IF 7.1 1区医学

Aging Cell Pub Date : 2026-10-01 DOI: 10.1111/acel.70749

Hao-Lin Zhang, Yue Wang, Caizhu Wang, Xin Guo, Huanhua Chen, Yu-Xuan Hou, Xuan Wu, Zi-Jian Wu, Wen-Lin Pan, Rui-Jie Ma, Ping-Shuang Lu, Jinhui Shu, Shao-Chen Sun

{"title":"Elamipretide Rejuvenates Oocyte Quality and Restores Female Fertility During Reproductive Aging.","authors":"Hao-Lin Zhang, Yue Wang, Caizhu Wang, Xin Guo, Huanhua Chen, Yu-Xuan Hou, Xuan Wu, Zi-Jian Wu, Wen-Lin Pan, Rui-Jie Ma, Ping-Shuang Lu, Jinhui Shu, Shao-Chen Sun","doi":"10.1111/acel.70749","DOIUrl":"https://doi.org/10.1111/acel.70749","url":null,"abstract":"Aging represents a major contributor to the deterioration of female fertility, with oocyte quality being the central determinant of ovarian aging, a key factor underlying infertility. Although several natural compounds with anti-aging activity have been documented, highly effective strategies to reverse ovarian aging remain elusive. Here, we report that the peptide elamipretide preserves ovarian function and sustains female fertility during maternal aging. We found that elamipretide administration increases litter size in aged mice and ameliorates oocyte quality decline. Metabolomic and transcriptomic profiling revealed substantial restoration of multiple biological processes in aged oocytes after elamipretide injection. Elamipretide improved both nuclear and cytoplasmic maturation of aged oocytes, accompanied by enhanced cytoskeletal dynamics, mitochondrial metabolism, and organelle reorganization. Mechanistically, elamipretide alleviated age-associated oocyte maturation defects through synergistic activation of the vitamin B6-VEGF axis. Furthermore, elamipretide significantly promoted maturation, fertilization, and cleavage of aged human oocytes. Elamipretide treatment also rescued the developmental competence of porcine oocytes under oxidative damage. Collectively, this study identifies a novel peptide therapeutic candidate for aging-related infertility, showing that elamipretide restores the quality of aged oocytes for fertility by coordinately boosting nuclear and cytoplasmic maturation via activation of the VEGF signaling pathway.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70749"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101550","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}

引用次数: 0

α-Synuclein Promotes Atherosclerosis by Impairing Macrophage Autophagic Flux. α-突触核蛋白通过损害巨噬细胞自噬通量促进动脉粥样硬化。

IF 7.1 1区医学

Aging Cell Pub Date : 2026-10-01 DOI: 10.1111/acel.70713

Mengting Qin, Xuying Xiang, Xiaoqing Guo, Shengnan Wang, Jiaojiao Chen, Dailiang Jiang, Yuhang Feng, Jiangnan Yu, Ling Mao

{"title":"α-Synuclein Promotes Atherosclerosis by Impairing Macrophage Autophagic Flux.","authors":"Mengting Qin, Xuying Xiang, Xiaoqing Guo, Shengnan Wang, Jiaojiao Chen, Dailiang Jiang, Yuhang Feng, Jiangnan Yu, Ling Mao","doi":"10.1111/acel.70713","DOIUrl":"10.1111/acel.70713","url":null,"abstract":"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 (Apoe-/-) 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. Flot1 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.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70713"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","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}

引用次数: 0

DNMT1 Regulates Testosterone Synthesis in Aged Rat Leydig Cells via FTO-Mediated HSP90AA1 m⁶A Levels. DNMT1通过fto介导的HSP90AA1 m6A水平调控老龄大鼠间质细胞的睾酮合成。

IF 7.1 1区医学

Aging Cell Pub Date : 2026-10-01 DOI: 10.1111/acel.70760

Yaqi Li, Yulei Duan, Zihang Tian, Yibing Gao, Yufei Qiao, Shuang Zhao, Wenyan Li, Zheng Gao, Siyun Niu

{"title":"DNMT1 Regulates Testosterone Synthesis in Aged Rat Leydig Cells via FTO-Mediated HSP90AA1 m6A Levels.","authors":"Yaqi Li, Yulei Duan, Zihang Tian, Yibing Gao, Yufei Qiao, Shuang Zhao, Wenyan Li, Zheng Gao, Siyun Niu","doi":"10.1111/acel.70760","DOIUrl":"10.1111/acel.70760","url":null,"abstract":"Testosterone levels decline progressively with age from the third decade of life, impairing spermatogenesis and contributing to age-related disorders, underscoring the importance of enhancing endogenous testosterone production. DNA methyltransferase 1 (DNMT1) promotes testosterone synthesis in Leydig cells (LCs), yet the underlying mechanism remains unclear. Here, we found that DNMT1 expression is downregulated in aging rat testes and senescent LCs in vitro, correlating with reduced testosterone levels. Gain- and loss-of-function experiments confirmed that DNMT1 positively regulates testosterone synthesis and alleviates LC senescence, and that DNMT1 overexpression reverses the senescent phenotype and restores testosterone production. Mechanistically, RNA-seq of DNMT1-knockdown LCs identified FTO as a downstream target; DNMT1 suppresses FTO expression by promoting Fto promoter methylation. catRAPID prediction and RIP-qPCR validated Hsp90aa1 mRNA as a direct FTO substrate; FTO regulates HSP90AA1 expression through m6A modification, with DNMT1 indirectly modulating HSP90AA1 via FTO. Using HSP90AA1 overexpression, pharmacological inhibition, and rescue experiments, we confirmed that the DNMT1-FTO axis inhibits LC apoptosis through HSP90AA1-mediated AKT activation, thereby promoting testosterone synthesis. Expression patterns of this axis in aging rat testes and senescent LCs further corroborated its involvement in age-related testosterone dysregulation. In vivo AAV-mediated testicular DNMT1 knockdown recapitulated these findings. Collectively, our study elucidates the physiological role of DNMT1 in age-related testosterone decline and delineates the mechanism by which DNMT1 governs LC senescence and steroidogenic function, providing a potential therapeutic target for reproductive system aging.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70760"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163868","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}

引用次数: 0

Senescent Fibroblasts Impair B Cell Proliferation via Cell-Cell Contact. 衰老成纤维细胞通过细胞间接触损害B细胞增殖。

IF 7.1 1区医学

Aging Cell Pub Date : 2026-10-01 DOI: 10.1111/acel.70766

Kassandra Vezyrgianni, Elizabeth MacLeod, Abigail Nutley, Yuchen Zhu, Alice E Denton

{"title":"Senescent Fibroblasts Impair B Cell Proliferation via Cell-Cell Contact.","authors":"Kassandra Vezyrgianni, Elizabeth MacLeod, Abigail Nutley, Yuchen Zhu, Alice E Denton","doi":"10.1111/acel.70766","DOIUrl":"10.1111/acel.70766","url":null,"abstract":"Ageing profoundly impairs vaccine efficacy, leaving older individuals highly susceptible to infectious diseases despite vaccination. Although B cells retain the intrinsic capacity to generate germinal centre (GC) responses in older people, age-associated defects in T cells, dendritic cells and follicular dendritic cells (FDCs) limit the development of high-affinity, class-switched antibody responses. Here, we hypothesised that senescent fibroblasts disrupt B cell activation and expansion, thus contributing to the diminution of the humoral response in ageing. To test this hypothesis, we established an in vitro system in which human tonsil-derived YK6 fibroblasts expressing CD40L are co-cultured with PBMC-derived B cells. B cell activation, proliferation, and phenotype in response to low- and high-stimulation conditions was determined in co-culture with control or bleomycin-treated YK6 fibroblasts. Control YK6 fibroblasts promoted B-cell activation and proliferation in both 2D and 3D cultures, whereas bleomycin-treated fibroblasts robustly inhibited B-cell proliferation without impairing early activation. Conditioned media from bleomycin-treated fibroblasts partially reduced B cell proliferation, although to a lesser extent than direct co-culture, suggesting cell-cell contact was key to inhibiting B cell proliferation. Bleomycin-treated YK6 fibroblasts upregulated genes associated with impaired lymphocyte responses, such as PDCD1LG2, which may impact B cell activation. Indeed, B cells co-cultured with bleomycin-treated fibroblasts failed to fully initiate glycolysis and were essentially unable to synthesise new protein. Together, these findings suggest that senescence-like changes in fibroblasts could restrict B-cell proliferative capacity, which may contribute to impaired B cell responses in ageing.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70766"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149190107","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}

引用次数: 0

IGF-1/SLC25A33 Maintains Blood-Labyrinth Barrier Integrity by Suppressing TGF-β/Smad2-Mediated Pericyte Activation in Age-Related Hearing Loss. IGF-1/SLC25A33通过抑制TGF-β/ smad2介导的周细胞激活在年龄相关性听力损失中维持血迷宫屏障完整性

IF 7.1 1区医学

Aging Cell Pub Date : 2026-10-01 DOI: 10.1111/acel.70712

Rui Xu, Jia Tang, Huan Lin, Qi Li, Yajin Feng, Xiaorong Zhang, Xiaohong Hu, Jiacai Yang, Yuhong Li, Yang Bai

{"title":"IGF-1/SLC25A33 Maintains Blood-Labyrinth Barrier Integrity by Suppressing TGF-β/Smad2-Mediated Pericyte Activation in Age-Related Hearing Loss.","authors":"Rui Xu, Jia Tang, Huan Lin, Qi Li, Yajin Feng, Xiaorong Zhang, Xiaohong Hu, Jiacai Yang, Yuhong Li, Yang Bai","doi":"10.1111/acel.70712","DOIUrl":"10.1111/acel.70712","url":null,"abstract":"Age-related hearing loss (ARHL) is a prevalent sensory disorder in the elderly, yet the molecular mechanisms underlying cochlear aging remain incompletely understood. While insulin-like growth factor 1 (IGF-1) has been implicated in ARHL, its role in the stria vascularis, particularly in pericyte-mediated blood-labyrinth barrier (BLB) regulation, is poorly defined. We performed transcriptomic analysis of FACS-purified pericytes from young and aged mouse stria vascularis. Functional studies were conducted using primary pericyte cultures, lentiviral gene modulation, and AAV-mediated in vivo delivery. Auditory function was assessed by auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE). Molecular changes were evaluated via qPCR, western blot, immunofluorescence, flow cytometry, and transmission electron microscopy (TEM). Transcriptomics revealed significant downregulation of Igf1 and Slc25a33 in aged pericytes, with enrichment of the TGF-β signaling pathway. IGF-1 deficiency suppressed SLC25A33 expression in vitro, leading to mitochondrial ROS (mtROS) accumulation, activation of TGF-β/Smad2 signaling, and pericyte phenotypic switching, characterized by increased α-SMA and decreased E-cadherin. In vivo, suppression of IGF-1 or SLC25A33 activated TGF-β/Smad2 signaling in the stria vascularis, disrupted BLB ultrastructure, and exacerbated hearing loss. Conversely, exogenous IGF-1 or SLC25A33 overexpression attenuated these effects and partially restored auditory function. Our findings identify a novel IGF-1/SLC25A33-TGF-β/Smad2 axis that regulates pericyte activation and BLB integrity in the aging cochlea. This pathway provides mechanistic insight into ARHL pathogenesis and highlights a potential therapeutic target for preserving hearing in older adults.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70712"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072907","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}

引用次数: 0

β-Catenin-Deficient Intervertebral Disc Cells Reduce Chemotactic Transcription and Myeloid Cell Recruitment to Injured Discs of Mice. 缺乏β- catenin的椎间盘细胞减少小鼠损伤椎间盘的趋化转录和髓系细胞募集。

IF 7.1 1区医学

Aging Cell Pub Date : 2026-10-01 DOI: 10.1111/acel.70740

Tori M Kroon, Jazz Munitz, Anna Ranzenigo, Martin Umali, William Wang, Jonathan J Huang, Abraham J P Teunissen, Nilsson Holguin

{"title":"β-Catenin-Deficient Intervertebral Disc Cells Reduce Chemotactic Transcription and Myeloid Cell Recruitment to Injured Discs of Mice.","authors":"Tori M Kroon, Jazz Munitz, Anna Ranzenigo, Martin Umali, William Wang, Jonathan J Huang, Abraham J P Teunissen, Nilsson Holguin","doi":"10.1111/acel.70740","DOIUrl":"https://doi.org/10.1111/acel.70740","url":null,"abstract":"Aging exacerbates the incidence of discogenic chronic low back pain by excessive inflammation and immune cell presence. Aging reduces intervertebral disc (IVD) Wnt signaling, which is associated with IVD cell differentiation, IVD cell proliferation and anti-inflammatory signaling. However, it is unclear how in vivo Wnt signaling-absent IVD cells, which model aged IVD cells, regulate chemotactic signaling and immune cell recruitment. We hypothesized that Wnt signaling-absent IVD cells attenuate chemotactic transcription and immune cell recruitment to naive IVD and in response to IVD injury. First, because aging reduces Wnt signaling in all IVD cells, we deleted β-catenin using the AcanCreERT2. β-catenin deletion reduced monocyte chemoattractant protein-1 (MCP1/CCL2) Ccl2 in male and female IVDs by 58% and 79%, respectively (n = 5-6/sex). Using positron emission tomography/computed tomography (PET/CT) imaging of myeloid cells in 5-month-old mice (n = 4 IVD/sex/grp), deletion of β-catenin reduced myeloid-derived cell burden in naive IVD by 79% and attenuated IVD injury-induced recruitment by 48%. Next, because nucleus pulposus (NP) cells begin losing Wnt signaling early in life, we deleted β-catenin using the ShhCreERT2. Compared to RNA-sequencing of WT IVD post injury (n = 3/grp), deletion of β-catenin in NP cells impaired the activation of immune cell pathways, such as MCP1/CCL2. Together, the chemotactic transcriptomic response and myeloid cell accumulation due to IVD injury were impaired by the absence of IVD Wnt signaling transcription cofactor β-catenin. These data suggest that low-grade IVD inflammation and chronic IVD immune cell accumulation in aged IVD cells are regulated by IVD Wnt signaling.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70740"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101697","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}

引用次数: 0

Protracted Fate Acquisition and Epigenetic De-Aging During Induced Neural Stem Cell Conversion of Human Blood Cells. 人血细胞诱导神经干细胞转化过程中的长期命运获取和表观遗传去衰老。

IF 7.1 1区医学

Aging Cell Pub Date : 2026-10-01 DOI: 10.1111/acel.70751

Lea Jessica Berg, Julia Franzen, Andreas Buness, Rachel Konang, Chao Sheng, Michael Peitz, Andreas Till, Wolfgang Wagner, Oliver Brüstle

{"title":"Protracted Fate Acquisition and Epigenetic De-Aging During Induced Neural Stem Cell Conversion of Human Blood Cells.","authors":"Lea Jessica Berg, Julia Franzen, Andreas Buness, Rachel Konang, Chao Sheng, Michael Peitz, Andreas Till, Wolfgang Wagner, Oliver Brüstle","doi":"10.1111/acel.70751","DOIUrl":"https://doi.org/10.1111/acel.70751","url":null,"abstract":"Transcription factor-based direct conversion of somatic cells represents an interesting avenue for generating induced neural stem cells (iNSCs) from peripheral blood without transit through a pluripotent stage. While this paradigm has been shown to be associated with epigenetic de-aging, the dynamics of this process have remained unclear. Here, we used overexpression of the two reprogramming factors SOX2 and cMYC to generate iNSCs from erythroid progenitors of donors ranging from neonatal to 101 years of age. Using an epigenetic aging clock algorithm, we corroborated our previous finding that iNSCs generated from aged donors show pronounced epigenetic de-aging, preserving around 13% and 5% of the original donor age at low and high passages, respectively. Studying the dynamics of epigenetic de-aging during iNSC conversion across time, we found that this process is largely protracted, continuing for several weeks and even under proliferation-inhibiting conditions. Transcriptomic differences between young and old donor-derived iNSCs dissipate with extended time in conversion, too. Concordant with this observation, established iNSC lines lack age-associated cellular hallmarks, similar to induced pluripotent stem cells and their derivatives. Interestingly, time course analysis of DNA methylation and RNA sequencing data revealed that acquisition of a bona fide NSC signature extends greatly beyond the time point when proliferative PAX6-positive iNSCs emerge. The unexpected slow dynamics of these processes make iNSC conversion an attractive model for dissecting the mechanisms underlying somatic transdifferentiation and epigenetic de-aging.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70751"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101636","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}

引用次数: 0

Correction to "A Non-Canonical Role for Hepatocyte MLKL in Promoting Mitochondrial Dysfunction and Senescence in the Aging Liver". 修正“肝细胞MLKL在促进衰老肝脏线粒体功能障碍和衰老中的非规范作用”。

IF 7.1 1区医学

Aging Cell Pub Date : 2026-10-01 DOI: 10.1111/acel.70746

引用次数: 0

Prodh2-Mediated Mitochondrial Stress Drives TNF-α-Induced Myoblast Dysfunction and Sarcopenia in COPD. prodh2介导的线粒体应激驱动TNF-α-诱导的COPD成肌细胞功能障碍和肌肉减少。

IF 7.1 1区医学

Aging Cell Pub Date : 2026-10-01 DOI: 10.1111/acel.70739

Gang Chen, Zhitao Shangguan, Jingjing Gong, Dalu Cheng, Penghong Chen, Jiandong Li, Qiong Lin

{"title":"Prodh2-Mediated Mitochondrial Stress Drives TNF-α-Induced Myoblast Dysfunction and Sarcopenia in COPD.","authors":"Gang Chen, Zhitao Shangguan, Jingjing Gong, Dalu Cheng, Penghong Chen, Jiandong Li, Qiong Lin","doi":"10.1111/acel.70739","DOIUrl":"https://doi.org/10.1111/acel.70739","url":null,"abstract":"Sarcopenia in chronic obstructive pulmonary disease (COPD) is driven by elevated tumor necrosis factor-alpha (TNF-α), yet the underlying mechanism remains unclear. Here, we identify the mitochondrial metabolic enzyme Prodh2 as a pivotal mediator. Prodh2 was significantly upregulated in sarcopenic COPD patients and a corresponding mouse model. Mechanistically, TNF-α induced Prodh2 transcription in myoblasts via a p53-dependent pathway. This upregulation triggered excessive mitochondrial reactive oxygen species, leading to the release of mitochondrial DNA (mtDNA). Cytosolic mtDNA subsequently activated the cGAS/STING innate immune pathway, causing myoblast apoptosis, proliferation arrest, and atrophy. While Prodh2 knockdown reversed these effects in vitro, muscle-specific knockdown of Prodh2 in vivo critically ameliorated muscle atrophy and restored strength. Our study unveils a novel TNF-α-p53-Prodh2-cGAS/STING axis that links chronic inflammation to sarcopenia through metabolic-immune crosstalk, validating Prodh2 as a promising therapeutic target.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70739"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101675","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}

引用次数: 0

Sex-Specific Neurogenic and Cognitive Responses in a Murine Model of Accelerated Aging. 加速衰老小鼠模型中的性别特异性神经源性和认知反应。

IF 7.1 1区医学

Aging Cell Pub Date : 2026-10-01 DOI: 10.1111/acel.70663

Ricardo Gómez-Oliva, Andrea Chamorro-Francisco, Isabel Atienza-Navarro, Livia Carrascal, María D Freire-Aragón, Rosario Hernández-Galán, Pedro Nunez-Abades, Mónica García-Alloza, Carmen Castro

{"title":"Sex-Specific Neurogenic and Cognitive Responses in a Murine Model of Accelerated Aging.","authors":"Ricardo Gómez-Oliva, Andrea Chamorro-Francisco, Isabel Atienza-Navarro, Livia Carrascal, María D Freire-Aragón, Rosario Hernández-Galán, Pedro Nunez-Abades, Mónica García-Alloza, Carmen Castro","doi":"10.1111/acel.70663","DOIUrl":"10.1111/acel.70663","url":null,"abstract":"Aging is associated with cognitive deterioration accompanied by a reduction in hippocampal neurogenesis. Murine models have been widely used to study aging and age-related cognitive decline, as they recapitulate many of the key features of the degenerative process. Among these, the SAMP8 strain represents a well-established model of accelerated aging, characterized by early-onset and progressive cognitive impairment, Alzheimer's disease-like neuropathology, and an initial increase in hippocampal neurogenesis that ultimately depletes the neural stem cell pool. Notably, most studies using murine models of aging or neurodegeneration have focused on males or mixed-sex cohorts, leaving sex-specific differences in neurogenesis and cognitive decline largely unexplored. Recent evidence indicates that diterpenoid treatment is associated with improved cognitive performance and enhanced neurogenesis in 6-month-old male SAMP8 mice. However, whether females exhibit similar responses remains unknown. In this study, we characterized sex differences in hippocampal neurogenesis in 6-month-old SAMP8 mice and examined potential sex-dependent effects of diterpenoid therapy. Our findings reveal sex-specific differences in physiological and pathological hippocampal neurogenesis and in responsiveness to ER272 treatment. Male SAMR1 mice displayed higher baseline neurogenesis than females, while male and female SAMP8 mice followed distinct neurogenic aging trajectories. ER272 was associated with improved cognitive performance and preservation of multiple neurogenic parameters in males but showed limited effects in females. These results suggest sex-specific mechanisms of brain aging and indicate that mixed-sex analyses may mask biologically relevant differences, highlighting the importance of considering sex in aging studies and therapeutic development.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70663"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134354","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}

引用次数: 0

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