Thursday, April 18, 2024
4/18/2024
ABSTRACT Aging is the strongest risk factor for a range of diseases including diabetes, heart disease, neurodegeneration, cancer, and stroke. A central characteristic of aging is increased adiposity. Adipose tissues are endocrine organs, and it is hypothesized that aging-induced adipose dysfunction causally influences disease etiology through the secretion of molecules that act across a diverse range of tissues to coordinate organismal homeostasis. Adipose is located in distinct depots throughout the body, and it is likely that specific depots differentially contribute to disease vulnerability. The role of the bone marrow adipose tissue (MAT) depot in aging-related disease etiology is not well established, and there is a fundamental knowledge gap regarding the qualitative phenotype and secretory profile of MAT during aging. The long-term objective of this research is to define the roles and mechanisms by which MAT influences health and disease throughout the lifespan. The objective of this R21 proposal is to determine the impact of aging on MAT phenotype and establish the potential contribution of MAT to the systemic profile of adipose-derived molecules during aging. Our central hypothesis is that aging induces a transcriptional response in MAT that alters its secretory profile, which influences systemic metabolic and inflammatory homeostasis by directly impacting circulating peptide, lipid, and metabolite composition; we further hypothesize the impact of aging on the MAT phenotype and secretome is sexually dimorphic. Our rationale for this project is that once it is known how aging influences MAT’s phenotype and contribution to circulating adipose- derived factors, it is likely we can pharmacologically target MAT to reprogram its secretome, producing novel and innovative approaches to maximize healthspan and reduce age-related disease vulnerability. Guided by strong preliminary data, our central hypothesis will be tested by pursuing two specific aims: 1) define the sex- specific transcriptional response of MAT to aging and determine the extent to which the transcriptional response relates to functional outcomes (i.e., proteome, metabolome, lipidome) and 2) establish the extent of transference from MAT to circulating peptide, lipid, and metabolite profiles during aging. At the completion of this project, we expect to have established that 1) MAT phenotype is sensitive to aging and the temporal impact of aging on MAT phenotype is sex-specific, 2) the molecular response to aging is unique in MAT compared to other adipose depots, and 3) MAT is a central contributor to the circulating pool of adipose-derived signaling molecules during aging. Such results will fundamentally advance the field of adipose tissue biology and will provide a positive translational impact by identifying MAT, and specific signaling pathways within MAT, as a prime therapeutic target for the prevention and treatment of aging-related diseases.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
