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.

慢性低度炎症是一种被称为炎症的年龄的标志，已与 代谢功能障碍。衰老，一种与年龄相关的永久性细胞周期停滞状态， 发生在响应诸如端粒功能障碍，DNA损伤和氧化应激之类的应激源中，并导致 释放包括细胞因子和趋化因子在内的许多炎症介质的释放。这些分泌的因素 共同称为衰老相关的分泌表型（SASP）。 SASP的一个功能是 募集免疫细胞以促进从组织中清除衰老细胞。同时增加衰老 固体器官（即肝脏，脂肪组织）和免疫细胞的负担，也称为免疫衰老， 可能有助于炎症，两者之间的相互作用，管理这些过程的机制， 以及它们如何导致代谢功能障碍的理解很少。最近，我们已经证明了 大量的T细胞和巨噬细胞在旧小鼠的脂肪和肝脏中积累，发现耗尽 这些小鼠中T细胞的细胞减少组织炎症并改善全身代谢。除了免疫 细胞积累，免疫衰老，特别是在自适应免疫系统中，也可能有助于 通过降低了招募免疫细胞清除受损细胞的能力，与年龄有关的功能障碍 组织并通过加剧局部炎症。确实，初步数据表明对旧小鼠的治疗 与已知的鼻溶剂鸡尾酒，达沙替尼和槲皮素（D＆Q），可减少脂肪组织衰老和 SASP，改善了代谢功能，并减少了老年小鼠脂肪中T细胞的积累。这些 数据暗示组织衰老在免疫细胞，炎症和代谢功能障碍的募集中。 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，炎症，以及这些相互作用如何在促进年龄的情况下损害代谢功能。