Nature agingPub Date : 2025-06-27DOI: 10.1038/s43587-025-00909-y
Leping Zhang, Zhe Xu, Jia Jing, Guoshi Chai, Guanglei Xie, Yanfei Ru, Qunyu Lv, Xiang Zuo, Qian Zhang, Jiatong Chen, He Jin, Ning Liu, Minghua Kong, Bin Shen, Mingxi Liu, Lei Jiang, Xi Wang, Yanxiao Zhang, Min Jiang
{"title":"Age-dependent accumulation of mitochondrial tRNA mutations in mouse kidneys linked to mitochondrial kidney diseases.","authors":"Leping Zhang, Zhe Xu, Jia Jing, Guoshi Chai, Guanglei Xie, Yanfei Ru, Qunyu Lv, Xiang Zuo, Qian Zhang, Jiatong Chen, He Jin, Ning Liu, Minghua Kong, Bin Shen, Mingxi Liu, Lei Jiang, Xi Wang, Yanxiao Zhang, Min Jiang","doi":"10.1038/s43587-025-00909-y","DOIUrl":"https://doi.org/10.1038/s43587-025-00909-y","url":null,"abstract":"<p><p>Heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutations are key drivers of mitochondrial diseases, yet their tissue-specific and cell-specific accumulation patterns during aging and the mechanistic links to pathology remain poorly understood. In this study, we employed DddA-derived cytosine base editor technology to generate three mouse models harboring distinct pathogenic mitochondrial tRNA mutations. These mutations exhibited age-dependent accumulation in the kidneys, leading to severe kidney defects that well recapitulate human mitochondrial kidney disease. Mitochondrial single-cell assay for transposase-accessible chromatin with sequencing (mtscATAC-seq) revealed unique heteroplasmy dynamics across different kidney cell types: podocytes exhibited a positive selection for mutant mtDNA, whereas tubular epithelial cells displayed neutral drift of mutations during aging. Integrative analyses combining mtscATAC-seq, single-cell RNA sequencing and spatially enhanced resolution omics sequencing further identified molecular changes in high-mutant defective cells, including increased AP-1 family transcription factor activity, tubular epithelial cell proliferation and immune activation, which contribute to disease progression. Our study underscores the importance of kidney function monitoring in patients with mitochondrial disease, particularly in older adults, and establishes robust preclinical models to facilitate the development of therapeutic strategies.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144513026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-06-27DOI: 10.1038/s43587-025-00907-0
Wei Xiang, Tongyi Zhang, Bingfei Li, Song Li, Bin Zhang, Shunzheng Fang, Lifeng Chen, Yunquan Gong, Bo Huang, Daibo Feng, Jinhui Wu, Jing Yuan, Yaran Wu, Xiaojing Yan, Runze Jin, Xiaoqi Zhang, Xiangqin Fang, Jiqin Lian, Lin Chen, Siru Zhou, Zhenhong Ni
{"title":"Senescent macrophages induce ferroptosis in skeletal muscle and accelerate osteoarthritis-related muscle atrophy.","authors":"Wei Xiang, Tongyi Zhang, Bingfei Li, Song Li, Bin Zhang, Shunzheng Fang, Lifeng Chen, Yunquan Gong, Bo Huang, Daibo Feng, Jinhui Wu, Jing Yuan, Yaran Wu, Xiaojing Yan, Runze Jin, Xiaoqi Zhang, Xiangqin Fang, Jiqin Lian, Lin Chen, Siru Zhou, Zhenhong Ni","doi":"10.1038/s43587-025-00907-0","DOIUrl":"https://doi.org/10.1038/s43587-025-00907-0","url":null,"abstract":"<p><p>Muscle atrophy around joints is a common issue for people with osteoarthritis (OA), but its causes are poorly understood. Here we demonstrate that chronic inflammation in quadriceps muscle coincides with OA in mice, characterized by an increase in macrophages, activation of inflammatory pathways and tissue vascularization. We show that, during OA progression, macrophages progressively exhibit increasing phenotypes of senescence and promote muscle atrophy through paracrine induction of ferroptosis. Mechanistically, iron overload-induced mitochondrial damage results in reduced asparagine metabolites, impairing coenzyme Q10 (CoQ10) synthesis by inhibiting mTORC1-HMGCR signaling. Ultimately, this cascade enhances lipid peroxidation and promotes ferroptosis in skeletal muscle cells. We show that the cardiac medication CoQ10 can attenuate muscle atrophy by inhibiting ferroptosis, thereby reducing pathological damage to OA joints. Our findings offer insights for the potential management of muscle atrophy in patients with OA.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144513027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-06-23DOI: 10.1038/s43587-025-00900-7
Yu Liu, Meiling Ge, Xina Xiao, Ying Lu, Wanyu Zhao, Kun Zheng, Kexin Yu, Yanting He, Qian Zhong, Lixing Zhou, Shan Hai, Xiaohui Liu, Na Jiang, Dan Du, Yan Zhang, Guo Cheng, Zhenmei An, Yi Zhao, Heng Xu, Biao Dong, Shuangqing Li, Binwu Ying, Huiyuan Zhang, Jirong Yue, Birong Dong, Lunzhi Dai
{"title":"Sarcosine decreases in sarcopenia and enhances muscle regeneration and adipose thermogenesis by activating anti-inflammatory macrophages.","authors":"Yu Liu, Meiling Ge, Xina Xiao, Ying Lu, Wanyu Zhao, Kun Zheng, Kexin Yu, Yanting He, Qian Zhong, Lixing Zhou, Shan Hai, Xiaohui Liu, Na Jiang, Dan Du, Yan Zhang, Guo Cheng, Zhenmei An, Yi Zhao, Heng Xu, Biao Dong, Shuangqing Li, Binwu Ying, Huiyuan Zhang, Jirong Yue, Birong Dong, Lunzhi Dai","doi":"10.1038/s43587-025-00900-7","DOIUrl":"https://doi.org/10.1038/s43587-025-00900-7","url":null,"abstract":"<p><p>Age-related changes in circulating metabolites influence systemic physiology and may contribute to diseases such as sarcopenia. Although metabolic dysregulation is closely linked to sarcopenia, the roles of specific metabolites remain unclear. In this study, we performed comprehensive plasma metabolomic and lipidomic analyses across two cohorts comprising 1,013 individuals, uncovering the metabolic characteristics of sarcopenia, including a notable decline in plasma sarcosine levels in both aging patients and those with sarcopenia. Functional studies in mice showed that sarcosine helps maintain muscle mass homeostasis during aging, promotes adipose thermogenesis and enhances muscle regeneration. We demonstrate here that sarcosine activated the GCN2 signaling pathway to enhance anti-inflammatory macrophage polarization, promoting adipose thermogenesis and muscle regeneration. These effects may increase energy expenditure and restore metabolic balance to reduce chronic inflammation and improve insulin sensitivity, which are crucial for managing sarcopenia. This study underscores the potential of sarcosine supplementation as an adjunctive strategy via macrophage modulation for preventing sarcopenia in older adults.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-06-23DOI: 10.1038/s43587-025-00904-3
Guoyu Lan, Mengjie Wang, Fernando Gonzalez-Ortiz, Laihong Zhang, Anqi Li, Binyin Li, Mingxing Jiang, Jie Yang, Xuhui Chen, Dai Shi, Xiang Fan, Yue Cai, Pan Sun, Lin Liu, Jieyin Li, Zhengbo He, Lili Fang, Xin Zhou, Linting Chen, Yiying Wang, Mingxu Li, Zhen Liu, Qingyong Wang, Linsen Xu, Liemin Zhou, Guanxun Cheng, Xinlu Wang, Pengcheng Ran, Lu Wang, Kun Sun, Ying Han, Yihui Guan, Kaj Blennow, Fang Xie, Tengfei Guo
{"title":"Comprehensive evaluation of plasma tau biomarkers for detecting and monitoring Alzheimer's disease in a multicenter and multiethnic aging population.","authors":"Guoyu Lan, Mengjie Wang, Fernando Gonzalez-Ortiz, Laihong Zhang, Anqi Li, Binyin Li, Mingxing Jiang, Jie Yang, Xuhui Chen, Dai Shi, Xiang Fan, Yue Cai, Pan Sun, Lin Liu, Jieyin Li, Zhengbo He, Lili Fang, Xin Zhou, Linting Chen, Yiying Wang, Mingxu Li, Zhen Liu, Qingyong Wang, Linsen Xu, Liemin Zhou, Guanxun Cheng, Xinlu Wang, Pengcheng Ran, Lu Wang, Kun Sun, Ying Han, Yihui Guan, Kaj Blennow, Fang Xie, Tengfei Guo","doi":"10.1038/s43587-025-00904-3","DOIUrl":"10.1038/s43587-025-00904-3","url":null,"abstract":"<p><p>Over 20% of patients with Alzheimer's disease (AD) worldwide are Chinese, although the efficacy of existing blood-based measures of AD biomarkers is largely unknown in Asian cohorts. Here we explored how plasma tau biomarkers correlated with cross-sectional and longitudinal AD-related outcomes and their diagnostic performance in 1,085 participants from three independent studies, including two Chinese cohorts, Greater-Bay-Area Healthy Aging Brain Study (n = 425) and Huashan (n = 297), and the North American Alzheimer's Disease Neuroimaging Initiative cohort (n = 363). Plasma p-tau217 performed best in classifying Aβ-positron emission tomography (PET) and tau-PET positivity throughout the AD continuum and correlated with all AD-related outcomes. A two-cutoff approach suggested that participants with intermediate plasma p-tau217 levels experienced rapid accumulation of Aβ-PET and entorhinal tau-PET, as well as accelerated hypometabolism and cognitive decline. Increased plasma p-tau217 was also associated with rapid longitudinal changes in Aβ-PET, tau-PET and neurodegeneration. These results suggest that plasma p-tau217 is superior in detecting multiple aspects of AD-related pathological changes and tracking disease progression.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-06-20DOI: 10.1038/s43587-025-00896-0
Guoqiang Sun, Xiaolong Fu, Yandong Zheng, Guodong Hong, Ziyi Liu, Bilan Luo, Jinghui Lei, Dongliang Lv, Miao Chang, Yu Xiao, Siwei Guo, Shuai Ma, Ling Lu, Weiqi Zhang, Juan Carlos Izpisua Belmonte, Jing Qu, Si Wang, Renjie Chai, Guang-Hui Liu
{"title":"Single-cell profiling identifies hair cell SLC35F1 deficiency as a signature of primate cochlear aging.","authors":"Guoqiang Sun, Xiaolong Fu, Yandong Zheng, Guodong Hong, Ziyi Liu, Bilan Luo, Jinghui Lei, Dongliang Lv, Miao Chang, Yu Xiao, Siwei Guo, Shuai Ma, Ling Lu, Weiqi Zhang, Juan Carlos Izpisua Belmonte, Jing Qu, Si Wang, Renjie Chai, Guang-Hui Liu","doi":"10.1038/s43587-025-00896-0","DOIUrl":"10.1038/s43587-025-00896-0","url":null,"abstract":"<p><p>Cochlear aging causes substantial hearing impairment in older adults, yet primate-specific mechanisms remain poorly characterized. Our comprehensive analysis combining single-cell and histopathological profiling in aging Macaca fascicularis demonstrates progressive cochlear degeneration featuring accelerated sensory hair cell loss, senescent spiral ganglion neurons with elevated neuroinflammation, and marked stria vascularis atrophy. We discovered that downregulation of transmembrane transport proteins, particularly SLC35F1, serves as a critical biomarker of hair cell aging. Functional validation through Slc35f1 knockdown in adult mice successfully recapitulated key aspects of age-related hearing loss, including hair cell degeneration and auditory function decline. Notably, we showed that long-term metformin administration at clinically relevant doses effectively delays cochlear aging in primates. These findings provide fundamental insights into the cellular and molecular basis of primate cochlear aging while establishing a foundation for developing targeted interventions against age-related hearing loss.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144337388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-06-17DOI: 10.1038/s43587-025-00901-6
David Furman, Johan Auwerx, Anne-Laure Bulteau, George Church, Virginie Couturaud, Laure Crabbe, Kelvin J A Davies, Anabelle Decottignies, Vadim N Gladyshev, Brian K Kennedy, Nicola Neretti, Carine Nizard, Karl Pays, Daisy Robinton, Vittorio Sebastiano, Rachel E B Watson, Meng C Wang, Knut Woltjen
{"title":"Skin health and biological aging.","authors":"David Furman, Johan Auwerx, Anne-Laure Bulteau, George Church, Virginie Couturaud, Laure Crabbe, Kelvin J A Davies, Anabelle Decottignies, Vadim N Gladyshev, Brian K Kennedy, Nicola Neretti, Carine Nizard, Karl Pays, Daisy Robinton, Vittorio Sebastiano, Rachel E B Watson, Meng C Wang, Knut Woltjen","doi":"10.1038/s43587-025-00901-6","DOIUrl":"https://doi.org/10.1038/s43587-025-00901-6","url":null,"abstract":"<p><p>Accumulating evidence indicates that biological aging can be accelerated by environmental exposures, collectively called the 'exposome'. The skin, as the largest and most exposed organ, can be viewed as a 'window' for the deep exploration of the exposome and its effects on systemic aging. The complex interplay across hallmarks of aging in the skin and systemic biological aging suggests that physiological processes associated with skin aging influence, and are influenced by, systemic hallmarks of aging. This bidirectional relationship provides potential avenues for the prevention of accelerated biological aging and the identification of therapeutic targets. We provide a review of the interactions between skin exposure, aging hallmarks in the skin and associated systemic changes, and their implications in treatment and disease. We also discuss key questions that need to be addressed to maintain skin and overall health, highlighting the need for the development of precise biomarkers and advanced skin models.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-06-09DOI: 10.1038/s43587-025-00879-1
Andrew R Gomez, Hyae Ran Byun, Shaogen Wu, A K M Ghulam Muhammad, Jasmine Ikbariyeh, Jaelin Chen, Alek Muro, Lin Li, Kenneth E Bernstein, Richard Ainsworth, Warren G Tourtellotte
{"title":"Boosting angiotensin-converting enzyme (ACE) in microglia protects against Alzheimer's disease in 5xFAD mice.","authors":"Andrew R Gomez, Hyae Ran Byun, Shaogen Wu, A K M Ghulam Muhammad, Jasmine Ikbariyeh, Jaelin Chen, Alek Muro, Lin Li, Kenneth E Bernstein, Richard Ainsworth, Warren G Tourtellotte","doi":"10.1038/s43587-025-00879-1","DOIUrl":"https://doi.org/10.1038/s43587-025-00879-1","url":null,"abstract":"<p><p>Genome-wide association studies have identified many gene polymorphisms associated with an increased risk of developing late-onset Alzheimer's disease (LOAD). Many of these LOAD risk-associated alleles alter disease pathogenesis by influencing innate immune responses and lipid metabolism of microglia (MG). Here we show that boosting the expression of angiotensin-converting enzyme (ACE), a genome-wide association study LOAD risk-associated gene product, specifically in MG, reduces amyloid-β (Aβ) plaque load, preserves vulnerable neurons and excitatory synapses, and significantly reduces learning and memory abnormalities in the 5xFAD amyloid mouse model of AD. ACE-expressing MG surround plaques more frequently and they have increased Aβ phagocytosis, endolysosomal trafficking and spleen tyrosine kinase activation downstream of the major Aβ receptors, triggering receptor expressed on myeloid cells 2 (Trem2) and C-type lectin domain family 7 member A (Clec7a). These findings establish a role for ACE in enhancing microglial immune function and they identify a potential use for ACE-expressing MG as a cell-based therapy to augment endogenous microglial responses to Aβ in AD.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-06-04DOI: 10.1038/s43587-025-00883-5
Matías Fuentealba, Laure Rouch, Sophie Guyonnet, Jean-Marc Lemaitre, Philipe de Souto Barreto, Bruno Vellas, Sandrine Andrieu, David Furman
{"title":"A blood-based epigenetic clock for intrinsic capacity predicts mortality and is associated with clinical, immunological and lifestyle factors.","authors":"Matías Fuentealba, Laure Rouch, Sophie Guyonnet, Jean-Marc Lemaitre, Philipe de Souto Barreto, Bruno Vellas, Sandrine Andrieu, David Furman","doi":"10.1038/s43587-025-00883-5","DOIUrl":"https://doi.org/10.1038/s43587-025-00883-5","url":null,"abstract":"<p><p>Age-related decline in intrinsic capacity (IC), defined as the sum of an individual's physical and mental capacities, is a cornerstone for promoting healthy aging by prioritizing maintenance of function over disease treatment. However, assessing IC is resource-intensive, and the molecular and cellular bases of its decline are poorly understood. Here we used the INSPIRE-T cohort (1,014 individuals aged 20-102 years) to construct the IC clock, a DNA methylation-based predictor of IC, trained on the clinical evaluation of cognition, locomotion, psychological well-being, sensory abilities and vitality. In the Framingham Heart Study, DNA methylation IC outperforms first-generation and second-generation epigenetic clocks in predicting all-cause mortality, and it is strongly associated with changes in molecular and cellular immune and inflammatory biomarkers, functional and clinical endpoints, health risk factors and lifestyle choices. These findings establish the IC clock as a validated tool bridging molecular readouts of aging and clinical assessments of IC.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144228015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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