Cellular Senescence Causes Age-Related Brown Adipose Tissue Dysfunction
Senescent cells accumulate in tissues with age, a circumstance that appears largely the result of the progressive failure of the immune system to destroy these errant cells in a timely fashion. Senescent cells provoke chronic inflammation and altered cell behavior via the senescence-associated secretory phenotype (SASP), their pro-inflammatory signaling actively maintaining a degraded state of tissue structure and function. Removing senescent cells has been shown to produce rapid, sizable rejuvenation in mice, reversal of many age-related conditions. Separately, researchers have linked the accumulation of senescent cells in aged tissues to scores of age-related diseases and forms of dysfunction. The example here, showing the negative effects of senescent cells on fat tissue, is but one of many.
Brown adipose tissue (BAT)-mediated thermogenesis declines with age. However, the underlying mechanism remains unclear. Here we reveal that bone marrow-derived pro-inflammatory and senescent S100A8+ immune cells, mainly T cells and neutrophils, invade the BAT of male rats and mice during aging. These S100A8+ immune cells, coupled with adipocytes and sympathetic nerves, compromise axonal networks.
Mechanistically, these senescent immune cells secrete abundant S100A8 to inhibit RNA-binding motif protein 3 expression. This downregulation results in the dysregulation of axon guidance-related genes, leading to impaired sympathetic innervation and thermogenic function.
Xenotransplantation experiments show that human S100A8+ immune cells infiltrate mice BAT and are sufficient to induce aging-like BAT dysfunction. Notably, treatment with S100A8 inhibitor paquinimod rejuvenates BAT axon networks and thermogenic function in aged male mice. Our study suggests that targeting the bone marrow-derived senescent immune cells presents an avenue to improve BAT aging and related metabolic disorders.