Strain by Strain

Strain by Strain

If the rodent results could be applied to humans, what life extension might we expect? Well, a 50 percent increase in life span would raise the current life expectancy in the United States from 77 years to about 115, but that is based on experiments in which food intake was restricted by 40 to 60 percent, immediately after weaning. You can find the complete table at see.nf/extrapolate, but even if you permanently reduce your daily calorie intake from 2500 to 1750 calories, a 30 percent reduction, starting in your early to mid-40s, it might extend life by a few years. The same holds true for calorie restriction to 2125 calories starting at age 30. But again, that’s only if we can extrapolate from rodents to humans.

A study of more than 40 mouse strains found that restricted calorie intake shortened life expectancy in three times as many strains as it lengthened. Reducing food by 40 percent, one of the most common experimental designs, lengthened life expectancy in five mouse strains, shortened it in 15, and had no significant effect in most. In one strain, female mice’ life expectancy increased while the males’ decreased. If we can’t even extrapolate the effects of restricted calorie intake from one mouse strain to another, how are we supposed to extrapolate them from mice to men or women? In see.nf/extrapolate I discuss additional problems with generalizing results to humans.

Calorie Restriction or Just Restricting Obesity?

One important criticism of the entire field is that even the most successful studies show the life-shortening effect of obesity rather than the life-extending effect of restricted calorie intake. In most calorie restriction experiments, the animals in the control group are allowed to eat ad libitum, meaning as much as they want. In that case, the observed benefit may lie less in the restriction than in the fact that the animals aren’t overeating.

Anyone who has a pet knows that if it eats as much as it wants, it will get fat. Middle-aged Labrador retrievers that could eat unlimited amounts when they were young ended up with ten kilos of body fat and lived only about eleven years. If you split a litter of puppies and restrict some to 75 percent of what the others eat ad libitum over the same period, they put on less than five kilos of fat and live, on average, 13 years. 9 of 24 calorie-restricted dogs (37.5 percent) outlived all their siblings that were allowed to eat as much as they wanted. Does that show that calorie restriction is good, or only that obesity is bad?

Ironically, this very aspect of such experiments may make them more transferable to humans. Almost three quarters (73.6 percent) of the adult US population are overweight or obese. The use of ad libitum control groups could therefore be the appropriate benchmark for comparison. Anyone who is severely obese throughout adulthood (BMI ≥ 35) loses at least 7 years of life and 19 years of health. It goes without saying that calorie restriction would do these people good, but most restriction studies provide no insight into whether people of normal weight would benefit from further restriction as well. Considerations about the control group play an important role in interpreting contradictory results from two well-known long-term studies in which monkeys were fed calorie-reduced diets.

Monkey Experiments with Restricted Diets

There were four studies on calorie restriction and life span in nonhuman primates. It is worth looking at the details, which I do extensively in see.nf/primatecr, but bottom line, if I had to summarize in one sentence what the primate data showed, it would be: If you’re overweight or eat junk, it’s a good idea to eat less.

Calorie Restriction with Optimal Nutrition: Catabolism

And what about human data? There will never be lifelong randomized controlled trials, but there are certainly short-term ones with volunteers who restricted their calorie intake, and numerous creative approaches to answering the question: Do you live longer if you eat less? For example, do people with anorexia live longer? Not at all. Anorexia nervosa is one of the deadliest mental disorders. People with anorexia die about ten times as often as the general population and suffer from various electrolyte disturbances, anemia, osteoporotic bone fractures, and cardiac arrhythmias. One such study found that it shortens a woman’s life expectancy by 25 years if she becomes chronically anorexic at 15.

Anorexia is an example of extreme calorie restriction. Nearly a third of those diagnosed with this disease who enter treatment have a BMI under 15—they weigh about half as much as an average US woman. Unlike laboratory protocols that prescribe calorie restriction without malnutrition, people with anorexia can suffer from nutrient deficiencies so severe from their starvation that they go blind. Their short lives therefore likely have no direct relevance to the question, quite apart from the fact that one in five victims of anorexia dies by suicide.

The only long-term study of extreme calorie restriction in humans was the infamous Minnesota Starvation Experiment, in which conscientious objectors during World War II volunteered as guinea pigs. Unlike calorie restriction studies that are designed not to fall below the recommended daily allowance of essential nutrients, the Minnesota Starvation Experiment involved deliberate malnutrition. The malnourished participants suffered from chronic weakness, painfully swollen legs, and severe psychological distress. Interestingly, however, half the subjects lived to see their 80th birthday and lived at least eight years longer than expected for men of their generation, although other factors typical of pacifists could have played a role as well.

Speaking of unusual groups: the self-styled CRONies (Calorie Restriction with Optimal Nutrition, “calorie restriction with optimal nutrition”) are active members of the Calorie Restriction Society, founded by Roy Walford, a researcher and practitioner in the field. In the 1980s, he tried to popularize the practice with his book The 120 Year Diet; unfortunately, he himself died far short of the promised 120 years at age 79 (from ALS). In see.nf/cronies I go through all the available scientific literature on CRONies. All in all, people who restrict their calorie intake for a long time seem to be in excellent health, but they’re also a rather unusual bunch of idealists who have taken their fate into their own hands. And as always, you don’t know until you study it. This is where CALERIE comes in, the first large, long-term clinical trial to examine the effects of calorie restriction.