Mechanisms of adipose tissue functional decline with aging.

About This Grant

Functional decline of visceral adipose tissue, both immunologically and metabolically, contributes to age-related diseases. Aging induces phenotypic alterations in immune cells and adipocytes within adipose tissue, leading to chronic low-grade inflammation and metabolic dysfunction including impaired lipolysis and glucose resistance. Notably, aged adipose tissue macrophages (ATMs) exhibit increased mitochondrial burden, altered chromatin accessibility, and amplified secretion of inflammatory cytokines, collectively driving visceral adipose dysfunction through interactions with other immune cells and white adipocytes. In the pre-F99 phase, I demonstrated that GDF3, a cytokine secreted selectively by ATMs, activates the canonical SMAD2/3 pathway and shifts the chromatin landscape of ATMs toward an inflammatory profile with age. GDF3 also worsens glucose sensitivity in old mice, suggesting a GDF3-mediated interaction between ATMs and adipocyte dysfunction during aging. In the F99 phase, I will investigate how the GDF3- SMAD2/3 axis impairs lipolysis in aged adipocytes. Adipocytes are heterogeneous and can be classified into subsets based on functionality. Age-related imbalance in these subsets, such as a decline in lipolytic adipocyte subset, may impair lipolysis, leading to reduced exercise capacity, dampened cold stress resilience, and exacerbated inflammation during infections in the elderly. However, adipocyte complexity remains largely understudied, particularly in the context of aging, due to the lack of accessible tools for single cell resolution analysis. I will continue developing methods to explore adipocytes at the single cell level, aiming to identify, characterize and target the lipolytic adipocyte subset affected by GDF3-SMAD2/3 signaling. The pathophysiologic role of mitochondria during aging, specifically the link between mitochondrial dysfunction and chronic inflammation, has been increasingly recognized. In the K00 phase, I will explore how mitochondrial (mt) dysfunction originating from bone marrow hematopoietic stem cells (HSCs) impacts ATMs. With an increasing frequency of ATMs originating from HSCs during aging, HSC-derived mt dysfunction may drive the heightened inflammatory phenotype observed in their progeny ATMs. I propose targeting mt dysfunction and inflammatory ATMs by inhibiting the cGAS-STING pathway, which is activated by mt stress. Since HSCs give rise to macrophages in multiple tissues, this research may have broad applicability beyond adipose tissue and result in novel therapeutic approaches to reduce inflammation and metabolic decline in the elderly. This proposal will yield new insights into the molecular mechanisms regulating age-related alterations in macrophages and adipocytes. Furthermore, I aim to target these identified mechanisms using genetic and pharmaceutical tools to mitigate adipose functional decline, ultimately alleviating age-related diseases.