Polyunsaturated fatty acids: An examination of their efficacy in aging and disease

Polyunsaturated fatty acids (PUFA), especially the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in fish oil, are known to have potent therapeutic effects in the treatment of inflammatory diseases such as rheumatoid arthritis, asthma, and cardiovascular disease. Several mechanisms have been proposed to explain how fatty acids exert their anti-inflammatory effects. These mechanisms include altered production of inflammatory eicosanoids, increased production of the protective molecules termed resolvins and protectins, and changes in gene expression through the action of fatty acids on various transcription factors.;PUFA may have a beneficial effect in aging because the aging process is characterized by an increase in systemic inflammation. We measured the fatty acid profile in aged animal models to determine whether the chronic inflammation associated with age was reflected in the ratio of n-6 to n-3 fatty acids. In the circulation, we found a decrease in the n-3 PUFA EPA in middle-aged mice but an increase in EPA in old mice, compared to young mice. In the brain, we found that old rats had higher levels of both pro-inflammatory n-6 PUFA and anti-inflammatory n-3 PUFA. Consequently, we concluded that in our rodent models, increased inflammation with age is not reflected in the fatty acid profile.;Next we studied calorie restriction, a mechanism that has been shown to increase mean and maximal lifespan in mammals, and we hypothesized that calorie restriction would lead to a decrease in n-6 fatty acids (i.e. AA) in older animals. We saw no effect of short-term calorie restriction, but long-term calorie restriction did show a decrease in the pro-inflammatory n-6 PUFA arachidonic acid. We studied several other dietary interventions aimed at decreasing the n-6 to n-3 PUFA ratio in animal models and found that supplementing the diet with 10% fish oil was sufficient to increase EPA and DHA while decreasing AA.;Finally we moved on to study the effects of supplementation with a combination of fish oil, containing EPA and DHA, and borage oil, containing a high concentration of the n-6 PUFA gamma-linolenic acid (GLA), on a healthy human population. We found that this combination was sufficient to increase circulating n-3 PUFA and decrease n-6 PUFA, leading to a decrease in the n-6 to n-3 ratio from greater than 15:1 to less than 10:1. We also showed that this combination decreased expression of the proximal signaling genes PI3Kalpha and PI3Kgamma and the expression of several inflammatory cytokines.;In conclusion, our studies suggest that dietary supplementation with fish oil or a combination of fish oil and borage oil can decrease the n-6 to n-3 PUFA ratio and this shift in circulating fatty acids can decrease the expression of an early step in signal transduction, as well as several important downstream effectors. These data suggest that changes in gene expression may be one way by which polyunsaturated fatty acids exert their potent effects in protection against inflammatory disease.