Matthew Lacey, Lucie Beresova, Alzbeta Srovnalova ...
· GeroScience
· Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital, Olomouc, Czech Republic.
· pubmed
Senescent cells accumulate with age and contribute to tissue dysfunction and chronic inflammation. Senolytic agents that selectively eliminate senescent cells hold therapeutic promise; however, few mechanistic classes have been established. Using Cell Painting-based morphological...
Senescent cells accumulate with age and contribute to tissue dysfunction and chronic inflammation. Senolytic agents that selectively eliminate senescent cells hold therapeutic promise; however, few mechanistic classes have been established. Using Cell Painting-based morphological profiling, we identified a distinct cluster of senolytic compounds comprised of both known and novel autophagy inhibitors, including AZ191, bafilomycin A1, chloroquine, daurisoline, dauricine, MCOPPB, and its derivative MS1108. These compounds selectively eliminated senescent cells by disrupting autophagic flux. Our findings reveal senescent cell dependence on autophagy as an essential survival mechanism, define the existence of a mechanistically distinct class of senolytics acting through autophagy inhibition, and demonstrate the predictive value of Cell Painting in aging-related drug discovery. Our results provide new insights into senescent cell vulnerability and expand the therapeutic landscape for aging-related pathologies by highlighting autophagy as a targetable dependency.
Longevity Relevance Analysis
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The paper claims that senescent cells depend on autophagy for survival, and that targeting this dependency with specific compounds can selectively eliminate these cells. This research is relevant as it addresses the underlying mechanisms of cellular senescence, which is a significant contributor to aging and age-related diseases, potentially leading to therapeutic strategies that target the root causes of aging.
Pedro Sant' Anna Barbosa Ferreira, Stella Trompet, Eline Slagboom ...
· GeroScience
· Department of Biomedical Data Sciences, section of Molecular Epidemiology, Leiden University Medical Center, Einthovenweg 20, 2333 ZA, Leiden, The Netherlands. psb.ferreira@lumc.nl.
· pubmed
Aging is a major risk factor for chronic diseases. Unlike the general population, members of long-lived families maintain exceptional health as they age, with over 10 years delayed onset of their first chronic disease. We therefore hypothesize that one of the key features explain...
Aging is a major risk factor for chronic diseases. Unlike the general population, members of long-lived families maintain exceptional health as they age, with over 10 years delayed onset of their first chronic disease. We therefore hypothesize that one of the key features explaining healthy survival up to high ages (longevity) is the absence of chronic disease risk alleles. We investigated this hypothesis in the Leiden Longevity Study, a cohort with data from more than 420 long-lived families in three generations and the Leiden 85-plus study. To analyze our data, we constructed a set of polygenic scores (PGS) covering the top diseases causing most deaths in the Netherlands. We showed that having an increasing number of long-lived ancestors is additively associated with lower genetic risk for coronary artery disease (CAD). Using accelerated failure time modelling, we further showed that a lower PGS for CAD explains up to 20% of the delay in cardiovascular disease incidence in descendants of long-lived families. Finally, we constructed a novel cholesterol-metabolism-PGS, based on gene-annotation enrichment analysis, that predicted time to all-cause mortality in two independent 90 + study populations. Our findings demonstrate that the absence of chronic disease risk alleles is one key feature linked to longevity and that alleles linked to cholesterol metabolism are a key component in healthy aging trajectories.
Longevity Relevance Analysis
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The paper claims that the absence of chronic disease risk alleles, particularly related to coronary artery disease, contributes to longevity and healthy aging. This research is relevant as it explores genetic factors that may underlie longevity and healthy aging, addressing root causes rather than merely treating symptoms of aging.
Xiaoxue Qiu, You Lu, Yuwei Tang ...
· Hepatocytes
· Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
· pubmed
Hepatocyte senescence is increasingly recognized as a pathogenic driver of metabolic dysfunction-associated steatohepatitis (MASH). Through single-nucleus transcriptomic profiling, we identified a discrete population of disease-associated hepatocytes (daHep) exhibiting enrichment...
Hepatocyte senescence is increasingly recognized as a pathogenic driver of metabolic dysfunction-associated steatohepatitis (MASH). Through single-nucleus transcriptomic profiling, we identified a discrete population of disease-associated hepatocytes (daHep) exhibiting enrichment for senescence markers in MASH livers. The emergence of senescent hepatocytes was associated with a marked induction of hepatic thymocyte selection associated (THEMIS) expression in both murine and human MASH. Genetic ablation of Themis, either globally or specifically in hepatocytes, resulted in significant expansion of daHep and senescent hepatocyte populations and exacerbated MASH pathology in mice. Single-nucleus transcriptomic analysis revealed a central role for THEMIS in shaping the cellular landscape of both parenchymal and nonparenchymal compartments within the MASH liver microenvironment. Conversely, adeno-associated virus-mediated overexpression of THEMIS suppressed hepatocyte senescence and attenuated diet-induced MASH. Mechanistic studies revealed that THEMIS deficiency promoted aberrant ERK phosphorylation and hepatocyte senescence. These findings establish THEMIS as a critical hepatoprotective factor that restrains hepatocyte senescence and mitigates metabolic liver disease progression.
Longevity Relevance Analysis
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THEMIS is identified as a critical hepatoprotective factor that restrains hepatocyte senescence and mitigates metabolic liver disease progression. The study addresses the role of hepatocyte senescence in metabolic dysfunction, which is a key aspect of aging and longevity research, focusing on mechanisms that could potentially reverse or mitigate age-related liver diseases.
Kan Yu, Nengzheng Wang, Xinyi Huang ...
· Enrofloxacin
· State Key Laboratory of Genetics and Development of Complex Phenotypes, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Collaborative Innovation Center of Genetics and Development, Human Phenome Institute, Center for Evolutionary Biology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, Shanghai, China.
· pubmed
Environmental antibiotic pollution is an underexplored contributor to gut aging and chronic intestinal diseases. We provide evidence that chronic exposure to enrofloxacin (ENR), a commonly detected veterinary antibiotic, accelerates gut aging and disease progression through a mit...
Environmental antibiotic pollution is an underexplored contributor to gut aging and chronic intestinal diseases. We provide evidence that chronic exposure to enrofloxacin (ENR), a commonly detected veterinary antibiotic, accelerates gut aging and disease progression through a mitochondria-centered mechanism. In a population-based cross-sectional analysis, recent antibiotic use was associated with increased biological age and a higher risk of diarrhea in middle-aged and older adults, supporting a link between antibiotic exposure and impaired gut health and aging processes. Using zebrafish and intestinal epithelial cell models, we demonstrate that low-dose ENR exposure impairs intestinal function, characterized by increased permeability, reduced mucus secretion, tight junction disruption, and chronic inflammation. Multi-omics profiling revealed that ENR induced gut microbial dysbiosis, reduced metabolic diversity, and intestinal hypoxia. Mitochondrial dysfunction, particularly impaired oxidative phosphorylation, was identified as the key driver of epithelial damage. Remarkably, treatment with pyrroloquinoline quinone, a mitochondrial-targeted antioxidant, reversed ENR-induced mitochondrial injury, restored intestinal integrity, reduced inflammation, and partially normalized the microbiome. Stratified analyses in the human cohort showed that higher gut microbiota-related diet quality and antioxidant capacity mitigated antibiotic-associated aging and diarrhea risk. These findings highlight mitochondrial protection and microbiota optimization as promising therapeutic strategies.
Longevity Relevance Analysis
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Chronic exposure to enrofloxacin accelerates gut aging and disease progression through mitochondrial dysfunction. The paper addresses a modifiable environmental factor contributing to gut aging, linking it to mitochondrial health and potential therapeutic strategies, which are central to understanding and mitigating aging processes.
Oleksandra Soldatkina, Laura Ventura-San Pedro, Natàlia Pujol-Gualdo ...
· Nature aging
· Life Sciences Department, Barcelona Supercomputing Center (BSC), Barcelona, Spain.
· pubmed
Female reproductive aging has systemic health implications, yet tissue-level dynamics remain poorly understood. Here we integrate deep learning analysis of 1,112 histology images with RNA sequencing from 659 samples across seven female reproductive organs in donors aged 20-70 yea...
Female reproductive aging has systemic health implications, yet tissue-level dynamics remain poorly understood. Here we integrate deep learning analysis of 1,112 histology images with RNA sequencing from 659 samples across seven female reproductive organs in donors aged 20-70 years. We uncover asynchronous trajectories: the ovary ages gradually, whereas the uterus shows an abrupt molecular and morphological shift around menopause. This uterine transition is independently supported by plasma proteomics data from a large population cohort, indicating that organ-linked aging signatures are detectable in circulation. Tissue segmentation highlights the myometrium as strongly age affected, with extracellular matrix remodeling and immune activation. Epithelial tissues also show coordinated age-related remodeling, with a sharp menopausal transition in the vaginal epithelium. Multi-omics factor analysis links these histological changes to nonlinear gene-expression shifts enriched for reproductive traits, including pelvic organ prolapse and age at menarche. Together, these findings establish menopause as a key inflection point in female aging and provide a tissue-resolved, multi-dataset framework for late-life health.
Longevity Relevance Analysis
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The paper claims that menopause represents a key inflection point in female reproductive aging, revealing asynchronous aging dynamics across various reproductive organs. This research is relevant as it explores the underlying mechanisms of aging in female reproductive organs, contributing to the understanding of systemic health implications associated with aging.
Eric K F Donahue, Kristopher Burkewitz
· Autophagy
· Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
· pubmed
Age-associated changes in organelle structure are often viewed as passive deterioration. Our recent work challenges this view by identifying an evolutionarily conserved, age-onset remodeling of the endoplasmic reticulum (ER) that is actively driven by ER-phagy. Across multiple ce...
Age-associated changes in organelle structure are often viewed as passive deterioration. Our recent work challenges this view by identifying an evolutionarily conserved, age-onset remodeling of the endoplasmic reticulum (ER) that is actively driven by ER-phagy. Across multiple cell types and organisms, the ER undergoes a reduction in volume and a shift from rough ER sheets to tubular networks. ER compositional shifts accompany these changes in morphology, with declines of the proteostasis machineries enriched within rough ER and preservation of lipid-associated enzymes tied to tubular subdomains. This remodeling occurs via autolysosomal targeting and degradation of the ER, establishing selective ER-phagy as a conserved aspect of the aging process. Notably, ER-phagy is also engaged by multiple longevity paradigms, resulting in precocious, spatial reorganization of the ER. Furthermore, ER-phagy is required for lifespan extension during mTOR impairment, indicating that ER turnover is adaptive and contributes to longevity. These findings reveal ER-phagy as a regulator of organelle architecture and age-dependent shifts in cell metabolism, thus illuminating important roles for selective autophagy in shaping organelle identity and function across the lifespan.
Longevity Relevance Analysis
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Selective ER-phagy is a conserved mechanism that actively remodels the endoplasmic reticulum during aging and contributes to lifespan extension. This paper is relevant as it addresses the underlying mechanisms of aging through autophagy, highlighting a potential pathway for promoting longevity.
Lin Shi, Yu-Long Liu, Meng-Ni Dai ...
· npj aging
· Jiangxi Province Key Laboratory of Aging and Disease, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, Nanchang, China.
· pubmed
Aging is driven in part by progressive deterioration of proteostasis and antioxidant defense, leading to cellular dysfunction and age-associated disease. The naturally occurring methylated inositol D-pinitol (DP) was reported to present metabolic, antioxidant, and anti-inflammato...
Aging is driven in part by progressive deterioration of proteostasis and antioxidant defense, leading to cellular dysfunction and age-associated disease. The naturally occurring methylated inositol D-pinitol (DP) was reported to present metabolic, antioxidant, and anti-inflammatory effects, as well as to extend the lifespan of D. melanogaster and C. elegans through the insulin/IGF-1 signaling pathway. But the mechanism of DP on delay aging remains poorly understand. Here, we showed that 200 μM of DP increased mean lifespan of C. elegans by 28.6%, as well as healthspan phenotypes including preserved locomotor function and delayed lipofuscin accumulation. DP also attenuated proteotoxicity and delays functional decline in C. elegans models of Parkinson's, Huntington's, and Alzheimer's diseases. Moreover, DP suppressed cellular senescence in multiple mammalian cell types. Genetic and reporter analyses show that DP activates conserved stress-response regulators Nrf2/SKN-1 and HSF-1 through the p38 MAPK signaling cascade to improve resistance to oxidative and thermal stress. DP further enhanced HLH-30-dependent autophagy and mitophagy activities, which are essential for lifespan extension. Together, these findings identify DP as a conserved modulator of proteostasis, redox homeostasis, and autophagy, positioning it as a promising, low-toxicity candidate for promoting healthy aging and mitigating age-related neurodegenerative pathology.
Longevity Relevance Analysis
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D-pinitol extends the lifespan of C. elegans by enhancing antioxidant defense, proteostasis, and autophagy signaling. The paper addresses mechanisms that contribute to aging and lifespan extension, focusing on the root causes of cellular dysfunction rather than merely treating age-related diseases.
Chaoqiang Chen, Zhidong Liu, Yanhang Sun ...
· Advanced science (Weinheim, Baden-Wurttemberg, Germany)
· Department of Orthopedics, The Eighth Affiliated Hospital ,Sun Yat-Sen University, Shenzhen, China.
· pubmed
Senile osteoporosis (SOP) is characterized by impaired osteogenesis of bone-marrow mesenchymal stem cells (MSCs). The underlying metabolic basis remains unclear. This study aimed to identify energy-regulating pathways sustaining MSC osteogenesis during aging. Progressive activati...
Senile osteoporosis (SOP) is characterized by impaired osteogenesis of bone-marrow mesenchymal stem cells (MSCs). The underlying metabolic basis remains unclear. This study aimed to identify energy-regulating pathways sustaining MSC osteogenesis during aging. Progressive activation of lipophagy was observed during MSC osteogenic differentiation, coupling lipid-droplet degradation with mitochondrial β-oxidation and ATP generation. Loss of the lipophagy receptor SPARTIN disrupted this process, leading to lipid accumulation, reduced CPT1A/CPT2 expression, suppressed oxidative phosphorylation, and impaired osteogenesis in vitro and in vivo. Conditional deletion of Spart in MSCs reproduced an osteoporosis-like phenotype in young mice. Reactivation of lipophagy using bone-tropic AAV9-LAP restored mitochondrial metabolism and bone mass in both Spart-CKO and SOP mice. Pharmacological activation with digoxin produced similar effects but induced cardiotoxicity. A senescent-neutrophil-membrane-coated nanoplatform (SNM@NP-DIG) enabled bone-targeted digoxin delivery, rescuing bone mass while minimizing cardiac injury. Overall, SPARTIN-mediated lipophagy is a critical metabolic regulator of MSC osteogenesis and represents a promising therapeutic target for senile osteoporosis.
Longevity Relevance Analysis
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SPARTIN-mediated lipophagy is a critical metabolic regulator of MSC osteogenesis and represents a promising therapeutic target for senile osteoporosis. The paper addresses the metabolic mechanisms underlying aging-related osteoporosis, focusing on enhancing stem cell function, which is directly relevant to longevity research.
Shalini Dimri-Wagh, Swarnabh Bhattacharya, Gharam Yassen ...
· Nature communications
· Department of Genetics & Developmental Biology, The Rappaport Faculty of Medicine & Research Institute, Technion Integrated Cancer Center, Technion-Israel Institute of Technology, Haifa, Israel. yashree.dimri@gmail.com.
· pubmed
Recent studies report that epithelial differentiated cells can undergo a reverse process called dedifferentiation in response to stem cell loss. However, the extent of this reversion and the plasticity of young versus aged-differentiated cells remain unclear. Here we show that de...
Recent studies report that epithelial differentiated cells can undergo a reverse process called dedifferentiation in response to stem cell loss. However, the extent of this reversion and the plasticity of young versus aged-differentiated cells remain unclear. Here we show that dedifferentiated corneal epithelial cells acquire a transcriptomic state closely resembling native stem cells, sustain tissue homeostasis across lifespan and efficiently repair repeated tissue injury. Transplantation of stage-specific genetically traceable aged differentiated epithelial cells onto a denuded niche reveals reversion into a stemness-like state, restoring both quiescent and active stem cell compartments. This plasticity operates within the epithelial lineage, allowing transitions along the differentiation axis, but remains restricted across lineages, as transplanted conjunctival cells fail to regenerate the corneal stem cell pool. Mechanistically, we identify niche-derived cytokines that trigger reprogramming in vivo and enhance stemness in primary human corneal epithelial cells, revealing a conserved and therapeutically exploitable pathway for epithelial regeneration.
Longevity Relevance Analysis
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The paper claims that aged differentiated corneal epithelial cells can dedifferentiate into a stemness-like state, enhancing tissue homeostasis and repair. This research is relevant as it explores mechanisms of cellular plasticity and regeneration that could address the underlying processes of aging and improve tissue repair across the lifespan.
Ioanna Skampardoni, Guray Erus, Ilya M Nasrallah ...
· Nature communications
· AI2D Center for AI and Data Science for Integrated Diagnostics, University of Pennsylvania, Philadelphia, PA, USA.
· pubmed
Machine learning can unravel heterogeneous patterns of brain aging and neurodegeneration, but existing methods offer limited insights into disease progression due to reliance on cross-sectional data. We introduce Coupled Cross-sectional and Longitudinal Non-negative Matrix Factor...
Machine learning can unravel heterogeneous patterns of brain aging and neurodegeneration, but existing methods offer limited insights into disease progression due to reliance on cross-sectional data. We introduce Coupled Cross-sectional and Longitudinal Non-negative Matrix Factorization (CCL-NMF) to capture dominant brain aging patterns by simultaneously leveraging cross-sectional and longitudinal neuroimaging data. CCL-NMF allows individuals to co-express multiple patterns, capturing mixed neuropathologic processes. Applied to neuroimaging data from 48,949 individuals from the harmonized iSTAGING study, CCL-NMF identifies seven distinct, reproducible, and biologically relevant neuroanatomical patterns. Subject-specific loading coefficients quantifying the individual expression of these patterns show distinct associations with cognition, genetic, and lifestyle factors. To support broader application, a regression-based tool was developed to estimate loadings in external cohorts without rerunning the full framework. By enabling individualized estimation of distinct brain aging patterns, these findings may improve risk assessment and therapeutic evaluation in neurodegenerative diseases. Although demonstrated using structural MRI, this framework is generalizable to other imaging modalities and biomarker types.
Longevity Relevance Analysis
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The paper claims that the Coupled Cross-sectional and Longitudinal Non-negative Matrix Factorization (CCL-NMF) method can identify distinct brain aging patterns that are associated with cognition, genetics, and lifestyle factors. This research is relevant as it seeks to understand and quantify brain aging processes, which are fundamental to addressing age-related diseases and potentially improving longevity through better risk assessment and therapeutic evaluation.
Yaoli Hou, Zhiying Zeng, Sheng He ...
· The journals of gerontology. Series A, Biological sciences and medical sciences
· Department of Medical Administration, the Second Affiliated Hospital, University of South China, Hengyang, 421001, Hunan, China.
· pubmed
Immunosenescence-the age-related decline of immune function-drives a state of chronic, sterile inflammation termed inflammaging. Far from passive deterioration, this process is actively orchestrated by distinct but interconnected hallmarks: erosion of lymphoid organs, myeloid-bia...
Immunosenescence-the age-related decline of immune function-drives a state of chronic, sterile inflammation termed inflammaging. Far from passive deterioration, this process is actively orchestrated by distinct but interconnected hallmarks: erosion of lymphoid organs, myeloid-biased hematopoiesis, accumulation of immune-evasive senescent cells, and metabolic-epigenetic reprogramming that locks cells into dysfunctional states. These core nodes form a self-perpetuating cycle that propagates pathology across multiple organ systems, fueling neurodegeneration, cancer, musculoskeletal decline, and gut dysbiosis. Critically, the field has transitioned from descriptive phenomenology to mechanism-based intervention. This review synthesizes emerging therapeutic strategies targeting specific nodes of the immunosenescence network. We examine senotherapeutics that sensitize senescent cells for immune clearance, HSC and thymic rejuvenation to restore lymphocyte production, and metabolic-epigenetic interventions to correct intracellular deficits. By integrating these insights, we propose a precision medicine framework that moves beyond broad immunosuppression toward rational combinatorial regimens. This roadmap aims to decouple protective immunity from pathological drivers, extending healthspan and redefining the paradigm of geriatric care.
Longevity Relevance Analysis
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The paper proposes a precision medicine framework targeting immunosenescence to extend healthspan. It is relevant as it addresses the underlying mechanisms of aging and seeks to develop interventions that could potentially mitigate age-related decline rather than merely treating symptoms.
Meng Ma, Juan Long, Yuting Chen ...
· Gene Regulatory Networks
· Department of Health Management & Institute of Health Management, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
· pubmed
Complex phenotypes, including aging, are influenced by a connected gene regulatory network with many interacting nodes. It has been proposed that some genes, termed "core genes," directly contribute to a trait, whereas "peripheral genes" influence the trait indirectly through net...
Complex phenotypes, including aging, are influenced by a connected gene regulatory network with many interacting nodes. It has been proposed that some genes, termed "core genes," directly contribute to a trait, whereas "peripheral genes" influence the trait indirectly through network interactions. Yet demonstrating such a layered architecture and assigning genes to layers remains challenging. Using yeast aging, we developed an approach to infer network architecture underlying complex traits. Through analysis of lifespans and gene expression profiles of yeast deletion strains, we identified master regulators (MRs) whose expression change accounts for lifespan changes across mutants. Experimental tests validated 7 out of 9 MRs predicted to extend lifespan with reduced expression, and 2 out of 2 MRs predicted to extend lifespan with increased expression. We define peripheral genes as those whose effect on lifespan can be accounted for by MRs. We explored downstream mechanisms for lifespan extension by analyzing expression profiles of lifespan-extending MR mutants. We identified a set of altered functional modules-groups of core genes that work together in biological functions, such as stress response, autophagy, proteostasis, and ribosome biogenesis. These modules were validated by single-cell studies using one MR as an example. Our study reveals a network architecture where peripheral genes link to MRs, which connect to functional modules of core genes to influence lifespan, generalizing the previously proposed peripheral/core gene architecture. Our approach may be applied to analyzing complex human traits by integrating genetic perturbation vs. phenotype and expression data, such as those from GWAS and eQTL studies.
Longevity Relevance Analysis
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The paper claims to identify master regulators and functional modules that influence lifespan in yeast through a gene regulatory network. This research is relevant as it addresses the underlying mechanisms of aging and lifespan extension, contributing to the understanding of complex traits related to longevity.
Yanzhuo Kong, Damola Adejoro, Christopher Winefield ...
· Saccharomyces cerevisiae
· College of Food and Chemical Engineering, Shaoyang University, Shaoyang, China.
· pubmed
Aging is commonly viewed as a passive consequence of accumulated damage; however, emerging evidence suggests that it may also represent an adaptive response to environmental stress. Here, we combined transcriptomic and metabolomic profiling of Saccharomyces cerevisiae to investig...
Aging is commonly viewed as a passive consequence of accumulated damage; however, emerging evidence suggests that it may also represent an adaptive response to environmental stress. Here, we combined transcriptomic and metabolomic profiling of Saccharomyces cerevisiae to investigate how short-term, long-term, and recovery phases of stress exposure shape cellular physiology and lifespan. Short-term stress-induced protective pathways and longevity-associated metabolites, including trehalose and 5'-methylthioadenosine, consistent with enhanced stress resilience and proteostasis. In contrast, prolonged stress activated heat shock proteins and epigenetic regulators, coupled with metabolic signatures associated with loss of proteostasis, reduced energy homeostasis, and shortened chronological lifespan. Upon recovery, beneficial metabolites such as S-adenosylhomocysteine were restored, highlighting the reversibility of stress-induced aging trajectories. Phylogenetic analysis demonstrated conservation of these stress- and aging-related genes across eukaryotes and prokaryotes, suggesting an evolutionary basis for aging as a long-term stress adaptation. Together, these findings suggest that aging-associated molecular changes are closely linked to conserved stress response pathways, with implications for understanding the hallmarks of aging.
Longevity Relevance Analysis
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The paper claims that aging is linked to conserved stress response pathways that can influence lifespan. This research explores the mechanisms of aging and stress adaptation, addressing fundamental aspects of longevity and potential interventions in aging processes.
Masaki Ohyagi, Minako Ito, Akihiko Yoshimura
· Inflammation and regeneration
· Division of Molecular Pathology, Research Institute for Biomedical Sciences, Tokyo University of Science, 2669 Yamazaki, Noda-City, Chiba, 278-0022, Japan. ohyanuro@gmail.com.
· pubmed
Senescence of T cells is strongly linked to organismal aging through two interconnected processes: chronic low-grade inflammation and reduced immune surveillance of senescent cells. T cells are particularly vulnerable to thymic involution, hematopoietic stem cell aging, repeated ...
Senescence of T cells is strongly linked to organismal aging through two interconnected processes: chronic low-grade inflammation and reduced immune surveillance of senescent cells. T cells are particularly vulnerable to thymic involution, hematopoietic stem cell aging, repeated homeostatic proliferation, chronic antigenic stimulation, and metabolic and mitochondrial dysfunction. As a result, aged T cells may lose their capacity to combat infection and eliminate senescent cells, while also contributing to inflammaging through the production of inflammatory cytokines. Recent preclinical studies in murine models have demonstrated that modulation of T-cell immunosenescence can ameliorate age-related diseases. These approaches include PD-1/PD-L1 blockade, senolytic chimeric antigen receptor T (CAR-T) cells, and CXCL4/platelet factor 4 (PF4). In addition, early-stage human clinical studies of caloric restriction, low-dose mTOR inhibition, thymic regeneration, and mesenchymal stromal/stem cell (MSC) therapy suggest that interventions targeting immunosenescence may provide health benefits. Moreover, in murine models of Alzheimer's disease, T cells infiltrating the brain may exert either disease-promoting or protective effects depending on the disease stage, highlighting an important point of intersection between T-cell-mediated immunosenescence and brain aging. This review summarizes the basic concepts of immunosenescence, the molecular basis of immune surveillance of senescent cells, age-associated T-cell subsets, their links to brain aging, and interventional strategies aimed at clinical translation, with particular emphasis on T-cell biology and the transcriptional regulatory network driven by NR4a.
Longevity Relevance Analysis
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The paper discusses the role of T cell senescence in aging and its potential interventions to ameliorate age-related diseases. This research is relevant as it addresses the underlying mechanisms of aging and explores strategies that could potentially extend healthspan and lifespan.