Genetic control of stem cells: implications for aging.

Stem cells are currently at the center of both controversy and notoriety. The harvest of human embryonic or fetal stem cells, at least with methods available now, necessarily involves the sacrifice of the embryo or fetus. This critical step in the procurement of stem cells has stimulated intense discussion at all levels of academia, government, and society in general. What societal benefits, if any, justify such a strategy for obtaining these stem cells? In other species it has been possible to generate virtually all cell types found in adult organs from embryonic stem cells. This ability has opened endless clinical possibilities for tissue and organ replacement through the transplantation of cells derived from embryonic stem cells. Luckily, there may be an alternative to this ethical dilemma. It is becoming increasingly clear that stem cells exist in many, if not all, adult tissues. Adult stem cells normally replenish tissue cells lost through the wear and tear of aging or damage from injury or disease. With the proper coaxing in tissue culture and when transplanted, these stem cells may regenerate the full repertoire of organotypic cells and thus may therapeutically regenerate tissues in vivo in much the same way as embryonic stem cells do. For several reasons, the best-studied stem cells are those of the blood-forming system. Mature blood cells generally have short functional life spans, usually measured in days, and therefore require replenishment at a steady pace throughout one's lifetime. Stem cells are intimately involved in this renewal and, because of the relative ease of access to the bone marrow, stem cells have been well studied. Second, bone marrow transplantation following radiation or high-dose chemotherapy in the treatment of cancer has fostered research on the basic biology and therapeutic uses of hematopoietic stem cells over the more than 30 years stem cell transplantation has been used clinically. It is my aim to review what is known about the genes controlling hematopoietic stem cell function. Identifying, and ultimately manipulating, the genes that regulate stem cell number, replication rate, and self-renewal capacity may have important clinical benefits. I discuss evidence suggesting that the characterization of least some of these stem cell genes will shed light on mechanisms important in the aging process. I advance the hypothesis that stem cells accumulate cellular damage during aging that diminishes their developmental potency and ability to replenish blood cells, particularly after hematopoietic stress. In this view, the impaired function of stem cells in hematopoietic and in other self-renewing tissues limits the longevity of animals, and perhaps of humans.