Aging Cell最新文献

{"title":"Synaptic Mitochondrial Oxidative Stress Contributes to Individual Variability in Age-Related Cognitive Inflexibility in Mice.","authors":"Rui Yamada, Hirotaka Nagai, Chisato Numa, Yunhui Zhu, Midori Nagai, Kohei Ota, Yusuke Kawashima, Nobuhiko Ohno, Tomoyuki Furuyashiki","doi":"10.1111/acel.70716","DOIUrl":"10.1111/acel.70716","url":null,"abstract":"<p><p>Aging is associated with impairments in cognitive flexibility, a key executive function supported by the medial prefrontal cortex (mPFC), yet the biological mechanisms underlying individual variability in age-related decline remain poorly understood. Here we investigated behavioral, ultrastructural, and proteomic correlates of cognitive inflexibility in mice across aging. Using a touchscreen-based attentional set-shifting task, we observed substantial individual variability in cognitive inflexibility among aged C57BL/6J mice. Volume electron microscopy of the mPFC revealed age-related reductions in synaptic density, but these structural changes did not correlate with cognitive performance. Instead, the proportion of synapses containing presynaptic mitochondria was inversely associated with cognitive flexibility in aged mice. To identify molecular correlates, we performed proteomic profiling of mPFC whole tissue and synaptosome fractions. Proteins associated with individual variability in cognitive inflexibility were largely distinct from those associated with chronological aging. Notably, synaptosomal proteins negatively correlated with cognitive performance were strongly enriched for mitochondrial pathways, including oxidative phosphorylation, mitochondrial translation, and the tricarboxylic acid cycle. Consistent with these findings, the mitochondria-targeted antioxidant MitoQ improved attentional set-shifting performance in aged mice without affecting initial learning. Proteomic analyses revealed that MitoQ reduced the abundance of synaptosomal mitochondrial proteins, particularly those involved in mitochondrial apoptotic signaling. Together, these results suggest that synaptic mitochondrial oxidative stress in the mPFC contributes to individual vulnerability to cognitive inflexibility. Targeting synaptic mitochondrial oxidative stress may therefore represent a promising strategy to preserve executive function during aging.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70716"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13572969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148962680","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":"Growth Hormone Receptor Antagonism Extends Lifespan.","authors":"Edward O List, Darlene E Berryman, Grace S Lach, Delaney F Minto, Keeley Weese, John J Kopchick","doi":"10.1111/acel.70697","DOIUrl":"10.1111/acel.70697","url":null,"abstract":"<p><p>Interventions that disrupt growth hormone (GH) action are recognized as some of the most potent methods for extending lifespan. Accordingly, GH receptor antagonists (GHA) represent potential therapeutics to improve healthspan. Somavert (Pegvisomant for injection), used for treating patients with acromegaly, is currently the only FDA approved GHA. This drug was based on our laboratory's early 1990s discovery that mutating a codon for a conserved glycine-at position 119 in bovine GH or 120 in human GH-to a variety of amino acids, including lysine, ultimately converted GH from an agonist to antagonist. Since Pegvisomant has poor affinity to rodent GHR, it has not been tested for its ability to extend lifespan in rodents. To address this gap, we evaluated survival in GHA transgenic mice, a mouse line that played a crucial role in the discovery and development of Pegvisomant and has been maintained in our lab since 1991. While a prior study with several limitations failed to detect lifespan extension in GHA mice, our current study addressing these limitations shows that both median and maximal lifespan were significantly increased in male (p = 0.044; p = 0.0037) and female GHA mice (p = 2 × 10^-8; p = 9 × 10^-6), with maximal lifespan extended by 186 and 265 days, respectively. Analysis of an independent cohort of 2-year-old mice revealed that GHA males and females were less frail with enhanced grip strength despite increased adiposity. These findings demonstrate for the first time that GH antagonism can improve health and extend lifespan.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70697"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13546677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148899974","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":"Higher Frontal Cortex Angiotensin Type 2 Receptor-Interacting Protein (ATIP) Levels Are Associated With a Lower Amyloid-Beta Burden in Postmortem Brains of Older Adults With Alzheimer's Disease.","authors":"Caglar Cosarderelioglu, Simion Kreimer, Alma I Plaza-Rodriguez, Pablo A Iglesias, C Conover Talbot, Helmy M Siragy, Ceereena Ubaida-Mohien, Francine Grodstein, Luigi Ferrucci, David A Bennett, Jeremy Walston, Peter Abadir","doi":"10.1111/acel.70686","DOIUrl":"10.1111/acel.70686","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by amyloid-β (Aβ) and tau accumulation. Dysregulation of the brain renin-angiotensin system, particularly hyperactivation of the angiotensin II type-1 receptor, contributes to AD pathogenesis. In contrast, activation of the angiotensin II type-2 receptor (AT₂R) has been linked to neuroprotection and reduced Aβ accumulation. However, the underlying mechanisms of AT₂R-related Aβ reduction and the role of AT₂R-interacting protein (ATIP), also known as AT₂R-binding protein, remain unclear. We aimed to explore the relationship between ATIP and Aβ and tau pathologies as well as brain AT₂R protein levels in older adults with AD. Using TOMAHAQ, a method that enables precise examination of numerous peptides across various samples in a single mass spectrometry analysis, we identified a specific human tryptic peptide that enables ATIP quantification. We applied this method to postmortem frontal-cortex samples to measure ATIP levels. Sixty individuals with AD were included, half of whom were users of angiotensin receptor blockers (ARBs). The ATIP peptide was quantifiable in 12 participants. Among these individuals, higher ATIP levels were associated with lower Aβ burden in the frontal-cortex and across multiple brain regions. This association remained significant after adjustment for age and ARB use. In contrast, ATIP levels were not significantly associated with AT₂R, which was quantified using TOMAHAQ. This suggests that the relationship between ATIP and Aβ burden may not depend on differences in AT₂R abundance. Although causality cannot be established, these findings may suggest a potential protective role for ATIP in AD that warrants further investigation.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70686"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13526323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148856792","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":"Clonal Mosaicism of Mitochondrial DNA Heteroplasmy as a Molecular Clock of Aging.","authors":"Renin Chang, Andy P Tsai, Boyang Wang, Kuan-Hao Tsui, Cheng-Yoong Pang, Chia-Jung Li","doi":"10.1111/acel.70718","DOIUrl":"10.1111/acel.70718","url":null,"abstract":"<p><p>The accumulation of somatic mitochondrial DNA (mtDNA) mutations across life is among the oldest and most debated proposed drivers of aging. A defining, counter-intuitive feature is that individual mutant molecules, although vanishingly rare when they arise, can come to dominate a cell's multi-copy mtDNA population through intracellular clonal expansion, producing a mosaic of respiratory-deficient cells across aging tissues. Here we synthesize current evidence to argue that clonal mosaicism of mtDNA heteroplasmy constitutes a quantifiable, tissue-specific molecular clock of aging. We trace foundational single-cell and multi-tissue observations of somatic mtDNA mutation, examine the causal evidence from mtDNA mutator mice, and dissect the debate between neutral genetic drift and cellular selection that governs clonal expansion. We then integrate recent single-cell and population-scale studies that have transformed the field: deep multi-tissue surveys revealing tissue-specific accumulation and a biphasic signature, biobank analyses linking heteroplasmy burden to mortality and organ-specific disease, and a two-step mechanism in which cryptic replication-error mutations become detectable through age-related clonal mosaicism. We discuss technologies such as single-cell mtDNA genotyping, duplex and long-read sequencing, and droplet digital PCR that now read the clock at single-molecule resolution, and we connect mutational accumulation to downstream aging phenotypes through mtDNA-driven innate immune signaling, cellular senescence and inflammaging. Finally, we position the mitochondrial clock alongside epigenetic and other aging clocks, highlighting concordance, complementarity, and what must be resolved before heteroplasmy can serve as a blood-based biomarker of biological age.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70718"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13569882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148954545","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":"Akkermansia muciniphila and Its Bioactive Derivatives: Emerging Regulators of Healthy Aging.","authors":"Ting Zhang, Jinyuan Niu, Xiaoyu Hu, Zhiang Hu, Yuan Gao, Jialiang Liu, Ning Chen, Yaomin Hu","doi":"10.1111/acel.70702","DOIUrl":"10.1111/acel.70702","url":null,"abstract":"<p><p>The global aging trend underscores the urgent need for innovative interventions against aging-related decline. Accumulating evidence identifies Akkermansia muciniphila (A. muciniphila) as a key gut microbiota regulator of aging, with its depletion associated with age-related diseases (ARDs), whereas its abundance is enriched in healthy centenarians. This review summarized current evidence linking A. muciniphila to aging, examining their causal relationship, the roles of its bioactive derivatives, underlying mechanisms in aging and ARDs, findings from human clinical trials, and challenges in therapeutic translation. Clinically, A. muciniphila depletion correlated with aging and various ARDs, while its supplementation effectively ameliorated neurodegenerative disorders, metabolic dysfunction, musculoskeletal decline, intestinal barrier dysfunction, and atherosclerosis. Mechanistically, A. muciniphila and its derivatives (Amuc_1100, Amuc_1409, extracellular vesicles, and metabolites such as SCFAs) exerted anti-aging effects by enhancing intestinal barrier function, maintaining metabolic homeostasis, suppressing chronic inflammation, and modulating immune function, ultimately improving glucolipid metabolism, insulin sensitivity, cognitive function, musculoskeletal health, and vascular health. Emerging clinical trials further demonstrated its translational potential in ameliorating age-related sarcopenia, metabolic dysfunction, and respiratory symptoms. Despite promising preclinical and clinical results, translational applications reserve challenges related to strain heterogeneity, antimicrobial resistance gene transfer risk, biosafety, production stability, and limited clinical validation in elderly populations. Future research should prioritize large-scale clinical trials to establish optimal dosage, safety, and long-term efficacy, while exploring combined microbiota-targeted therapies. Harnessing the diverse benefits of A. muciniphila may enable novel strategies for promoting healthy aging.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70702"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13543306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890510","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":"Muscle-Specific Upregulation of Timeless Mediates Exercise-Induced Amelioration of Age-Related Circadian Rhythm Disruption and Cardiac Dysfunction in Drosophila.","authors":"Deng-Tai Wen, Shouzhi Lv, Jing-Yao Sun, Ying-Qi Chen, Ying Lin, Zhong-Rui Du, Gang-Bin Sun, Tian-Shuo Yuan, Deyu Shu, Wen-Qi Hou","doi":"10.1111/acel.70708","DOIUrl":"10.1111/acel.70708","url":null,"abstract":"<p><p>The core genes of the circadian pathway, such as Timeless(Tim), not only participate in the regulation of biological rhythms, but also play significant roles in DNA damage repair, chronic inflammation, and cellular metabolism. However, it remains unclear whether exercise can delay the age-related phenotypic degeneration by regulating the muscle Tim gene. In here, we first carried out the expression regulation of the muscle Tim gene in the Drosophila by constructing the Mhc-gal4/Tim-UAS system, and then subjected the flies to a 4-week endurance exercise intervention. The results showed that the knockdown of the muscle Tim gene accelerated aging-related phenotypic deterioration in Drosophila, manifesting as increased nighttime activity, decreased climbing speed, elevated heart rate and reduced stroke volume, shortened time to hypoxic heart failure, and shortened lifespan. This is accompanied by reductions in muscle tissue levels of the Clk gene, Sir2 gene, PGC-1α gene, Mhc gene, MRCC-I protein, and SOD protein, along with a significant increase in ROS. Conversely, overexpression of the muscle Tim gene delayed aging-related phenotypic changes in aged Drosophila. Exercise not only effectively counteracts the acceleration of aging-related phenotypic deterioration caused by muscle Tim gene knockdown but also further delayed aging-related phenotypic changes in aged Drosophila on the basis of muscle Tim gene overexpression. In summary, this study highlights the role of the muscle Tim gene in the aging of skeletal muscles and the heart, as well as the relationship between exercise and the muscle Tim gene, providing strategies for the prevention and treatment of age-related diseases.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70708"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13550010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148904644","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":"Mitochondrial Haplotype Shapes the Trajectory of Ovarian Aging in Genetically Heterogeneous Rats.","authors":"Subhasri Biswas, Hoang V M Nguyen, Aubrey Converse, Satoshi Matsuzaki, Michael T Kinter, Kenneth M Humphries, Willard M Freeman, Sarah R Ocañas, Arlan Richardson, Francesca E Duncan, Tommy L Lewis, Michael B Stout","doi":"10.1111/acel.70710","DOIUrl":"10.1111/acel.70710","url":null,"abstract":"<p><p>Ovarian aging leads to permanent reproductive senescence and systemic hormonal changes that predispose women to age-associated comorbidities. Despite these observations, the intrinsic mechanisms driving age-related ovarian decline are poorly defined. Mitochondrial DNA (mtDNA) mutations and instability are strongly associated with aging; however, it remains unknown if naturally occurring mitochondrial genetic variation influences the trajectory of ovarian aging. To address this, we compared two genetically heterogeneous rat cohorts (OKC-HET^B and OKC-HET^W) that differ in mitochondrial haplotype on a randomized but equivalently distributed nuclear background. The OKC-HET^W haplotype was associated with accelerated loss of primordial follicles and pathological remodeling marked by fibrosis, macrophage infiltration, and multinucleated giant cells. These tissue-level pathologies were paralleled by mitochondrial dysfunction, characterized by decreased respiratory complex activity, ATP production, and mtDNA copy number. Mechanistically, we identified a haplotype-specific defect in mitochondrial genome maintenance. Although TFAM expression was normal, and total TFAM protein was elevated, OKC-HET^W ovaries showed reduced mitochondrial TFAM abundance, TFAM-mtDNA binding, and TOMM20, suggesting that impaired TOMM20-mediated import is associated with compromised mitochondrial genomic stability. Longitudinal transcriptomic and proteomic analyses further indicate that mitochondrial haplotype influences the rate of ovarian aging, with OKC-HET^W ovaries showing accelerated activation of inflammatory and fibrotic pathways alongside suppressed proteostasis and mitochondrial function. These defects corresponded to impairments in ovulation and a trend toward worsening oocyte quality. Collectively, our findings identify mitochondrial haplotype as a heritable modifier of ovarian aging rate that acts in concert with the nuclear genome, and a putative target for preserving ovarian function and female healthspan.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70710"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13562602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148928495","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":"Twisting the End Game: How Telomere Chromatin Modifications Shape Telomere Maintenance.","authors":"Jie Wang, Yuehui Su, Chao Chen, Yueying Li, Jiajia Han, Liping Du, Liyun Zheng, Ya-Long Dang, Ying Peng","doi":"10.1111/acel.70694","DOIUrl":"10.1111/acel.70694","url":null,"abstract":"<p><p>Cell division inevitably shortens telomeric DNA owing to the end-replication problem. Eukaryotic chromosomes possess specialized telomere structures to maintain genomic stability. In most proliferative cells, telomerase adds telomeric repeats during S-phase. In differentiated cells where telomerase is silenced, telomeres shorten progressively, thereby compromising genomic integrity. Consequently, cancer cells universally activate alternative telomere maintenance mechanisms during malignant transformation: ~80% reactivate telomerase, while a portion of the rest rely on BIR (break-induced replication)-mediated homologous recombination-based ALT (alternative lengthening of telomeres). Although these mechanisms are stable once established, the initial determinants influencing a cancer cell's choice remain poorly understood. This review discusses recent molecular insights into how telomeric chromatin properties profoundly impact this choice. After briefly introducing telomere chromatin characteristics and key players in its maintenance and dynamics, we discuss the mechanisms by which cancer cells acquire distinct telomere replication capabilities. In particular, we present an in-depth analysis linking telomere heterochromatin status to ALT. Furthermore, based on recent advances, we propose a coupled feedforward loop model explaining how the ALT state becomes \"locked in\" once initiated. Finally, we offer novel perspectives on rational, telomere-centric therapeutic interventions for ALT-positive cancers, focusing on strategies designed to disrupt such feedforward loops by manipulating telomeric chromatin structure.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70694"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13546678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148899720","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":"Transmembrane Protein PTCHD4 Is a Novel Regulator of Cellular Senescence and Age-Related Pathologies.","authors":"Mingyue Wang, Zhaoyun Yang, Qikai Wang, Zeping Li, Zhihua Huang, Le Wang, Xiaoning Sun, Donglin Yu, Wenhua Yu, Xiaoxia Bao, Zebin Mao, Yang Li","doi":"10.1111/acel.70711","DOIUrl":"10.1111/acel.70711","url":null,"abstract":"<p><p>Cellular senescence is a key driver of age-related pathologies. Our study focuses on PTCHD4, a transmembrane protein with previously undefined physiological functions in aging processes. We found that PTCHD4 expression was increased across multiple cellular senescence models and showed an age-associated increase in mouse tissues and human lung transcriptomic datasets. Functionally, PTCHD4 deficiency attenuated senescence progression, whereas its overexpression promoted this process. In vivo, PTCHD4 deficiency alleviated D-galactose-induced aging-related phenotypes and functional deterioration, accompanied by an extension of median lifespan in mice. In a bleomycin-induced pulmonary fibrosis model, PTCHD4 deficiency reduced collagen deposition, attenuated senescence- and inflammation-associated signals, and preserved pulmonary function. Mechanistically, PTCHD4 promoted aging-associated AKT activation, and restoration of AKT signaling reversed the anti-senescent effects of PTCHD4 deficiency. Taken together, these findings support PTCHD4 as a contributor to cellular senescence and age-associated tissue dysfunction, and suggest that the PTCHD4-AKT axis warrants further investigation as a candidate target in senescence-associated diseases.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70711"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13564249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943992","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":"The Secretome Derived From Human Umbilical Cord Mesenchymal Stem Cells Improves Skin Photoaging by Enhancing Mitophagy to Inhibit the cGAS-STING Pathway.","authors":"Tingting Tang, Meifen Lin, Jingjing Yang, Xinyu Yang, Xunhong Xu, Xuan Wang, Yarui Zhang, Qimei Chen, Shan Zhao, Chenhui Guo, Hao Zhang, Min Zhang, Lin Zhang, Xueer Wang","doi":"10.1111/acel.70701","DOIUrl":"10.1111/acel.70701","url":null,"abstract":"<p><p>Ultraviolet (UV)-induced skin photoaging is driven by cellular senescence and chronic inflammation. Although the secretome (SCT) derived from human umbilical cord mesenchymal stem cells (hUC-MSC SCT) exhibits regenerative potential, its role in combating photoaging remains to be elucidated. In this study, we show that SCT markedly ameliorates photoaging in UV-exposed mice, restoring epidermal barrier function, dermal collagen integrity, senescence-associated markers, and systemic inflammatory profiles. In UVB-irradiated human immortalized keratinocytes (HaCaT), SCT enhanced cellular viability, proliferation, and migration while alleviating cellular senescence. Mechanistically, SCT promoted mitophagy, as indicated by clearance of mitochondrial proteins (TOM20, TIM23, HSP60), reversal of p62 accumulation, and restoration of LC3B-II flux. By eliminating impaired mitochondria, SCT reduced cytosolic mtDNA leakage, thereby suppressing the overactivation of the cGAS-STING pathway and its downstream pro-inflammatory cytokines IL-6, IL-8, and IFN-β. Importantly, these protective effects were abolished by the mitophagy inhibitor Mdivi-1, whereas the STING inhibitor H151 effectively reversed the Mdivi-1-induced loss of protection, confirming that SCT acts through the hierarchical mitophagy-cGAS-STING axis. Together, our findings establish SCT as a promising cell-free therapeutic strategy for photoaging and highlight the mitophagy-cGAS-STING axis as a critical nexus linking mitochondrial quality control to sterile inflammation in aging tissues.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70701"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13563172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148928399","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}