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.

慢性低度炎症是年龄增长的一个标志，被称为炎症，与 代谢功能障碍。衰老是一种与年龄增长相关的永久性细胞周期停滞状态， 是对端粒功能障碍、DNA 损伤和氧化应激等应激源的反应而发生的，并导致 释放大量炎症介质，包括细胞因子和趋化因子。这些分泌因子 统称为衰老相关分泌表型（SASP）。 SASP 的功能之一是 招募免疫细胞以促进从组织中清除衰老细胞。衰老增加的同时 实体器官（即肝脏、脂肪组织）和免疫细胞的负担，也称为免疫衰老， 可能会导致炎症，两者之间的相互作用，控制这些过程的机制， 人们对它们如何导致代谢功能障碍知之甚少。最近，我们展示了 大量 T 细胞和巨噬细胞在老年小鼠的脂肪和肝脏中积聚，并发现耗尽 这些小鼠体内的 T 细胞减少了组织炎症并改善了全身代谢。除了免疫 细胞积累、免疫衰老，特别是在适应性免疫系统中，也可能导致 年龄相关的功能障碍，通过降低招募的免疫细胞清除受损细胞的能力 组织并加剧局部炎症。事实上，初步数据表明，对老年小鼠的治疗 与已知的抗衰老药物混合物达沙替尼和槲皮素 (D&Q) 一起使用，可以减少脂肪组织衰老， SASP 可改善代谢功能，并减少老年小鼠脂肪中 T 细胞的积累。这些 数据表明组织衰老与免疫细胞的募集、炎症和代谢功能障碍有关。 在这里，我们将阐明衰老对组织和免疫细胞衰老、T细胞/巨噬细胞的影响 积累和炎症，以及这些相互作用如何在年龄增长过程中损害代谢功能。