Pub Date : 2026-02-02DOI: 10.1016/j.mad.2026.112160
Ayesha Fauzi, Chloe Zi En Wong, Phoebe Yon Ern Tee, Ashlyn Wen Ning Yau, Elisha Ab Rashid, Yin Quan Tang, Adeline Yoke Yin Chia
Aging progressively alters stem cell function, undermining tissue homeostasis and contributing to age-related diseases. This review synthesises current evidence on the molecular and cellular mechanisms that drive stem cell aging, with emphasis on cellular stress responses, epigenetic regulation, telomere dynamics, metabolic control, and signalling pathway dysregulation. Accumulation of oxidative, genotoxic, and endoplasmic reticulum stress with age disrupts genomic stability and proteostasis, impairing self-renewal and regenerative capacity and, in specific contexts, promoting cellular senescence. Age-associated epigenetic alterations, including DNA methylation drift, histone modification changes, and chromatin remodelling defects, destabilise transcriptional programs required for stem cell quiescence, lineage commitment, and identity maintenance. Telomere shortening, driven by replicative history and oxidative damage, limits proliferation and induces DNA damage signalling. Senescence-associated secretory signalling affects its environments, disrupting stem cell niches and amplifying functional decline. Aging also perturbs nutrient- and energy-sensing pathways such as mTOR and AMPK, leading to impaired autophagy, mitochondrial dysfunction, and metabolic inflexibility. These signalling changes are accompanied by shifts in cellular metabolism and increased oxidative burden. Collectively, these mechanisms impair stem cell maintenance, differentiation capacity, and regenerative output. By integrating these processes, this review provides a framework for identifying regulatory targets relevant to preserving stem cell function in aging tissues.
{"title":"Mechanistic insights into stem cell aging: Pathways and processes.","authors":"Ayesha Fauzi, Chloe Zi En Wong, Phoebe Yon Ern Tee, Ashlyn Wen Ning Yau, Elisha Ab Rashid, Yin Quan Tang, Adeline Yoke Yin Chia","doi":"10.1016/j.mad.2026.112160","DOIUrl":"10.1016/j.mad.2026.112160","url":null,"abstract":"<p><p>Aging progressively alters stem cell function, undermining tissue homeostasis and contributing to age-related diseases. This review synthesises current evidence on the molecular and cellular mechanisms that drive stem cell aging, with emphasis on cellular stress responses, epigenetic regulation, telomere dynamics, metabolic control, and signalling pathway dysregulation. Accumulation of oxidative, genotoxic, and endoplasmic reticulum stress with age disrupts genomic stability and proteostasis, impairing self-renewal and regenerative capacity and, in specific contexts, promoting cellular senescence. Age-associated epigenetic alterations, including DNA methylation drift, histone modification changes, and chromatin remodelling defects, destabilise transcriptional programs required for stem cell quiescence, lineage commitment, and identity maintenance. Telomere shortening, driven by replicative history and oxidative damage, limits proliferation and induces DNA damage signalling. Senescence-associated secretory signalling affects its environments, disrupting stem cell niches and amplifying functional decline. Aging also perturbs nutrient- and energy-sensing pathways such as mTOR and AMPK, leading to impaired autophagy, mitochondrial dysfunction, and metabolic inflexibility. These signalling changes are accompanied by shifts in cellular metabolism and increased oxidative burden. Collectively, these mechanisms impair stem cell maintenance, differentiation capacity, and regenerative output. By integrating these processes, this review provides a framework for identifying regulatory targets relevant to preserving stem cell function in aging tissues.</p>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":" ","pages":"112160"},"PeriodicalIF":5.1,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1016/j.mad.2026.112158
Yingying Feng, Xiaochen Zhi, Ting Xiao, Lin Feng
Cancer-associated fibroblasts (CAFs) are a key cellular component of the tumor microenvironment (TME), which comprises distinct subtypes, each exhibiting unique and significant roles in cancer development. Senescent cancer-associated fibroblasts (senCAFs) are a newly identified subset of CAFs characterized by high expression of senescence-associated markers. Notably, senCAFs significantly promote tumor malignancy through the secretion of diverse senescence-associated secretory phenotype (SASP) factors, such as interleukin-6 (IL-6), interleukin-8 (IL-8), matrix metalloproteinases (MMPs), and transforming growth factor-β (TGF-β), thereby facilitating tumor cell proliferation, invasion, angiogenesis, immunosuppression, and resistance to cancer therapy. Consequently, targeting senCAFs—either through selective clearance of this cell subset or suppression of their SASP—represents a promising approach for cancer treatment. Emerging therapies include pharmacological inhibition of key SASP regulatory pathways (e.g., JAK/STAT3 and NF-κB) and antagonists targeting individual SASP components. Additionally, senolytic agents and therapies targeting senCAF-specific markers (e.g., TSPAN8) are being actively explored. Furthermore, immunotherapies, including CAR-T cells targeting senescence-associated surface proteins, provide intriguing avenues. These advances highlight senCAFs as attractive therapeutic targets and underscore the potential for integrating SASP inhibitors and senolytic agents into precision oncology paradigms.
{"title":"Senescent cancer-associated fibroblasts in cancer progression: From formation to therapeutic opportunities","authors":"Yingying Feng, Xiaochen Zhi, Ting Xiao, Lin Feng","doi":"10.1016/j.mad.2026.112158","DOIUrl":"10.1016/j.mad.2026.112158","url":null,"abstract":"<div><div>Cancer-associated fibroblasts (CAFs) are a key cellular component of the tumor microenvironment (TME), which comprises distinct subtypes, each exhibiting unique and significant roles in cancer development. Senescent cancer-associated fibroblasts (senCAFs) are a newly identified subset of CAFs characterized by high expression of senescence-associated markers. Notably, senCAFs significantly promote tumor malignancy through the secretion of diverse senescence-associated secretory phenotype (SASP) factors, such as interleukin-6 (IL-6), interleukin-8 (IL-8), matrix metalloproteinases (MMPs), and transforming growth factor-β (TGF-β), thereby facilitating tumor cell proliferation, invasion, angiogenesis, immunosuppression, and resistance to cancer therapy. Consequently, targeting senCAFs—either through selective clearance of this cell subset or suppression of their SASP—represents a promising approach for cancer treatment. Emerging therapies include pharmacological inhibition of key SASP regulatory pathways (e.g., JAK/STAT3 and NF-κB) and antagonists targeting individual SASP components. Additionally, senolytic agents and therapies targeting senCAF-specific markers (e.g., TSPAN8) are being actively explored. Furthermore, immunotherapies, including CAR-T cells targeting senescence-associated surface proteins, provide intriguing avenues. These advances highlight senCAFs as attractive therapeutic targets and underscore the potential for integrating SASP inhibitors and senolytic agents into precision oncology paradigms.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"230 ","pages":"Article 112158"},"PeriodicalIF":5.1,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1016/j.mad.2026.112159
Jee Hee Yoon , Yun Haeng Lee , Sekyung Oh , Kyeong Seon Lee , Ji Ho Park , Yoo Jin Lee , Byeonghyeon So , Duyeol Kim , Minseon Kim , Hyung Wook Kwon , Youngjoo Byun , Ki Yong Lee , Joon Tae Park
One of the main factors contributing to aging is reactive oxygen species (ROS), which are produced by dysfunctional mitochondria. Reducing ROS generation is considered an essential treatment for senescence, but no effective treatment has been developed yet. In this study, vitisin B, a tetramer of resveratrol, was found to be an efficient reagent that reduces mitochondrial ROS generation after screening phenylpropanoids (PPs), metabolites produced to overcome ROS-mediated stress in plants. Vitisin B induced mitochondrial functional recovery by activating mitophagy and removing dysfunctional mitochondria. Mitochondrial functional recovery by vitisin B decreased mitochondrial ROS, a by-product generated from dysfunctional mitochondria. In addition, ROS reduction by vitisin B restored senescence-associated phenotypes. RNA sequencing identified WBP2 N-Terminal Like (WBP2NL) as a gene essential for vitisin B-mediated senescence rejuvenation. Knockdown of WBP2NL exhibited effects similar to those of vitisin B, reducing mitochondrial ROS generation and consequently reversing senescence-associated phenotypes. This study elucidates a novel mechanism by which vitisin B reverses senescence by lowering mitochondrial ROS generation. This discovery opens the way to new therapeutic options to control aging by modulating mitochondrial ROS production.
{"title":"Vitisin B rejuvenates senescence via WBP2NL regulation","authors":"Jee Hee Yoon , Yun Haeng Lee , Sekyung Oh , Kyeong Seon Lee , Ji Ho Park , Yoo Jin Lee , Byeonghyeon So , Duyeol Kim , Minseon Kim , Hyung Wook Kwon , Youngjoo Byun , Ki Yong Lee , Joon Tae Park","doi":"10.1016/j.mad.2026.112159","DOIUrl":"10.1016/j.mad.2026.112159","url":null,"abstract":"<div><div>One of the main factors contributing to aging is reactive oxygen species (ROS), which are produced by dysfunctional mitochondria. Reducing ROS generation is considered an essential treatment for senescence, but no effective treatment has been developed yet. In this study, vitisin B, a tetramer of resveratrol, was found to be an efficient reagent that reduces mitochondrial ROS generation after screening phenylpropanoids (PPs), metabolites produced to overcome ROS-mediated stress in plants. Vitisin B induced mitochondrial functional recovery by activating mitophagy and removing dysfunctional mitochondria. Mitochondrial functional recovery by vitisin B decreased mitochondrial ROS, a by-product generated from dysfunctional mitochondria. In addition, ROS reduction by vitisin B restored senescence-associated phenotypes. RNA sequencing identified <em>WBP2 N-Terminal Like</em> (<em>WBP2NL</em>) as a gene essential for vitisin B-mediated senescence rejuvenation. Knockdown of <em>WBP2NL</em> exhibited effects similar to those of vitisin B, reducing mitochondrial ROS generation and consequently reversing senescence-associated phenotypes. This study elucidates a novel mechanism by which vitisin B reverses senescence by lowering mitochondrial ROS generation. This discovery opens the way to new therapeutic options to control aging by modulating mitochondrial ROS production.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"230 ","pages":"Article 112159"},"PeriodicalIF":5.1,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-17DOI: 10.1016/j.mad.2026.112157
Cheng-Yun Ma , Sheng-Rong Yeh , Yi-Hsuan Huang , Wei-Sheng Lin , Yi-Chung Lee , Ting-Fen Tsai , Shou-Zen Fan , Pei-Yu Wang
Spinocerebellar ataxia types 19 and 22 (SCA19/22) are neurodegenerative disorders caused by mutations in KCND3 (potassium voltage-gated channel subfamily D member 3). Previous studies have developed Kcnd3 F227del knock-in (KI) mice that successfully recapitulate the motor deficits and molecular pathogenesis observed in patients. However, the broader neurobehavioral consequences of the humanized Kcnd3 F227del mutation, and whether these phenotypes depend on functional Kcnd3, remain unclear. In this study, we employed a battery of behavioral assessments and found that the Kcnd3 F227del mutation may not only result in a loss of function but also act as a dominant, toxic gain-of-function variant associated with both ataxia and memory impairments. In contrast, Kcnd3 null mice exhibited primarily hyperactivity without major cognitive deficits. Furthermore, we demonstrated that dietary restriction (DR) effectively attenuates memory deficits but does not improve locomotor impairments in Kcnd3 F227del KI mice at behavioral, cellular, and neurostructural levels. Specifically, DR preserved neuronal survival, maintained dendritic architecture and spine density, and reduced neuroinflammation in the hippocampus. These findings offer new insights into the etiology of SCA19/22-related symptoms and suggest that DR may serve as a potential therapeutic strategy targeting cognitive deficits in patients carrying the KCND3 F227del mutation.
{"title":"Dietary restriction mitigates cognitive impairments in a mouse model of SCA19/22","authors":"Cheng-Yun Ma , Sheng-Rong Yeh , Yi-Hsuan Huang , Wei-Sheng Lin , Yi-Chung Lee , Ting-Fen Tsai , Shou-Zen Fan , Pei-Yu Wang","doi":"10.1016/j.mad.2026.112157","DOIUrl":"10.1016/j.mad.2026.112157","url":null,"abstract":"<div><div>Spinocerebellar ataxia types 19 and 22 (SCA19/22) are neurodegenerative disorders caused by mutations in <em>KCND3</em> (potassium voltage-gated channel subfamily D member 3). Previous studies have developed <em>Kcnd3</em> F227del knock-in (KI) mice that successfully recapitulate the motor deficits and molecular pathogenesis observed in patients. However, the broader neurobehavioral consequences of the humanized <em>Kcnd3</em> F227del mutation, and whether these phenotypes depend on functional <em>Kcnd3</em>, remain unclear. In this study, we employed a battery of behavioral assessments and found that the <em>Kcnd3</em> F227del mutation may not only result in a loss of function but also act as a dominant, toxic gain-of-function variant associated with both ataxia and memory impairments. In contrast, <em>Kcnd3</em> null mice exhibited primarily hyperactivity without major cognitive deficits. Furthermore, we demonstrated that dietary restriction (DR) effectively attenuates memory deficits but does not improve locomotor impairments in <em>Kcnd3</em> F227del KI mice at behavioral, cellular, and neurostructural levels. Specifically, DR preserved neuronal survival, maintained dendritic architecture and spine density, and reduced neuroinflammation in the hippocampus. These findings offer new insights into the etiology of SCA19/22-related symptoms and suggest that DR may serve as a potential therapeutic strategy targeting cognitive deficits in patients carrying the <em>KCND3</em> F227del mutation.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"230 ","pages":"Article 112157"},"PeriodicalIF":5.1,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1016/j.mad.2026.112156
Linghuan Wang , Yan Ma , Tianhu Wang , Weiwei Zhang , Zhiyi Fang , Tingting Lu , Yingjie Zhang , Yan Fang , Ting Sun , Dong Han , Feng Cao
Vascular smooth muscle cell senescence contributes critically to vascular remodeling and atherosclerosis, with mitochondrial dysfunction and impaired mitophagy recognized as major contributors. SRC, a stress-responsive tyrosine kinase, has been linked to aging, yet its role in vascular aging remains unclear. Here, we examined the role of SRC in regulating autophagy/mitophagy using in vitro and in vivo models. An accelerated vascular aging model was established using a high-fat diet and streptozotocin injection in ApoE-/- mice, while senescence in mouse aortic vascular smooth muscle cells (MOVASs) was induced by doxorubicin. Elevated expression of SRC and phosphorylated SRC (Tyr418) was confirmed in both models. Pharmacological inhibition of SRC with KX2–391 partially mitigated features of vascular aging, improved mitochondrial morphology, reduced plaque burden, and enhanced fibrous cap stability. In senescent MOVASs, SRC knockdown decreased FUNDC1 Tyr18 phosphorylation, enhanced mitophagic flux, and reduced senescence, whereas SRC overexpression produced opposite effects and impaired KX2–391–mediated protection. Moreover, FUNDC1 knockdown abolished the anti-senescence effects of KX2–391, confirming that FUNDC1 is essential for SRC-mediated regulation. Together, these findings establish the SRC–FUNDC1 axis as an important regulator of mitophagy and vascular aging, suggesting that SRC inhibition may offer therapeutic benefit against vascular senescence and atherosclerosis.
{"title":"SRC suppression attenuates vascular aging by activating FUNDC1-dependent mitophagy","authors":"Linghuan Wang , Yan Ma , Tianhu Wang , Weiwei Zhang , Zhiyi Fang , Tingting Lu , Yingjie Zhang , Yan Fang , Ting Sun , Dong Han , Feng Cao","doi":"10.1016/j.mad.2026.112156","DOIUrl":"10.1016/j.mad.2026.112156","url":null,"abstract":"<div><div>Vascular smooth muscle cell senescence contributes critically to vascular remodeling and atherosclerosis, with mitochondrial dysfunction and impaired mitophagy recognized as major contributors. SRC, a stress-responsive tyrosine kinase, has been linked to aging, yet its role in vascular aging remains unclear. Here, we examined the role of SRC in regulating autophagy/mitophagy using <em>in vitro</em> and <em>in vivo</em> models. An accelerated vascular aging model was established using a high-fat diet and streptozotocin injection in ApoE<sup>-/-</sup> mice, while senescence in mouse aortic vascular smooth muscle cells (MOVASs) was induced by doxorubicin. Elevated expression of SRC and phosphorylated SRC (Tyr418) was confirmed in both models. Pharmacological inhibition of SRC with KX2–391 partially mitigated features of vascular aging, improved mitochondrial morphology, reduced plaque burden, and enhanced fibrous cap stability. In senescent MOVASs, SRC knockdown decreased FUNDC1 Tyr18 phosphorylation, enhanced mitophagic flux, and reduced senescence, whereas SRC overexpression produced opposite effects and impaired KX2–391–mediated protection. Moreover, FUNDC1 knockdown abolished the anti-senescence effects of KX2–391, confirming that FUNDC1 is essential for SRC-mediated regulation. Together, these findings establish the SRC–FUNDC1 axis as an important regulator of mitophagy and vascular aging, suggesting that SRC inhibition may offer therapeutic benefit against vascular senescence and atherosclerosis.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"230 ","pages":"Article 112156"},"PeriodicalIF":5.1,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-05DOI: 10.1016/j.mad.2025.112148
Peizhi Deng , Siyu Tang , Jinron Zeng , Jianyun Lu
Frailty is linked to many chronic conditions, but its relationship with atopic dermatitis (AD) remains insufficiently defined. We assessed whether frailty predisposes to incident AD and explored inflammatory and genetic mechanisms. Baseline frailty was ascertained using both the physical frailty phenotype and a multidimensional frailty index, classifying participants as non-frail, pre-frail, or frail. Cox proportional hazards models with stratified analyses quantified associations with AD onset. To probe causality, we performed two-sample Mendelian randomization (TSMR) and generalized summary-data-based MR (GSMR). We further integrated circulating inflammatory markers and plasma proteomic data to illuminate biological pathways. Compared with non-frail participants, pre-frail and frail individuals had higher risks of incident AD after adjustment for established confounders; associations were stronger in adults < 65 years. TSMR and GSMR supported a potential causal effect of frailty on AD. Neutrophil count, eosinophil count, and C-reactive protein partially mediated the frailty-AD relationship. Proteomic analyses highlighted MMP12 as a promising AD-specific biomarker in frail individuals. Overall, frailty confers an elevated long-term risk of AD, with middle-aged adults displaying the greatest vulnerability. Several inflammatory cell measures and circulating proteins-including MMP12-may serve as early indicators of AD risk, informing earlier diagnosis and targeted monitoring in pre-frail and frail populations.
{"title":"Inflammatory and genetic mechanisms mediate the association between frailty and incident atopic dermatitis in middle-aged and elderly adults","authors":"Peizhi Deng , Siyu Tang , Jinron Zeng , Jianyun Lu","doi":"10.1016/j.mad.2025.112148","DOIUrl":"10.1016/j.mad.2025.112148","url":null,"abstract":"<div><div>Frailty is linked to many chronic conditions, but its relationship with atopic dermatitis (AD) remains insufficiently defined. We assessed whether frailty predisposes to incident AD and explored inflammatory and genetic mechanisms. Baseline frailty was ascertained using both the physical frailty phenotype and a multidimensional frailty index, classifying participants as non-frail, pre-frail, or frail. Cox proportional hazards models with stratified analyses quantified associations with AD onset. To probe causality, we performed two-sample Mendelian randomization (TSMR) and generalized summary-data-based MR (GSMR). We further integrated circulating inflammatory markers and plasma proteomic data to illuminate biological pathways. Compared with non-frail participants, pre-frail and frail individuals had higher risks of incident AD after adjustment for established confounders; associations were stronger in adults < 65 years. TSMR and GSMR supported a potential causal effect of frailty on AD. Neutrophil count, eosinophil count, and C-reactive protein partially mediated the frailty-AD relationship. Proteomic analyses highlighted MMP12 as a promising AD-specific biomarker in frail individuals. Overall, frailty confers an elevated long-term risk of AD, with middle-aged adults displaying the greatest vulnerability. Several inflammatory cell measures and circulating proteins-including MMP12-may serve as early indicators of AD risk, informing earlier diagnosis and targeted monitoring in pre-frail and frail populations.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"230 ","pages":"Article 112148"},"PeriodicalIF":5.1,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145915215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1016/j.mad.2025.112146
Zuzana Kocsisova , Brian M. Egan , Andrea Scharf , Xavier Anderson , Franziska Pohl , Aaron Anderson , Kerry Kornfeld
Aging is characterized by progressive degenerative changes in tissue organization and function, some of which increase the probability of mortality. Major goals of aging research are to elucidate the series of events that cause degenerative changes, and to identify environmental, pharmacological, and genetic factors that influence these changes; this information might lead to new strategies to extend health span and lifespan. Mechanistic studies of aging depend on accurate and precise descriptions of age-related changes, since these descriptions define the aging phenotype. Here, we review studies that describe age-related changes in C. elegans, including measurements of integrated functions such as behavior and reproduction, microscopic analyses of tissue organization, and biochemical studies of macromolecules. We discuss studies that analyze the relationships between different age-related changes. We consider the results in light of mechanistic and evolutionary theories of aging. Together, these studies provide fundamental insights into aging in C. elegans that may be relevant to aging in other animals.
{"title":"How to measure, analyze, and interpret age-related changes in Caenorhabditis elegans: Lessons for mechanistic and evolutionary theories of aging","authors":"Zuzana Kocsisova , Brian M. Egan , Andrea Scharf , Xavier Anderson , Franziska Pohl , Aaron Anderson , Kerry Kornfeld","doi":"10.1016/j.mad.2025.112146","DOIUrl":"10.1016/j.mad.2025.112146","url":null,"abstract":"<div><div>Aging is characterized by progressive degenerative changes in tissue organization and function, some of which increase the probability of mortality. Major goals of aging research are to elucidate the series of events that cause degenerative changes, and to identify environmental, pharmacological, and genetic factors that influence these changes; this information might lead to new strategies to extend health span and lifespan. Mechanistic studies of aging depend on accurate and precise descriptions of age-related changes, since these descriptions define the aging phenotype. Here, we review studies that describe age-related changes in <em>C. elegans,</em> including measurements of integrated functions such as behavior and reproduction, microscopic analyses of tissue organization, and biochemical studies of macromolecules. We discuss studies that analyze the relationships between different age-related changes. We consider the results in light of mechanistic and evolutionary theories of aging. Together, these studies provide fundamental insights into aging in <em>C. elegans</em> that may be relevant to aging in other animals.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"229 ","pages":"Article 112146"},"PeriodicalIF":5.1,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1016/j.mad.2025.112147
Yuhang Gong , Jie Xiang , Ben Wang , Leyi Hu , Shengzan Shao , Yangyang Wu , Ze Li , Chao Jiang , Jianxin Qiu , Liwei Ying , Zhenghua Hong , Haixiao Chen , Zhangfu Wang
Intervertebral disc degeneration (IDD) is an aging-associated disorder driven by chronic inflammation. Impaired autophagy is a hallmark of disc aging, but its upstream regulation remains unclear. Here, we identify Apelin-13 (APL13) as an endogenous peptide that restores autophagic competence in degenerative nucleus pulposus (NP) cells. APL13 alleviated IL-1β-induced senescence and pyroptosis. It also restored autophagic flux by promoting TFEB activation and nuclear translocation. Mechanistically, APL13 activated AMPK signaling pathways. It enhanced TFEB-dependent lysosomal and autophagy programs through both the AMPK-mTOR axis and the AMPK-FOXO3a-SKP2-CARM1 axis. In a lumbar spine instability mouse model, APL13 preserved disc structure, maintained ECM integrity, and reduced senescence-pyroptosis signaling in vivo. These findings position APL13 as a regulator of disc inflammaging. And the AMPK-TFEB axis emerges as a key pathway linking autophagy restoration to NP cell during IDD progression.
{"title":"Apelin-13 activates TFEB-mediated autophagy via AMPK to attenuate senescence and pyroptosis in nucleus pulposus cells during intervertebral disc degeneration","authors":"Yuhang Gong , Jie Xiang , Ben Wang , Leyi Hu , Shengzan Shao , Yangyang Wu , Ze Li , Chao Jiang , Jianxin Qiu , Liwei Ying , Zhenghua Hong , Haixiao Chen , Zhangfu Wang","doi":"10.1016/j.mad.2025.112147","DOIUrl":"10.1016/j.mad.2025.112147","url":null,"abstract":"<div><div>Intervertebral disc degeneration (IDD) is an aging-associated disorder driven by chronic inflammation. Impaired autophagy is a hallmark of disc aging, but its upstream regulation remains unclear. Here, we identify Apelin-13 (APL13) as an endogenous peptide that restores autophagic competence in degenerative nucleus pulposus (NP) cells. APL13 alleviated IL-1β-induced senescence and pyroptosis. It also restored autophagic flux by promoting TFEB activation and nuclear translocation. Mechanistically, APL13 activated AMPK signaling pathways. It enhanced TFEB-dependent lysosomal and autophagy programs through both the AMPK-mTOR axis and the AMPK-FOXO3a-SKP2-CARM1 axis. In a lumbar spine instability mouse model, APL13 preserved disc structure, maintained ECM integrity, and reduced senescence-pyroptosis signaling in vivo. These findings position APL13 as a regulator of disc inflammaging. And the AMPK-TFEB axis emerges as a key pathway linking autophagy restoration to NP cell during IDD progression.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"229 ","pages":"Article 112147"},"PeriodicalIF":5.1,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1016/j.mad.2025.112145
Mathew Shuen , Regis R. Lamberts , Sean Coffey , Philip W. Sheard
Ageing populations present substantial healthcare challenges, with cardiovascular disease (CVD) remaining the predominant cause of morbidity and mortality globally. Cardiac ageing is characterised by progressive cellular and molecular changes, contributing to structural and functional decline and predisposition to CVD. Component proteins (nucleoporins) of the Nuclear Pore Complex (NPC) and the nuclear lamina are both crucial for nuclear integrity and chromatin organisation, and have appeared as key players in cellular homeostasis of post-mitotic cells. Age-related changes in NPC composition and turnover, particularly in non-dividing cells, compromise nucleocytoplasmic compartmentalisation and drive genomic instability, cell death, and senescence. Emerging evidence implicates aberrant NPC components in the core hallmarks of cardiac ageing and in distinct heart diseases. Additionally, the nuclear lamina’s susceptibility to damage and its interactions with NPCs might exacerbate these effects. This review presents evidence linking NPC and nuclear lamina dysfunction to features of the ageing heart and suggests that age-related NPC alterations are potential drivers of cardiomyocyte and cardiac decline with age
{"title":"A role for long-lived nuclear envelope proteins in cardiac ageing","authors":"Mathew Shuen , Regis R. Lamberts , Sean Coffey , Philip W. Sheard","doi":"10.1016/j.mad.2025.112145","DOIUrl":"10.1016/j.mad.2025.112145","url":null,"abstract":"<div><div>Ageing populations present substantial healthcare challenges, with cardiovascular disease (CVD) remaining the predominant cause of morbidity and mortality globally. Cardiac ageing is characterised by progressive cellular and molecular changes, contributing to structural and functional decline and predisposition to CVD. Component proteins (nucleoporins) of the Nuclear Pore Complex (NPC) and the nuclear lamina are both crucial for nuclear integrity and chromatin organisation, and have appeared as key players in cellular homeostasis of post-mitotic cells. Age-related changes in NPC composition and turnover, particularly in non-dividing cells, compromise nucleocytoplasmic compartmentalisation and drive genomic instability, cell death, and senescence. Emerging evidence implicates aberrant NPC components in the core hallmarks of cardiac ageing and in distinct heart diseases. Additionally, the nuclear lamina’s susceptibility to damage and its interactions with NPCs might exacerbate these effects. This review presents evidence linking NPC and nuclear lamina dysfunction to features of the ageing heart and suggests that age-related NPC alterations are potential drivers of cardiomyocyte and cardiac decline with age</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"229 ","pages":"Article 112145"},"PeriodicalIF":5.1,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-16DOI: 10.1016/j.mad.2025.112144
Qiliang Yin , Yan Zhang , Xingcheng Yi , Jian Li , Yun Dai , Fengyan Jin , On behalf of the Committee of Experts on Hematology, China Society of Geriatrics, China Association of Gerontology and Geriatrics
It is generally believed that hematopoietic aging is a major driver or contributor of human aging. The hematopoietic system undergoes physiological or pathological changes with aging, which drive or contribute to the aging of almost all systems and organs in the body, leading to various age-related diseases, particularly malignant and non-malignant hematologic disorders. Although the term blood aging has been mentioned in a number of publications and is widely used in everyday life, its definition and research scope remain unclear to date. With the rapid advances in the aging research field involving overall, systemic/organ, cellular, and molecular aging, various aspects relevant to blood aging have permeated almost all areas of aging research, including hematopoietic stem/progenitor cell (HSC/HPC) aging, immunosenescence, inflammaging, etc. However, sharply contrasting with aging of other systems and organs, blood aging has not yet formed its own research field. This review article discusses the definition, scope, and mechanisms of blood aging and provides a comprehensive overview on this emerging area, encompassing physiological and pathological blood aging. Overall, this review aims to advance understanding of blood aging, clarify its definition and scope, and highlight underlying mechanisms, thereby providing a foundation for future research and strategies to promote healthy aging.
{"title":"Blood aging: From definition and mechanisms to clinical practice","authors":"Qiliang Yin , Yan Zhang , Xingcheng Yi , Jian Li , Yun Dai , Fengyan Jin , On behalf of the Committee of Experts on Hematology, China Society of Geriatrics, China Association of Gerontology and Geriatrics","doi":"10.1016/j.mad.2025.112144","DOIUrl":"10.1016/j.mad.2025.112144","url":null,"abstract":"<div><div>It is generally believed that hematopoietic aging is a major driver or contributor of human aging. The hematopoietic system undergoes physiological or pathological changes with aging, which drive or contribute to the aging of almost all systems and organs in the body, leading to various age-related diseases, particularly malignant and non-malignant hematologic disorders. Although the term <em>blood aging</em> has been mentioned in a number of publications and is widely used in everyday life, its definition and research scope remain unclear to date. With the rapid advances in the aging research field involving overall, systemic/organ, cellular, and molecular aging, various aspects relevant to blood aging have permeated almost all areas of aging research, including hematopoietic stem/progenitor cell (HSC/HPC) aging, immunosenescence, inflammaging, etc. However, sharply contrasting with aging of other systems and organs, blood aging has not yet formed its own research field. This review article discusses the definition, scope, and mechanisms of blood aging and provides a comprehensive overview on this emerging area, encompassing physiological and pathological blood aging. Overall, this review aims to advance understanding of blood aging, clarify its definition and scope, and highlight underlying mechanisms, thereby providing a foundation for future research and strategies to promote healthy aging.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"229 ","pages":"Article 112144"},"PeriodicalIF":5.1,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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