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

慢性低度炎症，一种被称为炎症的增龄标志，已被认为与 代谢功能障碍。衰老，一种与年龄增长相关的永久性细胞周期停滞状态， 发生于应激源，如端粒功能障碍、DNA损伤和氧化应激，并导致 包括细胞因子和趋化因子在内的一系列炎症介质的释放。这些隐藏的因素 统称为衰老相关分泌表型(SASP)。SASP的一个功能是 招募免疫细胞以促进衰老细胞从组织中清除。当衰老加剧时 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， 可能会导致炎症，两者之间的相互作用，管理这些过程的机制， 以及它们是如何导致代谢障碍的，人们对此知之甚少。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聚集并发现耗竭 这些小鼠体内的T细胞可以减少组织炎症，改善全身新陈代谢。除了免疫之外 细胞积累、免疫衰老，特别是在适应性免疫系统中，也可能有助于 与年龄相关的功能障碍，既降低了重新招募的免疫细胞清除受损细胞的能力 并通过加剧局部炎症。事实上，初步数据表明，对老年老鼠的治疗 使用一种已知的抗衰老药物鸡尾酒，达沙替尼和槲皮素(D&Q)，减少脂肪组织衰老和 SASP可改善衰老小鼠的代谢功能，减少T细胞在脂肪中的蓄积。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 积聚和炎症，以及这些因素如何相互作用，在年龄增长时损害代谢功能。

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.