HGPS is caused by a point mutation in the gene for lamin A, a type of protein that forms a network of laments beneath the inner nuclear membrane called the nuclear lamina. Atype lamins can directly bind to DNA and to chromatin, but because they are involved in a variety of processes, the exact molecular mechanism of HGPS remains unclear.Although WS and HGPS patients have little overlap of clinical symptoms, at the cellular level both these progeroid syndromes are associated with increased genomic instability: neurodegeneration, skeletal degeneration, impaired sexual development, cachexia, osteoporosis, cataracts, brittle hair and nails.TTD is caused by point mutations in the XPD gene, which encodes one of the two core transcription factor IIH helicases. In particular, ATM is involved in cell cycle progression and checkpoint response to DNA damage, including oxidative damage to DNA. In fact, many of the genes and pathways involved in human progeroid syndromes also result in progeroid syndromes when mutated in mice.Atm disruption in mice with short telomeres, however, results in symptoms of accelerated ageing. Taken together, the results from progeroid mice conrm the observations from human progeroid syndromes and thus will not be presented in detail here. Readers are referred to one of the many excellent reviews on this topic for more detailed information. Overall, ample evidence suggests that disruption of genes involved in DNA repair andor DNA metabolism can result in a premature ageing phenotype.A major point of criticism is that patients or animal models of progeroid syndromes show just a subset of the symptoms of normal ageing. In addition, at least WS is considered to have symptoms which signicantly overlap with the symptoms of normal ageing. Our opinion is that the fact that no progeroid syndrome is a perfect phenocopy of ageing is not surprising considering the multitude of factors that can inuence ageing in different tissues.The ability of a singlegene disruption to accelerate multiple aspects of human ageing, as in WS, is remarkable in itself given the complexity of the ageing process.Extrinsic sources comprise chemicals and radiations, such as UV damage, and viruses.Intrinsic sources include spontaneous chemical reactions and reactive oxygen species. It has been long purchase Amiodarone hydrochloride argued that the predictable patterns of ageing supports the greater importance of endogenous causes of DNA damage. A common cause of DNA damage is exposure to ROS, which has long been hypothesized to be involved in ageing.ROS include superoxide, hydrogen peroxide, hydroxyl radicals and singlet oxygen.Organisms have several defence mechanisms to cope with ROS, including antioxidant enzymes that eliminate ROS or convert them to less harmful molecules. However, the production of ROS can be so overwhelming that those defence mechanisms are not enough, resulting in oxidative stress.ROS can produce many different kinds of damage and mutations in DNA.For instance, the cytosine base alone can undergo oxidative damage producing at least different modied species. Some oxidatively modied bases block DNA replication, whilst others are mispaired and lead to base substitutions in the DNA.Interestingly, some of the progeroid syndromes caused by defective DNA repair discussed earlier such as XP and AT are associated with a high amount of hydroxydeoxyguanosine, a measure of oxidantinduced DNA damage, it is now widely accepted that oxidative damage to DNA tends to increase with age in mammalian tissues.