title: Evidence that hematopoietic stem cell function is preserved during aging in long-lived S6K1 mutant mice.
abstract: The mechanistic target of rapamycin (mTOR) signalling pathway plays a highly conserved role in aging; mice lacking ribosomal protein S6 kinase 1 (S6K1-/-) have extended lifespan and healthspan relative to wild type (WT) controls. Exactly how reduced mTOR signalling induces such effects is unclear, although preservation of stem cell function may be important. We show, using gene expression analyses, that there was a reduction in expression of cell cycle genes in young (12 week) and aged (80 week) S6K1-/- BM-derived c-Kit+ cells when compared to age-matched WT mice, suggesting that these cells are more quiescent in S6K1-/- mice. In addition, we investigated hematopoietic stem cell (HSC) frequency and function in young and aged S6K1-/-and WT mice. Young, but not aged, S6K1-/-mice had more LSK (lineage-, c-Kit+, Sca-1+) cells (% of bone marrow (BM)), including the most primitive long-term repopulating HSCs (LT-HSC) relative to WT controls. Donor-derived engraftment of LT-HSCs in recipient mice was unaffected by genotype in young mice, but was enhanced in transplants using LT-HSCs derived from aged S6K1-/- mice. Our results are the first to provide evidence that age-associated HSC functional decline is ameliorated in a long-lived mTOR mutant mouse.
authors.affiliation: Glasgow Ageing Research Network (GARNER), Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Selman
authors.affiliation: Glasgow Ageing Research Network (GARNER), Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Amy
authors.initials: A
authors.lastname: Sinclair
authors.affiliation: Metabolic Signaling Group, Medical Research Council Clinical Sciences Centre, Imperial College, London, UK.
authors.forename: Silvia M A
authors.initials: SM
authors.lastname: Pedroni
authors.affiliation: Metabolic Signaling Group, Medical Research Council Clinical Sciences Centre, Imperial College, London, UK.
authors.forename: Elaine E
authors.initials: EE
authors.lastname: Irvine
authors.affiliation: Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Michie
authors.affiliation: Metabolic Signaling Group, Medical Research Council Clinical Sciences Centre, Imperial College, London, UK.
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Withers
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000950:Antigens, Ly; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; C546843:mTOR protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: Gerotarget; HSC; S6K1; aging; mTOR; mammalian target of rapamycin