Eat less, live longer

Herodotus, a Greek historian of the 5th century BC, wrote of a magic fountain in the land of the Macrobians, which allowed them to live up to 120 years old. Centuries later in 1513, the Spanish explorer Juan Ponce de León led an expedition looking for the “Fountain of Youth.” Of course, he did not succeed.

To this day, we continue our quest to escape aging and death. However, the secret to extending our lifetime may not lie in some magical pool of water, but by eating fewer calories. Scientists call it “caloric restriction” or “CR,” the practice of reducing calorie intake without malnutrition. Since 1935, CR has been shown to increase longevity in many animals, including worms, spiders, flies, fish, mice and rats. It is, in fact, the only dietary intervention, which consistently extends lifespan in a broad range of species. In some cases, the increase can reach up to 50 percent!

But what about in humans? Have we finally discovered the modern “Fountain of Youth?" At the Wisconsin National Primate Research Center, a study led by Ricki Colman, senior scientist, is dedicated to answering this question. For the past 26 years, the researchers have been feeding a 30 percent calorie-reduced diet to one of our close relatives, a small type of monkey called rhesus macaque. The study provides precious insight on the effect of CR in primates, while igniting scientific and ethical debate.

Initiated in 1989, the study was one of the first of its kind—an animal study spanning over two decades. The challenges were also unprecedented. “One of the main difficulties was the change in technology. We still analyze our data with old programs in order to keep consistent,” says Colman. She pointed to an ancient desktop at the corner of her office saying “That’s why we still need to keep that.” Besides computer technology, experimental protocols and laboratory equipment also improved significantly. For example, the way researchers froze brain samples 20 years ago did not preserve certain features possible today.

“There are lots of things we wish we could have done back then,” says Colman. Equipment malfunction was an occasional nuisance. Halfway through the study, one of the lab freezers broke down and destroyed many valuable specimens.

Fortunately, obstacles were overcome and freezers were fixed. Colman published the results in Nature Communications in April 2014. It immediately made headlines. The monkeys on a CR diet were thinner, had less decline of muscle mass and looked noticeably younger. Incidences of both tumors and cardiovascular diseases decreased by 50 percent, and diabetes was largely prevented. Brain function also improved, with less deterioration in regions which control motor, executive function and stress-related emotion regulation. The CR monkeys were not only healthier than controls, but they also showed lower levels of stress and anxiety in certain behavioral tests.

But did they actually live longer? The answer is yes! The average lifespan of monkeys on a regular diet is approximately 26 years, but the CR monkeys lived on average 3 years longer, a whopping 10 percent increase. The statistics suggest at any point in time, the control monkeys had 2.9 times the rate of death from age-related causes compared to those on a CR diet.

The study, however, was not short of controversy. Another study at the National Institute on Aging, beginning in 1987, used rhesus monkeys of a different genetic origin, also feeding them a 30 percent calorie-reduced diet. In this 25-year study, CR largely prevented cancer and diabetes, but cardiovascular diseases remained unchanged. More puzzling, CR did not increase lifespan, contradicting the WNPRC results.

Colman believes this is mainly due to the difference in diet between the two studies (although genetic variability could also play a role). The diet used by the NIA contained protein and fat from natural ingredients including wheat, corn, soybean and fish, whereas the WNPRC study used a purified diet with a single protein source (lactalbumin) and fat derived mainly from corn oil. The food in the WNPRC study also contained much more sugar. In other words, the NIA diet was healthier than the WNPRC diet.

In addition, the control monkeys in the WNPRC study had unlimited access to food (imagine an all-you-can-eat buffet—every day), while the NIA control diet was restricted. It is no surprise the WNPRC control monkeys were a bit overweight and the NIA control monkeys were exceedingly thin.

The conflicting results of the two studies may simply suggest even a modest degree of dietary restriction, as in the NIA control monkeys, can improve health and survival. This explains why the lifespan of the NIA monkeys on a CR diet were not significantly longer than control. The controls were, in fact, already exceptionally long-lived—five of the 20 male controls lived past 40—which is extremely rare under the circumstances.

In the human world, the NIA monkeys would be considered health addicts, eating healthy food from natural ingredients and controlling their portions. The WNPRC monkeys, on the other hand, may more accurately reflect the high-sugar diet and over-eating of most modern Americans. With this in mind, the two studies are more complementary than contradicting.

There are no plans to repeat these studies, due to the unusually long duration and high cost of conducting aging studies in monkeys. Instead, Colman is using existing samples and data to figure out how calorie restriction increases longevity. Most scientists agree the mechanism involves an alteration of energy metabolism, although the details are still a mystery.

This effect, however, is not just due to losing weight by eating less. While reducing body fat may increase lifespan by preventing certain diseases, it does not actually “slow down” aging as is what happens with CR. The debate stirred by this study is not only scientific. The use of animals in biomedical research has always been controversial, especially when it comes to one of our closest relatives on the phylogenetic tree.

Rhesus monkeys are the most commonly used non-human primate species in biomedical studies, with a genome 93 percent identical to humans. They display many characteristics of aging parallel to humans, including decreased mobility, cataracts, cancer and cardiovascular disease—their hair even turns gray. They age roughly three times faster than humans (10 monkey years translates to about 30 human years), with a maximum lifespan of 40 years. These features make them ideal for studying the aging process. However, the idea of “starving” monkeys for the sake of research does not play well with animal rights activists.

“Everybody working on monkeys becomes a target,” said Colman. She regularly receives hate mail from activists who view her work as animal cruelty and torture. Some of her colleagues have even received razor blades in the mail and other suspicious packages. The Wisconsin Primate Center building, where her office and some of the monkeys are located, is locked 24 hours a day for security. The unobtrusive building itself is positioned at a remote end of the UW-Madison campus, presumably to avoid unwanted attention.

Despite all the threats and pressure, Colman is undeterred. She says, “I am a big believer of animal research, I think it is invaluable. I feel strongly about what I do and take pride in that. I wouldn’t do it if I didn’t think experiments were done properly and humanely.”

In Colman’s opinion, the lay public has been largely supportive of the study. Colman is clearly passionate about working with monkeys. Her crammed office is decorated with monkey pictures and stuffed animals. Her genuine care for the animals shows deeply when she talks about watching the animals get sick and, eventually, die.

Colman says, “It’s really hard. Really, really hard. I try to be experimentally detached and treat them like patients. But over the course of the study, you get to know their personalities. I know them so well I could tell if there’s something wrong immediately after entering the room … I get nervous whenever the phone rings, just hoping it’s not bad news.” Unfortunately, she has received quite a lot of bad news over the years. From the original 76 animals, only 14 are still alive. The study continues with the remaining animals.

So, are you ready to try a CR diet? Not so fast. Colman says “this study was not meant to be a prescription for humans, it’s only to understand the aging process.” Researchers believe the effect of CR on humans may not be as compelling as seen in animal studies. Say you were a healthy 25-year-old male. To extend your lifetime by 5 years on a CR diet, you presumably would have to decrease your calorie intake by 20 percent, for the rest of your life! If this were even possible, would it be worth it?

CR is not just about eating half a burger or throwing away the last bite of cheesecake. It is about eating foods not just low in calories, but also nutrient-rich, like fruits and vegetables. Simply reducing portion size without supplementing other necessary nutrients will not work. The key is to reduce calories while staying satisfied and well nourished.

In fact, a growing number of human volunteers are already trying out this type of low-calorie high-nutrient diet, called the Calorie Restriction with Optimal Nutrition diet. There is even a CR Society, established way back in 1994, with members identifying themselves as “CRONies." Studies on long-term CRONies suggest CR can indeed prevent certain aspects of human aging, including atherosclerosis and decline in heart function. Not to mention most CRONies are notably thin, which could further prevent diseases related to obesity.

But it is not all good news. Experiencing an initial period of agonizing hunger is the norm. Other side effects include feeling chilled (due to slower metabolism), decreased stamina and lowered libido. The CR Society website says “any significant dietary change should be done in consultation with a knowledgeable physician.” If done improperly, serious conditions, like malnutrition, anemia, bone-loss or anorexia could occur. A 25 percent calorie reduction would be ideal, but a 50 percent reduction could starve you to death.

Although CR seems to have a positive effect on human health, we still do not know whether it actually increases lifespan in humans. Performing a long-term human study in a controlled laboratory setting does not seem like a viable (or ethical) option. Colman’s study in monkeys might be the closest we can get.

With more research, drugs mimicking the effect of CR, without the pain of starvation, may arrive in the future. We will not all live to be 120, but the possibility of living a healthy, happy and extended old age is not at all a myth. This is something Herodotus and Juan Ponce de León could never have imagined.

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