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.
Highlights
Somatic stem cells replenish many tissues throughout life
Known as hematopoietic stem cells (HSCs), continuously regenerate the cells that comprise the blood, including the immune system, which fails with age
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
Summary
Somatic stem cells replenish many tissues throughout life. If the rejuvenating effect of stem cells were perfect, senescing cells would be replaced indefinitely; but even in highly regenerative tissues such as the skin, the gut, and the hematopoietic system, agerelated decline in function is well established [1]. Hematopoietic stem cells (HSCs) continuously replenish the blood and immune system throughout life. Data from mice support an age-related decline in stem cell function [1], suggesting that older HSCs are inadequate to cope with the demands of blood production. A recent study of aged hematopoietic stem and progenitor cells suggested that increased expression of particular proto-oncogenes may underlie some of these observed changes [4]
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