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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« The Ames Test and the Real World | Main | Close To the Vest »

August 1, 2002

Breathing and Aging

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Posted by Derek

I've written about the idea that aging is related to oxidative damage (most recently on June 3.) There's a lot of support for it, and the documented life-extending properties of caloric restriction are thought by many to be tied into this hypothesis. CR has worked in (for example) fruit flies and rodents, and some slow-moving experiments suggest that it works in larger animals up to primates. The less you eat, the less you metabolize, the fewer reactive oxygen species you generate, and the less damage you do to your cellular machinery. It makes a lot of sense.

Too much sense, I suppose. As is the relentless way of science, the waters have been thoroughly muddied by a report in the July 18 issue of Nature (a summary is here.) [Note added on August 1: these links don't seem to work without a subscription to Nature. I'll see if I can find free ones and post those.] These researchers studied yeast, using the number of divisions a cell can go through as a measure of lifespan. Some of their earlier work supported the CR trend, since they found that yeast grown in reduced-glucose conditions went on dividing for 30% longer.

They were even able to tie this effect to the presence of a particular gene, SIR2. That codes for a histone deacetylase, which would puts it squarely in the gene transcription / regulation area. There's a lot to write about those, of course, but for those who don't follow the field, the short story is that DNA needs to be wound and unwound from histone proteins in order to be transcribed into RNA. Acetylation and deacetylation of the histones is one of the key switches for those processes, although there are others. And there are things that regulate them, and things that regulate the regulators, and things that modulate the effect of the regulation of the thing that cancels the actions of the. . .ah, cell biology. Nothing like it.

But when they looked at things more closely, they found that the calorically-restricted yeast actually have three times the respiration rate! So much for the simple hypothesis. A closer look showed that a key factor is the way that yeast can switch back and forth between respiration (when there's enough oxygen) and fermentation (when there isn't.) Carbon dioxide is the waste product of the first process, which yields more bang for the buck. And as the world well knows, ethanol is the waste product of the second one. Grow yeast under conditions where they do both, and you've got beer. When there's just enough food to survive, it seems, the yeast switch entirely over to respiration for its greater efficiency.

As it turns out, not only do the CR yeast respire faster, but if you mutate them to where they can't respire at all, caloric restriction doesn't increase life span. So what about all the foul free radicals produced by all that respiration? The CR yeast were shown to be more sensitive to free radical sources (which usually means that their existing machinery for detoxifying such things is already stretched near its limit) but these cells showed no increase in the usual suspects (like superoxide dismutatase.)

The free-radical production and protection pathways are clearly more complicated than they seemed. (And, of course, anyone who buys superoxide dismutase tablets at a health food store is clearly a fool, but that's been obvious long before this paper came out.) What would make the story neat and clean is if the SIR2 histone deactylase turned out to be regulating unknown genes that are involved in detoxifying free radicals. That's probably too rational, but it's the first thing to check.

Does any of this apply to larger things than yeast? No one knows yet if mammals on CR diets respire more (although I'll bet that folks are checking as we speak.) SIR2 works the same way in roundworms (C. elegans, the biologist's friend,) and there are homologous genes in higher animals. It's part of some highly conserved metabolic pathway, whatever it is. If we can get our hands on it, there may be hope for an extended life span during which we could actually have a pizza every so often.

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