Genomic instability
Human DNA is exposed constantly to all kinds of possible mutagens. These can be exogenous such as radiation and chemicals, or endogenous such as free radicals, the by-products of energy production from the electron transport chain. Powerful cellular DNA repair machinery can fix the majority of the damage; however, some will inevitably escape repair, so mutations and damage accumulate with time. Thus, the older the cell, the higher the likelihood of accumulated genetic instability. This may range from small point mutations to large chromosome breaks and translocations; the implications can be anything from a silent mutation that codes for the same amino acid, to the activation of oncogenes or silencing of tumour suppressor genes.
Accumulated DNA damage is implicated directly in carcinogenesis and other age-associated disorders, such as neurodegenerative diseases. Hereditary non-polyposis colorectal cancer (HNPCC) is caused by a defect in mismatch repair of DNA that leads to microsatellite instability, and a high risk of colorectal and other types of cancer, particularly at a younger age than sporadic colorectal cancer. In sporadic cancers, a defect mechanism similar to that in HNPCC occurs through epigenetic silencing of mismatch repair enzymes, which leads to microsatellite instability. Notably, epigenetic changes and microsatellite instability occur more frequently with older age. Various forms of genomic instability are found across several cancer types and are also associated with age . Thus, finding means to increase DNA stability could potentially reduce the incidence of cancer, cardiovascular diseases and Alzheimer’s disease. One suggested way is through dietary restriction. Eating fruits and vegetables has been associated with increased DNA repair and less DNA damage.
