates the evolutionary response of the trait mean, unless counteracted by strong selection for late reproduction. Hence, not only the genetic variance of the trait but also the genetic variance in age at reproduction contributes to a trait's evolvability, even if the trait was initially unrelated to age at reproduction. I further show that stable generation time requires selection of intermediate strength for later reproduction and that episodes of strong selection tend to shorten average generation time. After a proof of principle by individual-based simulations, I present a formalization of this theory in a quantitative genetic framework, leading to a relatively simple extension of the breeder's equation. Finally, I discuss empirical evidence and implications for senescence and life history evolution.

Aging is an irreversible degenerative process marked by declining physiological function. Developing therapeutics to delay aging and prolong healthy life represents a significant research focus. The dried roots of Asparagus cochinchinensis (Lour.) Merr. (Asparagi Radix, AR), a traditional Chinese medicine, possesses various pharmacological properties, including antioxidative, antitumor, and anti-inflammatory effects, and is commonly used in anti-aging formulas. Although steroidal saponins are its major active components, the specific compounds responsible for its anti-aging effects remain unidentified, and their mechanistic basis is unclear. This study evaluated the anti-aging effects of AR-derived total saponin extracts (ATSE) in Caenorhabditis elegans and elucidated underlying mechanisms. We prepared multiple ATSE batches from distinct geographical sources and assessed their bioactivity through lifespan and healthspan analyses (brood size, pharyngeal pumping), stress resistance, assays (oxidative, thermal), senescence biomarkers (lipofuscin accumulation, SOD activity, ROS levels). Mechanistic insights were obtained using transgenic strains and qRT-PCR, while ELSD-HPLC fingerprinting and spectrum-effect correlation identified active compounds. Key findings demonstrated that ATSE from Sichuan (T1) most effectively prolonged C. elegans lifespan (p < 0.01), enhanced stress resistance, increased SOD activity, and decreased ROS levels. The lifespan extension was primarily mediated through the FOXO/DAF-16 signaling pathway, while spectrum-effect analysis further identified (25S)-officinalisnin-II as the most active compound, extending C. elegans longevity under oxidative stress by 13.91%. Our research revealed AR's anti-aging mechanism and identified a key active compound, laying the foundation for quality-controlled AR therapeutics and providing new insights for the development of anti-aging drugs from traditional Chinese medicine.

Biguanides, including metformin, the world\'s most prescribed oral hypoglycemic, extend health-span and lifespan in vertebrates and invertebrates. Given the widespread use and apparent safety of metformin, it is assumed that its effects are not associated with toxicity, except when in marked excess. Here we determine that accumulation of damaging reducing equivalents is an unanticipated toxicity associated with biguanides, the defense against which requires post-transcriptional protection of de novo fatty acid biosynthesis. We demonstrate that biguanide treatment during impaired fatty acid biosynthesis drives NADPH toxicity, leading to catastrophic elevation of NADH/GSH reducing equivalents and accelerated death across metazoans. Multiple NADPH-generating interventions require fatty acid biosynthesis to prevent markedly shortened survival, indicating that this defense mechanism is broadly leveraged. We propose that fatty acid biosynthesis is a tunable rheostat which can minimize biguanide-induced reductive stress whilst maximizing its pro-longevity outcomes and serve as an exploitable vulnerability in reductive stress sensitive cancers.

This review highlights recent findings on the versatile serpin protein, pigment epithelium-derived factor (PEDF), as pertains to its roles in ageing and development, including its linked functions as an antioxidant and in stem cell support. The anti-oxidative properties of PEDF channel through several well-known pathways such as nicotinamide adenine dinucleotide phosphate oxidase. PEDF also supports stem cell survival in various tissues, leading to certain types of differentiation of such cells, for example, in bone. Mesenchymal stem cells engineered to overexpress PEDF have profound effects on neighbouring cells, which can be exploited therapeutically. PEDF can attenuate both the p53 and peroxisome proliferator-activated receptor-gamma pathways. This review provides a comprehensive, first-of-its-kind overview of the protein, listing a majority of all the relevant studies reported to date.

Mapping behavior of individual vertebrate animals across lifespan is challenging, but if achieved, could provide an unprecedented view into the life-long process of aging. We created the first platform for high-resolution continuous behavioral tracking of a vertebrate animal across natural lifespan from adolescence to death--here, of the African killifish. This behavioral screen revealed that animals follow distinct individual aging trajectories. The behaviors of long-lived animals differed markedly from those of short-lived animals, even relatively early in life, and were linked to organ-specific transcriptomic shifts. Machine learning models accurately predicted age and even forecasted an individual\'s future lifespan, given only behavior at a young age. Finally, we found that animals progressed through adulthood in a sequence of stable and stereotyped behavioral stages with abrupt transitions suggesting a novel structure for the architecture of vertebrate aging.

During brain aging, terminally differentiated neuroglia exhibit metabolic dysfunction and increased oxidative damage, compromising their function. These cellular and molecular alterations impair their ability to maintain myelin sheath integrity, contributing to age-related white matter degradation. Calorie restriction (CR) is a well-established intervention that can slow biological aging and may reduce age-related metabolic alterations, thereby preserving the molecular function of aging glia. Here we present a single nucleus resolution, transcriptomics dataset evaluating the molecular profile of oligodendrocytes and microglia in the brain of aging rhesus monkeys following lifelong, 30% calorie restriction. Oligodendrocytes from CR subjects exhibited increased expression of myelin-related genes and showed enrichment in glycolytic and fatty acid biosynthetic pathways. In CR subjects, a subpopulation of oligodendrocytes upregulated cell adhesion gene, NLGN1 and were in closer proximity to axons. Microglia from CR subjects upregulated amino acid and peptide metabolism pathways and showed a reduced myelin debris signature. Our findings reveal cell-type specific transcriptional reprogramming in response to long term CR and highlight potential protective mechanisms against myelin pathology in the aging primate brain.

The functional significance of long non-coding RNAs (lncRNAs) remains a subject of debate, largely due to the complexity and cost associated with their validation experiments. However, emerging evidence suggests that pseudogenes, once viewed as genomic relics, may contribute to the origin of functional lncRNA genes. In this study spanning eight species, we systematically identified pseudogene-associated lncRNA genes using our PacBio long-read sequencing data and published RNA-seq data. Our investigation revealed that pseudogene-associated lncRNA genes exhibit heightened functional attributes compared to their non-pseudogene-associated counterparts. Notably, these pseudogene-associated lncRNAs show protein-binding proficiency, positioning them as potent regulators of gene expression. In particular, pseudogene-associated sense lncRNAs retain protein-binding capabilities inherited from parent genes of pseudogenes, thereby demonstrating greater protein-binding proficiency. Through detailed functional characterization, we elucidated the unique advantages and conserved roles of pseudogene-associated lncRNA genes, particularly in the context of gene expression regulation and DNA repair. Leveraging cross-species expression profiling, we demonstrated the prominent contribution of pseudogene-associated lncRNA genes to aging-related transcriptome changes across nine human tissues and eight mouse tissues. Overall, our findings demonstrate enhanced functional attributes of pseudogene-associated lncRNA genes and shed light on their conserved and close association with aging.

L-Quebrachitol (QBC), a derivative of L-inositol, exhibits antioxidant and antimetabolic disorder properties; however, its antiaging effects remain unexplored. This study isolated QBC from sea buckthorn leaves using the CaO/resin purification-methanol precipitation method. The structure was confirmed using nuclear magnetic resonance (NMR), X-ray diffraction (XRD), ultraperformance liquid chromatography-mass spectrometry (UPLC-MS), and fourier transform infrared spectroscopy (FTIR). QBC was found to extend the lifespan of