Saturday, April 27, 2024
4/27/2024
PROJECT SUMMARY The “pillars of aging” hypothesis entails that chronic unresolved inflammation, coupled with metabolic dysfunction and macromolecular damage are among the key mechanisms that impairs cellular renewal and regenerative processes that contribute to aging and chronic diseases. Inflammation is a protective mechanism that has evolved to protect against pathogens and tissue injury that enables a host to survive life-threatening challenges by restoration of homeostasis. How then does a protective response like inflammation become chronic, drive aging and serve as a trigger of chronic disease? In absence of overt infections in aging, alterations in the gut microbiota (dysbiosis) or potential translocation of microbiota derived PAMPs to liver, mesenteric and omental adipose tissue could contribute to the mechanism of age-related inflammation. In line with this possibility, recent studies have demonstrated profound changes in the microbiome associated with aging and suggest that the microbiome may play a causal role in certain aspects of inflammaging. We recently discovered that aging is associated with formation of tertiary lymphoid structures, called Fat-associated lymphoid clusters (FALCs), in the visceral adipose tissue. The FALCs, unlike lymph nodes are disorganized non-encapsulated non-classical lymphoid tissues associated to adipocytes contain T cells, B cell and macrophages. Moreover, we found that B cells expand with age in the FALCs and display a unique transcriptional profile reminiscent of antigen-experienced B cells. Based on our original findings, the central hypothesis of this application is that translocation of gut microbes to visceral adipose tissue results in FALC formation and age-related inflammation leading to metabolic dysfunction. We will test the mechanism of how preventing the translocation of microbiota protects against FALC formation and inflammaging.
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