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Oxidants and mitogenesis as causes of mutation and cancer: the influence of diet
1Division of Biochemistry and Molecular Biology, University of California, Berkeley 94720.
Abstract:
A very high level oxidative damage to DNA occurs during normal metabolism. In each rat cell, the steady-state level of this damage is estimated to be about 10(6) oxidative adducts, and about 10(5) new adducts are formed daily. This endogenous DNA damage appears to be a major contributor to cancer and aging. The oxidative damage rate in mammalian species with a high metabolic rate, short life span, and high age-specific cancer rate such as in rats is much higher than the rate in humans, long-lived mammals with a lower metabolic rate, and a lower age-specific cancer rate. It is argued that deficiency of micronutrients, that protect against oxidative DNA damage, is a major contributor to human cancer. Epidemiological studies, a large body of experimental evidence, and theoretical work on the mechanisms of carcinogenesis point to mitogenesis as a major contributor to cancer. Dividing cells, compared to nondividing cells, are at an increased risk for mutations due to: 1.) conversion of DNA adducts to mutations; 2.) chance of mitotic recombination, gene conversion, and nondisjunction; and, 3.) increased exposure of DNA to mutagens. Mitogenesis also increases the probability of gene amplification and loss of 5-methylcytosine. Dietary interventions that lower mitogenesis, such as calorie restriction, decrease cancer incidence.
Insights
Oxidative DNA damage from normal metabolism contributes to aging and cancer. Lowering cell division (mitogenesis) through interventions like calorie restriction can reduce cancer risk.
Area of Science:
- Biochemistry
- Molecular Biology
- Gerontology
Background:
- Normal metabolic processes generate significant oxidative damage to DNA.
- Endogenous DNA damage is a key factor in aging and cancer development.
- Species with higher metabolic rates exhibit greater oxidative DNA damage rates.
Purpose of the Study:
- To investigate the role of oxidative DNA damage in cancer and aging.
- To explore the link between metabolic rate, DNA damage, and cancer incidence across species.
- To evaluate the contribution of mitogenesis and micronutrient deficiency to cancer.
Main Methods:
- Estimation of steady-state oxidative DNA adducts and daily adduct formation in rat cells.
- Comparative analysis of oxidative damage rates, metabolic rates, lifespan, and cancer rates in rats versus humans.
- Review of epidemiological studies, experimental evidence, and theoretical work on carcinogenesis mechanisms.
Main Results:
- Rats have significantly higher oxidative DNA damage rates than humans, correlating with higher metabolic and cancer rates.
- Mitogenesis increases mutation risk in dividing cells through DNA adduct conversion and other genetic events.
- Micronutrient deficiency and increased mitogenesis are implicated as major contributors to human cancer.
Conclusions:
- Endogenous oxidative DNA damage is a significant factor in aging and cancer.
- Mitogenesis is a critical driver of cancer development, increasing DNA mutation risk.
- Dietary interventions reducing mitogenesis, such as calorie restriction, show promise in decreasing cancer incidence.