{"title":"对衰老相关细胞状态进行有针对性的部分重编程可改善衰老小鼠模型的健康指标","authors":"Sanjeeb Kumar Sahu, Pradeep Reddy, Jinlong Lu, Yanjiao Shao, Chao Wang, Mako Tsuji, Estrella Nuñez Delicado, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte","doi":"10.1126/scitranslmed.adg1777","DOIUrl":null,"url":null,"abstract":"<div >Aging is a complex multifactorial process associated with epigenome dysregulation, increased cellular senescence, and decreased rejuvenation capacity. Short-term cyclic expression of <i>octamer-binding transcription factor 4</i> (<i>Oct4</i>), <i>sex-determining region Y-box 2</i> (<i>Sox2</i>), <i>Kruppel-like factor 4</i> (<i>Klf4</i>), and <i>cellular myelocytomatosis oncogene</i> (<i>cMyc</i>) (<i>OSKM</i>) in wild-type mice improves health but fails to distinguish cell states, posing risks to healthy cells. Here, we delivered a single dose of adeno-associated viruses (AAVs) harboring <i>OSK</i> under the control of the <i>cyclin-dependent kinase inhibitor 2a</i> (<i>Cdkn2a</i>) promoter to specifically partially reprogram aged and stressed cells in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS). Mice showed reduced expression of proinflammatory cytokines and extended life spans upon aged cell–specific <i>OSK</i> expression. The bone marrow and spleen, in particular, showed pronounced gene expression changes, and partial reprogramming in aged HGPS mice led to a shift in the cellular composition of the hematopoietic stem cell compartment toward that of young mice. Administration of AAVs carrying <i>Cdkn2a-OSK</i> to naturally aged wild-type mice also delayed aging phenotypes and extended life spans without altering the incidence of tumor development. Furthermore, intradermal injection of AAVs carrying <i>Cdkn2a</i>-<i><i>OSK</i></i> led to improved wound healing in aged wild-type mice. Expression of <i>CDKN2A</i>-<i>OSK</i> in aging or stressed human primary fibroblasts led to reduced expression of inflammation-related genes but did not alter the expression of cell cycle–related genes. This targeted partial reprogramming approach may therefore facilitate the development of strategies to improve health and life span and enhance resilience in the elderly.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8000,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Targeted partial reprogramming of age-associated cell states improves markers of health in mouse models of aging\",\"authors\":\"Sanjeeb Kumar Sahu, Pradeep Reddy, Jinlong Lu, Yanjiao Shao, Chao Wang, Mako Tsuji, Estrella Nuñez Delicado, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte\",\"doi\":\"10.1126/scitranslmed.adg1777\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >Aging is a complex multifactorial process associated with epigenome dysregulation, increased cellular senescence, and decreased rejuvenation capacity. Short-term cyclic expression of <i>octamer-binding transcription factor 4</i> (<i>Oct4</i>), <i>sex-determining region Y-box 2</i> (<i>Sox2</i>), <i>Kruppel-like factor 4</i> (<i>Klf4</i>), and <i>cellular myelocytomatosis oncogene</i> (<i>cMyc</i>) (<i>OSKM</i>) in wild-type mice improves health but fails to distinguish cell states, posing risks to healthy cells. Here, we delivered a single dose of adeno-associated viruses (AAVs) harboring <i>OSK</i> under the control of the <i>cyclin-dependent kinase inhibitor 2a</i> (<i>Cdkn2a</i>) promoter to specifically partially reprogram aged and stressed cells in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS). Mice showed reduced expression of proinflammatory cytokines and extended life spans upon aged cell–specific <i>OSK</i> expression. The bone marrow and spleen, in particular, showed pronounced gene expression changes, and partial reprogramming in aged HGPS mice led to a shift in the cellular composition of the hematopoietic stem cell compartment toward that of young mice. Administration of AAVs carrying <i>Cdkn2a-OSK</i> to naturally aged wild-type mice also delayed aging phenotypes and extended life spans without altering the incidence of tumor development. Furthermore, intradermal injection of AAVs carrying <i>Cdkn2a</i>-<i><i>OSK</i></i> led to improved wound healing in aged wild-type mice. Expression of <i>CDKN2A</i>-<i>OSK</i> in aging or stressed human primary fibroblasts led to reduced expression of inflammation-related genes but did not alter the expression of cell cycle–related genes. This targeted partial reprogramming approach may therefore facilitate the development of strategies to improve health and life span and enhance resilience in the elderly.</div>\",\"PeriodicalId\":21580,\"journal\":{\"name\":\"Science Translational Medicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":15.8000,\"publicationDate\":\"2024-09-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science Translational Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.science.org/doi/10.1126/scitranslmed.adg1777\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/scitranslmed.adg1777","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Targeted partial reprogramming of age-associated cell states improves markers of health in mouse models of aging
Aging is a complex multifactorial process associated with epigenome dysregulation, increased cellular senescence, and decreased rejuvenation capacity. Short-term cyclic expression of octamer-binding transcription factor 4 (Oct4), sex-determining region Y-box 2 (Sox2), Kruppel-like factor 4 (Klf4), and cellular myelocytomatosis oncogene (cMyc) (OSKM) in wild-type mice improves health but fails to distinguish cell states, posing risks to healthy cells. Here, we delivered a single dose of adeno-associated viruses (AAVs) harboring OSK under the control of the cyclin-dependent kinase inhibitor 2a (Cdkn2a) promoter to specifically partially reprogram aged and stressed cells in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS). Mice showed reduced expression of proinflammatory cytokines and extended life spans upon aged cell–specific OSK expression. The bone marrow and spleen, in particular, showed pronounced gene expression changes, and partial reprogramming in aged HGPS mice led to a shift in the cellular composition of the hematopoietic stem cell compartment toward that of young mice. Administration of AAVs carrying Cdkn2a-OSK to naturally aged wild-type mice also delayed aging phenotypes and extended life spans without altering the incidence of tumor development. Furthermore, intradermal injection of AAVs carrying Cdkn2a-OSK led to improved wound healing in aged wild-type mice. Expression of CDKN2A-OSK in aging or stressed human primary fibroblasts led to reduced expression of inflammation-related genes but did not alter the expression of cell cycle–related genes. This targeted partial reprogramming approach may therefore facilitate the development of strategies to improve health and life span and enhance resilience in the elderly.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine.
The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.