Welcome to Your Brain (8 page)

been found in yeast, worms, flies, fish, dogs, cows, and even monkeys. Calorie restriction

reduces cancer, cardiovascular disease, and other age-related problems in rodents and

monkeys. It also protects the brains of rodents with experimentally induced Huntington’s

disease, Alzheimer’s disease, Parkinson’s disease, or stroke. It’s hard to study lifespan

extension in humans because our lives are so long already, but there is evidence that calorie

restriction has some beneficial effects on human health, like reducing blood pressure and

cholesterol.

There’s a catch, of course. We’re talking about
really
low-calorie diets, which provide

about two-thirds of the calories of a normal diet, while still providing required nutrients,

such as vitamins and minerals. Many of the same effects can be achieved by a starve-and-

binge strategy organized around a normal calorie intake, where you eat nothing one day and

then double your calories the next. Most people couldn’t stick to such a diet, but there are a

few longevity researchers who have been doing it for years.

Calorie restriction seems to work by affecting insulin signaling pathways, which are

important regulators of energy storage in the body. Calorie-restricted mice have much

lower insulin levels than their well-fed siblings and are much more sensitive to the effects

of insulin. Under a normal diet, insulin sensitivity declines with age. This effect is even

stronger under a high-calorie diet. Declining insulin sensitivity is a predictor of type 2

diabetes.

Changes triggered by calorie restriction begin with the activation of a receptor for a

group of signaling molecules called sirtuins. In mammals, the receptor is called SIRT1, and

it is expressed throughout the body. A chemical called resveratrol, which is found in red

wine, increases production of SIRT1 in rodents. Resveratrol promotes health and extends

the life-span of mice that are fed a high-calorie diet. The drug doesn’t prevent the mice

from gaining weight, but it does make them live 15 percent longer. We like red wine too,

but don’t get your hopes up just yet: the doses used in that study were equivalent to five

hundred bottles per day. Another study reported that mice fed resveratrol showed better

athletic performance on a treadmill, but those doses were higher still, equivalent to three

thousand bottles per day. We couldn’t drink that much in a year, let alone in a day. For now,

these studies provide hope for your children or grandchildren; at this stage, though, there’s

not enough evidence for the safety and effectiveness of such supplements to justify their

widespread use.

Many of these regulators, including leptin, insulin, and other hormones, act in the brain by

influencing opposing groups of arcuate neurons. Melanocortin neurons decrease available energy by

reducing food intake and increasing energy expenditure. Meanwhile, neuropeptide Y neurons increase

available energy by promoting food intake and reducing energy expenditure. Leptin directly activates

the melanocortin neurons and inhibits the neuropeptide Y neurons. The process is a bit more

complicated than that, though, because the neuropeptide Y (pro-feeding) neurons also strongly inhibit

the melanocortin (anti-feeding) neurons. The melanocortin neurons, in contrast, do not have any direct

influence on the neuropeptide Y neurons. As a result, this brain circuit is biased toward the promotion

of eating and weight gain.

Melanocortin neurons are also found in the brainstem, a part of the brain that regulates

fundamental processes like breathing and heart rate. The nucleus of the solitary tract in the brainstem

receives input from nerves that originate in the gut, which carry signals related to intestinal expansion

or contraction, the chemical contents of the digestive system, and neurotransmitters released in

response to nutrients, including some of the ones discussed above. The nucleus of the solitary tract

then sends information forward to the hypothalamus, including the arcuate nucleus. Brainstem neurons

seem to be particularly important for signaling when an animal is ready to stop eating, through various

proteins produced in the gut.

The melanocortin system might seem like a good target for weight-loss drugs, since weight

regulation can be strongly affected in mice by genetically altering these receptors and by manipulating

the neurotransmitters that activate them. Unfortunately, it may be difficult to avoid side effects

because drugs that affect melanocortin receptors also influence blood pressure, heart rate,

inflammation, kidney function, and male and female sexual function. Mutations in the melanocortin

system in humans are rare and do not account for much of the obesity in the population, though when

they occur, they do lead to problems with weight regulation.

When leptin was discovered about ten years ago, researchers were optimistic that it might prove

to be the magic bullet that would reduce appetite and cause weight loss. As it turns out, though, many

overweight people already have high levels of leptin in their bloodstream but don’t respond normally

to the hormone, showing what scientists call “leptin resistance.” In most people, leptin resistance is a

consequence of obesity. This leptin resistance is similar to insulin resistance, which is triggered by

weight problems and is the cause of adult-onset diabetes. Obesity caused by overeating causes leptin

to become less effective at activating signals that instruct the arcuate nucleus to reduce the body’s

weight.

Although the discovery of leptin has not led to an effective drug for weight loss, there is a drug

based on another pathway that shows some promise. Anyone who’s ever gotten the munchies from

smoking marijuana knows that pot’s active ingredient, delta-9-tetrahydrocannabinol (THC),

stimulates hunger even in animals that are well fed. A drug called rimonabant blocks the receptor that

responds to THC and reduces food intake even in hungry animals. Perhaps more importantly, it has

the same effect on those that have already been fed. Animals that eat when they are not hungry may be

a fairly good model of human obesity.

Practical tip: Tricking your brain into helping you lose weight

If your brain works against you when you want to lose weight, then how can you

achieve the results you want? Basically, you need to arrange your weight-loss strategy to

take your brain’s reactions into account. Most importantly, that means keeping your

metabolic rate as high as possible. It also means finding a strategy that is sustainable. Your

brain will always be working toward its own automatically set goals, so any changes you

make to your eating and exercise habits will also need to be permanent to remain effective.

Temporary changes give temporary results, period. This approach may not sound as

glamorous as the latest grapefruit diet, but it does have one substantial advantage: it works.

Your metabolic rate determines how many calories your body burns at rest. Severely

low-calorie diets never work in the long run because the very real risk of starvation in our

evolutionary past has produced brains that are expert at protecting the body from severe

weight loss. One of the main ways that your brain achieves that goal is by slowing down

metabolism in times of famine, in some people by up to 45 percent. If your weight was

stable on two thousand calories per day, it may also be stable on twelve hundred calories a

day after this metabolic compensation kicks in—only now your life is a lot more difficult.

Worse yet, when you increase your food intake, you’re likely to gain weight before your

metabolism adjusts back. Like starvation, sleep deprivation strongly depresses metabolism,

so it’s important to get enough sleep if you want to keep your weight down. Stress is

another culprit, as the stress hormone corticotropin releasing factor tips the body’s energy

balance in favor of conservation. Metabolism also tends to slow down as you age, which is

why people tend to gain weight as they get older, at a rate of about one pound per year.

Exercise is the most effective way to improve this situation, both because the exertion

itself triggers your body to increase its use of energy and because muscles burn more

calories at rest than fat does. Exercise can boost metabolism by 20 to 30 percent, and the

effect lasts up to fifteen hours. Yoga may be a particularly good exercise because many

people find that it also reduces stress.

Weight gain and fat storage increase when humans and other animals are fed a few big

meals rather than many small ones. Therefore, you should split your calories into small

meals spread out over the entire day rather than eating only once or twice a day. In one

study, people on a laboratory-controlled diet were able to boost their metabolism by eating

in the morning—enough to add two hundred to three hundred calories a day to their diets

without gaining weight. This means that a small breakfast pays for itself in metabolic

improvement. People who eat the same number of calories gain less weight if they eat in the

morning than if they eat in the evening. Of course, it’s important to make sure that your

frequent meals are actually small! Total calorie intake remains a major determinant of

weight, whenever you eat.

A history of repeated weight gain and loss makes it more difficult to maintain a healthy

weight. People who’ve lost at least ten pounds have to eat less (forever) than people who

have always been slim. In one study, formerly overweight people had to eat 15 percent

fewer calories than their always-thin counterparts to maintain the same weight. For this

reason, one of the best gifts you can give your children is to feed them a healthy diet when

they’re small. Early food exposure influences dietary preferences in adulthood, and eating

habits formed in childhood follow many of us around for the rest of our lives.

Contrary to popular belief, eating correctly doesn’t involve deprivation and hunger. If

you are constantly hungry, you’re probably not eating right. Your brain’s hunger sensors

respond to stomach fullness and to fat and sugar in the bloodstream. To reduce hunger, try

combining a large amount of low-calorie food like salad or vegetable soup with a small

amount of fat. Finally, find some passion in your life beyond eating. It’s much easier to keep

your weight down if you have other interesting things to think about. Trips between the

television and refrigerator do not count as exercise or as a hobby.

In several large clinical trials, obese people who took rimonabant for one year lost about ten

pounds more than people who were given a placebo. Treated patients also showed a significant

increase in HDL (“good”) cholesterol and a decrease in triglycerides, which was partly independent

of the weight loss, suggesting that rimonabant has direct effects on lipid metabolism that might reduce

heart attack risk. This isn’t the kind of weight loss that would change anyone’s life, but if it’s widely

used, the drug is likely to reduce the medical cost of obesity complications. Unfortunately, people in

the trial who went off the drug typically gained all the weight back in the following year, so it may

need to be taken chronically to maintain weight loss. That’s good news for the drug company but bad

news for patients.

The receptor that is blocked by rimonabant does not exist to be activated by marijuana, of course,

but by brain-synthesized neurotransmitters that are known as endogenous cannabinoids or

endocannabinoids. One study reported that people with a mutation in an enzyme that breaks down one

of the endocannabinoids, who thus have abnormally high levels of receptor activation, are

significantly more likely to be overweight than people without the mutation. This evidence suggests

that the cannabinoid system may influence the genetic risk of obesity in the general population. A later

study failed to confirm this finding, though, so it’s not yet clear whether these mutations are important

in many cases of human obesity.

Is the current epidemic of obesity in the U.S. caused by individual differences in genes that help

regulate food intake? Not exactly. The efficiency of your cannabinoid and melanocortin systems

probably does influence your personal risk of becoming obese, but, in general, people get fat in the

modern world because their brains are helping them to store up fat in anticipation of the next big

famine. When faced with an excess of good-tasting food, laboratory animals tend to get fat, and so do

people. Genetic differences probably determine which people gain weight early in this process and

which people require a stronger stimulus, but constant exposure to an excess of tasty food will

eventually break down almost anyone’s willpower. For this reason, you’d be better off putting your

energy into changing your environment so that the available choices are healthy ones rather than

spending your mental energy trying to resist the urge to reach for that chocolate bar. Your brain will

thank you, and so will your waistline.

Part Two

Coming to Your Senses

Looking Out for Yourself: Vision

How to Survive a Cocktail Party: Hearing

Accounting for Taste (and Smell)