Tissues have widely varying levels of baseline proliferative activity and regenerative potential. In high-turnover tissues, resident stem cells have been documented to generate large numbers of specialized cell progeny and thereby maintain tissue cellularity and functionality over a lifetime. In tissues with lower proliferative or regenerative capacity, such as the heart, the identification of stem cells has been more difficult, although their existence in some low-proliferative-capacity organs such as the brain has been documented10. Intuitively, it would seem reasonable to posit that preserving an adequate pool of tissue stem cells with robust potential for renewal would be vital to maintaining organ function with advancing age. Such a view is supported by the premature ageing phenotypes observed in mice with conditional deletion of the genes encoding ATR (ataxia telangiectasia and Rad3 related), FOXO transcription factors or ATM (ataxia telangiectasia mutated); these mice exhibit tissue stem-cell defects or diminished oxidative defence and ROS-induced stem-cell depletion (Box 2). Although these genetic models are suggestive, a major question remains about whether numerical or functional decline in tissue stem cells contributes to declining health in
