The Deadliest Sin - Wholebeing...

crease. If you have arthritis, your symptoms will improve. The pillwill help you regulate your appetite and you’ll probably find youprefer healthier foods. You’ll feel better, younger even, and youwill test younger according to a variety of physiologic measures.Your blood volume will increase, and you’ll burn fats better. Evenyour immune system will be stimulated. There is just one catch.

There’s no such pill. The prescription is exercise.“We’ve spent years studying numerous nutritional and lifestyle

factors,” says Frank Hu, associate professor of nutrition and epi-demiology at the Harvard School of Public Health (SPH). “Goodnutrition is essential for health,” but once-promising discoveries,including antioxidant supplements like beta-carotene, haveturned out not to be magic pills. “The single thing that comesclose to a magic bullet, in terms of its strong and universal bene-fits, is exercise.”

During the last 10 years, epidemiologists like Hu have clearlydemonstrated exercise’s protective e≠ects against many seriousdiseases. And yet, as one medical researcher studying exercise inelderly populations put it, “Exercise is often overlooked.” Thougha large body of epidemiological re-search shows its protective effectsagainst numerous maladies, therehas been less research into howthese e≠ects actually takeplace. Exercise can

change virtually every tissue in the body, but because it works bymany di≠erent pathways—metabolic, hormonal, neurological, andmechanical—understanding why and how it works, in an inte-grated way, is not easy. We know exercise is good for us. But why?

The Sedentary AmericanSeventy-five percent of the population of the UnitedStates fails to meet even the minimum government recommenda-tion for daily exercise: 30 minutes of walking or its equivalent, ac-cumulated in bouts as short as 8 to 10 minutes. The recommenda-tions have in some ways become easier over the last three decades(see “Exercise: A Changing Prescription,” page 43), but we havegiven up physical activity of any kind even faster.

“America loves to think of itself as a youthful nation focused onfitness, but behind the vivid media images of robust runners,Olympic Dream Teams, and rugged mountain bikers is the trou-bling reality of a generation of young people that is, in large mea-

sure, inactive, unfit, and increasingly overweight.”So begins Promoting Better Health, a Centers for

Disease Control (CDC) report. “Walkingand bicycling by children aged 5 to 15dropped 40 percent between 1977 and1995,” it continues. Even in schools, budget

constraints have led to suspension ofphysical education classes. Steven

Gortmaker, professor of so-ciety, human development,and health at SPH, and col-

leagues recently used a tracking de-

The Deadliest SinFrom survival of the fittest to staying fit just to survive:

scientists probe the benefits of exercise—and the dangers of sloth.

by Jonathan Shaw

In the bottle before you is a pill, a marvel of modern medicine that will regulate

gene transcription throughout your body, helping prevent heart disease, stroke, diabetes,

obesity, and 12 kinds of cancer—plus gallstones and diverticulitis. Expect the pill to im-

prove your strength and balance as well as your blood lipid profile. Your bones will become

stronger. You’ll grow new capillaries in your heart, your skeletal muscles, and your brain,

improving blood flow and the delivery of oxygen and nutrients. Your attention span will in-

I l l u s t r a t i o n s b y S e r g e B l o c h

Exercise.final 2/7/04 4:18 PM Page 36

Harvard Magazine 37

vice to measure the minute-by minute physical activity of school-age children throughout the day. The highest levels of activity, hetold a group of public-health professionals at an October 2003seminar on the “Worldwide Childhood Obesity Epidemic,” occurduring the hours when children travel to and from school. Since1980, the percentage of American children who are overweighthas doubled.

In 2003, the CDC declared obesity the most important public-health issue in the United States. Obesity increases the risk fortype 2 diabetes, cardiovascular disease, and some cancers. Two-thirds of Americans are now overweight or obese. In Michigan,

half the men are overweight—34 pounds on average—and theproblem has been steadily growing for more than 25 years. Chil-dren and teenagers are contracting “adult-onset” diabetes at arapidly increasing pace. As Dr. Kenneth Cooper, M.P.H. ’62, one ofthe country’s foremost experts on physical activity (he coined theword aerobics) puts it, “In Texas, we may have the first generationin which the parents will outlive their kids,” as obese childrenwho develop diabetes before 14 years of age can expect their lifes-pan to be reduced by 17 to 29 years.

This epidemic is not confined to any particular region of theUnited States. It is ubiquitous, Gortmaker says, in rural and

Epidemiologist Frank Hu’s researchcontributes to themounting evidencethat exercise can prevent or delay manyfatal diseases.

P h o t o g r a p h s b y J o h n S o a r e s


38 March - Apr il 2004

urban communities, among both the wealthy and the poor.The cause? Epidemiologists call it an energy imbalance: too

much food and too little activity.The imbalance is small, equivalent to the caloric content of one

sugar-sweetened drink per day, Gortmaker says, suggesting thatgiving that up, or forgoing a few bites at dinner, could preventfurther weight gain. Soda, fast food, and the super-sizing of por-tions are frequently cited as culprits on the intake side of theequation, because a typical fast-food meal (double cheeseburger,soda, fries, and a dessert) can contain, at 2,200 kilocalories,enough energy to power a 120-pound person through an entiremarathon. Even so, by some estimates, this country’s per capitacaloric intake in the last 20 years has not increased enough to ac-count for the increased body mass in the same period. For that,we have to look to other changes in lifestyle.“Obviously, there is no longer any need for physical activity fortransportation, food-seeking, or daily survival,” says JoAnn

Manson, M.D., chief of preventive medicine at Brigham andWomen’s Hospital in Boston and a professor at SPH and HarvardMedical School (HMS). “We have labor-saving devices every-where. You can get through the day expending virtually no en-ergy, doing virtually no physical activity. Many people do choosethat lifestyle.”

The modern lifestyle is a radical departure from the one inwhich we evolved. Though scholars disagree on the relativeamount of time that our hunter-gatherer ancestors spent run-ning versus walking, the evidence suggests that they covered alot of ground either way: 10 to 20 kilometers a day walkingamong men, says professor of biological anthropology RichardWrangham, “and about half that for women. Chimpanzees, bycomparison, walk only 2 to 4 kilometers a day, and all other apeswalk even less. The ordinary thought,” he says, “is that womenwould have done this every day, because they would havebeen the providers of the staple foods.” Activity levelswere probably more variable with men: “[They]would have been bringing in the morechancy foods as well as relaxing after aparticularly heavy day the day before.”Wrangham’s colleague, professor ofanthropology Daniel Lieberman, thinks running haslong played an important role in human societies. He pointsnot only to anthropological evidence (the running tradi-tions of Native Americans, for example), but also to a hostof musculoskeletal adaptations that he says can only be ex-plained as adaptations for running, such as theAchilles tendon, which “has no function in walk-ing, is absent in chimpanzees, and first appearsin the genus Homo.” Either way, the humanrecord tells a story of frequent, long distance,aerobic exercise.

Epidemiologists debate the merits ofwalking versus running, but agreethat studies link increasingactivity levels to better health

along a continuum ranging from extreme sedentary behaviors tothe “vigorous exercise” of subjects who run more than 20 miles aweek. Hu believes that in discussions of the benefits of exercise,the extreme low end of the spectrum—sedentary behavior—istoo often neglected. Being sedentary is an independent risk factorfor coronary heart disease (CHD), notes Manson, even among peoplewho do exercise. “We found in the Women’s Health Initiative [astudy of more than 160,000 postmenopausal women aged 50 to79] that the longer you sit each day, the greater your risk of car-diovascular disease, even after you adjust for time spent in recre-ational activity.” She tells her patients to get up and walk aroundas much as possible, and to reduce screen time (TV, video games,working at the computer). “The key is to minimize sitting,” shesays. Hu agrees. Given that the average American spends 4 to 5hours a day watching television, he says, “For most people, it isnot su∞cient to address only the exercise side of the coin. Equallyimportant is the sedentary side of the coin.”

One sedentary behavior in particular has drawn the attentionof public-health researchers. In a landmark study that comparedwatching TV to reading, sitting at a desk, and driving, Hu foundthat TV watching is far more likely to lead to obesity and diabetesthan any of the other sedentary behaviors. First, Hu explains,“when people watch TV, they eat.” Second, they tend to make badfood choices: TV watchers eat more junk food and fast food. Andwhen people watch TV, their metabolic rate (the rate at whichenergy is burned) drops lower than when they sit and read orwork on a computer. “The reason is that TV watching is com-pletely passive,” says Hu. “It is almost like sleeping—sit back andrelax—that’s the message.” People who watch TV also tend tospend a lot of time at it (women watch at least an hour more perday than men). And so prolonged TV watching—Hu calls it “amajor public-health hazard”—displaces other activities that

would be better for people’s health. Gortmaker, who pioneeredstudies of television watching among American children (60percent of whom have a television in the room where theysleep), notes that among youth, time spent watching televi-

sion is the one behavioral variable most predictive of obesity.

The Case for Physical Activity

An estimated 18 million Americansnow have diabetes, a leading cause

of heart disease, stroke, blind-ness, kidney disease, and nerve

damage. If current trends con-tinue, the CDC estimates,more than one in three chil-dren born in the year 200o

will develop diabetes duringtheir lifetime. This is shocking, but not sur-

prising given the American lifestyle. When re-searchers want to model the disease, they feed

mice a high-fat or high-sugar diet and don’t letthem exercise. “Within a few weeks or months,”says Hu, “they will become obese and they will be-

“We have labor-saving devices everywhere. You can get through the day expending

virtually no energy, doing virtually no physical activity. Many people choose that lifestyle.”

Exercise.final 2/7/04 4:21 PM 8

Harvard Magazine 39

come diabetic.” Modern society has put us inalmost the same environment, he says, “withan unlimited amount of calories and foodsand also very little physical activity.”

Diabetes is a metabolic disorder that leadsto excess sugar in the blood. More than 90percent of diabetes is the type 2, or “adult-onset,” form of the disease that can be pre-vented or delayed by exercise. In type 2 dia-betes, cells that normally take up sugar inresponse to the body’s secretion of insulin be-come “insulin resistant,” causing blood-sugarlevels to spike. (People with type 1 diabetesare sensitive to insulin, but require injectionsof the hormone because they have lost theability to make enough for themselves.) In theNurse’s Health Study (a large study of femaleregistered nurses begun in 1976 and based atChanning Laboratory, Brigham and Women’sHospital), Hu found that even walking—amoderate-intensity activity—for 30 to 45minutes per day lowered the risk of develop-ing type 2 diabetes by 30 to 40 percent. “Thisreduction is remarkable,” he says. “There isnothing else that has stronger and quickere≠ects than physical activity for preventingdiabetes.”

“We know that if you get diabetes, there isno cure,” Hu continues. “You will live withthe disease for the rest of your life.” Exercisecan help manage diabetes in several ways.Because 75 percent of people with diabeteswill die of cardiovascular disease, it is ex-tremely important to prevent or delay the onset of the diseaseamong this population. Walking a half hour to an hour a day low-ers a diabetic’s risk of dying from heart disease by 40 to 50 per-cent. A number of drugs are good at controlling blood pressure,he says, “but none of them is as e≠ective as exercise in delaying orpreventing cardiovascular complications and preventing deathsamong people with diabetes.”

Among healthy people, exercise can raise levels of HDL, or“good” cholesterol, improve clotting factors, lower blood pressure,and decrease inflammation. All of these factors, says Hu, reducethe risk of cardiovascular disease: “We have found that both vigor-ous exercise and walking can substantially reduce the risk of heartattacks and—this was somewhat of a surprise—both kinds ofstroke.” (Ischemic stroke, caused by insu∞cient blood flows in thearteries of the brain, is very similar to heart disease. Hemorrhagicstroke occurs when vessels in the brain rupture and bleed.) “Eventhough their pathophysiology is very di≠erent,” says Hu, “exercisecan decrease the risk of both.” Long-term exercise causes the en-dothelial cells lining the blood vessels to synthesize nitric oxide, arelaxing factor that increases blood flow. People with insu∞cientnitric oxide in their system are more likely to have sti≠ blood ves-sels, hypertension, and other inflammatory factors, he explains.“That’s the common pathway leading to both kinds of strokes, andthat is why exercise is beneficial in each case.”

For similar reasons, exercise has been shown to help fight erec-tile dysfunction, says Eric Rimm, SPH associate professor of epi-

demiology and nutrition and assistant professor of medicine atHMS. In a study of older men, Rimm found that exercise enhancesthe relaxation response necessary for an erection and improvesvascular reactivity to stimulation. Nitric oxide again plays a keyrole, but all the other improvements in circulation associated withexercise can also contribute to improved function. In a Germanstudy comparing the e≠ects of exercise to Viagra (sildenafil) and aplacebo treatment, men with erectile dysfunction and mild tomoderate circulation problems engaged in a two-year program ofsquatting exercises and pelvic and leg lifts designed to improveblood flow to the pelvis, buttocks, and upper leg muscles. Eightypercent of the exercisers reported better erections, compared with74 percent taking sildenafil and 18 percent on the placebo.

How much exercise is enough? Some controversy remainsabout the optimal amount and intensity of exercise required toreap protective benefits against cardiovascular disease. “Somepeople say you need to do vigorous exercise in order to achievethe benefits,” explains Hu. “Others have said that, no matterwhat kind of exercise you do, if you have the same amount of en-ergy expenditure, you will get the same benefit.” Hu thinks thatboth are probably right. “For the majority of Americans, it isprobably not very useful to distinguish moderate- from vigor-ous-intensity exercise; the highest priority is simply to increasetheir energy expenditure. No matter what they do,” he says, “it isbetter than sitting on the couch.”

But people who already exercise can probably reap additional

Diabetes researcher

Laurie Goodyear

studies the cellular

and molecular effects

of exercise.



benefit by increasing the intensity of their activity. “We havefound that among men, the intensity itself can give you additionalcardiovascular protection above and beyond the total amount ofexercise you do,” Hu says. Vigorous aerobic exercise may be bestat burning visceral fat, the metabolically active intra-abdominaladipose tissue that the liver draws on for energy when other fuelsources run low. Fat is not just an energy reserve, researchers havelearned in recent years. It can produce and regulate hormonesthat cause inflammation of the cardiovascular system. Any exer-cise that gets rid of visceral fat will improve health.

And the optimal amount of exercise? Early studies suggestedthat when you reached a certain amount of activity, your benefitwould plateau. “Our data so far don’t support this assumption orhypothesis,” says Hu. “Basically, the more the better. There is astraight dose-response relationship in both men and women. Forpreventing heart disease and stroke,” he says, “there is no limit tothe benefits of exercise.”

But changes in blood pressure and vascular relaxation are not

the only e≠ects of exercise on the cardiovascular system, Hu says.Exercise increases the stability of the heart beat, reduces impor-tant markers for inflammation in the blood like C-reactive pro-tein, and causes changes in blood lipids (like the size of choles-terol particles) that are still being characterized and understood.It also reduces the coagulability of the blood, by changing the se-cretion of thrombogenic factors (hormones that control clotting),so that blood can flow more easily to working muscles. This pre-vents the formation of clots in the blood, further reducing the riskof heart attack and stroke.

Smart Muscle and Cellular Fuel Sensors

When you eat carbohydrates, either simple sugars orstarch, both are converted to glucose and your blood-glucose lev-els rise quickly. Because long-term high blood-sugar levels are notgood for your body, brain, or heart, the pancreas immediately re-sponds by secreting the hormone insulin to counter the surge. In-sulin decreases blood sugar by signaling skeletal muscles (as op-posed to muscles like the heart) to increase their uptake ofglucose from the blood, and helps to inhibit the production ofnew glucose by the liver. In this way, insulin plays an importantrole in maintaining the proper blood-sugar level.

If you are physically active and lean, your tissues are very sensi-tive to the e≠ects of insulin, so you need only a small amount to bee≠ective at controlling blood glucose. But if you are obese orsedentary, the muscles and liver are less sensitive to insulin, sothat glucose uptake by muscle is reduced and the liver may con-tinue to produce glucose even when your body doesn’t need it.Such people are termed “insulin resistant” and tend to havehigher blood sugar. Insulin resistance, a component of metabolicsyndrome or syndrome X, is present in nearly a quarter of allAmericans older than 20, and in 40 percent of those over the ageof 60. Many people live with the condition for years withoutknowing it, until they develop diabetes.

Even for a person with type 2 diabetes, however, a single boutof exercise sends glucose “right into the muscle, and you have in-creases in glucose uptake that are normal or near normal,” saysthe Joslin Diabetes Center’s Dr. Laurie Goodyear,who studies molecular effects of exercise. Thissuggested to Goodyear and others in the fieldthat even though exercise and insulin can bothincrease glucose uptake by the muscle, theymust work by di≠erent mechanisms.

Insulin circulating in the blood normallyworks by attaching to insulin recep-tors on the surface of a muscle cell.This activates a complex seriesof signaling proteins that in-struct glucose transporterswithin the cell to come tothe cell membrane, wherethey pick up blood glu-cose and carry it into thecell, where it is eitherstored as glycogen or un-dergoes numerous reac-tions that result in the gen-eration of energy.

If you exercise every day,

1991

1995

2002

No Data <10% 10%-14% 15%-19% 20%-24% *25%

The prevalence of obesity (a body mass index of 30 or more, equivalent to 30 pounds overweight for a 5-foot, 4-inch, woman or 40 pounds for a 5-foot, 10-inch, man) has grown rapidly for a quarter century. In 1997, the Centersfor Disease Control added a new category for states in which 20 percent ormore of the population is obese; the 25 percent category followed in 2001.

Source: Behavioral Risk Factor Surveillance System, CDC

Americans’ Bulging ProfileAdult Obesity, 1991-2002


Harvard Magazine 41

the number of glucose transporters in your muscles increases, mak-ing the muscles themselves even more susceptible to the actions ofinsulin. “This allows less insulin secretion,” says Goodyear, “and abetter overall regulation of glucose levels in the body.” That e≠ect,depending on the type of exercise and the way you eat “could lastfor 24 to 48 hours after the exercise bout,” says Goodyear. “I thinkthis is the fundamental way that exercise can reduce the risk of de-veloping diabetes and can delay the development of diabetes.”

A major factor that controls the sensitivity of muscles to the in-sulin signal is the level of glycogen (stored fuel), she says: “Themore you deplete glycogen levels, the more sensitive the muscleswill become.” Thus, longer and more vigorous activity—joggingfor 60 minutes, for example—will have longer-lasting e≠ects onglucose uptake than a short walk.

But the reason exercise works so well in treating people whoalready have type 2 diabetes has nothing to do with insulin: theyalready have insulin in the bloodstream, but the muscles don’t re-spond. The current challenge in Goodyear’s field, therefore, is tofigure out how this separate exercise e≠ect works.

When a muscle contracts, glucose transporters move to the cellmembrane—just as they do in the presence of insulin. This sug-gested to researchers that perhaps exercise activates the sameprotein-signaling pathways as insulin. Not so, says Goodyear. Sheand other scientists have since discovered that a molecule calledAMP kinase may be a key to the regulation of glucose transport

by exercise. The molecule, which is already known to reg-ulate fatty acid oxidation, is now the subject of an

“explosion of research,” Goodyear says. “It

turns out that AMP kinase is probably doing lots of things in thecell besides regulating glucose transport.” It may even regulatePGC-1, a gene transcription protein that HMS professor of cell bi-ology Bruce Spiegelman has shown can increase the number ofmitochondria (energy-producing structures) in muscle cells, in-crease fatty acid oxidation, and even induce switches in musclefiber type—all adaptations to endurance exercise, says Goodyear.For the purposes of glucose transport, AMP kinase acts as a kindof cellular fuel sensor. Pharmaceutical companies are interested inthe molecule as a possible drug target—perhaps a first for thefield of exercise research.

Despite the possibility of AMP kinase-based medicines forpeople with diabetes, Goodyear’s research has led her to concludethat it is not the only molecule involved in exercise-induced glu-

From Elite to Everyman

Genetic endowments aside, an elite en-durance athlete and the average dailywalker are, in their adaptations to exercise,different less in kind than in degree. “Adap-tations to training take place along a contin-uum,” says Jennifer Sacheck, a postdoctoralfellow at Harvard Medical School studyingthe biochemistry of activity and inactivity.The person who works out every day foran hour will show better adaptation totraining stress than someone who exercisesthree times a week for 20 minutes.

But the elite are not only training more,they are careful and systematic about whatthey do. Many use heart-rate monitors togauge the intensity of their workouts, sothey can exercise at a percentage of theirmaximum heart rate (roughly, 220 minusone’s age). Most of their workouts, perhaps80 percent of them during the course of ayear, take place in what is called “zone 1,”when the heart beats at roughly 70 to 75percent of its maximum. This is an easypace once initial training adaptations haveoccurred; the challenge of a zone-1 work-out is said to lie in its length, which mayrange from one hour most days up to two

to three hours once a week. An enduranceathlete’s season will begin with months ofthis long, slow, distance training, thoughtspecifically to increase capillarization ofmuscles and to enhance the mechanisms ofaerobic energy metabolism. As the compet-itive season approaches, the athlete beginsto introduce high-intensity intervals intothe training, typically working up to two ofthese a week. For example, a series of four,four-minute intervals performed at 90 to95 percent of the maximum heart rate (achallenging pace) might be performed withthe goal of increasing the stroke volume ofthe heart. Always, the athlete is trying tostress the body, but to avoid injury, becausethe hard-won adaptations to training are allreversible, some in as little as a few weeks.

R e s i s t a n c etraining is usuallypart of the ath-lete’s routine also,in order to buildstrength and avoidthe loss of leanmuscle mass overtime. Most impor-tant of all, the eliteathlete stays com-

mitted to training year round, with perhapsa few weeks or a month off each year topursue other kinds of physical activity.

For the rest of us, lack of motivation canbe a major obstacle to exercise—and evenpeople who want to exercise regularly canhave difficulty incorporating activity intotheir busy daily lives. Doing something en-joyable, and making it part of a daily rou-tine—perhaps by walking or biking part ofthe way to and from work—are provenstrategies. Here are some additional thingsthat Sacheck and JoAnn Manson, chief ofpreventive medicine at Brigham andWomen’s Hospital in Boston, and a profes-sor at Harvard’s public health and medicalschools, have found can motivate the sloth-ful, and keep them on track.

• Knowledge. Learn more about what exercise can do for you.

• Aspiration. Have a goal towork toward. Make it realistic.

• Monitor progress. Use a pe-dometer, or perhaps keep a logof what you do. These tools willlet you track your progress.

• Authority. Ask your doctor toprescribe a course of exercise.

• Patience. Changes in the body occur slowly. People who aretrying to lose weight in particu-lar need to give it time.

• Social support. Having aspouse, friends, or exercisepartner share your efforts will improve consistency.

• Reveille. People who exercise in the morning can often avoidthe inevitable distractions thatcome up in the course of a day.

• Variety. Try out new activities.Weight-train, row, swim, or

rollerskate. Cross-training is good for physical and mentalwell-being.

• Strategy. Increase your activ-ity by taking the stairs insteadof an escalator or elevator, or getting off one stop early whenriding public transportation. Gofor walking meetings with col-leagues.

• Options. Have indoor and out-door options so that you can’tmake excuses whenever the weather is bad.Try a new class,join a gym, or purchase home exercise equipment.

• Self-abnegation. If not foryourself, then do it for your family!

For more, read The 30-Minute Fit-

ness Solution: A Four-Step Plan for

Women of All Ages, by JoAnn Man-son and Patricia Amend (HarvardUniversity Press).


cose transport. Her laboratory is now searching for another “mys-tery” signaling protein that may complete our understanding ofhow exercise improves glucose transport.

Goodyear emphasizes that she is describing just one of the ben-eficial e≠ects of exercise. “In addition to the metabolic e≠ects,”she says, “exercise changes the phenotype [or pattern of gene ex-pression and hence structure] of the muscle in a positive way.”When muscle contracts, she says, “It sends some sort of signal toturn on the transcriptional machinery that will increase the ex-pression of proteins promoting better oxidation of fuels, betterglucose transport, and decreased muscle fatigue. We all knowthat when you train, your muscles perform better. Protein syn-thesis is enhanced. We are trying to find the signals that lead tothese beneficial changes in muscle,” she says, “but of course thereare changes going on throughout the whole body. All the di≠erentcells and tissues are a≠ected in some way.”

The Cancer ConnectionIncreasing evidence suggests that exercise’s e≠ects on in-sulin sensitivity and glucose uptake may be important not only forpeople with diabetes, but also for those at risk for certain cancers.

What is it that makes high levels of insulin so unhealthy? In-sulin is a growth hormone, and to the extent it is oversecreted, it

may lead some cells to the uncontrolled proliferation seen in can-cer tumors. Alternatively, its detrimental e≠ects may be linked toits role in fat metabolism. Even though insulin and exercise worksimilarly in triggering glucose uptake by the muscles, they areradically di≠erent in their e≠ects on fat. While exercise promotesfatty-acid uptake into the muscle, where it is burned, insulin pro-motes fat storage. Fat, as already mentioned, does more than juststore calories. It can produce and regulate hormones with detri-mental e≠ects on health.

Several types of cancer whose incidence is dramatically reducedin people who exercise seem to have a connection to insulin sensi-tivity and glucose metabolism. “There are now 60 studies or soshowing that people who walk briskly as little as three or fourhours a week have about a 40 percent reduction in their risk of de-veloping colorectal cancer,” says SPH and HMS associate professorEdward Giovannucci. Even that surprising figure probably under-estimates the maximum protection we can get. Exercise levelsamong Americans are so low that in large epidemiological studiesof what people actually do, “Even the top exercisers are doing verylittle,” says Giovannucci, “compared to the levels of activity seen inpre-industrialized societies, where rates of colon cancer are 90 to95 percent lower than in the U.S.” Some 147,500 Americans get col-orectal cancer each year, and 57,000 die of the disease; insulin has

been implicated in its pathogenesis.Pancreatic cancer, which is nearly always

fatal, may also have an insulin connection.“Diabetics are at higher risk for pancreaticcancer,” says Giovannucci, “and at the sametime, people who exercise seem protected.It hasn’t been studied a lot,” he cautions,“but it looks very promising.” Two othercancers that are connected to obesity—uterine and kidney cancer—have not yetbeen studied in relation to exercise, Giovan-nucci says, “but we have frequently foundthat in diseases where obesity is a risk fac-tor, exercise is protective.”

Exercise does not seem to reduce one’srisk of developing prostate cancer—but vig-orous exercisers may reduce their risk ofdying from the cancer once they get it, eitherby reducing the growth of the tumor or en-hancing their ability to withstand it. In theHealth Professionals Follow-Up Study(which followed 51,529 men in the healthprofessions), Giovannucci found a 50 per-cent reduction in the risk of dying fromprostate cancer among men at the top end ofvigorous exercisers.

In Outer Space and on Earth“A lot of the epidemiological e≠ects [ofexercise] that have been uncovered were un-expected,” says HMS professor of cell biol-ogy Alfred Goldberg, who studies the atro-

Exercise levels among Americans are so low that in large epidemiological studies of what

people actually do, “Even the top exercisers are doing very little....”

Cell biologist Alfred

Goldberg and

post-doctoral fellow

Jennifer Sacheck

study the biology of

use and disuse in

skeletal muscle.


Harvard Magazine 43

phy of muscle and bone. “They’re related to indirect e≠ects—forexample, [the e≠ects] of exercise on lipid metabolism, as inatherosclerosis. But we are still far from understanding exactlyhow it works.” Better understood is what is happening with mus-cle and bone during exercise.Goldberg approaches this sub-ject from a unique perspective:he is an adviser to NASA’sspace biomedical researchprogram. “One of the bigproblems for astronauts istremendous loss of bone andmuscle,” he reports. Whenyou lose bone mass, what’sleft becomes brittle andsusceptible to fracture. Italso releases calciumphosphate and organiccomponents that canmake you much moresensitive to renalstones. That is why theloss of bone that takesplace with extremedisuse—whether in

space, in wasting diseases, as part of aging, or during extremebedrest—can lead to kidney disease.

Goldberg is co-leader of a team trying to prevent the loss ofmuscle, which he says, is “absolutely necessary for a long-termspace program.” The rate of muscle loss—including heart muscleloss—during spaceflight is so great, he says, that “unless this

problem is solved, by the time an astronaut got to Mars hewouldn’t be strong enough to walk around or even to go outto repair the space vehicle if necessary.”

Goldberg’s group has discovered that, at the cellularlevel, the muscular response to disuse is very similar towhat is seen in fasting, cancer, AIDS, and renal failure. Hesays, “We’ve identified a whole group of genes that areturned on, according to a specific program, whenever atissue atrophies. Sometimes this program is turned onby disease, and sometimes it is turned on by disuse.”His group has dubbed the most critical of these genes

atrogin. It tags proteins for destruction—withoutdestroying cells—by a process that isstill not fully understood.

Goldberg and his colleagues hope tofind a biochemical way to turn o≠ thisgenetically controlled program of at-rophy. Exercise turns it o≠ by causingrelease of a

Exercise: A Changing Prescription

The first formal epidemiologic study link-ing activity to better health took place inthe late 1940s, when a researcher in Lon-don, Jeremy Morris, and his colleagues com-pared double-decker bus drivers to conduc-tors. The conductors ran up and downstairs all day collecting tickets while the dri-vers sat at the wheel. “Morris found that theconductors had lower rates of heart dis-ease,” says I-Min Lee, an associate professorat both the Medical School and the Schoolof Public Health. Critics dismissed the studyon a variety of grounds, insisting that theother factors it documented—lower bloodpressure among the conductors, and lowerbody weight (indicated by the smaller waistsof their trousers)—could explain the differ-ences in rates of heart disease.

But as evidence for the health benefits ofactivity mounted, the question became,What sort of exercise is needed? The firstofficial recommendations were formulatedin the 1970s: adults were advised to engagein at least 20 minutes of continuous vigorousexercise, three times a week. The goal ofthese initial recommendations—which be-came the basis for the phrase, “No pain, nogain”—was to improve physical fitness.Then,in 1990, a group of researchers investigatingphysical activity began to question the ne-

cessity of working out intensely for health, asopposed to fitness, benefits. They worriedthat the recommendations had become abarrier to the average citizen, contributingto low rates of physical activity amongAmericans. An expert panel convened bythe Centers for Disease Control and theAmerican College of Sports Medicine re-examined the literature, and in 1995 issuednew guidelines, advising every Americanadult to accumulate at least 30 minutes ofmoderate-intensity physical activity a day.The idea that you could walk instead of jogand accumulate activity by adding togetherexercise bouts of at least 8 to 10 minuteseach marked a “radical departure,” says Lee.“At that time, there was little direct evi-dence examining the value of moderate-versus vigorous-intensity activity on diseaseoutcomes like heart disease. There wereeven fewer data regarding the accumulationof physical activity.” Researchers (includingLee) began to conduct studies testing thenew approach. Their findings have shownclearly that moderate-intensity activity isbeneficial against chronic diseases such asheart disease, stroke, and diabetes.

But what does moderate mean? “We canlook at intensity in two ways,” Lee says,“oneither an absolute or a relative scale.”Using absolute measures, a 75-year-old manand a 25-year-old man walking briskly at

four miles per hour are said to be engagedin identical, moderate-intensity activity. Butin a relative sense, the 75-year-old mightrate his effort as fairly hard, while the 25-year-old might say the pace was easy. Cur-rent physical activity recommendationsgenerally give examples of physical activitythat are “moderate” in intensity for mostyoung to middle-aged persons. But, forolder people, who tend to be less fit, per-haps even lighter-intensity physical activitycan qualify as “moderate.”

In fact, the Harvard Alumni Health Study(a study of Harvard College alumni who ma-triculated between 1916 and 1950 foundedby Professor Ralph Paffenbarger, one of thepioneers of epidemiologic studies on physi-cal activity and health) found that when thealumni were in their forties, vigorous exer-cise predicted greater longevity and lowerrisk of cardiovascular disease. “As theyaged,” Lee says, “relative intensity became abetter predictor of heart-disease risk.”

Is the intermittent approach to activityvalid? Lee and her colleagues found in theHarvard study that as long as the energyexpended was the same, it did not matterwhether the exercise was carried out all atonce in a single bout or broken up intoseveral shorter bouts: the greater the en-ergy expenditure, the lower the risk ofheart disease.

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growth factor called IGF-1 (insulin-like growth factor-1) whichstimulates the production of new proteins while reducing thebreakdown of old ones (except during fasting). But exercise is noteasy in a space capsule under zero-gravity conditions.

The Physical Response to Training

“Muscles adapt to the kind of work that they do,” says Gold-berg. We all possess a mix of muscle fibers, some better for shortbursts of activity, some superior for endurance. “The dark meat ofa chicken or a turkey or a fish is muscle that is continually active.”These muscles have a large blood flow and lots of mitochondria intheir cells, and they burn fats and glucose all the time. The meat isdark because it is full of iron, which carries oxygen and is used bythe mitochondria to burn fuels. These are the type of muscle fibersfound in greater abundance in the legs of marathoners. In contrast,“The big muscles you see in a weightlifter,” says Goldberg, “are thepale white muscles used for maximum strength in a short time.”

But exercise is more than just a problem of the muscles work-ing, Goldberg points out. A marathoner will have more dark mus-cle fibers that are fatigue resistant, but will also exhibit manyother kinds of specialized adaptations. The body has to mobilizeenough energy to keep the muscles working by delivering oxygen,

fats, and glucose. That means the circulatory system has to workwell. The heart has to adapt to pump more blood and the red cellsneed to be able to carry oxygen better. The circulation has to beable to carry away waste, like carbon dioxide and lactic acid; cir-culating hormones need to mobilize the energy, whether fromblood glucose or fats, to keep the muscles working. The circula-tory system must also redistribute the heat generated in workingmuscles by delivering it to the heart, where it is pumped to thesurface and radiated (when you turn red) or spread by the evapo-ration of sweat. “A person who is trained,” says Goldberg, “has tohave all these systems working pretty well.”

People who engage regularly in vigorous aerobic exercise un-dergo some remarkable adaptations. Not only will they developmore mitochondria, glucose transporters, and oxidative enzymesin their muscles, they will grow new capillaries in the skeletal

muscles, the heart, and the brain. The left ventricle of the heartwill grow larger, and pump even more e≠ectively as total bloodplasma volume increases. The number of circulating red bloodcells will also rise, improving the ability to carry oxygen. Bloodpressure will go down, as will the heart rate at rest.

Peak bone density in the young will improve, and in adults, therate of bone mass loss will slow with exercise, says anthropolo-gist Daniel Lieberman, who recently completed an experimentproviding the first definitive proof of this e≠ect. Even the jointschange, he says, as “mechanical loading leads to enormous andprevalent e≠ects throughout the skeleton.”

Muscles will quickly become much stronger, even without get-ting bigger. This is thought to be the result of improved musclefiber “recruitment patterns,” as the neuromuscular system learnsto contract just the right combination of fibers within a muscle inorder to complete a particular task e∞ciently. Strength gains mayalso come from improved synchronization, the coordinated firingof individual motor neurons that control muscle fiber. Musclesand liver will learn to store more fuel in the form of glycogen, fur-ther improving endurance. Circulating levels of cortisol, an anti-inflammatory hormone and mood enhancer, will go up, as will ep-inephrine and norepinephrine, hormones that regulate, amongother things, the burning of adipose tissue.

Many of these positive adaptations involve common physiologi-cal markers of aging, including blood pressure, cardiac output,cholesterol levels, endurance, and strength, says SPH and HMSassociate professor I-Min Lee. “Almost everything that declinesphysiologically as you grow older improves with exercise.”

Staying Young by Keeping Fit

Jennifer sacheck is a postdoctoral fellow in AlfredGoldberg’s laboratory. She likes to run marathons, row in theHead of the Charles Regatta, and race to the top of Mount Wash-ington (not all in one day, of course). A former national-levelrower, Sacheck has a master’s degree in exercise physiology and aPh.D. in nutritional biochemistry. Now she is studying the bio-chemical basis of use and disuse in muscle tissue in order to under-stand both what is lost with age and what exercise can do to pre-vent or reverse that.

Not all changes from aging can be reversed, she explains. Themaximum heart rate goes down about one beat per year. Thenumber of motor neurons decreases. And the ability to increasemuscle mass declines.

But her work with older populations has convincedher that there are lifelong benefits to both strengthand aerobic training. “Don’t tell me that someoneis old when they are 50,” she says. “I’ve had 90-year-olds lifting weights, still reaping thebenefits. Resistance training helps withbalance, stability, and the strength ofthe core muscles” that girdle theback and the abdomen. Thisreduces the risk of falls andhip fractures. “Strength train-ing also helps maintain muscle mass,”she continues. In an aging person, musclemass helps keep the resting metabolic ratefrom falling. (Muscle mass is the most impor-tant determinant of energy needs at rest.)

Fuel for an Active Lifestyle

Everyone should eat a balanced diet, but exercisers in particular

should pay attention to the following advice, says nutritional bio-

chemist Jennifer Sacheck.

• Drink plenty of water before, during, and after exercise.Your heart

and body work much harder when you become dehydrated.

• Within 30 minutes after exercise, consume a carbohydrate-rich food

along with a little bit of protein: a multigrain sandwich with lettuce,

tomato, and a slice of lean turkey, for example.That is the best way to

replenish intramuscular energy stores. It will also keep you from get-

ting so hungry that you reach for the potato chips when you get home.

• Include nonfat dairy, whole grains, and lots of different-colored fruits

and vegetables in your diet. Lean meat, fish, nuts, tofu, and the combi-

nation of beans and rice, bread and lentils, peas and corn, and cereal

and milk are good protein sources. Many nuts, such as pistachios, al-

monds, cashews, hazelnuts, macadamias, pecans, peanuts, and natural

peanut butter, are also a source of healthy fats.

THE DEADLIEST SIN (continued from page 43)

Exercise.final 2/7/04 4:25 PM 8

Harvard Magazine 99

Resistance training can also help people who are dieting—whichcan actually lower the metabolic rate, through mechanisms verylike the atrophy that Goldberg and Sacheck study—by increasingor maintaining muscle mass. When muscle mass is lost, the body’senergy requirements go down, requiring even further reductions incaloric intake in order to lose weight. (Physicians like JoAnn Man-son—who will actually write an exercise prescription for her pa-tients—usually recommend starting with easy or moderate-inten-sity exercise and then practicing caloric restriction). Resistanceexercise also helps prevent osteoporosis, a condition that ulti-mately affects 50 percent of all American women, and is increas-ingly common among men as they, too, live longer lives.

“Older patients with rheumatoid arthritis can also benefit fromexercise,” says Maura Iversen, S.D. ’96, a clinical researcher atBrigham and Women’s Hospital and instructor in medicine atHMS. “The concern,” she says, “has been whether weight-bearingactivity on a joint with minimal cartilage would benefit the jointor wear it out.” With the advent of magnetic resonance imaging,it is now possible to measure changes in cartilage and the jointsurface itself. This is an area of new and growing exploration.What researchers have found is that in healthy joints, “when youmove, you actually improve the lubrication of the joint,” she says.“Movement leads to better cellular turnover in the synovial fluid,which provides nutrition to the cartilage and maintains cartilagehealth. We know that exercise can improve physical functionand now have the capability to examine its impact on cartilage.”

Iversen recently completed a pilot study of chronic low-backpain in elderly patients and found that a 12-week program of en-durance exercise on a stationary bicycle led to modest improve-ments in patients’ ability to perform the activities of daily living.The exercise program also led to enhancements in mood.

Exercise, it turns out, is particularly useful in treating the milddepression often experienced by elders due to declining functionand increasing isolation. “Keeping your heart and body in shape isjust a side benefit to exercise’s major e≠ects on the brain,” asserts

John Ratey, an HMS associate clinical professor of psychiatry.“The brain is where all the action is.” During exercise, “the in-crease in cerebral blood flow creates more capillaries, more con-duits for blood to flow in the brain. So you are building a reservoirand protecting the brain, in a way, from strokes in the future.”

The increase in cerebral blood flow causes many interestingthings to happen. Exercise increases production of a growth factorcalled BDNF, or brain-derived neurotrophic factor. “I call it Mira-cle-Gro, brain fertilizer,” Ratey says, “because it keeps the neuronsyoung and healthy and makes them more ready to connect witheach other. It also encourages neurogenesis—the creation of newnerve cells.” This may have a cognitive benefit. Studies have shownthat older adults with higher levels of cardiorespiratory fitness ex-perience a slower rate of cognitive decline over time.

But exercise does more than just maintain the health of thebrain. “In a way, exercise can be thought of as a psychiatrist’sdream treatment,” says Ratey. “It works on anxiety, on panic dis-order, and on stress in general, which has a lot to do with depres-sion. And it generates the release of neurotransmitters—norepi-nephrine, serotonin, and dopamine—that are very similar to ourmost important psychiatric medicines. Having a bout of exerciseis like taking a little bit of Prozac [an antidepressant and anti-anxiety agent] and a little bit of Ritalin [which boosts the atten-tion system], right where it is supposed to go.” He says there arenow many studies which show that “exercise is as good or betterthan some of our antidepressants.”

Why? When we move, we have a sense of purpose, of compe-tence, and of accomplishment. “People don’t get the fact that ourfrontal cortex evolved to make us better movers,” Ratey pointsout. “The higher functions—the executive function, thinking, ab-straction, and philosophy—all evolved from the moving brain.”

“We’re animals,” he says. “We should be moving.”

Jonathan Shaw ’89, managing editor of this magazine, once ran a marathon, but

is now a long-distance cross-country skier.

has about him a strong sense of intellectual honesty. He’s a tough,smart guy.”

Lawyers as Peacemakers “What drew me back to Harvard,” says Mnookin, “were,first, it’s my school, and, second, because of the work of RogerFisher, Howard Rai≠a, Jim Sebenius, Bruce Patton, Bill Ury, andothers, the Program on Negotiation had an international pres-ence and a potential impact on the profession that was irre-sistible.”

Today, as director of the Harvard Negotiation Research Pro-ject, one of nine such projects at PON, Mnookin is helping totrain a new generation of scholars who want to do research innegotiation and dispute resolution. The Hewlett Foundation hasonce again chipped in, funding a fellows program that each yearbrings up to seven young scholars to PON.

Part of his project’s mission is to strengthen the theoreticalunderpinnings and empirical scholarship related to his field. Heis at work on a book about the limits of negotiation. “I havespent the past 15 years of my academic career studying negotia-tion, and, like other negotiation imperialists, I find negotiations

omnipresent and have a strong preference for resolving conflictthrough negotiations,” admits Mnookin. “But I do not believethat it always makes sense to negotiate. This book asks how oneshould think about whether to enter into negotiations or insteadrefuse to negotiate.”

He and others are devising new negotiation and ADR teachingunits with the long-term goal of reorienting the traditional cur-riculum of American law schools. He wants graduates of any ofthem to have the intellectual and interpersonal skills they needto help clients solve problems more e≠ectively, to know how togive their clients assistance that goes far beyond the advice thatlawyers typically give in litigation and in managing corporatetransactions. He wrote Beyond Winning “primarily for lawyers whofeel sickened by the trench warfare and exhausted by cases thatdrag on unnecessarily for years, lawyers who want to change theway things work but don’t know how—lawyers who even won-der whether they picked the right profession.”

Early in the book, Mnookin sets out a guiding principle: “Be-cause of their skills and experience, lawyers have what AbrahamLincoln described as a ‘superior opportunity to do good.’ Theycan be peacemakers.”

Christopher Reed is executive editor of this magazine.

PEACEMAKERS (continued from page 60)


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