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.

Peter