Senescent immune cells accumulation promotes brown adipose tissue dysfunction during aging

by Selleckchem | Oct 11 2023

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.

Comments:

The passage you provided describes a study that investigated the decline of brown adipose tissue (BAT)-mediated thermogenesis with age and uncovered a potential underlying mechanism. The researchers found that pro-inflammatory and senescent immune cells, specifically S100A8+ T cells and neutrophils derived from the bone marrow, invade the BAT of aging male rats and mice. These immune cells, along with adipocytes and sympathetic nerves, disrupt the axonal networks within the BAT.

The study further elucidated the molecular mechanism involved. The senescent immune cells secrete a significant amount of S100A8 protein, which inhibits the expression of RNA-binding motif protein 3 (RBM3) in the adipose tissue. This downregulation of RBM3 leads to dysregulation of genes related to axon guidance, resulting in impaired sympathetic innervation and compromised thermogenic function in the BAT.

To validate the relevance of these findings to humans, xenotransplantation experiments were conducted. The study demonstrated that human S100A8+ immune cells infiltrated the BAT of mice and were sufficient to induce BAT dysfunction resembling the aging-associated decline observed in humans.

Importantly, the researchers tested the potential therapeutic implications of their findings. Treatment with an S100A8 inhibitor called paquinimod was able to rejuvenate the axon networks and thermogenic function in aged male mice with BAT dysfunction.

In summary, this study suggests that targeting bone marrow-derived senescent immune cells, particularly those expressing S100A8, could be a promising strategy to improve BAT aging and related metabolic disorders. The research provides insights into the cellular and molecular mechanisms underlying the decline of BAT-mediated thermogenesis with age and highlights a potential avenue for intervention.