Secret Life of the Grown-Up Brain (21 page)

“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.

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.”

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.”