If you wanted to prolong the life of a worm or a fly, there's a simple method of doing so: severely restrict its caloric intake. When fed a very low-cal diet, these lab animals saw their lifespans extended, and showed few of the signs of aging. This encouraged people to see if the same approach would work on animals that are more closely related to humans, and the first results looked promising, in that caloric restrictions appeared to extend the lives of mice and even a primate.

But since that early promise, things haven't been looking as good. And now, a separate study done with macaques has found no benefit of caloric restriction, and suggests that the initial positive results are the product of some specific experimental design choices.

While the term "caloric restriction" may sound like a diet, it's really a very different process. Instead of focusing on specific types of food and cutting intake slightly, caloric restriction is agnostic about the source of the calories, but makes severe demands on the total count, usually cutting it by about a quarter compared to a healthy baseline. This obviously results in leaner animals, but it also appeared to stave off age-related death, while keeping some animals free of age-related disorders like diabetes and cardiovascular disease.

In response to some of the initial findings, two labs (one in Wisconsin, one at the National Institute on Aging) set up a long-term experiment where they started macaques on a diet that cut calories by 30 percent. The studies have now been going for decades, and the Wisconsin one has been reporting some very positive results: cancer, diabetes, and heart disease were down, longevity has been up. This has gotten a lot of people rather excited.

And that excitement explains why a negative result, coming from the National Institute on Aging (NIA), has ended up gracing the pages of Nature. Just as in Wisconsin, the authors tracked the long-term health and survival of macaques and, after about 30 years (three past the typical lifespan of a macaque and excluding deaths due to accident or injury), they saw... nothing much at all. Calorie-restricted macaques lived slightly longer, but the difference wasn't statistically significant, and the authors calculated that there was only a one percent chance that it could become statistically significant before all the animals were dead.

There were a few indications that the animals on the diet were somewhat healthier—cholesterol and triglycerides were down, for example—but it didn't seem to translate into greater longevity.

How could that possibly happen? Although the experiments were extremely similar in design, there were enough differences to potentially skew the results. The diet used in the NIA study was derived from natural components, while the one used in Wisconsin came from a process in which isolated chemicals were combined, which could have a significant effect on various trace nutrients. One additional effect of this is that the Wisconsin diet derived nearly a third of its calories from sucrose, while that figure was under four percent at the NIA.

Another key difference: the control group in Wisconsin could eat all it wanted, while the one at the NIA was kept to a specific limit in relation to the experimental animals. In other words, the Wisconsin controls may have actually been more obese and less healthy than they might have been otherwise.

Genetic differences also may have played a role, as the animals were derived from different areas in Asia. In mice, caloric restriction's effect on longevity is very sensitive to genetic differences between mouse strains.

Does that mean that severe caloric restriction is bunk? Probably not; there were clear indications that it improves general health, and there may be individuals who are predisposed to benefitting from it. But it certainly should give pause to anyone naïvely expecting that hopping on the diet will necessarily have a profound effect on their aging. And, if it wasn't obvious enough, cutting 30 percent out of your daily calorie intake is hard. Fortunately, you now have less reason to try.

Nature, 2012. DOI: 10.1038/nature11432 (About DOIs).