Aging Cell最新文献

{"title":"Association of Epigenetic Age Acceleration and Mitochondrial DNA-Based Aging Metrics Provides Insights Into Mechanisms of Aging-Related Diseases.","authors":"Mengyao Wang, Yinan Zheng, Meng Lai, Emmanuel Saake, Xue Liu, Xiuqing Guo, Kent D Taylor, Tianxiao Huan, Roby Joehanes, Drew R Nannini, Kai Zhang, Nicole J Lake, Christina A Castellani, Stephen S Rich, Jerome I Rotter, Yongmei Liu, Laura M Raffield, April P Carson, Myriam Fornage, Jiantao Ma, Dan E Arking, Lifang Hou, Daniel Levy, Chunyu Liu","doi":"10.1111/acel.70279","DOIUrl":"https://doi.org/10.1111/acel.70279","url":null,"abstract":"<p><p>Investigating the interplay between mitochondrial DNA (mtDNA) variations and epigenetic aging metrics may elucidate biological mechanisms associated with age-related diseases. We estimated epigenetic age acceleration (EAA) metrics from DNA methylation data and derived mtDNA metrics, including heteroplasmic variants and mtDNA copy number (mtDNA CN) from whole genome sequencing. Linear regressions and meta-analyses were conducted to assess associations between EAA and mtDNA metrics, adjusting for chronological age, self-identified sex, and other covariates in 6,316 participants (58% female, 41% non-White Americans). Mediation analysis was conducted to examine whether EAA mediated the relationship between mtDNA CN and metabolic traits. A higher burden of rare heteroplasmic variants was associated with accelerations of first-generation EAA metrics, while a lower level mtDNA CN was associated with accelerations of second- and third-generation EAA metrics. For example, one standard deviation (SD) higher MSS, a score based on the predicted functions of rare heteroplasmic variants, was associated with a 0.22-year higher EAA by the Hannum method (p = 1.3E-6) among all participants, while one SD lower mtDNA CN was associated with higher DunedinPACE (β = -0.005, p = 6.0E-4). No significant association was observed between the heteroplasmy burden of common variants and EAAs. Furthermore, we observed DunedinPACE mediated 11.1% and 10.8% of the associations of mtDNA CN with obesity and T2DM in older FHS participants, respectively. Our analysis indicated that higher levels of heteroplasmy burden of rare variants and lower mtDNA CN were associated with accelerated epigenetic aging, and these associations showed stronger magnitudes among older participants.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70279"},"PeriodicalIF":7.1,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145353151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Nuclear Hormone Receptor nhr-76 Induces Age-Dependent Chemotaxis Decline in C. elegans.","authors":"Rikuou Yokosawa, Kentaro Noma","doi":"10.1111/acel.70277","DOIUrl":"https://doi.org/10.1111/acel.70277","url":null,"abstract":"<p><p>A decline in food-searching behavior of post-reproductive animals can benefit the population and possibly be programmed by the genome despite its detrimental effect on an individual. We investigated the genetic program of age-dependent decline in chemotaxis behavior toward an odorant secreted from bacterial food in C. elegans. Through a novel forward genetic screen, we identified the gene encoding a nuclear hormone receptor, nhr-76, whose mutants ameliorate the age-dependent chemotaxis decline. We found that NHR-76 downregulates odorant receptor expression during aging in a ligand-binding-domain-dependent manner. Since NHR-76 expression and localization remain unchanged with age, its activity may be modulated through the ligand-binding domain, leading to age-dependent chemotaxis decline. Our findings imply that post-reproductive behavioral decline can be genetically programmed.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70277"},"PeriodicalIF":7.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein Catabolites as Blood-Based Biomarkers of Aging Physiology: Findings From the Dog Aging Project.","authors":"Benjamin R Harrison, Maria Partida-Aguilar, Abbey Marye, Danijel Djukovic, Mandy Kauffman, Matthew D Dunbar, Blaise L Mariner, Brianah M McCoy, Yadid M Algavi, Efrat Muller, Shiri Baum, Tal Bamberger, Dan Raftery, Kate E Creevy, Anne Avery, Elhanan Borenstein, Noah Snyder-Mackler, Daniel E L Promislow","doi":"10.1111/acel.70226","DOIUrl":"https://doi.org/10.1111/acel.70226","url":null,"abstract":"<p><p>Our understanding of aging has grown through the study of systems biology, including single-cell analysis, proteomics and metabolomics. Studies in lab organisms in controlled environments, while powerful and complex, fall short of capturing the breadth of genetic and environmental variation in nature. Thus, there is now a major effort in geroscience to identify aging biomarkers that might be applied across the diversity of humans and other free-living species. To meet this challenge, the Dog Aging Project (DAP) aims to identify cross-sectional and longitudinal patterns of aging in complex systems, and how these are shaped by the diversity of genetic and environmental variation among companion dogs. Here we surveyed the plasma metabolome from the first year of sampling of the Precision Cohort of the DAP. By incorporating extensive metadata and whole genome sequencing, we overcome the limitations inherent in breed-based estimates of genetic effects, and probe the physiological basis of the age-related metabolome. We identified effects of age on approximately 36% of measured metabolites. We also discovered a novel biomarker of age in the post-translationally modified amino acids (ptmAAs). The ptmAAs, which are generated by protein hydrolysis, covaried both with age and with other biomarkers of amino acid metabolism, and in a way that was robust to diet. Clinical measures of kidney function mediated about half of the age effect on ptmAA levels. This work identifies ptmAAs as robust indicators of age in dogs, and points to kidney function as a physiological mediator of age-associated variation in the plasma metabolome.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70226"},"PeriodicalIF":7.1,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-Cell RNA Sequencing Identifies Accumulation of Fcgr2b + Virtual Memory-Like CD8 T Cells With Cytotoxic and Inflammatory Potential in Aged Mouse White Adipose Tissue.","authors":"Archit Kumar, Martin O'Brien, Vincent B Young, Raymond Yung","doi":"10.1111/acel.70278","DOIUrl":"https://doi.org/10.1111/acel.70278","url":null,"abstract":"<p><p>Aging and obesity are associated with pro-inflammatory changes in adipose tissue. Overlapping mechanisms, such as the infiltration of inflammatory macrophages and T cells into visceral adipose tissue, have been implicated in contributing to inflammation. However, a comparative analysis of both states is needed to identify distinct regulatory targets. Here, we performed single-cell RNA sequencing of stromal vascular fractions (SVF) isolated from gonadal white adipose tissue (gWAT) of young mice fed either a normal or a high-fat diet, and aged mice fed a normal diet. Our analysis revealed that physiological aging, compared to high-fat diet-induced obesity, was associated with an accumulation of phenotypically distinct CD8 T cells resembling virtual memory (VM) CD8 T cells. These cells expressed high levels of Cd44, Sell, Il7r, Il2rb, lacked Itga4, and exhibited elevated Fcgr2b expression which was associated with pseudotime differentiation trajectories. Flow cytometry confirmed an age-associated increase in Fcgr2b + CD49d- VM-like CD8 T cells in gWAT. Notably, these Fcgr2b-expressing cells exhibited a cytotoxic profile and expressed granzyme M. Functional analysis using recombinant granzyme M revealed its potential in inducing inflammation in mouse fibroblasts and macrophages. Together, our study has identified Fcgr2b + CD49d- VM-like CD8 T cells in the adipose tissue of aged mice with regulatory, cytotoxic, and inflammatory potential.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70278"},"PeriodicalIF":7.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Ad Libitum-Fed Diet That Matches the Beneficial Lifespan Effects of Caloric Restriction but Acts via Opposite Effects on the Energy-Splicing Axis.","authors":"Amanda E Brandon, Tamara Pulpitel, Carsten Schmitz-Peiffer, Lewin Small, Alistair M Senior, Sophie Stonehouse, Letisha Prescott, Alyssa Face, K Saiful Islam, Jenny E Gunton, Jacob George, David Raubenheimer, Gregory J Cooney, David G Le Couteur, Stephen J Simpson","doi":"10.1111/acel.70269","DOIUrl":"https://doi.org/10.1111/acel.70269","url":null,"abstract":"<p><p>Caloric restriction (CR) with fasting extends lifespan but is difficult to maintain in humans. Here, we compared conventional CR with periods of fasting to an ad libitum-fed low-protein, high-carbohydrate (LPHC) diet diluted 25% with non-digestible fibre. Both approaches similarly enhanced longevity and metabolic health in mice relative to a control diet. Proteomic analysis of liver tissue revealed that CR increased proteins associated with energy and mitochondrial pathways. By contrast, the LPHC diet reduced these pathways but increased the abundance of proteins associated with RNA metabolism and spliceosome pathways. These results for LPHC support the \"energy-splicing resilience\" axis theory of ageing. Our results suggest that ad libitum-fed diets can be designed to replicate, and potentially enhance, the geroprotective benefits of CR, albeit via different mechanisms, potentially offering a more sustainable dietary approach to longevity extension.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70269"},"PeriodicalIF":7.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Metabolic Transition Between Fasting and Feeding Alters Aging-Associated Metabolites, Lowers BCAAs, and Stimulates FGF21 Production in Humans.","authors":"Maria Lastra Cagigas, Nancy T Santiappillai, Serena Commissati, Giovanni Fiorito, Andrius Masedunskas, Gayathiri Rajakumar, Isabella de Ciutiis, Alan Goldhamer, Brian K Kennedy, Andrew J Hoy, Luigi Fontana","doi":"10.1111/acel.70270","DOIUrl":"https://doi.org/10.1111/acel.70270","url":null,"abstract":"<p><p>Fasting-based interventions are gaining momentum as strategies to modulate longevity. Conversely, the same metabolic adaptations that once ensured survival during starvation now contribute to the global obesity epidemic. While previous studies have characterized metabolic changes during fasting, few have examined the refeeding phase, and most lack an integrated analysis of key hormonal and metabolic regulators, including insulin, leptin, adiponectin, free T3, FGF21, and the plasma metabolome. To address this gap, we profiled 134 plasma metabolites using mass spectrometry, covering pathways involved in lipid, amino acid, and ketone metabolism, in a cohort of 20 adults (mean age 52.2 ± 11.8 years, 55% women, BMI 28.8 ± 6.4 kg/m²) undergoing medically supervised prolonged fasting (mean duration 9.8 ± 3.1 days), followed by plant-based refeeding (5.3 ± 2.4 days). Fasting reduced metabolic rate, reflected by lower free T3 levels (p < 0.0001), and markedly reprogrammed the plasma metabolome, including shifts in seven aging-associated metabolites (glucose, 3-hydroxybutyric acid, glycine, glutamine, alanine, phenylalanine, and tyrosine). Notably, plasma branched-chain amino acid (BCAA) levels remained stable during fasting, suggesting active tissue release to support energy homeostasis alongside ketogenesis. Upon refeeding, 81% of metabolite levels normalized, yet BCAAs declined sharply (valine -45%, leucine -52%, isoleucine -48%; all p < 0.001), consistent with insulin-stimulated tissue uptake. Changes in BCAAs were inversely associated with a fivefold increase in FGF21 levels (243.2-1176 pg/mL, p = 0.0007), which occurred exclusively during refeeding, unlike in rodent models where FGF21 levels rise during fasting. Together, our findings identify refeeding as a critical window for modulating aging-related metabolites and highlight the importance of post-fast refeeding dynamics.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70270"},"PeriodicalIF":7.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Organ-Specific Dedifferentiation and Epigenetic Remodeling in In Vivo Reprogramming.","authors":"Beom-Ki Jo, Seung-Yeon Lee, Hee-Ji Eom, Jumee Kim, Hyuk-Jin Cha","doi":"10.1111/acel.70268","DOIUrl":"https://doi.org/10.1111/acel.70268","url":null,"abstract":"<p><p>The advent of in vivo reprogramming through transient expression of the Yamanaka factors (OCT4, SOX2, KLF4, and c-MYC) holds strong promise for regenerative medicine, despite ongoing concerns about safety and clinical applicability. This review synthesizes recent advances in in vivo reprogramming, focusing on its potential to restore regenerative competence and promote rejuvenation across diverse tissues, including the retina, skeletal muscle, heart, liver, brain, and intestine. We highlight mechanistic parallels and distinctions between injury-induced dedifferentiation and OSKM-mediated reprogramming, emphasizing the roles of dedifferentiation, transient regenerative progenitors, and epigenetic remodeling. Critical safety considerations-such as teratoma formation, organ failure, and loss of cell identity-are discussed alongside strategies designed to mitigate these risks, like cyclic induction and targeted delivery. Finally, we briefly note the growing translational interest in this field, alongside directing readers to recent reviews for detailed coverage of biotech initiatives. Collectively, this work underscores the transformative potential of in vivo reprogramming for both tissue regeneration and rejuvenation, while stressing the importance of precise spatiotemporal control for its safe clinical application.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70268"},"PeriodicalIF":7.1,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145327926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dietary Copper Intake and Biological Aging Among US Adults, NHANES 2003-2018.","authors":"Liujie Zheng, Guoqiang Li, Jingcheng Cao, Zihang Zhao, Liping Zhang, Zhiyong Hou","doi":"10.1111/acel.70272","DOIUrl":"https://doi.org/10.1111/acel.70272","url":null,"abstract":"<p><p>While the health effects of dietary copper intake have been widely studied, no research to date has specifically examined its association with biological aging. Here, we aim to explore the relationship between dietary copper intake and biological aging, while examining the mediating role of dietary inflammatory index (DII). This cross-sectional study included 18,160 adults from the 2003 to 2018 National Health and Nutrition Examination Survey (NHANES). Weighted multivariable linear regression models, subgroup analysis, trend tests, and restricted cubic spline (RCS) were used to analyze the relationship between dietary copper intake and biological aging. Biological aging was measured from different perspectives including phenotypic age (PhenoAge) and phenotypic age acceleration (PhenoAgeAccel). Additionally, mediation analysis explored the mediating role of DII in the above relationships. In this study, we found dietary copper intake was negatively associated with biological aging. Specifically, each 1-unit increase in dietary copper intake was associated with a 1.12-year decrease in PhenoAge and a 1.45-year decrease in PhenoAgeAccel. RCS models revealed a non-linear relationship between dietary copper intake and biological aging (p for nonlinear < 0.001). Specifically, the inverse association was stronger at lower intake levels, with the protective effect plateauing at higher values. Mediation analysis further indicated that DII mediated the above relationships. This study demonstrates a significant negative association between dietary copper intake and biological aging. Public health strategies that increase dietary copper intake may help reduce the burden of biological aging.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70272"},"PeriodicalIF":7.1,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145327880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Baricitinib Augments Lonafarnib Therapy to Preserve Colonic Homeostasis and Microbial Balance in a Mouse Model of Progeria.","authors":"Moritz Schroll, Yacine Amar, Peter Krüger, Klaus Neuhaus, Karima Djabali","doi":"10.1111/acel.70273","DOIUrl":"https://doi.org/10.1111/acel.70273","url":null,"abstract":"<p><p>Hutchinson-Gilford Progeria Syndrome (HGPS) is a fatal genetic disorder caused by progerin, a mutant lamin A variant that disrupts nuclear architecture and drives systemic cellular dysfunction. Gastrointestinal (GI) involvement in HGPS remains poorly understood, despite growing evidence of gut abnormalities and microbial dysbiosis in progeroid mouse models. Here, we provide the first comprehensive characterization of colonic pathology in Lmna^G609G/G609G mice and assess the therapeutic impact of baricitinib (Bar), a JAK-STAT inhibitor, lonafarnib (FTI), the only FDA-approved therapy, and their combination on colonic health. Bar + FTI combination therapy most effectively lowered progerin levels, preserved colonic architecture and epithelial regeneration markers, while also reducing inflammation, cellular senescence, and early fibrotic changes. Notably, FTI monotherapy aggravated inflammation via STAT1 activation, an effect reversed by Bar co-administration. Bar also emerged as the primary driver in mitigating colonic tissue senescence, highlighting its role in supporting intestinal homeostasis. In addition, we observed marked microbial dysbiosis in HGPS mice, particularly in late-stage disease. While both monotherapies induced distinct shifts in gut microbiota, combination therapy preserved a profile more closely resembling healthy controls. These findings expand the current understanding of GI involvement in HGPS and identify the colon as a site where JAK-STAT inhibition enhances the therapeutic profile of FTI.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70273"},"PeriodicalIF":7.1,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145327849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age Deceleration and Reversal Gene Patterns in Dauer Diapause.","authors":"Khrystyna Totska, João C V V Barata, Walter Sandt, David H Meyer, Björn Schumacher","doi":"10.1111/acel.70253","DOIUrl":"https://doi.org/10.1111/acel.70253","url":null,"abstract":"<p><p>The aging process is characterized by a general decrease in physical functionality and poses the biggest risk factor for a variety of diseases such as cancer, cardiovascular diseases, and neurodegenerative disorders among others. Understanding the naturally evolved mechanisms that slow aging and rejuvenate an animal could reveal important concepts on how to prevent age-associated diseases and even revert aging. The C. elegans dauer stage is a robust and long-lived alternative developmental state that, after dauer exit, has a normal adult lifespan with fully retained fecundity. To understand how longevity during dauer and rejuvenation following dauer exit is mediated, we characterized the gene expression changes during dauer and upon exit. We assessed how biological age, as determined via BiT Age, a transcriptome aging clock, is affected during dauer and upon dauer exit. During the dauer stage, we measured a decelerated increase in age compared to the chronological age and an age reversal following dauer exit. Transcriptomic analyses revealed major metabolic shifts and enhanced biomolecular degradation that are reversed during exit. Moreover, we show that transcription-blocking lesions can induce lasting transcription stress in dauers that is rapidly resolved by transcription-coupled nucleotide excision repair during dauer exit. Our data provide new insights into the underlying mechanisms of naturally occurring age deceleration and rejuvenation.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70253"},"PeriodicalIF":7.1,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}