Mechanistic analyses of stem cells from these three representative tissues have linked several molecular pathways to age-associated changes. First is the PI(3)K pathway, which can profoundly alter both the numbers and activity of stem cells and is strongly linked to ageing and lifespan regulation. For example, disruption of FOXO proteins, which are key downstream components of the PI(3)K pathway, results in the ROS-induced depletion of tissue stem cells21,22. Similarly, deletion of another downstream pathway component, TSC1 (a negative regulator of mammalian target of rapamycin (mTOR)), causes profound HSC failure in association with increased ROS concentrations and inappropriate mobilization from the bone marrow niche23. The importance of this TSC1–mTOR signalling axis has been validated at the pharmacological and genetic levels: the hyperproliferative HSC phenotype and consequent bone marrow failure in Pten knockout mice can be reversed by treatment with rapamycin, an mTOR inhibitor24, and the deletion in mice of the gene encoding ribosomal protein S6 kinase 1 (Rps6kb1), a downstream mediator of mTOR activity, can extend lifespan with decreased age-related pathologies25.
