Introduction and Objective: Brown adipose tissue (BAT) presents a promising target to combat obesity and metabolic diseases. In humans, BAT mass and activity substantially decline with aging. However, the mechanisms underlying the age-related decline in BAT remain poorly understood. Due to their genetic and physiological similarities to humans, non-human primates (NHPs) provide a powerful model for studying BAT aging.Methods: We integrated snRNA-seq and spatial transcriptomics analyses of supraclavicular and axillary BAT from female and male African green monkeys (Chlorocebus aethiops sabaeus) across the lifespan, and complemented these analyses with functional studies using bona fide human brown adipocyte models in vitro.Results: Aging induced coordinated transcriptional reprogramming of adipocytes, with upregulation of metabolic, extracellular matrix, and stress-response genes, and downregulation of mitochondrial fatty acid oxidation and thermogenic programs. Together, these changes reflect a shift from a metabolically active, thermogenic state to impaired oxidative metabolism and BAT dysfunction. Importantly, we uncovered an age-dependent inflammatory reprogramming of the immune microenvironment (“inflammaging”) in BAT. Within these immune niches, aging was associated with a shift from anti-inflammatory macrophages toward metabolically activated and pro-inflammatory macrophages. Immune response enrichment analysis revealed coordinated activation of inflammatory cytokine response programs across several immune cell populations. Using bona fide human brown adipocyte models in vitro, we further defined immune regulatory mechanisms that control the thermogenic program and identified signaling pathways that determine brown adipocyte vulnerability or resilience to inflammation.Conclusion: Our study provides new mechanistic insights into how the local immune microenvironment drives age-related decline of BAT thermogenesis and lays the foundation for developing therapeutic strategies to restore its function in aging and obesity.
L. Wang: None. K. Kavanagh: None. F. Shamsi: None.
American Diabetes Association (1-26-PDF-0680), American Heart Association Award (24CDA1271852)
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