. A growing body of evidence suggests that adipose tissue is at the center of mechanisms and pathways involved in longevity, the genesis of age-related diseases, inflammation, and metabolic dysfunction. One process that is involved in adipose tissue dysfunction and its systemic effects is cellular senescence. It is well-recognized that senescent cells accumulate in adipose tissue in obesity and with aging. However, the mechanisms eliciting cellular senescence in adipose tissue remain elusive and more research in this area is needed to develop effective senolytic therapies. The remodeling of the extracellular matrix (ECM) is essential for healthy adipose tissue formation and plasticity. The ECM provides structural and anchoring support to the cells, but it also regulates many aspects of the cell?s dynamic behavior by binding to cell-surface integrins and syndecans. Because of its pivotal function, the attachment of ?healthy cells? to the ECM is needed for correct cell proliferation and survival, and lack of cell-ECM contact can lead to cell death. However, other strategies, such as autophagy activation, are employed by the cell to survive in the absence of ECM contact. We reported that mutations in the Syndecan (Sdc) gene reduce energy metabolism and life span in the fruit fly Drosophila melanogaster. We also found that flies with reduced Sdc expression in the fat body had lower phosphorylation levels of Akt, a regulator of autophagy, but also increased fat levels and were more resistant to starvation than controls. Moreover, fat body-specific Sdc knockdown flies displayed higher expression of the Angiotensin converting enzyme-related gene. Mammalian adipocytes express components of the renin-angiotensin systems (RAS) and prolonged activation of local RAS increases oxidative stress and triggers cellular senescence in several tissue/organ cells. Thus, based on these observations and our findings in flies our hypothesis is that deficiency of Sdc activity in the fat tissue promotes autophagy to maintain cellular and tissue homeostasis in the absence of cell-ECM contact. However, this survival strategy in young individuals ultimately leads to fat tissue dysfunction and accelerated aging through activation of RAS-induced cellular senescence. To test our hypothesis and start delineating the mechanism (s) through which Sdc regulates autophagy and cellular senescence, we propose to use adipocyte-specific Sdc4 knockout (KO) mice. Our preliminary studies show that global and adipocyte-specific Sdc4 KO female mice have more total fat mass than controls at a young age, supporting the feasibility of the model. Findings from this project will likely have significant translational value since our genetic studies in humans showed that a variant in the SDC4 gene is associated with adiposity in children and with increased triglyceride levels and decreased likelihood to become centenarian in a cohort of healthy elderly individuals. The same genetic variant was also found associated to body mass index, hypertension, and increased prevalence of coronary artery disease in a cohort of middle- aged individuals, corroborating the idea that SDC4 plays a critical role in age-related phenotypes.
. Adipose tissue is a complex and multi-depot organ, with a function that is vital for metabolic and vascular health. Cellular senescence is a process associated with the adipose tissue dysfunction that occurs with aging and obesity. The studies in this research proposal are important as they will shed new light on the role of a member of the syndecan family in fat cell senescence.