Please bear with me for this one, as I want to address a comment that was left on my blog regarding fish, namely how it exerts its beneficial effects. Apparently, the folks over at PHD believe fish oil is beneficial by way of hormesis, which is the idea that the exposure to small doses of a toxin fortifies our resistance to it upon subsequent exposures.
In the case of fish oil, the previously mentioned decomposition products, derived mainly from DHA and EPA hydroperoxides, are the toxins that elicit hormetic responses. Toxic in themselves, these lipid hydroperoxides are the starting material for a host of highly toxic decomposition products, including 4-hydroxyhexenal (4-HHE), which is the one that is usually evoked to discuss the potentially beneficial hormetic effect of fish oil.
4-HHE corresponds to 4-hydroxynonenal (4-HNE), which is generated from linoleic acid (LA) and arachidonic acid (AA). Compared to 4-HNE, there have been fewer studies conducted with respect to the toxicity of 4-HHE. However, I think it would be reasonable to assume, given their structural similarities, that 4-HNE and 4-HEE would produce similar effects in the body. (2-hydroxyheptanal, also derived from LA, has similar effects to 4-HNE.) Regardless, 4-HNE can be, and is probably, produced from EPA and DHA as well.1
In the case of fish oil, the previously mentioned decomposition products, derived mainly from DHA and EPA hydroperoxides, are the toxins that elicit hormetic responses. Toxic in themselves, these lipid hydroperoxides are the starting material for a host of highly toxic decomposition products, including 4-hydroxyhexenal (4-HHE), which is the one that is usually evoked to discuss the potentially beneficial hormetic effect of fish oil.
4-HHE corresponds to 4-hydroxynonenal (4-HNE), which is generated from linoleic acid (LA) and arachidonic acid (AA). Compared to 4-HNE, there have been fewer studies conducted with respect to the toxicity of 4-HHE. However, I think it would be reasonable to assume, given their structural similarities, that 4-HNE and 4-HEE would produce similar effects in the body. (2-hydroxyheptanal, also derived from LA, has similar effects to 4-HNE.) Regardless, 4-HNE can be, and is probably, produced from EPA and DHA as well.1
4-HNE is highly reactive and highly toxic, plain and simple. It’s also physiologically relevant because LA and AA are the major PUFA found in mammalian tissue, especially in phospholipids and lipoproteins. Aldehydes like these, and their oxidation products, like oxime and pyrazoline, have been found to accumulate in old age,2 atherosclerosis, and inflammatory conditions like rheumatoid arthritis.3
It’s interesting to me that 4-HEE, which belongs to the same class of molecules as 4-HNE, is now being postulated to be primarily responsible for the cardioprotective effects of fish oil. (In my opinion, which may mean nothing to you, this explanation has arisen in response to realization that much of the fish oil sold and found in the body is already rancid.) 4-HNE, as I alluded to in my last blog post, is found in LDL particles and it is by this route that 4-HNE becomes deposited in atherosclerotic plaques.4
These aldehydes are also potent glycators of amine groups found in certain lipids and amino acid residues of proteins. Glycation, or more precisely the formation of a Schiff base, is the first step in the generation of advanced glycation end products (AGE), and they are formed from both glucose and PUFA, despite what internet diet experts would have you to believe. Diabetics, who suffer from higher rates of AGE generation than nondiabetics do, have been found to have high levels of these precursor lipid peroxidation products.5
EPA and DHA, immediately upon their ingestion, become incorporated into tissue lipids, including cardiolipin. Cardiolipin is a special phospholipid found only in the inner mitochondrial membrane, and it is closely tied to the efficiency with which we produce energy, or ATP: the higher the cardiolipin saturation index, the lower the proton conductance, and the more ATP we produce. What is more, a higher saturation index renders mitochondria highly resistant to damage by free radicals and reactive oxygen species (ROS), including those produced by fish oil, and is associated with lower levels of ROS in vivo. (Hormesis is not needed.)
Caloric restriction increases the saturation index of membranes, namely by downregulating the expression and decreasing the activity of the desaturase enzymes, resulting in a higher ratio of LA to AA and ALA to DHA and EPA. This is the main mechanism by which caloric restriction exerts its beneficial effects. Taking fish oil in hopes of inducing a questionably beneficial hormetic effect, by raising the concentration of EPA and DHA in membranes, would produce the exact opposite effect.
As to hormesis, I don’t think we need to add to our, already high, free radical burden. In fact, in mammals, low levels of cellular ROS are associated with the highest maximum lifespan years, for a given metabolic rate. Further, these reactive PUFA oxidation products are detected in even young, healthy tissue, albeit in smaller amounts than in those that are old or diseased.
I could enumerate the systematic reviews, published just this year, showing, one after another, the lack of beneficial effects of fish oil supplementation for the various conditions that fish oil, for years, has been promoted to help. But, you could do that on your own, and I’m pressed for time as it is. (I have no business writing this post.) Thankfully, save for this egregious example, people haven’t been recommending to take large doses of this stuff.
In closing, the people who recommend to take fish oil and to eat lots of fish to increase our long-chain omega-3 intakes are the same people who promote ancestral diets. Yet, a substantial amount of people throughout human history have had to rely on land-foods, not fish, so their omega-3s would have been coming ALA, not EPA and DHA. Nonetheless, as I stated in my previous post, small amounts of whole oily fish is probably benign, as whole fish, for instance, contains potent lipid peroxide scavengers called furan fatty acids.6
It’s interesting to me that 4-HEE, which belongs to the same class of molecules as 4-HNE, is now being postulated to be primarily responsible for the cardioprotective effects of fish oil. (In my opinion, which may mean nothing to you, this explanation has arisen in response to realization that much of the fish oil sold and found in the body is already rancid.) 4-HNE, as I alluded to in my last blog post, is found in LDL particles and it is by this route that 4-HNE becomes deposited in atherosclerotic plaques.4
These aldehydes are also potent glycators of amine groups found in certain lipids and amino acid residues of proteins. Glycation, or more precisely the formation of a Schiff base, is the first step in the generation of advanced glycation end products (AGE), and they are formed from both glucose and PUFA, despite what internet diet experts would have you to believe. Diabetics, who suffer from higher rates of AGE generation than nondiabetics do, have been found to have high levels of these precursor lipid peroxidation products.5
EPA and DHA, immediately upon their ingestion, become incorporated into tissue lipids, including cardiolipin. Cardiolipin is a special phospholipid found only in the inner mitochondrial membrane, and it is closely tied to the efficiency with which we produce energy, or ATP: the higher the cardiolipin saturation index, the lower the proton conductance, and the more ATP we produce. What is more, a higher saturation index renders mitochondria highly resistant to damage by free radicals and reactive oxygen species (ROS), including those produced by fish oil, and is associated with lower levels of ROS in vivo. (Hormesis is not needed.)
Caloric restriction increases the saturation index of membranes, namely by downregulating the expression and decreasing the activity of the desaturase enzymes, resulting in a higher ratio of LA to AA and ALA to DHA and EPA. This is the main mechanism by which caloric restriction exerts its beneficial effects. Taking fish oil in hopes of inducing a questionably beneficial hormetic effect, by raising the concentration of EPA and DHA in membranes, would produce the exact opposite effect.
As to hormesis, I don’t think we need to add to our, already high, free radical burden. In fact, in mammals, low levels of cellular ROS are associated with the highest maximum lifespan years, for a given metabolic rate. Further, these reactive PUFA oxidation products are detected in even young, healthy tissue, albeit in smaller amounts than in those that are old or diseased.
I could enumerate the systematic reviews, published just this year, showing, one after another, the lack of beneficial effects of fish oil supplementation for the various conditions that fish oil, for years, has been promoted to help. But, you could do that on your own, and I’m pressed for time as it is. (I have no business writing this post.) Thankfully, save for this egregious example, people haven’t been recommending to take large doses of this stuff.
In closing, the people who recommend to take fish oil and to eat lots of fish to increase our long-chain omega-3 intakes are the same people who promote ancestral diets. Yet, a substantial amount of people throughout human history have had to rely on land-foods, not fish, so their omega-3s would have been coming ALA, not EPA and DHA. Nonetheless, as I stated in my previous post, small amounts of whole oily fish is probably benign, as whole fish, for instance, contains potent lipid peroxide scavengers called furan fatty acids.6
References
1. Beckman, J. K., Howard, M. J. & Greene, H. L. Identification of hydroxyalkenals formed from omega-3 fatty acids. Biochemical and biophysical research communications 169, 75–80 (1990).
2. Sawada, M. & Carlson, J. C. Changes in superoxide radical and lipid peroxide formation in the brain, heart and liver during the lifetime of the rat. Mechanisms of ageing and development 41, 125–37 (1987).
3. Muus, P., Bonta, I. L. & Den Oudsten, S. A. Plasma levels of malondialdehyde, a product of cyclo-oxygenase-dependent and independent lipid peroxidation in rheumatoid arthritis: a correlation with disease activity. Prostaglandins and medicine 2, 63–5 (1979).
4. Berliner, J. A. et al. Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation 91, 2488–96 (1995).
5. Sato, Y. et al. Lipid peroxide level in plasma of diabetic patients. Biochemical medicine 21, 104–7 (1979).
6. Spiteller, G. Furan fatty acids: occurrence, synthesis, and reactions. Are furan fatty acids responsible for the cardioprotective effects of a fish diet? Lipids 40, 755–71 (2005).
