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Eating less may help the body age more slowly. Rather than promote starvation, CU researchers are testing a nutritional supplement that mimics the same effects of caloric restriction.

In 1935 in upstate New York, a little-known animal husbandry researcher named Clive McKay looked into the rat cage in his lab and found an unexpected window into the Fountain of Youth.

Conventional wisdom at the time held that the more animals were fed, the better they’d fare. But McKay noticed something different: Long after the well-fed rats began to show signs of aging, those on a nutrient-dense but super-low-calorie diet retained a silky sheen to their fur, remained alert and agile and lacked the age-related health problems of their more gluttonous peers. In the end, the calorie-restricted mice also lived about 300 days longer — nearly a third of a lifetime in rat years. 

Fast forward to 2020, and studies in everything from fruit flies and worms to monkeys and people have confirmed that sharply restricting calories (by 20-40 percent) while maintaining essential nutrients can fend off age-related diseases and, in some cases, extend lifespan. The problem: People like to eat, so almost no one is willing to do it. And it can be dangerous. 

“From a public health perspective, caloric restriction is not a practical strategy,” said professor Doug Seals, director of ��ƷSM����ӰƬ’s Integrative Physiology of Aging Laboratory. 

So in recent years, Seals and his research trainees have taken a different path toward that elusive Fountain of Youth, testing a novel nutritional compound that stimulates the same physiological pathways that calorie restriction (CR) does. The compound, a form of Vitamin B called nicotinamide riboside (NR), is one of several so-called CR-mimetics under investigation in labs around the country, in what researchers are calling an exciting renaissance in the quest to slow biological aging and extend both lifespan and “healthspan” — the period of life that we remain healthy with good physical and cognitive function.

Already, in a small, first-of-its-kind study, Seals’ team found NR can improve blood pressure and reduce arterial stiffness (a risk factor for cardiovascular disease and cognitive impairments) in older adults. 

Now, with a $2.5 million, five-year grant from the National Institute on Aging, they’re conducting a study of about 100 more adults to assess the compound’s impact on the heart, brain and body. 

Meanwhile, Seals and his CU Anschutz colleague, professor Michel Chonchol, also are assessing the effects of NR in patients with chronic kidney disease (a major disease of aging that is on the rise). At the University of Delaware, assistant professor Christopher Martens — who began his study of CR-mimetics as a postdoctoral researcher in Seals’ lab — is testing NR in older patients with mild cognitive impairment. 

And several investigators, including in Seals’ laboratory, are looking at forms of intermittent fasting as another potential approach to mimic CR and delay aging.

“We are gaining a better understanding of how the aging process works at the cellular level and how calorie restriction affects it, and coming up with therapies that mimic that,” said Martens. “It’s an exciting time for aging research.”

The CR-Healthy Aging Connection

To better understand why eating less might prompt the body to age more slowly, one need only think back to hunter-gatherer days, when humans were forced to go long periods without food. Scientists believe the body evolved to sense that deficiency and respond accordingly, with cells switching on an array of molecular pathways — including activation of antioxidant and anti-inflammatory compounds — to conserve energy and protect cells, making them more resistant to stress.

“In general, when we shift from the normal diet that we eat now to a calorie-restrictive diet, our cells tend to activate defensive enzymes that protect us so we can live to see another day when food becomes more available,” said Martens.

While large human studies testing the concept long-term are, for good reason, hard to find, a few anecdotes from history lend credence to the theory, he noted.

For instance, when food rations were issued in Denmark during World War I, and in Norway during World War II, death rates and prevalence of cardiovascular disease decreased.

And when eight people living in a self-contained environment near Tucson, Arizona, called Biosphere 2 were forced to slash their food intake for two years due to poor crop yields, their blood pressure, blood glucose and serum cholesterol levels all declined, according to a 2002 study.

Research also has shown that people will not comply with a low-calorie diet.

In one recent study called the CALERIE study, 143 people were asked to cut their calorie intake by 25 percent for two years. They could only cut it by about 11 percent, and while they did see some cardiovascular benefits, they also lost bone and muscle mass and, in some cases, their sex drive.

Calorie-restriction mimetics, including supplements, could possibly bypass those downsides.

“There are a number of different supplements out there targeting these same pathways involved in caloric restriction, but we believe NR is among the most promising,” said Daniel Craighead, an integrative physiology postdoctoral researcher heading up the ��ƷSM����ӰƬ NR study.

How It Works 

NR is a key building block for a compound called nicotinamide adenine dinucleotide (NAD+), which plays an important role in helping vital cell-protective enzymes called sirtuins do their job.

Notably, NAD+ declines with age, but caloric restriction prompts the body to conserve it.

The idea: Rather than starving themselves to kick-start this protective process, older adults could take so-called NAD+ precursors like NR.

So far, the research is promising. 

For a 12-week pilot study, published in the journal Nature Communications in 2018, Seals’ team looked at 24 lean and healthy men and women, ages 55 to 79, and found that 1,000 mg daily of NR boosted levels of NAD+ by 60 percent. 

They also found that in participants with elevated blood pressure or early-stage hypertension, systolic blood pressure was about 10 points lower after supplementation. 

A drop of that magnitude could translate to a 25 percent reduction in cardiovascular disease risk, the authors noted.

“I definitely wouldn’t call it an anti-aging miracle pill, but it does look like a very promising nutraceutical that is safe and activates some of the same biological pathways that caloric restriction does,” said Craighead. 

In the new study, 100 people will be divided into two groups, with half taking 1,000 mg per day of NR for three months and half taking a placebo. Along the way, the researchers will measure their vascular health, blood flow to their brain and changes in cognition and physical fitness along the way.

“If confirmed, this could be something people could take to improve their cardiovascular health and enjoy more healthy years of life,” said Craighead.

Time-Restricted Feeding 

Nutritional supplements aside, Seals’ team is also looking into whether “time-restricted feeding” (eating only within an eight-hour window of the day) might also kick-start some of those same cellular-defense mechanisms as constant dieting. 

In a study to be published in the aging research journal GeroScience, they found that six weeks of time-restricted feeding improved blood glucose control and increased endurance exercise capacity in healthy adults ages 55-79. And unlike calorie-restricted diets, 85 percent of the participants were able to adhere to the eight-hour eating window.

Seals and his fellow researchers stress that the science is young, and it’s too early to recommend supplements or fasting with any certainty to aging adults.

But participants in their study say they’re cautiously optimistic.

Since Dec. 3, 74-year-old Ian MacFadyen has been popping two blue capsules in the morning and two at night, not knowing whether he’s taking NR or a placebo pill. He says he feels no difference yet, but he’s happy to be contributing to the science. 

“We all know that, inevitably, youth starts slipping away. So you might as well do all you can to preserve it,” he said. 

And if science comes up with a pill that works?

“I’d take it for sure.”

Illustration by Paul Blow