Nature agingPub Date : 2025-09-09DOI: 10.1038/s43587-025-00964-5
Sundeep Khosla, David G Monroe, Joshua N Farr
{"title":"Towards a personalized approach in senolytic trials.","authors":"Sundeep Khosla, David G Monroe, Joshua N Farr","doi":"10.1038/s43587-025-00964-5","DOIUrl":"https://doi.org/10.1038/s43587-025-00964-5","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":19.4,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031668","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 : 2025-09-09DOI: 10.1038/s43587-025-00947-6
Jianying Zhang, He-Ling Wang, Sofie Lautrup, Hilde Loge Nilsen, Jonas T. Treebak, Leiv Otto Watne, Geir Selbæk, Lindsay E. Wu, Torbjørn Omland, Eija Pirinen, Tin Cho Cheung, Jun Wang, Mathias Ziegler, Ole-Bjørn Tysnes, Rubén Zapata-Pérez, Santina Bruzzone, Carles Canto, Michela Deleidi, Georges E. Janssens, Riekelt H. Houtkooper, Morten Scheibye-Knudsen, Masaya Koshizaka, Koutaro Yokote, Eric Verdin, Vilhelm A. Bohr, Charalampos Tzoulis, David A. Sinclair, Evandro Fei Fang
{"title":"Emerging strategies, applications and challenges of targeting NAD+ in the clinic","authors":"Jianying Zhang, He-Ling Wang, Sofie Lautrup, Hilde Loge Nilsen, Jonas T. Treebak, Leiv Otto Watne, Geir Selbæk, Lindsay E. Wu, Torbjørn Omland, Eija Pirinen, Tin Cho Cheung, Jun Wang, Mathias Ziegler, Ole-Bjørn Tysnes, Rubén Zapata-Pérez, Santina Bruzzone, Carles Canto, Michela Deleidi, Georges E. Janssens, Riekelt H. Houtkooper, Morten Scheibye-Knudsen, Masaya Koshizaka, Koutaro Yokote, Eric Verdin, Vilhelm A. Bohr, Charalampos Tzoulis, David A. Sinclair, Evandro Fei Fang","doi":"10.1038/s43587-025-00947-6","DOIUrl":"10.1038/s43587-025-00947-6","url":null,"abstract":"Beyond their classical functions as redox cofactors, recent fundamental and clinical research has expanded our understanding of the diverse roles of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) in signaling pathways, epigenetic regulation and energy homeostasis. Moreover, NAD and NADP influence numerous diseases as well as the processes of aging, and are emerging as targets for clinical intervention. Here, we summarize safety, bioavailability and efficacy data from NAD+-related clinical trials, focusing on aging and neurodegenerative diseases. We discuss the established NAD+ precursors nicotinic acid and nicotinamide, newer compounds such as nicotinamide riboside and nicotinamide mononucleotide, and emerging precursors. We also discuss technological advances including in industrial-scale production and real-time detection, which are facilitating NAD+ research and clinical translation. Finally, we emphasize the need for further large-scale studies to determine optimal dose, administration routes and frequency, as well as long-term safety and interindividual variability in response. Levels of the metabolic coenzyme NAD+ decline during aging, which is linked to many age-related diseases. Zhang et al. review recent clinical and translational evidence testing NAD+ supplementation in age-related diseases, highlighting therapeutic challenges and opportunities.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 9","pages":"1704-1731"},"PeriodicalIF":19.4,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031534","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 : 2025-09-05DOI: 10.1038/s43587-025-00926-x
Daisy Sproviero, César Payán-Gómez, Chiara Milanese, Sander Barnhoorn, Shixiang Sun, Akos Gyenis, Domenico Delia, Tammaryn Lashley, Jan H. J. Hoeijmakers, Jan Vijg, Pier G. Mastroberardino
{"title":"A blood-based DNA damage signature in patients with Parkinson’s disease is associated with disease progression","authors":"Daisy Sproviero, César Payán-Gómez, Chiara Milanese, Sander Barnhoorn, Shixiang Sun, Akos Gyenis, Domenico Delia, Tammaryn Lashley, Jan H. J. Hoeijmakers, Jan Vijg, Pier G. Mastroberardino","doi":"10.1038/s43587-025-00926-x","DOIUrl":"10.1038/s43587-025-00926-x","url":null,"abstract":"Aging is the main risk factor for Parkinson’s disease (PD), yet our understanding of how age-related mechanisms contribute to PD pathophysiology remains limited. We conducted a longitudinal analysis of blood samples from the Parkinson’s Progression Markers Initiative cohort to investigate DNA damage in PD. Patients with PD exhibited disrupted DNA repair pathways and biased suppression of longer transcripts, indicating age-related, transcription-stalling DNA damage. Notably, at the intake visit, this DNA damage signature was detected only in patients with more severe progression of motor symptoms over 3 years, suggesting its potential as a predictor of disease severity. We validated this signature in independent PD cohorts and confirmed increased DNA damage in peripheral blood cells and dopamine neurons of the substantia nigra pars compacta in postmortem PD brains. Our study sheds light on an aging-related mechanism in PD pathogenesis and identifies potential markers of disease progression, providing a diagnostic platform to prognosticate disease progression. Aging is a risk factor for Parkinson’s disease; however, how DNA damage accumulation, a hallmark of aging, contributes to its pathophysiology remains incompletely understood. Here, the authors identify a blood-based DNA damage signature that is associated with disease progression in patients with Parkinson’s disease.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 9","pages":"1844-1861"},"PeriodicalIF":19.4,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12443628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-09-03DOI: 10.1038/s43587-025-00955-6
Nicholas S. Reed, Alison R. Huang, Josef Coresh
{"title":"Midlife hearing loss and dementia risk","authors":"Nicholas S. Reed, Alison R. Huang, Josef Coresh","doi":"10.1038/s43587-025-00955-6","DOIUrl":"10.1038/s43587-025-00955-6","url":null,"abstract":"Hearing loss is common among older adults and has reported associations with a higher risk of dementia. Machado-Fragua et al. offer evidence that shows midlife hearing loss is modestly associated with a higher incidence of late-life dementia, and highlight considerations of duration of exposure, measurement, intervention timing and public health awareness for dementia risk reduction.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 9","pages":"1654-1656"},"PeriodicalIF":19.4,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144994894","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 : 2025-09-03DOI: 10.1038/s43587-025-00943-w
Seda Koyuncu, Yaiza Dominguez-Canterla, Rafael Alis, Nassima Salarzai, Dunja Petrovic, Nuria Flames, David Vilchez
{"title":"The aging factor EPS8 induces disease-related protein aggregation through RAC signaling hyperactivation","authors":"Seda Koyuncu, Yaiza Dominguez-Canterla, Rafael Alis, Nassima Salarzai, Dunja Petrovic, Nuria Flames, David Vilchez","doi":"10.1038/s43587-025-00943-w","DOIUrl":"10.1038/s43587-025-00943-w","url":null,"abstract":"Aging is a major risk factor for neurodegenerative diseases associated with protein aggregation, including Huntington’s disease and amyotrophic lateral sclerosis (ALS). Although these diseases involve different aggregation-prone proteins, their common late onset suggests a link to converging changes resulting from aging. In this study, we found that age-associated hyperactivation of EPS8/RAC signaling in Caenorhabditis elegans promotes the pathological aggregation of Huntington’s disease-related polyglutamine repeats and ALS-associated mutant FUS and TDP-43 variants. Conversely, knockdown of eps-8 or RAC orthologs prevents protein aggregation and subsequent deficits in neuronal function during aging. Similarly, inhibiting EPS8 signaling reduces protein aggregation and neurodegeneration in human cell models. We further identify the deubiquitinating enzyme USP4 as a regulator of EPS8 ubiquitination and degradation in both worms and human cells. Notably, reducing USP-4 upregulation during aging prevents EPS-8 accumulation, extends longevity and attenuates disease-related changes. Our findings suggest that targeting EPS8 and its regulatory mechanisms could provide therapeutic strategies for age-related diseases. Aging is a risk factor for neurodegenerative diseases associated with protein aggregation. Here the authors identify age-related hyperactivation of EPS8/RAC signaling in C. elegans as a driver of pathological protein aggregation, highlighting EPS8 and its regulators as potential therapeutic targets.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 9","pages":"1750-1770"},"PeriodicalIF":19.4,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12443605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144994960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-09-02DOI: 10.1038/s43587-025-00952-9
Elsie Gonzalez-Hurtado, Claire Leveau, Keyi Li, Manish Mishra, Rihao Qu, Emily L. Goldberg, Sviatoslav Sidorov, Payal Damani-Yokota, Stephen T. Yeung, Camille Khairallah, David Gonzalez, Taverlyn M. Shepard, Christina Camell, Maxim N. Artyomov, Yuval Kluger, Kamal M. Khanna, Vishwa Deep Dixit
{"title":"Nerve-associated macrophages control adipose homeostasis across lifespan and restrain age-related inflammation","authors":"Elsie Gonzalez-Hurtado, Claire Leveau, Keyi Li, Manish Mishra, Rihao Qu, Emily L. Goldberg, Sviatoslav Sidorov, Payal Damani-Yokota, Stephen T. Yeung, Camille Khairallah, David Gonzalez, Taverlyn M. Shepard, Christina Camell, Maxim N. Artyomov, Yuval Kluger, Kamal M. Khanna, Vishwa Deep Dixit","doi":"10.1038/s43587-025-00952-9","DOIUrl":"10.1038/s43587-025-00952-9","url":null,"abstract":"Age-related inflammation or ‘inflammaging’ increases disease burden and controls lifespan. Adipose tissue macrophages (ATMs) are critical regulators of inflammaging; however, the mechanisms involved are not well understood in part because the molecular identities of niche-specific ATMs are unknown. Using intravascular labeling to exclude circulating myeloid cells followed by single-cell sequencing with orthogonal validation via multiparametric flow cytometry, we define sex-specific changes and diverse populations of resident ATMs through lifespan in mice. Aging led to depletion of vessel-associated macrophages, expansion of lipid-associated macrophages and emergence of a unique subset of CD38+ age-associated macrophages in visceral adipose tissue with inflammatory phenotype. Notably, CD169+CD11c− ATMs are enriched in a subpopulation of nerve-associated macrophages (NAMs) that declines with age. Depletion of CD169+ NAMs in aged mice increases inflammaging and impairs lipolysis suggesting catecholamine resistance in visceral adipose tissue. Our findings reveal NAMs are a specialized ATM subset that control adipose homeostasis and link inflammation to tissue dysfunction during aging. Gonzalez-Hurtado, Leveau and colleagues characterize adipose resident tissue macrophages across lifespan in mice, finding that nerve-associated macrophages, which mitigate inflammation and control lipolysis and catecholamine resistance, are lost during aging.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 9","pages":"1828-1843"},"PeriodicalIF":19.4,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12443591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144983446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-09-01DOI: 10.1038/s43587-025-00950-x
Jiyeon Lee, Ryeonghwa Kang, Sohui Park, Ibrahim O Saliu, Minsoo Son, Jaymie R Voorhees, Julie M Dimitry, Elsa I Quillin, Lauren N Woodie, Brian V Lananna, Li Gan, Young-Ah Goo, Guoyan Zhao, Mitchell A Lazar, Thomas P Burris, Erik S Musiek
{"title":"REV-ERBα regulates brain NAD<sup>+</sup> levels and tauopathy via an NFIL3-CD38 axis.","authors":"Jiyeon Lee, Ryeonghwa Kang, Sohui Park, Ibrahim O Saliu, Minsoo Son, Jaymie R Voorhees, Julie M Dimitry, Elsa I Quillin, Lauren N Woodie, Brian V Lananna, Li Gan, Young-Ah Goo, Guoyan Zhao, Mitchell A Lazar, Thomas P Burris, Erik S Musiek","doi":"10.1038/s43587-025-00950-x","DOIUrl":"10.1038/s43587-025-00950-x","url":null,"abstract":"<p><p>Nicotinamide adenine dinucleotide (NAD<sup>+</sup>) is a critical metabolic co-enzyme implicated in brain aging, and augmenting NAD<sup>+</sup> levels in the aging brain is an attractive therapeutic strategy for neurodegeneration. However, the molecular mechanisms of brain NAD<sup>+</sup> regulation are incompletely understood. In cardiac tissue, the circadian nuclear receptor REV-ERBα has been shown to regulate NAD<sup>+</sup> via control of the NAD<sup>+</sup>-producing enzyme NAMPT. Here we show that REV-ERBα controls brain NAD<sup>+</sup> levels through a distinct pathway involving NFIL3-dependent suppression of the NAD<sup>+</sup>-consuming enzyme CD38, particularly in astrocytes. REV-ERBα deletion does not affect NAMPT expression in the brain and has an opposite effect on NAD<sup>+</sup> levels as in the heart. Astrocytic REV-ERBα deletion augments brain NAD<sup>+</sup> and prevents tauopathy in P301S mice. Our data reveal that REV-ERBα regulates NAD<sup>+</sup> in a tissue-specific manner via opposing regulation of NAMPT versus CD38 and define an astrocyte REV-ERBα-NFIL3-CD38 pathway controlling brain NAD<sup>+</sup> metabolism and neurodegeneration.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":19.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144983528","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 : 2025-08-28DOI: 10.1038/s43587-025-00945-8
Cheyenne Rechsteiner, Francesco Morandini, Sei Joong Kim, Andrei Seluanov, Vera Gorbunova
{"title":"Unlocking longevity through the comparative biology of aging","authors":"Cheyenne Rechsteiner, Francesco Morandini, Sei Joong Kim, Andrei Seluanov, Vera Gorbunova","doi":"10.1038/s43587-025-00945-8","DOIUrl":"10.1038/s43587-025-00945-8","url":null,"abstract":"The comparative biology of aging leverages the remarkable diversity in aging rates and lifespans across species to uncover naturally evolved adaptations that promote longevity, disease resistance and injury resilience. The beauty of comparative biology is that it discovers adaptations that evolved outside of the protected laboratory environment, shaped by natural selection under real-world pressures. In this Review, we outline key approaches in comparative biology of aging studies, including the study of public mechanisms, which are shared between species, and private mechanisms, which are species-specific. Additionally, we present insights gained through high-throughput omics technologies—including genomics, transcriptomics, epigenomics, proteomics and metabolomics—and illustrate how these findings advance our understanding of how to ameliorate the hallmarks of aging, enhance cancer resistance and improve regeneration, with a focus on mammals. Finally, we offer practical guidance for designing and interpreting comparative studies aimed at understanding and translating longevity mechanisms. Rechsteiner and colleagues explore how studying lifespan and disease resistance across species reveals natural adaptations that promote longevity. The authors summarize new discoveries and discuss approaches and recommendations for comparative aging research.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 9","pages":"1686-1703"},"PeriodicalIF":19.4,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144983748","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}