There have been attempts to optimize DNA repair mechanisms in mammals through genetic manipulations but by and large these have been unsuccessful. A classic example is the pm mouse strain which has an activated p yet surprisingly displays signs of premature ageing. Given the complexity of DNA repair pathways, perhaps upregulating a single DNA repair protein merely shifts the ratelimiting step to another protein and fails to have an impact on ageing.Cellular responses to DNA damage involve a large number of proteins.ATM and ATR are among the key mediators of the signal transduction pathway in response to DNA damage.A largescale proteomic analysis revealed over proteins phosphorylated by ATM and ATR in response to DNA damage and painted a picture of a highly interconnected network. This work further exemplies the complexity of the pathways involved and how incomplete our understanding of these networks still is.Possibly the only mouse model hinting that improving DNA repair may delay ageing comes from cancerresistant mice with telomerase constitutively expressed.Cancerresistant mice with enhanced expression of p and other tumour suppressors, p and pARF, have a normal ageing process. It is not clear whether ageing is delayed in these animals or whether DNA repair is improved but these ndings do point towards some level of protection from agerelated degeneration via optimization of pathways associated with cancer and DNA damage responses.Although it is clear that DNA damage and mutations increase with age, the molecular, cellular and physiological mechanisms leading to degeneration are poorly understood.One emerging hypothesis is that alterations in DNA damage or in DNA repair pathways impact on cellular processes that either limit cell division or increase cell loss. Dysfunctional telomeres, in turn, activate DNA damage responses which trigger cell cycle arrest. A more specic hypothesis of the above is that DNA damage accumulating in stem cells has a particular strong contribution to ageing alterations as these will be more easily propagated in tissues and hence impair tissue regeneration.For example, disruption of ATR in adult mice results in stem cell loss and premature ageing. Similarly, it has been suggested that the premature ageing observed in the aforementioned pm mice may be caused by loss of cellularity due to stem A.A variety of intrinsic and extrinsic sources can result in DNA damage.An array of complex DNA repair mechanisms evolved to repair DNA damage, yet these are not perfect.DNA lesions in cells can lead to mutations, cell cycle arrest, blocked transcription, apoptosis and many other problems which in turn result in loss of cell function and cell death.With biological time, the accumulation of DNA damage in an increasing number of cells may lead to loss of stem cells and disruption of tissue homeostasis which causes ageing of the organism.In haematopoietic stem cells DNA damage has been shown to accumulate with age and contribute to functional decline. Therefore, stem cell ageing caused by DNA damage accumulation remains one powerful downstream mechanism of DNA alterations with age. Overall, the path from DNA damage to ageing involves multiple interacting molecular and cellular processes.