DEGENERATION OF HUMAN ONCOGENES AND MITOCHONDRIAL GENES OCCURS IN CELLS THAT EXHIBIT AGE-RELATED PATHOLOGY

The development of a new class of assays to determine in vivo mutation frequencies has provided new perspectives on the timing, location, an d distribution of somatic mutagenesis in mitochondrial genes and in on cogenes of the aging human body. This descriptive information has led to the inference of new models for age-related pathophysiology and onc ogenesis. Mutations of mitochondrial genes rise rapidly with age to fr equencies a thousand-fold higher than those of nuclear genes, Genotypi c selection analysis has revealed that mitochondrial mutations accumul ate predominantly in nonmitotic cells whose age-dependent loss is asso ciated with pathology. Random mitochondrial mutation is most likely to inactivate Complex I, deficiency of which induces mitochondrial super oxide formation and cell death, Genotypic selection of oncogenic mutat ions at the BCL2 and p53 loci has revealed that the cell specificity o f oncogenic mutations in persons without cancer correlates well with s ites of tumor origin, indicating that cells bearing such mutations are the likely precursors of future tumors, Quantitative variation in hum an BCL2 mutation frequency is extensive, and BCL2 mutation frequency r ises with age, concordant with increased risk for lymphoma, The clonal ity and persistence of BCL2 mutations suggests two specific testable m echanisms of lymphomagenesis. BCL2 mutation frequency rises in persons exposed to cigarette smoke, and more p53 mutations occur in skin expo sed to sunlight than in unexposed skin, Thus, in addition to their lik ely relevance to future cancer risk, the dose-response relationship be tween exposure and oncogenic mutations indicates promise for their fut ure use as in vivo biodosimeters of human exposure to carcinogens.