Dysregulation of Hematopoietic Stem Cells with Age.

Aging is an inexorable process marked by an accumulation of traits that ultimately limit the normal function of the organism. Stem cells have long been of interest to the study of aging due to their potential to rejuvenate somatic tissues. However, several groups have now shown that stem cells themselves are subject to the effects of aging. In the hematopoietic system, stem cells markedly decline in function with time, and display characteristic behaviors such as skewing of differentiation toward myeloid development. Current studies focus on both the broad effects of aging on stem cells, and also on the role of specific genes in the aging process. Our laboratory has used gene expression profiling to examine the global gene expression changes that occur in purified hematopoietic stem cells in a time course of aging in mice. Of around 14,000 genes profiled, we identified ~1500 that were age-induced and ~1600 that were age-repressed. Genes associated with the stress response, inflammation, and protein aggregation dominated the upregulated expression profile, while the downregulated profile was marked by genes involved in the preservation of genomic integrity and chromatin remodeling. Regional analysis suggested dysregulation of many gene clusters rather than alterations of a small number of aging-specific genes. These studies suggest that hematopoietic stem cells are subject to extensive epigenetic changes over time. This epigenetic dysregulation lays a fertile ground for secondary events that may enhance the impact of genetic changes, thus driving both functional attenuation and the increased propensity for neoplastic transformation with age. The influence of the aging environment on stem cells is only now being explored. The composition of the bone marrow changes with age, and this can clearly exert effects on the types and proportions of progenitors. Furthermore, environmental conditions that typify the aging state, such as chronic inflammation, can directly impact the stem cells. A broad view of aging bone marrow environment and stem cells, as well as current molecular data addressing these issues, will be presented.