Third are cellular mortality pathway molecules such as the p16 tumour suppressor, which, judging from increased p16 expression in aged human and mouse tissues, including in HSCs, NSCs and islet β-cells in mice30, seems to be involved in the ageing process. Accordingly, mice lacking p16 show enhanced HSC, NSC and islet β-cell function with age30. Last are the mitochondrial pathways. There is increasing recognition that intact mitochondrial function is crucial for the maintenance of stem cells, as evidenced by compromised HSC function, profound anaemia and lymphopenia in mice expressing a mutant form of mitochondrial DNA polymerase-γ that is associated with increased mitochondrial DNA mutations31. Recent evidence also indicates that loss of BMI1, a negative regulator of the Ink4a/Arf locus (also known as Cdkn2a), is associated with decreased mitochondrial function manifesting as decreased electron transport flux, resulting in increased ROS concentrations and stem-cell compromise32. ROS have also been shown to accelerate telomere shortening and activate the p53–p21 axis, as well as modulate signalling pathways essential for maintaining HSC and NSC quiescence, as revealed by loss of oxidative defence in the setting of FOXO deficiency 21,33,34.
