Aging Cell最新文献

{"title":"The Senokine Gas6 Promotes Aortic Valve Calcification Through CaMKII–DRP1–Mediated Terminal Scission of Mitochondrial-Derived Vesicles","authors":"Yaoyu Zhang,&nbsp;Jialiang Zhang,&nbsp;Yanjiani Xu,&nbsp;Wenhua Lei,&nbsp;Fei Xu,&nbsp;Junli Li,&nbsp;Zisong Wei,&nbsp;Bo Su,&nbsp;Shuang Liu,&nbsp;Jing Zhou,&nbsp;Hongde Li,&nbsp;Junpeng Ran,&nbsp;Weiya Li,&nbsp;Tuerhongjiang Tuerdi,&nbsp;Xiaojiao Wang,&nbsp;Zhi Fang,&nbsp;Fangyang Huang,&nbsp;Mao Chen","doi":"10.1111/acel.70758","DOIUrl":"https://doi.org/10.1111/acel.70758","url":null,"abstract":"<p>Calcific aortic valve disease (CAVD) is an age-associated valvular disorder in which calcification expands from discrete foci into adjacent tissue. We investigated whether mitochondrial-derived vesicles (MDVs) released by human valvular interstitial cells (hVICs) exert pro-calcific effects on recipient cells and how MDV release is regulated. Using ex vivo hemodynamic perfusion of human CAVD tissue, multi-omics profiling, live-cell single-organelle tracking, MDV transfer assays, and in vivo Gas6 deletion, we found that calcifying hVICs hypersecreted MDVs that exerted pro-calcific effects in recipient hVICs. High-resolution imaging showed that mitochondria remodeled into donut-shaped structures under pro-osteogenic conditions; these structures served as physical platforms for MDV budding. Human CAVD valve tissues and hVICs treated with pro-osteogenic medium also exhibited senescence-associated features. Multi-omics profiling identified growth arrest-specific 6 (Gas6), a senokine, among 36 concordantly upregulated candidates. Functional analyzes showed that Gas6 promoted terminal MDV scission while leaving donut-shaped mitochondrial precursor formation intact. Mechanistically, Gas6 promoted intracellular Ca²⁺ accumulation, calcium/calmodulin-dependent protein kinase II (CaMKII) activation, and dynamin-related protein 1 (DRP1) phosphorylation at Ser616, supporting a Ca²⁺–CaMKII–DRP1 axis that facilitates terminal MDV scission. Pharmacological inhibition of CaMKII or DRP1 reduced MDV hypersecretion and subsequent recipient-cell calcification, and Gas6 deletion in vivo attenuated valvular stenosis, calcification, and fibrotic remodeling. These findings identify Gas6-dependent terminal MDV scission as a mechanism contributing to the intercellular propagation of valvular calcification in a CAVD context characterized by senescence-associated features.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 11","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70758","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149222808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Featured Cover","authors":"Tatiana M. Moreno,&nbsp;Stephanie R. Heimler,&nbsp;Ryan J. Moran,&nbsp;Hava Shoshana Barkai,&nbsp;Lina Scandalis,&nbsp;Larissa Traxler,&nbsp;Ashley Neil,&nbsp;Stephen Dozier,&nbsp;Jaclyn Bergstrom,&nbsp;Alexandre R. Colas,&nbsp;Sanjeev S. Ranade,&nbsp;Anne G. Bang,&nbsp;Jerome Mertens,&nbsp;David Wing,&nbsp;Anthony J. Molina,&nbsp;Caroline Kumsta","doi":"10.1111/acel.70764","DOIUrl":"https://doi.org/10.1111/acel.70764","url":null,"abstract":"<p>Cover legend: The cover image is based on the article <i>Autophagy Flux Is Remodeled Sex- and Cell Type-Specifically During Human Aging, and Is Linked to Reduced Physical Function in Older Adults</i> by Tatiana M. Moreno <i>et al.,</i> https://doi.org/10.1111/acel.70734.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 10","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70764","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149146395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aging Disrupts Tissue Homeostasis and Constrains Blastema-Mediated Regeneration in the Cladonema Medusa","authors":"Ren Kanehisa,&nbsp;Hiroko Nakatani,&nbsp;Sho Takatori,&nbsp;Taisuke Tomita,&nbsp;Masayuki Miura,&nbsp;Yu-ichiro Nakajima","doi":"10.1111/acel.70727","DOIUrl":"10.1111/acel.70727","url":null,"abstract":"<p>Regenerative capacity varies widely across animals, yet aging is often accompanied by declining tissue homeostasis and regenerative potential. In many species, regeneration of complex structures relies on epimorphic programs that form a blastema, coordinating cell proliferation and pattern reorganization after injury. Although aging-associated regeneration defects have been documented in several bilaterian models, how aging shapes regeneration in early-branching metazoans with robust regenerative abilities remains unclear. Here, we investigate aging and regeneration in the medusa stage of <i>Cladonema pacificum</i>, a cnidarian that retains high regenerative capacity within a finite lifespan. We show that aging in <i>Cladonema</i> medusae is accompanied by progressive morphological and functional deterioration, including shrinkage of the umbrella and manubrium, tentacle shortening, and reduced reproductive output, along with increased DNA damage. At the cellular level, aging is associated with depletion of differentiated cell populations, including nematocytes and neurons, as well as reductions in stem cell-associated populations and proliferative activity in the tentacle bulb. Consistent with these changes, tentacle regeneration is markedly impaired in aged medusae and is characterized by delayed wound closure, defective blastema formation and incomplete functional recovery. Together, our findings indicate that aging disrupts both tissue homeostasis and blastema-mediated regeneration in <i>Cladonema</i> medusae, establishing a tractable model for studying aging–regeneration interactions and supporting the view that aging imposes broadly shared constraints on regenerative systems across metazoans.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 10","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Regenerative to Degenerative Niche: Multicellular Crosstalk and Population Dynamics in Skeletal Muscle Aging","authors":"Seongwan Kim,&nbsp;Min Ju Kim,&nbsp;Yong Ryoul Yang","doi":"10.1111/acel.70733","DOIUrl":"10.1111/acel.70733","url":null,"abstract":"<p>Skeletal muscle aging is increasingly recognized as a failure of tissue-level coordination rather than a consequence of isolated defects in individual cell types. Recent advances in single-cell, spatial, and multimodal omics have revealed that aging remodels the abundance, functional states, and interactions of muscle-resident populations, shifting the tissue from a regenerative niche toward a degenerative niche. In this Review, we summarize current evidence supporting this conceptual transition by focusing on multicellular crosstalk and population dynamics within the aging muscle microenvironment. We discuss how age-dependent remodeling of muscle stem cells, fibro-adipogenic progenitors, immune cells, vascular cells, and neuromuscular components collectively disrupts the temporal coordination required for effective regeneration. Rather than acting independently, these populations become locked in maladaptive signaling circuits that promote persistent inflammation, fibrosis, senescence, impaired vascular support, and neuromuscular dysfunction, ultimately compromising tissue repair and muscle function. We further distinguish ligand-receptor interactions inferred from single-cell atlases from signaling pathways that have been functionally validated in vivo, highlighting the importance of establishing causal mechanisms underlying intercellular communication. Finally, we discuss emerging therapeutic strategies aimed at restoring multicellular coordination—including modulation of stromal, immune, vascular, and neuromuscular interactions—rather than targeting single cell populations in isolation. We propose that rebuilding regenerative communication networks, instead of simply eliminating dysfunctional cells, represents a promising framework for developing interventions against sarcopenia and age-related muscle decline.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 10","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ghrelin Alleviates Aging-Related Cognitive Impairment by Regulating Autophagy-Related Signaling via the SHBG/JNK1/Beclin1 Axis in Microglia","authors":"Lixing Zhou,&nbsp;Ying Cheng,&nbsp;Wanyu Zhao,&nbsp;Xuelian Sun,&nbsp;Fengjuan Hu,&nbsp;Meiling Ge,&nbsp;Yan Zhang,&nbsp;Gongchang Zhang,&nbsp;Birong Dong,&nbsp;Xiaolei Liu","doi":"10.1111/acel.70732","DOIUrl":"10.1111/acel.70732","url":null,"abstract":"<p>Cognitive impairment (CI) associated with aging and immunosenescence is linked to metabolic alterations. Microglial senescence and dysregulated autophagy have been implicated as major contributors to this process, but the underlying metabolic regulators remain unclear. This study aimed to identify key metabolic regulators of CI and elucidate their underlying mechanisms. Human cohort analyses, older and D-galactose (D-gal)-induced mouse models, and microglial cell models were integrated to investigate the metabolic regulation of CI. Clinical analyses identified ghrelin as the factor most strongly associated with CI. Older and D-gal mice exhibited CI, microglial senescence, enhanced inflammation, and elevated ghrelin. Ghrelin treatment improved cognitive function, attenuated microglial senescence, and suppressed inflammation, whereas high-dose ghrelin induced growth hormone secretagogue receptor (GHSR) desensitization. Sex hormone-binding globulin (SHBG) showed mainly cytoplasmic localization, was identified as a potential mediator of ghrelin signaling in microglia, and its expression was downregulated following ghrelin treatment. Transcriptomic profiling revealed significant enrichment of autophagy-related pathways in ghrelin-treated microglia. Ghrelin altered autophagy-related markers, as indicated by increased Beclin1 and LC3 and decreased p62. SHBG overexpression or JNK1 inhibition attenuated the ghrelin-induced alterations in autophagy-related markers and anti-senescent effects, whereas Beclin1 overexpression partially rescued these inhibitory effects caused by SHBG overexpression. In conclusion, ghrelin alleviated aging-related CI, with mechanistic evidence indicating that the modulation of microglial autophagy-related mechanisms through the SHBG/JNK1/Beclin1 axis may contribute to its protective effects, thereby providing a potential therapeutic strategy for aging-related CI.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 10","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dietary CoQ10 Ameliorates Age-Related Megakaryocyte Dysfunction via COPS3-Mediated Activation of Autophagy","authors":"Yixuan Xu,&nbsp;Yu-heng Mao,&nbsp;Fenglin Song,&nbsp;Fang He,&nbsp;Yueying Wu,&nbsp;CaiXia Wang,&nbsp;Minghan Wang,&nbsp;Shuangfeng Xie,&nbsp;Heyu Ni,&nbsp;Yan Yang","doi":"10.1111/acel.70726","DOIUrl":"10.1111/acel.70726","url":null,"abstract":"<p>Age-related megakaryocyte (MK) dysfunction disrupts platelet production and may increase thrombotic risk, but whether coenzyme Q10 (CoQ10) restores MK homeostasis through autophagy remains unclear. Male C57BL/6J mice aged 1, 9, 15, 19, 21, or 23 months received CoQ10 for 12 weeks. Bone marrow MK proliferation, CD41/CD61 expression, DNA polyploidy, autophagy-associated proteins, and platelet phenotypes were evaluated. H₂O₂-induced senescent MEG-01 cells were used for pharmacological modulation with rapamycin and LY294002, bafilomycin A1-based autophagic flux assays, and COPS3 knockdown. CoQ10 enhanced MK proliferation, maturation, and polyploidization in aged mice. Changes in the LC3-II/LC3-I ratio and p62 in bone marrow MKs were consistent with enhanced autophagy. Proteomic analysis identified increased COPS3 abundance in MKs from CoQ10-treated 24-month-old mice. In senescent MEG-01 cells, responses to rapamycin and LY294002 supported the involvement of autophagy-related signaling in the effects of CoQ10. CoQ10 increased COPS3 expression even under autophagy-inhibitory conditions and produced greater bafilomycin A1-sensitive LC3-II accumulation, supporting increased autophagic flux. COPS3 knockdown attenuated CoQ10-induced changes in autophagy-associated markers and partially diminished its effects on MK maturation and polyploidization, indicating that COPS3 contributes to, but may not solely mediate, these responses. CoQ10 did not alter platelet counts in naturally aged mice but was associated with reduced platelet aggregation and activation. Together, these findings suggest that CoQ10 ameliorates age-related MK dysfunction and platelet hyperreactivity, in part through COPS3-associated autophagy regulation. These findings provide a mechanistic basis for further investigation of CoQ10 as a nutritional strategy for age-related platelet dysfunction.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 10","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"α-Synuclein Promotes Atherosclerosis by Impairing Macrophage Autophagic Flux","authors":"Mengting Qin,&nbsp;Xuying Xiang,&nbsp;Xiaoqing Guo,&nbsp;Shengnan Wang,&nbsp;Jiaojiao Chen,&nbsp;Dailiang Jiang,&nbsp;Yuhang Feng,&nbsp;Jiangnan Yu,&nbsp;Ling Mao","doi":"10.1111/acel.70713","DOIUrl":"10.1111/acel.70713","url":null,"abstract":"<p>Atherosclerosis, recognized as a prototypical age-associated vascular disease, is driven by macrophage foam cell formation. Individuals with Parkinson's disease (PD) exhibit an elevated risk for stroke. While α-synuclein (α-Syn) is known for its neuronal role in PD, its presence in the circulation and potential vascular effects remain unexplored. Here, we identify α-Syn as a previously unrecognized circulating factor that promotes atherosclerosis. α-Syn was detected in human atherosclerotic plaques. Genetic deletion of α-Syn reduced atherosclerotic lesion size and macrophage lipid accumulation in a mouse model of atherosclerosis induced by overexpression of proprotein convertase subtilisin/kexin type 9 (PCSK9). On the contrary, administration of exogenous α-Syn accelerated atherosclerosis in Apolipoprotein E knockout (<i>Apoe</i>^−/−) mice. Mechanistically, α-Syn promoted macrophage foam cell formation by impairing autophagic flux, accompanied by activation of PI3K-mTOR signaling. Proteomic analysis identified the membrane raft protein flotillin-1 (FLOT1) as a candidate upstream mediator. <i>Flot1</i> knockdown reduced α-Syn internalization, PI3K phosphorylation, autophagy impairment, and lipid accumulation, while pharmacological inhibition of PI3K or mTOR attenuated the effects of α-Syn. Together, these findings identify a FLOT1-associated pathway through which extracellular α-Syn disrupts macrophage autophagy and promotes atherosclerosis.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 10","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13620287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"uPAR-Targeting T Cell Engager Exerts Senolytic Effects in Mice and Non-Human Primates With Serum Aminotransferase Activity as a Safety Monitor","authors":"Jian Deng,&nbsp;Xiaozhu Zeng,&nbsp;Jing Guo,&nbsp;Lihong Li,&nbsp;Shirui Zou,&nbsp;Nan Liu,&nbsp;Shuai He,&nbsp;Lanzhen Yan,&nbsp;Qiong Wang,&nbsp;Yongjie Zhu,&nbsp;Ben Wang,&nbsp;Dong Yang,&nbsp;Longbao Lv,&nbsp;Xudong Zhao","doi":"10.1111/acel.70742","DOIUrl":"10.1111/acel.70742","url":null,"abstract":"<p>Senolytic CAR-T cells targeting uPAR induce dose-dependent toxicities. Although dosage adjustment mitigates these toxicities in laboratory mice, clinical translation remains challenging owing to the unpredictability of CAR-T cell proliferation across heterogeneous patient populations. In contrast, bispecific T-cell engagers (BiTEs) offer a safer alternative with superior dose-titratability. Here, we have developed a GFD-CD3 BiTE by employing the growth factor-like domain (GFD) of the natural ligand uPA as the targeting moiety to target uPAR-positive senescent cells. Dose-range finding studies revealed that high-dose GFD-CD3 predominantly induced hepatotoxicity through T cell–mediated attack on hepatic endothelial cells. Crucially, under transaminase-guided monitoring, low-dose GFD-CD3 effectively eliminated senescent cells and alleviated age-related pathologies in aged mice and non-human primates without adverse effects. These findings establish GFD-CD3 as a clinically translatable senolytic agent and provide the compelling preclinical evidence for BiTE as a senolytic strategy.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 10","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13620297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep Learning Predicts Hematopoietic Stem Cell Aging From 3D Chromatin Images","authors":"Pablo Iáñez Picazo,&nbsp;Eva Mejía-Ramírez,&nbsp;Dario Di Bari,&nbsp;Elena Vitali,&nbsp;Maria Carolina Florian,&nbsp;Paula Petrone","doi":"10.1111/acel.70656","DOIUrl":"10.1111/acel.70656","url":null,"abstract":"<p>The functional decline of the hematopoietic system during aging affects organismal function and contributes to reduced healthspan. Quantifying hematopoietic aging holds great scientific and clinical relevance. Alterations in chromatin architecture are a well-established hallmark of aging that encode rich and informative signatures of the aging process, yet they remain largely unexplored as quantitative markers. Here, we present an interpretable deep learning approach based on convolutional neural networks, ChromAgeNet, that learns changes in the spatial features of chromatin architecture upon aging of hematopoietic stem cells (HSCs). We trained our algorithm on 3D microscope images of DAPI-stained HSC nuclei to discriminate between young and aged murine HSCs, achieving an AUROC of 0.77 ± 0.03. This approach outperforms classical machine learning models trained on handcrafted chromatin features from the same dataset. We then applied explainable artificial intelligence techniques, identifying chromatin entropy, peripheral heterochromatin, and chromatin condensates as predictive markers. As a proof of concept, we evaluated the potential of our model as a phenotypic screening tool for aged HSCs treated with epigenetic drugs to detect rejuvenation. Altogether, we demonstrate that changes in chromatin organization can be modeled via machine learning to predict age-associated chromatin states in the hematopoietic compartment. Our developed framework, ChromAgeNet, serves as an interpretable algorithm to unravel the intricate relationship between chromatin changes and stem cell aging, and advance high-throughput drug screening for rejuvenation therapies.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 10","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149068871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autophagy Flux Is Remodeled Sex- and Cell Type-Specifically During Human Aging, and Is Linked to Reduced Physical Function in Older Adults","authors":"Tatiana M. Moreno,&nbsp;Stephanie R. Heimler,&nbsp;Ryan J. Moran,&nbsp;Hava Shoshana Barkai,&nbsp;Lina Scandalis,&nbsp;Larissa Traxler,&nbsp;Ashley Neil,&nbsp;Stephen Dozier,&nbsp;Jaclyn Bergstrom,&nbsp;Alexandre R. Colas,&nbsp;Sanjeev S. Ranade,&nbsp;Anne G. Bang,&nbsp;Jerome Mertens,&nbsp;David Wing,&nbsp;Anthony J. Molina,&nbsp;Caroline Kumsta","doi":"10.1111/acel.70734","DOIUrl":"10.1111/acel.70734","url":null,"abstract":"<p>Autophagy is widely proposed to decline with age; however, direct evidence across human cell types remains limited. Moreover, it is unclear whether age-associated changes in autophagy-gene transcription are accompanied by corresponding changes in autophagic activity, and whether autophagic activity relates to physiological function during aging. We performed transcriptomic and functional autophagy analyses across subject-matched human cell types from a healthy aging cohort. Autophagy-related gene expression increased with age in primary dermal fibroblasts and, to a lesser extent, in induced neurons (iNs). However, autophagy flux was cell type- and sex-specific and uncoupled from transcriptional remodeling. Autophagy flux decreased in male fibroblasts, remained stable in female fibroblasts, and increased in female iNs with age. In freshly isolated peripheral blood mononuclear cells (PBMCs), autophagy flux became increasingly heterogeneous with age and trended higher in older individuals, independent of sex. Associations between autophagy flux and physiological function varied across the adult lifespan; however, in adults aged &gt; 70 years, higher autophagy flux was associated with reduced physical function. In a pilot intervention study, PBMC autophagy flux decreased following 12 weeks of mild exercise in parallel with improved physical function, suggesting that autophagic activity in PBMCs is responsive to physiological intervention in late life. Together, these findings show that autophagy is remodeled in a cell type-, sex- and physiological function-dependent manner during aging, challenge the view that autophagy uniformly declines with age, and suggest that elevated autophagy flux in older adults may reflect compensatory responses to age-associated stress rather than enhanced autophagic capacity.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 10","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149068741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}