Research Project
10490499
PROJECT SUMMARY The mTOR pathway regulates longevity as well as stem cell function, and inhibition of mTOR dramatically extends lifespan in model organisms and laboratory animals. While the role of mTOR has been investigated in many tissues, studies on the role of mTOR in regulating lifespan have taken place almost exclusively in the context of pan-tissue knockout strains, and possible tissue-specific roles of mTOR in regulating longevity have not been explored. The aging hematopoietic system undergoes numerous changes including increased myeloid cell production, decreased lymphocyte production, reduced red cell output, and decreased hematopoietic stem cell (HSC) self-renewal. It has been proposed that aging HSCs promote age-related diseases by establishing and/or perpetuating the systemic inflammation observed in aging due to their altered ability to give rise to cells of the innate and cellular immune responses. Consistent with this hypothesis, recent studies from our group and others indicate that HSCs may directly regulate longevity. While most studies investigating hematopoietic aging have focused on cell-intrinsic mechanisms that regulate HSC aging, a growing body of work has firmly established the role of the bone marrow microenvironment in promoting HSC aging. Indeed, our work has demonstrated that bone marrow endothelial cells (BMECs) are major contributors to this process. Intriguingly, in contrast to HSCs where reductions in mTOR activity are thought to promote HSC activity, low mTOR activity in BMECs leads to an enhancement of HSC aging phenotypes. Thus, while many have suggested that systemic mTOR inhibition may be a potential strategy to reverse aging, this view is based on an incomplete picture regarding the role of mTOR in cell-extrinsic regulation of HSC aging. Given recent published and unpublished data confirming that the hematopoietic system is an important contributor to longevity, it is critical to not only clarify the role of mTOR in HSC aging, but determine if hematopoietic aging contributes to other important age- related phenotypes. Moreover, it will be important to determine if hematopoietic regulation of longevity is due to alterations in HSC function and/or their downstream progeny. Given the importance of developing rationally designed strategies to prevent/reverse organismal aging and the potential of inhibiting/reversing HSC aging to promote both healthspan and lifespan, we propose to determine the mTOR-dependent cell-intrinsic and cell- extrinsic mechanisms that regulate HSC aging. Finally, given the uncertainty surrounding direct inhibition of mTOR as a unitary strategy to ameliorate hematopoietic aging, it is important to identify novel regulators of HSC aging. We have identified such a candidate in Thrombospondin-1 (TSP1), and thus will test whether TSP1 inhibition can not only inhibit/reverse HSC aging phenotypes, but also improve health- and lifespan.
