Oxidative damage to DNA: relation to species metabolic rate and life span.

Abstract

Oxidative damage to DNA is caused by reactive by-products of normal metabolism, as well as by radiation. Oxidized DNA bases excised by DNA repair enzymes and excreted in urine were measured in four different species to determine the relation between specific metabolic rate (ml of 02 consumed per gram of body weight per hr) and oxidative DNA damage. An average of 6.04 nmol of thymine glycol per kg/day and 2.58 nmol of thymidine glycol per kg/day were found in mouse urine and 1.12 nmol of thymine glycol per kg/day and 0.95 nmol of thymidine glycol per kg/day were found in monkey urine. On a body weight basis, mice excrete 18 times more thymine glycol plus thymidine glycol than do humans, and monkeys excrete 4 times more thymine glycol plus thymidine glycol than do humans. When results among mice, rats, monkeys, and humans are compared, specific metabolic rate correlates highly with oxidative DNA damage. These findings are consistent with the theory that free radicalinduced DNA damage may play a central role in the aging process.efforts focused on one DNA oxidation product, the thymine glycol lesion (5,6-dihydro-5,6-dihydroxythymine) because this lesion has suitable properties of repair, product excretion, stability (for recovery and measurement of its repair products), and traceability of the origin of the repair products to cellular DNA. Background levels of thymine glycol and thymidine glycol in the human were determined, and a total oxidative damage rate to DNA was estimated as ==300 hits per cell per day in human for just these two oxidized bases (8,9). Hydroxymethyluracil, another known oxidative DNA damage product, was also assayed and accounted for another 700 hits per cell per day (8, 9). Because many known oxidative DNA damage products have been described, we suspect that the total damage rate is thousands of hits per cell per day. The rat has a damage rate about 15 times that of the human (8, 9). In this paper, we report the background levels of thymine glycol and thymidine glycol in mouse and monkey and compare the levels in all four species to specific metabolic rate and life span.Free radicals that are formed in the body as a consequence of aerobic metabolism can produce oxidative damage to macromolecules in somatic cells (1)(2)(3)(4)(5). This type of damage may be an important factor in aging and age-dependent diseases such as cancer and heart disease (6). Circumstantial evidence implicating free radicals in aging includes the impressive inverse correlation between the specific metabolic rate (ml of 02 consumed per gram of body weight per hr of a given species and the life span of that species (for review, see ref. 7). One explanation for this inverse correlation is that smaller animals, with higher metabolic rates, consume greater quantities of oxygen (on a body-weight basis) and so produce harmful free-radical by-products at a higher rate, leading to a higher rate of damage to critical cellular targets. The higher rate of damage to cells might then cause a higher rate of cellular aging.Many...

Role of free radicals in liver diseases

“…There is a large body of evidence indicating that ROS play a pathogenetic role in carcinogenesis [35]. During the initiation phase of this process, ROS may interact directly with DNA, damaging specific genes that control cell growth and differentiation, among others [36]. They can also increase the activity of carcinogenic xenobiotics by facilitating their activation to reactive compounds [37].…”

Do mitochondrial DNA fragments promote cancer and aging?

“…Oxidative damage to DNA could be a major factor in cancer and aging [7,24,25,28]. Damage is caused by reactive oxygen species, lipid hydroperoxides and their radical and aldehydic degradation products [29,30], and oxidation products of aromatic amino acids and purines.…”

“…Oxygen-dependent DNA damage is also observed with aflatoxin B~ [40] and phorbol esters [41,42]. The formation of thymine glycol and thymidine glycol in vivo has been used as a possible assay for oxidative DNA damage [28,43]. Very recently, the formation of 8-hydroxydeoxyguanosine in DNA by oxygen radicals was reported [44][45][46][47][48][49].…”

“…Several models relate oxidative DNA damage to aging and cancer [28]. For example, free radicals could react with nuclear DNA and produce somatic mutations including point or frameshift mutations, deletions, and strand breaks.…”

The Szilard Hypothesis on the Nature of Aging Revisited

“…In general, the accumulated data have revealed that similar genes affect the aging process in different species but that they act in networks that get more complex and redundant when moving up the evolutionary ladder (Kuningas et al 2008). It is well established that the amount of DNA damage per unit time correlates negatively with life span across species (Adelman et al 1988). In addition, the DNA repair capacity correlates with life expectancy in different mammals (Hart and Setlow 1974;Burkle et al 2005).…”