Abstract

Ageing is due to the accumulation of damage, which arises because of evolved limitations in mechanisms for maintenance and repair. Accumulated damage may cause genomic instability, which in organisms with renewable tissues may result in cancer. To keep cancer at bay, two different tumour suppression mechanisms evolved: caretakers and gatekeepers. Caretakers protect the genome against mutations, while gatekeepers induce cell death or cell cycle arrest of potentially tumourigenic cells. It has been hypothesised that decreased activity of a caretaker may reduce life span, by increasing cancer risk, while the effects of increased activity of a gatekeeper on cancer risk and life span may be antagonistically pleiotropic. Apoptosis and senescence will promote early-life survival by curtailing the development of cancer, but may eventually limit longevity. This article reviews the evidence for this hypothesis. We conclude that several different findings indeed hint at an important role for gatekeeper mediated processes in ageing and its related pathologies. The relative contribution of apoptosis and senescence in specific age-related pathologies remains to be established.