Epigenetic Drivers of Hematopoietic Stem Cell Aging
2013 new Scholar Award in aging
The process of aging involves a progressive decline in physiology and function of our tissues. Current research suggests that we age, in part, due to reduced function of self-renewing stem cells that are required for tissue rejuvenation of many tissue types. Our understanding of why and how stem cells decline in function during aging is incomplete. The question of how stem cells age is presently best addressed using the blood (hematopoietic) system, where hematopoietic stem cells (HSCs) are easily purified and studied in well-validated assays such as bone marrow transplantation. A number of health conditions involving the blood system are more prevalent in aged populations including immune deficiency, anemia, bone marrow failure and predisposition to acute myeloid leukemia (AML). All of these contribute significantly to increased morbidity and mortality. Our research focuses on how epigenetic mechanisms contribute to HSC aging. Epigenetics, the study of changes in gene activity that are not caused by changes in the DNA sequence, is emerging as an exciting new frontier in stem cell aging. Our research focuses on a specific form of epigenetic regulation, called DNA methylation. We use cutting-edge techniques to define specific epigenetic changes that occur during HSC aging, and combine this with unique mutant mouse models to test whether these changes accelerate aging. Our research also examines how therapies that are known to rejuvenate HSCs, such as rapamycin, are dependent upon inducing epigenetic changes. Together, our results will define epigenetic mechanisms that promote or prevent HSC aging, offering a means to extend human healthspan by preventing or reversing age-associated immune deficiency, anemia, marrow failure, and predisposition to cancer.