mTOR hyperactivation drives HSC aging; rapamycin restores hematopoietic stem-cell function.
| Evidence tier | C Animal in vivo |
| Study type | 4 - Animal Study |
| Model system | Mouse (HSC) |
| Journal | Science signaling |
| Year | 2009 |
| Peer reviewed | Yes |
| Source | DOI 10.1126/scisignal.2000559 · PMID 19934433 · Free full text (PMC4020596) |
Age-related declines in hematopoietic stem cell (HSC) function may contribute to anemia, poor response to vaccination, and tumorigenesis. Here, we show that mammalian target of rapamycin (mTOR) activity is increased in HSCs from old mice compared to those from young mice. mTOR activation through conditional deletion of Tsc1 in the HSCs of young mice mimicked the phenotype of HSCs from aged mice in various ways. These included increased abundance of the messenger RNA encoding the CDK inhibitors p16(Ink4a), p19(Arf), and p21(Cip1); a relative decrease in lymphopoiesis; and impaired capacity to reconstitute the hematopoietic system. In old mice, rapamycin increased life span, restored the self-renewal and hematopoiesis of HSCs, and enabled effective vaccination against a lethal challenge with influenza virus. Together, our data implicate mTOR signaling in HSC aging and show the potential of mTOR inhibitors for restoring hematopoiesis in the elderly.
| Intervention | Genetic (Tsc1 deletion) + rapamycin |
| Target | mTOR / TSC1 |
| Model | Mouse (hematopoietic stem cells) |
| Effect | mTOR is elevated in aged HSCs; rapamycin rejuvenates HSC function and immune response |