Effect of aging on colonic chemoprevention by dietary curcumin
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The incidence of cancer is highly dependent on age. The hypothesis of this thesis was that aging may alter the efficacy of dietary chemoprevention. This hypothesis was tested by evaluating the effect of age on inhibition of colonic aberrant crypt foci (ACF) by dietary curcumin. Three different ages of male F344 rats were fed either the control diet or diet containing 0.6% curcumin and given injections of a colon carcinogen, azoxymethane (AOM). Curcumin reduced the number of colonic ACF in young and old, but not middle-aged rats. Resistance of middle-aged rats to colonic chemoprevention by curcumin seems to be due to age-related differences in colon carcinogensis rather than curcumin metabolism. Liver cyclooxygenase-2 mRNA expression, measured as an indicator of biological activity of curcumin, was similarly affected by curcumin regardless of ages. Also, curcumin similarly affected arachidonic acid metabolism, which is regarded as one of chemopreventive mechanisms of curcumin, in the colon of young and middle-aged rats. The involvement of apoptosis was investigated as a potential mechanism responsible for age-related differences in curcumin chemoprevention. A time course study of colonic apoptosis following AOM injections demonstrated that older animals were more susceptible to AOM-induced apoptosis. The effect of aging on curcumin-induced apoptosis in the colon was evaluated at 0, 8, and 16 hours after AOM injection. Curcumin increased both basal and AOM-induced apoptosis in young and old but not in middle-aged rats. Activation of caspase-9 only in young rats fed curcumin indicates that curcumin-induced apoptotic pathway is mediated by mitochondria in young but not in old. AOM may also induce apoptosis by a mitochondrial-independent pathway. In conclusion, these studies support the hypothesis that aging modulates colonic chemoprevention by curcumin. This dissertation represents the first documentation of an age-related difference in efficacy of dietary chemoprevention. The differential response to curcumin-induced apoptosis is proposed as a mechanism. Further study is needed to confirm whether this phenomenon occurs in humans and contributes to the lack of agreement between efficacy of dietary chemoprevention in preclinical studies with young animals and clinical studies with adult humans.