Does Calorie Restriction Extend Lifespan in Mammals?

Until about two years ago, the story went something like this: calorie restriction extends lifespan in yeast, worms, flies, and rodents.  Lifespan extension by calorie restriction appears to be biologically universal, therefore it's probably only a matter of time until it's demonstrated in humans as well.  More than 20 years ago, independent teams of researchers set out to demonstrate the phenomenon in macaque monkeys, a primate model closer to humans than any lifespan model previously tested.

Recent findings have caused me to seriously question this narrative.  One of the first challenges was the finding that genetically wild mice (as opposed to inbred laboratory strains) do not live longer when their calorie intake is restricted, despite showing hormonal changes associated with longevity in other strains, although the restricted animals do develop less cancer (1).  One of the biggest blows came in 2009, when researchers published the results of a study that analyzed the effect of calorie restriction on lifespan in 41 different strains of mice, both male and female (2).  They found that calorie restriction extends lifespan in a subset of strains, but actually shortens lifespan in an even larger subset.  Below is a graph of the effect of calorie restriction on lifespan in the 41 strains.  Positive numbers indicate that calorie restriction extended life, while negative numbers indicate that it shortened life:

If we take the results of this study at face value, it suggests that under the conditions of this experiment:

1. Calorie restriction is more likely to shorten life than lengthen it in mice. 
2. The effects of calorie restriction on lifespan depend on an animal's genetic background.
3. The calorie restriction literature may suffer from publication bias.

In 2009, researchers at the University of Wisconsin published preliminary results from the first primate calorie restriction experiment (3).  The analysis suggested that restricted macaques suffered fewer "age-related deaths".  Many people, including myself, found this somewhat questionable since total deaths from all causes were not significantly different (the experiment is ongoing, so there may eventually be a significant difference).  Also, the diet was appalling-- a refined feed made of sugar, isolated starch and other purified ingredients.  Animals in both groups died of gastrointestinal ailments.  The restricted group was protected from obesity, diabetes and cardiovascular disease, and they certainly looked much better.  Eating less of a poor diet seems to protect against disease, and may or may not extend life.

Today, a new study was published that casts further doubt on the idea that calorie restriction extends lifespan in mammals, including primates (4).  Researchers from the National Institute on Aging placed macaques on an unrefined (whole food based) diet for 26 years, with or without 30 percent calorie restriction.  They did this in two experiments, one starting with young monkeys and one starting with older monkeys.  Both experiments showed that calorie restriction does not extend lifespan under these conditions, although it does prevent obesity and cancer, and apparently maintains a youthful appearance.

It's worth mentioning that the control (unrestricted) monkeys in the first experiment were truly given as much food as they wanted to eat (ad libitum), while those in the second experiment were given an amount of food that allowed them to reach a normal weight but not become overweight.  Therefore, one could argue that the control group in the second experiment was slightly calorie restricted.  They certainly gained less fat than in the previous experiment, but their diet was also far superior.

I think when you consider all the evidence to date, the take-away message is that eating a nutritious diet and staying relatively lean will probably prolong your life, while calorie restriction may or may not.  It probably does reduce the risk of specific diseases however.  Currently, a number people around the world are restricting their calorie intake in the hope of living longer.  I wish these pioneers the best of luck.  Hopefully we'll have the answer to this question eventually, but if I were a bettin' man I wouldn't put my money on the idea that calorie restriction will extend lifespan at this point.