This research intends to elucidate the precise genetic mechanisms contributing to aging phenotypes in mammals. Mounting evidence suggests the age-related decline in the function of tissue-specific stem cells is a central mechanism for mammalian aging. The hematopoietic system demonstrates several prevalent age-related declines in function such as anemia and poor immune responses. Hematopoietic malignancies, however, are more common with age, suggesting a link between tissue function and tumorigenesis. The well-characterized hematopoietic system therefore offers an excellent opportunity to test how genetic regulation of hematopoiesis affects hematopoietic function with age. The tumor suppressor p16lnk4a (pi 6 hereafter) is a proven regulator of age-associated HSC function, but studies have relied upon germline knockout mice which may not reflect the effects of acute somatic pi 6 loss as is observed frequently in mammalian tumors. By comparing young and old mice this work aims to (1) determine how acute somatic loss of p16 affects the proliferation of hematopoietic stem and progenitor cells, and (2) identify if pi 6 regulates cell-autonomous cell fate decisions during hematopoiesis. The role of p16 in regulating age-related changes in hematopoiesis will be tested using inducible loss of p16 accomplished through specific induction of Cre-recombinase using a hematopoietic-specific promoter. The composition and function of HSCs, progenitors, and peripheral blood will be analyzed in young mice (12 weeks old) and old mice (>52 weeks old) both before and after acute loss of p16. To assess the role of p16 in cell fate decisions, the relative production of lymphoid and myeloid progenitors as well as differentiated T cells, B cells, and granulocytes will be analyzed. Techniques used will include detailed flow cytometry, ex vivo cell culture, bone marrow transplants, immunoblotting, and quantitative real-time PCR. This research is fundamental to understanding the mechanisms of aging at a cellular level, and especially for understanding the balance between cancer and aging. Greater understanding of the genetic control of aging will enable the development of new targeted therapies for afflictions common in the aged, as well as the development of cancer therapeutics that avoid pro-aging effects. Further, unraveling the genetic underpinnings of aging will be essential for planning the management of age-related illnesses as the mean age of our nation's population continues to rise
| Liu, Yan; Johnson, Soren M; Fedoriw, Yuri et al. (2011) Expression of p16(INK4a) prevents cancer and promotes aging in lymphocytes. Blood 117:3257-67 |
| Johnson, Søren M; Torrice, Chad D; Bell, Jessica F et al. (2010) Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition. J Clin Invest 120:2528-36 |
