According to previous studies, a low-calorie diet provides health benefits and increases lifespan in mammals, including primates. Yet a long-term investigation in rhesus monkeys finds no effect on longevity. See Letter p.318
For more than 75 years, we have known that reducing food consumption increases longevity and preserves various aspects of health in mice and rats. For many researchers, these observations offered an investigational tool for probing underlying mechanisms of the ageing process. For other researchers and for the public at large, however, the observations suggested the more immediate hope that calorie restriction might improve health and extend life in humans — the fountain of youth could be as close as one's dinner plate.
To address whether such simple dietary intervention might have beneficial effects in primates that are long-lived like humans, two independent studies using rhesus monkeys were initiated in the late 1980s, one at the US National Institute on Aging (NIA) in Bethesda, Maryland, and the other at the Wisconsin National Primate Research Center (WNPRC) in Madison. Periodic reports from the studies have provided some indications of improved health1,2and, possibly, increased lifespan3 in the animals. However, on page 318 of this issue, Mattison et al.4 report that the NIA data indicate that calorie restriction has no effect on the animals' longevityFootnote 1.
In the NIA study, rhesus monkeys of different ages were subjected to a 30% calorie restriction (Fig. 1). The authors grouped the data into a young-onset group (animals that were 1–14 years old when enrolled in the study) and an old-onset group (aged 16–23 when enrolled). To give perspective to these ages, sexual maturity in captive rhesus monkeys occurs at 4–5 years of age, and median longevity had previously been reported5 as 27 years. Mattison et al. found that, for both age groups, the treated animals lived no longer than untreated monkeys. Nearly 50% of the young-onset animals are still alive, but the researchers' projections from current survival patterns indicate a likelihood of less than 0.1% that the calorie-restricted animals will survive longer than the controls.
To explore possible health benefits of the treatment, the authors regularly took blood samples from the animals to measure levels of glucose, cholesterol and triglyceride lipids. Cholesterol levels were significantly lower in treated males than in untreated males, but were unaffected in females. Moreover, the calorie-restricted old-onset monkeys had significantly lower triglyceride levels, as well as marginally lower glucose, than the controls. However, the young-onset treated animals showed no difference in glucose concentrations, and their triglyceride levels were marginally lower in males only, when compared with untreated controls of the same age group.
Calorie restriction did not alter causes of death. It may be premature to predict the final effect on ageing-related diseases because half of the animals in the young-onset group are still alive, but the dietary intervention seems to have reduced the incidence of cancer and, possibly, diabetes — although it might have slightly increased the incidence of cardiovascular disease. All of these ageing-related diseases did appear marginally later in the restricted monkeys, however.
Mattison and colleagues' results contrast in some ways with those reported for the WNPRC study3, which enrolled only young rhesus monkeys (7–14 years old). The WNPRC researchers found no statistically significant effect of calorie restriction on overall longevity, but the survival patterns (with roughly 50% of the animals still alive) suggested a clear trend towards longer life for the treated subjects. Moreover, when deaths due to non-ageing-related causes such as gastrointestinal bloat or anaesthesia (which was required for some experimental procedures) were eliminated from the WNPRC analysis, calorie restriction did show a statistically significant, positive effect on survival.
However, some of us in the field were concerned about the interpretation of the WNPRC study. The deaths that had been eliminated from the analysis made up nearly half of the total deaths, and there were more of such deaths in the restricted group than in the control group. So, it was possible that some of the non-ageing-related deaths might be linked to the treatment. Interestingly, Mattison and colleagues' data also indicate a higher incidence of non-ageing-related deaths in calorie-restricted young-onset animals than in controls.
What might account for the differences between the studies' results? One possibility is diet composition. Whereas the diets were broadly similar in their overall content of carbohydrates, proteins and fats, they differed in the specific types of such nutrients. For instance, sucrose made up 28.5% of the carbohydrate present in the WNPRC diet, but only 3.9% of that in the NIA diet. Possibly related to this difference, more than 40% of the WNPRC control animals and only 12.5% of the NIA controls developed diabetes — although this metabolic malfunction was completely absent in the WNPRC calorie-restricted animals, but not in the treated animals in the NIA study.
Another difference is that the NIA controls were given an apportioned amount of food to prevent obesity, whereas the WNPRC controls were fed ad libitum (that is, they could eat as much as they pleased). Consequently, NIA control animals weighed less and were considerably longer-lived than the WNPRC controls. One interpretation of this observation is that the NIA controls were partially restricted, which would account for the lack of a survival effect of the treatment in the NIA study. Nevertheless, all animals in both studies — even in the calorie-restricted groups — weighed more than wild-caught monkeys6.
Taken together, the contrasting results raise an intriguing question about the nature and robustness of restricting calorie intake in primates. Is calorie restriction anything more than the elimination of excess fat? That might be concluded if one interprets the control animals in the NIA study as being restricted to a healthy weight, such that further restriction had little additional effect on longevity. However, researchers who use rodent models have long assumed that calorie restriction results in more than just leanness and that it extends life beyond its normal limits. It is known, for instance, that calorie restriction improves survival in obese and non-obese mice and rats7, even at very high restriction levels8, and that survival is affected by calorie restriction in a different way from exercise-driven leanness9.
The same question arises in on-going studies comparing overweight10,11 or lean12 people with normal-weight controls. If calorie restriction defines only the food intake needed to maintain a healthy body weight, then pharmacological mimicry of such an effect might improve the health of only the fraction of the population that is overweight. And, in that case — somewhat disappointingly — no spectacular increase in health or longevity should be expected.
*This article and the paper under discussion4 were published online on 29 August 2012.
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