Aging poses the greatest risk for the development of chronic conditions such as diabetes and cardiovascular disease. Adipose tissue is a primary promoter of chronic systemic inflammation, which underlies many age- related diseases; however, the mechanisms responsible for driving age-related adipose tissue inflammation are not fully understood. A further limitation is that much of our current knowledge is based on studies using models of obesity rather than aging. With aging, adipose tissues undergo many obesity-independent changes including an alteration in resident immune cell populations, a decline in progenitor cell function, and increased cellular senescence which may collectively promote the heightened state of chronic sterile inflammation in the aged. The goal of this project is to elucidate the role of visceral adipose tissue (VAT)-resident gamma delta (??)-T cells on age-dependent adipose tissue inflammation. This project is centered on our novel finding that VAT of aged mice contains nearly 5 fold more ??T17 cells (IL-17 producing ??-T cells) than young-adult mice. Our data show that aged mice lacking ??-T cells have reduced systemic and VAT inflammation, decreased markers of cellular senescence in VAT, and an improved metabolic phenotype. These novel data strongly support our hypothesis that accumulation of ??-T cells in VAT promotes preadipocyte senescence and chronic inflammation in the aged. However, the manner with which these cells come to accumulate in VAT with age, and the mechanisms for their action specifically in VAT are not known.
Specific Aim 1 will define VAT- resident ??-T cells and their age-specific roles.
Specific Aim 2 will delineate mechanisms leading to ??-T cell accumulation in adipose tissue.
Specific Aim 3 will test the hypothesis that ??-T cells promote cellular senescence in adipose tissue. These studies will utilize mice which are genetically deficient in ??-T cells (T cell receptor delta knockout (TCR?-/-)) as well as various in vivo and in vitro techniques including surgical manipulations, transcriptome analyses, flow cytometry, and primary cell culture. Collectively, this project will establish the novel concept that VAT-resident ??-T cells are drivers of chronic inflammation and will elucidate mechanisms underlying this process. The generated data will aid in the identification of strategies to reduce the burden of a long list of age-related disorders, for which chronic inflammation is a common denominator.
Aging is a major risk factor for chronic inflammation which is strongly linked to the development of age- associated disease. The proposed project will investigate the influence of adipose tissue gamma delta (??)-T cells on chronic inflammation in the aged.
