Abstract
Aging hematopoietic stem cells (HSCs) exhibit defective lineage specification that is thought to be central to increased incidence of myeloid malignancies and compromised immune competence in the elderly. Mechanisms underlying these age-related defects remain largely unknown. We show that the deacetylase Sirtuin (SIRT)1 is required for homeostatic HSC maintenance. Differentiation of young SIRT1-deleted HSCs is skewed toward myeloid lineage associated with a significant decline in the lymphoid compartment, anemia, and altered expression of associated genes. Combined with HSC accumulation of damaged DNA and expression patterns of age-linked molecules, these have striking overlaps with aged HSCs. We further show that SIRT1 controls HSC homeostasis via the longevity transcription factor FOXO3. These findings suggest that SIRT1 is essential for HSC homeostasis and lineage specification. They also indicate that SIRT1 might contribute to delaying HSC aging.
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•SIRT1 deacetylase is essential for homeostatic maintenance of HSCs•SIRT1 regulates HSC homeostasis via the longevity factor FOXO3•SIRT1 is essential for HSC lineage specification•Young SIRT1-deleted HSCs have overlapping features with old HSCs
SIRT1 deacetylase is essential for homeostatic maintenance of HSCs and for HSC lineage specification. Differentiation of young SIRT1-deleted HSCs is myeloid biased, defective in lymphoid cell production, leads to anemia, and recapitulates the main features of aged HSCs, suggesting that SIRT1 might contribute to delaying HSC aging. The longevity transcription factor FOXO3 mediates the SIRT1 effects on HSC homeostasis.