Keep Moving and Keep Your Wits - Healthier Brains - The Secret Life of the Grown-up Brain: The Surprising Talents of the Middle-Aged Mind - Barbara Strauch 

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

Part III. Healthier Brains

Chapter 9. Keep Moving and Keep Your Wits

Exercise Builds Brains

Kevin Bukowski is forty-seven years old, and though he’d always been a runner, he’d slacked off lately. Then, offered free gym membership as part of a research study, Bukowski got serious about exercise. He woke up at five A.M. in his home in upstate New York, got onto a bus at six, and an hour later was on a treadmill in the gym across from Columbia University’s medical center in Manhattan, where he works helping to coordinate clinical trials. Every day, three or four times a week, Bukowski did the same routine: twenty minutes on the treadmill, twenty minutes of sit-ups. And what happened? At the end of five months, Bukowski was happy to find that he’d lost a few pounds, his body mass index went down, and he felt better “emotionally, physically, and spiritually. I just had more energy and I was not as tired at the end of a long day.”

But most important of all, his dentate gyrus went wild. His dentate gyrus? Hardly seems like something to get out of bed for, whatever it is. Dentate gyrus?

Well, yes. Over the past few years, the dentate gyrus, a small section of the hippocampus, an area crucial for memory, has emerged as a superstar in the story of the brain as it ages. And the dentate gyrus, it turns out, is particularly fond of exercise. Not long ago, in fact, the dentate gyrus caused a bit of a stir at a Columbia University lab. Early one afternoon, a group of scientists was watching a small computer monitor. The slide showed what had happened to the brain of a mouse that had spent weeks scampering on its little wheel, as many as twenty thousand rotations a day.

As the researchers watched the screen, tiny green dots appeared in the microscopic view of the mouse’s brain. The dots were new brain cells tagged with a dye that made them glow bright green. There were hardly any green dots in the brains of the mice that had not exercised, but in the mouse that faithfully and voluntarily ran on its wheel, there they were, as clear as day—small green dots in the middle of his dentate gyrus. Exercise had prompted the birth of new neurons—neurogenesis. And the scientists, seasoned veterans all, could hardly believe their eyes, in particular Scott Small, in whose lab the new baby neurons were born. “To see those green dots light up in the mice,” said Small when I spoke with him about that day. “To see it so clearly, new brain cells that came with exercise, it was impossible to ignore. My colleagues started putting on their sneakers.”

Over the past several years, neuroscience has been on a serious hunt to figure out how to nudge our brains in the right direction as they age. Are there real things that can help real brains in the real world? Education seems to buffer the brain. And there are a lot of other ideas—and loads of exaggerated claims—out there. Sudoku? Deep wave meditation?

At this point, the most promising answer is exercise. In one rigorous study after another, exercise has emerged as the closest thing we have to a magic wand for the brain, the best builder of branches, baby neurons, and, along with education, perhaps, the mental padding of cognitive reserve.

Scientists have suspected for decades that exercise, in particular aerobic exercise, is good for the brain, just as it’s good for the heart. Like all our cells, brain cells need oxygen, and the more our blood can spread oxygen around, the better. Blood flow is blood flow. What we’re told to do for our hearts—keep our cholesterol and blood pressure under control to make sure our arteries are as nimble as possible, for instance—turns out to be just as good, perhaps even better, for our brains. And Scott Small, with his green dots, is at the forefront of what is now an all-out effort to figure out how exactly this works.

Energetic and talkative, Small, at forty-six, is doing what he can to maintain his own middle-aged brain. He loves a fast game of tennis and recently took up snowboarding. The question is, as he reaches his sixties, seventies, and even eighties, will all that moving around leave his frontal lobes as finely tuned as his forehand?

In the spring of 2007, Small published an extraordinary study that suggests that the answer is yes. The study, starting with animals, first divided forty-six mice into two groups. For two weeks, one set of mice was kept in cages with running wheels and the other without, after which time the researchers scanned the mice to see what was happening to the blood flow in their brains. In fact, Scott Small’s lab was one of the first to develop the techniques to scan the brains of tiny mice, a step that not only lets researchers see what is happening brain cell by brain cell but can validate findings from sometimes difficult-to-interpret human brain-scanning studies. In this study, for instance, the mice were injected with a substance—now banned in humans—that clings to new cells and allows scientists to see precisely where new brain cells form. Then the researchers looked at microscopic slices of the mice brains.

Small and his colleagues found what they expected. The mice that had run on their wheels had increased blood flow in their dentate gyruses, those tiny sections of the memory-crucial hippocampus. The increase was there long after the mice stopped exercising, too, which meant it did not come from the transient boost in metabolism that regularly occurs while exercising. And right in the middle of those mouse brain dentate gyruses, Small and his team also saw those green dots of new brain cells. There were nearly twice as many green-dotted new brain cells in the exercising mice as in the nonexercisers.

For Small and his colleagues, it was a powerful finding, a clear sign that exercise was not only a potent producer of new neurons, as some earlier results had suggested, but also seemed to “selectively target” the brain’s dentate gyrus—right in the middle of the brain’s memory machinery—an area that appears to decline with the normal aging processes. This means that exercise may, in fact, help boost our memories as we age.

“The hippocampus is really a circuit of different regions,” Small says, “and exercise targets this specific area of that hippocampus, the dentate gyrus.”

While it’s true that Small’s green-dot study was tiny, it makes sense in part because it builds on solid research by other top neuroscientists. In fact, some of the first clear evidence that exercise boosts our brains came from the coauthor on the Small exercise study, Fred Gage.

One of the most well-known neuroscientists working today, Gage was the first to find that running—and running alone—could give birth to new brain cells. In the late 1990s, Gage and his colleagues, including Henriette van Praag, at the Salk Institute in La Jolla, California, decided to see what would happen if mice were allowed to run as much as they wanted, which usually meant four or five hours a night, or up to five kilometers.

Gage then put the mice to a classic test. He placed them in a tank of murky water and let them find a tiny platform hidden below the surface that they could land on. This is called the Morris water maze and is one of best ways to determine how smart a mouse is—a kind of mouse IQ test, if you will. Mice don’t really like to swim, so when they’re dunked they try as hard as possible to find the little platform. Those that locate it faster on subsequent dunkings are considered cognitively ahead of their peers.

What Gage and his colleagues found was that the mice that exercised the most were not only much better at finding the platform on the second and third tries but also had twice as many new neurons in their brains.

And where were the new neurons? Just where he and Small later found them in the Columbia University mice—in the middle of the dentate gyrus. “Our results indicate that physical activity can regulate hippocampal neurogenesis, synaptic plasticity and learning,” Gage concluded in his 1999 paper. In later studies, he found that exercise woke up the newborn neuron machinery in elderly mice, too.

Of course, these experiments were conducted only on mice. But Gage, once called the “impresario of neuroscience,” was determined. He was on the trail to find the roots and promise of neurogenesis.

100 Wrongheaded Years

Like most new concepts, the idea that an adult brain—animal or human—could actually grow new brain cells got off to a bad start, a prime example of how science moves ahead in fits and starts at best. Until recently, most neuroscientists had not budged from conclusions drawn in 1913 by Spanish researcher and Nobel Prize winner Santiago Ramón y Cajal, who confidently wrote: “In the adult brain nervous pathways are fixed and immutable. Everything may die; nothing may be regenerated.”

It was an idea that seemed to make sense. But it was wrong. Gage himself has written about why it was so hard to believe that this idea could be incorrect in a 2003 article in Scientifi c American:

For most of its 100 years history, neuroscience has embraced a central dogma: a mature adult’s brain remains a stable, unchanging, computer-like machine with fixed memory and processing power. You can lose brain cells, the story has gone, but you certainly cannot gain new ones.

How could it be otherwise? If the brain were capable of structural change, how could we remember anything? For that matter, how could we maintain a constant self-identity? Although the skin, liver, heart, kidneys, lungs and blood can all regenerate new cells to replace damaged ones, at least to a limited extent, until recently scientists thought that such regenerative capacity did not extend to the central nervous system, which consists of the brain and the spinal cord. Accordingly, neurologists had only one counsel for patients: “Try not to damage your brain because there is no way to fix it. ”

As far as anyone recalls, the first hint that this might not be so came from a young scientist at the Massachusetts Institute of Technology, Joseph Altman. As Sharon Begley writes in Train Your Mind, Change Your Brain, which traces the history of neurogenesis (and, interestingly, relates the latest neuroscience to the teachings of Buddhism), Altman was itching to test out a new technique that allowed researchers to tag newly formed DNA in cells with a radioactive substance.

In the early 1960s, he decided to use it to see if he could find any new neurons in the brains of adult rats. And he did. He then went on to find newly formed brain cells in the brains of cats and even guinea pigs. He published his findings in a scientific journal, but it attracted little attention and he soon transferred to Purdue University and dropped the still-too-controversial concept of neurogenesis.

The idea, however, did not go away. Studies in the early 1980s in songbirds, in particular canaries, found that they, too, created new neurons, even as adult canaries. Each spring, as the canaries learn a new mating song, new sets of neurons are created and migrate into their song-making brain area, which becomes correspondingly huge.

Then, in the late 1990s, Fred Gage found that the same thing happened in rats. Adult rats that lived in stimulating environments—with other rats, toys, and wheels—as well as rats that exercised, created many more new brain cells. He also found that exercise alone produced new neurons. Later, other researchers found new neurons in adult monkeys as well.

Next came humans, and for this study Gage teamed up with Swedish neuroscientist Peter Eriksson, who had obtained brain slices from older Swedish cancer patients who had been injected with a substance that would tag dividing cells. They were able to show that even adult humans were producing new neurons. And where were those baby neurons showing up? “We demonstrate that new neurons . . . are generated from dividing progenitor cells in the dentate gyrus of adult humans,” Gage wrote when his research was published in the journal Nature Medicine in 1998. “Our results further indicated that the human hippocampus retains its ability to generate neurons throughout life.” It was a study that changed brain-research forever.

Exercise Equates with New Brain Cells

And it did not stop there. Gage, along with Small, went on to extend the green-dot mouse study at Columbia to include humans as well. That was where Kevin Bukowski came in. Piggybacking on an exercise study that was being conducted by his colleague Richard Sloan, a behavior psychologist at Columbia University, Small decided to take a peek at the dentate gyruses of eleven people who were in Sloan’s experiment. (The Sloan study asked whether high-intensity exercise could cut down on markers of inflammation, which can harm cells. It did.)

After Small scanned the brains of the humans, he found pretty much what he’d found in mice. The humans, like Bukowski, who had exercised the most had twice the blood flow as the nonexercisers, and the increase occurred in that crucial memory area, the dentate gyrus.

What’s more, the dentate gyrus blood flow jumped the most in those who became the most fit, as measured by their level of VO2 max, or the maximum amount of oxygen they took in as they exercised, the gold standard for measuring fitness. And that same most-fit group also improved the most in cognitive tests.

“We were not sure what we would see, but it was one of those days when the muses of science were smiling on us,” says Small.

Because the researchers could not cut open Kevin Bukowski’s head, and radioactive substances that tag new cells are now off limits for use with humans, the study did not technically prove that new neurons were born in Bukowski’s brain. They can point to no green dots. Still, because of the striking increase in the level of blood flow—a measure that correlated directly with the growth of brain cells in mice—Small and others feel safe in saying that exercising appears to promote the birth of new brain cells.

“We can’t validate the finding in humans, but by inference we can say that exercise drives neurogenesis,” Small says.

That leaves, of course, the question of what difference any of this means to us. What’s so special about a few more neurons? Can a few brain cells here and there hold off the assault of aging? Put another way, are a handful of baby neurons in something so small and obscure as the dentate gyrus really a good enough reason to turn off the TV and get out on the track?

In fact, when I went to see Gage at his California lab, this was the main question on my mind.

Gage’s office is on the bottom floor of a row of concrete buildings that make up the Salk Institute for Biological Studies in La Jolla. The buildings, with their unadorned style, famously designed by Louis Kahn, make the most of their astonishing setting—on a high isolated bluff overlooking the Pacific Ocean. Inside are dozens of working labs that produce some of the most important biological research in the world.

Despite its prominence, the institute is a surprisingly informal place, with bikes leaning against walls and open-air hallways. After I finally found his office in the maze of concrete, Gage was relaxed and informal. Dressed in a short-sleeved yellow shirt, he was, at age fifty-seven, still trim and athletic and bounded up to greet me with a big handshake and a genial grin.

After we settled into his small office, I asked him, “Why should we care about these baby neurons?”

The question made Gage laugh.

After all, he has spent the last ten years working to prove that new neurons exist at all, an idea, he says, that has only recently reached a point of “growing acceptance.” It takes a strong and energetic mind to take on the next challenging questions of what these new little neurons do, how they do it, and, why, in fact, we should care.

Gage, of course, has just that kind of strong and energetic mind and these are precisely the questions he is now addressing.

“The new brain cells are integrated into the existing circuit, no question,” Gage told me. “But the question now is, how do they do it and why?”

At this point, he still shakes his head over how long it took to convince the scientific community that neurons are, in fact, continually born in grown-up brains. Doubts persisted, he said, because “for the longest time we thought that the brain was like a computer and if you threw a new wire into that existing circuit you would just screw it all up. Now we know that is not the case,” he told me as we sat in his tiny office. “The brain is an organ. It is tissue that is changing all the time and it is regulated by our environment. Our brains are affected by what we do.”

We now know, too, that the new brain cells—which are stem cells, the very earliest and most versatile version of cells—are primarily produced in that tiny area of the hippocampus, the dentate gyrus. We know that about half of the new cells die off and half survive. And we know that they are produced in a variety of ways. We get new neurons when we focus on a task that’s highly complex or even when we’re focused on a specific goal (such concentrated brain activity produces theta waves, the same kind of waves that are produced with meditation—so the claim that theta waves help our brains may not, in fact, be just hype).

And we know that exercise—regular exercise, which includes just about anything that increases heart rate and blood flow—leads to a boomlet of such babies.

“Just look at this,” said Gage, wheeling his chair around to click on his office computer, where a slide appeared. One squiggle of magenta on the screen was the enlarged picture of a mouse hippocampus. On top of that was a sliver of dark blue, the dentate gyrus. Extending out of that sliver were dozens of branches—mature neurons. And scattered among those branches were tiny bright-green dots. The same dots—the same baby neurons—that made believers—and joggers—out of the workers in Scott Small’s lab.

These new brain cells that I was looking at on the computer screen, Gage explained, had been produced in only an hour and a half in the brain of a mouse that had exercised. And seeing those green dots for the first time, I must admit, was impressive, inspirational, even. And this was just one small brain slice from one short moment in the life of one small mouse.

“The thing we have to remember is that neurogenesis is not an event, it’s a process,” Gage said. “And there’s no question, physical activity makes new brain cells proliferate.”

Details, of course, are still being worked out, but Gage is convinced—by his own work and that of others—that exercise produces new brain cells in a fairly straightforward way. When muscles contract, they produce growth factors, with names like VEGF and IGF. Normally, those growth-factor molecules are too large to make it through the blood-brain barrier, but for reasons that are still unknown, exercise makes that barrier more porous, allowing those growth factors, once referred to as Miracle-Gro for the brain, to get through and help stimulate the neurons. (The same thing has been shown to happen with serotonin, which is increased in the brain with exercise and also makes new brain cells grow.)

After that, things get fuzzier. The number of new neurons we produce, as Gage says, “has tremendous genetic variability.” No one knows exactly how many we churn out overall. In all likelihood, it’s a relatively small number, perhaps, Gage says, in the “single digit percentages,” compared with the total number of brain cells.

So what exactly are they doing?

Bringing New and Old Together

Through a complex system of math modeling, backed now with more animal data, Gage has recently developed a new and fascinating theory about newly generated brain cells. He believes that the cells are crucial for our entire lives, and are doing nothing less than “helping us make sense of the world.” In particular, he says, they “help us adapt to the new,” to fold new experiences into our existing view of the world.

“If we were spending our whole lives in this room, we would not need new brain cells,” Gage told me, gesturing toward the walls of his cluttered office. “But the new brain cells help us integrate the new with the old. Without them, we would never want anything to change because anything new would be too complicated.”

When sensory input first comes into the brain—to put all this in its simplest form—it goes to its outermost layer, the cortex. The input then travels to the hippocampus, which consolidates information, memories, and learning. The hippocampus binds the varied sensory experiences together into a sensible chunk—and then sends that back to the cortex for long-term memory storage.

But before the information even gets to the central hippocampus, it is first filtered by the gatekeeping dentate gyrus, which is thought to perform an opposite task—it breaks sensations into even smaller pieces. It is, as Gage puts it, “a pattern separator.” Brain cells in the dentate take note of subtle differences and similarities—a leaf a bit greener, tea slightly hotter. Mature brain cells in the dentate encode those minute differences and pass them on to the hippocampus.

So how do baby neurons fit into all that? Initially, Gage believed that the new cells—since they’re formed in the dentate—must somehow help it do its job, that is, break up information. But, Gage told me almost proudly, “I was really wrong.”

Instead, it now appears that new neurons may actually act to tie disparate information together—and place that information in a specific time frame. Gage now believes that new neurons help us make associations. If we hear a Beach Boys song and smell the salt from the beach, those two impressions—Beach Boys song and salt smell—will be forever tied together in time and place. In fact, the more neurogenesis you have, Gage says, “the more you link together things that are different” into a pattern that will hang together in your brain.

Our memories are notoriously unreliable, in part because we are constantly pulling up old memories and “retagging” them with new information, then restoring the memory in a modified form. Baby neurons, Gage believes, help us with that process, tying together different sensations that occur at the same time—and helping us fit the new with the old, the song we know with the sand we are sitting on.

With chronic stress, new neuron production is slowed or grinds to a halt. To explain this, Gage uses an example of a soldier in Iraq with post-traumatic stress disorder, PTSD. Imagine, Gage said, that “you have a soldier in Iraq and he is under chronic stress and therefore not producing new neurons. [Then there’s a] stark event, say, he sees his buddy’s head blown off.”

If neurogenesis were occurring, even that stark event would—when the soldier recalled it later—be retagged with new information and the soldier might be able to soften the memory by mixing it with more random—and gentler—everyday sensations and information before it is restored as a less upsetting memory.

“Neurogenesis links different things together and that helps us generalize experiences and rationalize them,” Gage explained. Without a stream of new neurons, Gage believes, such a memory would be stored only in mature brain cells and there it would stay—“the event would stay as the event,” as stark and real as it was.

Gage thinks this is one way that talk therapy might work. If we recall bad memories in a safer environment—and if we are not under stress and new neurons are being produced—those memories will be mingled with gentler thoughts—nice office, calm therapist, flowers on the table—and that may be what helps us make sense of—and live with—some of our most disturbing memories over time.

Gage has also developed a model of how all this might happen. In essence, when input comes into mature neurons, it’s encoded. But that encoding is then quickly halted by a neurotransmitter that inhibits brain activity, GABA. If the encoding were not stopped at some point, the older neuron would be constantly readjusting to new information.

But new baby neurons are set up quite differently. For the first seven days of their life, before they have formed connections with other neurons, Gage says, they are actually excited by GABA, rather than shut down. That means that as they are born, they will soak up some GABA from nearby mature neurons, and get excited at the very nanosecond that older neurons are both being activated and then shutting down.

As a result, the new baby neurons encode information from all their neighboring mature neurons—salt, sand, song—tying it all together in time in a mixed memory that stays with us until it resurfaces and is remixed and restored again. The new neurons have time-stamped memories.

This idea is still unproven, of course, but it is—perhaps not surprisingly, given its source—an elegant and compelling one.

Gage believes this may be the way that neurogenesis can alleviate depression, helping us maintain interest in our world. When we get sick we often become immobile, and with “that lethargy we stop producing new neurons, leaving us both less cognitively aware and depressed,” he says.

After all, he adds, “what is depression but a lack of interest in the new, the feeling ‘Is that all there is?’ We need new neurons to help us adapt to the new, to put it in context. Sometimes to get excited about things, you have to recognize how this cool new thing is like other cool things we knew about in the past. Neurogenesis helps us do that.”

In Gage’s view, in fact, the whole system might have developed to allow us to deal with the new. While this, he admits, is getting into the often fuzzy area of evolutionary theory, again, it is such an interesting thought that it seems worth mentioning.

“Just think about it,” Gage said. “As soon as the primitives walked out toward the savanna, the walking would have stimulated the production of new neurons that they would need to prepare for their new environment, to adapt to it and integrate it with their old environment.”

There is little question that in general neurogenesis declines with age, sometimes starting in middle age. But we also now know that, as Gage puts it, “the cells are there and we can reactivate” the process.

But we need to get up out of our chairs. Indeed, Gage is such a believer in the power of exercise to keep those baby brain cells blooming that he runs “a lot” so he will then be able to play squash “with the young guys” four or five times a week. He and his wife try to walk whenever they can. And he recommends we all at least try to do something for thirty minutes a day—to get that dentate gyrus up and pumping and get our dose of fresh new neurons.

“This is not about finding a drug,” he said. “This is a lifestyle thing. The drug companies don’t like to hear that, but we can affect what happens in our brains with what we do.”

Boosting Brain Volume

There’s also emerging evidence that exercise helps the brain in more global ways as well. It’s still uncertain how much exercise a brain needs, or, as one scientist said to me: “In exercise, we don’t yet know the dosage.” By and large it appears that anything that increases your heart rate helps.

But that doesn’t mean you have to sign up for the New York City Marathon. And for that bit of good news, we can thank Art Kramer, the neuroscientist at the University of Illinois at Urbana-Champaign. Kramer is interested in the exercise-brain connection not only as a top scientist but also as a middle-aged man with a worrisome family history. Always a bit of a jock, Kramer boxed as a young man, then moved on to running and track, and now tries to get onto the stationary bike when he can. He also plays a game of squash that smashes twenty-year-olds.

Still, his father died young, and if he did not take drugs to control it, his cholesterol would be about 400. Like most of us reaching the middle of our lives, Kramer is concerned. Is he doing enough? Should he exercise more? Does any of this make any difference?

“It doesn’t matter how long we can live, it matters how long we can keep going functionally,” Kramer pointed out, quite logically, when I spoke with him recently. And so what are we to do to keep functioning well, and prove, with solid science, that what we’re doing really works? So far, Kramer, doing his part, has found encouraging news about fairly moderate levels of exercise.

In one of his latest studies, published in 2006, for instance, Kramer and his colleagues found that those over age sixty who did regular stints of aerobic exercise for six months had increased brain volumes in their frontal lobes’ gray matter, which includes the neurons, and in the white matter of their corpus callosum, the nerve bridge that connects right brain to left brain—and whose age-linked deterioration has been associated with slower thinking.

The exercise in this case was a fairly mundane program of brisk walking. Those who spent about an hour walking around a gym three times a week—at a pace of three miles an hour—had brain volumes of people three years younger.

“Significant increases in brain volume, in both gray and white matter regions, were found as a function of fitness training for the older adults who participated in the aerobic fitness training but not for the older adults who participated in the stretching and toning [nonaerobic] control group,” Kramer concluded in the study in the Journal of Gerontology.

“These results suggest that cardiovascular fitness is associated with the sparing of brain tissue in aging humans. Furthermore, these results suggest a strong biological basis for the role of aerobic fitness in maintaining and enhancing central nervous system health and cognitive function in older adults.”

That impressive study came after a stream of similar research by Kramer and his colleagues. One study in 2003 found that those over age sixty who exercised regularly—again, that meant aerobic exercise such as running or walking quickly—had less brain tissue loss than non-exercisers. And in a study published in 1999 in the prominent science journal Nature, Kramer reported that a group of 124 relatively unfit people over age sixty, after walking rapidly (17.7 minutes per mile) for forty-five minutes three days a week (and especially those who managed to get up to a mile-long loop around the university at a good clip of 16 minutes per mile) were much better at complex tests, in particular those that involved “task switching,” the same frontal-lobe challenge that faced Mark Moss’s middle-aged monkeys. For the humans in Kramer’s study, this test also involved rapidly answering questions such as “Is this an odd or even number?”

The exercisers were also better at focusing and ignoring irrelevant information. Such frontal-lobe executive functions, as we’ve said, are crucial for a whole range of everyday activities, especially when we have to do two things at once.

Kramer’s studies also mirror solid tests in animals over recent years, including one at Oregon Health & Science University that found that monkeys that ran on a treadmill for five days a week for twenty weeks had much higher blood volume in their brains’ capillaries than sedentary monkeys—and it was the oldest and least fit monkeys that had the biggest gains. As Kramer says: “We know from all this research that there are a few good things for the brain—and one is exercise.”

Kramer says that he, too, is still not completely sure how all this happens in the brain and is now probing deeper to see if he can find more clues. It could be the dentate gyrus and it could be a combination of effects in the brain. “What all this precisely means on a molecular level we just don’t know but we can speculate,” Kramer says.

“We want to know what the nature of the volume change is,” he told me. “Is it the growth of blood vessels or the number of synapses or white matter or gray matter? We just don’t know yet.”

When I last spoke with him, he had decided to extend his human walkers’ study and then take their blood to see what genes are modulated and “who does better and why.” He will also check the participants’ blood for the presence of markers for inflammation linked to cardiovascular problems and possibly Alzheimer’s (a number of conditions, including obesity and smoking, are now thought to produce a kind of low level of chronic inflammation in the body, which over time may wear down cell defenses and lead to disease).

If he could, Kramer would love to do a spinal tap on volunteers and look for nerve growth factor, the Miracle-Gro, in the nervous system of study participants, but that’s not something one does with living humans. “We can’t get a slice of their hippocampuses, either,” he said, a bit sadly. Still, the thought that something as simple as exercise can have real benefits for our brains is just the kind of optimistic thought that may very well appeal to our positive-seeking middle-aged brains.

And it’s an idea that now makes perfect sense to people like Kevin Bukowski. Having ignored his brain for years—much like the rest of us—he is now giving it much more respect. Like most of us in middle age, Bukowski is busy. He has a demanding job, assisting and coordinating scientific trials at a major medical center. He has a seven-year-old daughter. He is taking care of his mother. But at age forty-seven, he feels somehow sharper and “calmer . . . there is a maturity factor there now.

“I just feel now at my age that I am doing a lot. But I feel I can really handle it all now and that makes me feel good. It is kind of surprising but here I am at middle age and it’s not bad; in fact, I feel more secure knowing I can deal with all this.”

But he is also now convinced that to maintain all that, he has to stay on the treadmill. And so he is setting out to do what he can. He is training his middle-aged body and brain—for a triathlon.