Stem cells use distinct self-renewal programs at different ages.

Stem cells expand in number during development and persist throughout life by undergoing self-renewing divisions. The question of how stem cells self-renew throughout life is a fundamental problem in cell biology, with broad implications for understanding development, tissue regeneration, cancer, and aging. Recent insights demonstrate that self-renewal programs depend on key transcriptional regulators that are often shared among stem cells in different tissues but that often change between stem cells at different stages of life: Embryonic, fetal, young adult, and old adult stem cells are maintained by different self-renewal programs. Self-renewal programs change over time to contend with changes in tissue growth and repair demands as well as the increasing risk of malignant transformation during aging. The downstream mechanisms by which these programs regulate the cell cycle, developmental potential, and timing of differentiation are just starting to be elucidated. One key requirement for self-renewal is repression of the p16(Ink4a) and p19(Arf) tumor suppressors. This is accomplished by overlapping transcriptional regulators whose expression and function change with age, so as to maintain self-renewal potential throughout life while allowing increased expression of p16(Ink4a) and p19(Arf) in aging stem cells. This reduces stem cell function in aging tissues but also reduces cancer incidence.