More than a decade ago, researchers at the Pennington Biomedical Research Center in Baton Rouge began recruiting young, healthy Louisianans to voluntarily go hungry for two years. In addition to cutting their daily calories by 25 percent, the dozens who enrolled also agreed to a weekly battery of tests; blood draws, bone scans, swallowing a pill that measures internal body temperature.
All that sticking and scanning and starving was in the name of the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy, or Calerie—the largest human clinical trial ever to look at the effects of calorie restriction on aging. The National Institutes of Health-funded study also included sites at Washington University in St. Louis and Tufts in Boston. But only the Pennington participants had to also spend 24 sedentary hours inside a sealed room that recorded the contents of their every breath.
These are the measures that scientists (and some study participants) are willing to go to understand how a spartan diet impacts the aging process. Calorie restriction is one of the least ridiculous strategies in the burgeoning field of longevity science. Studies going back to the mid-1930s have shown over and over that cutting calories by 25-50 percent lets yeast, worms, mice, rats, and monkeys live longer, healthier lives, free from age-related disease. But there’s far less consensus on the mechanisms through which it works.
Which is probably why attempts to mimic fasting with medicines have so far all failed FDA approval. Calerie was designed to ask that question in humans and the first randomized control trial to do so. The researchers chose a 25 percent restriction (between 500 and 800 calories) because it seemed humanly feasible and still likely to show an effect, based on previous animal studies. With 10,000 Americans turning 65 every day, the stakes for good science supporting healthy human aging have never been higher. Unfortunately, the latest results don’t exactly clear things up.
In a paper published Thursday in Cell Metabolism, researchers from Pennington reported for the first time on their whole room calorimeter experiments—the sealed metabolic chambers they stuck participants in for 24 hours. Pennington is one of the few places in the world with these hotel-room-sized microenvironments, the most rigorous way to measure how many calories a person burns and where they come from—fat, protein, or carbohydrates.
After a night of fasting, participants entered the calorimeter promptly at 8:00am, and until 8:00am the following day they weren’t allowed to leave or exercise. Researchers delivered meals through a small, air-locked cupboard. As fresh air circulated into the room, the air flowing out went through a series of analyzers to measure the ratio of carbon dioxide to oxygen. Nitrogen measurements from urine samples help calculate a total picture of each participant’s resting metabolism.
The picture that emerged was that cutting calories, even modestly, lowered people’s metabolism by 10 percent. Some of that could be attributed to weight loss (on average folks lost 20 pounds over two years). But according to the study’s authors, the majority of the change had more to do with altered biological processes, which they observed through other biomarkers like insulin and thyroid hormones. “Restricting calories can slow your basal metabolic rate—the energy you need to sustain all normal daily functions,” says endocrinologist and lead author Leanne Redman. When the body uses less oxygen to generate all its required energy, it produces fewer byproducts of metabolism, things like free radicals that can damage DNA and other cellular machinery. “After two years, the lower rate of metabolism and level of calorie restriction was linked to a reduction in oxidative damage to cells and tissues.”
Now, the study wasn’t long enough to show that calorie restriction definitively increased lifespans; That trial would take decades. But Redman contends that this data rejuvenates support for two old but embattled theories of human aging: the slow metabolism ‘rate of living’ theory and the oxidative damage theory. The first says that the slower an organism’s metabolism, the longer it will live. The second states that organisms age because cells accumulate free radical damage over time.
Other Calerie researchers don’t buy it. “You can have a low resting metabolic rate because you’re dying of starvation,” says Luigi Fontana, an internist who led the Washington University trial. “Does that make it a biomarker of longevity? No. You can be calorie restricted by eating half a hamburger and a few fries each day but will you live longer? No, you will die of malnutrition.”
Fontana's own work with Calerie trial data suggests changes to specific insulin pathways matter more than overall metabolism decrease. He also points to studies where rats were made to swim in cold water for hours a day, dropping their metabolism. They didn’t live any longer than room temperature rats. In other studies, scientists overexpressed enzymes that protected mice from free radicals. They didn’t live any longer either. Redman’s data is interesting, he says, but it’s not the whole picture. “Twenty years ago the dogma was the more calorie restriction the better,” he says. “What we are finding now is that it’s not the number that matters. Genetics, the composition of the diet, when you eat, what’s in your microbiome, this all influences the impact of calorie restriction.”
But even if studying what happens to the human body when you cut calories hasn’t yet explained how cells age, that doesn’t mean it doesn’t have potentially huge health benefits. “Calorie restriction is the only intervention known to delay the onset and progression of cancer,” says Rafael de Cabo, chief of the National Institute on Aging’s Translational Gerontology Branch. His team recently completed a 25-year study of calorie restriction in rhesus monkeys. While they didn’t see as drastic lifespan improvements as another monkey study, de Cabo’s team did observe lower rates of cancer and metabolic diseases. “If we could get people who work in situations with a lot of environmental pollutants to reduce their calories it would be extremely protective,” he says. “But as we very well know, no one is going to be able to withstand eating so little for their entire life.”
Maybe no one knows that more than Jeffrey Peipert. The 58-year-old ob-gyn participated in the Washington University trial nine years ago, hoping to bring down his weight, which he’d struggled with his whole life. When he went in, his blood pressure was 132 over 84; after a few months on a restricted calorie regimen it dropped to 115 over 65. A year in he lost 30 pounds. But six months later he quit. It was just too much work. “It took away my energy, my strength, it definitely took away my sex drive,” says Peipert. “And tracking calories every day was a total pain in the neck.”
Today he’s gained all the weight back and has to take a pill for hypertension. But at least he feels like he’s living well, even if he maybe won’t live as long.
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