A study of people who reduced the calories they consumed has found the strongest evidence yet that such restrictions can slow down human metabolism. The results raise hopes that a low-calorie lifestyle — or treatments that mimic the biological effects of restricted eating — could prolong health in old age and even extend life.


Past work in many short-lived animals, including worms, flies and mice, has shown that calorie restrictions reduce metabolism and extend lifespan. But experiments in longer-living humans and other primates are more difficult to conduct and have not yet drawn clear conclusions.


The study was part of the multi-centre trial called CALERIE (Comprehensive Assessment of Long term Effects of Reducing Intake of Energy), sponsored by the US National Institutes of Health. The randomized, controlled trial tested the effects of 2 years of caloric restriction on metabolism in more than 200 healthy, non-obese adults.


“The CALERIE trial has been important in addressing the question of whether the pace of ageing can be altered in humans,” says Rozalyn Anderson, who studies ageing at the University of Wisconsin–Madison. She leads one of two large, independent studies on calorie restriction in rhesus monkeys, and began her research career studying calorie restriction in yeast. “This new report provides the most robust evidence to date that everything we have learnt in other animals can be applied to ourselves.”


Precise measurements

Published on 22 March in Cell Metabolism, the latest study1 looked at 53 CALERIE participants who had been recruited at the Pennington Biomedical Research Center in Baton Rouge, Louisiana. This facility is home to 4 of the world’s 20 or so state-of-the-art metabolic chambers, which are like small, sealed hotel rooms that measure minute-by-minute the amount of oxygen that occupants use and how much carbon dioxide they exhale. This allows researchers to track how the occupants use energy with unprecedented precision, says Anderson. The ratio between the two gases, combined with analysis of nitrogen in occupants’ urine, indicates whether the occupant is burning fat, carbohydrate or protein.


The trial participants, aged between 21 and 50, were randomized into two groups: 34 people in a test group reduced their calorie intake by an average of 15%, and 19 people in a control group ate as usual. At the end of each of the two years, they all underwent a range of tests related to overall metabolism and biological markers of ageing, including damage associated with oxygen free radicals released during metabolism. They were also placed in the metabolic chamber for 24 hours.


The scientists found that participants on the diet used energy much more efficiently while sleeping than did the control group. This reduction in their base metabolic rate was greater than would be expected as a result of the test group’s weight loss, which averaged nearly 9 kilograms per participant. All the other clinical measurements were in line with reduced metabolic rate, and indicated a decrease in damage due to ageing.


Model metabolism

Caloric restriction has been known for decades to extend life in different species. In the 1990s, scientists began to identify the genes and biochemical pathways actively involved in longevity in the short-lived worm Caenorhabditis elegans, and in the fly Drosophila melanogaster. These include pathways relevant to insulin sensitivity and the function of mitochondria — tiny structures in cells that use oxygen to generate energy. Subsequent studies revealed that calorie restrictions alter similar pathways in mice and monkeys. Mice on restricted diets can live up to 65% longer than mice allowed to eat freely, and the ongoing monkey studies hint at longer survival and reduced signs of ageing.


“The Rolls-Royce of a human longevity study would carry on for many decades to see if people do actually live longer,” says Pennington physiologist Leanne Redman, the lead author of the latest study. CALERIE ran for just two years, and was designed to see whether a calorie-restricted diet in humans induces some of the same metabolic, hormonal and gene-expression adaptations that are thought to be involved in slowing ageing in other species during long-term caloric restriction.


Few people would want, or be able, to restrict their diet as severely as the participants in the study. “But understanding the biology of how restricting calories extends life will allow us to find easier ways to intervene,” says Anderson.


Redman would like to repeat the study, combining less-ambitious calorie restriction with a diet containing antioxidant food to control oxidative stress, or with a drug such as resveratrol, which mimics key aspects of calorie restriction.


Other scientists are starting to try out the effect of restricting calories for just a few days every month. Such intermittent restriction has been found to be as effective as continuous calorie restriction in protecting mice against diseases of ageing such as diabetes and neurodegeneration2. “I think that’s going to be a way to get all the benefits, without the problems of constant dieting,” says gerontologist Valter Longo of the University of Southern California in Los Angeles, who is embarking on clinical trials of intermittent calorie restriction in various disorders.


REFERENCE: Redman, L. M. et al. Cell Metab.http://dx.doi.org/10.1016/j.cmet.2018.02.019 (2018).