Restrict calories to live longer, study says, but critics say more proof is needed

By Sandee LaMotte, CNN

People of normal weight may be able to extend their life span by restricting calories, according to a new study that attempted to measure the pace of aging in people asked to cut their calorie intake by 25% over two years.

“We’ve known for nearly 100 years that calorie restriction can extend healthy life span in a variety of laboratory animals,” said senior author Daniel Belsky, an associate professor of epidemiology at Columbia University Mailman School of Public Health.

“It does this by changing biology in ways consistent with a slowing of the process of aging, although the specific mechanisms of how this occurs are still under investigation,” said Belsky, who studies longevity. “We decided to drill down to the cellular level in people to see if the same is true.”

The study used what are commonly known as “biological clocks” to determine the pace of aging in its participants. Bioclocks are designed to measure how old people are biologically compared with their real ages chronologically.

“Our study found evidence that calorie restriction slowed the pace of aging in humans,” said colead author Calen Ryan, an associate research scientist at the Robert N. Butler Columbia Aging Center at Columbia.

“Our findings are important because they provide evidence from a randomized trial that slowing human aging may be possible,” Ryan said in a statement.

But longevity scientist Dr. Peter Attia dismissed the study results as “noise.”

“I just don’t see any evidence that any of the biologic clocks have meaning,” Attia, who was not involved in the study, said via email. He hosts “The Drive,” a podcast dedicated to explaining and applying longevity research to everyday life.

“The only validation that matters — which to my knowledge has not been done, but hopefully will be — is to see if ‘biologic age’ can predict future life better than chronological age,” he said.

Biological age predictors are controversial, said calorie restriction researcher Pankaj Kapahi, a professor at the Buck Institute for Research on Aging in Novato, California.

“At best, they’re telling you something about a very small aspect of aging,” said Kapahi, who was not involved in the study. “For example, grip strength is also a biological age predictor, how active you are is a predictor, and we all know people who fall apart physically but are cognitively all there, so you also need to test cognitive aging.

“Some researchers are trying to boil it down with bio-aging tests,” he added. “This is a much more complex problem, and I think it’s an overstatement to say the tests really predict biological age.”

The CALERIE study

Decades of research in animals have shown that calorie restriction produces health benefits, even slowing the pace of aging. Would the same be true in people?

A study in the 1950s asked people to reduce 50% of their calories, leading to malnutrition or a lack of key micronutrients in participants. Later research often focused on calorie reduction in people whose body mass index would be considered medically obese.

The first clinical trial of calorie restriction in people at normal weight (a BMI of about 20 to 25) started in 2007. It was called CALERIE, or the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy.

Because of the malnutrition found in the earlier study that cut calories drastically, CALERIE asked 143 adults between the ages of 21 and 50 to cut 25% of the calories they typically ate for a two-year period. Another group of 75 people maintained their normal diets, serving as a control group.

During the trial, all manner of tests were done at six-month intervals to gather information on weight loss, change in resting metabolic rate, impact on cognitive function and markers of inflammation, cardiovascular health and insulin sensitivity.

The results of CALERIE, published in 2015, found that on average people in the restricted group were able to cut 14% of their calories, or about half of the 25% goal. However, that amount reduced their fat mass by about 10% and decreased their cardiometabolic risk factors with no adverse effects on quality of life, researchers said. There were also reductions in tumor necrosis factor alpha, a protein that promotes insulin resistance and obesity-induced type 2 diabetes.

A number of other studies have used blood samples and other data collected on the CALERIE participants to explore other ways modest calorie restriction might benefit the body. For example, Yale University researchers found restricting calories increased the health of the thymus, an organ that produces immune system T cells — one of the body’s key warriors against invaders.

A difference in findings

The new study, published Thursday in the journal Nature Aging, culled DNA sequences from white blood cells taken at 12-month intervals from participants in CALERIE. Belsky’s team then analyzed methylation marks — signs of epigenetic changes — on the DNA, looking for symptoms of aging.

Epigenes are proteins and chemicals that sit like freckles on each gene, waiting to tell the gene “what to do, where to do it, and when to do it,” according to the National Human Genome Research Institute.

“Increasingly, changes to our cells’ epigenomes, the systems that control which genes in the genome are turned on and off, are being recognized as drivers of the aging process,” said anti-aging expert David Sinclair, a professor of genetics in the Blavatnik Institute at Harvard Medical School and codirector of the Paul F. Glenn Center for Biology of Aging Research.

“Clocks that measure these changes are proving to be indicators of future health and what interventions might slow and even reverse the aging process,” said Sinclair, who was not involved in the study.

In the new study, researchers used two epigenetic clocks — PhenoAge and GrimAge — and a new tool Belsky recently invented in conjunction with Duke University. This third bioclock, called DunedinPACE, attempts to determine the pace of aging from a single blood test, Belsky said.

The PhenoAge and GrimAge bioclocks showed no signs of reduced aging in the blood samples of participants in CALERIE, said Belsky, who is also a scientist with Columbia’s Robert N. Butler Aging Center.

However, DunedinPACE, the clock created by Belsky’s and Duke’s teams, did find a 2% to 3% reduction in the pace of aging, “which in other studies translates to a 10-15 percent reduction in mortality risk, an effect similar to a smoking cessation intervention,” according to a statement from Columbia.

Controversy over bioclocks

Critics of the study, however, were not impressed. The performance of the DunedinPACE test was “mediocre at best,” Attia said, finding only a weak association with biological aging.

The fact that the two other bioclocks found no anti-aging benefits was no surprise, said the Buck Institute’s Kapahi: “These biological age predictors don’t agree with each other and don’t necessarily agree with other biological measures.

“It’s going to confuse the public, and unfortunately people are buying these tests when there’s very little useful information that comes out of them.”

While it’s true epigenetic biomarkers are not yet ready to be used in clinical trials, “many different studies in many different datasets and populations have shown these algorithms are predictive of differences between people in who gets sick and who lives or dies,” Belsky countered.

“This is not a game over moment. It’s more like game on,” Belsky said. “What we have now is a proof of concept — a methylation biomarker that shows faster aging in people we know to be at higher risk for disease, disability and death, and slower aging in people who we know to be at lower risk.”

Does caloric restriction work?

Putting aside the debate over how slower aging is measured, there is a role for caloric restriction in extending life, especially in “overnourished” individuals, Attia said.

“I don’t want a reader to think this intervention (calorie restriction) is of no value, only that (the study) does not ‘prove’ a reduction in the pace of aging,” he said in an email.

Time-restricted eating and dietary restriction of certain foods are two additional ways to curb “overnutrition,” which Attia believes is the biggest driver of insulin resistance, type 2 diabetes and other chronic diseases.

“I am not aware of any evidence that one ‘strategy’ or method is superior. The best one is the one that works for a person, but calorie restriction certainly works for some, and therefore is clearly beneficial,” Attia said. “All of these interventions will lead to a longer and better life, but these aging clocks tell us less than zero about that process.”

There are many other ways to curb aging as well, Kapahi said.

“We’re trying to learn more about aging and we are, but calorie restriction is just one intervention,” he said. “You likely need to do that in combination with exercise, with good sleep, with a positive attitude and good mental health. All these things combined will likely play a much bigger role in slowing aging.”

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