Aging somatic mutation

Mitochondrial DNA is also prone to noninherited (somatic) mutations. Somatic mutations occur in the DNA of certain cells during a person s lifetime, and typically are not passed to future generations. Because mitochondrial DNA has a limited ability to repair itself when it is damaged, these mutations tend to build up over time. A buildup of somatic mutations in mitochondrial DNA has been associated with some forms of cancer and an increased risk of certain age-related disorders such as heart disease, Alzheimer disease, and Parkinson disease. Additionally, research suggests that the progressive accumulation of these mutations over a person s lifetime may play a role in the normal process of aging. 

The somatic mutation theory is based, in part, on the idea that background radiation and/or various endogenous mutagens produce random chromosome damage in all cells. Over time, the genetic loci become sufficiently altered such that various critical functions fail and the cell dies. The fact that irradiation of laboratory animals results in accelerated aging and premature death lends some support to this hypothesis. However, since irradiation produces free radicals, it could be considered part of that theory. 

Genetic and epigenetic phenomena are intimately related. In general, genetic events are related to the sequence information of DNA, and thus include the consequences of the transmission of a particular DNA sequence (e.g., the inheritance of DNA mutations or polymorphisms) or the acquisition of DNA sequence variations (e.g., the accumulation of somatic mutations in aging or cancer development). These genetic issues are discussed in some of the subsequent chapters. On the other hand, there have been inconsistent views regarding... 

MSI is identified in 90% of HNPCC-related CRC as opposed to only 15% to 20% of sporadic CRC. MSI in sporadic CRC is attributed to inactivation of gene expression of hMLHl through biallelic methylation rather than as somatic mutations or loss of hetero2ygosity (LOH) as seen in HNPCC-related CRC. Further, patients whose tumors demonstrate MSI have better survival and better response to chemotherapy than those whose tumors do not express MSI. No association between tumor MSI and survival was seen, however, in young patients under the age of 30. ... 

The genetics of mutations in mtDNA are defined by maternal inheritance, replicative segregation, threshold expression, a high mtDNA mutation rate, and the accumulation of somatic mutations with age. The maternal inheritance pattern reflects the exclusive transmission of mtDNA from the mother to her children. The egg contains approximately 300,000 molecules of mtDNA packaged into mitochondria. These are... 

Martijn E. T. Dolle, Wendy K. Snyder, Jan A. Gossen, Paul H. M. Lohman and Jan Vijg, Distinct spectra of somatic mutations accumulated with age in mouse heart and small intestine. Proceedings of the National Academy of Sciences USA, 97 (2000), 8403-8408. 

Our knowledge of tumor suppressor genes comes from seminal studies on the familial tumor syndrome retinoblastoma. Analysis of the frequency and age of onset of the disease in affected children revealed that bilateral disease had a much earlier onset than unilateral disease. The bilateral form of the disease is inherited by a germ-hne mutation and is therefore present in all tissues, including both retinas, whereas the unilateral disease is due to a locally restricted somatic mutation... 

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