title: Aging-like phenotype and defective lineage specification in SIRT1-deleted hematopoietic stem and progenitor cells.
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.
authors: Department of Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Pauline
authors: P
authors: Rimmelé
authors: Department of Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Carolina L
authors: CL
authors: Bigarella
authors: Department of Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA ; Developmental and Stem Cell Biology Multidisciplinary Training Area, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Raymond
authors: R
authors: Liang
authors: Department of Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Brigitte
authors: B
authors: Izac
authors: Department of Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Rebeca
authors: R
authors: Dieguez-Gonzalez
authors: Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Gaetan
authors: G
authors: Barbet
authors: Department of Experimental Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Michael
authors: M
authors: Donovan
authors: Department of Lab Medicine, Children's Hospital, Boston, MA 02115, USA.
authors: Carlo
authors: C
authors: Brugnara
authors: Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA ; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Julie M
authors: JM
authors: Blander
authors: Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors: David A
authors: DA
authors: Sinclair
authors: Department of Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA ; Developmental and Stem Cell Biology Multidisciplinary Training Area, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA ; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA ; Division of Hematology and Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA ; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Saghi
authors: S
authors: Ghaffari
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D019070:Cell Lineage; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D014157:Transcription Factors; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1