Aging Hematopoietic Stem Cells Decline in Function and Exhibit Epigenetic Dysregulation

Abstract

Age-related defects in stem cells can limit proper tissue maintenance and hence contribute to a shortened lifespan. Using highly purified hematopoietic stem cells from mice aged 2 to 21 mo, we demonstrate a deficit in function yet an increase in stem cell number with advancing age. Expression analysis of more than 14,000 genes identified 1,500 that were age-induced and 1,600 that were age-repressed. Genes associated with the stress response, inflammation, and protein aggregation dominated the up-regulated expression profile, while the down-regulated profile was marked by genes involved in the preservation of genomic integrity and chromatin remodeling. Many chromosomal regions showed coordinate loss of transcriptional regulation; an overall increase in transcriptional activity with age and inappropriate expression of genes normally regulated by epigenetic mechanisms was also observed. Hematopoietic stem cells from early-aging mice expressing a mutant p53 allele reveal that aging of stem cells can be uncoupled from aging at an organismal level. These studies show that hematopoietic stem cells are not protected from aging. Instead, loss of epigenetic regulation at the chromatin level may drive both functional attenuation of cells, as well as other manifestations of aging, including the increased propensity for neoplastic transformation. Aging is marked by a decline in function of the entire organism. The effect of age on the regenerative capacity of adult stem cells, which should rejuvenate tissues throughout life, is poorly understood. Bone marrow stem cells, also known as hematopoietic stem cells (HSCs), continuously regenerate the cells that comprise the blood, including the immune system, which fails with age. Here, we show that older HSCs were less able to regenerate the blood system than young HSCs. Paradoxically, the HSC number increased concomitantly, leading to no major difference in overall blood production, even though the immune system did exhibit some defects. To determine why these changes occurred, we looked at global patterns of gene expression in young versus old HSC. Stem cells exhibited an elevated inflammatory response and a decline in factors, called chromatin regulators, that orchestrate DNA accessibility and gene expression. Additional evidence supports the idea that loss of overall gene regulation (epigenetic regulation) is a major event during aging. Whereas much of aging research is concentrated on accumulation of mutations in DNA rather than on global regulatory mechanisms, we speculate that these epigenetic changes could drive many of the manifestations of age. This view also may explain the increased incidence of cancer with age.