Senescent immune cells accumulation promotes brown adipose tissue dysfunction during aging.

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 adipose 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.