Poly-unsaturated fatty acids & Lipid peroxidation

[RRM]

Have you read this post?

Yes, protein and carb-carbonyls also form AGEs/ALEs (Maillard reaction), which is also inhibited by our antioxidant defense.

On a longer term I think the effect will be increased more and more. 7 weeks is not very long.

Its actually that the long term effects of lipoxidation that triggers the anti-lipidoxidation defense.
...only after 14 weeks "expression and activity of key enzymes involved in antioxidant and phase II detoxification pathways ... were elevated in hearts from mice fed the n-3 PUFA diet" Anderson EJ et al
So, in the long term the effects of lipidoxidation will be minimized.
"long-term supplementation with a small dosage of coenzyme Q(10) might represent a good anti-aging therapy in rats fed on a PUFA-based diet." Quiles JL et al

What are the huge benefits of relatively high levels of omega 3 you are constantly talking about?

I never used those words; please check out the very first post in this thread...
(under "Biological functions")
Btw: "severe n-3 PUFA deficiency occurred in the mice fed on a palm oil diet ... short life in mice may be caused by n-3 PUFA deficiency and, therefore, the fatty acid may be essential in enjoying a long life." Suzuki H et al

[overkees]

No effect of n-3 long-chain polyunsaturated fatty acid (EPA and DHA) supplementation on depressed mood and cognitive function: a randomised controlled trial.
In conclusion, substantially increasing EPA+DHA intake for 3 months was found not to have beneficial or harmful effects on mood in mild to moderate depression. Adding the present result to a meta-analysis of previous relevant randomised controlled trial results confirmed an overall negligible benefit of n-3 LCPUFA supplementation for depressed mood.

No effect of 12 weeks’ supplementation with 1 g DHA-rich or EPA-rich fish oil on cognitive function or mood in healthy young adults aged 18-35 years.
These findings, taken together with other recent reports of null effects, suggest that dietary supplementation with n-3 PUFA in healthy, normally developing and impairment-free populations is unlikely to result in cognitive enhancement.

Effect of fish-oil supplementation on mental well-being in older subjects: a randomized, double-blind, placebo-controlled trialIn this randomized, double-blind, placebo-controlled trial we observed no effect of EPA+DHA supplementation for 26 wk on mental well-being in the general older population studied.

Effect of fish oil supplementation on quality of life in a general population of older Dutch subjects: a randomized, double-blind, placebo-controlled trial.Supplementation with high or low doses of fish oil for 26 weeks did not influence the QOL of healthy older individuals

The positive effects of fish oils on mood and cognitive effects are highly questionable.

[overkees]

Beneficial to the heart? Not likely:

Of 15,159 titles and abstracts assessed, 48 RCTs (36,913 participants) and 41 cohort studies were analysed. The trial results were inconsistent. The pooled estimate showed no strong evidence of reduced risk of total mortality (relative risk 0.87, 95% confidence interval 0.73 to 1.03) or combined cardiovascular events (0.95, 0.82 to 1.12) in participants taking additional omega 3 fats. The few studies at low risk of bias were more consistent, but they showed no effect of omega 3 on total mortality (0.98, 0.70 to 1.36) or cardiovascular events (1.09, 0.87 to 1.37). When data from the subgroup of studies of long chain omega 3 fats were analysed separately, total mortality (0.86, 0.70 to 1.04; 138 events) and cardiovascular events (0.93, 0.79 to 1.11) were not clearly reduced. Hooper et al

Of the 3635 citations retrieved, 20 studies of 68,680 patients were included...
Overall, omega-3 PUFA supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke based on relative and absolute measures of association.Rizos EC et al

[RRM]

What are the ... benefits of relatively high levels of omega 3 ...?

...check out the very first post in this thread... (under "Biological functions")

In that section, I summed up a number of functions, to which you responded.

Beneficial to the heart? Not likely

Fair enough, the reviews that you link to are convincing.
Your other response, however does not correspond with my claims:

Omega-3 fatty acids play a critical role in the development and function of the central nervous system.Logan AC
Omega-3 fatty acids are an essential component of CNS membrane phospholipid acyl chains, critical to the dynamic structure and function of neuronal membranes.Bourre JM et al
ALA and LA can act as sources for second messengers within and between neurons.Lock CA et al
Synaptic membranes in the brain contain high levels of DHA, critical for transmission and membrane fluidity Heron DS et al
beneficial influence of DHA on the preservation of synaptic function in aged individuals Oster T el al
The positive effects of fish oils on mood and cognitive effects are highly questionable.

And you concluded this based on studies that are about:
mood and cognitive function in depressed individuals Rogers PJ et al
scores on various (anxiety and) depression scales by elderly van de Rest O et al
cognitive tasks and mood measures in healthy young adults Jakcon PA et al
physical health, psychological health, social relationships, and satisfaction with environment in elderly van de Rest O et al

If you want to say that there is no evidence that omega-3 supplementation does not routinely prevent of cognitive decline later in life,
then use this one:
"We identified seven relevant trials, four among cognitively healthy older people, and three among individuals with pre-existing cognitive decline or dementia, and overall conclude that there is no evidence to support the routine use of n-3 LCPs supplements for the prevention, or amelioration, of cognitive decline in later life." Dangour AD
Here is a review clinical trials that investigate effects of n-3 PUFA supplementation on mental health and behavior. Free Full Text

[RRM]

Omega-3 fats are most susceptible to lipid peroxidation.
So, if we want to find evidence of the effect of lipid peroxidation on the heart mitochondria,
epidemiological studies must show that omega-3 supplementation leads to more heart attacks and more deaths.

Of 15,159 titles and abstracts assessed, 48 RCTs (36,913 participants) and 41 cohort studies were analysed.
... no strong evidence of reduced risk of total mortality.. or combined cardiovascular events
... no effect of omega 3 on total mortality ... or cardiovascular events
...long chain omega 3 fats ..total mortality ..and cardiovascular events ...not clearly reduced. Hooper et al

Of the 3635 citations retrieved, 20 studies of 68,680 patients were included,
.... No statistically significant association was observed with all-cause mortality...
cardiac death... sudden death... myocardial infarction and stroke Rizos EC et al

But no...
So, if even supplemental omega-3 does not influence lifespan / cardiac health, what dietary intakes do?
This may mean that the influence of lipid peroxidation on health is relatively insignificant,
probably due to our anti-oxidant defense stepping up when confronted with lipid peroxidation products.

[overkees]

But then one might also say that lipoxidation due to cooking will be buffered by the antioxidant system too.
It is more the continual burden you put on the system.

This one is very interesting. 30% of their energy came from fat. 7% of the fats was DHA. So that 2.16% of their total caloric intake was DHA. This was compared on rats that were fed 80% palm oil and 20% soybean oil as 30% of total energy. The DHA oil–fed rats had greater phospholipid hydroperoxide accumulations in plasma (191–192% of control rats), liver (170–230%) and kidney (250–340%), whereas the α-tocopherol level was reduced concomitantly (21–73% of control rats).

I think this antioxidant defense must not be put to the test if it is not needed. Therefore it still is very usefull to find out what levels of omega 3 are the bare minimum for essentiality, if there are any. And what levels are beneficial.

[RRM]

But then one might also say that lipoxidation due to cooking will be buffered by the antioxidant system too.
It is more the continual burden you put on the system.

Endogenous enzymatic lipoxidation serves a biological role.
PUFAs also serve an essential role, with no elevation in the Wai diet (and with adapted antioxidant defense).
So, lipoxidation from cooking (and supplementation) IS the extra burden.

The DHA oil–fed rats had greater phospholipid hydroperoxide accumulations ... reduced α-tocopherol

This test lasted only 3 weeks...
It takes time before the antioxidant defense system responds to an increase in lipid peroxidation products.
(adjustment to a change in diet)

[overkees]

What do you think about this one in humans?
A randomized, double-blind, placebo-controlled trial likewise showed that six grams per day of long chain omega3s increased lipid peroxides and MDA in healthy men, regardless of whether they were supplemented with 900 IU of vitamin E . It lasted 6 weeks.
Do you think if it was continued longer effects would've lowered due to the antioxidany system stepping up?

Questions I've got now:
You were talking about controlled oxidation in enzymatic complexes. The research above was about MDA MDA is particularly dangerous because it can leave the membrane and damage proteins, DNA, and other important cellular structures. How well does the antioxidant system that steps up prevent this bad guy?
To what extent do you think the antioxidant system can prevent uncontrolled oxidation? E.g. How much fish oil is too much for the antioxidant system?
If an antioxidant provides its action it transforms into a radical itself that can damage other things. It is better to minimize the unnecessary oxidations.
The antioxidants self, if they neutralize the free radicals formed, they can become free radicals themselve, can't these cause additional harm?
Do you think that permanent fish consumption would therefore be a better idea than occasional fish oil consumption?
Are the benefits according to you only achievable with the everyday consumption of fatty fish? I know you eat 300g salmon on most days. Isn't it better to replace some of it with red meat for example?

What I think now is that your system can make more than enough omega3s and omega6s from a relatively small ingestion of PUFAs. I think the inhibition system is optimized for this. I think that because fish oils inhibit the desaturases very well, the body is telling us that it is important to cease the production of extra LCPUFAs. If there is little to no inhibition and a proper nutrition with enough biotin, vitamin b6 and calcium then the desaturases can work properly and make more than enough LCPUFAs from the natural whole foods in the diets. Eating grass fed red meat is therefore enough for the benefits and optimal in my point of view. And the occasional consumption of a very small amount of herring or salmon is even better (Once or twice a week).

To motivate this even further: I think that if there is not too much omega3s and omega6s in the tissues that the production of MA can increase pretty quickly if there is a shortage of food. Like in the case we've got an infection, most people will get sick and will not eat anything, same for animals. What happens is the MA will increase and be protective and antiinflammatory for a lot of things as shown in the mead acid topic. If the inflammation issue is over, people will consume their normal foods and the omega3s and omega6s will start reappearing again.

[RRM]

What do you think about this one in humans?

That supplementation of both omega-3 and vitamin E doesnt help to reduce lipid oxidation...
Leave it up to your body; its antioxidant defense is way more sophisticated than that.
Similar as you should not induce dietary essential fatty acid deficiency...

You were talking about controlled oxidation in enzymatic complexes. MDA is particularly dangerous because it can leave the membrane and damage proteins, DNA, and other important cellular structures.

You mean enzymatic lipoxidation.
Thats not about not leaving the membrane, but about not leaving the enzymatic complex.

If an antioxidant provides its action it transforms into a radical itself that can damage other things. It is better to minimize the unnecessary oxidations.
The antioxidants self, if they neutralize the free radicals formed, they can become free radicals themselve, can't these cause additional harm?

Yes, antioxidants get oxidized themselves, but these products are less reactive, ending the chain reaction.
The oxidized forms of vitamin C, for example, are relatively unreactive, and do not cause any cellular damage.

[Kasper]

The oxidized forms of vitamin C, for example, are relatively unreactive, and do not cause any cellular damage.

That's is quite a big statement, can you back this up with reference ?
What about vitamin E ?
I've read that astaxanthin (found in wild salmon) can't get become a radical itself, and is able to turn vitamin C and vitamin E radicals back in its antioxidant state.

[RRM]

The oxidized forms of vitamin C, for example, are relatively unreactive, and do not cause any cellular damage.

That's is quite a big statement, can you back this up with reference?

Its not that big a statement.
A radical reacting with non-radical always creates another radical,
so that such a chain reaction would only be ended when 2 radicals react with eachother,
which would make the body relatively saturated with radicals (as low saturation strongly inhibits the chance of 2 radicals reacting).
And that, of course, is undesirable.
Thats why there are antioxidants. These compounds are called anti-oxidants because they can also end a specific radical chain reaction.
If they cannot, they are not anti-oxidants, but just another non-radical.
Thats why anti-oxidants usually produce less reactive compounds upon oxidation.

The (main) oxidized product of vitamin C is dehydroascorbic acid (DHvit.C) Leung K et al,
which is transported into the cell by facilitative hexose transporters (GLUTs). Angulo C et al, which is inhibited by flavonoids, which also inhibit uptake of vit.C. Park JB et al
At high concentrations DHvit.C (and vit.C) does inhibit mitogenic stimulation of lymphocytes,
but remains noncytotoxic Ramirez I et al Free Full Text, preserving cellular integrity.Ozaki M et al
DHvit.C is reduced to vitamin C by glutathione peroxidase Jung CH et al, coupled with the conversion of GSH to GSSG.Ozaki M et al
Only when DHvit.C reacts with chromium (which may react with various reductants to produce...), the resulting intermediates may induce strand breaks in DNA. Stearns DM et al
(chromium is scavenged by managanese)

What about vitamin E ?
I've read that astaxanthin (found in wild salmon) can't get become a radical itself, and is able to turn vitamin C and vitamin E radicals back in its antioxidant state.

Yes, and Ive read that vitamin C reconverts radical cations of the carotenoids into carotenoids,
and that carotenoids may indeed 'repair' the various tocopherol radical cations. Mortensen A
Inversely, alpha-, beta-, and gamma-tocopherol may reduce all the carotenoid radical cations,
but astaxanthin, canthaxanthin, and beta-apo-8'-carotenal radical cations are scavenged more rapidly than the other carotenoid cations.
delta-tocopheroxyl radical can be reduced by lycopene and beta-carotene. Mortensen A et al
The order of antioxidant power seems to be:
lycopene > beta-carotene > zeaxanthin > alpha-carotene > beta-cryptoxanthin > lutein > alpha-tocopherol > capsaicin > chlorophyll a > chlorophyll b > astaxanthin > canthaxanthin.
Buratti S et al

[RRM]

Why does the body use PUFAs for essential functions while they are so oxidant sensitive?

Its not a faulty design; everything has a purpose in nature.
It is because they are oxidant sensitive.
Not just enzymatic lipid peroxidation, but also non-enzymatic lipid peroxidation serves a purpose.
Enzymatic lipid peroxidation is involved in autophagy, and non-enzymatic lipid peroxidation is involved in apoptosis.
The former being the more clean and efficient method of recycling (in the lysosome),
and the latter being the more messy method of recycling (in the liver), required for more serious damage.

That is why there is no correlation between omega-3 supplementation and life-span in epidemiological studies;
as these lipoxidation processes are just part of the big plan of our body,
with various controlling mechanisms (including anti-oxidants).

[RRM]

MA can increase pretty quickly if there is a shortage of food. ... as shown in the mead acid topic.

No, that is not shown in the mead acid topic.
Protein energy malnutrition usually comes with PUFA deficiency.
In the studies quoted (about protein energy malnutrition), its the low levels of PUFAs that are associated with elevated mead acid.

[overkees]

there is no correlation between omega-3 supplementation and life-span in epidemiological studies

Maybe not in lifespan, but alzheimers disease is clearly the result of an antioxidant system that wasn't enough to inhibit the formation of excessive acrolein that is found in AD. So shouldn't we prevent the formation of these compounds or are you all saying this is genetics at work?
Also, why can't mead acid provide the autophagy and apoptosis task in your opinion?
And still, the higher suspectibility in lipid oxidation might also be a trigger itself for autophagy that is not needed. If there is stress omega 6 will be released from the tissues and might induce cell destruction that is not needed.

I still think that it is very good to establish good intake amounts for especially LA, but also the other dietary PUFAs. Autophagy is often a good thing, but how much sensitivity do we actually need? I still think a high saturated to high unsaturated fatty acid intake is beneficial.

[dime]

Also, why can't mead acid provide the autophagy and apoptosis task in your opinion?

Good point, but we don't know this at the moment. I'm just guessing it would also induce autophagy, as most other PUFA seem to do.