Sep 25 2008

Calorie Restriction for Life Extension

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There is a fairly direct correlation between scientific medicine and life expectancy, both historically and geographically. This makes sense – as we get better at preventing and treating diseases people will live longer. But the ultimate “disease” is aging itself. As we get older, our cells age, their DNA is damaged and the repair mechanisms are less effective. In short, our cells wear out.

Some researchers have therefore focused their efforts on discovering what, exactly, is happening to our cells as they age and can these processes be stopped or reversed. The motto of these researchers is “death in an engineering problem.” It is not inevitable – it is simply a challenge. Researcher Aubrey de Grey has been one of the most visible proponents of so-called “rejuvenation research.”

I have watched this research with an open mind but skeptical eye. Theoretically there does not have to be anything inevitable about aging. It is just another physical process. There is not theoretically reason why it should not be possible to intervene in whatever processes constitute aging.

However, I think aging will be a much tougher nut to crack than the rejuvenation enthusiasts imagine. Once we pick the low-hanging fruit, we are likely to find that some effects of aging are very difficult to address. Further, once we start trying to fix some of the effects of aging, only then will we discover what the true implications of such interventions are. There may be a host of downstream effects that then have to be addressed.

One of the current lines of research in life extension is calorie restriction. Mice who are fed a low-calorie diet (just enough to stay alive) live substantially longer (20-40%) than mice fed a more typical diet.  This is an impressive and reproducible effect. Some people, in fact, have decided to live with a calorie-restricted diet in order to reap the life-extension benefits seen by mice. Calorie restriction research has also gone beyond merely demonstrating an effect, towards looking at what the specific effects of calorie restriction are on cells and in specific diseases. Some research shows benefit, other research does not.

While the notion of calorie restriction to prolong life makes some sense – if a candle burns more slowly it will last longer – I have always had a problem extrapolating from mice to humans when it comes to life extension. The two primary reasons for my hesitance are: mice models of human disease are sometimes useful, but other times do not predict human responses; and mice only live months in the lab (a well-cared for mouse can live a few years), which makes it difficult to extrapolate to the 80 year life span of a human.

This latter fact has always been a real sticking point for me. It seems likely that the processes of aging that kill off a mouse in months would differ from those that take years in a human. Not necessarily in every way, but probably in some important ways. Looking through the literature I find that this is probably true – some metabolic factors turn out to be the same in humans and mice, while others differ.

A recent study looks at what at present is the likely primary mechanism by which calorie restriction extends life in mice – IGF-1. Insulin-like growth factor 1 is decreased by calorie restriction. Research also shows that if you knock out the gene for IGF-1 mice will live longer.  What the new study does is look at IGF-1 levels in humans on a calorie-restricted diet. They found no difference from normal controls. Therefore calorie restriction does not seem to lower IGF-1 levels in humans as it does in mice, and this may negate the longevity effect seen in mice.

But, there is more to this research. They did find that those on a low protein diet did have lower IGF-1 levels. And, when they had some of those on the low-calorie diet change to a lower protein diet their IGF-1 levels decreased. So perhaps it is low-protein and not low calorie that is the key (which, if true, throws a monkey wrench into the low-carb/high-protein diet craze).

What this research shows is that animal metabolism is a complex interwoven web and when you pull on one thread you cannot always predict all of the consequences. It also shows that while humans and mice are similar enough to make mice a useful model for research, there are differences and so mouse research is always considered preliminary and not definitive. It paves the way for human research, but not does replace it. Specifically, the question is whether or not mice are a good model of human aging, and I think there is good reason to conclude – probably not.

It is too soon to go on a protein restricted diet, and I would seriously reconsider a calorie-restricted diet if you think it will make you live longer. But this research is likely to teach us a great deal about human metabolism and the mechanisms of aging, and will also likely lead to specific recommendations for healthy living. But we are a long way from the elixir of life, despite the enthusiasm of the early adopters.

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