What's the key to everlasting youth? For years now, evidence has steadily accumulated, from studies on mice, flies, worms, and even yeast, that cutting calories is the secret to a long lifespan - at least in a wide range of non-human organisms. But does this work in humans?

This question is tantalizing, yet frustratingly difficult to get a handle on. The fact that you can increase lifespan in organisms from yeast to mice by calorie restriction strongly implies that this should be true in humans as well - I find it incredibly unlikely that we're an exception to such a widespread phenomenon. And yet this idea is obviously extremely difficult to test directly in humans: it's impossible (without putting someone in some sort of Truman-show like scenario) to accurately measure and tightly control the calorie intake of hundreds or thousands of humans for their entire lives. Retrospective surveys of eating habits are notoriously inaccurate - at least when we consider the degree of accuracy we want to test the idea that calorie reduction increases lifespan.

The great thing about science though is that we don't have to test everything directly. Researchers can get extremely clever when it comes to designing indirect tests of a hypothesis. And while a single indirect test may not be very convincing, the results of many different lines of indirect evidence can become extremely persuasive.

I wouldn't put the lifespan effects of calorie restriction on humans in the extremely convincing category yet, however researchers are following several avenues that so far appear to be fruitful.

There are studies like the following, which by themselves can be underwhelming, but together are beginning to add up to a fairly consistent picture:

Animal studies suggest that diets low in calories and rich in unsaturated fatty acids (UFA) are beneficial for cognitive function in age. Here, we tested in a prospective interventional design whether the same effects can be induced in humans. Fifty healthy, normal- to overweight elderly subjects (29 females, mean age 60.5 years, mean body mass index 28 kg/m(2)) were stratified into 3 groups: (i) caloric restriction (30% reduction), (ii) relative increased intake of UFAs (20% increase, unchanged total fat), and (iii) control. Before and after 3 months of intervention, memory performance was assessed under standardized conditions. We found a significant increase in verbal memory scores after caloric restriction (mean increase 20%; P < 0.001), which was correlated with decreases in fasting plasma levels of insulin and high sensitive C-reactive protein, most pronounced in subjects with best adherence to the diet (all r values < -0.8; all P values <0.05). Levels of brain-derived neurotrophic factor remained unchanged. No significant memory changes were observed in the other 2 groups. This interventional trial demonstrates beneficial effects of caloric restriction on memory performance in healthy elderly subjects.

Another strategy is to go after the genes involved. There are known genes in worms and yeast that clearly play a role in the beneficial effects of calorie restriction; do these genes have the same effects in mice and humans? (Note that this is not a question of whether humans and mice have the same genes - they do; the genes we're talking about are remarkably conserved over distant evolutionary relationships, which is more evidence that calorie-restriction has an effect on some very fundamental processes.)

A paper in this week's issue of Nature is part of this latter strategy. The authors looked at the growth of tumors transplanted into mice on a severely restricted diet, and identified a cellular signaling pathway (active inside the tumors) that generated tumors resistant to the normally anti-tumor effects of severe calorie restriction. (Note that 'anti-tumor effects' here means anti-tumor effects in mice with transplanted tumors, and nothing more.)

What possibilities do studies like this raise? The obvious possibility is that, if we all reduce our calorie intake by 20-30% (and this would probably have to be a long-term reduction), there may be anti-cancer, mental health, and other lifespan benefits. On the other hand, there could be significant severe side effects over a long period of time (after all, mice, yeast, and worms don't live to be 80, 90, 100 years old), especially in people who are not in general good health - we're talking about a very significant reduction in calorie intake here. (And it's not clear that just a mild calorie reduction will produce the same types of benefits.)

Instead of going on a subsistence diet to prevent or treat cancer, we can try to design drugs - drugs that mimic the effects of calorie restriction on particular cellular signaling pathways. Studies like the one in this week's Nature lengthen our list of possible anti-cancer drug targets. It's not at all trivial to go from an attractive cellular signaling pathway to an effective drug treatment (and so this idea is just speculation until proven otherwise), but anti-cancer drugs that mimic the anti-tumor effects of calorie restriction might just happen to have other beneficial, life-span-enhancing side-effects. And Big Pharma marketers will go wild over a fountain-of-youth pill.