The Secret Life of the Grown-up Brain: The Surprising Talents of the Middle-Aged Mind - Barbara Strauch (2010)

Part III. Healthier Brains

Chapter 10. Food for Thought

And a Few Other Substances, as Well

In 2008, the giant British drug company GlaxoSmithKline announced it would pay $720 million to a small Massachusetts biotechnology company that’s been working for years to prove that we can extend our lives by drinking a lot of red wine.

Specifically, the company had been trying to develop a pill with a high concentration of resveratrol, the ingredient in red wine that some believe may hold a key to keeping our cells, including our brain cells, healthy and nimble.

But Glaxo was not paying for something that’s known to work in actual humans. It paid $720 million to a company whose work so far had shown that resveratrol can extend the life of yeast and, to a certain extent at extremely high doses, rodents.

Is this madness?

Clearly, we want very much for it not to be madness. The idea that something as simple as the wine we drink—or the food we eat—can make us think better and live longer is highly seductive. Indeed, it’s hard to think of a topic more steeped in hope—and hype—than the brain and food.

As I write this, I’ve just returned from a Whole Foods supermarket, where a young woman—hired as a kind of modern-day circus barker—was handing out free samples of a new bottled tea. “Try it! You’ll love it!” she nearly shouted to shoppers as they pushed their carts. “It’s got MORE antioxidants than green tea! More antioxidants for your brain!

I took one of her tiny plastic cups of tea and in one gulp drank it down. Was I smarter? Sharper? Was my middle-aged brain better braced with those antioxidants sloshing around?

Hmmm . . . well . . . maybe.

Uncertain Connections

Even those who study all this for a living are confused. While a consensus has emerged over the benefits of exercise and, to a certain degree, education, agreement on what works beyond that falls off a steep cliff.

“The message seems to change every year,” says Mark Moss, the neuroscientist at Boston University, with a sigh.

Part of the problem in talking about food and the brain is that, on one level, it’s a no-brainer. Who hasn’t heard a parent tell—or been a parent who’s told—a child, “Eat your fruits and vegetables!” or “Fish is brain food!”? Rules about which foods we’re supposed to eat or not eat have been with us pretty much from the beginning. Even the sacred Hindu text the Bhagavad Gita, in which a young warrior is advised by an all-knowing god Krishna, talks about what to eat.

“There are three kinds of food as well,” Krishna advises. “Here are the distinctions among them:

“Foods that are the sattvic are drawn to promote vitality, health, pleasure, strength, and long life, and are fresh, firm, succulent, and tasty.

“Foods that please the rejasic are bitter or salty or sour, hot or harsh or pungent, and cause pain, disease, and discomfort.

“Foods of the tamasic are stale, overcooked, tasteless, contaminated, impure, filthy, putrid, and rotten.”

So there you go, diet advice from 5000 B.C.

With all that, we certainly think we know what we’re supposed to eat. We know too much refined sugar or grain or salt is bad for our general health, as are the wrong kinds of fat.

We may ignore all that, but we do know it. What few people realize is that most nutritional advice is based on one particular kind of research—large population studies. These wide-swath studies have, in fact, found that diets high in fiber generally protect against colon cancer and those high in vitamin C reduce the risk of stroke. Researchers can trace the amount of fat in the diet to the rate of breast cancer in a population and watch those rates change as people move from one food culture to another. Japanese women do not suffer from the same rates of breast cancer as American women do, but after just two generations of living here, Japanese-American women, on average, have the same breast cancer rates as any other ethnic group. Similar population—or epidemiological—studies have repeatedly found that high blood pressure is associated with an increased risk of heart disease and that obesity is linked to many chronic diseases.

Still, if you peer closer, such correlations can disappear. Studies that keep track of specific foods and specific people often fail to find any effect at all. Just a few years ago, the now-famous Women’s Health Initiative, the kind of giant, randomized, controlled clinical trial that’s considered the Rolls-Royce of research, failed to confirm that a low-fat diet prevented breast cancer, for instance.

Long-term studies of the antioxidants vitamins E and C and beta-carotene that looked at their effects on individual people also found they do not prevent heart disease, and similar studies failed to confirm that diets high in fiber ward off colon cancer.

Certainly, a few foods have been directly linked to health. If we have a serious deficiency in our diets, adding a specific nutrient helps—folic acid for pregnant women to prevent neural tube defects in babies, for instance.

But our modern Western diets, as junk-food-filled as they may be, are also astonishingly varied and rich, with low-cost, fortified, and abundant food. Most of us get what we need and do not have serious deficiencies that can be easily corrected by adding this or that nutrient.

In light of all this, can we really expect that a glass of wine or a plate of spinach will make any real difference? Or is our fate prewritten in our genes and we’re just fiddling around the edges or, worse, fooling ourselves?

Blood-Brain Barrier

And given such a dismal track record of food and overall health, can we possibly know anything about food and the brain? Can we figure out what we should put in our mouths to nudge our complicated neurons?

Until recently, this question was not even asked. For years, scientists believed diet had little impact on our brains because they thought most nutrients didn’t cross the blood-brain barrier. The blood-brain barrier is real. Cells lining blood vessels in the brain are packed close together to keep out certain large molecules and maintain a chemical balance. Some bacteria are barred, for instance, and infections in the brain are rare for that reason. Paula Bickford, a neuroscientist who studies nutrition at the University of South Florida and the James A. Haley Veterans’ Hospital, says that for a long time most scientists believed that even vitamin E did not cross the barrier. In one study Bickford conducted, in which she gave high levels of oxygen to rats to see if it would induce damage, one reviewer of her work asked her why she was wasting her time because “nothing could affect the brain.” And that, Bickford says, “was just ten years ago!”

And there were other roadblocks as well. Until recently, most believed the brain was on a downhill slalom course from our mid-twenties, losing as many as 40 percent of its cells as it aged. Why bother worrying about a brain that is programmed from the get-go to decay? Did anyone really think another forkful of carrots was going to stop that from happening?

Now, though, we know that much of that doesn’t hold up. The brain does not lose large numbers of neurons as it ages. Nutrients do cross the blood-brain barrier and are, in fact, essential for the brain. As a result, there’s now renewed interest in figuring out how we can tweak our blood—stir in some growth factors from exercise or maybe some special ingredient in this food or that—to benefit our brains.

As Mark Moss in Boston says, “We never thought what was happening in the body was getting to the brain. We thought that the brain was protected. But we are finding that the blood-brain barrier can be breached. Believe it or not, the circulation people never talked to the brain people and now we are talking . . . and it’s a big, big deal.”

By nature a conservative lot, scientists don’t like to put their money on something until they understand how it might happen, the mechanism. Scientists are more willing to look at the food-brain link now because they’ve identified ways it could work.

And what are the mechanisms by which food might bolster our brains? They involve the same substances touted for years in terms of overall health—antioxidants such as vitamins C and E, along with anything that acts as an anti-inflammatory, from fish oil to aspirin.

Why should we go there again? It’s a legitimate question. Some suggest that we need to pay even more attention to the brain and food because the brain uses so much energy (at rest it uses 10 percent of the body’s oxygen and in mental activity up to 50 percent), leaving it both sensitive to and in greater need of certain nutrients. Others don’t go that far, but say that we’ve oddly missed the boat by thinking that the brain does not react to what we eat.

“The brain is not uniquely sensitive but it is sensitive to what we eat,” says Bickford. “And now we’re realizing more and more that what you eat can affect cognition.”

Antioxidants and Inflammation

The theory of antioxidants and aging has been around now for more than thirty years, and it’s intriguing that it’s now at center stage again—in research into the brain as it ages.

The idea goes like this: When our cells (including our brain cells) burn oxygen to make energy, a byproduct called a free radical is produced and thrown off. A free radical is essentially a molecule that’s missing an electron. And because it lacks that electron, it is unstable and wants to steal electrons from other cells. It grabs those electrons where it can, causing damage to other cells willy-nilly in the process. That damage is called oxidative stress and many believe it’s one of the main culprits in normal aging.

So eliminating as many free radicals as possible seems like a good idea. When we’re young, free radicals are often neutralized by another molecule, an antioxidant, in a continual repair program. But as we age—for reasons that are still not fully understood—that process becomes less efficient; the antioxidants can’t keep up with the hordes of free radicals (which are also produced by exposure to environmental insults such as pollution, ultraviolet light, and radiation), and more brain cells are left dented and nicked.

Then, a few years ago, another potential aging mechanism was identified: inflammation. Inflammation occurs when the body is injured and white blood cells rush in to do repairs. With that incoming surge, there can be collateral damage. Like fire engines driving up on a nearby lawn as they speed to a house to put out a fire, the cells rushing in to help out often harm surrounding healthy cells. And if the brain or the body is in a state of chronic low-level inflammation, there’s likely to be a buildup of damage. Unable to cope, cells—including brain cells—begin to shut down and die. Long-term inflammation (which many now believe can also come from chemical processes that accompany obesity or even excessive stress) may contribute to a number of chronic diseases, from heart disease to Alzheimer’s.

So, if the evil twins of brain aging are oxidative stress and inflammation, the questions are: Will eating foods high in antioxidants or anti-inflammatory agents make a difference? Does it have to be real food or can it be a supplement or a vitamin pill? And can we make an impact on our very complicated brains if we start gorging on antioxidants and anti-inflammatories at middle age, or is that too late?

No one thinks a lack of antioxidants or too many inflammatory foods are the root causes of neurodegenerative diseases. But nearly everyone now thinks they are, at the very least, somehow part of the normal aging process in the brain, and therefore possible targets for intervention.

“My own view is that antioxidant damage and inflammation are in the background and they make cells more susceptible to other insults such as neurodegenerative diseases,” Bickford says. “If we get insults like that, we are less able to function at 100 percent and make repairs, then we start to see failures.”

Normal aging in the brain, many believe, comes about in part because repair mechanisms slow down. That process is complex but does seem to include antioxidant damage and inflammation, and both, Bickford says, “can be affected by nutrition,” including what we eat in middle age.

“When a cell is dead it’s hard to bring it back to life,” she says, “but certainly in middle age and up until the point of no return, I think there is room for repair.”

Brain Foods

With all this new information, science has now embarked on a merry chase to figure out which foods give our brains the biggest bang for our buck. Several years ago, the U.S. Department of Agriculture, with researchers at Tufts University in Boston, developed a method to screen and rank foods for their antioxidant capacity. The list is known as ORAC, for oxygen radical absorbance capacity, and it’s one of the main reasons we suddenly started eating bowls full of blueberries. Just to give you the top twenty-five, the list goes like this:

Prunes, raisins, blueberries, blackberries, garlic, kale, cranberries, strawberries, raw spinach, raspberries, Brussels sprouts, plums, alfalfa sprouts, steamed spinach, broccoli, beets, avocados, oranges, red grapes, red peppers, cherries, kiwifruit, baked beans, pink grapefruit, and kidney beans. (A key to this is color—generally, darker is better.)

Down the list a ways are carrots, coming in at forty, and tomatoes, at forty-two.

So does that mean we have the answer? Have a hearty breakfast of prunes and kale and, if you’re not up for a glass of red wine (red grapes) that early, a cup of black tea (also high in antioxidants) and call it a day?

Not entirely. Despite a growing belief in the potential of foods such as blueberries and spinach to help stave off aging in the cells of the brain as well as the body, it’s important to remember that, in terms of the brain, there have been no long-term clinical trials in humans to test all this. Not one.

Most smaller trials of vitamin C or E or ginkgo biloba and cognition have been mixed at best. There are ongoing large human trials to see if curcumin, which is the turmeric found in a lot of Indian food (Indians have a lower rate of Alzheimer’s than some other populations), or even caffeine (which we all know can give a needed jolt to nerve cells), can help ward off Alzheimer’s. But there are no full-scale controlled trials to figure out whether what we eat can help us remember what movie we saw last night.

“There’s always a push to address a disease, but with normal aging we always have the question, what is the product that a drug company can sell?” says Bickford. Consequently, there is less funding for research into normal brain aging, which, she says, is a shame.

Still, that does not mean that science has given up. After a recent summit meeting of cognitive-aging scientists organized by the National Institute on Aging, I had dinner with two of the leading neuroscientists working on aging and the brain, Denise Park and Laura Carstensen. As I joined them at their table in at a Washington, D.C., restaurant, they were talking about the subject that has now taken center stage—possible interventions to improve our brains. Many, including those who study rats, monkeys, genes, and humans, say they now believe more strongly than ever that eventually it will be possible to slow down or even halt or reverse the aging process in the brain.

Most scientists at the conference spoke glowingly of exercise, the current star in brain-aging research. But others talked about the anti-aging potential of a whole range of substances, most of which are antioxidants or work as anti-inflammatories. Some touted spirulina, a kind of algae, which is what fish eat to get all those good omega-3 fatty acids, which can reduce inflammation. Why not skip a step and just eat the algae ourselves?

Others spoke confidently of “druggable” targets in the brain, where it might very well be possible to boost repair processes by taking a pill—nutrient-derived or otherwise. A growing number of neuroscientists have gone so far as to form their own companies to both research potential agents and, presumably, cash in when they find something that works.

At this point, each neuroscientist seems to have his or her own pet formula. Some continue to believe that, for females at least, estrogen might work. For years, test tube and animal studies have consistently found that estrogen seems to nourish the brain, making connections grow in areas like the hippocampus, where memories are formed.

But that does not mean that adding a dollop of estrogen to an aging human brain is necessarily a good idea. Indeed, any recommendation of estrogen these days is messy at best. First, the big studies appeared to find that hormone therapy (estrogen) decreased dementia, then later, more rigorous studies found that estrogen not only didn’t help keep us mentally sharp but actually increased the rate of dementia, not to mention raising the risk of breast cancer and strokes. Some now argue that even those results were flawed because they did not study women who were young enough—at the start of menopause, for instance—when their brain cells were still stable and healthy enough to soak up estrogen’s bounty. But no one has yet been able to prove conclusively that there is such a critical window. And given its known risks, estrogen is now shrouded in confusion and fear.

Some scientists, such as Roberta Diaz Brinton, a neuropharmacologist at the University of Southern California, are trying to develop plant-based estrogens that target only the brain and not the breast. Having spent years watching estrogen’s effects in the lab, Brinton, along with a fair number of others, believes the hormone is essential to stabilizing and maintaining a neuron’s energy metabolism and “keeping the cell in a survival mode.” Some small human scanning studies have found increased metabolism in the frontal lobes of women given estrogen.

When I spoke with Brinton, I told her of a friend who was convinced that her brain at menopause had gone haywire, but then, after a few years, it came back and seemed to work fine. In Brinton’s eyes, this is entirely possible, because menopause is “all about getting your brain to adjust to a lower level of estrogen,” and once it does, things can improve.

In middle age, “The female brain changes from a reproductive brain to a nonreproductive brain,” Brinton added. “Just as all those neurochemical circuits came into place at puberty . . . later, at peri-menopause, the brain is upregulated for estrogen and then downregulated . . . and circuits, the bridges, are being dismantled. Some are left behind, but the system, the pathways, are being dismantled. After all that the brain is left unreceptive to estrogen. Menopause is all about shutting the brain off to estrogen and it’s an adaptive process.”

Still, the underlying message about estrogen, menopause, and the brain is—again—variability. “There’s a spectrum of responses that probably depends on how estrogen-dependent a woman is. As estrogen levels plummet back to prepubescent levels, some women get confused and unfocused and are generally miserable until brain chemicals stabilize. Others say, ‘Hey, What’s the big deal?’ ”

In the end, though, researchers like Brinton are not giving up on estrogen, despite its current bad reputation. Encouraged by recent reports that the new kinds of antidepressants such as Prozac work in part by increasing neurogenesis (the birth of new brain cells), some other scientists have formed research companies to look into those drugs, seeking the right combination.

Will Animals Point the Way?

It used to be that serious science lived in its own cloistered world. True science was undertaken for the sake of knowledge, and any legitimate researcher who openly talked of devoting precious lab time to making something for real people in the real world was not taken seriously. Certainly, anyone who even suggested they might want to sell what they were studying was quickly relegated to the snake-oil club. But not anymore. “There’s been a real shift,” Park said as we ate dinner that night in Washington. “Everyone is openly talking about interventions, even drugs.”

One major reason for that shift, of course, is that scientists now believe that the brain does not undergo complete disintegration as we age. It’s now known that we do not, under normal circumstances, lose large numbers of neurons. And if our neurons remain mostly intact, that means we may not need a complete renovation. Perhaps we can just do the kitchen, or a downstairs bathroom. If we don’t have to actually bring dead neurons back to life, but instead simply jump-start a nerve signal here or there, maybe we can figure out how to do that. Maybe it is possible to keep the brain running much longer at its tough-minded, middle-aged level by just tinkering a bit around the edges.

And maybe some of that tinkering could be accomplished simply with the foods we eat. “This is not the way of big pharmacology companies,” says Bickford, who was trained in pharmacology. “But maybe because I am a child of the sixties, I find the idea that there is a simple way to do this just such an optimistic thought.”

That optimism, given the lack of human data so far, is being fed by an increasingly rich trove of research on the aging brains of animals. What’s true in a rat is not necessarily true in a human, but some of the animal results are intriguing.

“We don’t know everything but we do know a lot,” says Bickford. “In many ways, just over the past few years, really, nutrition and neuroscience have come of age.”

A number of basic test-tube experiments have shown that brain tissue taken from older animals is more sensitive to oxidative stressors than similar tissue from young animals. By middle age, there are already indicators of increased inflammation in the brains of animals. But food seems to help. In animal studies, Bickford found that older rats fed a diet of dried spinach learned new tasks much faster than those fed plain rat chow. Rats fed diets enriched with blueberries, spinach, or spirulina had less brain-cell loss and improved recovery of movement following a stroke.

James Joseph at Tufts University and his colleagues Mark A. Smith and Barbara Shukitt-Hale have done dozens of experiments trying to zero in on what it is exactly in a blueberry that might be helping the brain. In one study, older rats (about sixty years old in human terms) that were already showing cognitive decline were fed extracts of two of the fruits highest on the ORAC scale, blueberries and strawberries, and did better on cognitive and motor tests. And when their brain tissue was examined, it had lower levels of markers for oxidative stress and inflammation.

In another Tufts experiment, after four-month-old mice with a clinically induced form of Alzheimer’s ate blueberry extract, they did as well in memory tests in middle age as mice that did not have Alzheimer’s and considerably better than mice with dementia that did not eat blueberries. And that was true even though the brains of the Alzheimer mice that had eaten blueberries and those that had not had the same amount of plaque damage in their brains. What’s more, the blueberry-eating mice also had increased activity in molecules that are part of the learning and memory pathways. The mice were somehow protected. Is this cognitive reserve in mice? Mouse escapees?

Other Tufts studies suggest that blueberries can even increase the birth of new neurons in the dentate gyruses of older mice, the same part of the brain that’s involved in memory and the same section of the hippocampus that’s affected by exercise in mice and humans. The studies have so convinced James Joseph, he has taken to calling blueberries “brainberries” and starts his day with a big cup of them himself.

One of the most famous studies involving animals and nutrition was done by Carl Cotman at the University of California at Irvine and his colleagues, who found that beagles fed a diet of fruits, vegetables, and vitamins and allowed to exercise could, even in old age, learn new tricks faster than dogs that did not have such good habits. (The dogs who did the best had their diets fortified mostly with antioxidants, including tomatoes, carrot granules, citrus pulp, spinach flakes, and vitamins E and C.)

And this may be a good example of brain maintenance. Dr. William Milgram, the study’s lead author, said that even a relatively dumb dog, whose name was Scamps, appeared to do better after two years of the fortified diet than other dogs as they aged. “What happened,” Milgram said, “was that he remained the same while the dogs in other groups showed the expected deterioration.”

Monkeys and Myelin

At the moment, one of the most ambitious efforts to pin down what food or substance might work is under way in Boston, where Mark Moss is trying to figure out—in a rigorous scientific way—how to slow down aging in the brains of middle-aged monkeys.

Moss, as we’ve mentioned earlier, thinks some normal aging (from memory loss to balance problems) can be traced to the gradual disintegration of the white matter in the brain, the fatty coating on the neurons’ long spiked tails that sends signals across the brain. If the white matter—or myelin—is damaged, signals slow down or even get lost.

It’s clear that as white matter increases as we age—into our fifties and sixties—we seem to get smarter, to see a more integrated picture of the world. But at some point, the repair process of the myelin breaks down. No one knows when that tipping point is, but many, including Moss, believe that somewhere during middle age, we end up “on the cusp” between effective repair and the beginnings of decline. Could we jump in at that point and slow or halt the aging process or boost repairs with some kind of food or substance?

When I first spoke with Moss at his Boston office, he had assembled a team of biophysicists who were completing sophisticated mathematical modeling to determine which substance might work best. Research on monkeys, like that on humans, is both expensive and difficult, with complex rules to protect the animals. So before proceeding, Moss wanted the team to figure out which agent had the best shot of helping.

At that point, his list was long and included antioxidants such as grape seed extract, anti-inflammatory agents such as spirulina and aspirin, and even statins, which lower cholesterol levels and may help blood vessels in the brain as well.

When I last spoke with Moss he told me that they had finally decided to test a number of things. One group of monkeys will engage in rigorous, carefully measured exercise (including a “very large hamster wheel”), and have their blood pressure and heart rates monitored. Another group will be given a food-based antioxidant, probably grape seed extract. And a third group of monkeys will be given an anti-inflammatory or a statin. The trial will go on for three years (equivalent to about a decade in humans) and then the monkey brains will be scanned and examined to see how their white matter fared and whether, even if we start at middle age, we can make a real difference in how brains age.

“I think you will see a rapid application of all this,” Moss told me. “I think we will go the doctor, who will say, ‘Hey, Mr. Jones, your kidney function is fine but your white matter voxels are a little low here and there.’ We already have the technology to do that and I think we will be able to intervene. I believe it will happen because baby boomers are not going to take no for an answer—we want to keep going and going and, by god, we will do it.”

There are those who can’t wait. They see the animal data and simply can’t resist. Paula Bickford eats a balanced diet but also takes spirulina and fish oil as well as a concoction she’s cooked up herself (which she believes may stimulate stem cells in the body to do better repair as we age) that includes green tea and, of course, blueberries. Even Mark Moss, who scoffs at much of this, told me, a bit sheepishly, that he had increased his run to five miles a day and was—why not?—“also taking some grape seed extract.”

Indeed, the idea of using a range of substances to boost our brains is no longer a fringe thought. While some worry that brain enhancement in any form might only increase the divide between the haves and the have-nots because some will have access to such substances and some may not, it is an idea that is increasingly discussed out loud.

Late last year, none other than The Economist, the normally staid British news magazine, had a half-page editorial backing the use of certain drugs that can work as cognitive enhancers, saying that “such drugs promise to do a lot of good.” If scientists, for instance, used such drugs to help them focus and “unravel the mysteries of the universe, so much the better.”

“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.

Low, Low Calorie Diet

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?

“I don’t think we will find one chemical in something like a blueberry that is the active ingredient,” Bickford says. “I think we are going to find it is a lot of chemicals working together, that it is more synergistic.”

And just as we search for what we should eat, it is just as important to know what we shouldn’t. Again, there are very few studies that show that specific foods, like steak, are bad for the brain, but we do know that certain patterns of eating can lead to conditions, such as obesity or type 2 diabetes, that can be harmful. Most of this new research is based on linkage studies and does not necessarily prove cause and effect, but does indicate what we should pay attention to.

There are recent suggestions that type 2 diabetes, the most common kind, which is often related to obesity, may increase the risk for dementia, for instance. It’s still unclear if it’s the diabetes or the obesity or both that may increase the risk, because not everyone with diabetes gets Alzheimer’s and not all those who get Alzheimer’s are diabetic.

But in recent years, a number of large studies have found that those with type 2 diabetes are twice as likely to develop Alzheimer’s. It may be that the cardiovascular problems caused by diabetes block blood flow to the brain or cause strokes, contributing to dementia. The same kind of plaque that builds up in the brain with Alzheimer’s also accumulates in the pancreas with type 2 diabetes. It’s also possible that abnormalities of glucose metabolism and insulin levels in the brain may be harmful. Those with type 2 diabetes often have insulin resistance—when their cells cannot use insulin well—so the pancreas makes extra insulin, which builds up in the blood and can lead to inflammation and possible harm to the brain.

One of the new studies, by researchers from the Karolinska Institute in Sweden, found that even people who had borderline diabetes were 70 percent more likely than those with normal blood sugar to develop Alzheimer’s. Another study, in Finland, published in the Archives of Neurology in 2005, found that being overweight in midlife—even without diabetes—increased the risk of dementia. The researchers looked at the records of 1,449 randomly selected men and women when they were fifty-one and then again when they were seventy-two and found that midlife obesity, like high blood pressure and high cholesterol, doubled the risk for dementia—and that those who had all three risk factors were six times as likely to become demented.

Again, the reasons are unknown, but with a number of studies showing the same findings, it begins to appear that being obese in middle age is not the best thing you can do for your brain. One of the most recent studies, by Scott Small at Columbia, used brain scanners and found a tie between glucose levels and—again—that tiny area of the hippocampus, the dentate gyrus, that is so crucial to memory. Small found that unregulated spikes in glucose were linked to lower blood volume in the brain’s dentate gyrus. The effect came with levels of glucose that aren’t necessarily seen with diabetes, but with the normal aging process as we reach middle age. And it is known that physical activity and a proper diet—one that leans much more on fruits and vegetables than on highly sugared sodas and snacks—can help regulate blood sugar.

About 20 million people in the United States have type 2 diabetes. The number has doubled in the past two decades and is expected to keep increasing because rates of obesity are rising. Worldwide, diabetes is also increasing, up to 230 million cases from 30 million in the past twenty years.

Obesity rates, too, remain high. According to the Centers for Disease Control and Prevention, 34 percent of U.S. adults aged twenty and over were obese in 2008. Alzheimer’s now affects one in ten people over age sixty-five and nearly half the people over eighty-five. About 4.5 million Americans have it, and taking care of them costs $100 billion a year. The number of patients is expected to grow, possibly reaching 11.3 million to 16 million by 2050.

But those projections about dementia do not include a possible increase from obesity-related diabetes. In fact, when scientists talk about the potential for those in middle age now to avoid the destructive deterioration of dementia and retain their high levels of cognitive function into old age, there’s often a caveat. That is, if current trends toward increasing obesity continue, then, as one nutritional researcher put it, “all bets are off.”