Friday, October 30, 2009

Worms and Stress: Live Long and Prosper

This is a very interesting paper about worms. The central thing to remember is that it is about WORMS. Most of us are not worms, but all of us do have mitochondria. Worm mitochondria are, I suspect, quite similar to human mitochondria, at least as far as basic signaling mechanisms are concerned.

Glucose, as a molecule, is full of oxygen. One oxygen atom per pair of hydrogen atoms. You just need to add an oxygen molecule for each carbon atom to get just over 40 molecules of ATP. Fats are different. There are only two oxygen atoms down at one end of that long string of carbon and hydrogen. To extract the stored energy requires much more molecular oxygen, so makes more use of mitochondrial respiration.

The electron transfer chain leaks free radicals. Running your metabolism on fat requires more use of the electron transfer chain. That means more free radicals.

Generally free radicals are considered to be a Bad Thing.

Actually, if you think about it, having your white blood cells throw free radicals at invading bacteria suggests that free radicals are one reason we are all still alive. Nothing is all bad.

So worms, under glucose restriction, generate far more free radicals than those able to access glucose.

Here's the best bit: The ones making all the free radicals also live longer. Don't forget, it's only a worm!

Why do they live longer? Because mitochondria can only work by using oxygen to run the respiratory chain. If using mitochondrial respiration was damaging, we wouldn't do it! It's POTENTIALLY damaging. Given the few billion years we've had, metabolism would have stopped this free radical production if it needed to. Evolution hasn't made the respiratory chain leak proof. Why? Free radical generation is the signal that mitochondrial respiration is happening and it's time to up regulate the cell's routine protection against free radical damage that has stood the test of time. This does not involve going off and eating some poor plant to steal its antioxidants.

Catalase, superoxide dismutase and glutathione peroxidase will do for a start. These are local antioxidant enzymes produced where they are needed, when they are needed by a cell which needs them to run its power plants safely. The fact that they seem to have overall benefits, apart from the smooth running of the mitochondria, is a useful spin off. And they don't involve eating anything green.

There are a few summary points to the study:

Glucose restriction by any technique extends lifespan in worms.

Glucose supplementation produces a dose related shortening of life span in worms.

Glucose supplemented worms store FAT!

N-acetylcysteine, ascorbate or a vitamin E derivative (Trolox) each eliminates the life extension provided by glucose restriction in worms.

Here's the consolation for people knocking back the antioxidants: They probably do no harm directly, just eliminates any benefit from glucose restriction. If you live on glucose, well shrug...

This is how this research group view the impact of their work on diabetes management:

"In light of our findings, the current body of evidence tentatively calls into question the efficacy of increasing cellular glucose uptake in diabetics and suggests that other methods of lowering blood glucose (Isaji, 2007; Wright et al., 2007) may be preferable to achieve normal life expectancy in human type 2 diabetes patients."

The two refs cited refer to techniques for extracting glucose through the kidneys or possibly reducing its uptake through the gut. No consideration seems to be given to not actually putting quite so much glucose in to the system in the first place!


If anyone finds this remotely interesting, while not feeling particularly worm-like, you can go and look at the evidence in Jenny Ruhl's post on antioxidants in humans.

I'd just like to point you towards this particular one. I was surprised that as little as 1000mg of ascorbate per day with 400iu of vitamin E had a measurable effect. But, if the study is replicable, it might well fit in with the observational evidence.

Really must give up the chocolate (only kidding, my liver will save me!).

Peter

23 comments:

rosenfeltc said...

Great Article. Just one question, the whole Liver will save me thing is that meaning that you prefer to get your required amount of daily glucose through minimal carbs instead of protein conversion through the liver because it might stress it?

Reason, I'm asking is because I've been eating only meat and drinking only water for a little over 6 months now and I've been feeling overall a lot better then how I felt on my previous "pyramind food guide" diet but I was wondering if you think that it's better to stay out of ketosis all the time or eat some carbs?

One other thing I can say is that I really do think my brain functions better on ketones, correlation doesn't equal causation but my exam scores have gone up an average of 6 points with no extra studying.

Anyways, keep up the great work, one of these days I'm going to read all your posts (so many).

Kurt G. Harris MD said...

"This does not involve going off and eating some poor plant to steal its antioxidants."

Peter, your writing is priceless.

Vegetables are not magic.

Keep up the great work.

StephenB said...

From the study cited: "Supplementation with antioxidants may preclude these health-promoting effects of exercise in humans."

I wonder what else would block exercise's benefits? I do hope vitamins A, K, and D wouldn't. Nutrition certainly gets complicated.

Peter said...

Hi Rosenfeltc,

My guess is that my liver probably excretes most antioxidants before they can do significant harm, C elegans may not do this quite so well. That's why I was surprised that as little as 1000mg of ascorbate affected human training response (though excretion here is most renal). I think it's also worth adding that there are circumatances where overwhelming free radical production needs treating. I find the work on high dose iv ascorbate in burns, pancreatitis or paraquat poisoning are pretty convincing. But this is ascorbate as a pharmaceutical, not a vitamin. I think the anticancer effect of iv ascorbate is probably real and also non-physiological.

StephenB,

I think Jenny's comments about getting nutrients at food levels from food is worth listening to. I did mega dose C and my personal experience was that I had rather more colds and so needed rather more C... The main things we lack is a time-tested food culture as HGs seem to have and access to food not modified by humans. Oxalate rich veggies probably never formed bulk calories for many/any of us, as came through in the comments to the renal stones post. Vitamin D is the interesting one here. I still feel mega dosing is somewhat controversial, especially on a background of a low inflammation diet.

Peter

Peter said...

Kurt,

The free radicals from hyperglycaemia are different, I'll see about a post on these soon... Not all free electrons are good!

Peter

Nigel Kinbrum BSc(Hons)Eng said...

< nerd >According to my book Metabolism at a Glance, one molecule of glucose aerobically yields 31 (previously 38) molecules of ATP.< /n >

Peter said...

Hi Nigel,

Possibly even less than that if there are a few extra uncoupling proteins pushed in to the inner membrane...

Peter

mark said...

rosenfeltc, no carbs gives me tachycardia and some mania. The result is I get ill from restlessness and am overly intense. Stan (Heretic) has written about it before and Peter also.

http://en.wikipedia.org/wiki/Tachycardia

Take it with a grain of salt. Tachycardia from prolonged ketosis or carb restriction or low carb isn't the same as from another source. Techycardia just means "high heart rate." It's like "feeling ill" - flul? cold? autoimmune? mono? etc.


But I also think my brain functions better on ketones. Same, generally a lot smarter, focused, creative, etc. since being strict in low carbing, but I need to stay out of ketosis ALL the time to avoid getting sick. The mania, though, is something for doing work.

Peter, a poster by the name of Ken has posted a lot about Vitamin D on your blog in a negative light. I wonder if Vitamin D will come out looking bad in the end as he has claimed.

On t-nation.com, a bodybuilding site, there is an article called "evil antioxidants".

http://www.tmuscle.com/free_online_article/sports_body_training_performance_nutrition/evil_antioxidants

This is a decent site. Unlike Jebb and the drug advisor whose jobs are affected by whether they lie or not, this website allowed an author to post about that, despite the fact that they sell antioxidant products. The article I linked to gives a couple of refs which I don't have the time to lookup, but want to post here for reference for anyone who wants to work with them.

I'm going to be throwing out the N-acetyl cysteine. Only things I take now are zinc and magnesium before bed. I take vinpocetine when I need to do work and read and study. I have some refs on it if you are interested in "cognitive enhancement." Cold-fx looks good to me if I am ever coming down with anything. But then, you don't get ill. I have the TC of 320, but I don't have your immunity. I think mono screwed me up bad. But the interesting thing is that I get sick a lot less than when I first got mono, which was all the time, and at this point have a immune system comparable or better to other people eating SAD. Huge improvement with low carb (5 years) OD 2 years eating.

Your comments about mitochondria and evolution and free radical damage are spot on. Makes me think about the problem of PUFA and how JK isn't against them strongly. Then i think about macrophages endocytosing LDL and oxidation's good/bad becomes contextually dependent. Is a glycosylated LDL molecule oxidized? Or is it just augmented? Maybe all the problem is in glycation of LDL and not oxidation.


Thanks so much for the post and blog.

Mark.

mark said...

That link didn`t come out from T-nation.com

You can search on their upper right corner for evil antioxidants and the article will pop up.

The author is Dr. Lonnie Lowery

Mark.

medium-chain-triglycerides.com said...

Hello Peter,
while we're on the topic of Liver...

I'm currently working through reading your article here. I'm aware that MCTs must be transported to the liver to be metabolized.
Maybe over time this could put undue stress on the liver or potentiate insulin resistance, I don't know (?). Also there is at least one study that has demonstrated faster production of oxygen radicals with MCFAs.

Last night I overfed on a large load of MCTs completely in lieu of LCTs, just to experiment. I woke up to some digestive discomfort, but also 40 mg - 80 mg (moderate-heavy) ketosis. (No known health conditions.)

Any speculations on the long-term consequences of such a ketogenic diet would be greatly appreciated.

Thanks for putting out useful articles.

pyker said...

Very interesting stuff. That last study you mention, the one mentioned in Jenny Ruhl's post, got a bit of press when it came out. An interesting argument about a flaw in the study wrt vitamin C and insulin sensitivity in particular is here: http://www.imminst.org/forum/index.php?showtopic=29955&st=0&p=322283&#entry322283. I'm not sure what to make of it.

peebix said...

Do you have any comment on studies that show tea is beneficial for health, often ascribed to its antioxidants?

By the way, why did the the exercise study combine vitamin C and vitamin E? Doesn't that cause confounding factors, or is there maybe some underlying reason why it makes sense to test the combination?

Thanks.

mark said...

Peebix,

The physicians health study linked through Jenny's blog was interesting. Many years of follow up, slightly increased mortality for the groups with real vitamin C &E. PLacebo both was second lowest. It's in figure 1, at the bottomish. It's in table 2, also. Figure 3 gives cardiovascular mortality, better to refer to figure 1 and table 2.

The full-text is available for it and in it they used a real E + placebo C, placebo E +real C, real E + real C, and placebo E + placebo C. They did it all. http://jama.ama-assn.org/cgi/reprint/300/18/2123

The study's focus was non-fatal endpoints, but the mortality is there in the data.

Combined with all of these intervention antioxidant studies, they look nuetral at best slightly harmful at worst. Maybe a little more than slightly harmful.

Peter has written about antioxidants in tea in the fruit and vegetables series on the right hand labels of the blog. Tea antioxidants didn't come out well.

lightcan said...

As I can see, the jury is still out on the antioxidants. I read with interest the debate on the thread to which there was a link a few posts up (on imminst.org)
I don't think we can simplify and generalise regarding the antioxidants. Doctors generally say eat a 'healthy' diet, there's no need for supplements, there's no evidence that they are beneficial. They would say that anyway. Get vaccinated instead or take some statins. What is a healthy diet for them? How do they assess the health status of the patient? On the other hand, dr. B.G. has a different opinion, just to mention one credible source (IMO).

lightcan said...

Maybe I shouldn't lump together antioxidants (Vit A, E, C, A lipoic acid and others) and supplements in general. There is a need for vitamins, everybody agrees. How much one individual needs depends on many things. Do we need to supplement if we consider that our intake is less than optimal? Do we just worry about the minimum, do we just let the body up its antioxidant mechanism?
Living on a high fat, low carb diet with rare fruit and cooked veg doesn't give you a lot of vit C. So, do you supplement with ascorbic acid that's not very bio available? Is there a point to it?
According to this review
http://www.ajcn.org/cgi/content/full/76/4/703
taking vit E for its antioxidant properties in CHD should be done in the first stage of the disease, in childhood and not later when the disease moves to a different stage. Interesting discussion of the trials, of the difference in quantity, quality of the supplements used and of the different absorbtion potential in individuals that wasn't assessed.

donny said...

Naked mole rats can live to 28 years and toss out radical oxygen species like mad. Of course, they live on tubers... but insulin levels, in a few studies I've looked at were "unmeasurable."
I've been worried about those CRONies for some time. They go out of their way to get the same micronutrients they'd get from eating a full-calorie diet-- I'd hate for somebody to go through a life of sack and ashes, just to be hit with this sort of a catch-22 in their sooner than they'd hoped old age.

Ken said...

Sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction, intermittent fasting, exercise and dietary phytonutrients: "Mitohormesis" for health and vitality.

Mitohormesis (Mitochondrial Hormesis) .

In the trials antioxidants were most deleterious to smokers so I'm doubtful that extra vitamin D would be useful to those on a high carb diet.

Flavoniods such as polyphenols may be pro-oxidant and possibly have an oestrogenic effect - they are likely very mild poisons. Will ingesting them in a certain amount and combination bring a net benefit in practice by supercharging the body's defences - I dunno.

I don't think that 'vitamin' D is like flavoiods - or all that similar to antioxidants - but the Ristow studies give me added confidence that there is good reason for not overwhelming the naturaly selected homeostatis of vitamin D by ingesting evolutionarily unprecedented amounts of 'D' (even in winter). Sunbathing may not raise your vitamin D much but it is probably deleterious all the same.

Bris said...

There is a suggestion that antioxidants work via hormesis. In other words they are mildly toxic and any benefits are really due to the body counteracting this toxicity.

Peter said...

Lightcan,

Some antioxidants certainly have pharmaceutical effects. Alpha lipoic acid in diabetic neuropathy for one seems to be effective. However I would put this in the category of iv ascorbate, (10,000mg/d http://www.ncbi.nlm.nih.gov/pubmed/14606098) for pancreatitis which will get you out of the ICU quicker and not in a coffin either.

On the plant front I think WHEL and PPT suggest phytochemicals in bulk are probably neutral rather than harmful. It's the wrong type of vitamin E or synthetic carotenoids that look to be less helpful. You can guarantee that if we modify a useful substance we will screw up. But if perfection is required I do wonder about the general principle involved.

Vitamins are context specific in my book. Ascobate need is probably higher on a diet producing hyperglycaemia, B1 is markedly carb dependent. My guess would be that E is PUFA specific. I've got suspicions that D3 requirement might be diet specific too.....

BTW there is this abstract out there:

http://www.ncbi.nlm.nih.gov/pubmed/9758570

which is probably massively overburdened with confounding factors that Willett is unlikely to have thought about.

Donny,

Yes, that needs thinking about. The tubers are pertinent to the post I'm trying to get together about hyperglycaemia and free radical generation. Unfortunately the paper is very badly written so I'm now wondering about their hypothesis...

The CRONies are interesting. They get the benefits of switching to mitochondrial respiration while losing weight, but once at maintenance emaciation level they will be running completely on glucose. The free radical benefits of mitochondrial respiration will be lower on glucose than on fat and I'm not sure the cytoplasmic free radicals carry the health benefits of those from the mitochondria. Of course the mole rats tend to argue against this.... Oh, and of course the CRONies will never generate much mitochondrial NADH so shuttling cytoplasmic NADH will be easy. The sorbitol pathway will be inactive so cytoplasmic free radical generation will probably drop too. Then what?

Ken,

I still wonder about D and the SAD, the intervention studies that are starting to trickle in are looking better for D than any I have seen for C. Even if you consider mega dosing to be pharmacology, I have to admit to being a pharmacology user on occasions, as in the pancreatitis studies using ascorbate.... But I agree this is not answering the basic question of what is the "correct" amount!

Peter

lightcan said...

Thank you Peter, I see, pharmacology treating pathology (megadoses of vitamins or minerals) and vitamin needs are context (diet and the rest) dependent. So, that's sorted, I only need to find out what's wrong with me.

Jack C said...

Peter,

I came to this post as a result of the your response on your July 4, 2010 post.

Another study (Spain) found that 1 gram of vitamin C resulted in reduced exercise endurance capacity and reduced expression of factors involved in mithochondrial biogenesis. (PMID 18175748)

CoQ10 is a powerful antioxidant (as well as a pro-oxidant) but because it is endogenously produced it would seem that, somehow, it would not interfere with beneficial free radical production during exercise even when supplemented as long as supplementation is not excessive. What do you think?

The effectiveness of CoQ10 in preventing oxidative stress in rats was evaluated in PMID 18544898

Regarding the need for vitamin supplementation, it is noted that six B vitamins are required for CoQ10 synthesis all of which are synthesized by beneficial bacteria in a healthy gut. Those with gut dysbiosis, such as those with IBS, are likely to be deficient in the vitamins needed to make CoQ10 and thus will benefit from CoQ10 supplementation.

Peter said...

Free full text too! Have yet to read properly but great.

Q10: Sysnthesis decreases with age. What happens if you dump the starch and eat fat and use your mitochondria to the max? Now there's a study for Volek or the like........

Thanks

Peter

Peter said...

Jack,

I've read the paper. I love it.

Re Q10, they cite

http://www.ncbi.nlm.nih.gov/pubmed/9401591

and

http://www.ncbi.nlm.nih.gov/pubmed/8869734

Are these worrying?

Peter