27 Jan 2017

By analyzing two previous contradictory studies, scientists have arrived at the tantalizing conclusion that caloric restriction (CR) extends survival in rhesus monkeys. As senior authors Rozalyn Anderson, University of Wisconsin, Madison, and Rafael de Cabo, National Institute on Aging, Baltimore, report in the January 17 Nature Communications, the result in a nonhuman primate suggests scientists will be able to apply what they have learned about caloric restriction in shorter-lived animal models such as yeast and mice to humans. “In monkeys, what and how much they eat absolutely influence how they age,” said Anderson. Given the genetic similarity to people, she said, “There’s every reason to believe that would also be true in humans.”

Leonard Guarente, MIT, who was not involved in the study, voiced his support for the findings. “There was doubt before about whether caloric restriction really worked in nonhuman primates, but this makes a strong case that it does,” he said. “It’s another indication that some of the fruits of basic research on aging may well yield interventions that help with human diseases,” he told Alzforum.

The analysis combined two experiments begun in the late 1980s that tested whether caloric restriction improved health and survival in monkeys. One came from the University of Wisconsin, where scientists studied 76 adult monkeys (Jul 2009 news). The other, from NIA, included 121 monkeys aged 1 to 23 (Aug 2012 news). Both studies put half the monkeys on a CR diet. At the NIA, some animals started the diet when they were young, and some when they were older. 

In the end, both studies agreed that there was a health benefit to CR if not an improvement in longevity. Animals on a restricted diet developed age-related conditions—such as bone and muscle loss, cancer, diabetes, and cardiovascular disease—at half the rate of control animals. Cynthia Kenyon, Calico LLC, San Francisco, found this compelling. “In both cases, you see an effect of diet on healthspan—the ability to avoid all diseases,” she told Alzforum. “That’s important, because as a society, we are concerned about quality of life.” However, the two studies disagreed about whether CR lengthened survival. At UW, it halved the rate of death compared to control monkeys, but the NIA researchers found no difference.

Why the discrepancy? The authors of the two studies, plus statisticians at the University of Birmingham, Alabama, who helped analyze the original data, put their heads together to try to reconcile the outcomes. They compared in detail the monkeys’ caloric intake, weight, dietary composition, feeding schedule, etc., and found a few important differences.

One was a disparity in control groups. While UW controls ate as much as they wanted, those at NIA were on a defined diet intended to prevent overfeeding. The latter animals were not restricted per se, but they ate and weighed less than controls at UW, such that they more closely resembled the UW CR group. The smaller difference between consumption in the NIA control and CR groups could explain their similar survival times, the authors agreed. If they compared all NIA monkeys to the UW controls, they could see that monkeys on a defined or restricted diet lived longer than those who indulged.

Another major confound appears to have been the age at which monkeys began the restricted diet. About half the NIA animals were younger than 5 when they started, while all UW monkeys entered the study above the age of 7. Starting CR when animals were young or adolescent imparted no benefit, and young starters actually died at a higher rate than controls. “That’s not something we could have predicted based on rodent studies,” said Anderson. In mice, the earlier scientists restrict diet, the longer animals live (for a review, see Speakman and Hambly, 2007). 

Taken together, the data suggest that CR does in fact extend lifespan in monkeys. “This confirms what a lot of researchers have thought—that diet makes aging malleable in a nonhuman primate,” said Stephen Ginsberg, New York University Medical Center, who was not involved in the work. Ginsberg holds a joint appointment at the Nathan Kline Institute in Orangeburg, New York. “It’s quite significant—the implication is that it’s translatable to humans.” That people would widely adopt a 30 percent cut in calories seems unlikely. A more practical idea would be to watch weight gain in middle age and try to avoid the "middle-age spread," noted Anderson. A balanced diet that avoids obesity would go a long way toward preventing lifestyle-associated disorders, even if it didn’t delay aging as such, she told Alzforum. Pharmacological mimetics could activate the same pathways as CR, she added. “If we can harness the mechanisms that delay aging, we can get at the root causes for a whole host of age-related diseases, rather than tackling them one at a time,” she said.

Evidence from the lab of Eric Ravussin, Louisiana State University, Baton Rouge, and others, points to cardiovascular and metabolic benefits of caloric restriction in people (Jun 2005 news; Ravussin et al., 2015). However, only sparse observational studies exist to suggest that CR modifies lifespan in humans, said Ravussin (Heilbronn and Ravussin, 2003). The jury is still out on what maximum lifespan CR might achieve, since some of the NIA monkeys are still living. However, based on the current results, he bets maximum lifespan will go up as well. This could translate to more centenarians among people who might adopt a CR-based diet or treatment.—Gwyneth Dickey Zakaib

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References

News Citations

1. The Picture of Health? Aging Better—On Fewer Calories 10 Jul 2009
2. Caloric Restriction Does Not Make Primates Live Longer 30 Aug 2012
3. Oakland: Caloric Restriction Set for Primate Time? 14 Jun 2005

Paper Citations

1. Speakman JR, Hambly C. Starving for life: what animal studies can and cannot tell us about the use of caloric restriction to prolong human lifespan. J Nutr. 2007 Apr;137(4):1078-86. PubMed.
2. Ravussin E, Redman LM, Rochon J, Das SK, Fontana L, Kraus WE, Romashkan S, Williamson DA, Meydani SN, Villareal DT, Smith SR, Stein RI, Scott TM, Stewart TM, Saltzman E, Klein S, Bhapkar M, Martin CK, Gilhooly CH, Holloszy JO, Hadley EC, Roberts SB, CALERIE Study Group. A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity. J Gerontol A Biol Sci Med Sci. 2015 Sep;70(9):1097-104. Epub 2015 Jul 17 PubMed.
3. Heilbronn LK, Ravussin E. Calorie restriction and aging: review of the literature and implications for studies in humans. Am J Clin Nutr. 2003 Sep;78(3):361-9. PubMed.

Further Reading

Papers

1. Colman RJ, Beasley TM, Kemnitz JW, Johnson SC, Weindruch R, Anderson RM. Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat Commun. 2014 Apr 1;5:3557. PubMed.

News

1. Dietary Resveratrol Makes Little Difference to Health 14 May 2014
2. Amino Acid Mimicry Leads Researchers to New Resveratrol Target 31 Dec 2014
3. Brain-Specific Sirtuin Expression Delays Aging in Mice 6 Sep 2013
4. Can Diet Influence Alzheimer’s Disease Biomarkers? 17 Jun 2011