本田財団レポート No.108
第２５回本田賞授与式 記念講演（２００４年１１月１７日）「研究進捗レポート：最良の食生活を求めて」
ハーバード大学パブリックヘルス校
栄養部門主任教授

ウォルター C．ウィレット

The Search for Optimal Diets:
A Progress Report
Commemorative Lecture at the Twenty-Fifth Honda PrizeAwarding Ceremony on the 17th November 2004 in Tokyo

Walter C. Willett
Professor of Epidemiology and Nutrition,
Harvard School of Public Health

財団法人

本田財団

ウォルター・C・ウィレット
ハーバード大学パブリックヘルス校
栄養部門主任教授

Professor of Epidemiology and Nutrition,
Harvard School of Public Health■Personal History■略歴1945 年

米国ミシガン州ハートで生まれる

1945

Born in Hart, Michigan, USA

1970 年

ミシガン大学医学部で医学博士号

1970

M.D. University of Michigan Medical School

1973 年

ハーバード大学公衆衛生大学院で修士号（公衆衛生）

1980 年

ハーバード大学公衆衛生大学院疫学科で博士号（公衆衛生）

1980〜84 年

ハーバード大学公衆衛生大学院衛生学科
助教授

1984〜87 年

ハーバード大学公衆衛生大学院衛生学科
準教授

1986〜92 年

ハーバード大学医学部 講師

1987 年〜

ハーバード大学公衆衛生大学院疫学
栄養学教授

1991 年〜1992 年〜

1973

M.P.H. Harvard School of Public Health

1980

Dr. P.H. Harvard School of Public Health,
Epidemiology

1980-84

Assistant Professor of Epidemiology, Department of
Epidemiology,
Harvard School of Public Health

1984-87

Associate Professor of Epidemiology, Department of
Epidemiology,

1986-92

Lecturer in Medicine, Harvard Medical School

1987-

Professor of Epidemiology and Nutrition, Harvard
School of Public Healthハーバード大学公衆衛生大学院栄養学科
学科長

1991-

Chairman, Department of Nutrition, Harvard
School of Public Healthハーバード大学医学部 教授

1992-

Professor of Medicine, Harvard Medical School

Harvard School of Public Health■受賞歴（1990 年以降）

■Awards (from 1990 onward)

1994 年 全米ガン協会よりガン予防賞

1994

American Cancer Society Cancer Prevention Award

1996 年 米国予防腫瘍学協会より功労賞

1996

Distinguished Achievement Award, American Society
for Preventive Oncology

1997 年 近代栄養学国際賞

1996
2001 年 ゼネラル・モーターズ・ガン研究基金よりチャールズ・ 1997
S・モット賞
2001
2003 年 国民薬学賞優秀賞（公衆衛生研究・交流）
2003

執筆活動：
1998 年 「食事調査のすべて（第一出版）

栄養疫学[第 2 版]」

このレポートは、平成 16 年（2004 年）11 月 17 日のです。

International Award for Modern Nutrition
The Charles S. Mott Prize for most outstanding recent
contribution related to the cause or prevention ofcancer. General Motors Cancer Research Foundation
People’s Pharmacy Award for Excellence in Researchand Communications for the public HealthPublications:2001 年 「太らない、病気にならない、おいしいダイエット」（光文社）
他に 900 以上の論文が出版されているJohn Snow Award, APHA

1998

“Nutritional Epidemiology”

2001“Eat, Drink, and Be Healthy”

other over 900 articles has published.

ホテルオークラにおいて行われた第 25 回本田賞受賞記念講演の要旨をまとめたも

17 November, 2004

The Search for Optimal Diets: A Progress Report
Walter Willett, M.D., Dr.P.H.

Good evening ladies and gentlemen.
Being here this evening to receive an award from the Honda Foundation is a great honor, andI wish to thank all those who have made this possible. In particular I would like to thank the
Honda Foundation for recognizing the efforts of those who work to improve our environment,
and to Mr. Ishihara and Mr. Ban for their kind hospitality in making the arrangements for thisvisit. I am especially grateful that several of my colleagues from Japan are able to join us thisevening.
Before beginning, I would like to acknowledge the work of many colleagues with whom I
have worked to better understand the relation between diet and health. Dr. Frank Speizer
started the Nurses’ Health Study in 1976, which provided a launching pad for my research.
Drs. Meir Stampfer, Graham Colditz, David Hunter, JoAnn Manson, Sue Hankinson, Eric
Rimm, Ed Giovannucci, Frank Hu and many others have been an integral part of this work
for many years. Many dozens of other colleagues, post doctoral fellows, and students havecontributed to this work; I will mention a few of them specifically later. I am also grateful to
Dr. Bruce Ames, a former Honda Foundation awardee, for nominating me. Dr. Ames has
been an intellectual inspiration to me and countless others for many years.

Today I will describe our work on the development of the field of nutritional epidemiology.
Like any aspect of science, progress is enhanced by the intellectual interactions of many
individuals. I would in particular like to recognize the contributions of the late Dr. Tsuyoshi
Hirayama, who envisioned that much could be learned from the study of dietary habits inlarge populations.
The Development of Nutritional Epidemiology
The foundation of modern epidemiology, which aims to understand the causes of humandisease, largely rests on work of Sir Richard Doll and colleagues in England. Half a century- 31 -

ago, Doll documented a clear relation between cigarette smoking and lung cancer, which
established a paradigm for the identification of modifiable causes of disease. Nutritional
epidemiology uses epidemiologic methods to understand the role of nutritional factors in thecause and prevention of disease. The development of this field was fueled by studies of rates
of disease among different countries. Most importantly, the incidence rates of most majordiseases were found to vary greatly among countries. For example, rates of breast cancer inmost parts of Asia, Latin America, and Africa were less than one fifth the rates in northern
Europe, and these rates were strongly correlated with per capita intake of fat. In the 1960’s,
for example, breast cancer rates in Japan were very low and so was fat intake, about 10% ofcalories (figure 1).

figure 1

Rates of colon cancer varied even more dramatically, and these were associated with intakeof red meat; again fifty years ago Japan had among the world’s lowest rates (figure 2).

figure 2- 32 -

Also, in an international study initiated by Dr. Ancel Keys, coronary heart disease mortality
rates differed more than ten-fold among countries; rates were low in Japan and in the
Mediterranean countries (figure 3) and were approximately ten-fold higher in Northern
European countries and the U.S. Interestingly, total fat intake was high in both the lowest
risk area, the Greek island of Crete, and in the highest risk area, northern Finland. However,
the type of fat differed greatly as it was olive oil in Crete and butter in Finland.

figure 3

The strong correlations among countries between aspects of diet and disease rates should beinterpreted with great caution because many other aspects of diet and lifestyle, including
physical activity and reproductive patterns, also differed between the traditional cultures in
Asia, the Mediterranean, and Africa and those of Europe and North America. One possible
explanation for the large differences in disease rates among countries could be variation in
genetic factors. This possibility was addressed by examining populations that migrated fromcountries with low rates to countries with high rates. In almost every instance, the cancer andheart disease rates of migrating populations have become similar to those of the new homecountry.

For example, among Japanese populations migrating to Hawaii, after two

generations rates of breast cancer were similar to those of Caucasians in the U.S. (figure 4).
Not all has been bad for migrants, though, because the rates of stomach cancer, which were
extremely high in Japan, declined dramatically upon moving to Hawaii.

These studies of

migrants were fundamentally import because they clearly indicated that the high rates of
specific cancers and of cardiovascular disease seen in some populations were not inevitable.
This provided a strong incentive to identify the causal factors, with the expectation that mostof these diseases could potentially be prevented if these factors were modified.
- 33 -

figure 4

As time has passed, we have also seen that disease rates within countries can change
dramatically, for example, rates of colon cancer have been rising strikingly within Japan andhave now even surpassed those of the U.S., the speed at which these disease patterns canchange is truly remarkable. On the other hand rates of stomach cancer have declined sharply
in the U.S. during the last eighty years, where it is now a rare cause of death, and more
recently decreases are occurring in Japan. This provides further evidence that environmental
and lifestyle factors, not genetics, are the primary determinants of disease rates.
Given this background, many epidemiologists have worked to identify the specific factorsthat influence risks of important chronic diseases. Our research group has established threelarge prospective studies (figure 5).

figure 5- 34 -

The Nurses’ Health Study began in 1976 under the leadership of Dr. Frank Speizer andenrolled 121,000 women, initially to study the long term effects of oral contraceptives. In
1989 we enrolled 52,000 men who were also health professionals, and in 1989 we enrolled
another 116,000 younger women to study risk factors in early adult life. In each study,
medical history, smoking, physical activity, and diet are collected every 2-4 years and theoccurrence of major diseases is monitored. This allows us examine specific aspects of diet,and changes in diet over time, controlling for family history of specific diseases, smoking,and other behaviors. We have also collected toenail clippings, which are used to measureintake of trace minerals and heavy metals, and blood samples, which are used for hormonaland nutrient analyses and to determine genetic risk factors using DNA.
The central challenge in nutritional epidemiology has been to measure dietary intake ofindividuals in a way that was sufficiently inexpensive to study large populations, which isessential for studies of cancer and heart disease, and to be able to repeat the assessments ofdiet over time. Many thought that this was impossible. Almost every epidemiologist who
has considered this challenge has concluded that some form of a food frequency
questionnaire (FFQ) was the most reasonable method (figure 6).

figure 6

Thus, using a series of pilot studies, we carefully selected the most important foods in the U.S.
diet, approximately 130 items, and included them on our questionnaire. For each food we ask
about the average use over the past year, not just in the past few days, because it will belonger term intake that is related to risk of cancer and cardiovascular disease. We also
include a detailed assessment of nutritional supplement use on the questionnaires. Our forms
are optically scannable, which greatly reduces the cost and time for processing. The data on
food intake are then linked to a comprehensive food composition database that converts
information on food consumption to intake of nutrients. Because of skepticism that the dietsof free living individuals could be measured, we have examined the validity of this- 35 -

information in many ways.

For example, we studied in great detail several hundred

participants who had completed our standardized dietary questionnaire; participants
completed meal by meal records of everything they ate, using a scales to measure quantity,during four one-week periods over a year. When we compared nutrient intakes calculated
from the food frequency questionnaire and from the diet records, good correlations were seen
between methods. The data from this detailed study can also be used as a form of calibrationin which the intakes assessed by the standardized questionnaires used in our large populations
can be converted to more quantitative measures of intake (figure 7).

figure 7

My colleagues and I have developed a series of statistical methods that use this data to correct
for measurement errors when we assess the relation of dietary intake to risk of disease, but I
won’t go into these details here. Also, we examined the relation between dietary intakes andfactors measured in blood known to be influenced by diet. For example, the food frequency
questionnaire correctly predicted the relation between intake of folic acid and blood levels ofhomocysteine, a risk factor for cardiovascular disease (figure 8).

figure 8- 36 -

We have further shown that the repeated measurements of diet over time improve themeasurement of long term dietary intake.

Thus, we can be confident that our methods toassess long term diet do provide useful information and can be used to test dietary hypotheses
in human populations. This has been the most critical step in the development of nutritional
epidemiology.

Findings on diet and diseaseIn our large studies we have examined many aspects of diet in relation to risks of many
diseases, including heart disease, stroke, diabetes, many cancers, kidney stones, gallstones,
and degenerative diseases of the nervous system, including decline in cognitive function.
Here I will provide just a few examples.
Cardiovascular Disease
Trans fatty acids, or trans fat, have become a common component of many foods worldwide,
including fast foods that are sold almost everywhere . Trans fats are created by a process
called partial hydrogenation that is used to convert natural liquid vegetable oils to solid fats
(figure 9).

figure 9

For example, American fast food companies buy blocks of trans fat to prepare the Frenchfries sold all over the world. In the process of partial hydrogenation, unsaturated fatty acids,
which are naturally bent, become straightened out, which can potentially alter their biological
function (figure 10).

The natural unsaturated fats can reduce blood cholesterol levels,- 37 -

reduce the chances that clots will form in the coronary arteries, and decrease the probabilityof fatal heart rhythm disturbances, thereby reducing the risk of heart disease. I became
concerned about the effects of partial hydrogenation and the artificial trans fats that it
produces , and we began to study trans fats in the late 1970’s. After 14 years of follow-up in
the Nurses’ Health Study, nearly 1000 women had developed coronary heart disease.

Asshown (figure 11), we found that trans fat was strongly associated with risk of heart disease.
On the other hand, and as expected, natural monounsaturated and polyunsaturated fat wererelated to lower risk of heart disease when compared to the same percentage of calories fromcarbohydrate. Thus, replacing trans fat in the diet with natural unsaturated fats can have large
effect in reducing risk of heart disease. I should note that in this figure and those that follow,
all of the relative risks are adjusted for age, smoking, physical activity, and other variables
that may affect the outcome.

figure 10

figure 11- 38 -

In contrast to Western countries, where coronary heart disease has been the leading cause ofdeath, hemorrhagic stroke has been a major reason for death in Japan. Some of my Japanesecolleagues have identified very low intake of animal protein and saturated fat, whichcharacterized the Japanese diet in the 1950’s, as possible risk factors. Thus, Dr. Iso came tovisit us and examine these relationships in our cohorts, which provided confirmation for thishypothesis (figure 12).

figure 12

Looked at another way, high intake of refined starch, such as white rice, was related togreater risk of hemorrhagic stroke; in contrast, intake of fiber from whole grain products suchas whole wheat or brown rice was associated with lower risks of stroke. We have also seenthat greater consumption of fish is associated with lower risks (figure 13).

figure 13- 39 -

Type 2 Diabetes
Rates of type 2 diabetes (the form of diabetes that usually starts in adulthood, but which isincreasing seen in overweight adolescents) are increasing rapidly worldwide, including inboth the U.S. and Japan.

This is turning out to be a particularly serious issue for many

Asian populations, which until recently had very low rates of diabetes; for this reason I will
focus on this issue for a few minutes. The strongest factor for type 2 diabetes is over weight,
which can be expressed as body mass index (figure 14).

figure 14

In the U.S., the rates of diabetes in Japanese Americans have recently surpassed those of
Caucasian Americans, even though Japanese American still weigh less, and I have heard thatlarge increase are also occurring in Japan. There is now convincing evidence that genetic
variation, what we have for years called the “thrifty gene”, contributes to this higher risk.
Some of my Australian colleges conducted a detailed study among healthy young adults fromdifferent ethnic groups who were matched for body weight. Even though all appeared
perfectly healthy, those from Asia had greatly reduced insulin sensitivity, a precursor of
diabetes, compared to those with a European or Arabian background (figure 15). Similarly,
in our cohorts we have found a nearly two-fold increase in risk of type 2 diabetes in womenwith Asian or Hispanic backgrounds after controlling for body weight, diet, physical activity,and other lifestyle factors (figure 16). Because the populations of Asia had low rates ofdiabetes just a few years ago, we know that diabetes is not inevitable, and we have therefore
looked hard to find the responsible nongenetic factors.

Trans fat turns out to be one

contributing aspect of diet (figure 17), and higher intake of polyunsaturated fat reduces risk,
just as these types of fat influence likelihood of developing heart disease (figure 18).

- 40 -

figure 15

figure 16

figure 17- 41 -

figure 18

Dietary glycemic load, meaning high intake of refined starches and sugar, was also related tohigher risk (figure 19) and fiber from cereal products is related to lower risk (figure 20).

If

we examined intake of cereal fiber intake and glycemic load at the same time, we found thatwomen with high dietary glycemic load and low cereal fiber intake, which would include
those who ate large amounts of white bread or white rice, had two and one half times the riskof diabetes compared to women with low glycemic load and high cereal fiber intake (figure
21).

Also, women who drank one coke or other sugar sweetened soda beverage daily, avery large source of sugar for many people, had nearly double the risk of type 2 diabetes(figure 22).

figure 19- 42 -

figure 20

figure 21

figure 22- 43 -

One fundamentally important discovery over the last decade has been that the adverse
metabolic effects of a high dietary glycemic load are greatly magnified in persons with agreater higher degree of insulin resistance. In other words, large surges of blood glucose dueto the ingestion of high intakes of refined starch or sugar have a greater negative effect onblood lipid fractions in persons who cannot move glucose efficiently into cells because of
insulin resistance. In our large population studies, we cannot measure insulin resistancedirectly, so we use body mass index as a surrogate because it is the most important cause of
insulin resistance. As an example, as dietary glycemic load increases, we see increasinglevels of fasting levels of triglycerides in the blood, which is a sensitive indicator of theadverse metabolic changes that occur with insulin resistance and type 2 diabetes. This
increase is seen in women with a BMI of less than 25, but the rise is four times greater among
women who have higher insulin resistance due to being overweight (figure 23). Similarly,
we saw an overall two-fold increase risk of coronary heart disease with high dietary glycemicload, but in the very leanest women there was little increase in risk (figure 24).

These

findings have implications for all populations, but especially for those in Asia, both becauseof the common genetic predisposition to insulin resistance and because traditional diets basedon white rice have a high glycemic load. With changes in lifestyle that lead to reductions inphysical activity and even small gains in weight, insulin resistance develops, and the same
diet that was compatible with low rates of diabetes can then become a cause of high rates ofdiabetes. This provides an interesting and important example of how nutrition can interact
with other aspects of our environment and lifestyle to influence our health and well being.

figure 23- 44 -

figure 24

Alcohol and Folic Acid
Another important interaction we have observed is that between alcohol consumption andfolic acid. Many studies from all regions of the world have shown that persons who consume
moderate amounts of alcoholic beverages, but not large amounts, have lower risks of heartdisease. That is what we found in our cohort studies as well. Although the evidence is verystrong, some people have questioned whether alcohol itself is protective, and have proposedthat some other component of these beverages is responsible. However, using DNA samples
that we collected and stored, we found that a common variant of the gene for alcohol
dehydrogenase-3 (ADH3), an enzyme which metabolizes alcohol, was associated with bothblood levels of HDL cholesterol (the good cholesterol) and risk of heart disease, dependingon alcohol consumption (figure 25).

figure 25- 45 -

Specifically, the form of this gene that leads to slower breakdown of alcohol, and thus longer
time for alcohol to circulate, was related to higher HDL among moderate drinkers, but notamong nondrinkers. Similarly, the slowly metabolizing form of this gene was related tolower risk of heart disease among alcohol drinkers, but little association was seen among
nondrinkers.

Because people receive one form or another of this gene from their parents

more or less at random, and this gene is specifically involved in alcohol metabolism, theseassociations provide strong evidence that alcohol itself does reduce risk of heart disease.
When we looked at alcohol consumption and folic acid intake at the same time, we found that
there was only a modest benefit of folic acid among nondrinkers (figure 26).

figure 26

However, among drinkers, higher intake of folic acid was associated with a substantiallylower risk, probably in part because folic acid reduces blood levels of homocysteine. This isconsistent with other data indicating that alcohol consumption can inactivate folic acid andthus increase the requirements of this vitamin. Interestingly, most persons in the highest
category of folic acid intake achieved this by taking a multiple vitamin.
In contrast to heart disease, alcohol consumption modestly increases risks of breast and coloncancer (figure 27).

- 46 -

figure 27

Even one drink a day can increase breast cancer risk by about 10 percent. Fortunately, thisexcess risk appears to be limited to women who have inadequate intake of folic acid (figure
28).

figure 28

Among women with adequate folic acid intake, those who consumed alcohol did notexperience an increase in risk of breast cancer. In an analysis led by Dr. Giovannucci, we
saw a similar pattern for colon cancer; overall, risk of colon cancer increased with greater
alcohol consumption, but if folic acid intake was adequate there was little increase in risk.
Thus, adequate folic acid intake is important for everyone, but especially for those who
consume alcohol, even if only one drink a day. Although eating many fruits and vegetables
will increase intake of folic acid, and has many other health benefits, the most reliable way toassure adequate folic acid intake is to consume a multiple vitamin containing folic acid.
- 47 -

Breast Cancer
Because of the strong correlation among countries between national per capita intake of fat
and rate of breast cancer, we have examined this relation in detail within the Nurses’ HealthStudy. In our first report after six years of follow-up, we found no association. Because of
the strong belief in this relationship, this finding was controversial. However, with longer
follow-up the number of cases of breast cancer has grown rapidly and we have still seen no
relation between fat intake in mid life or later and risk of breast cancer, and this lack ofassociation has now been seen in many studies. For example, after fourteen years of followup, nearly 3000 women in the Nurses’ Healthy Study had developed breast cancer and there
was still no association (figure 29).

figure 29

If anything, the risk was slightly higher among women with the lowest fat intake. We arenow examining the results after twenty years of follow-up, and still there is no hint of apositive association.
This of course leaves unanswered the reason for the large difference in rates of breast cancer
between the U.S. and Japan, which have been particularly strong for postmenopausal women.
Our findings indicate that much of this difference is due to two factors: weight gain during
adult life and the use of postmenopausal hormones, which have been widely used by U.S.
women (figure 30).

- 48 -

figure 30

As can be seen, all women who used postmenopausal hormones had an elevated risk of breast
cancer, and among those who never used them, risk of breast cancer increased steadily withweight gain after age 18. Thus, the only women at relatively low risk were those who neverused hormone replacements and who also avoided weight gain during adult life.

In ourpopulation only about 5% of women fell into this low risk category, but at least until recently
most Japanese women were in this low risk group. The combination of hormone replacement
therapy and weight gain accounted for about half of breast cancer deaths in our population,and thus the majority of the difference between the U.S. and Japanese rates of breast cancer.
Recently, we have been able to examine dietary factors during early adult life and risk ofbreast cancer during the premenopausal years within the Nurses’ Healthy Study II cohort.
These women were 25 to 42 year of age when we enrolled them in 1989. As in the earlier
study in somewhat older women, we found little relation between total fat intake and risk ofbreast cancer. However, when we broke this down into animal fat and vegetable fat, weobserved an increasing risk of breast cancer with higher intake of animal fat, but not withvegetable fat (figure 31).

- 49 -

figure 31

This positive association with animal fat was only seen with breast cancers that had estrogen
receptors, which suggested a hormonal basis of the relation. When we examined the sourcesof animal fat separately, we found that the elevated risk was mainly due to high fat dairy
products. This has led us to investigate the possibility that hormones in milk products might
be contributing to the increase in risk. While this work is ongoing, the topic has become ofgreat interest to us for several reasons. First, the methods of producing milk have changed
greatly over the last several decades, which have had a major impact on the hormone content
of milk. Presently in the U.S., and in Japan as I understand, to increase production cows are
now pregnant most of the time while they are being milked, which is not normal mammalian
behavior. Many hormones including estrogens, progesterone, and insulin-like growth factor1 (IGF-1) are greatly increased during pregnancy, and these are excreted in the milk. Thus, itwill be important to know whether these amounts of hormones have physiological effects. In
several cross-sectional analyses we found that milk consumption is positively associated withblood levels of IGF-1, which is of concern because IFG-1 levels have been associated withhigher risks of premenopausal breast cancer and cancers of the colon and prostate. The effectof milk on IFG-1 levels has now been supported by several randomized trials. IGF-1 haslong been known to be a primary factor in promoting growth of children, and height ispositively associated with risk of breast cancer, both in comparisons among countries (figure32) and within populations (figure 33).

Thus, increases in milk consumption may in part

explain the large increases in both height and breast cancer within Japan during the last
several decades. Also, in a recent analysis we found that milk consumption, including intake
of low fat milk, was related to higher prevalence of teenage acne, which further supports apossible role for hormones in milk as a contributing factor in human disease.

- 50 -

figure 32

figure 33

Prostate Cancer
Cancer of the prostate has been a leading cause of cancer death in men living in Westerncountries, and like other “Western” cancers, rates are rising rapidly in Japan. Prospective
studies of diet and prostate cancer have been relatively few because most of the early studies
included only women, thus research in this area is less well developed. The study of prostatecancer is also complicated by the fact that most men develop a rather benign form of thiscancer by the time that they are 60 or 70 years of age, and only a minority become aggressive,
spread, and cause death.

Thus far, several nutritional factors have emerged as being

potentially important. One of the most consistent findings in epidemiologic studies has been
- 51 -

a positive association between milk consumption and risk of prostate cancer, especially theaggressive or fatal forms. For example, in an earlier study by colleagues in California, men
who drank large amounts of milk had about three times the risk of death due to prostatecancer compared to those who drank little (figure 34) Initially this was thought to be due todue to the fat content of milk, but in a careful examination, we did not find support for this.
As noted above, milk does raise blood levels of IFG-1 levels, which may explain part of therelation. However, the results of our analyses suggest that the large amounts of calcium inmilk may be responsible because both calcium supplements and high milk intake appeared toincrease the risk of prostate cancer (figure 35).

We have also seen that lycopene, thepigment in tomatoes that makes them red, may be a protective factor.

Both higher

consumption of tomato products, especially tomato sauce, and blood levels of lycopene wereassociated with lower risk of prostate cancer (figure 36).

figure 34

figure 35- 52 -

figure 36

Vitamin D: ongoing work
At present, vitamin D is one of the most active topics of our research. Vitamin D is different
than most other nutrients because the main natural source is from sunlight, which activates
vitamin D in the skin. Fatty fish is really the only substantial natural source, but we now also
get vitamin D from fortified foods and from supplements.

For years we have known thatvitamin D is essential for the prevention of rickets in children, and there is now muchevidence that the intakes of both adults and children in many parts of the world aresuboptimal. Part of the reason for low blood levels of vitamin D is that we have migrated
from the warm, sunny climates where we evolved and are now living in areas where sunlightis much less. In fact, in parts of the world close to or above the 40th degree parallel, which
includes much of the U.S and Japan, the sun is not high enough above the horizon to activate
vitamin D during the winter months, and the blood levels of many people drop to thedeficiency range. Levels are also much lower in persons with darker skin simply because themelanin blocks the ultraviolet rays, which leads to lower rates of skin cancer but also lower
synthesis of vitamin D. Modern behaviors also lead to lower levels of vitamin D. Instead of
spending daylight hours hunting, farming, or walking outdoors as our grandparents did, we
spend most of our daylight hours in cars, subways, or inside building, which prevents
sunlight from reaching our skin. Even more recently, we have learned to avoid sunlight as amethod of reducing the aging of skin and skin cancer.
Many recent lines of evidence indicate that there is a high price for not having enoughvitamin D. Not surprisingly, we found that women with low intakes of vitamin D have an
elevated risk of bone fractures, as shown in the Nurses’ Health Study (figure 37).
- 53 -

figure 37

Randomized trials have shown that the current recommended amounts, 400 international
units per day in the U.S., are not enough to reduce fracture risk; approximately double thisamount is required. However, we have also come to appreciate that there are many otherconsequences of inadequate vitamin D, including elevated risks of cancer, muscle weakness
and falls in the elderly, and possibly multiple sclerosis and other conditions.

Using blood

samples that we collected from participants in the Nurses’ Health Study in 1989, we recently
reported that women with low blood levels of vitamin D have approximately twice the futurerisk of colon cancer compared to women with higher levels (figure 38).

figure 38

Importantly all of these women had blood vitamin D levels that are considered normal bycurrent standards, which suggests that our definition of normal vitamin D status needs to bechanged. In our ongoing work, we find that both men and women who have higher intakes ofvitamin D from fortified foods and supplements have lower rates of many cancers, including- 54 -

cancers of the colon, breast, prostate, and lung. Thus it appears that taking adequate amountsof vitamin D, which is higher than the currently recommended intakes, can have enormous
health benefits. For most people, the easiest and best way to achieve adequate intake will be
as supplements.
A related finding is that too much vitamin A in the form of retinol appears to counteract thebeneficial effects of vitamin D. In natural diets, most of the vitamin A comes in the form ofbeta-carotene, which is obtained from orange and green, leafy vegetables. Vitamin A in theform of retinol is abundant in few natural sources, liver being the primary one. However,many people now consume quite large amounts of vitamin A as retinol because this is used tofortify foods, such as milk and breakfast cereals, and is the form usually used in vitaminsupplements. In the Nurses’ Health Study we found that women with higher intakes ofretinol, even at the amounts that are currently being recommended, had a higher risk of hip
fractures than women with lower intakes (figure 39).

figure 39

Subsequent work by others has shown that retinol can interfere with the action of vitamin D
by blocking the receptor for vitamin D in cells.

Thus, vitamin A supplements should

primarily be in the form of beta-carotene rather than retinol.

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The Combined Benefit of Multiple Healthy Behaviors
These few examples indicate how various aspects of diet can impact our wellbeing, either
adversely or beneficially. We have recently conducted a series of analyses to estimate thepotential combined effect of multiple healthy diet and lifestyle choices on risk of several
important health outcomes (figure 40).

figure 40

To do this for myocardial infarction or death from coronary heart disease, we defined a low
risk group, which was characterized by not smoking, BMI below 25, moderate physicalactivity, healthy diet (defined as low trans fat, high ratio of polyunsaturated to saturated fat,low glycemic load, high cereal fiber, fish intake twice a week or more, and adequate folicacid), and moderate alcohol consumption, which is of course optional. Surprisingly to us,
only 3% of the women in the Nurses’ Health Study were in this low risk group. However,based on 14 years of follow-up, we found that over 80% of coronary heart disease might havebeen avoided if everyone had adopted these behaviors. We have also found that almost allthese same behaviors, with the exception of folic acid and fish intake, are related to risk oftype 2 diabetes. In a similar analysis, we found that over 90% of type 2 diabetes might havebeen avoided with these healthy behaviors, which again reinforces the conclusion that thisdisease is not inevitable, even for those with a genetic predisposition (figure 41). Many ofthese same dietary and lifestyle factors are also related to risks of important cancers. For
example, we found that not smoking cigarettes, regular physical activity physical activity,
avoidance of overweight, and a dietary pattern with low amounts of red meat and adequate
folic acid were related to lower risks of colon cancer (figure 42). We found that over 70% ofcolon cancer in our population could be avoided by the adoption of these healthy behaviors.

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Our recent findings for vitamin D suggest that the avoidable percent can be increased evenfurther by taking 800 to 1000 international units as a supplement.

figure 41

figure 42

This description of our work provides only a small sample of what we have learned over thelast 25 years. Because much of this can be directly beneficial to those who are interested in
improving their health, with the help of my colleagues I have written a nontechnical book fora general audience called “Eat, Drink, and Be Healthy: The Harvard Medical School Guide
to Healthy Eating”. My technical book, meant as a textbook for those who want to conduct
this type of research, or to interpret findings from such studies, is called “Nutritional
Epidemiology” (figure 43). I am deeply honored and grateful that my Japanese colleagues,
Drs. Tanaka and Maeda, who are themselves leading scientists, have translated these books
into Japanese so that they are available to readers in this country (figure 44).
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figure 43

figure 44

Of course, it is reasonable to ask why anyone in Japan would want to read about a book about
diet and health based largely on data from the U.S. because Japan at present has the best life
expectancy of any large country. Indeed, we in the West can benefit by learning about
nutrition and health in Japan, including the great appreciation for the quality and presentationof food. However, it is a reality that many people in Japan are incorporating Western foods
into their diets, and it will be important to understand that some of these can have adverse
effects, whereas some of these foods can be both enjoyable and healthy.

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Nutritional Epidemiology and Eco-technology
When I first learned that I would be receiving an award from the Honda Foundation for ecotechnology, I was very surprised because I had not thought of my work as eco-technology.
However, upon learning more about the world vision of Mr. Honda, I have come toappreciate the breadth of his understanding and goals. Human health and well being certainly
fits within his goals, and it is interesting to consider how our work has used technology toachieve them. The results that I have described this evening are completely dependent on
many forms of technology, including sophisticated biochemical methods to define andmeasure components of diets, and also modern methods of genetic analysis. From the
beginning, our research has been completely dependent on powerful computing hardware andsoftware, and our demands have grown enormously as the amount of data has multiplied
many times and our statistical methods have become more complex. Thus, in a very directway, we have used many forms of modern technology to understand the consequences ofsimple human acts, such as choices among the foods we put in our mouths.
Our research has also emphasized the importance of the environment in human health anddisease, with the food aspect of the environment being a critical component. Until very
recently, humans were obligated to eat primarily what could be produced by their local
environment. Thus, northern Europe was heavily dependent on dairy foods, which allowed
survival in a cold and hostile climate, fish became a dominant part of the diet of Japan, which
is surrounded by the sea, and olive oil was a key element of the Mediterranean cuisine
because the olive tree provided a reliable source of food energy in a arid and rugged
countryside.

Not all of these were equally conducive to long term health, and we havelearned much from these natural experiments.

Today, because of improved transportation

and better preservation technology, we have choices that were unknown to earlier generations.
It is my hope that through better information about the consequences of these options,individuals and the food industry will be able to make more informed decisions that will
enhance human well being.
Finally, healthy food can only be produced from a healthy environment. Thus, all the effortsof Soichiro and Benjiro Honda to sustain our global environment are ultimately linked with
the issues that I have described today. In closing I again want to thank the Honda Foundation
and all those who have made this event possible for their continuing efforts to make the world
a better place in which to live.

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