Therefore, it is crucial, even if often hard, to interpret experimental results in light of how they inform the ageing process. With technical advances permitting detection of new forms of DNA damage and mutations, the DNA damage theory of ageing has changed over the years. In contrast, DNA damage refers to physical or chemical alterations in the structure of the double helix.In other words, mutations change the informational content of a DNA molecule, whilst damage modies the structure of a DNA molecule.The DNA damage theory of ageing postulates that the main cause of the functional decline associated with ageing is the accumulation of DNA damage and ensuing cellular alterations and disruption of tissue homeostasis. Although damage to other kinds of molecules found in cells may also inuence ageing, DNA damage is particularly important because, unlike other cellular components which can normally be replaced, DNA must last the lifetime of the cell. Damage to the DNA can have multiple effects, depending on the type of damage and genomic region affected. In particular, DNA damage can dysregulate gene expression and cell function, impair transcription, cause cell cycle arrest and. DNA damage can also lead to mutations when the DNA is repaired andor replicated.Hence, the DNA damage theory of ageing can be interpreted in different ways, depending on how one interprets the relative contribution of each of these effects of DNA damage on the ageing process.Although the focus of our review is on damage to the nuclear DNA in ageing has also been proposed.The mtDNA is much more prone to damage than nDNA, since mtDNA is not protected by histone proteins and it is close to the site of reactive oxygen species generation in the mitochondrial membrane.In addition, overall the repair of mtDNA is less efcient than the repair of nDNA.Because the effects of disruption of certain DNA repair pathways in accelerating ageing are arguably the strongest evidence to date supporting the DNA damage theory of ageing this is initially reviewed herein.Most of these diseases are caused by defects in DNA repair genes, supporting the idea that the balance between DNA damage and repair determines the rate of ageing.Only progeroid syndromes caused by singlegene defects are included because the causal mechanisms are better understood.On the other hand, WS patients show no increased tendency for neurodegeneration, and the immune system remains normal.The WRN protein is involved in several important biological processes, related to DNA replication, recombination, apoptosis and telomere metabolism, but its major function seems to be the reinitiation of stalled replication forks.The cells of WS patients show signicant chromosomal abnormalities, increased frequency of deleterious mutations and accumulation of DNA doublestrand breaks. WS broblasts reach the stage of replicative senescence considerably faster than normal broblasts. HGPS patients show the following symptoms: premature loss of hair and subcutaneous fat, postnatal growth is severely disturbed, osteolysis, decreased joint mobility from the second to third year, thinning of the skin, limited sexual development and severe vascular problems in the brain and elsewhere strokes occur at the median age of years.