The replenishment of spent cells is a common theme in a newly appreciated and growing number of mammalian organs. In most cases, stem cells fuel this process over a lifetime. Recent evidence suggests that an animal's absolute number of hematopoietic stem cells is conserved, and is irrespective of body size and lifespan. What mechanistic strategies and adaptations allow the same-sized population of stem cells to replenish mature cell populations that in the human are several thousand-fold larger than those in the mouse, over a lifespan that is forty-fold longer in humans than in mice? The first aim of this proposal will determine the changes in stem cell number, cell cycle status, responsiveness to cytokines, and apoptosis rate from young to old age in both species. Human umbilical cord blood stem cells from newborns will be compared to bone marrow stem cells from humans greater than 75 years old. A parallel comparison will be made between bone marrow stem cells of 2 month old and 24 month old mice. Inter-species similarities and differences in these parameters during aging will provide insight to the physiological mechanisms employed at the cellular level.
The second aim will determine the similar and contrasting inter-specific strategies employed at the molecular level. Hematopoietic stem cells from both humans and mice, at young and old age, will be purified by cell sorting. The repertoire of expressed genes in each stem cell population will be determined by extracting RNA from the purified populations and hybridizing it to gene sets of human and mouse, respectively, on microarrays. Comparative species analysis of gene expression during aging of stem cells is expected to reveal several patterns of special interest. Those genes whose expression is turned on, increased, or maintained during aging in human, but not in the mouse, suggest candidates that might account for maintenance of stem cell function over a long lifespan in humans. Those whose expression changes in a parallel pattern in both species suggests conserved genes fundamentally important for dealing with the rigors of aging. Those whose expression declines with age in the mouse, but not the human, suggests candidates that are responsible for the maintenance of the longevity of stem cell function. Patterns of gene expression in stem cells during aging will reveal molecular pathways important in defining longevity and may suggest molecular targets of intervention in the treatment of age-related disorders, including cancer.
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