Verified by 
What’s the first thing you think of when you hear the words “calorie restriction”? For most people, they think of dieting for weight loss. But for scientists, especially those who study aging, calorie restriction refers to a well-supported strategy for health and longevity.
Indeed, it has been long known that restricting food intake slows aging and extends lifespan in lab animals. The discovery of this phenomenon by Clive McCay all the way back in 1935 at Cornell is what kickstarted the study of aging because it showed that lifespan was not immutable.
As a review celebrating the 75th anniversary of Clive McCay’s original discovery put it: “The ability of calorie restriction to extend life and delay the age-related functional decline has, arguably, contributed more than any other model to the overall understanding of the biological processes of aging and longevity.”
McCay, who was a nutritionist by training, wanted to understand the relationship between undernutrition, growth, and lifespan. So, he designed a low-calorie diet for lab rodents by giving them a measured amount of food to provide all the nutrients they needed to be healthy, but nothing extra. What he found was remarkable: Compared to rats on uninhibited (or what scientists refer to as ad libitum) feeding, the ones on the restricted diet ate about two thirds as much and lived about 33 percent longer.
Thanks to further studies building on this finding, we now know that restricted mice and rats not only live longer but are much healthier for their entire lives than ad libitum rodents. Diseases that normally take their toll in aging rodents, such as cancer in mice and kidney disease in rats, are held at bay in restricted animals.
Other studies have shown that the response to calorie restriction must be ancient, the result of natural selection for survival during food scarcity, since this regimen also increases longevity in worms, flies, and even yeast.
The most important question, of course, is whether calorie restriction could hold the key to healthier lives for humans.
Currently, the best evidence we have is long-term studies in our closest relatives, non-human primates, as well as a few shorter-term studies in humans. The results so far have been promising. Two studies, one at the National Institutes on Aging and the other at the University of Wisconsin, looked at calorie restriction in rhesus monkeys over the course of decades. Both studies reported health benefits and a slowing of the effects of aging. After some initially confusing early data, both also ultimately showed increased longevity in a 2017 joint paper.
In 2018, a short-term human study found that participants who cut calories by 15% for two years experienced metabolic changes similar to what we see in rodents and monkeys: lowered blood sugar and cholesterol, and an increase in insulin sensitivity, all of which are physiological changes associated with the slowing of aging in rodents.
However, it’s possible that for humans there could be counterbalancing negative effects, such as suppression of the immune system. The problem with doing the long-term studies needed to address these issues is that it is difficult to find study subjects willing to reduce their calories and stick with it for years or decades because this spartan diet is unpleasant and can have uncomfortable side effects (low sex drive for one).
This roadblock makes the case for developing drugs or supplements that work as calorie restriction mimetics. But we first need to understand how calorie restriction works at a mechanistic level. For many decades after McCay’s studies, it was thought that metabolic rate (which is a measure of how fast the body consumes oxygen) slows down when food is limited, and this, in turn, decreases the production of toxic molecules known as reactive oxygen species, which are a by-product of normal metabolism and also involved in accelerating aging.
In accordance with this theory, metabolic rate seemed to be inversely proportional to life span across a spectrum of mammalian species. However, many cracks have appeared in this theory, such as finding exceptionally long-lived species (bats, naked mole rats) that have unexceptional metabolic rates. Instead, research over the past 25 years has led to the discovery of specific genes and pathways that natural selection may have anointed to respond to calorie restriction and provide health benefits and longevity.
All of this leads us to now: when the discovery of these genes and pathways portends the emergence of calorie restriction mimetics, which might deliver some of the benefits without any of the difficulties or side effects. How far off are we from developing these mimetics? We’ll dive more deeply into this question in the next column.
