Aging of hematopoietic stem cells (HSCs) is associated with intrinsic cellular changes that affect their function and contribute to age-related immune decline and increased leukemia incidence. This study investigated the functional and molecular properties of long-term HSCs (LT-HSCs) from young and old mice, revealing that aging leads to increased self-renewal, altered capacity to generate committed myeloid and lymphoid progenitors, and reduced lymphoid potential. Gene expression profiling showed a systemic down-regulation of genes involved in lymphoid specification and function, and up-regulation of genes involved in myeloid fate and function. Additionally, old LT-HSCs expressed elevated levels of genes associated with leukemic transformation, suggesting that age-dependent gene expression changes at the stem cell level may underlie the shift in lineage potential toward myelopoiesis. The study also found that the frequency of LT-HSCs increases with age, and that these cells retain their ability to generate mature blood cells despite changes in lineage potential. Microarray analysis identified 907 age-regulated genes in LT-HSCs, with 59% of these genes characterized and annotated. These genes were involved in signal transducer activity, receptor activity, and other cellular processes critical for HSC self-renewal and lineage commitment. The expression of genes involved in myeloid specification was up-regulated, while those involved in lymphoid specification were down-regulated, indicating a shift in lineage potential with age. The 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 myeloid leukemias in the elderly. These changes are intrinsic to the stem cells and not merely a result of the aging microenvironment. The study highlights the importance of understanding the molecular mechanisms underlying HSC aging to develop strategies for improving immune function and preventing age-related diseases.Aging of hematopoietic stem cells (HSCs) is associated with intrinsic cellular changes that affect their function and contribute to age-related immune decline and increased leukemia incidence. This study investigated the functional and molecular properties of long-term HSCs (LT-HSCs) from young and old mice, revealing that aging leads to increased self-renewal, altered capacity to generate committed myeloid and lymphoid progenitors, and reduced lymphoid potential. Gene expression profiling showed a systemic down-regulation of genes involved in lymphoid specification and function, and up-regulation of genes involved in myeloid fate and function. Additionally, old LT-HSCs expressed elevated levels of genes associated with leukemic transformation, suggesting that age-dependent gene expression changes at the stem cell level may underlie the shift in lineage potential toward myelopoiesis. The study also found that the frequency of LT-HSCs increases with age, and that these cells retain their ability to generate mature blood cells despite changes in lineage potential. Microarray analysis identified 907 age-regulated genes in LT-HSCs, with 59% of these genes characterized and annotated. These genes were involved in signal transducer activity, receptor activity, and other cellular processes critical for HSC self-renewal and lineage commitment. The expression of genes involved in myeloid specification was up-regulated, while those involved in lymphoid specification were down-regulated, indicating a shift in lineage potential with age. The 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 myeloid leukemias in the elderly. These changes are intrinsic to the stem cells and not merely a result of the aging microenvironment. The study highlights the importance of understanding the molecular mechanisms underlying HSC aging to develop strategies for improving immune function and preventing age-related diseases.