Wednesday, February 5, 2025
2/5/2025
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.
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