BIOMARKERS OF AGING - CORRELATION OF DNA I-COMPOUND LEVELS WITH MEDIAN LIFE-SPAN OF CALORICALLY RESTRICTED AND AD-LIBITUM FED RATS AND MICE

I-compounds are species-, tissue-, genotype-, gender-, and diet-depend ent bulky DNA modifications whose levels increase with animal age. Whi le a few of these DNA modifications represent oxidation products, the majority of I-compounds appear to be derived from as yet unidentified endogenous DNA-reactive intermediates other than reactive oxygen speci es. Circadian rhythms of certain I-compounds in rodent liver imply tha t levels of these DNA modifications are precisely regulated. Caloric r estriction (CR), the currently most effective method available to reta rd aging and carcinogenesis, has been previously shown to elicit signi ficant elevations of I-compound levels in tissue DNA from Brown-Norway (BN) and F-344 rats as compared to age-matched ad libitum fed (AL) an imals. The present investigation has extended this work by examining l iver and kidney DNA I-compound levels in three genotypes of rats (F-34 4, BN, and F-344 x BN) and two genotypes of mice (C57BL/6N and B6D2F1) under identical experimental conditions in order to determine whether correlations exist between I-compound levels, measured in middle-aged animals, and median lifespan. Levels of a number of liver and kidney I-compounds were found to display genotype- and diet-dependent, statis tically significant positive linear correlations with median lifespan in both species. In particular, the longer-lived hybrid F-344 x BN rat s and B6D2F1 mice tended to exhibit higher I-compound levels than the parent strains. CR enhanced I-compound levels substantially in both ra ts and mice. Thus, I-compounds, measured at middle age, reflected the functional capability ('health') of the organism at old age, suggestin g their predictive value as biomarkers of aging. The positive linear c orrelations between levels of certain I-compounds (designated as type I) and lifespan suggest that these modifications may be functionally i mportant and thus not represent endogenous DNA lesions (type II), whos e levels would be expected to correlate inversely with lifespan.