The study investigates the intrinsic alterations in hematopoietic stem cells (HSCs) that underlie the aging process. The authors found that long-term HSCs (LT-HSCs) from old mice exhibit increased self-renewal, a reduced capacity to generate lymphoid progenitors, and an increased capacity to generate myeloid progenitors. Microarray analysis revealed that aging is associated with down-regulation of genes involved in lymphoid specification and function and up-regulation of genes involved in myeloid specification and function. Additionally, old LT-HSCs express elevated levels of genes involved in leukemic transformation. These findings suggest that age-dependent changes in gene expression at the stem cell level contribute to the decline in immune function and the increased incidence of leukemia in the elderly. The study highlights the importance of understanding these intrinsic alterations to better comprehend the mechanisms of hematopoietic aging.The study investigates the intrinsic alterations in hematopoietic stem cells (HSCs) that underlie the aging process. The authors found that long-term HSCs (LT-HSCs) from old mice exhibit increased self-renewal, a reduced capacity to generate lymphoid progenitors, and an increased capacity to generate myeloid progenitors. Microarray analysis revealed that aging is associated with down-regulation of genes involved in lymphoid specification and function and up-regulation of genes involved in myeloid specification and function. Additionally, old LT-HSCs express elevated levels of genes involved in leukemic transformation. These findings suggest that age-dependent changes in gene expression at the stem cell level contribute to the decline in immune function and the increased incidence of leukemia in the elderly. The study highlights the importance of understanding these intrinsic alterations to better comprehend the mechanisms of hematopoietic aging.