title: The impact of altered p53 dosage on hematopoietic stem cell dynamics during aging.
abstract: 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 hematopoietic stem cell (HSC) dynamics in mice with varying p53 activities. Reduced p53 activity in p53+/- mice was associated with higher numbers of proliferating hematopoietic 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.
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, and Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, OH, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Dumble
authors.forename: Lynette
authors.initials: L
authors.lastname: Moore
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Chambers
authors.forename: Hartmut
authors.initials: H
authors.lastname: Geiger
authors.forename: Gary
authors.initials: G
authors.lastname: Van Zant
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Goodell
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Donehower
mesh_terms: D000375:Aging; D000818:Animals; D002452:Cell Count; D049109:Cell Proliferation; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D016159:Tumor Suppressor Protein p53