Tissue senescence and age-associated metabolic dysfunction: the role of immune cell mediated inflammation

组织衰老和年龄相关的代谢功能障碍：免疫细胞介导的炎症的作用

• 批准号: 10585818
• 负责人: Lisa A Lesniewski
• 金额: $ 43.29万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585818
• 关键词: Adaptive Immune System; Adipocytes; Adipose tissue; Age; Aging; Antibodies; Cell Aging; Cell Cycle Arrest; Cells; Chronic; DNA Damage; Dasatinib; Data; Disease; Elderly; Functional disorder; Glucose Intolerance; Hepatocyte; Homeostasis; Immune; Impairment; Inflammaging; Inflammation; Inflammation Mediators; Injections; Insulin Resistance; Liver; LoxP-flanked allele; Macrophage; Mature T-Lymphocyte; Mediating; Metabolic; Metabolic dysfunction; Metabolism; Modeling; Mus; Organ; Outcome; Oxidative Stress; Pharmaceutical Preparations; Phenotype; Process; Proteins; Quercetin; Role; Solid; T cell therapy; T-Cell Depletion; T-Lymphocyte; Tamoxifen; Tissues; Toxin; Visceral; age effect; age related; aged; cell injury; chemokine; cytokine; immunosenescence; improved; lipid metabolism; middle age; novel; recruit; response; senescence; stressor; systemic inflammatory response; telomere

Chronic low-grade inflammation, a hallmark of advancing age termed inflammaging, has been implicated in metabolic dysfunction. Senescence, a state of permanent cell cycle arrest associated with advancing age, occurs in response to stressors such as telomere dysfunction, DNA damage, and oxidative stress, and leads to the release of a host of inflammatory mediators including cytokines and chemokines. These secreted factors are collectively termed the senescence associated secretory phenotype (SASP). One function of SASP is the recruitment of immune cells to promote clearance of senescent cells from tissues. While increased senescent burden in both solid organs (i.e.; liver, adipose tissue) and immune cells, also known as immunosenescence, likely contributes to inflammaging, the interplay between the two, the mechanisms governing these processes, and how they lead to metabolic dysfunction are poorly understood. Recently, we have demonstrated substantial T cell and macrophage accumulation in the adipose and liver of old mice and found that depletion of T cells in these mice reduces tissue inflammation and improves systemic metabolism. In addition to immune cell accumulation, immunosenescence, particularly in the adaptive immune system, may also contribute to age-related dysfunction by both reducing the ability of recruited immune cells to clear damaged cells from tissues and by exacerbating local inflammation. Indeed, preliminary data suggest that treatment of old mice with a known senolytic drug cocktail, dasatinib and quercetin (D&Q), reduces adipose tissue senescence and SASP, improves metabolic function, as well as reduces T cell accumulation in adipose of aged mice. These data implicate tissue senescence in the recruitment of immune cells, inflammaging, and metabolic dysfunction. Here, we will elucidate the effects of aging on tissue and immune cell senescence, T cell/macrophage accumulation, and inflammation, as well as how these interact to impair metabolic function in advancing age.

慢性低度炎症是衰老的标志，被称为炎症