The impact of altered p53 dosage on hematopoietic stem cell dynamics during aging

A temporal decline in tissue stem cell functionality may be a key component of mammalian aging. The tumor suppressor p53 has recently been implicated as a potential regulator of aging. We examined age-associated hernatopoietic stem cell (HSC) dynamics in mice with varying p53 activities. Reduced p53 activity in p53(+/-) mice was associated with higher numbers of proliferating hernatopoietic stem and progenitor cells in old age compared with aged wild-type (p53(+/+)) mice. We also assessed HSC dynamics in a p53 mutant mouse model (p53(+/m)) with higher apparent p53 activity than wild-type mice. The p53 hypermorphic (p53(+/m)) mice display phenotypes of premature aging. Many aged p53(+/m) organs exhibit reduced cellularity and atrophy, suggesting defects in stem-cell regenerative capacity. HSC numbers from old p53(+/m) mice fail to increase with age, unlike those of their p53(+/+) and p53(+/-) counterparts. Moreover, transplantation of 500 HSCs from old p53(+/m) mice into lethally irradiated recipients resulted in reduced engraftment compared with old wild-type p53(+/+) and p53(+/-) HSCs. Thus, alteration of p53 activity affects stem-cell numbers, proliferation potential, and hematopoiesis in older organisms, supporting a model in which aging is caused in part by a decline in tissue stem cell regenerative function. (Blood. 2007;109:1736-1742) (c) 2007 by The American Society of Hematology.