Tuesday, April 08, 2008

Metabolism nuts and bolts

Nick Lane has produced an interesting book in Power, Sex, Suicide. When it gets down to basics, the electron transport chain of the mitochondria is a bit like a cracked sewage pipe. If that supplies all the information you wanted to know about aging, stop reading now.

What he means is that it leaks unpleasant stuff but usually only in small amounts unless there is a blockage, which fills the pipe and increases leakage pressure. Otherwise just a little of the nasty stuff escapes.

Just to leave sewer analogies aside for a while, what is the electron transport chain? It's a set of very complex molecular structures embedded in the innermost membrane of the mitochondria. It takes an electron (from where, later) and passes it through a series of "mills" and "conduits" until eventually it off loads it on to an oxygen molecule (this is why we breathe, oxygen isn't needed for much else). As it goes through the "mills" its energy is used to pump hydrogen ions from the innermost recesses of the mitochondria in to the outer zones. The more electrons through the mill, the more pumping. The hydrogen ions want to get back in. The only route back in is through a turnstyle. As the turnstyle turns, rotated by a returning hydrogen ion, a mechanism pushes an extra phosphate group on to an ADP molecule to form an ATP molecule. ATP is exported and used as the energy currency of the cell. Most, but not all, ATP is made this way. There are other routes back for hydrogen ions too, but that's another story.

Back to the sewer metaphor. The electron transfer chain leaks. It leaks raw electrons. Electrons react with anything and everything. Many things affect the rate of leakage and the consequences of leakage, but ultimately the knock on effect of this is damage to the mitochondrial DNA, which codes for certain essential components of the electron transport chain... As the DNA degrades over the years the electron chain components become more leaky and more damage is done and we age.

So much comes from PSS. There are very detailed and mostly convincing arguments for this view of aging and a number of other aspects of Life the Universe and Everything. The answer does not appear to be 42.

That got me thinking. Back to Moseby's Crash Course in Metabolism and Nutrition. A quick comparison of the break down of glucose and palmitic acid comes out with this: Glucose goes through glycolysis to pyruvate. Pyruvate enters the mitochondria, gets converted to acetyl CoA and drops in to the ubiquitous tricarboxylic acid cycle (unless your metabolism is VERY strange, like H. pylori). Palmitic acid, my favourite calorie source, gets an executive ticket straight in to the mitochondria where it undergoes beta oxidation to acetyl CoA and after that it could have been sugar (ie acetyl CoA from any source goes down the same cyclical plug hole).

So the difference in metabolism is between glycolysis and beta oxidation. These provide electrons for the electron sewer in different forms. You can't shift electrons around "neat" unless you are using some copper wire or the like. Neat electrons are what do all of the damage. No, electrons are shifted about as chemical electron equivalents. One is NADH, the other is FADH2. Doesn't matter what these stand for. Converting glucose to Acetyl CoA provides a little NADH and that's it. Converting palmitic acid to acetyl CoA provides a whole load of "electrons", in the form of an equal amount of NADH and FADH2. After that it's all acetyl CoA and the same as glucose. But for every calorie of glucose you burn, you generate a higher proportion of NADH to FADH2 than by burning palmitic acid. So what?

NADH puts its electron in to the start of the electron transport chain at complex I. Complex I is leaky. FADH2 puts its pair of electrons in to complex II, which isn't. There is some leakage at complexes III and IV, but complex I one is the worst and fatty acids partially bypass it. I'd like to keep my mitochondria as happy as possible, as they decide when my cells are going to age and die. The later the better. Minimising leakage seems like a good idea (although some is necessary for health, read PSS).

The biochemistry suggests that running your metabolism on fat may release less free radicals than running it on glucose. As I am hopelessly biased in favour of fat metabolism and I enjoy the nuts and bolts of biochemistry, this makes me happy.

It also puts some logic and a mechanism on to Cynthia Kenyon's comment (in reply to being asked why she restricts her carbohydrate intake, ie is it to extend her life expectancy):

"That's not necessarily why I do it. I do it because it makes me feel great and keeps me slender. And I don't feel really tired after a meal. But I think if I wanted to eat in a way that extended lifespan this is how I would do it. In fact, I stopped eating carbohydrates the day we found that putting sugar on the worms' food shortened their lifespans."

I know what she means about feeling good and staying awake after a meal.

Personally I think old age is a not the problem, it's getting there without those diseases normally associated with it that would be nice. If you can become aged and stay disease free, the longer it goes on for the better.



Stephan Guyenet said...


You clearly have a good grasp of PSS. Better than mine!

I just wanted to say, since that book was published the ROS theory of aging has taken some pretty big hits. There's this mouse called the "mitochondrial mutator mouse" that has a defective proofreading enzyme. Young MMMs can have significantly higher levels of mtDNA mutation than old wild-type mice, yet display no signs of aging.

I think we're going to find eventually that aging is a controlled process, not simply a passive wearing out of the gears.

Peter said...

Hi Stephan,

Nick Lane argues that free radicals signal from the mitochondria to the nucleus, more free radicals being the request for more of the nuclear DNA coded respiratory chain components ('cos it's leaking). If this system fails, no spare parts arrive and free radicals increase further until they eventually oxidise the inner mitochondrial membrane, collapse the proton gradient and result in the death of that mitochondrion. Other mitochondria divide to take its place. This eliminates the majority of mitochondria with damaged DNA and favours those with best functional DNA. Eventually even the "best" mitochondria accumulate enough damage to leak enough free radicals to signal cellular apoptosis. This eliminates damaged cells, producing tissue wastage without catastrophic failure (which results in necrosis and tissue inflammation). Tissues shrink or turn over (if they can) as appropriate. Maintaining adequate mitochondria-to-nucleus signaling needs free radicals and is suppressed by antioxidants, hence the minimal benefits from these substances. Also if they don't penetrate the mitochondria they can't stop collapse of the inner membrane, so won't stop the mitochondrion "dying". But as it's damaged anyway, it needs to be replaced, so stopping it "dying" may not be a good idea.

As regards the MMMs, what do old MMMs look like? If Nick Lane is correct, they should remain normal until they run out of undamaged mitochondria to power the cell, at which point neat and tidy apoptosis should occur...

I think a lot of Lane's ideas are based on the work of Barja which does not all coincide with my own thoughts on food choices. Barja feels protein is indirectly the main source of leakage of electrons in mitochondria. It has to be very indirect as far as I can see. He also looked at carb restriction but only reduced carbs by 40%, not enough to make a difference (assuming he started from lab mouse chow).

Both Barja and Lane suggest the jury is still out but neither think the idea is dead yet.

I'm curious about the MMM mice... Oh, found a study. Were these the mice?


Stephan Guyenet said...

Here are the two original papers:



The mitochondrial stuff from PSS is coming back to me now. I'm not sure if the recent data challenge his hypothesis or if you can work around it.

I'm a little fuzzy on the details, but I think they learned after the two papers above that their technique for measuring mtDNA mutations was overestimating. I couldn't find the more recent paper but I'll take a look later.

Dr. B G said...

You guys are giving me PTSD from my poor biochem days.... ohhh, but it's sorta coming back to me now!!

Peter, I LOVE that quote from Kenyon. Where may I ask did you find it? (she's here at UCSF in the Bay Area) I think she has some really neat observations. (I don't think she's figured out yet but DAF-12 is VDR and PPAR combined... mmmmmmhhhhh... yeah, I think so :) ) When did you get into worms, the most elegant longevity model?

So would you say that lipid peroxidation is like metabolism of jet fuel? (not so efficient, but super duper power-yielding) esp compared with glucose metabolism? that's my impression, but don't know how 'off' I am... you're the expert :) THANKS!! g

Stephan Guyenet said...


I think Nick Lane's theory about natural selection of mitochondria occurring in the cell is a neat idea, and it may well be true. However, I'm guessing it was born of necessity because the evidence hasn't been supporting less sophisticated (and more easily falsifiable) versions of the theory.

And don't forget the fact that naked mole rats seem to do fine with massive amounts of ROS damage in their cells. They outlive their closest relatives by an order of magnitude, but not by reducing ROS and protein/lipid/DNA damage.

Anonymous said...

Peter, I have one problem with this article. You compared palmitic acid (saturated fat) to glucose, without mentioning what other fats will do, esp PUFAs. Also, you said that some leakage is required, but how do you know what the ideal level would be?

I am confident, based on evidence, that it's better to eat sugar than corn oil, soybean oil, rapeseed or canola oil, sunflower, peanut oil, safflower, canola, etc. Potatoes, raw honey, and other natural carbs are probably better still. There's a continuum. I would say that beef fat is better than pork fat. A lot of studies have used lard to cause disease, but coconut oil or butter was safe in the same context.

Just a little PUFA oil is bad. Beef fat by itself doesn't cause cancer, but if you add 3% sunflower it will generate cancer. Clearly, the PUFAs are to blame. Beef has 3-4% PUFAs. Sunflower oil has 60%. Studies fed animals beef fat and safflower oil and then blamed saturated fat, but the diet was roughly 40% PUFAs and 30% Saturated Fat. They never even bothered to consider that PUFA may have been the problem. Palm oil is not as good as coconut oil, butter, and beef fat. It's not fair to say that all fats are equal. The lower the PUFAs are, the better.


Most people today eat lots of PUFA, including people on low-carb diets. For example, anyone who eats store- bought mayonnaise, salad dressings, restaurant cooking oil, or prepared food (even low-carb) is most likely eating a lot of PUFA oils. Chicken and turkey are also fairly high, if you eat the skins. Above a certain threshold, PUFAs seem to be toxic. Even native Eskimos had pathologic bleeding as a result of their high omega-3 intake. I've also heard of people who tried JK's diet and the moderate high-PUFAs from pork seem to have caused problems.

So, while palmitic acid might cause less "leakage" than glucose, that's a long way from proving that fat in general is better than carbs. Where are the long-term studies, of total mortality and morbidity, that prove fat is better than un-refined carb? Note: I don't consider any flour to be an unrefined carbohydrate. Sugar and HFCS are also off the list.

Peter said...

Hi Bruce,

As far as I can see the oxidation of PUFA is a modified form of beta oxidation which should feed reducing equivalents in to a combination of complex I and complex II, much the same as saturated fats. All glucose will have the go through cytosolic glycolysis and have the reducing equivalents passed in the the mitochondria through one of the two NADH shuttles. I can see marked differences in many other features of oxidative stability between the fat types but they look remarkably similar within the context of beta oxidation. I feel you have to look outside the mitochondria for the issues with PUFA.

Obviously normoglycaemia is physiological but hyperglycaemia is a massive free radical generator. Whatever form your carbs come in, the crucial aspects seems to be normoglycaemia. I think insulinaemia is a separate but related issue. When people are insulin resistant on a moderate carb or high carb diet they are in the worst of all worlds. High glycation, high insulin, probably high lipid peroxidation of PUFA. If insulin sensitivity is good then there is far more scope for normoglycaemic carb intake with modest insulin levels.

The thing about people who are actively ill with modern diseases is that they are almost certainly insulin resistant, as this defines many of the diseases. Unless you can identify and fix that core insulin resistance then carb restriction becomes necessary. Not so for an insulin sensitive person. It depends how broken you are...

From the personal point of view I just feel happiest living as though I'm insulin resistant, that seems much better than finding out the hard way if I've assumed I'm not, by a coronary etc...


PS The native eskimo may well have had prolonged bleeding times but they were completely free of cancer, no detectable cases at all, while ever they were clear of sugar and flour, according to Stefansson. The carcinogenic effects of PUFA, certainly the omega 3s, do not seem to occur in the context of a native diet. Of course lab rats never get that option, with either omega 3s or 6s...