Stem Cell Aging: Potential Effects on Health and Mortality

Aging in a statistical sense is the increasing probability of death with increasing time of an organism’s existence (1, 2). Can we extrapolate this to self-regenerating tissues and most particularly to the stem cells that drive the replenishment of lost and damaged cells throughout life? To be succinct, how close is the linkage between the vitality of the stem cell population and organismal longevity? These questions are currently without clear answers and the nature of the linkage, if any, is likely to be complicated, but is nonetheless conceptually compelling. However, in the most straightforward and blunt analysis, limiting numbers of hematopoietic stem cells, for example, resulting in aplastic anemia is an infrequent cause of death (3). Moreover, the hallmark property that distinguishes stem cells from most other somatic cells, their ability to self-replicate, in theory should provide a life-long supply. It was shown many years ago that hematopoietic stem cells could be transplanted into myeloablated recipients and continue to produce large numbers of differentiated blood cells over a time period that greatly exceeded the lifespan of the donor mouse (4). Serial transplants, in which an original bone marrow graft is passaged through a series of recipients, put even greater demands on stem cell proliferation and differentiation and thus demonstrate the tremendous regenerative potential of these cells. However, the number of transplant iterations that may be carried out is limited using marrow from young mice (5, 6), and further reduced if donors are old (6, 7). In fact it is restricted to less than five, depending on mouse strain, and although it has been argued that the limitation is not so much a result of diminished stem cell potential as in the transplantation procedure itself (8), it is now clear that stem cells’ regenerative properties diminish during the enforced stress of transplantation and during aging (9–15). Thus, there are growing indications that decrements in stem cell numbers and perhaps more importantly, function, play a role in the aging process. For example, it is well known that age-related decline in the immune system is associated with diminished ability to stave off infection and probably accounts for diminished surveillance and killing of malignant cells (16–21). Whether or not the primary lesion for immune decline resides, at least partially, at the stem cell level is without a definitive answer. For example, in the case of the involution of the thymus, more complicated scenarios, including effects on the thymic epithelium, have been invoked (21).