The Greatest Challenge

SUSAN WAS STRESSED out. It had been more than a year since the remodeling contractor had taken over her kitchen, yet she had begun to fear the interludes of silence more than the construction racket itself. Silence meant work had stopped, for whatever reason, and that meant the job would take even longer. She had no idea when she would get her kitchen back, let alone her life. It was terribly unsettling, as anyone who has survived a remodeling project can attest: strangers traipsing in and out all day, no control over your time, sheetrock dust everywhere — utter confusion. All the while, the contractor himself seems perfectly at home in your house, if and when he shows up.

A woman in her forties, Susan had always been an active, outgoing person: mother of three school-age boys, head of the PTA, an equestrian, a professional volunteer with a full schedule of commitments. But suddenly she was forced to stick around the house all day, waiting for the workmen to arrive, often only to have them cancel. It was enough to drive anyone batty. She was a shut-in in her own ripped-up home, and she didn’t know what to do with herself. To take the edge off, she started having a glass of wine. And then another. Before long, she found herself uncorking a nice chardonnay before lunchtime. “Always chardonnay,” she says. “It’s the only thing I drink.”

Susan’s world was shrinking, and so too, as I’ll explain, was her brain. She came in to see me because she was worried that her coping mechanism was becoming an addiction. As she sat in my office, we discussed ways she could break the cycle of reaching for the wine whenever she felt stressed. I wanted to help her find something she could do immediately, right at home, first to distract her, but also to relieve the feeling of stress. She wasn’t much for the gym, but she was fairly athletic, and somehow it came out that she liked to jump rope. Perfect. I suggested she start jumping rope every time she felt the stress coming on.

The next time I saw her, she told me she had jump ropes stashed on different floors of the house, and she’d been able to stop using wine to relieve her stress. Even with just those short bursts of activity, she immediately felt more in control, like the master of her own fate. She also felt a genuine relief — less tension in her muscles and less distracting activity in her mind. She explains it this way: “I feel like it kind of reboots my brain.”


Everyone knows stress, but do they really? It comes in many shapes and sizes, acute and chronic — social stress, physical stress, metabolic stress, to name a few. Most people use the word indiscriminately for both cause and effect. That is, the stress the world exerts upon us — “There is a lot of stress at work right now” — as well as the feeling we get inside when everything seems like too much: “I’m so stressed, I can’t think straight.” Scientists themselves don’t always distinguish between the psychological state of stress and the physiological response to stress.

Stress is such a malleable term partly because the feeling can span a wide emotional range, from a mild state of alertness to a sense of being completely overwhelmed by the push and pull of life. At the far end of the spectrum is what you know as being stressed out — a lonely place where issues that might ordinarily seem like challenges take on the proportions of insurmountable problems. Stay there too long, and we’re talking about chronic stress, which translates emotional strain into physical strain. This is where the ripple effects of the body’s stress response can lead to full-blown mental disorders such as anxiety and depression, as well as high blood pressure, heart problems, and cancer. Chronic stress can even tear at the architecture of the brain.

But how to make sense of such a woolly concept as stress? By keeping in mind its biological definition. Above all, stress is a threat to the body’s equilibrium. It’s a challenge to react, a call to adapt. In the brain, anything that causes cellular activity is a form of stress. For a neuron to fire, it requires energy, and the process of burning fuel creates wear and tear on the cell. The feeling of stress is essentially an emotional echo of the underlying stress on your brain cells.

You probably wouldn’t think of getting out of a chair as stressful — it doesn’t feel stressful — but, biologically speaking, it most definitely is. It doesn’t compare with, say, losing a job, but here’s the thing: Both events activate parts of the same pathways in the body and the brain. Standing up triggers neurons needed to coordinate the movement, and dreading unemployment generates plenty of activity, since emotions are a product of neurons signaling one another. Likewise, learning French, meeting new people, and moving your muscles all make demands on your brain; all are forms of stress. As far as your brain is concerned, stress is stress — the difference is in degree.


How the body and brain respond to stress depends on many factors, not the least of which is your own genetic background and personal experience. Today there is an ever-widening gap between the evolution of our biology and our society. We don’t have to run from lions, but we’re stuck with the instinct, and the fight-or-flight response doesn’t exactly fly in the boardroom. If you get stressed at work, would you slap your boss? Or turn and run? The trick is how you respond. The way you choose to cope with stress can change not only how you feel, but also how it transforms the brain. If you react passively or if there is simply no way out, stress can become damaging. Like most psychiatric issues, chronic stress results from the brain getting locked into the same pattern, typically one marked by pessimism, fear, and retreat. Active coping moves you out of this territory. Instincts aside, you do have some control over how stress affects you. And, as Susan would agree, control is key.

Exercise controls the emotional and physical feelings of stress, and it also works at the cellular level. But how can that be, if exercise itself is a form of stress? The brain activity caused by exercise generates molecular by-products that can damage cells, but under normal circumstances, repair mechanisms leave cells hardier for future challenges. Neurons get broken down and built up just like muscles — stressing them makes them more resilient. This is how exercise forces the body and mind to adapt.

Stress and recovery. It’s a fundamental paradigm of biology that has powerful and sometimes surprising results.

In the 1980s, the U.S. Department of Energy (DOE) commissioned a study on the health impacts of sustained radiation exposure. They compared two groups of nuclear shipyard workers from Baltimore who had similar jobs except for a single key difference: one group was exposed to very low levels of radiation from the materials they handled, and the other was not. The DOE tracked the workers between 1980 and 1988, and what they found shocked everyone involved.

Radiation made them healthier. The twenty-eight thousand workers exposed to radiation had a 24 percent lower mortality rate than their thirty-two thousand counterparts who were not exposed to radiation. Somehow, the toxins that everyone assumed and feared were ruining the workers’ health were doing just the opposite. Radiation is a stress in that it damages cells, and at high levels it kills them and can lead to the development of diseases such as cancer. In this case, the radiation dose was apparently low enough that instead of killing the cells of the exposed workers, it made them stronger.

Maybe stress isn’t so bad after all. But because the study “failed” — it didn’t show the expected malignant effect of radiation — it was never published. From what we’ve since learned about the biology of stress and recovery, stress seems to have an effect on the brain similar to that of vaccines on the immune system. In limited doses, it causes brain cells to overcompensate and thus gird themselves against future demands. Neuroscientists call this phenomenon stress inoculation.

What’s gotten lost amid all the advice about how to reduce the stress of modern life is that challenges are what allow us to strive and grow and learn. The parallel on the cellular level is that stress sparks brain growth. Assuming that the stress is not too severe and that the neurons are given time to recover, the connections become stronger and our mental machinery works better. Stress is not a matter of good and bad — it’s a matter of necessity.


Triggered by a primitive call to survive, the body’s stress response is a built-in gift of evolution without which we wouldn’t be here today. The response ranges from mild to intense depending on the cause. Severe stress activates the emergency phase, commonly known as the fight-or-flight response. It’s a complex physiological reaction that marshals resources to mobilize body and brain, and engraves a memory of what happened, so we can avoid it next time. Where was that lion, exactly? The threat has to be fairly intense for the body to get involved, but any degree of stress activates fundamental brain systems — those that manage attention, energy, and memory. If we strip away everything else, our ingrained reaction to stress is about focusing on the danger, fueling the reaction, and logging in the experience for future reference, which I think of as wisdom. It is only in recent years that scientists have begun to recognize and describe the role of stress in the formation and recall of memories. The development of this understanding is exciting because it sheds light on why — (and how) — stress can have such a profound effect on the way we perceive the world.

The fight-or-flight response calls into action several of the body’s most powerful hormones and scores of neurochemicals in the brain. The brain’s panic button, called the amygdala, sets off the chain reaction on receiving sensory input about a possible threat to the body’s natural equilibrium. Being hunted would certainly qualify, but so would being the hunter. The amygdala’s job is to assign intensity to the incoming information, which may or may not be obviously survival related. It’s not just about fear, but any intense emotional state, including, for example, euphoria or sexual arousal. Winning the lottery or dining with a supermodel can trigger the amygdala. These events may not seem stressful, but remember, our brains don’t distinguish between “good” and “bad” demands on the system. And in an evolutionary light, good fortune and a good date are related to survival — prospering and procreating.

The amygdala connects to many parts of the brain and thus receives a wide array of input — some of it routed through the high-level processing center of the prefrontal cortex, and some of it wired indirectly, bypassing the cortex, which explains how even a subconscious perception or memory can trigger a stress response.

Within ten milliseconds of sounding the alarm, the amygdala fires off messages that cause the adrenal gland to release different hormones at different stages. First, norepinephrine triggers lightning-fast electrical impulses that travel through the sympathetic nervous system activate the adrenal gland to dump the hormone epinephrine, or adrenaline, into the bloodstream. Heart rate, blood pressure, and breathing increase, contributing to the physical agitation we feel under stress. At the same time, signals carried by norepinephrine and corticotropin-releasing factor (CRF) travel from the amygdala to the hypothalamus, where they are handed off to messengers that take the slow train through the bloodstream. These messengers prompt the pituitary gland to activate another part of the adrenal gland, which releases the second major hormone of the stress response: cortisol. This relay from the hypothalamus to the pituitary to the adrenal gland is known as the HPA axis, and its role in summoning cortisol and in turning off the response makes it a key player in the story of stress. Meanwhile, the amygdala has signaled the hippocampus to start recording memories and another dispatch has been sent to the prefrontal cortex, which decides whether the threat truly merits a response.

Humans are unique among animals in that the danger doesn’t have to be clear and present to elicit a response — we can anticipate it; we can remember it; we can conceptualize it. And this capacity complicates our lives dramatically. “The mind is so powerful that we can set off the [stress] response just by imagining ourselves in a threatening situation,” writes Rockefeller University neuroscientist Bruce McEwen in his book The End of Stress as We Know It. In other words, we can think ourselves into a frenzy.

There is an important flip side to McEwen’s point: We can literally run ourselves out of that frenzy. Just as the mind can affect the body, the body can affect the mind. But the idea that we can alter our mental state by physically moving still has yet to be accepted by most physicians, let alone the broader public. It’s a fundamental theme of my work, and it’s particularly relevant in the context of stress. After all, the purpose of the fight-or-flight response is to mobilize us to act, so physical activity is the natural way to prevent the negative consequences of stress. When we exercise in response to stress, we’re doing what human beings have evolved to do over the past several million years. On one level, it’s that simple. Of course, there are many levels to explore.


The overarching principle of the fight-or-flight response is marshaling resources for immediate needs in lieu of building for the future — act now, ask questions later. The hormonal rush of epinephrine focuses the body, increasing heart rate and blood pressure and dilating the bronchial tubes of the lungs to carry more oxygen to the muscles. Epinephrine binds to muscle spindles, and this ratchets up the muscles’ resting tension so they’re ready to explode into action. Blood vessels in the skin constrict to limit bleeding in the event of a wound. Endorphins are released in the body to blunt pain. In this scenario, biological imperatives like eating and reproduction are put on the back burner. The digestive system shuts down; the muscles used to contract the bladder relax so as not to waste glucose; and saliva stops flowing.

If you’ve ever faced a nerve-racking public-speaking situation, you’ve experienced this shift in the form of a racing heart and cotton mouth. Your muscles and your brain get stiff, and you lose all hope of being flexible and engaging. Or, if the processed signal from the cortex to the amygdala breaks up, you can’t think and you freeze. Technically, the full-blown stress response should be called “freeze or fight or flight.” None of this is particularly helpful when you’re up at the podium, but the body responds in essentially the same way whether you’re staring down a hungry lion or a restless audience.

Two neurotransmitters put the brain on alert: norepinephrine arouses attention, then dopamine sharpens and focuses it. An imbalance of these neurotransmitters is why some people with attention-deficit/hyperactivity disorder (ADHD) come across as stress junkies. They have to get stressed to focus. It’s one of the primary factors in procrastination. People learn to wait until the Sword of Damocles is ready to fall — it’s only then, when stress unleashes norepinephrine and dopamine, that they can sit down and do the work. A need for stress also explains why ADHD patients sometimes seem to shoot themselves in the foot. When everything is going well, they need to stir up the situation, and they subconsciously find a way to create a crisis. I have one patient who, after a series of dysfunctional relationships, finally found a guy she really admires and who treats her well. Yet every time things are good, she picks a fight. Reminding her of the stress-junkie pattern helps her to be aware of her tendencies and — I hope — catch herself before she starts trouble.


To fuel the anticipated activity of the muscles and the brain, epinephrine immediately begins converting glycogen and fatty acids into glucose. Traveling through the bloodstream, cortisol works more slowly than epinephrine, but its effects are incredibly widespread. Cortisol wears a number of different hats during the stress response, one of which is that of traffic cop for metabolism. Cortisol takes over for epinephrine and signals the liver to make more glucose available in the bloodstream, while at the same time blocking insulin receptors at nonessential tissues and organs and shutting down certain intersections so the fuel flows only to areas important to fight-or-flight. The strategy is to make the body insulin-resistant so the brain has enough glucose. Cortisol also begins restocking the shelves, so to speak, replenishing energy stores depleted by the action of epinephrine. It converts protein into glycogen and begins the process of storing fat.

If this process continues unabated, as in chronic stress, the action of cortisol amasses a surplus fuel supply around the abdomen in the form of belly fat. (Unrelenting cortisol also explains why some marathon runners carry a slight paunch despite all their training — their bodies never get a chance to adequately recover.) The problem with our inherited stress response is that it mobilizes energy stores that don’t get used. More on that later.

During the initial phase of the stress response, cortisol also spurs the release of insulin-like growth factor (IGF-1), which is a crucial link in fueling the cells. The brain is a conspicuous consumer of glucose, using 20 percent of the available fuel even though it accounts for only about 3 percent of our body weight. But it has no capacity to store fuel, so cortisol’s role in providing a steady flow of glucose is critical to proper brain function. Operating on a fixed budget of fuel, the brain has evolved to shift energy resources as necessary, meaning that mental processing is competitive. It’s simply not possible to have all of our neurons firing at once, so if one structure is active, it must come at the expense of another. One of the problems with chronic stress is that if the HPA axis is guzzling all the fuel to keep the system on alert, the thinking parts of the brain are being robbed of energy.


Recording memories of stressful situations is an adaptive behavior with obvious evolutionary benefits. It’s the wisdom of our collective experience that has allowed us to survive, and cortisol has played a major role. Neuroendocrinologist Bruce McEwen first found cortisol receptors in the hippocampus in rat brains in the 1960s, and then in rhesus monkeys, and now we know they exist in humans. The finding initially alarmed scientists because the stress hormone had been shown to be toxic to brain cells in a petri dish. “What is cortisol actually doing to affix these memories?” he asks. “All we can say is that if you don’t have adequate cortisol receptors in the hippocampus at the time these memories are being formed, the learning process is less efficient. The exact details are still being worked out.”

It seems that, like stress itself, cortisol isn’t simply good or bad. A little bit helps wire in memories; too much suppresses them; and an overload can actually erode the connections between neurons and destroy memories. The hippocampus provides context for the memory — the what, how, where, and when — and the amygdala provides the emotional content — the fear or the excitement. With direction from the prefrontal cortex, the hippocampus can compare memories and say, “Don’t worry; it’s a stick, not a snake,” and so has the capacity to shut off the HPA axis directly and put an end to the stress response. As long as it’s not overexcited.

Within minutes of the alarm bell, cortisol, CRF, and norepinephrine — the major stress agents in the brain — bind to cell receptors that boost glutamate, the excitatory neurotransmitter responsible for all of the signaling in the hippocampus. Increasing glutamate activity speeds up the flow of information in the hippocampus and changes the dynamic at the synapses, so that each time a message is sent, the signal fires more easily, thus requiring less glutamate. Initially, then, the stress response enhances long-term potentiation (LTP), the fundamental mechanism of memory.

Short-term memory probably results from this initial increase in the excitability of hippocampal neurons. Then, as levels of cortisol peak, cortisol turns on genes inside the cells that make more proteins used as building material for cells: more dendrites, more receptors, and bulkier synapses. This is where things get curious. The beefed-up cells cement the survival memory and shield the neurons in that circuit from other demands. A neuron might be part of any number of memories. But if a potential memory comes along during stress, it has a more difficult time recruiting neurons to be part of its own new circuit. It needs to clear a certain threshold to make an impression.

This likely explains why memories not related to the stressor are blocked during the stress response. It also helps explain why constantly high levels of cortisol — due to chronic stress — make it hard to learn new material, and why people who are depressed have trouble learning. It’s not just lack of motivation, it’s because the hippocampal neurons have bolstered their glutamate machinery and shut out less important stimuli. They’re obsessed with the stress.

Human studies also show that excess cortisol can block access to existing memories, which explains how people can forget where the fire exit is when there’s actually a fire — the lines are down, so to speak. With too much stress, we lose the ability to form unrelated memories, and we might not be able to retrieve the ones we have. The next time you’re forced to participate in a fire drill, consider that the neurological point of the exercise is to make those circuits stronger, to burn in the memory. With an overload of stress, as I’ll explain later, you get the petri dish effect — cortisol eroding neurons.


The stress response is elegantly adaptive behavior, but because it doesn’t get you very far in today’s world, there’s no outlet for all that energy buildup. You have to make a conscious effort to initiate the physical component of fight or flight.

The human body is built for regular physical activity, but how much? In a 2002 article in the Journal of Applied Physiology, researchers studied this very question, by looking at our ancestors’ pattern of physical activity, which they call the Paleolithic rhythm. From the time Homo sapiens emerged two million years ago, until the agricultural revolution, ten thousand years ago, everyone was a hunter-gatherer, and life was marked by periods of intense physical activity followed by days of rest. It was feast or famine. By calculating how much our forebears “exercised” and comparing it to figures from today, it’s easy to see where the problem lies: Our average energy expenditure per unit of body mass is less than 38 percent of that of our Stone Age ancestors. And I think it’s fair to say that our calorie intake has increased quite a bit. The kicker is that even if we followed the most demanding governmental recommendations for exercise and logged thirty minutes of physical activity a day, we’d still be at less than half the energy expenditure for which our genes are encoded. Paleolithic man had to walk five to ten miles on an average day, just to be able to eat.

Today we don’t have to expend much energy to find food, and we certainly don’t have to use our brains to figure out how to get our next meal. This situation has come about only in the past century or so, but it takes tens of thousands of years for our biology to evolve — there’s a mismatch between our lifestyle and our genes. Human genes are thrifty by nature, so we end up stockpiling calories while we’re sitting at our desks.

In the context of stress, the great paradox of the modern age may be that there is not more hardship, just more news — and too much of it. The 24/7 streaming torrent of tragedy and demands flashing at us from an array of digital displays keeps the amygdala flying. The negative and the hectic and the hopeless heap on the stress, but we figure we can handle it because we always have. Up to a point. Then, we just want to relax and take a break, so we grab a drink and plop down in front of the TV or go sit on a beach somewhere. It’s no wonder that obesity has doubled in the past twenty years — our lifestyle today is both more stressful and more sedentary.

Maybe you’ve seen ads for drugs that slim down the belly by blocking cortisol. The belly is just doing its job, stockpiling energy stores as insurance against the next famine. With chronic stress, that stockpile ends up around the midsection, in the form of a spare tire. This is detrimental not only to our physique, but also to our health, because fat stores can easily make their way into the arteries of the heart and cause blockage. For anyone skeptical of the notion that stress can kill, herein lies one of the physical links between stress and heart attacks.

Compounding the buildup of fat, after a stressful event, we often crave comfort foods. Our body is calling for more glucose, and simple carbohydrates and fat — like those glistening in a box of Dunkin’ Donuts — are readily converted into fuel. And in modern life, people tend to have fewer friends and less support, because there’s no tribe. Being alone is not good for the brain.

A common protocol scientists use to induce the physiological stress response in rats is to remove them from their social structure; simply isolating them activates stress hormones. The same is true in humans: It’s stressful to be shunned or isolated. Loneliness is a threat to survival. Not coincidentally, the less physically active we are, the less likely we’ll be to reach out and touch someone. Studies show that by adding physical activity to our lives, we become more socially active — it boosts our confidence and provides an opportunity to meet people. The vigor and motivation that exercise brings helps us establish and maintain social connections.

There’s nothing wrong with your desire to take a break. The issue is how you choose to spend that time. It’s the comfort foods, the quick fats and sugars, the alcohol to take the edge off, or, for some people, drugs or other addictions that cause problems. If you exercise or even just socialize, you’re tapping into the evolutionary antidote to stress.

Sometimes it’s a simple matter of substitution, as my patient Susan can attest. She doesn’t always jump rope religiously, but when she lapses, she reminds herself of how the exercise makes her feel. “When I do get into a good routine of exercise, it replaces that exhilarating feeling or that sense of well-being I get if I drink wine or eat or something,” she says. “It replaces whatever that desire or craving is, that thing in the brain. And then it frees me up to think beyond that and look to the future.”


It’s well known that the way to build muscles is to break them down and let them rest. The same paradigm applies to nerve cells, which have built-in repair and recovery mechanisms activated by mild stress. The great thing about exercise is that it fires up the recovery process in our muscles and our neurons. It leaves our bodies and minds stronger and more resilient, better able to handle future challenges, to think on our feet and adapt more easily.

Regular aerobic activity calms the body, so that it can handle more stress before the serious response involving heart rate and stress hormones kicks in. It raises the trigger point of the physical reaction. In the brain, the mild stress of exercise fortifies the infrastructure of our nerve cells by activating genes to produce certain proteins that protect the cells against damage and disease. So it also raises our neurons’ stress threshold.

The cellular stress-and-recovery dynamic takes place on three fronts: oxidation, metabolism, and excitation.

When a nerve cell is called into action, its metabolic machinery switches on like the pilot light in a furnace. As glucose is absorbed into the cell, mitochondria turn it into adenosine triphosphate (ATP) — the main type of fuel a cell can burn — and just as with any energy conversion process, waste by-products are produced. This is oxidative stress. Under normal circumstances, the cell also produces enzymes whose job it is to mop up waste such as free radicals, molecules with a rogue electron that rupture the cell structure while careening around trying to neutralize the electron. These protective enzymes are our internal antioxidants.

Metabolic stress happens when the cells can’t produce adequate ATP, either because glucose can’t get into the cell or because there’s not enough of it to go around.

Excitotoxic stress occurs when there is so much glutamate activity that there isn’t enough ATP to keep up with the energy demand of the increased information flow. If this continues for too long without recovery, there’s a problem. The cell is on a death march — forced to work without food or resources to repair the damage. The dendrites begin to shrink back and eventually cause the cell to die. This is neurodegeneration, the mechanism underlying diseases such as Alzheimer’s, Parkinson’s, and even aging itself. It’s largely through intensive study of these diseases that scientists have discovered the body’s natural countermeasures to cellular stress.

And this explains why Mark Mattson, who is chief of the neurosciences lab at the National Institute on Aging, is so stingy with the food for his lab rats. In many of his experiments, Mattson uses dietary restriction to cause mild cellular stress — there isn’t enough glucose to produce adequate amounts of ATP — and he’s found that mice and rats that are given a third of their normal calories live up to 40 percent longer than average. His work has helped identify protective molecules unleashed during various types of stress, including aerobic exercise.

Some of the most powerful ingredients in the cascade of repair molecules are the growth factors brain-derived neurotrophic factor (BDNF), IGF-1, fibroblast growth factor (FGF-2), and vascular endothelial growth factor (VEGF), which I discussed in chapter 2. BDNF is of particular interest to stress researchers because of its dual role in energy metabolism and synaptic plasticity. It’s activated indirectly by glutamate, and it increases the production of antioxidants in the cell as well as protective proteins. And as I’ve mentioned, it also stimulates LTP and the growth of new nerve cells, strengthening the brain against stress. The advantage of using exercise to inoculate the brain against stress is that it ramps up growth factors more than other stimuli do. In addition to being produced in the brain, FGF-2 and VEGF are also generated by muscle contractions and then travel through the bloodstream into the brain to further support the neurons. This process is a prime example of how the body affects the mind.

The growth factors represent a key link between stress, metabolism, and memory. “The complexity of our brain evolved mainly so we can compete for limited resources,” Mattson says. “It makes sense that during evolution, organisms had to compete intellectually to figure out how to find food.”

Mattson’s latest work will change the way we look at some of our healthiest foods. An enormous industry has sprung up to promote the cancer-fighting properties of foods and products that contain antioxidants. Eat more antioxidant-rich broccoli, the logic goes, and you’ll live a longer and healthier life. True, perhaps, but not for the reasons the marketing folks would have you believe.

It turns out that these foods are particularly beneficial not only because they contain antioxidants but also because they contain toxins. “Many of the beneficial chemicals in plants — vegetables and fruits — have evolved as toxins to dissuade insects and other animals from eating them,” Mattson explains. “What they’re doing is inducing a mild, adaptive stress response in the cells. For example, in broccoli, there’s a chemical called sulforaphane, and it clearly activates stress response pathways in cells that upregulate antioxidant enzymes. Broccoli has antioxidants, but at the level you could get from your diet, they’re not going to function as antioxidants.”

Just as with the nuclear shipyard workers, a mild toxin generates an adaptive stress response that bolsters cells. It’s the same process generated by dietary restriction and exercise. The title of one of Mattson’s journal articles says it all: “Neuroprotective signaling and the aging brain: Take away my food and let me run.”

Resilience is the buildup of these waste-disposing enzymes, neuroprotective factors, and proteins that prevent the naturally programmed death of cells. I like to think of these elements as armies that remain on duty to take on the next stress. The best way to build them up is by bringing mild stress on yourself: using the brain to learn, restricting calories, exercising, and, as Mattson and your mother would remind you, eating your vegetables. All these activities challenge the cells and create waste products that can be just stressful enough. The paradox is that our wonderful ability to adapt and grow doesn’t happen without stress — we can’t have the good without a bit of the bad.


As with everything in the brain, the stress response depends on a delicate balance of all the ingredients I’ve mentioned (and many, many that I haven’t). If mild stress becomes chronic, the unrelenting cascade of cortisol triggers genetic actions that begin to sever synaptic connections and cause dendrites to atrophy and cells to die; eventually, the hippocampus can end up physically shriveled, like a raisin.

There are a number of scenarios in which the body fails to shut off the flow of stress hormones. The most obvious is simply unrelenting stress. If we never get a break, the recovery process never gets started, the amygdala keeps firing, and the production of cortisol spills over healthy levels. Sometimes the fight-or-flight switch gets stuck in the on position. It can be a function of genetics, according to epidemiological surveys: if you put a random group of people in a stressful public speaking situation, those whose parents suffered from hypertension still show elevated levels of cortisol twenty-four hours after the speech. Or it can be environmental: prenatal rats whose mothers are subjected to repeated stress grow up to have a lower stress threshold than their normal counterparts. Which is to say they get stressed out more easily, both physically and psychologically.

People with low self-esteem also have a lower stress threshold, although scientists aren’t sure which condition precedes the other. And anybody, regardless of their nature and upbringing, will exhibit the ill effects of chronic stress if there is no outlet for frustration, no sense of control, no social support. Essentially, if there is no hope, our brains don’t shut off the response.

Everybody’s threshold for stress is different, and that point can change in response to influences from the environment or our genetics or our behavior or any combination thereof. As with the neurochemistry of the brain, our stress threshold is always changing. While the process of aging naturally lowers the threshold, we can hitch it up quite a few notches through aerobic exercise. There is no specific point at which scientists can say stress shifts from building up to tearing down. But they certainly know the effects when they see them.


Although stress engraves memories important to survival, too much of it cannibalizes the very structure that does the engraving. While cortisol initially encourages LTP by increasing glutamate transmission in the hippocampus, as well as the flow of BDNF, serotonin, IGF-1, and the like, it activates genes that eventually suppress information reaching those same circuits. One grave context trumps a variety of less important ones. The system becomes less flexible, prioritizing along increasingly rigid lines.

A surplus of glutamate also causes physical damage to the hippocampus. The neurotransmitter acts by allowing electron-snatching calcium ions into the cell, and they create free radicals. Without enough antioxidants on patrol, the free radicals punch holes in the walls, and the cell can rupture and die.

Out at the dendrites, there’s trouble too. If the brauches stew too long in the out-of-balance broth of chronic stress, they pull back in an effort to keep the cell from dying, “like a turtle retracting its head,” according to McEwen. And because growth factors and serotonin aren’t flowing, the process of neurogenesis is interrupted. The new stem cells that are born every day don’t turn into new neurons, so there’s a shortage of building material to reroute signals and break the cycle.

Monica Starkman at the University of Michigan studies Cushing’s syndrome, an endocrine dysfunction in which the body is continually flooded with cortisol. The scientific name for the disorder speaks volumes: hypercortisolism. Its symptoms are eerily similar to those of chronic stress: weight gain around the midsection; breaking down muscle tissue to produce unnecessary glucose and then fat; insulin resistance and possibly diabetes; panic attacks, anxiety, depression, and increased risk of heart disease. One of the many correlations Starkman has shown is that the extent of hippocampal shrinkage and memory loss is directly proportional to elevations in cortisol.

While chronic stress is bullying the hippocampus — pruning its dendrites, killing its neurons, and preventing neurogenesis — the amygdala is having a field day. The stress overload creates more connections in the amygdala, which keeps firing and calling for cortisol, even though there’s plenty of the hormone available, and the negative situation feeds on itself. The more the amygdala fires, the stronger it gets. Eventually the amygdala takes control of its partnership with the hippocampus, repressing the context — and thus the connection to reality — and branding the memory with fear. The stress becomes generalized, and the feeling becomes a free-floating sense of fear that morphs into anxiety. It’s as if everything is a stressor, and this colors perception and leads to even more stress. “The animal becomes more anxious even while its cognitive skills are being eroded,” says McEwen.

When you suffer from chronic stress, you lose the capacity to compare the situation to other memories or to recall that you can grab a jump rope and immediately relieve the stress or that you have friends to talk to or that it’s not the end of the world. Positive and realistic thoughts become less accessible, and eventually brain chemistry can shift toward anxiety or depression.

Chronic stress isn’t the only cause of anxiety and depression, and it doesn’t necessarily lead to either of those disorders. But it is clearly at the root of much of our woe, both physiologically and psychologically, and I’ll be returning to the biology of chronic stress throughout the coming chapters.

In a way, the fact that chronic stress underlies many of our problems is great news because we know that how we respond to stress dramatically affects what it does to our bodies and minds. Most of our evolution took place when we were hunter-gatherers, and while there’s nothing we can do about that, there is something we can do with that knowledge. As McEwen writes in The End of Stress as We Know It, “It’s not inevitable or normal for the very system designed to protect us to become a threat in itself.”


You know by now that the function of the brain is to transmit information, from one synapse to the other, and that this requires energy. Likewise, since exercise influences metabolism, it serves as a powerful way to influence synaptic function, and thus the way we think and feel. Throughout the body, exercise increases blood flow and the availability of glucose, the essentials for cell life. More blood carries more oxygen, which the cells need to convert glucose to ATP and feed themselves. The brain shifts blood flow from the frontal cortex to the middle brain, home to the structures we’ve talked so much about, the amygdala and hippocampus. This mode of prioritizing might explain why researchers have found that higher cognitive functions are impaired during intense exercise.

It’s what happens after exercise that optimizes the brain. In addition to raising the fight-or-flight threshold, it kick-starts the cellular recovery process I have described. Exercise increases the efficiency of intercellular energy production, allowing neurons to meet fuel demands without increasing toxic oxidative stress. We do get waste buildup, but we also get the enzymes that chew it up, not to mention a janitorial service that disposes of broken bits of DNA and other by-products of normal cellular use and aging — both of which are thought to help prevent the onset of cancer and neurodegeneration. And while exercise induces the stress response, if the activity level isn’t extreme, it shouldn’t flood the system with cortisol.

One of the ways exercise optimizes energy usage is by triggering the production of more receptors for insulin. In the body, having more receptors means better use of blood glucose and stronger cells. Best of all, the receptors stay there, which means the newfound efficiency gets built in. If you exercise regularly, and the population of insulin receptors increases if there is a drop in blood sugar or blood flow, the cell will still be able to squeeze enough glucose out of the bloodstream to keep working. Also, exercise increases IGF-1, which helps insulin manage glucose levels.

In the brain, IGF-1 doesn’t have as much to do with getting energy into the cells as it does with regulating glucose throughout the body. What’s fascinating is that in the hippocampus, IGF-1 increases LTP, neuroplasticity, and neurogenesis. It’s another way exercise helps our neurons bind. Exercise also produces FGF-2 and VEGF, which build new capillaries and expand the vascular system in the brain. More and bigger highways means more efficient blood flow.

At the same time, aerobic exercise increases BDNF production. Taken all together, these factors combine forces to make the brain bloom and prevent the damaging effects of chronic stress from taking hold. In addition to cranking up the cellular repair mechanisms, they also keep cortisol in check and increase the levels of our regulatory neurotransmitters serotonin, norepinephrine, and dopamine.

On a mechanical level, exercise relaxes the resting tension of muscle spindles, which breaks the stress-feedback loop to the brain. If the body isn’t stressed, the brain figures maybe it can relax too. Over time, regular exercise also increases the efficiency of the cardiovascular system, lowering blood pressure. Cardiologists have recently discovered that a hormone called atrial natriuretic peptide (ANP), which is produced by muscle tissue in the heart, directly tempers the body’s stress response by putting the brakes on the HPA axis and quelling noise in the brain. What’s so interesting about ANP is that it increases as the heart rate increases during exercise, thus illustrating another pathway by which physical activity relieves both the feeling of stress and the body’s response to it.

The stress of exercise is predictable and controllable because you’re initiating the action, and these two variables are key to psychology. With exercise, you gain a sense of mastery and self-confidence. As you develop awareness of your own ability to manage stress and not rely on negative coping mechanisms, you increase your ability to “snap out of it,” so to speak. You learn to trust that you can deal with it — an extremely important factor for my patient Susan; by jumping rope she inhibits the feeling of stress and the runaway brain activity that can go along with it. “Knowing my brain chemistry — that is the best for me,” Susan says. “It’s my motivation to get out there. Once I’m in a good place, that motivation is easier — jumping rope almost turns into a need.”

Susan has the level of understanding I hope to instill in everyone who reads this book. At every level, from the microcellular to the psychological, exercise not only wards off the ill effects of chronic stress; it can also reverse them. Studies show that if researchers exercise rats that have been chronically stressed, that activity makes the hippocampus grow back to its preshriveled state. The mechanisms by which exercise changes how we think and feel are so much more effective than donuts, medicines, and wine. When you say you feel less stressed out after you go for a swim, or even a fast walk, you are.


Bob was stressed out. It was 1969; he had finished his medical residency; and he was just out of the navy, where he debriefed shell-shocked soldiers sent directly from Vietnam to his base in Boston. But work wasn’t the problem — he was a young psychoanalyst and he was quite capable. It was personal stuff: both his father and his father-in-law died in quick succession, and all the emotions he ignored as a teenager after his mother died came rushing back and hit him like a sledgehammer.

Physically too, he was a wreck. He was so stressed that he began having strange choking fits that made it difficult to breathe. He had only recently recovered from a year-long battle with viral meningoencephalitis, a runaway inflammation of the brain that is often fatal, and now he was back in the hospital. This time, he thought it might be throat cancer. There was no indication back then that he would go on to become president of the American Psychoanalytic Association or a faculty member at Harvard or a consultant to Major League Baseball’s rookie career development program. In fact, for Dr. Robert Pyles, at age thirty-three, there was no indication he would live another year.

The X-rays revealed a flurry of snowballs in his lungs that turned out to be disseminated sarcoidosis, a cancerlike disease of the lymph system that typically goes on to invade other organs and kills you. “I’m almost positive that these things occurred because I was under a tremendous amount of stress and depression at the time,” Pyles says. “I think what happened was, my immune system was so compromised that I got the second disease.”

I’ve discussed the effects of chronic stress on the brain, but the effects on the body are equally powerful. Chronic stress is linked to some of our most deadly diseases. If repeated spikes in blood pressure damage the vessels, plaque can build up at those areas and lead to atherosclerosis. As I mentioned earlier, an unchecked stress response can stockpile fat around the midsection, which studies have shown to be more dangerous than fat stored elsewhere. The overload of cortisol from chronic stress lowers IGF-1 while maintaining glucose levels in the bloodstream, setting up a metabolic imbalance that can lead to diabetes. More broadly, an incessant flow of cortisol clamps down on the immune system, leaving the body wide open to any number of diseases. The results can be deadly.

Pyles wasn’t hopeful. At that time, there was no treatment for disseminated sarcoidosis, let alone a cure. One day, he was a Harvard-educated young doctor starting a family and a practice at the dawn of a new decade, and the next, he was handed a death sentence. “I didn’t know what to do,” he says. “I got more panicked and stressed. What I started doing was, I started to run.”

He had been quite an athlete in his school years, but he’d let himself go — to the point where he’d packed 190 pounds onto his five-foot-nine frame. “I had gotten out of college, and like everybody else I didn’t do any exercise,” he says. “I could only run a maybe a quarter of a mile or half a mile. I would say to myself, If I can run that far, I guess I’m not going to die today. After a while I was up to a mile, and then it got to be three miles and then five and then eight. I found that if I got past a certain point, where it was really uncomfortable, it was as though something would click in my psyche, and I could go on for a long time.”

Pyles kept running. He wasn’t running for his life but for his sanity. The only thing a patient with disseminated sarcoidosis could do was go in for X-rays every three months or so and let them count the snowballs. But for Pyles, the disease seemed to be holding steady. The months turned into years, the mileage turned into marathons, and then the X-ray film started coming back clearer. After about five years, the disease had disappeared.

This was during an era when if you were sick, a doctor’s first recommendation would be to rest. Dr. Kenneth Cooper had only recently coined the term aerobics, and we hadn’t yet come to accept the health benefits of cardiovascular fitness. Despite his medical training, Pyles didn’t recognize that the stress had turned into depression and neither did his analyst. “I think what the running did for me is it gave me some sense of being in control — something I could do,” Pyles says. “The thing about the depression and the illness is that I felt completely helpless, like I couldn’t do anything. There was no way to even fight them at the time.”

His doctor wrote up his case for the medical literature, deeming his recovery a miracle cure. But when he suggested it might have something to do with the running, his doctor “just pooh-poohed it completely,” Pyles says.

Pyles never intended for running to become such a central part of his life. He gave up smoking a pipe and quit eating meat, because it made him feel heavy. He merged his growing personal interests with his profession, going into practice as a sports psychiatrist for injured athletes who fall into depression because they can’t exercise. He’s had injuries of his own, of course, but except for a stretch when he was sidelined with a fractured leg, he has run two marathons a year since he started. That’s forty-seven in all.

“Back then, doctors had no appreciation whatsoever for exercise as being beneficial in any way,” Pyles says. “I still think it’s dramatically underappreciated. Particularly in psychiatry. For people who grew up as intellectuals, there’s almost an aversion to it.”

Pyles attributes this partly to the founding principles of Freudian psychoanalysis. Doing something to avoid talking about our emotions is seen as “acting out.” This is the origin of the psychiatrist’s couch — the idea is to immobilize the patient and force the emotions to manifest themselves verbally. From this point of view, exercise is a prime example of acting out — dealing with our emotions physically rather than verbally. We’re not working on our problems.

Just the opposite turned out to be true for Pyles, who is now seventy-two. His active coping mechanism dramatically redefined both his life and his career. “Exercise saved my life,” he says. “I think running really put me back with the unitary nature of body and mind — it’s all one thing. We’re not split into pieces.”


Since the office is a primary source of stress for a lot of people, it’s a good place to look for the benefits of exercise. More and more companies are encouraging their employees to take advantage of in-house gyms or health club memberships, and some health insurance companies reimburse clients for club fees. Their generosity is informed by studies showing that exercise reduces stress and makes for more productive employees. In 2004 researchers at Leeds Metropolitan University in England found that workers who used their company’s gym were more productive and felt better able to handle their workloads. Most of the 210 participants in the study took an aerobics class at lunchtime, for forty-five minutes to an hour, but others lifted weights or practiced yoga for thirty minutes to an hour. They filled out questionnaires at the end of every workday about how well they interacted with colleagues, managed their time, and met deadlines. Some 65 percent fared better in all three categories on days they exercised. Overall, they felt better about their work and less stressed when they exercised. And they felt less fatigued in the afternoon, despite expending energy at lunchtime.

Other studies show that employees who exercise regularly have fewer sick days. Northern Gas Company employees who participate in the corporate exercise program take 80 percent fewer sick days. General Electric’s aircraft division conducted a study during which medical claims by employees who were members of its fitness center went down 27 percent, while nonmembers’ claims rose by 17 percent. And according to a report published in the late 1990s by Coca-Cola, health-care claims averaged $500 less for its employees who joined the company’s fitness program, compared with those who didn’t.

More general research supports the notion that exercise combats stress-related diseases, which, obviously, can keep people out of work. Both stress and inactivity — the twin hallmarks of modern life — play big roles in the development of arthritis, chronic fatigue syndrome, fibromyalgia, and other autoimmune disorders. Reducing stress by any means, and especially exercise, helps patients with their recovery from these diseases. The diseases result from a weakened immune system, and as is evident in the example of Robert Pyles, exercise can dramatically improve immune function. In recent years, doctors have started recommending exercise for cancer patients, both to help boost the immune response and to fend off stress and depression. Nobody says exercise cures cancer, but research suggests that activity is clearly a factor in some forms of the disease: twenty-three of thirty-five studies show an increased risk of breast cancer for those women who are inactive; physically active people have 50 percent less chance of developing colon cancer; and active men over sixty-five have a 70 percent lower chance of developing the advanced, typically fatal form of prostate cancer.

It all comes back to the evolutionary paradox that even though it’s much easier to survive in the modern world, we experience more stress. The fact that we’re much less active than our ancestors were only exacerbates matters. Just keep in mind that the more stress you have, the more your body needs to move to keep your brain running smoothly.