Rees-Baylis, E., Wang, D., Li Richter, X.-Y. ...
· evolutionary biology
· Institute of Ecology and Evolution, University of Bern, Bern, Switzerland
· biorxiv
Sex differences in ageing and lifespan are widespread across taxa, yet their evolutionary causes remain debated. A leading hypothesis suggests these differences are adaptive and driven by sex-specific life-history trade-offs, but formal theoretical support is lacking. To address ...
Sex differences in ageing and lifespan are widespread across taxa, yet their evolutionary causes remain debated. A leading hypothesis suggests these differences are adaptive and driven by sex-specific life-history trade-offs, but formal theoretical support is lacking. To address this, we developed a mathematical model to investigate how such trade-offs shape lifespan evolution in a monogamous mating system. In the model, individuals evolve to optimise a trade-off between reproduction and survival -- mediated by mating opportunities in males and offspring production in females. By systematically varying trade-off strengths, we show that either sex can evolve greater longevity, but male-biased longevity evolves under a broader set of conditions -- consistent with patterns in monogamous species. This asymmetry arises because female longevity is more constrained: the trade-off between offspring production and survival directly affects the fertility of both sexes. In contrast, the male trade-off for mating opportunities has a weaker indirect effect on female fertility, allowing selection to more readily favour longer male lifespans. We also show that extrinsic density-dependent mortality can disproportionately affect the intrinsically longer-living sex, and obscure the magnitude of this evolved difference. Together, our results provide new theoretical insights into the adaptive bases of sex-biased longevity and highlight the importance of life-history trade-offs in shaping lifespan evolution.
Longevity Relevance Analysis
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The paper claims that sex-biased longevity patterns are shaped by asymmetric life-history trade-offs between reproduction and survival. This research is relevant as it explores the evolutionary mechanisms underlying lifespan differences, contributing to the understanding of aging processes.
Ong, R. C. S., Tang, A.
· neuroscience
· University of Western Australia
· biorxiv
Repetitive transcranial magnetic stimulation (rTMS) is an attractive tool to promote healthy brain ageing in older adults and treat age-related neurological conditions. Despite its popularity, the neurological processes and plasticity mechanisms altered by rTMS in the aged brain,...
Repetitive transcranial magnetic stimulation (rTMS) is an attractive tool to promote healthy brain ageing in older adults and treat age-related neurological conditions. Despite its popularity, the neurological processes and plasticity mechanisms altered by rTMS in the aged brain, and where these changes occur in the brain are unknown. Furthermore, it is not known why different rTMS protocols induce different changes in the aged brain, or why rTMS is less effective in older adults compared to younger adults. Using spatial transcriptomics, we uncovered that rTMS primarily acts on genes related to synaptic plasticity in both cortical and subcortical circuits in aged mice, but the specific changes were dependent on the brain region and even down to individual cortical layers in the motor and somatosensory cortices. Comparing our results from aged mice to young adult mice revealed that rTMS acts on a larger variety of neural plasticity mechanisms in the young adult brain, and that rTMS was less effective at altering gene expression related to neural plasticity in the aged brain, but this varied between brain regions and the protocol of rTMS applied. These findings provide a comprehensive map of the mechanisms altered by rTMS across the aged brain and highlight the need to consider the effect of ageing when optimising rTMS protocols for older populations.
Longevity Relevance Analysis
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The paper claims that repetitive transcranial magnetic stimulation (rTMS) induces different neural plasticity mechanisms in the aged brain compared to younger brains. This research is relevant as it explores the underlying mechanisms of neural plasticity in aging, which could inform strategies to promote healthier brain aging and address age-related neurological conditions.
Ravindran, S., Corripio-Miyar, Y., Pick, J. L. ...
· ecology
· Institute of Ecology and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh, UK
· biorxiv
The hormone insulin-like growth factor 1 (IGF-1) is a key player in the insulin/IGF-1 signaling (IIS) pathway. Extensive biogerontological research demonstrates that this evolutionarily conserved nutrient-sensing pathway plays a causal role in the regulation of growth, reproducti...
The hormone insulin-like growth factor 1 (IGF-1) is a key player in the insulin/IGF-1 signaling (IIS) pathway. Extensive biogerontological research demonstrates that this evolutionarily conserved nutrient-sensing pathway plays a causal role in the regulation of growth, reproduction and longevity under laboratory conditions. However, its potential role as a mediator of adaptive life-history variation in highly variable natural environments remains unclear. We measured IGF-1 concentrations in blood samples from approximately four-month-old wild Soay sheep lambs (n=669), collected over nine summers. We tested whether IGF-1 (i) was positively correlated with proxies of resource availability, (ii) was associated with morphological traits measured concurrently, and (iii) predicted subsequent fitness-related traits. Plasma IGF-1 concentrations were higher in males compared to females, and positively correlated with measures of resource availability in both sexes. IGF-1 was lower in years of high population density when per capita food availability was reduced; in twin lambs who have fewer available resources compared to singletons; and in lambs born to young and old mothers, who have poor maternal provisioning compared to mothers of intermediate age. Higher IGF-1 levels in summer were correlated with higher body mass, faster post-natal somatic growth and increased skeletal size, measured at the same time. These associations were independent of our proxies of resource availability. Lambs with higher summer IGF-1 were more likely to survive their first winter and reproduce the following spring. The association between IGF-1 and reproduction was independent of our resource availability proxies, whereas the association with first-winter survival was not. The association between summer IGF-1 and reproduction was mediated by positive associations with summer body mass. Our study reveals population-level phenotypic plasticity in circulating IGF-1, also finding IGF-1 to be positively associated with key morphological traits and positively predict fitness traits in early life. These findings highlight IGF-1 as a candidate physiological mechanism underpinning plastic responses to variation in food availability and influencing life-history traits in a wild mammal.
Longevity Relevance Analysis
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The study claims that plasma IGF-1 concentrations in wild Soay sheep predict early life-history traits and fitness-related outcomes. This research is relevant as it explores the role of IGF-1, a key player in the insulin/IGF-1 signaling pathway, in influencing life-history traits and potential longevity mechanisms in a natural setting, contributing to our understanding of biological factors that may affect aging and survival.
Babygirija, R., Green, C. L., Sonsalla, M. M. ...
· physiology
· University of Wisconsin-Madison
· biorxiv
Dietary protein is a critical regulator of metabolic health and aging in diverse species. Recent discoveries have determined that many benefits of a low protein diet are the result of reduced consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and va...
Dietary protein is a critical regulator of metabolic health and aging in diverse species. Recent discoveries have determined that many benefits of a low protein diet are the result of reduced consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Intriguingly, each BCAA has distinct physiological and molecular effects, with restriction of isoleucine alone being sufficient to improve metabolic health and extend the lifespan of mice. While restriction of protein or all three BCAAs improves cognition in mouse models of Alzheimers disease (AD), the impact of restricting each individual BCAA on the progression and development of AD is unknown. Here, we investigate the effect of restricting each individual BCAA on metabolic health, AD pathology, molecular signaling, and cognition in the 3xTg mouse model. We find that restriction of isoleucine and valine, but not leucine, promotes metabolic health. Restriction of each BCAA had distinct effects on AD pathology and molecular signaling, with transcriptomic analysis of the brain revealing both distinct and shared, and highly sex-specific, molecular impacts of restricting each BCAA. Restricting any of the three BCAAs improved short-term memory in males, with isoleucine restriction having the strongest effect, while restricting valine had the greatest cognitive benefits in females. We identify a set of significantly altered pathways strongly associated with reduced AD pathology and improved cognitive performance in males. Our findings suggest that restricting any of the BCAAs, particularly isoleucine or valine, may form the basis of a novel sex-specific approach to prevent or delay the progression of AD.
Longevity Relevance Analysis
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Restricting individual branched-chain amino acids can improve metabolic health and cognitive function in Alzheimer's disease models. The study addresses dietary interventions that may influence aging-related diseases, specifically targeting mechanisms that could delay the progression of Alzheimer's disease, which is relevant to longevity research.
Victoria-Chavez, R., Lamas, M.
· molecular biology
· Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional
· biorxiv
The regenerative response of retinal cells to injury and aging depends on the epigenomic plasticity that enables the dedifferentiation and neuronal differentiation capacities of Muller glial cells (MG). In mammals, this regenerative ability is extremely limited, and disruptions i...
The regenerative response of retinal cells to injury and aging depends on the epigenomic plasticity that enables the dedifferentiation and neuronal differentiation capacities of Muller glial cells (MG). In mammals, this regenerative ability is extremely limited, and disruptions in epigenetic mechanisms, particularly those involving DNA methylation and demethylation, may underlie this restricted potential. To explore this possibility, we aimed to develop DNA methylation-targeting molecular tools to enhance the dedifferentiation and neurogenic capacity of primary MG cultures derived from mouse retina. Using CRISPR/dCas9-based gene regulation technology, we selectively and transiently inhibited Dnmt3a, a de novo DNA methyltransferase previously implicated in maintaining transcriptional repression. Our results show that Dnmt3a knockdown leads to sustained upregulation of pluripotency-associated genes, including Ascl1, Lin28, and Nestin, as measured by RT-qPCR and immunofluorescence. This epigenetic modulation also promoted increased cell proliferation and migration, both hallmarks of a regenerative response. Furthermore, Dnmt3a knockdown, either alone or in combination with neurogenic stimuli, induced MG to acquire neuronal-like morphologies and express the early neuronal marker {beta}III-tubulin. These findings suggest that Dnmt3a acts as a repressive regulator of MG plasticity, likely serving as an epigenetic barrier that counteracts injury-induced demethylation events. Overall, our study identifies Dnmt3a as a critical modulator of MG fate and highlights the potential of its targeted downregulation to facilitate reprogramming. By prolonging the transient progenitor-like state of MG, DNMT3a inhibition may serve as a complementary approach to unlock the neurogenic and regenerative potential of the mammalian retina, offering promising avenues for future therapeutic strategies.
Longevity Relevance Analysis
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Transient inhibition of DNMT3a enhances the regenerative and neurogenic potential of mouse retinal Müller glia. This research addresses the epigenetic barriers to regeneration in mammalian tissues, which is relevant to understanding and potentially mitigating age-related decline in regenerative capacity.
Jie Li, Qiyang Chen, Fuliang Xiao ...
· Food science & nutrition
· Chongqing Academy of Agricultural Sciences Chongqing China.
· pubmed
Although tea polyphenols have antiaging potential, the molecular interplay between black tea components and cellular longevity remains unclear. This study has pioneered a dual approach combining
Although tea polyphenols have antiaging potential, the molecular interplay between black tea components and cellular longevity remains unclear. This study has pioneered a dual approach combining
Longevity Relevance Analysis
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The paper claims that black tea aqueous extract can extend yeast longevity through the activation of antioxidant genes. This research is relevant as it explores the molecular mechanisms underlying longevity and aging, focusing on potential interventions that could influence lifespan extension.
Yingqi Xu, Maohao Li, Congxue Hu ...
· Genome medicine
· College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
· pubmed
The decline in organ function due to aging significantly impacts the health and quality of life of the elderly. Assessing and delaying aging has become a major societal concern. Previous studies have largely focused on differences between young and old individuals, often overlook...
The decline in organ function due to aging significantly impacts the health and quality of life of the elderly. Assessing and delaying aging has become a major societal concern. Previous studies have largely focused on differences between young and old individuals, often overlooking the complexity and gradual nature of aging.
Longevity Relevance Analysis
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The paper proposes a novel aging assessment model to uncover heterogeneity in organ aging and screen for aging-related drugs. This research addresses the complexity of aging and aims to assess and potentially mitigate the decline in organ function, which is central to longevity studies.
Junjie Cao, Xuan Wang, Keyi Huang ...
· IEEE journal of biomedical and health informatics
· Not available
· pubmed
As the aging population continues to grow, falls among older adults have become a significant public health concern worldwide. Data-driven approaches for effective fall risk prediction, which integrate standard functional tests with 3D skeleton data from depth sensors, are gainin...
As the aging population continues to grow, falls among older adults have become a significant public health concern worldwide. Data-driven approaches for effective fall risk prediction, which integrate standard functional tests with 3D skeleton data from depth sensors, are gaining increasing attention. However, the complex physiological and functional interactions among skeletal keypoints during ambulation pose challenges for multidimensional feature extraction in most predictive models. In this study, we developed a novel approach based on preprocessed 3D skeleton data, named Multivariate SpatialTemporal Gated Transformer (MSTG-Transformer). This approach consists of three main stages. First, gait cycle sequences are constructed to sophisticatedly depict the movement patterns of subjects, amplifying the distinctions between groups. Then, spatial and topological features are extracted via convolutional modules, and a dual-stream encoder block is employed to encode the features of 3D skeleton data across both time steps and time channels. Finally, a voting scheme is used to determine fall risk by integrating the classification results of individual gait cycle segments. Validation experiments on a real-world dataset demonstrate that our proposed approach outperforms classical methods, achieving a superior prediction accuracy of 0.9510 ± 0.0240. Additionally, our study highlights the crucial role of potential interactions between skeletal keypoints in accurately predicting fall risk.
Longevity Relevance Analysis
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The paper claims that the MSTG-Transformer model can accurately predict fall risk in older adults by analyzing 3D skeleton data. This research is relevant as it addresses a significant public health concern related to falls in the aging population, aiming to improve safety and quality of life for older adults.
Zhaoqi Yan, Yifeng Xu, Ting Peng ...
· Biogerontology
· Department of Rehabilitation Medicine, The Third Hospital of Nanchang, Nanchang People's Hospital, 240 Zhanqian West Road, Xihu District, Nanchang City, 330009, Jiangxi Province, China.
· pubmed
This cross-sectional investigation seeks to examine the association between dietary omega-3 fatty acids (including α-linolenic acid [ALA], eicosapentaenoic acid [EPA], and docosahexaenoic acid [DHA]) and biomarkers of cellular aging, specifically DNA methylation age (Horvathage) ...
This cross-sectional investigation seeks to examine the association between dietary omega-3 fatty acids (including α-linolenic acid [ALA], eicosapentaenoic acid [EPA], and docosahexaenoic acid [DHA]) and biomarkers of cellular aging, specifically DNA methylation age (Horvathage) and telomere length (Horvathtelo), in older adults. Our analysis leveraged nationally representative data from 2,136 participants aged ≥ 50 years in the 1999-2002 NHANES cycles. Multivariable linear regression models with survey weights were constructed to evaluate dose-response relationships, complemented by restricted cubic splines (RCS) for nonlinearity detection. Machine learning optimization included comparative evaluation of nine algorithms through five-fold cross-validation, with model interpretability enhanced via SHapley Additive exPlanations (SHAP) analysis. Higher omega-3 intake (Tertile 3 [T3] vs Tertile 1 [T1]) demonstrated inverse associations with HorvathAge (β = -1.07), particularly for ALA intake (T3 ≥ 1.512 g/d: β = -1.11). Contrastingly, moderate-to-high omega-3 intake (T2 ≥ 0.917 g/d: β = 0.04; T3: β = 0.04) and individual components (ALA_T3: β = 0.04; DHA_T3 ≥ 0.041 g/d: β = 0.05; EPA_T3 ≥ 0.011 g/d: β = 0.03) exhibited positive correlations with HorvathTelo. RCS modeling revealed distinct patterns: linear inverse correlation for HorvathAge versus nonlinear J-shaped association with Horvathtelo. Among ML models, Linear Support Vector Machines achieved superior predictive performance. SHAP feature importance analysis consistently ranked omega-3 composite measures highest, followed by constituent components (ALA > DHA > EPA). Our findings suggest a potential dual role of omega-3 in biological aging modulation: higher intake associates with decelerated epigenetic aging while maintaining telomere length homeostasis. These observations underscore the importance of considering both composite measures and individual components in nutritional gerontology research.
Longevity Relevance Analysis
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Higher omega-3 intake is associated with decelerated epigenetic aging and maintenance of telomere length. The study investigates dietary factors that may influence biological aging, addressing potential root causes of aging rather than merely treating age-related symptoms.
Hyejin Mun, Chang Hoon Shin, Mercy Kim ...
· Aging
· Department of Oncology Science, College of Medicine, University of Oklahoma, Oklahoma City, OK 73104, USA.
· pubmed
Signaling pathways and transcriptional regulation during cellular senescence have been investigated; however, energy metabolism is one of the understudied areas. Senescent cells secrete pro-inflammatory cytokines and release proteins and RNAs via exosomes that contribute to organ...
Signaling pathways and transcriptional regulation during cellular senescence have been investigated; however, energy metabolism is one of the understudied areas. Senescent cells secrete pro-inflammatory cytokines and release proteins and RNAs via exosomes that contribute to organismal aging. Although senescent fibroblasts in solid organs are in a low oxygen environment, these fibroblasts have more active glucose metabolism and consume more oxygen than proliferating ones. A critical gap in our knowledge is how senescent fibroblasts facilitate glucose metabolism and organismal aging by creating a distinct microenvironment. Our high throughput profiling of mRNAs and proteins from Human Diploid Fibroblasts (HDFs) revealed that the expression of pyruvate metabolic enzymes is inhibited by the anti-senescent RNA-binding protein (RBP) AUF1 (AU-binding Factor 1). Our studies revealed that AUF1 promotes the decay of mRNAs encoding two enzymes: PGAM1 (phosphoglycerate mutase 1), a glycolytic enzyme involved in the pyruvate synthetic pathway, and PDP2 (Pyruvate Dehydrogenase Phosphatase 2), which activates Pyruvate Dehydrogenase. We also demonstrated that AUF1 is phosphorylated by a Serine/Threonine kinase, MST1 (Mammalian Ste20-like kinase 1; encoded by STK4), resulting in the inactivation of AUF1, which leads to target mRNA stabilization and senescence. Overexpression of PGAM1 and PDP2 predicts an acceleration of pyruvate production and subsequent citrate metabolism, leading to cellular senescence and aging. Thus, our studies revealed regulatory mechanisms of glycolysis-driven cellular senescence by AUF1-mediated decay of
Longevity Relevance Analysis
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AUF1 regulates glycolysis and cellular senescence by promoting the decay of specific mRNAs. The paper addresses mechanisms underlying cellular senescence and energy metabolism, which are critical factors in the aging process and organismal longevity.
Yangxin Yu, Xinhang Lv, Zhuowei Chen ...
· Journal of medicinal chemistry
· Key Laboratory of Tropical Biological Resources of Ministry of Education and Hainan Engineering Research Center for Drug Screening and Evaluation, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, Hainan, P. R. China.
· pubmed
Psoriasis is a multifactorial inflammatory disorder characterized by therapeutic resistance and high recurrence rates, with complex unmet clinical demands necessitating novel therapeutic strategies. Recently, emerging evidence has revealed pathological accumulation of senescent c...
Psoriasis is a multifactorial inflammatory disorder characterized by therapeutic resistance and high recurrence rates, with complex unmet clinical demands necessitating novel therapeutic strategies. Recently, emerging evidence has revealed pathological accumulation of senescent cells (SnCs) in psoriatic lesions, suggesting their critical involvement in disease persistence and relapse. Our previous studies demonstrated that precision photodynamic therapy (PDT) effectively eliminates SnCs and mitigates senescence-associated pathologies, positioning senotherapy as a potential breakthrough for psoriasis management. Building on these foundations, we developed SnC-targeted photosensitizers (H
Longevity Relevance Analysis
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The paper claims that combining activatable photodynamic therapy with Crisaborole can effectively target and eliminate senescent cells in psoriasis, leading to improved treatment outcomes. This research is relevant as it addresses the accumulation of senescent cells, which is a key factor in aging and age-related diseases, suggesting a potential therapeutic strategy that could impact longevity.
Emma M Tinney, Aaron E L Warren, Amanda O'Brien ...
· Alzheimer's & dementia (New York, N. Y.)
· Department of Psychology Northeastern University Boston Massachusetts USA.
· pubmed
Age-related cognitive decline occurs, in part, due to diminishing white matter integrity. Higher cardiorespiratory fitness (CRF) is associated with better cognitive performance, but the neurobiological mechanisms underlying this association remain uncertain. Previous magnetic res...
Age-related cognitive decline occurs, in part, due to diminishing white matter integrity. Higher cardiorespiratory fitness (CRF) is associated with better cognitive performance, but the neurobiological mechanisms underlying this association remain uncertain. Previous magnetic resonance imaging (MRI) studies have suggested that CRF-related changes in white matter microstructure might prevent or slow age-related cognitive decline, but have been limited by small sample sizes and methodological limitations. Specifically, most prior studies used tensor-based diffusion-weighted MRI metrics, which are insensitive to complex white matter architectures, including crossing fibers.
Longevity Relevance Analysis
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Higher cardiorespiratory fitness is associated with better cognitive performance in older adults through the mediation of white matter microstructure. This study addresses the neurobiological mechanisms linking fitness and cognitive decline, which is pertinent to understanding and potentially mitigating age-related cognitive deterioration.
Yanjun Li, Qi Huang, Jin Jiang ...
· Nature medicine
· Vanke School of Public Health, Tsinghua University, Beijing, China.
· pubmed
Accurate and convenient assessment of individual aging is crucial for identifying health risks and preventing aging-related diseases. Nonetheless, current aging proxies often face challenges such as methodological limitations, weak associations with adverse outcomes and limited g...
Accurate and convenient assessment of individual aging is crucial for identifying health risks and preventing aging-related diseases. Nonetheless, current aging proxies often face challenges such as methodological limitations, weak associations with adverse outcomes and limited generalizability. Here we propose a framework that leverages large language models (LLMs) to estimate individual overall and organ-specific aging using only health examination reports. We validated this approach across six population-based cohorts, encompassing over 10 million participants and demonstrated effectiveness and reliability. Our results showed that the LLM-predicted overall age achieved a concordance index (C-index) of 0.757 (95% CI 0.752-0.761) for all-cause mortality, significantly outperforming other aging proxies such as telomere length, frailty index, eight epigenetic ages and four machine-learning models predictions. The overall age gap was strongly associated with multiple aging-related phenotypes and health outcomes, showing a hazard ratio of 1.055 (95% CI 1.050-1.060) for all-cause mortality. For organ-specific aging, LLM-predicted ages and age gaps also demonstrated superior performance in predicting corresponding organ-specific diseases compared to machine-learning models. Additionally, we examined the dynamic aging assessment capability of LLMs and applied age gaps to identify proteomic biomarkers associated with accelerated aging and to develop risk prediction models of 270 diseases. Interpretability analyses were also conducted to explore the decision-making process of LLMs. In conclusion, our LLM-based aging assessment framework offers a precise, reliable and cost-effective approach for estimating overall and organ-specific aging. It has potential for personalized aging assessment and health management in large-scale general populations.
Longevity Relevance Analysis
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The paper claims that a large language model can accurately predict biological age and organ-specific aging, outperforming traditional aging proxies. This research is relevant as it addresses the assessment of biological aging, which is a critical aspect of understanding and potentially mitigating aging-related diseases.
Jacques, M., Seale, K., Voisin, S. ...
· bioinformatics
· Monash University
· biorxiv
Aging involves widespread epigenetic remodeling across tissues, yet the nature and consistency of these changes remain unclear. We conducted a meta-analysis of more than 15,000 human methylomes spanning 17 tissues, identifying both conserved and tissue-specific aging signatures. ...
Aging involves widespread epigenetic remodeling across tissues, yet the nature and consistency of these changes remain unclear. We conducted a meta-analysis of more than 15,000 human methylomes spanning 17 tissues, identifying both conserved and tissue-specific aging signatures. We examined linear changes via differentially methylated positions, variability shifts via variably methylated positions, and Shannon-entropy to capture methylation disorder. Network analysis revealed fragile co-methylation modules largely resistant to beneficial perturbation. Key disruptors, including PCDHGA1, MEST, HDAC4, and HOX genes, exacerbated aging signals across tissues. Notably, a resilient module enriched for NAD salvage metabolism supports therapeutic targeting of NAD in aging. PCDHGA1 emerged as a conserved cross-tissue driver, suggesting protocadherin-mediated adhesion plays a broader role in maintaining structural and signaling stability in multiple organ systems. Our open-access atlas provides a foundational resource for dissecting the molecular architecture of human aging and identifying testable targets for intervention, biomarkers, and translational epigenetic therapies.
Longevity Relevance Analysis
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The paper identifies conserved and tissue-specific aging signatures through DNA methylation analysis. This research is relevant as it explores the molecular mechanisms of aging, aiming to uncover potential therapeutic targets and biomarkers for interventions in the aging process.
Ruonan Liu, Zheng Zhu, Yuanyue Zhu ...
· GeroScience
· Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Geriatric Medical Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
· pubmed
Gut microbiota (GM) is implicated in aging biology, yet its dual regulatory role in the distinct yet interconnected processes of lifespan extension and aging remains poorly understood. This study employed genetic approaches to identify GM taxa exerting causal effects on longevity...
Gut microbiota (GM) is implicated in aging biology, yet its dual regulatory role in the distinct yet interconnected processes of lifespan extension and aging remains poorly understood. This study employed genetic approaches to identify GM taxa exerting causal effects on longevity and aging and assess the mediation role of cerebrospinal fluid (CSF) proteins. We leveraged summary statistics of the GM taxa (207 taxa, 7738 participants from the Dutch Microbiome Project), the CSF proteins (7008 aptamers, 3506 participants), and the longevity and aging phenotypes (UK Biobank, Longevity Genomics, and Edinburgh DataShare) from the largest genome-wide association studies so far. We performed bidirectional Mendelian randomization (MR) to explore causal relationships between GM and longevity and aging and two mediation analyses, the two-step MR and the multivariable MR (MVMR), to discover potential mediating proteins. Nine taxa exhibited causal associations with longevity-related phenotypes, such as the Bacteroides vulgatus and Blautia. Three taxa demonstrated causal associations with aging-related phenotypes, such as Streptococcus. Among them, Streptococcus was causally associated with aging (β = 0.3310, P = 0.0019) and lifespan-shortening (β = - 0.0247, P = 0.0184), while Bacteroides vulgatus associated with aging (β = 0.3884, P = 0.0204) and lifespan-promoting (β = 0.0354, P = 0.0198). Mediation MR analysis found that CSF protein CD28 mediated the causal effects of Streptococcus on longevity (mediation proportion 11.7%, P = 0.0394). These findings establish genetic links between GM, CSF proteins, and longevity and aging-related outcomes, advancing gut-brain axis understanding while offering insights for future mechanistic exploration and clinical investigation.
Longevity Relevance Analysis
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The paper identifies specific gut microbiota taxa that have causal associations with longevity and aging, suggesting potential mechanisms through which gut health may influence lifespan. This research is relevant as it explores the underlying biological connections between gut microbiota and aging, contributing to the understanding of longevity.
Zhuoyan Lyu, Anatoly B Kolomeisky
· The journal of physical chemistry letters
· Department of Chemistry, Rice University, Houston, Texas 77005, United States.
· pubmed
Although understanding the biology of ovarian aging and the timing of menopause is critical for supporting women's reproductive health, many aspects of these processes remain unclear. Stimulated by observations of transitions between different stages of functional units of ovaria...
Although understanding the biology of ovarian aging and the timing of menopause is critical for supporting women's reproductive health, many aspects of these processes remain unclear. Stimulated by observations of transitions between different stages of functional units of ovarian units (follicles), a novel stochastic framework has recently been introduced. However, many important aspects of these biological phenomena have been overlooked. In this work, we present a theoretical investigation on synchronization in menopause timing, the role of follicle death, and the temporal dependence of transition rates. Our theoretical method views the depletion in the number of follicles as a multistage stochastic process governed by stage-specific transition and death rates. The narrow distributions of times before menopause are shown to be the result of synchronization when the transition rates between different stages become comparable. We also found that the deaths of the follicles, known as atresia, accelerate the maturation of the follicles. It is suggested that this might be a possible explanation of oversupply when women are born with many more follicles than they need for reproduction. Furthermore, we developed a novel stochastic model of ovarian aging with time-dependent transition rates, and it is shown that this method accounts well for the available data on follicle depletion. Our analysis suggests that there is a specific age at which follicle depletion accelerates. The presented theoretical approach offers novel insights into the mechanisms of complex biological processes, suggesting potential directions for future improvements in women's health.
Longevity Relevance Analysis
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The paper claims that the synchronization of transition rates in ovarian aging leads to narrow distributions of menopause timing. This research is relevant as it investigates the biological mechanisms underlying ovarian aging, which is a critical aspect of women's health and longevity.
Zachary Miller, Laura-Marie Twardowski, Brenda F Reader ...
· Lung
· Department of Internal Medicine, Division of Pulmonary Critical Care and Sleep Medicine, Davis Heart Lung Research Institute, The Ohio State University, Columbus, OH, USA.
· pubmed
Ageing significantly impacts lung function and increases susceptibility to chronic lung diseases. The lung is a complex organ with multiple cell types that undergo cellular age-related perturbations or hallmarks. As knowledge of ageing mechanisms has progressed, we have a better ...
Ageing significantly impacts lung function and increases susceptibility to chronic lung diseases. The lung is a complex organ with multiple cell types that undergo cellular age-related perturbations or hallmarks. As knowledge of ageing mechanisms has progressed, we have a better understanding how intracellular adaptations impact cellular crosstalk and integrate to increase the susceptibility to age-related diseases in the lung. Herein, we discuss the prospects of exhaustion of lung progenitor cells, disrupted lung cell plasticity, perturbation in fibroblasts, impaired adaptive immune responses and alterations in lung microenvironment in the promotion of ageing and age-related lung diseases. Additionally, the ageing process trajectory of the lung depends on a combination of biological, genetic, metabolic, biomechanical and sociobehavioural factors that range from protective phenotypes to accelerated ageing phenotypes. We propose the concept of AgEnOmics, which expands the temporal dimension of lung ageing by distinguishing between chronological ageing and accelerated lung ageing phenotypes. Based on this concept, we define biomarkers of biological ageing that will help to define accelerated ageing and early interventions in biological ageing-related lung diseases.
Longevity Relevance Analysis
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The paper proposes the concept of AgEnOmics to distinguish between chronological and accelerated lung ageing phenotypes. This research is relevant as it addresses mechanisms of lung ageing and potential biomarkers for early interventions, contributing to the understanding of root causes of age-related diseases.
Alper Cevirgel, Marieke van der Heiden, Sudarshan A Shetty ...
· Aging cell
· Center for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
· pubmed
Immune aging is associated with decreased vaccine responses, but biomarkers for vaccine responsiveness remain unidentified. We analyzed immunotypes describing pre-vaccination immune cell profiles and their associations with triple vaccine responsiveness to influenza, pneumococcal...
Immune aging is associated with decreased vaccine responses, but biomarkers for vaccine responsiveness remain unidentified. We analyzed immunotypes describing pre-vaccination immune cell profiles and their associations with triple vaccine responsiveness to influenza, pneumococcal, and SARS-CoV-2 vaccines in adults aged 25-78 years. Additionally, we developed an innovative measure, immune entropy, to quantify cumulative perturbations in the immune cell subset network. Specific immunotypes were associated with either weak or robust triple vaccine responsiveness. In addition, immune entropy was inversely related to vaccine responsiveness regardless of age. In a validation cohort of older adults, higher immune entropy was also associated with a lower antibody response to the BNT162b2 vaccine. A separate cohort of kidney transplant recipients, typically exhibiting diminished vaccine responses, demonstrated significantly increased immune entropy compared to healthy counterparts. Our findings suggest immunotypes and immune entropy as potential indicators to identify individuals at risk for suboptimal vaccine responses, potentially guiding personalized vaccination strategies.
Longevity Relevance Analysis
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Pre-vaccination immune profiles and immune entropy can predict vaccine responsiveness in adults. The study addresses immune aging and its impact on vaccine efficacy, which is pertinent to understanding and potentially mitigating age-related declines in immune function.
Lenart, P., Psalmon, S., Towbin, B. D.
· evolutionary biology
· University of Bern
· biorxiv
For most animals, intrinsic senescence-induced mortality increases with age, while deaths from extrinsic threats, such as predation or accidents, decline during development as individuals grow and mature. Age-dependent modulation of extrinsic mortality is known to influence the e...
For most animals, intrinsic senescence-induced mortality increases with age, while deaths from extrinsic threats, such as predation or accidents, decline during development as individuals grow and mature. Age-dependent modulation of extrinsic mortality is known to influence the evolution of aging, yet how the timing of mortality shapes evolutionary forces remains poorly understood. To address this, we developed two complementary mathematical models that integrate survival benefits arising during development with the progressive increase in mortality associated with senescence. Agent-based simulations and deterministic analyses revealed a strong and consistent influence of the timing of developmental survival benefits on their evolutionary impact: early-life survival benefits reduced the selection for slower aging, while late-acting benefits enhanced it. This difference arises because early-life benefits more strongly accelerate population growth than late-life benefits, diminishing the relative evolutionary advantage of increased longevity. Our results underscore the importance of mortality timing in the evolution of aging and provide a theoretical framework for connecting developmental trajectories to aging dynamics.
Longevity Relevance Analysis
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The timing of developmental survival benefits influences the evolutionary selection for aging rates. This paper is relevant as it explores fundamental aspects of aging evolution, which could inform strategies for longevity and lifespan extension.
Okamura, Y. T., Wang, T.-W., Kawakami, S. ...
· cell biology
· The Institute of Medical Science, The University of Tokyo
· biorxiv
A plethora of senolytic compounds and technologies have been identified. However, the efficacy of these treatments in eliminating senescent cells and the suppression of chronic inflammation remains to be substantiated in vivo. Here, we employ single-cell RNA sequencing and find t...
A plethora of senolytic compounds and technologies have been identified. However, the efficacy of these treatments in eliminating senescent cells and the suppression of chronic inflammation remains to be substantiated in vivo. Here, we employ single-cell RNA sequencing and find the selective elimination of highly inflammatory fibroblasts, endothelial cells in the lung, and proximal tubule cells in the kidney from the GLS1 inhibitor BPTES-treated aged mice. The eliminated fibroblasts share typical phenotypes with in vitro human senescent cells. These cells predominantly express Dpp4 (CD26) and Cadm3, showing activated IFN signaling and lysosomal membrane damage. Cells eliminated by BPTES in lungs exhibit transcriptomes similar to those eliminated in p16-DTR mice, where DTR expression is limited in p16-expressing cells. BPTES treatment results in the T cell population shift from cytotoxic to a protective state, suggesting the suppression of age-related chronic inflammation. CellChat analysis revealed that multiple cytokine signals are transmitted from inflammatory fibroblasts and proximal tubular cells to immune cells in lungs and kidneys. These results provide evidence that GLS1 inhibitor functions as a bona fide senolytic drug to eliminate inflammatory cells, including a subset of senescent cells, and suppresses age-related chronic inflammation.
Longevity Relevance Analysis
(5)
The paper claims that the GLS1 inhibitor BPTES selectively eliminates inflammatory senescent cells and suppresses age-related chronic inflammation in vivo. This research is relevant as it addresses the elimination of senescent cells, which are considered a root cause of aging and age-related diseases, thereby contributing to the understanding of potential therapeutic strategies for longevity.
Pouneh K Fazeli, Matthew L Steinhauser
· Endocrine reviews
· Neuroendocrinology Unit, Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
· pubmed
The adaptive starvation response allows us to survive periods of starvation - a characteristic of the environment in which humans evolved. We are now in an evolutionary transition from a global environment which was characterized by periods of famine to a world where obesity and ...
The adaptive starvation response allows us to survive periods of starvation - a characteristic of the environment in which humans evolved. We are now in an evolutionary transition from a global environment which was characterized by periods of famine to a world where obesity and caloric excess have become a new reality, but the mechanisms of fasting physiology remain relevant. First, many parts of the world are still plagued by famine with insufficient food resources and therefore the adaptive mechanisms required for survival during periods of decreased caloric intake are not simply relevant to our evolutionary past. Second, the obesity epidemic provides strong rationale for understanding the biology of fasting, as the same efficiencies that have evolved to allow us to survive periods of starvation also likely drive a genetic predisposition to obesity, and therefore some of the adaptive mechanisms may be maladaptive in the setting of food excess. A third compelling reason to explore the biology of fasting is that in model organisms, caloric restriction without overt starvation, is an intervention that prolongs lifespan. The purpose of this review is to provide an overview of the biology of fasting. We will highlight potential mechanisms of benefit from fasting as well as examine data from model organisms and humans that indicate potential health risks to fasting, particularly related to bone fragility. Finally, we will review clinical studies to date that have investigated the effects of fasting on metabolic outcomes and suggest signals of benefit.
Longevity Relevance Analysis
(4)
The paper claims that fasting may promote metabolic health and longevity through adaptive mechanisms that evolved for survival during starvation. The relevance lies in its exploration of fasting as a potential intervention for longevity and metabolic health, addressing both evolutionary biology and modern health challenges related to obesity.
Hongyu Lin, Kazunori Sasaki, Farhana Ferdousi ...
· GeroScience
· Tsukuba Life Science Innovation (T-LSI) Program, University of Tsukuba, 305-8577, Tsukuba, Japan.
· pubmed
This study is the first to investigate the anti-aging effects of the newly synthesized compound, 3,4,5-tri-feruloylquinic acid (TFQA), in vivo using the senescence-accelerated mouse prone 8 (SAMP8) model, through integrated whole-transcriptomic and biochemical analyses. Oral admi...
This study is the first to investigate the anti-aging effects of the newly synthesized compound, 3,4,5-tri-feruloylquinic acid (TFQA), in vivo using the senescence-accelerated mouse prone 8 (SAMP8) model, through integrated whole-transcriptomic and biochemical analyses. Oral administration of TFQA (1 mg/kg body weight) for 37 days led to significant cognitive improvements, as demonstrated by enhanced performance in the Morris water maze (MWM) test, including reduced escape latency and increased time spent in the target zone, target crossings, distance traveled, and swimming speed. Gene Ontology (GO) analysis of hippocampal microarray data revealed that TFQA upregulated genes associated with neurotransmitter and synaptic functions, while downregulating inflammatory pathways. Protein-protein interaction (PPI) analysis indicated that neurotrophin signaling was a critical upstream regulator in TFQA-treated mice. Further biochemical validation showed elevated levels of neurotransmitters (serotonin, noradrenaline, and dopamine) in the brain. Additionally, mRNA expression of tumor necrosis factor (Tnf), an inflammatory cytokine, was significantly reduced in the brain. Examination of the neurotrophins involved in neurotrophin signaling revealed that TFQA most prominently regulated brain-derived neurotrophic factor (Bdnf) co-expressed genes, which was validated by increased Bdnf expression in both the brain and serum of SAMP8 mice. Bioluminescence imaging demonstrated that a single oral dose of TFQA significantly increased BDNF expression in the brains of BDNF-IRES-AkaLuc mice. Binding studies showed that TFQA has a strong affinity for the tyrosine receptor kinase B (TrkB) receptor. In summary, TFQA holds potential as a neuroprotective agent, mitigating learning and memory deficits in aging mice via neurotrophin signaling, particularly through BDNF upregulation.
Longevity Relevance Analysis
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The paper claims that the synthetic compound TFQA enhances learning and memory in aging mice through neurotrophin signaling. This research is relevant as it explores a potential intervention targeting cognitive decline associated with aging, addressing mechanisms that could contribute to longevity and improved quality of life in the elderly.
Peizhong Qin, Qi Wang, You Wu ...
· Aging
· Department of Medical Genetics, School of Basic Medicine, Institute for Brain Research, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
· pubmed
Improving gut health by altering the activity of intestinal stem cells is thought to have the potential to reverse aging. The aged Drosophila midgut undergoes hyperplasia and barrier dysfunction. However, it is still unclear how to limit hyperplasia to extend lifespan. Here, we s...
Improving gut health by altering the activity of intestinal stem cells is thought to have the potential to reverse aging. The aged Drosophila midgut undergoes hyperplasia and barrier dysfunction. However, it is still unclear how to limit hyperplasia to extend lifespan. Here, we show that early midgut injury prevents the abrupt onset of aging hyperplasia and extends lifespan in flies. Daily transcriptome profiling and lineage tracing analysis show that the abrupt onset of aging hyperplasia is due to the collective turnover of developmentally generated "old" enterocytes (ECs). Early injury introduces new ECs into the old EC population, forming the epithelial age mosaic. Age mosaic avoids collective EC turnover and facilitates septate junction formation, thereby improving the epithelial barrier and extending lifespan. Furthermore, we found that intermittent time-restricted feeding benefits health by creating an EC age mosaic. Our findings suggest that age mosaic may become a therapeutic approach to reverse aging.
Longevity Relevance Analysis
(4)
Early midgut injury creates an age mosaic of gut epithelial cells that prevents aging hyperplasia and extends lifespan in Drosophila. This research addresses a potential mechanism for reversing aspects of aging, focusing on the root causes rather than merely treating symptoms.
Chuanle Wang, Wei Chen, Ruofei Li ...
· Cell & bioscience
· MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol and Guangzhou Key Laboratory of Healthy Aging Research, School of Lifesciences, Sun Yat-Sen University, Guangzhou, 510275, China.
· pubmed
Telomere homeostasis is pivotal in various biological processes including ontogeny, reproduction, physiological aging, and the onset of numerous diseases such as tumors. In human stem cells and approximately 85% of tumor cells, telomerase formed by TERT and TERC RNA complex is re...
Telomere homeostasis is pivotal in various biological processes including ontogeny, reproduction, physiological aging, and the onset of numerous diseases such as tumors. In human stem cells and approximately 85% of tumor cells, telomerase formed by TERT and TERC RNA complex is responsible for elongating telomeres. However, the intricate and precise regulatory mechanisms governing telomerase remain largely elusive.
Longevity Relevance Analysis
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Disruption of ZC3H15 leads to compromised telomere length maintenance due to telomerase entrapment within Cajal bodies. The study addresses telomere maintenance, which is crucial for cellular aging and longevity, thereby contributing to our understanding of the mechanisms underlying aging and age-related diseases.
Zihan Zhou, Zhenhua Zhou, Chunying Ye ...
· Molecular human reproduction
· Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
· pubmed
Thin endometrium (TE) is generally recognized as a contributing factor to reduced pregnancy rates and adverse perinatal outcomes, yet the pathogenesis of the disease remains elusive. We conducted an analysis and validation of the single-cell RNA sequencing (scRNA-seq) data pertai...
Thin endometrium (TE) is generally recognized as a contributing factor to reduced pregnancy rates and adverse perinatal outcomes, yet the pathogenesis of the disease remains elusive. We conducted an analysis and validation of the single-cell RNA sequencing (scRNA-seq) data pertaining to TE and demonstrated that insulin-like growth factor binding protein 2 (IGFBP2) expression is down-regulated, resulting in the senescence of endometrial epithelial cells. In both human primary endometrial epithelial cells and the Ishikawa cell line (a well-established endometrial-derived epithelial cell), the introduction of recombinant human IGFBP2 protein effectively alleviates hydrogen peroxide (H2O2)-induced cellular senescence. Notably, it demonstrates superior performance compared to the well-known anti-aging agent Dasatinib in specific aspects. Specifically, transfecting IGFBP2 protein siRNAs promotes cyclin dependent kinase inhibitor 1A (P21) accumulation through the phosphatidylinositol 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) signaling pathway by regulating phosphatase and tensin homolog deleted on chromosome ten (PTEN) activity. Furthermore, administering IGFBP2 protein or Dasatinib to TE mouse models, which was established by endometrial curettage combined with H2O2 instillation, restored endometrial thickness by inhibiting senescence. Our findings demonstrate that down-regulation of IGFBP2 protein plays a pivotal role in mediating the senescence of endometrial epithelial cells in TE. This offers novel insights into elucidating the pathogenesis of TE and identifying potential new therapeutic targets.
Longevity Relevance Analysis
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Down-regulation of IGFBP2 mediates the senescence of endometrial epithelial cells in thin endometrium. The study addresses a mechanism related to cellular senescence, which is a key aspect of aging and longevity research, potentially offering insights into therapeutic targets for age-related reproductive issues.
Qiaofeng Ye, Aaliya Ahamed, Idan Shalev ...
· The journals of gerontology. Series A, Biological sciences and medical sciences
· Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA 16802, USA.
· pubmed
Evolutionary theories of aging indicate trade-offs between reproduction and longevity. Epigenetic clocks, such as PhenoAge, GrimAge, and DunedinPoAm, were designed to reflect biological age and be used as surrogates for mortality and healthspan. The current study investigated the...
Evolutionary theories of aging indicate trade-offs between reproduction and longevity. Epigenetic clocks, such as PhenoAge, GrimAge, and DunedinPoAm, were designed to reflect biological age and be used as surrogates for mortality and healthspan. The current study investigated the connection between reproductive profiles, epigenetic aging and mortality among post-menopausal women (50-85 years) with data from the National Health and Nutrition Examination Survey across the United States (N = 770). Using latent profile analysis, we identified four distinct reproductive profiles: high gravidity but average parity (Class 1); high gravidity and parity (Class 2); premature menopause (Class 3); an average profile (Class 4). Women of Class 3 had an accelerated pace of aging as indicated by DunedinPoAm, but not an older epigenetic age as measured by PhenoAge or GrimAge. The association was significant among women who had ever used female hormones (β = 0.521; 95%CI 0.014-1.027). Women of Class 1 or 2 did not exhibit accelerated epigenetic aging. Women of Class 3 had higher mortality (HR = 1.40, 95%CI 1.08-1.81), and 36.3% of the effect was mediated through accelerated DunedinPoAm. Findings suggest that women with reproductive profiles characterized by premature menopause may have altered epigenetic aging trajectories. Pace of aging may be more sensitive to the impact of reproductive profile variations than the status of biological age as indicated by PhenoAge or GrimAge. Clinically monitoring the pace of biological aging among women with premature menopause and an appropriate application of hormone replacement therapy may minimize the negative consequence of accelerated biological aging and reduce premature mortality.
Longevity Relevance Analysis
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The study claims that reproductive profiles characterized by premature menopause are associated with altered epigenetic aging trajectories and increased mortality risk. This paper is relevant as it explores the connections between reproductive health, epigenetic aging, and longevity, addressing potential mechanisms that could influence biological aging and mortality in post-menopausal women.
Maggie E Zink, Leslie Zhen, Jacie R McHaney ...
· Noise
· Department of Communication Science and Disorders, School of Health and Rehabilitation Sciences, University of Pittsburgh, Pittsburgh, United States.
· pubmed
Middle age represents a critical period of accelerated brain changes and provides a window for early detection and intervention in age-related neurological decline. Hearing loss is a key early marker of such decline and is linked to numerous comorbidities in older adults. Yet, ~1...
Middle age represents a critical period of accelerated brain changes and provides a window for early detection and intervention in age-related neurological decline. Hearing loss is a key early marker of such decline and is linked to numerous comorbidities in older adults. Yet, ~10% of middle-aged individuals who report hearing difficulties show normal audiograms. Cochlear neural degeneration (CND) could contribute to these hidden hearing deficits, though its role remains unclear due to a lack of objective diagnostics and uncertainty regarding its perceptual outcomes. Here, we employed a cross-species design to examine neural and behavioral signatures of CND. We measured envelope following responses (EFRs) - neural ensemble responses to sound originating from the peripheral auditory pathway - in young and middle-aged adults with normal audiograms and compared these responses to young and middle-aged Mongolian gerbils, where CND was histologically confirmed. We observed near-identical changes in EFRs across species that were associated with CND. Behavioral assessments revealed age-related speech-in-noise deficits under challenging conditions, while pupil-indexed listening effort increased with age even when behavioral performance was matched. Together, these results demonstrate that CND contributes to speech perception difficulties and elevated listening effort in midlife, which may ultimately lead to listening fatigue and social withdrawal.
Longevity Relevance Analysis
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Cochlear neural degeneration contributes to speech perception difficulties and increased listening effort in middle-aged adults. The paper is relevant as it addresses underlying neurological changes associated with aging, specifically focusing on auditory processing and its implications for social engagement and cognitive health in midlife.
Farnaz Karimani, Mehdi Eivani, Afsaneh Asgari Taei ...
· Melatonin
· Neuroscience Research Center, Institute of Neuroscience and Cognition, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
· pubmed
Aging is commonly associated with cognitive decline, particularly in memory, and is linked to neuronal hyperexcitability and disrupted sleep-related oscillations in key brain regions such as the hippocampus and prefrontal cortex. Melatonin has been proposed as a potential therape...
Aging is commonly associated with cognitive decline, particularly in memory, and is linked to neuronal hyperexcitability and disrupted sleep-related oscillations in key brain regions such as the hippocampus and prefrontal cortex. Melatonin has been proposed as a potential therapeutic agent to counteract age-related cognitive impairments. In this study, 24-month-old male Wistar rats were treated with melatonin (10 mg/kg, intraperitoneally) for 30 days. Local field potentials were recorded from the hippocampus and prefrontal cortex to assess neuronal activity. Memory performance was evaluated using the novel object recognition test, and qPCR measured expression levels of inflammatory and amyloidogenesis markers. Melatonin treatment significantly reduced neuronal hyperexcitability, enhanced delta and theta oscillations, and increased sleep spindle amplitude, which were associated with improved memory performance. Additionally, melatonin attenuated the expression of pro-inflammatory markers without affecting the expression of amyloidogenesis-related genes. These findings suggest that melatonin may enhance cognitive function in aging by modulating neuronal excitability, sleep oscillations, and neuroinflammatory processes.
Longevity Relevance Analysis
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Melatonin treatment improves cognitive function in aged rats by reducing neuronal hyperexcitability and enhancing sleep oscillations. This study addresses mechanisms related to cognitive decline in aging, which is a core aspect of longevity research.
Jing Wang, Xiang Ren, Huan Lu ...
· Advanced science (Weinheim, Baden-Wurttemberg, Germany)
· Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, 430030, China.
· pubmed
Aging increases the vulnerability of kidneys to injury and impairs their regenerative capacity. SIRT3 expression declines with aging and is associated with multiple age-related pathologies. The expression profile and functional role of SIRT3 in renal aging remain unclear. Here, S...
Aging increases the vulnerability of kidneys to injury and impairs their regenerative capacity. SIRT3 expression declines with aging and is associated with multiple age-related pathologies. The expression profile and functional role of SIRT3 in renal aging remain unclear. Here, SIRT3 expression in aging kidneys is assessed and analyzed for its promoter methylation patterns using methylation-specific PCR (MSP). It is found that aging exacerbates UUO-induced renal fibrosis, associated with downregulated SIRT3 expression. Mechanistically, age-related SIRT3 downregulation is mediated by hypermethylation of its promoter region. SIRT3 knockout exacerbated renal fibrosis in young mice subjected to UUO, whereas SIRT3 overexpression attenuated fibrosis in aged UUO mice. Integration of RNA-seq and immunoprecipitation-mass spectrometry (IP-MS) analyses revealed that SIRT3 deficiency leads to hyperacetylation of GSK3β at lysine 15 (K15). This K15 hyperacetylation inhibited GSK3β activity, consequently stabilizing its substrate β-catenin. Furthermore, self-assembled PEG-PCL-PEG micelles are designed and synthesized to encapsulate hydrophobic honokiol (HKL). These micelles significantly enhanced the aqueous solubility and oral bioavailability of free HKL, maintained stable blood concentrations, and ultimately improved its anti-fibrotic efficacy. These findings propose novel therapeutic strategies for managing renal fibrosis in the aging population and provide a foundation for developing new drugs and combination therapies.
Longevity Relevance Analysis
(4)
Restoration of SIRT3 expression in aged mice alleviates UUO-induced renal fibrosis by reducing GSK-3β hyperacetylation. The paper addresses the decline of SIRT3 with aging and its role in renal fibrosis, proposing a potential therapeutic strategy that targets a root cause of age-related decline in kidney function.
Bradley A Ruple, Nicholas A Carlini, Jason S Kofoed ...
· American journal of physiology. Endocrinology and metabolism
· Geriatric Research, Education, and Clinical Center, George E. Wahlen Department VA Medical Center, Salt Lake City, Utah.
· pubmed
Aging is associated with alterations in immune cell function, contributing to age-related diseases and frailty. As peripheral blood mononuclear cells (PBMCs) are key drivers of the immune response, we investigated their transcriptome using RNA-sequencing before and immediately af...
Aging is associated with alterations in immune cell function, contributing to age-related diseases and frailty. As peripheral blood mononuclear cells (PBMCs) are key drivers of the immune response, we investigated their transcriptome using RNA-sequencing before and immediately after a single bout of high-intensity knee-extension exercise in young (Young; n=7, 23 ± 4 years) and older individuals (Old; n=8, 65 ± 7 years). We used bioinformatics analyses to identify the biological processes and pathways that may be altered with age and in response to acute exercise. At baseline, 665 genes differed between Young and Old with notable differences in pathways involved in DNA Damage/Telomere Stress Induced Senescence, NAD Signaling Pathway, and Oxidative Stress Induced Senescence. After the exercise bout, 53 genes were differentially expressed in Young, while 1,026 genes changed in Old. In Young, the enriched processes and predicted pathways were linked to natural killer cells, while in Old these pathways were associated with cell signaling immune responses. Lastly, 26 genes exhibited similar responses to exercise between groups, enriching the biological process of natural killer cell-mediated immunity regulation. Our findings indicate that PBMC gene expression and the response to acute exercise are altered with aging, where exercise induced more pronounced PBMC transcriptomic adaptations in the Old. Additionally, while aging is associated with increased expression of genes linked to cellular dysfunction and suppressed immune function, acute exercise attenuated these age-related differences by downregulating the genes related to those pathways. Finally, acute exercise activated similar immune related pathways in both age groups.
Longevity Relevance Analysis
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The paper claims that acute exercise induces significant transcriptomic adaptations in peripheral blood mononuclear cells that differ with age. This research is relevant as it explores the biological mechanisms underlying immune function changes with aging and how exercise may mitigate these effects, addressing a root cause of age-related decline.
Tyler D Robinson, Yutong L Sun, Paul T H Chang ...
· GeroScience
· Rotman Research Institute, 3560 Bathurst Street Baycrest, Toronto, Ontario, M6A 2E1, Canada. [email protected].
· pubmed
One of the most promising interventional targets for brain health is cerebral perfusion, but its link to white matter (WM) aging remains unclear. Motivated by existing literature demonstrating links between declining cortical perfusion and the development of WM hyperintensities, ...
One of the most promising interventional targets for brain health is cerebral perfusion, but its link to white matter (WM) aging remains unclear. Motivated by existing literature demonstrating links between declining cortical perfusion and the development of WM hyperintensities, we posit that regional WM hypoperfusion precedes deteriorating WM integrity. Using the Human Connectome Project Aging (HCP-A) data set, we examine tract-wise associations between WM microstructural integrity (i.e. fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) and perfusion (i.e. cerebral blood flow and arterial transit time) in ten major bilateral WM tracts. Results show that tracts displaying the largest CBF decline in aging do not necessarily display the largest ATT decline, and vice versa. Moreover, significant WM perfusion-microstructure canonical correlations were found in all tracts, but the drivers of these correlations vary by both tract and sex, with female subjects demonstrating more tracts with large microstructural variations contributing to the correlations. Importantly, age-effects on arterial transit time peak at a younger age than those of all other parameters investigated, preceding age-related microstructural differences and CBF in several tracts. This study contributes compelling evidence to the vascular hypothesis of WM degeneration and highlights the utility of blood-flow timing as an early marker of aging.
Longevity Relevance Analysis
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Regional white matter hypoperfusion precedes deteriorating microstructural integrity in aging. This study investigates the vascular aspects of white matter aging, which is relevant to understanding and potentially mitigating the root causes of age-related cognitive decline.
Zhao, K., Xie, H., Fonzo, G. A. ...
· neuroscience
· Stanford University
· biorxiv
As populations age, identifying the neurobiological basis of cognitive resilience is critical for delaying or preventing Alzheimers disease (AD). While most older adults experience memory decline, a subset known as superagers (SA) maintains youthful memory into late life, offerin...
As populations age, identifying the neurobiological basis of cognitive resilience is critical for delaying or preventing Alzheimers disease (AD). While most older adults experience memory decline, a subset known as superagers (SA) maintains youthful memory into late life, offering a unique window into protective mechanisms against neurodegeneration. Here, we identified a functional connectivity (FC) signature, termed Alzheimer\'s-resilient connectome (ARC), that robustly differentiates SA from age-matched patients with AD. Using resting-state fMRI in a discovery cohort (N = 290), we identified ARC derived from machine learning classifiers that distinguished SA from AD with high accuracy (AUC = 0.85), and validated the replicability of the ARC in an independent replication cohort (N = 143). ARC involved prefrontal, temporal and insular networks and was strongly associated with brain age. When applied to cognitively unimpaired (CU) adults (discovery cohort: N = 818 and replication cohort: N = 497), ARC-based subtyping revealed SA-like and AD-like subgroups with similar baseline cognitive performance but markedly divergent longitudinal trajectories. SA-like CU individuals showed slower cognitive decline, reduced amyloid-{beta} accumulation, and lower risk of conversion to mild cognitive impairment and AD, reinforcing the ARC signature as a potential early indicator of resilience. Genome-wide association analysis identified CLYBL and FRMD6 as novel genetic modulators associated with these divergent aging phenotypes. Together, our findings position ARC as a sensitive and generalizable biomarker of resilience, enabling early risk stratification and precision prevention for AD.
Longevity Relevance Analysis
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The paper claims that the Alzheimer's-resilient connectome (ARC) can serve as an early biomarker for cognitive resilience against Alzheimer's disease. This research is relevant as it explores neurobiological mechanisms that could contribute to delaying or preventing age-related cognitive decline, addressing root causes of aging and neurodegeneration.
Sophie Dürauer, Hyun-Seo Kang, Christian Wiebeler ...
· Ubiquitin
· Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany.
· pubmed
The DNA-dependent protease SPRTN maintains genome stability by degrading toxic DNA-protein crosslinks (DPCs). To understand how SPRTN's promiscuous protease activity is confined to cleavage of crosslinked proteins, we reconstitute the repair of DPCs including their modification w...
The DNA-dependent protease SPRTN maintains genome stability by degrading toxic DNA-protein crosslinks (DPCs). To understand how SPRTN's promiscuous protease activity is confined to cleavage of crosslinked proteins, we reconstitute the repair of DPCs including their modification with SUMO and ubiquitin chains in vitro. We discover that DPC ubiquitylation strongly activates SPRTN independently of SPRTN's known ubiquitin-binding domains. Using protein structure prediction, MD simulations and NMR spectroscopy we reveal that ubiquitin binds to SPRTN's protease domain, promoting an open, active conformation. Replacing key interfacial residues prevents allosteric activation of SPRTN by ubiquitin, leading to genomic instability and cell cycle defects in cells expressing truncated SPRTN variants that cause premature aging and liver cancer in Ruijs-Aalfs syndrome patients. Collectively, our results reveal a ubiquitin-dependent regulatory mechanism that ensures SPRTN activity is deployed precisely when and where it is needed.
Longevity Relevance Analysis
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The paper claims that ubiquitin activates the SPRTN protease, which is crucial for maintaining genome stability and preventing premature aging and cancer. This research is relevant as it addresses mechanisms that contribute to genomic stability, a key factor in aging and age-related diseases.
Bozack, A. K., Khodasevich, D., Nwanaji-Enwerem, J. C. ...
· nutrition
· Stanford University
· medrxiv
Fatty acids are involved in disease risk and aging processes. In the US National Health and Nutrition Examination Survey (1999-2002), we tested for associations of total, saturated (SFA), monounsaturated (MUFA), polyunsaturated (PUFA), and subtypes of dietary fatty acids with DNA...
Fatty acids are involved in disease risk and aging processes. In the US National Health and Nutrition Examination Survey (1999-2002), we tested for associations of total, saturated (SFA), monounsaturated (MUFA), polyunsaturated (PUFA), and subtypes of dietary fatty acids with DNA methylation-based aging biomarkers, adjusting for age, BMI, total energy intake, and sociodemographic and behavioral factors (N=2,260). Higher SFA and MUFA were associated with greater GrimAge2, an aging biomarker of mortality; PUFA was associated with lower Horvath1, Hannum, and PhenoAge (p<0.05). Omega-3 and the PUFA:SFA ratio were negatively associated with Horvath1, Hannum, Vidal-Bralo, and PhenoAge. Notably, a one-unit increase in PUFA:SFA was associated with 1.05 years lower PhenoAge (95% CI=-1.87, -0.22). There were consistent trends of positive associations of SFA subtypes and negative associations of PUFA subtypes with epigenetic aging; associations of MUFA subtypes varied. Future studies, including randomized controlled trials, are needed to investigate causality and downstream clinical outcomes.
Longevity Relevance Analysis
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Higher saturated and monounsaturated fatty acids are associated with increased epigenetic aging, while polyunsaturated fatty acids are linked to decreased aging biomarkers. This study investigates dietary factors that may influence the biological aging process, which is directly relevant to longevity research.
Yi, Y.-J., Johansson, J., Garcia-Garcia, B. ...
· neuroscience
· Institute for Cognitive Neurology and Dementia Research
· biorxiv
Cognitive ageing is marked by progressive decline in episodic memory and dopaminergic function, yet the extent to which individual differences in dopaminergic system integrity influence memory under motivational contexts remains unclear. In this study, we investigated how baselin...
Cognitive ageing is marked by progressive decline in episodic memory and dopaminergic function, yet the extent to which individual differences in dopaminergic system integrity influence memory under motivational contexts remains unclear. In this study, we investigated how baseline D2/D3 receptor availability (BPND0) in key dopaminergic pathways relates to reward-modulated memory performance in healthy older adults. Thirty-three healthy seniors (aged 64-85) underwent two session concurrent MR-PET imaging with [18F]fallypride involving scene categorisation task with high- and low-motivational contexts. We quantified BPND0 across nine dopaminergic regions of interest and examined their relationships with recognition memory performance at short (~15m) and long (~24h) delays. Baseline D2/D3 receptor availability showed high test-retest reliability and regionally distinct profiles, suggesting it reflects a stable neurochemical characteristic in healthy ageing, and principal axis factor analysis revealed two partially independent dopaminergic subsystems (dorsal striatal vs mesolimbic) based on interindividual patterns in receptor densities. Region-specific associations further linked D2/D3 receptor availability to distinct memory outcomes. Higher caudate D2/D3 receptor availability was associated with a liberal response bias (increased hits and false alarms both), whereas higher putamen D2/D3 predicted more durable long-term memory retention. Greater thalamic D2/D3 receptor availability correlated with fewer short-term false memories, while greater D2/D3 receptor availability in the amygdala was associated with better recognition at longer delays. In contrast, higher midbrain (substantia nigra and ventral tegmental area) D2/D3 availability which was linked to poorer reward-related memory performance. These findings suggest several complementary dopaminergic circuits supporting episodic memory. Our results highlight dopaminergic neuromodulation as a key factor in cognitive ageing and a potential target for interventions to bolster memory in late life.
Longevity Relevance Analysis
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Higher D2/D3 receptor availability in specific dopaminergic regions is linked to distinct memory outcomes in healthy older adults. The study addresses the neurochemical underpinnings of cognitive ageing, suggesting potential targets for interventions aimed at improving memory in the aging population.
Elder, M. A., Ellmore, T. M.
· neuroscience
· The City College of New York
· biorxiv
Age-related differences in white matter structure are increasingly understood as nonlinear, regionally specific, and behaviorally relevant. Using whole-brain fixel-based analysis (FBA), we examined how recognition memory speed relates to micro- and macrostructural white matter pr...
Age-related differences in white matter structure are increasingly understood as nonlinear, regionally specific, and behaviorally relevant. Using whole-brain fixel-based analysis (FBA), we examined how recognition memory speed relates to micro- and macrostructural white matter properties across a sample spanning young to middle adulthood. Slower response times were associated with higher fiber density (FD) in left frontoparietal tracts, nonlinear increases in fiber cross-section (log(FC)) in the anterior corpus callosum, and elevated combined fiber density and cross-section (FDC) in posterior callosal and cingulum pathways. These associations were most pronounced among individuals in the later decades of this age range, suggesting that white matter morphology reflects both extended maturation and emerging age-related decline. In a separate, hypothesis-driven analysis, we applied deterministic tractography to reconstruct the fornix and extracted mean fractional anisotropy (FA) along its length. Greater fornix FA and younger age together explained 34% of the variance in retrieval speed. These findings highlight regionally distinct structural contributions to memory performance and support lifespan models emphasizing individual variability and neuroplasticity in white matter development. This integrative approach underscores the value of combining whole-brain and tract-specific analyses to advance our understanding of white matter contributions to cognitive aging.
Longevity Relevance Analysis
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The paper claims that specific white matter properties are associated with recognition memory speed in young to middle adulthood. This research is relevant as it explores the relationship between brain structure and cognitive aging, contributing to our understanding of how white matter integrity may influence cognitive decline, which is a key aspect of longevity research.
Yidan Pang, Siyuan Zhu, Peng Ding ...
· MedComm
· Department of Orthopaedics Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai China.
· pubmed
Obesity and aging are major risk factors for diseases such as Type 2 diabetes mellitus, dementia, and osteoporosis. High-fat diet (HFD) consumption is one of the most important factors contributing to obesity. To elucidate and provide resources on how long-term HFD to aging (LHA)...
Obesity and aging are major risk factors for diseases such as Type 2 diabetes mellitus, dementia, and osteoporosis. High-fat diet (HFD) consumption is one of the most important factors contributing to obesity. To elucidate and provide resources on how long-term HFD to aging (LHA) affects the bone marrow and solid organs, we established an LHA mice model and demonstrated that LHA caused a shift from osteogenesis to adipogenesis in the bone marrow microenvironment. Single-cell transcriptomics of bone marrow cells highlighted LHA-driven perturbations in immune cell populations with distinct metabolic adaptations to LHA. We demonstrated that bone marrow macrophages of the LHA group upregulated Chil3 and Fabp4, which are associated with inflammatory response and regulation of adipocytes. Moreover, we identified the Ptn-Sdc3 axis and Cxcl12-Cxcr4 axis between bone marrow macrophages and brain epithelial cells as possible candidates for crosstalk between bone marrow and brain in LHA mice. Our findings indicated the bone marrow microenvironment as a central hub of LHA-induced pathology, where adipogenic reprogramming and myeloid cell dysfunction collectively drive skeletal and systematic inflammation. This resource highlights therapeutic opportunities targeting bone marrow to mitigate obesity-accelerated aging.
Longevity Relevance Analysis
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Long-term high-fat diet consumption shifts the bone marrow microenvironment from osteogenesis to adipogenesis, impacting aging-related inflammation. This study addresses the underlying mechanisms of aging and obesity, linking metabolic changes in the bone marrow to broader implications for age-related diseases.
Chenke Jiang, Yihong Gan, Shengyu Chen ...
· Aging clinical and experimental research
· School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China.
· pubmed
Observational studies have shown that physical activity and sedentary behavior are associated with aging. However, whether these associations underlie causal effects remains unknown. Thus, this study aimed to assess the genetic correlation and causal relationships between genetic...
Observational studies have shown that physical activity and sedentary behavior are associated with aging. However, whether these associations underlie causal effects remains unknown. Thus, this study aimed to assess the genetic correlation and causal relationships between genetically predicted physical activity, sedentary behavior, and aging.
Longevity Relevance Analysis
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The paper claims to assess the genetic correlation and causal relationships between genetically predicted physical activity, sedentary behavior, and aging. This research is relevant as it explores the underlying causal mechanisms linking lifestyle factors to aging, which could inform strategies for longevity and age-related health improvements.
Critchlow, A. J., Hiam, D., O'Bryan, S. ...
· endocrinology
· Deakin University
· medrxiv
Whether and how ovarian hormone fluctuations mediate the skeletal muscle response to ageing in females remains to be elucidated. We examined a tightly controlled, cross-sectional cohort of 96 females between 18-80 years of age to map the functional and molecular trajectory of mus...
Whether and how ovarian hormone fluctuations mediate the skeletal muscle response to ageing in females remains to be elucidated. We examined a tightly controlled, cross-sectional cohort of 96 females between 18-80 years of age to map the functional and molecular trajectory of muscle ageing and determine its relationship with female sex hormones. Across every decade, we quantified body composition using dual-energy x-ray absorptiometry, muscle morphology using peripheral quantitative computed tomography and voluntary and evoked muscle strength. Circulating sex hormone concentrations were measured with gas chromatography mass spectrometry and immunoassays. Morphology and gene expression of vastus lateralis muscle samples were assessed with immunohistochemical staining and RNA sequencing, respectively. After adjusting for the relevant variables, age was negatively associated with muscle mass, strength, and muscle fibre size, and positively associated with hybrid type I/II fibre prevalence and fibrosis. We found 37 unique patterns of gene expression across individual decades of age. Immune signalling, cellular adhesion, and extracellular matrix organisation pathways were the most upregulated with age, while mitochondrial function pathways were the most downregulated. Independently of age, circulating oestradiol and progesterone, but not testosterone, concentrations were positively associated with lean mass and negatively associated with hybrid muscle fibres across the lifespan. Oestrogen receptor binding sites were significantly enriched in upregulated genes in pre- versus post-menopausal muscle, suggesting a reduction in the translation of oestrogen target genes after menopause. The effects of sex hormone fluctuations across the female lifespan should therefore be considered in the development of therapies to mitigate age-related muscle wasting.
Longevity Relevance Analysis
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The paper claims that fluctuations in female sex hormones significantly influence muscle mass and function across the lifespan. This research is relevant as it addresses the biological mechanisms underlying age-related muscle deterioration in females, which is a critical aspect of aging and longevity.
STOLZ, A., XUAN, C., FREITAS, C. ...
· cell biology
· INSERM UMR1287, Universite Paris Saclay, Gustave Roussy Cancer Center, 94805 Villejuif, France
· biorxiv
Chronic inflammation that accompanies aging impairs the function of hematopoietic stem cells (HSCs) and promotes expansion of TET2-mutated cells, leading to clonal hematopoiesis of indeterminate potential (CHIP). The molecular mechanisms underlying these processes are still uncle...
Chronic inflammation that accompanies aging impairs the function of hematopoietic stem cells (HSCs) and promotes expansion of TET2-mutated cells, leading to clonal hematopoiesis of indeterminate potential (CHIP). The molecular mechanisms underlying these processes are still unclear. We recently showed that age and stresses like irradiation reduce the heterochromatin mark H3K9me3, leading to the epigenetic derepression of transposable elements such as LINE-1/L1, and L1-induced HSC functional changes through DNA damage and transcriptomic alterations. However, the impact of TEs on the clonal expansion of Tet2-/- HSCs upon chronic inflammation is unknown. Here we show that in wild type (WT) HSC, chronic inflammation induced by repeated low doses of lipopolysaccharide (LPS) triggers H3K9me3 loss at L1. We further show that L1s are involved in LPS-induced DNA damage and reduction of HSC clonogenicity. In contrast, Tet2-/- HSCs resist LPS-induced L1 epigenetic derepression and associated DNA damage. As a result, WT HSCs show decreased competitiveness against Tet2-/- HSCs upon chronic inflammation. These findings identify epigenetic control of L1s as a key mediator of inflammation-induced HSC dysfunction and clonal expansion of Tet2-mutant cells.
Longevity Relevance Analysis
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The paper claims that Tet2-deficient HSCs resist L1-induced DNA damage during chronic inflammation, leading to their clonal expansion. This research is relevant as it explores the underlying mechanisms of hematopoietic stem cell dysfunction in the context of chronic inflammation and aging, potentially addressing root causes of age-related clonal expansion and its implications for longevity.
Nguyen, T. D., Khan, Y. Z., Hossen, F. ...
· cell biology
· University of Illinois Chicago
· biorxiv
As the innermost lining of blood vessels, endothelial cells (ECs) regulate blood flow, maintain vascular tone, and limit inflammation for vessel health. EC-derived nitric oxide (NO), synthesized by endothelial nitric oxide synthase (eNOS), is a vasodilator essential for improving...
As the innermost lining of blood vessels, endothelial cells (ECs) regulate blood flow, maintain vascular tone, and limit inflammation for vessel health. EC-derived nitric oxide (NO), synthesized by endothelial nitric oxide synthase (eNOS), is a vasodilator essential for improving blood flow and vascular homeostasis. The RhoA/ROCK pathway regulates eNOS levels, where overactivation decreases eNOS expression and downstream NO production. As such, RhoA/ROCK hyperactivity and increased pMLC have been identified as major contributors to age-associated vasoconstriction and hypertension. Intriguingly, recent studies identify Sun1, a key component of the linker of nucleoskeleton and cytoskeleton (LINC) complex, as a major regulator of RhoA/ROCK activity. Moreover, endothelial aging deteriorates nuclear pore complexes (NPCs) (i.e. nucleoporin [Nup93]) and impairs nucleocytoplasmic transport, thereby insinuating a role for nuclear envelope components in vessel homeostasis. Here, we show that targeted loss of endothelial Nup93 in adult mice significantly reduces eNOS expression and NO bioavailability for consequent defects in NO-dependent vasodilatory responses. In vitro knockdown of Nup93 in primary human ECs also decreases both eNOS expression and NO production. Mechanistically, we find that loss of Nup93 significantly reduces endothelial Sun1 levels for a concomitant increase in RhoA activity. Indeed, restoring Sun1 protein levels in Nup93-deficient ECs mitigates RhoA activity to rescue both eNOS expression and NO production. Taken together, we demonstrate endothelial Nup93, through Sun1 stabilization, as a novel regulator of eNOS-NO signaling and vessel reactivity, contributing to the growing importance of nuclear membrane components in EC and vascular biology.
Longevity Relevance Analysis
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Endothelial Nup93 regulates eNOS expression and NO production through Sun1 stabilization, impacting vascular function. The study addresses mechanisms underlying endothelial aging and vascular health, which are critical for longevity and age-related vascular diseases.
The maintenance of mitochondrial proteins homeostasis, which is essential for proper cell function, is affected in pathophysiological ageing, yet several underlying mechanisms remain unexplored. We show that in normal and accelerated ageing cells, POLG1, the enzyme responsible fo...
The maintenance of mitochondrial proteins homeostasis, which is essential for proper cell function, is affected in pathophysiological ageing, yet several underlying mechanisms remain unexplored. We show that in normal and accelerated ageing cells, POLG1, the enzyme responsible for mitochondrial DNA replication, is degraded by the protease cathepsin B, which is overexpressed, escapes from lysosomes, and is stabilized by the chaperone activity of another protease, HTRA3. This degradation is in part counteracted by RAC1, a small GTPase also stabilized by HTRA3. POLG1 depletion, that occurs in progeroid Cockayne syndrome and senescent cells, is linked respectively to impairment or downregulation of the CSB protein, which promote cellular senescence. Our experiments in engineered cells, demonstrate that senescence itself, and not the absence of CSB, triggers the accumulation of cathepsin B and HTRA3, leading to POLG1 degradation. In summary, we uncover a complex, multi-step process that controls the degradation of POLG1 in mitochondria, a process that is activated by cell senescence and becomes more pronounced in Cockayne syndrome cells, providing new insight in the regulation of mitochondrial proteostasis in ageing and progeroid disorders.
Longevity Relevance Analysis
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The paper claims that the protease-chaperone HTRA3 stabilizes cathepsin B, leading to the degradation of POLG1 in the context of cellular senescence and mitochondrial dysfunction. This research is relevant as it explores mechanisms underlying mitochondrial protein homeostasis and degradation processes that contribute to aging and age-related disorders, potentially offering insights into the root causes of cellular senescence.
Luciana Yamamoto de Almeida, Catharine Dietrich, Ashleigh S Hanner ...
· Aging cell
· Craniofacial Anomalies and Regeneration Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, Maryland, USA.
· pubmed
Large-scale bone defects require complex surgical procedures to repair, but full restoration of the bone is not guaranteed due to the significant tissue loss involved. In contrast, fractures can frequently be treated with conservative techniques. Particularly, ribs have a remarka...
Large-scale bone defects require complex surgical procedures to repair, but full restoration of the bone is not guaranteed due to the significant tissue loss involved. In contrast, fractures can frequently be treated with conservative techniques. Particularly, ribs have a remarkable ability to spontaneously regenerate large-scale bone defects. However, we show here that skeletal maturity and age are associated with a decrease in the regenerative potential of human ribs. To investigate skeletal maturity and age-related cellular and transcriptional changes during large-scale bone regeneration, we used a mouse model that mimics the regenerative clinical features of human ribs. Unlike immature mice, mature mice lose the ability to regenerate after rib resection, and instead of bone, the resected rib space is repaired with abundant fibronectin cells. In addition, bone repair in mature mice presents reduced immune cell infiltration, which coincides with decreased levels of circulatory pro-inflammatory factors. To address the role of cell-cell communication and test whether skeletal maturity and age-related changes in immune cells and circulatory factors influence bone regeneration, we used immunodeficient mouse strains and performed heterochronic parabiosis. In immature mice, defective immune cell function altered callus composition rather than inhibiting bone regeneration. Remarkably, under parabiosis, a systemic pro-regenerative response is triggered exclusively in resected immature mice and is capable of partially rescuing bone regeneration in mature mice otherwise unable to regenerate spontaneously. Collectively, these findings suggest that therapeutic strategies focused on identifying pro-regenerative immune factors are promising for supporting the regeneration of large bone defects.
Longevity Relevance Analysis
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The paper claims that age-related changes in immune cells and circulatory factors impair bone regeneration, suggesting that targeting these factors could enhance regenerative capacity in older individuals. This research is relevant as it addresses the mechanisms underlying age-related decline in regenerative potential, which is a key aspect of longevity and aging.
Douglas M Ruden
· Epigenomics
· C. S. Mott Center for Human Growth and Development, Institute for Environmental Health Sciences, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, USA.
· pubmed
Aging is a complex biological process involving coordinated changes across multiple molecular systems. Traditional reductionist approaches, while valuable, are insufficient to capture the full scope of aging's systemic nature. Multiomics - integrating data from genomics, transcri...
Aging is a complex biological process involving coordinated changes across multiple molecular systems. Traditional reductionist approaches, while valuable, are insufficient to capture the full scope of aging's systemic nature. Multiomics - integrating data from genomics, transcriptomics, epigenomics, proteomics, and metabolomics - provides a comprehensive framework to study aging as an interconnected network. In this Perspective, I explore how multiomic strategies, particularly those leveraging epigenomic and single-cell data, are reshaping our understanding of aging biology. Epigenetic alterations, including DNA methylation and histone modifications, are not only hallmarks but also powerful biomarkers of biological age. I discuss advances in multiomic aging clocks, cross-tissue atlases, and single-cell spatial technologies that decode aging at unprecedented resolution. I also build on a prior review I wrote with colleagues, Epigenomics. 2023;15(14):741-754, which introduced the concept of pathological epigenetic events that are reversible (PEERs) - epigenetic alterations linked to early-life exposures that predispose to aging and disease but may be therapeutically modifiable. This Perspective examines how PEERs and multiomics intersect to inform biomarkers, geroprotective interventions, and personalized aging medicine. Finally, I highlight integration challenges, ethical concerns, and the need for standardization to accelerate clinical translation. Together, these insights position multiomics as a central pillar in the future of aging research.
Longevity Relevance Analysis
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The paper claims that multiomics can reshape our understanding of aging biology and inform biomarkers and interventions. This research is relevant as it addresses the systemic nature of aging and explores potential therapeutic avenues to modify epigenetic alterations linked to aging and disease.