More work needed: Omege-3 fatty acids and antioxidants

In the past, I have argued that antioxidants aren't necessarily good for you, since some level of oxidation is required to support metabolism. As with many areas of public health research, there are contradictions. An example is the role of poly unsaturated fatty acids (PUFAs) in health. Many studies of human and animal populations have shown a health enhancing effect, but biochemists worry about the potential for these highly reactive molecules to oxidize and form free radicals. Perhaps they can be good in some cases, and bad in others?

Seeing the Forest for the Trees
The problem of scaling up from biochemical and molecular biology to whole organism physiology is seems to be a classic example of research at different levels yielding different results. For example, studies of the amount of food waste Americans throw away come to very different conclusions about food waste compared to studies that sum total food produced and imported and subtract food consumed in this country. Another example are national estimates of CO2 production by industry versus measurements of actual CO2 increases in the atmosphere. A third example is the classic mismatch between single-leaf gas exchange measurements and whole forest flux readings. The effort to reconcile differing conclusions from different levels of inquiry seems especially productive.

Evidence of scale-dependent mismatch in Omega-3 fatty acid research
One issue, of course, are the many different kinds of omega-3 fatty acids. One kind in particular, DHA (EPA, also) seems especially important for health benefits. But even this specific molecule is controversial:

"Docosahexaenoic acid (DHA) has a significant role in neural membrane phospholipid metabolism, immune responses and the aging process. The difference in antioxidant testing results between animal and human studies and between in vitro and in vivo effects is discussed in terms of different end-points of oxidation. This chapter concludes with seven important unsettled nutritional questions that need future research. With so many unanswered questions, the conclusion is drawn that it would be imprudent to make dietary recommendations to the public before the mechanisms of polyunsaturated lipid nutrition, in vivo activity of antioxidants, and in vivo lipid peroxidation are better understood." LIPID OXIDATION — SECOND EDITION. Edwin N. Frankel. 2005.

"Free radicals and reactive oxygen species produced in cells may attack PUFAs resulting in the formation of more free radicals, specifically hydroperoxides. The hydroperoxides, in turn, may damage DNA ultimately leading to cancer. These effects have indeed been observed in some in vitro experiments, but not in actual human beings. Many studies have shown that fish oils actually retard aging and suppress so- called free radical diseases such as atherosclerosis and cancer. Other studies have shown that a daily EPA + DHA intake in excess of 2.3 grams decreases the production of superoxide, a potent cancer promoter. At least one in vitro and one animal experiment have observed that EPA + DHA kill human breast cancer cells via the formation of hydroperoxides, but that this effect is strongly inhibited by vitamin E. Thus, at this point, it is not entirely clear whether EPA + DHA exert part of their beneficial effect through an increase or a decrease in the production of free radicals and reactive oxygen species. The researchers recommend more work in this area, but emphasize that the major benefits of fish oils probably are associated with their ability to inhibit the synthesis of arachidonic acid-derived, pro-inflammatory eicosanoids."
Larsson, SC, et al. Dietary long-chain n-3 fatty acids for the prevention of cancer: a review of potential mechanisms. American Journal of Clinical Nutrition, Vol. 79, June 2004, pp. 935-45

It seems that omega-3s may actually increase oxidative stress, but possibly only in the right areas: "In mammary tumours, it is observed that long-chain fatty acids not only increase apoptosis, but also increase lipid peroxidation, and the apoptotic effect can be reversed by antioxidants. The rationale for use of n-3 FA dietary supplements in counteracting BC progression needs to be tested... while at the same time, the effect on whole-body lipid peroxidation needs to be monitored. "

British Journal of Nutrition (2002), 87:193-198 Cambridge University Press Review article n-3 Fatty acids and lipid peroxidation in breast cancer inhibition Basil A. Stoll

There is some evidence that antioxidants can protect against unwanted damage from reactive PUFAs, but also some evidence that PUFAs are inherently dangerous: "DHA enhances the susceptibility of the liver and kidney to lipid peroxidation concomitant with higher levels of DHA in these tissues, as shown by the fatty acid composition. In addition, Vitamin E is unable to protect membranes of the liver and kidney rich in DHA from lipid peroxidation, even after ingestion of the highest level of Vitamin E. "

British Journal of Nutrition (1997), 78:655-669 Cambridge University Press

General Nutrition. Changes in susceptibility of tissues to lipid peroxidation after ingestion of various levels of docosahexaenoic acid and vitamin E. Kazuhiro Kubo, Morio Saito, Tadahiro Tadokoro and Akio Maekawa

In conclusion, "The arachidonic acid cascade is arguably the most elaborate signaling system neurobiologists have to deal with." Piomelli, Daniele (2000). "Arachidonic Acid". Neuropsychopharmacology: The Fifth Generation of Progress.