{"title":"Aging microenvironment induces CD8+ T cell exhaustion by suppressing hepatic β-hydroxybutyrylate synthesis","authors":"Yifeng Xiao,Yanling Zhang,Zihao Zhao,Zijian Zhang,Xiaohui Zhang,Pengju Chen,Jin Gu,Haichuan Zhu,Peng Jiang,Jie Cheng","doi":"10.1016/j.cmet.2026.08.009","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.08.009","url":null,"abstract":"The metabolic mechanisms by which aging blunts CD8+ T cell antitumor and pathogen defense remain unknown. We demonstrate that the aged microenvironment induces CD8+ T cell exhaustion by reducing β-hydroxybutyrate (3HB) bioavailability. Aging represses hepatic BDH1-dependent 3HB synthesis, restricting SLC16A1-mediated 3HB uptake. Hepatic BDH1 ablation recapitulates age-associated CD8+ T cell dysfunction, compromising antiviral and antitumor immunity, whereas 3HB supplementation reverses these deficits via protein β-hydroxybutyrylation. Using a 3HB-derived chemical probe, 3Halk, together with functional screening, we identify PRKAR1B as a primary effector of 3HB signaling. PRKAR1B β-hydroxybutyrylation inhibits the transcription factor cyclic AMP (cAMP)-responsive element modulator (CREM), which activates T cell exhaustion-related gene expression. Age-associated 3HB depletion enhances CREM-dependent transcription, sustaining CD8+ T cell exhaustion. Consistently, the aged microenvironment compromises chimeric antigen receptor (CAR) T antitumor activity, which is substantially restored by 3HB treatment. Collectively, this study uncovers a hepatic metabolism-derived 3HB-CREM axis governing CD8+ T cell immunosenescence, highlighting 3HB as a viable immunorestorative strategy to improve immunotherapy outcomes in aged individuals.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"43 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148877367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2026-08-27DOI: 10.1016/j.cmet.2026.07.020
Max C. Petersen,Gordon I. Smith,Sarah S. Farabi,Hector H. Palacios,Mahalakshmi Shankaran,Marc K. Hellerstein,Bruce W. Patterson,Samuel Klein
{"title":"Effect of diet macronutrient content on the cardiometabolic response to weight loss: A randomized clinical trial","authors":"Max C. Petersen,Gordon I. Smith,Sarah S. Farabi,Hector H. Palacios,Mahalakshmi Shankaran,Marc K. Hellerstein,Bruce W. Patterson,Samuel Klein","doi":"10.1016/j.cmet.2026.07.020","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.07.020","url":null,"abstract":"The influence of diet macronutrient content on the cardiometabolic effects of weight loss in people with metabolically unhealthy obesity (prediabetes and hepatic steatosis) has important clinical implications. We evaluated the cardiometabolic effects of moderate (∼10%) weight loss induced by three popular diets with markedly different macronutrient composition (very-low-carbohydrate ketogenic, Mediterranean, and very-low-fat plant-forward). Weight loss increased muscle insulin sensitivity by ∼50% in all groups but caused a two-to-three-fold greater increase in hepatic insulin sensitivity in the very-low-carbohydrate group than the other groups (p < 0.001). Intrahepatic triglyceride content, hepatic de novo lipogenesis, glycated hemoglobin, and 24-h serial plasma glucose and insulin decreased most in the very-low-carbohydrate group. There were no differences among groups in LDL-cholesterol, apolipoprotein B, or 24-h plasma triglyceride concentrations. These results demonstrate that a very-low-carbohydrate diet has greater cardiometabolic benefits, particularly in hepatic metabolic function, than matched 10% weight loss induced by a Mediterranean or very-low-fat diet in people with metabolically unhealthy obesity.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"16 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148821555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2026-08-26DOI: 10.1016/j.cmet.2026.08.002
Rie Matsuzaki,W. Michael Caudle,Timothy R. Sampson
{"title":"The microbiota at the interface of environmental toxicants and the brain","authors":"Rie Matsuzaki,W. Michael Caudle,Timothy R. Sampson","doi":"10.1016/j.cmet.2026.08.002","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.08.002","url":null,"abstract":"Throughout life, humans are exposed to a diverse array of xenobiotics originating from diet, pharmaceuticals, and environmental contaminants. Positioned at the interface between the host and the external environment, the gut microbiota is uniquely situated to both sense and modify the effects of these exposures prior to systemic circulation and delivery to their host targets. Growing evidence indicates that the microbiota play critical roles in shaping xenobiotic fate through both direct metabolic transformation and modulation of host detoxification pathways, barrier integrity, and immune signaling. In this review, we summarize the impacts of disease-relevant environmental neurotoxicants on both the brain and microbial composition. We further integrate emerging mechanistic insights illustrating how microbiota-dependent processes can influence host toxicant responses and detoxification capacity, ultimately modifying exposure outcomes. Collectively, these findings position the gut microbiota as central mediators between environmental exposures and neurological health, providing a framework to better understand potential risk-modifying relationships.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"11 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148821631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2026-08-19DOI: 10.1016/j.cmet.2026.08.012
Alexander S. Banks,Ja Young Kim-Muller,Teresa L. Mastracci,Natalie M. Kofler,Li Qiang,Rebecca A. Haeusler,Michael J. Jurczak,Dina Laznik,Garrett Heinrich,Varman T. Samuel,Gerald I. Shulman,Virginia E. Papaioannou,Domenico Accili
{"title":"Dissociation of the Glucose and Lipid Regulatory Functions of FoxO1 by Targeted Knockin of Acetylation-Defective Alleles in Mice","authors":"Alexander S. Banks,Ja Young Kim-Muller,Teresa L. Mastracci,Natalie M. Kofler,Li Qiang,Rebecca A. Haeusler,Michael J. Jurczak,Dina Laznik,Garrett Heinrich,Varman T. Samuel,Gerald I. Shulman,Virginia E. Papaioannou,Domenico Accili","doi":"10.1016/j.cmet.2026.08.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.08.012","url":null,"abstract":"","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"35 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148768885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2026-08-17DOI: 10.1016/j.cmet.2026.08.005
Sora Q. Kim, Sangho Yu, Christopher D. Morrison
{"title":"Protein restriction and the hallmarks of aging: A coordinated physiological adaptive response?","authors":"Sora Q. Kim, Sangho Yu, Christopher D. Morrison","doi":"10.1016/j.cmet.2026.08.005","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.08.005","url":null,"abstract":"","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"6 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148755351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2026-08-12DOI: 10.1016/j.cmet.2026.07.023
Elisabetta Mereu, Diego Balboa, Johannes Liebig, Aitor Gonzalez-Herrero, Anna Martinez Casals, Mariya Mardamshina, Fanny Mollandin, Felix Schicktanz, Alexander Sudy, Luca Tosti, Maarten van Agen, Valerie Vandenbempt, Dana Avrahami, Frederic Ballllosera Navarro, Edgar Bernardo, Frida Björklund, Robert Lorenz Chua, Marten Engelse, Javier García-Hurtado, Nathalie Groen, Maaike Hanegraaf, Pablo Iañez, Katharina Jechow, Björn Konukiewitz, Christian Lawerenz, Nadja Lewandowski-Hoppe, Domenica Marchese, Mauro J. Muraro, Silvia Pellegrini, Valeria Sordi, Ulrike Taron, Foo Wei Ten, Timo Trefzer, Sven Twardziok, Johannes Wirth, Françoise Carlotti, Eelco de Koning, Jorge Ferrer, Benjamin Glaser, Holger Heyn, Emma Lundberg, Lorenzo Piemonti, Katja Steiger, Alexander van Oudenaarden, Wilko Weichert, Christian Conrad, Roland Eils
{"title":"A single-cell multi-omic atlas of the human pancreas reveals potential for cellular plasticity across development, health, and disease","authors":"Elisabetta Mereu, Diego Balboa, Johannes Liebig, Aitor Gonzalez-Herrero, Anna Martinez Casals, Mariya Mardamshina, Fanny Mollandin, Felix Schicktanz, Alexander Sudy, Luca Tosti, Maarten van Agen, Valerie Vandenbempt, Dana Avrahami, Frederic Ballllosera Navarro, Edgar Bernardo, Frida Björklund, Robert Lorenz Chua, Marten Engelse, Javier García-Hurtado, Nathalie Groen, Maaike Hanegraaf, Pablo Iañez, Katharina Jechow, Björn Konukiewitz, Christian Lawerenz, Nadja Lewandowski-Hoppe, Domenica Marchese, Mauro J. Muraro, Silvia Pellegrini, Valeria Sordi, Ulrike Taron, Foo Wei Ten, Timo Trefzer, Sven Twardziok, Johannes Wirth, Françoise Carlotti, Eelco de Koning, Jorge Ferrer, Benjamin Glaser, Holger Heyn, Emma Lundberg, Lorenzo Piemonti, Katja Steiger, Alexander van Oudenaarden, Wilko Weichert, Christian Conrad, Roland Eils","doi":"10.1016/j.cmet.2026.07.023","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.07.023","url":null,"abstract":"","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"166 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148715633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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