Secret Life of the Grown-Up Brain (22 page)

“Some worry about the unfair advantage and peer pressure that comes from these drugs,” the magazine went on. “[But] is it ‘natural’ to prop up the aging body with a nip and a tuck, but to restrict help for the aging mind to brain-training on the Nintendo? It may even be that like Viagra, society largely welcomes the arrival of a chemical that does, far better what omega-3s, ginseng, vitamins and all the other quackery have failed to do. Unless of course, you want to outlaw double espressos, too.”

Indeed, even before
The Economist
weighed in, another British magazine also went to bat for brain boosting. The leading scientific journal
Nature
conducted a survey of its scientifically inclined readers and found that one in five of the fourteen hundred respondents were already taking prescription drugs such as Ritalin and Provigil to increase their concentration or focus. The drugs are approved for various disorders, such as attention deficits or narcolepsy, but can legally be used “off label” to boost concentration.

Adding something to your system is not the answer for everyone, though. One of the most extreme of the current food-researcher guinea pigs is Mark Mattson, chief of the neurosciences lab at the National Institute on Aging. However, his idea is not taking
more
of something but much, much less.

For the past twenty years, Mattson has been researching the idea of severely restricting the amount of calories consumed, which is the only intervention that has consistently been shown to lengthen the life span of everything from worms and fruit flies to mice.

Although there’s no good solid data yet on humans, Mattson is doing his part to help. Since graduate school, he has been cutting way back on food. He now eats only two thousand calories a day, which, he told me, is “low for an American male” but “not that low.” Mostly, he eats complex carbohydrates and “lots of fruits and vegetables.” The father of two (who eat like the rest of us), he also coaches the high school cross-country team and “runs with the kids.” All this has left him stick-thin. At five feet nine inches, he weighs only 125 pounds. Indeed, when I saw him recently, he was wearing a striped shirt, and some of the stripes looked wider than he was.

A good-natured man of fifty, Mattson is aware that not everyone could do what he does, but for him, he says, “it works.”

So I asked him, “What did you have for breakfast?”

“Well, actually, I didn’t eat breakfast. Normally I don’t,” he answered, thereby swatting away a century of nutritional advice.

Mattson has no idea if his low-calorie diet will prolong his life. So far he’s fine and has “no diseases.” But a one-person study sample is hardly science. “Yes,” Mattson added, laughing, “I am an example of one.”

In fact, no one knows how long humans can live. Clearly there is some built-in genetic program for all animals; otherwise we would not have such natural variety. The average fruit fly lives for only 2 months, an elephant for 70 years, and a turkey buzzard for 118 years. Why is that? Is it the fast metabolism of the fruit fly compared to the elephant, with humans falling somewhere in between? No one knows. The longest-living human we know of in recent history was a French woman, Jeanne Louise Calment, who died in 1997 at age 122. (She was a smoker who loved chocolate, poured olive oil on all of her food, took up fencing at age 85, rode a bike until she was 100, and lived on her own until age 110. Of course, as a French woman, she spent a lifetime sipping red wine resveratrol, too.)

There is now a growing subculture of scientists such as Mattson and other dedicated ultrathin folks who are trying to see if they can extend their lives—and keep their brains whirring along at high levels—by eating less—a lot less.

The idea has been around since 1935, when scientists at Cornell University found, pretty much by accident, that rats that ate less not only lived longer but also had fewer chronic diseases as well. Since then, a steady stream of animal studies has repeatedly shown that caloric restriction, which generally means reducing normal caloric intake by about 30 percent, can extend the life of animals as much as 30 to 40 percent, as well as delay or prevent such chronic diseases as diabetes and atherosclerosis and neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and stroke. There’s some evidence that it can also prompt the birth of new neurons.

It would be unethical to force humans to reduce calories, but some accidental experiments suggest that this might work with us as well. The food shortages in some European countries during the world wars were associated with a decrease in deaths from heart disease, whose rates increased again after the wars ended. The people of Okinawa, practicing their cultural belief called
hara hachi bu,
would eat until they were 80 percent full, routinely consuming 30 percent fewer calories than average Japanese residents. They not only had 35 percent lower death rates from both cardiovascular disease and cancer than the average Japanese population, but until their diet became more Westernized, more residents lived to one hundred than just about any other place on earth.

Also, the eight men and women who participated in Biosphere, an experiment that involved living in a completely closed-off self-sustaining bubble, ended up eating 22 percent fewer calories. As a result, they had, on average, a 17 percent decrease in body weight and marked reductions in risk factors for heart disease, including reduced blood pressure as well as lower levels of glucose and fat.

A recent review of caloric-restriction studies published in the
Journal of the American Medical Association
emphasized that “these associations do not prove causality between decreased calorie intake and increased survival,” but added, more optimistically, “these data support the notion that the common link between aging and chronic disease is not inevitable and that it is possible to live longer without experiencing cumulative increase in serious morbidity and disability.”

There is now even a Calorie Restriction Society, nine hundred strong and growing, whose members will happily tell you the proper method for weighing arugula and whose recent book,
The CR Way: Using the Secrets of Caloric Restriction for a Longer Healthier Life,
has a handy recipe for a “Delectable Dessert Sandwich,” which consists of a piece of bread sprinkled with pumpkin pie spice.

No one knows exactly why reducing calories seems to extend life. It may be that calorie reduction works simply because with less energy burned, there are fewer free radicals produced and less damage to cells. Mattson believes that lowering calories works in other, more important ways as well. A low-calorie diet, he says, puts the body in a state of mild starvation, which in turn puts the body under mild stress and, in turn, activates a continuous stream of helpful repairs.

“The best way to look at this is an analogy with muscle cells,” Mattson told me. “Exercise stresses muscle cells with increased energy demand. A lot of free radicals are produced during exercise and the mild stress activates signaling pathways that lead genes to make proteins that protect cells against stress. Intuitively, it makes sense.”

And, he added, “The same proteins that are increased in muscle cells in response to stress are also increased in nerve cells in the brain with exercise, cognitive stimulation and dietary-energy restriction.”

In particular, Mattson said, mild stress on nerve cells produces a magical repair substance called brain-derived neurotrophic factor, or BDNF, clearly one of the current celebrity substances in aging-brain research. “Over the past ten years,” he said, “a huge literature has emerged that this BDNF is important for synaptic plasticity, promoting survival of neurons and instigation of neurogenesis.”

Mattson’s most recent research was the first to show that monkeys put on a six-month diet with 30 percent fewer calories and given a toxin that destroys dopamine cells in the same way as Parkinson’s disease had higher levels of dopamine and better motor functions than monkeys that had the same brain-assaulting toxins and ate regular amounts of food. What’s more, those same monkeys had much higher levels of BDNF in their brains.

It remains to be seen whether monkeys with such a reduced diet will live longer. A twenty-year experiment at the National Institute on Aging is still ongoing, though early results are promising. It also remains to be seen if all this could really work in humans over the long run. Most animal diet experiments not only reduce the calories of one set of experimental animals but also
increase
the caloric intake of animals in the control group, which usually gets considerably less exercise as well.

“We know that humans who overeat will not do so well,” Mattson said. “The question is, can we take someone who is not overeating, who is normal weight, and, with reducing calories, find that they, too, would have further benefit. We still don’t know that for sure. But my guess is that there would be some benefit.”

One reason Mattson and others believe in the reduced-calorie idea is that to them it makes evolutionary sense. When food is scarce and the cells sense this through stress, ancient survival mechanisms kick in to protect the organism until food is plentiful again. Those mechanisms include an increase in repair as well as a temporary suspension of reproduction. A severe reduction in calories (think anorexia) shuts down the reproductive system in females because “if there is no food you can’t reproduce because there is no food for the children,” Mattson pointed out.

Still, severe malnourishment can lead to death. No one knows when a good reduction in calories turns into a bad one that would bring a number of damaging effects. Animals that are fed 50 percent less than would be normal will die. Mattson believes that about two thousand calories for an average male and eighteen hundred for an average female—as long as the diet includes all the necessary nutrients—would likely prevent the body from being harmed and still provide the mild stress necessary to prompt cell protection. At this point, he thinks the idea has real merit.

“Reducing calories activates mild stress that upregulates growth factors that protect the cell against aging and disease,” he said.

And this may very well be how antioxidants are really working as well. Mattson thinks it is the toxins in such things as the skin of a red grape (which is there to ward off insects and what gives us the resveratrol) that produce this mild stress that prompts beneficial repairs.

Still, it may not be enough to simply eat piles of antioxidants. To get an impact that way, the dosages would have to be enormous (fifteen thousand glasses of red wine a day, for instance). Such dosage issues may very well be why experiments with supplements generally have not worked in humans.

But we might still get some help from certain foods at more normal levels through the toxic effect. Resveratrol, even at the level of a glass of wine a day, Mattson believes, might be enough to mildly stress cells. (Similar toxins are found in other foods that are antioxidants, such as garlic and broccoli.) And that stress, again, may help boost maintenance systems.

“The benefits in fruits and vegetables might not be because of the antioxidants but because the toxins are producing this mild stress,” Mattson said.

In the end, Mattson believes we may eventually crack all this in an easier way. It’s true that very few of us will get up in the morning eagerly anticipating that piece of bread with pumpkin pie spice. So he and others are doing their best to isolate the various chemical toxins in plants and, with luck, stuff them or their biological equivalents neatly into a pill. And if that pill can be found, he believes it may be most beneficial in middle age.

“There is evidence to show that exercise, cognitive stimulation, and nutrition can work in middle age,” he said.

In fact, a study sponsored by the National Institute on Aging reported in July 2008 that the compound resveratrol slowed age-related deterioration and functional decline of middle-aged mice. Although resveratrol did not make the mice live longer, those that had the substance added to their regular diet, starting in middle age, had lower cholesterol and fewer cataracts, as well as significantly better balance and coordination, than the mice that did not get their dose of resveratrol. Researchers responding to the study, published in the journal
Cell Metabolism,
suggested that resveratrol, naturally found in grapes and nuts, may induce some of the same effects of caloric restriction. As I finished research for this book, scientists were awaiting a similar trial of resveratrol in monkeys.

“Research is attempting to understand the process of aging and to determine how interventions can influence this process,” said Richard. J. Hodes, director of the National Institute on Aging. “Dietary restriction has well-documented health benefits in mammals, and the study of possible mimetics of it, such as resveratrol, are of great interest. Resveratrol has produced significant effects in animal models, now including mice, where it mimics some, but not all, consequences of caloric restriction.”

Still, it’s entirely possible that even after all this, we may simply end up back at the same place we started, proving, as Bickford says, that “the old wives’ tales and our mothers were right when they said, simply, ‘Eat your fruits and vegetables.’ ” One of the more ambitious recent studies to address this, by Columbia University’s Nick Scarmeas, in fact found that those who ate the so-called Mediterranean diet, heavy on vegetables, had a lower risk of developing mild cognitive impairment over a four-year period, perhaps by improving cholesterol levels, blood-sugar levels, and blood-vessel health overall, or possibly by reducing inflammation.

It certainly makes sense. But we still don’t know how, exactly, it might work. After all, even something as simple as the herb thyme, as Michael Pollan, author of
In Defense of Food,
points out, has dozens of antioxidants, with names like terpineol, alanine, anethole, apigenin, ascorbic acid, tryptophan, vanillic acid, selenium, tannin, and on it goes. Which one will prove to be the magic bullet for the brain?