Aging Hematopoietic Stem Cells Decline in Function and Exhibit Epigenetic Dysregulation

TLDR

Age-related defects in stem cells impair tissue maintenance and contribute to shortened lifespan. By analyzing highly purified hematopoietic stem cells from mice aged 2 to 21 months, the study demonstrates a functional decline accompanied by an increased stem cell number with advancing age. Transcriptomic profiling identified 1,500 age‑induced and 1,600 age‑repressed genes, with up‑regulated stress, inflammation, and protein‑aggregation pathways and down‑regulated genomic‑integrity and chromatin‑remodeling genes, indicating that epigenetic dysregulation drives functional attenuation and heightened neoplastic risk.

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.