The Best Dietetic Priciples To Life Extension Text

Causes of Death in the US

McGinnis JM, Foege WH. JAMA. 1993 Nov 10;270(18):2207-12

JAMA. 1993 Nov 10;270(18):2207-12. Links
Comment in:
JAMA. 1994 Mar 2;271(9):659-60; author reply 660-1.
JAMA. 1994 Mar 2;271(9):659; author reply 660-1.
Actual causes of death in the United States.
McGinnis JM,
Foege WH.
US Department of Health and Human Services, Washington, DC 20201.
OBJECTIVE--To identify and quantify the major external (nongenetic) factors that contribute
to death in the United States. DATA SOURCES--Articles published between 1977 and 1993
were identified through MEDLINE searches, reference citations, and expert consultation.
Government reports and complications of vital statistics and surveillance data were also
obtained. STUDY SELECTION--Sources selected were those that were often cited and those
that indicated a quantitative assessment of the relative contributions of various factors to
mortality and morbidity. DATA EXTRACTION--Data used were those for which specific
methodological assumptions were stated. A table quantifying the contributions of leading
factors was constructed using actual counts, generally accepted estimates, and calculated
estimates that were developed by summing various individual estimates and correcting to
avoid double counting. For the factors of greatest complexity and uncertainty (diet and
activity patterns and toxic agents), a conservative approach was taken by choosing the lower
boundaries of the various estimates. DATA SYNTHESIS--The most prominent contributors
to mortality in the United States in 1990 were tobacco (an estimated 400,000 deaths), diet and
activity patterns (300,000), alcohol (100,000), microbial agents (90,000), toxic agents
(60,000), firearms (35,000), sexual behavior (30,000), motor vehicles (25,000), and illicit use
of drugs (20,000). Socioeconomic status and access to medical care are also important
contributors, but difficult to quantify independent of the other factors cited. Because the
studies reviewed used different approaches to derive estimates, the stated numbers should be
viewed as first approximations. CONCLUSIONS--Approximately half of all deaths that

occurred in 1990 could be attributed to the factors identified. Although no attempt was made
to further quantify the impact of these factors on morbidity and quality of life, the public
health burden they impose is considerable and offers guidance for shaping health policy
priorities.
PMID: 8411605 [PubMed - indexed for MEDLINE]

Causes of Death in the US

Table 2. Actual Causes of Death in the United States in 1990 and 2000

Mokdad AH et al. JAMA. 2004 Mar 10;291(10):1238-45

JAMA. 2004 Mar 10;291(10):1238-45. Links
Erratum in:
JAMA. 2005 Jan 19;293(3):293-4.
JAMA. 2005 Jan 19;293(3):298.
Comment in:
JAMA. 2004 Jun 23;291(24):2941-2; author reply 2942-3.
JAMA. 2004 Jun 23;291(24):2941; author reply 2942-3.
JAMA. 2004 Mar 10;291(10):1263-4.

Actual causes of death in the United States, 2000.
Mokdad AH,
Marks JS,
Stroup DF,
Gerberding JL.
Division of Adult and Community Health, Centers for Disease Control and Prevention,
Atlanta, Ga, USA. amokdad@cdc.gov
CONTEXT: Modifiable behavioral risk factors are leading causes of mortality in the United
States. Quantifying these will provide insight into the effects of recent trends and the
implications of missed prevention opportunities. OBJECTIVES: To identify and quantify the
leading causes of mortality in the United States. DESIGN: Comprehensive MEDLINE search
of English-language articles that identified epidemiological, clinical, and laboratory studies
linking risk behaviors and mortality. The search was initially restricted to articles published

during or after 1990, but we later included relevant articles published in 1980 to December
31, 2002. Prevalence and relative risk were identified during the literature search. We used
2000 mortality data reported to the Centers for Disease Control and Prevention to identify the
causes and number of deaths. The estimates of cause of death were computed by multiplying
estimates of the cause-attributable fraction of preventable deaths with the total mortality data.
MAIN OUTCOME MEASURES: Actual causes of death. RESULTS: The leading causes of
death in 2000 were tobacco (435 000 deaths; 18.1% of total US deaths), poor diet and
physical inactivity (365 000 deaths; 15.2%) [corrected], and alcohol consumption (85 000
deaths; 3.5%). Other actual causes of death were microbial agents (75 000), toxic agents (55
000), motor vehicle crashes (43 000), incidents involving firearms (29 000), sexual behaviors
(20 000), and illicit use of drugs (17 000). CONCLUSIONS: These analyses show that
smoking remains the leading cause of mortality. However, poor diet and physical inactivity
may soon overtake tobacco as the leading cause of death. These findings, along with
escalating health care costs and aging population, argue persuasively that the need to establish
a more preventive orientation in the US health care and public health systems has become
more urgent.

Related Links
Actual causes of death in the United States. [JAMA. 1993] PMID: 8411605
The modifiable factors contributing to leading causes of death in South Carolina. [J S C Med
Assoc. 1999] PMID: 10389384
Youth risk behavior surveillance--United States, 2001. [MMWR Surveill Summ. 2002]
PMID: 12102329
Youth risk behavior surveillance--United States, 1999. [MMWR CDC Surveill Summ. 2000]
PMID: 12412614
Surveillance for traumatic brain injury deaths--United States, 1989-1998. [MMWR Surveill
Summ. 2002] PMID: 12529087
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Short-term calorie restriction
=> ↑ longevity of tumor-bearing rats
Periodically diet-restricted rats
(food regimen: alternate day ad libitum
feeding followed by alternate day fasting)
Rats Diet- 9 days
unrestricted after t. i.
surviviving 80
10 days
(%) control rats after t. i.
60 66.7%
9 days after
n = 3-4-month-old tumor
10 days 50 %
ttumor-bearing 40 inoculation
Fisher rats) after t. i.

20
20.8 %
12.5 %
0
Short-term alternate day-dietary-restriction initiated 1 week before
intraperitoneal inoculation of ascites tumor cells
Siegel I, et al. Cancer Invest. 1988;6(6):677-80

Siegel I, Liu TL, Nepomuceno N, Gleicher N. Effects of short-term dietary restriction on
survival of mammary ascites tumor-bearing rats. Cancer Invest. 1988;6(6):677-80 Department
of Obstetrics and Gynecology, Mount Sinai Hospital Medical Center, Chicago, Illinois.We
studied the effects of short-term dietary restriction on the survival of3-4-month-old tumor-free
and tumor-bearing Fisher rats. The diet-restricted foodregimen consisted of alternate day ad
libitum feeding followed by alternate dayfasting. Diet-unrestricted control rats were fed ad
libitum daily. Sixtumor-free rats on the diet-restricted regimen compensated for the
dietaryrestriction by an increase in food consumption during the alternate feedingdays, and
lost an average of only 2-3% of their weight in 13 days. Sixtumor-free rats on a daily ad
libitum feeding regimen gained an average of 6.8%in 15 days. The above dietary-restricted
regimen was initiated 1 week before 24rats were inoculated intraperitoneally with 15 million
Mat 13762 ascites tumorcells. Sixteen of 24 (66.7%) diet-restricted tumor-bearing hosts and
5/24(20.8%) diet-unrestricted tumor-bearing hosts survived at 9 days after tumorinoculation
(p less than 0.005). Twelve of 24 (50%) diet-restrictedtumor-bearing hosts, and 3 of 24
(12.5%) diet-unrestricted tumor-bearing hosts,survived at 10 days after tumor inoculation (p
less than 0.025). Thus, thesurvival of tumor-bearing rats was enhanced by short-term
relatively milddietary restrictions. We suggest that relatively mild dietary restrictionsshould
be included in clinical trials designed to inhibit cancer growth and enhance the survival of
human cancer patients.PMID: 3245934 [PubMed - indexed for MEDLINE]

↑ Glucose diet => ↓ life span of mice
Average life
Average life span
span of the 70
of 7 oldest mice
mice

1000 -6,4 %
Survival Control diet
20 % glucose
800 diet
-10 %
(days ) 600
400
200
0
n = 70 n = 70 n=7 n=7
p < 0.05 p < 0.05

Mlekusch W et al. Mech Ageing Dev 1996 Nov 29;92(1):43-51

Mech Ageing Dev. 1996 Nov 29;92(1):43-51. Links

A glucose-rich diet shortens longevity of mice.
Mlekusch W,
Lamprecht M,
Ottl K,
Tillian M,
Reibnegger G.
Institute of Medical Chemistry and Pregl Laboratory, Karl-Franzens-Universitat-Graz,
Austria.

High plasma levels of glucose and insulin over long-time periods play an important role in the
genesis of diabetic complications. There is evidence that the long term consumption of
glucose-rich diet by rats is detrimental to insulin sensitivity. We investigated the effect of a
glucose-rich diet on longevity of 70 female mice which were compared to 70 mice on a
control diet. The average age of death of the control group was 568 +/- 139 days compared to
511 +/- 170 for the glucose group and the seven oldest mice of the control group died at age
890 +/- 52 days, while the seven oldest mice of the glucose group died at 833 +/- 49 days.
These differences are statistically significant (P < or = 0.05). Our work shows that a life-long
intake of a diet with 20% of total energy derived from glucose leads to a significant reduction
of the average and maximal life-span in female mice and thus, supports previous observations
of detrimental effects of high glucose intake over long periods.

Starch intake => ↑ risk of Prostate cancer

HIGHEST quintile of intake of
Prostate cancer
(odds Ratio) Starch
1.5 LOWEST Linolenic Linoleic
quintile +40 % acid (Ω3) acid (Ω6)
large-scale 1 -30 % -20%
Italian cohort
study; 1294
cases 0.5
1.4 0.7 0.8

0 p < 0.05 p< 0.05 p< 0.05

Bidoli E et al. Ann Oncol. 2005 Jan;16(1):152-7

Ann Oncol. 2005 Jan;16(1):152-7. Links

Macronutrients, fatty acids, cholesterol and prostate cancer risk.
Bidoli E,
Talamini R,
Bosetti C,
Negri E,
Maruzzi D,
Montella M,
Franceschi S,
La Vecchia C.
Servizio di Epidemiologia e Biostatistica, Centro di Riferimento Oncologico, Aviano (PN),
Italy. epidemiology@cro.it
BACKGROUND: The role of selected macronutrients, fatty acids and cholesterol in the
etiology of prostate cancer was analyzed using data from a case-control study carried out in
five Italian areas between 1991 and 2002. PATIENTS AND METHODS: Cases were 1294
men with incident, histologically confirmed prostate cancer, and admitted to the major
teaching and general hospitals of study areas. Controls were 1451 men admitted for acute,

non-neoplastic conditions to the same hospital network. Information on dietary habits was
elicited using a validated food frequency questionnaire including 78 food groups and recipes.
Odds ratios (OR) and 95% confidence intervals (CI) were estimated for increasing levels of
nutrient intake. RESULTS: A direct association with prostate cancer was found for starch
intake (OR = 1.4 in the highest versus the lowest quintile of intake; 95% CI: 1.1-1.8), whereas
an inverse association emerged for polyunsaturated fatty acids (OR = 0.8; 95% CI: 0.6-1.0).
Among polyunsaturated fatty acids, linolenic acid (OR = 0.7; 95% CI: 0.6-0.9) and linoleic
acid (OR = 0.8; 95% CI: 0.6-1.0) were inversely related to prostate cancer. When the six
major macronutrients were included in the same model, the adverse effect of high intake of
starch and monounsaturated fatty acids was statistically significant together with the
protective effect of polyunsaturated fatty acids. Results were consistent in separate strata of
age, body mass index and family history of prostate cancer. CONCLUSIONS: Starch and
monounsaturated fatty acids were directly associated with prostate cancer risk and
polyunsaturated fatty acids were inversely associated.

Stroke Cancer CVD
Apoptosis –
Cell proliferation +

Hypertension Atherosclerosis Diabetes Dyslipidemia
Metabolic Syndrome
Gonadal and adrenal
IGF1 stimulation Sex
Bioavailability + Hormones +

Pathogenesis Insulin +
SHBG -

FFA +
TNF a +
IL-6 +
Insulin resistance (IR) NADPH oxidase +
Antioxidant
Resistin + enzymes -
Adiponectin -

Aromatase +

Inflammation Oxidative Stress
ER Stress ROS
Risc Factor

Genetics Obesity Lifestyle Environment

Adapded from: Jee SH et al. Yonsei Med J. 2005 Aug 31;46(4):449-55

Yonsei Med J. 2005 Aug 31;46(4):449-55. Links

Obesity, insulin resistance and cancer risk.
Jee SH,
Kim HJ,
Lee J.
Department of Epidemiology and Health Promotion, Graduate School of Public Health,
Yonsei University, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-752, Korea.
jsunha@yumc.yonsei.ac.kr
Obesity is a known cause of metabolic syndrome which includes Type II diabetes,
hypertension, and dyslipidemia. It is well documented that insulin resistance contributes to the
mortality and the incidence of metabolic syndromes including central obesity, dyslipidemia,
hyperglycemia and hypertension. Both obesity and diabetes are emerging topics for
researchers to consider as having a possible causal association with cancer since the two
factors have been viewed as risk factors for cancer. The present paper introduced the

hypothesis of a possible causal relationship between obesity, insulin resistance and cancer and
reviews relevant existing studies in this area. More efforts and studies are needed to clarify
the mechanisms and the common risk factors which might be incorporated into interventions
to prevent cancer and cardiovascular diseases as top causes of death.

Relationship between fasting serum
glucose and risk of cancer
Hazard ratios for
all cancer deaths
by fasting serum
glucose levels in
Korean men
according to body
mass index, 1993-
2002

Jee SH et al. JAMA 2005 Jan 12;293(2):194-202

JAMA. 2005 Jan 12;293(2):194-202. Links
Comment in:
JAMA. 2005 Jan 12;293(2):235-6.
JAMA. 2005 May 11;293(18):2210-1; author reply 2211.

Fasting serum glucose level and cancer risk in Korean men and women.
Jee SH,
Ohrr H,
Sull JW,
Yun JE,
Ji M,
Samet JM.
Department of Epidemiology and Health Promotion, Graduate School of Public Health,
Yonsei University, Seoul, Korea. jsunha@yumc.yonsei.ac.kr
CONTEXT: Diabetes is a serious and costly disease that is becoming increasingly common in
many countries. The role of diabetes as a cancer risk factor remains unclear. OBJECTIVE: To
examine the relationship between fasting serum glucose and diabetes and risk of all cancers
and specific cancers in men and women in Korea. DESIGN, SETTING, AND
PARTICIPANTS: Ten-year prospective cohort study of 1,298,385 Koreans (829,770 men and
468,615 women) aged 30 to 95 years who received health insurance from the National Health
Insurance Corp and had a biennial medical evaluation in 1992-1995 (with follow-up for up to
10 years). MAIN OUTCOME MEASURES: Death from cancer and registry-documented
incident cancer or hospital admission for cancer. RESULTS: During the 10 years of follow-
up, there were 20,566 cancer deaths in men and 5907 cancer deaths in women. Using Cox
proportional hazards models and controlling for smoking and alcohol use, the stratum with the

highest fasting serum glucose (> or =140 mg/dL [> or =7.8 mmol/L]) had higher death rates
from all cancers combined (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.22-1.37
in men and HR, 1.23; 95% CI, 1.09-1.39 in women) compared with the stratum with the
lowest level (<90 mg/dL [<5.0 mmol/L]). By cancer site, the association was strongest for
pancreatic cancer, comparing the highest and lowest strata in men (HR, 1.91; 95% CI, 1.52-
2.41) and in women (HR, 2.05; 95% CI, 1.43-2.93). Significant associations were also found
for cancers of the esophagus, liver, and colon/rectum in men and of the liver and cervix in
women, and there were significant trends with glucose level for cancers of the esophagus,
colon/rectum, liver, pancreas, and bile duct in men and of the liver and pancreas in women.
Of the 26,473 total cancer deaths in men and women, 848 were estimated as attributable to
having a fasting serum glucose level of less than 90 mg/dL. For cancer incidence, the general
patterns reflected those found for mortality. For persons with a diagnosis of diabetes or a
fasting serum glucose level greater than 125 mg/dL (6.9 mmol/L), risks for cancer incidence
and mortality were generally elevated compared with those without diabetes. CONCLUSION:
In Korea, elevated fasting serum glucose levels and a diagnosis of diabetes are independent
risk factors for several major cancers, and the risk tends to increase with an increased level of
fasting serum glucose.

Caffeine drinking => ↑ mammary
carcinoma incidence
Female BD2F1 mice Female C3H mice
Change in DMBA-induced BC spontaneous BC
incidence Caffeine 500 mg/l
of + 117 %
mammary 120
carcinoma 100 Caffeine 250 mg/l Caffeine 500 mg/l
80
+ 20 % + 40 % Caffeine 250 mg/l
60
(% more mice 40 + 13 %
with 20
breast cancer) 0
NS p < 0.05 NS p < 0.05
Increased incidence of DMBA carcinogen-induced mammary carcinoma’s in BD2F1 &
C3H mice drinking caffeine in drinking water starting at 8 weeks of age to experiment
termination. Mammary gland development was sign. increased in high caffeine BALB/c
mice.
Welsch CW et al. Cancer Res 1988 Apr 15;48(8):2078-82

Cancer Res. 1988 Apr 15;48(8):2078-82. Links
Influence of caffeine consumption on carcinomatous and normal mammary gland
development in mice.
Welsch CW,
DeHoog JV,
O'Connor DH.
Department of Anatomy, Michigan State University, East Lansing 48824.
The influence of caffeine consumption on the development of 7,12-
dimethylbenz(a)anthracene-induced mammary carcinomas in BD2F1 female mice and
spontaneous mammary carcinomas in nulliparous C3H mice was examined. Caffeine (250
and 500 mg/liter of drinking water) was administered to BD2F1 mice commencing 1 week
after a series of 6 weekly 7,12-dimethylbenz(a)anthracene intubations, until experiment

termination. Caffeine was administered to C3H mice (via drinking water) commencing at 8
weeks of age to experiment termination. In BD2F1 mice receiving 250 and 500 mg of
caffeine, mammary carcinoma multiplicity (number of mammary carcinomas/mouse) was
increased by 20 and 40%, respectively. In C3H mice receiving 250 and 500 mg caffeine,
mammary carcinoma multiplicity was increased by 13 and 117%, respectively. In both
BD2F1 and C3H mice, the higher dose level of caffeine resulted in a significant (P less than
0.05) increase in mammary carcinoma multiplicity. Caffeine consumption did not
significantly effect the percentage of mice bearing mammary carcinomas or the mean latency
period of mammary tumor appearance. In a second series of studies, the influence of caffeine
consumption on mammary gland development in female BALB/c mice was assessed in vivo
and in vitro (organ culture). In mice consuming caffeine (500 mg/liter of drinking water),
mammary gland development was significantly (P less than 0.05) increased compared to
control mice; this difference in mammae development was more conspicuous in mice treated
with mammotropic hormones. In the organ culture studies, mammary glands derived from
caffeine (500 mg/liter of drinking water) consuming BALB/c mice were more responsive in
vitro to a mammotropic hormonal developmental growth stimulus than were mammae derived
from control mice (P less than 0.05). These results provide evidence that caffeine
consumption can enhance mammary tumorigenesis in C3H and carcinogen-treated BD2F1
female mice and, in addition, enhance developmental growth of the normal female mouse
(BALB/c) mammary gland.

Coffee => breast cancer risk: ↓ in
lean women,↑ in obese women
Lean women Heavier women
(BMI ≤ 24) (BMI ≥ 24)
Drinking ≥ 5 cups/day
2.5
Breast
Cancer 2 Drinking < 2 cups of Drinking < 2 cups of
coffee/day coffee/day
(Relative 1.5 2.1

Risk) Drinking ≥ 5 cups/day
1
1 1
0.5
0.5
0
Coffee consumption reduces the risk of breast cancer in lean women, but might increase it
in relatively obese women. This interaction between coffee intake & BMI was statist. sign.
n = 152 breast cancer cases among 14,593 Norwegian women ; mean follow-up = 12 yrs
Vatten et al. Br J Cancer. 1990 Aug;62(2):267-70

Br J Cancer. 1990 Aug;62(2):267-70. Links
Coffee consumption and the risk of breast cancer. A prospective study of 14,593
Norwegian women.
Vatten LJ,
Solvoll K,
Loken EB.
Department of Oncology, University Hospital, Trondheim, Norway.
The association between coffee consumption and the incidence rate of breast cancer has been
analysed in 152 incident cases of breast cancer that developed among 14,593 Norwegian

women during a mean follow-up of 12 years. At the time of inquiry they were between 35 and
51 years of age, and at the end of follow-up between 46 and 63. There was an overall weak
negative association between daily intake of coffee and risk of breast cancer, which was not
statistically significant. However, the association with coffee varied, depending on the body
mass index (BMI) of the women. In the lean (Quetelet less than 24; population mean) there
was an inverse relation between coffee intake and risk of breast cancer (chi 2 trend = 5.07, P =
0.02). In this group, women who reported drinking 5 cups or more per day had an age-
adjusted IRR of 0.5 (95% confidence intervals, 0.3 and 0.9) compared to women who had 2
cups or less. In women with Quetelet's index equal to or greater than 24 there was a positive
relation between coffee intake and breast cancer risk (chi 2 trend = 2.33, P = 0.13), where the
corresponding age-adjusted IRR was 2.1 (95% confidence intervals, 0.8 and 5.2). This
interaction effect between coffee intake and BMI was statistically significant (chi 2
interaction = 10.2, 3 d.f., P = 0.02). In summary, the results of this study suggest that coffee
consumption reduces the risk of breast cancer in lean women, whereas coffee might have the
opposite effect in relatively obese women.

Coffee => ↑ risk of bladder cancer
Heaviest
Heaviest coffee smokers
drinkers (highest quartile)
(highest quartile)
2.7
2,5
Relative 2.1
risk of 2 (95% CI:
bladder 1,5 Lowest quartile
1.8 to 4.0)
(95% CI:
cancer 1.3-3.2)
1
1
0,5
p < 0.05
p < 0.05
0

Coffee consumption was assoc. + increased risk for bladder cancer among the heaviest
coffee drinkers after adjustment for cigarette smoking & other dietary risk factors. The
effect was more pronounced among nonsmokers, esp. among those 65 yrs & older.
These findings support the contention that coffee is a weak carcinogen. After adjustment
for age, education, & dietary risk factors by multiple regression, risk of bladder cancer
was found to increase with increasing pack-years of cigarette use.

Vena JE et al. Ann Epidemiol. 1993;3(6):586-91

Ann Epidemiol. 1993 Nov;3(6):586-91. Links
Coffee, cigarette smoking, and bladder cancer in western New York.
Vena JE,
Freudenheim J,
Graham S,
Marshall J,
Zielezny M,
Swanson M,
Sufrin G.
Department of Social and Preventive Medicine, School of Medicine and Biomedical Sciences,
State University of New York at Buffalo.
The association between consumption of coffee and bladder cancer and the effect
modification of cigarette smoking was investigated as part of a comprehensive case-control
study. The study population consisted of 351 case patients with histologically confirmed

transitional cell carcinomas of the bladder among white males and 855 white male control
subjects selected from Erie, Niagara, and Monroe counties in New York from 1979 to 1985.
Usual diet, coffee consumption, and cigarette use were estimated by comprehensive
interviews using a detailed food frequency questionnaire. After adjustment for age, education,
and dietary risk factors by multiple logistic regression, risk was found to increase with
increasing pack-years of cigarette use with an odds ratio in the highest quartile of 2.7 (95%
confidence interval, 1.8 to 4.0) when compared to the lowest quartile. Coffee consumption
was associated with an increased risk for bladder cancer among the heaviest coffee drinkers
after adjustment for cigarette smoking and other dietary risk factors (odds ratio, 2.1; 95%
confidence interval, 1.3 to 3.2). The effect was more pronounced among nonsmokers,
especially among those 65 years and older. These findings support the contention that coffee
is a weak carcinogen.

Caffeine increases BP
Laboratory studies over the last 20 yrs =>
consistently demonstrated
=> caffeine dose of 2 to 3 cups of brewed coffee
=> ↑ blood pressure (BP) at rest: + 7 to + 10 mm Hg
when administered either to "caffeine-naive" individuals or to
habitual coffee drinkers after overnight abstinence.
=> ↑ BP reach a max. 30 to 60 minutes after caffeine
administration & persist for several hours.

Lane JD et al. Psychosomatic Med 2002; 64:595-603
64:595-

Psychosom Med. 2002 Jul-Aug;64(4):595-603. Links

Caffeine affects cardiovascular and neuroendocrine activation at work and home.
Lane JD,
Pieper CF,
Phillips-Bute BG,
Bryant JE,
Kuhn CM.
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center,
Durham, NC 27710, USA. jdlane@acpub.duke.edu
OBJECTIVE: This study investigated the effects of moderate doses of caffeine on ambulatory
blood pressure and heart rate, urinary excretion of epinephrine, norepinephrine, and cortisol,
and subjective measures of stress during normal activities at work and at home in the evening.
METHODS: Healthy, nonsmoking, habitual coffee drinkers (N = 47) participated in 3 days of
ambulatory study. After a day of ad lib caffeine consumption, caffeine (500 mg) and placebo
were administered double-blind in counter-balanced order on separate workdays. Ambulatory
blood pressure and heart rate were monitored from the start of the workday until bedtime.

Urinary excretion of catecholamines and cortisol was assessed during the workday and
evening. RESULTS: Caffeine administration significantly raised average ambulatory blood
pressure during the workday and evening by 4/3 mm Hg and reduced average heart rate by 2
bpm. Caffeine also increased by 32% the levels of free epinephrine excreted during the
workday and the evening. In addition, caffeine amplified the increases in blood pressure and
heart rate associated with higher levels of self-reported stress during the activities of the day.
Effects were undiminished through the evening until bedtime. CONCLUSIONS: Caffeine has
significant hemodynamic and humoral effects in habitual coffee drinkers that persist for many
hours during the activities of everyday life. Furthermore, caffeine may exaggerate
sympathetic adrenal-medullary responses to the stressful events of normal daily life. Repeated
daily blood pressure elevations and increases in stress reactivity caused by caffeine
consumption could contribute to an increased risk of coronary heart disease in the adult
population.

Coffee => ↑ serum cholesterol
Serum Cholesterol
200
(mg/dl)
196 Increase of 1 cup of coffee per day = increase
of 2 mg/dl total cholesterol
192
(p < 0.001)
188

184
n = 2109 healthy nonsmokers aged 25-65 yrs
180
(mean follow-up = 16.7 months)

176

0 1 2 3 4 5 6 7 8 9 10
cups/day
A dose-response was found among those who decreased regular coffee consumption,
those who continued the same dose, & those who increased consumption. The same
trend was observed among those who quit drinking regular coffee, those who never
drank coffee, & those who started to coffee.
Wie M et al. J Clin Epidemiol. 1995 Oct;48(10):1189-96

J Clin Epidemiol. 1995 Oct;48(10):1189-96. Links

The impact of changes in coffee consumption on serum cholesterol.
Wei M,
Macera CA,
Hornung CA,
Blair SN.
Department of Internal Medicine, School of Medicine, University of South Carolina,
Columbia 29208, USA.
To investigate the possible association between changes in coffee consumption and serum
cholesterol levels, information was obtained from 2109 healthy nonsmokers aged 25-65 years
at two clinic visits to a preventive medical center between 1987 and 1991 (mean interval
between visits: 16.7 months). After adjusting for age and changes in other potential
confounders, about 2 mg/dl total cholesterol increase was associated with an increase of one
cup of regular coffee per day (p < 0.001). A dose-response was found among those who
decreased regular coffee consumption, those who continued the same dose, and those who

increased consumption. The same trend was observed among those who quit drinking regular
coffee, those who never drank coffee, and those who started to drink coffee. No change in
cholesterol level was found among those continuing to consume the same quantity of regular
coffee compared to those who never drank coffee. The change in cholesterol level was not
related to consumption of decaffeinated coffee, regular tea, decaffeinated tea, or cola with
caffeine. To our knowledge, this is the first follow-up study correlating change in coffee
consumption with change in serum cholesterol in a large group of men and women.

↑ citrus fruits & ↑ intake of vit. C, vit. B2 & linoleic acid
=> ↓ all- cause mortality in very elderly people
CITRUS FRUIT
consumption SUPPLEMENT intake

LOW
(< 1 x/wk) HIGH LOW
HIGH HIGH
1 (≥ 2 x/wk) VIT. C HIGH LINOLEIC
VIT. B2 ACID
1.0 -48 %
MORTALITY

-50 %
-60 %
0.5 0.52
(95% CI =
0.28 - 0.95)
0
5-year cohort study among n = 162 self-sufficient residents in a public home for elderly

Frequent consumption of citrus fruit, and high intake of vitamin C, riboflavin, &
linoleic (Ω6) acid are associated with longevity
Fortes C et al. Epidemiology. 2000 Jul;11(4):440-5

Epidemiology. 2000 Jul;11(4):440-5. Links

Diet and overall survival in a cohort of very elderly people.
Fortes C,
Forastiere F,
Farchi S,
Rapiti E,
Pastori G,
Perucci CA.
Department of Epidemiology, Lazio Regional Health Authority, Rome, Italy.
We conducted a 5-year cohort study among 162 self-sufficient residents in a public home for
the elderly in Rome, Italy, to evaluate the association between the consumption of specific
food groups and nutrients and overall 5-year survival. We used a validated, semiquantitative
food-frequency questionnaire to assess diet at baseline. Individuals consuming citrus fruit at
least twice a week had an adjusted risk of dying that was half that of individuals who
consumed citrus fruit less than once a week [relative risk (RR) = 0.52; 95% confidence
interval (CI) = 0.28-0.95] (with adjustment for gender, age, education, body mass index,
smoking status, cognitive function, and chronic diseases). The adjusted RRs of mortality were
0.38 (95% CI = 0.14-1.01) for consumption of milk and yogurt at least three times a week vs
less than once a week; 0.21 (95% CI = 0.08-0.35) for moderate consumption of espresso
coffee (1-2 cups weekly) vs less than once a week; and 0.35 (95% CI = 0.17-0.69) for > 2
cups a week of espresso coffee vs less than once a week. High levels of intake of ascorbic

acid, riboflavin, and linoleic acid were associated with 50-60% decreases in mortality risk.
High consumption of meat was associated with a higher risk of mortality (RR = 9.72; 95% CI
= 2.68-35.1) among subjects with chronic diseases. Our findings indicate that frequent
consumption of citrus fruit, milk, and yogurt; low consumption of meat; and high intake of
vitamin C, riboflavin, and linoleic acid are associated with longevity.

↑↑ Fruit & vegetable intake => ↓ mortality
Relative risk
of dying Fruit & vegetable intake
(11-yr mortality) (2th) Lowest (3th) Average (4th) Higher
(1st) Lowest (5th) Highest
quintile quintile quintile
1.2 quintile quintile
-6% - 11 %
1 - 22 %
1.08
0.8 1.0 (0.88- 0.94 0.87
1.33) (0.75- 0.78
0.6 (0.68-
(0.61-
1.17) 1.10)
0.4 1.01)
0.2
0
n = 15,792 (age 45-64 yrs) P for trend = 0.02

Over an 11-y follow-up period, the relative hazards of death for quintiles 2-5 of fruit &
vegetable intake were 1.08 (95% CI: 0.88-1.33) , 0.94 (0.75-1.17) , 0.87 (0.68-1.10) , & 0.78
(0.61-1.01), resp. Neither fruit, nor vegetable fiber intake were associated with incident
cardiovascular death (P =.98, =.95 resp.)
Steffen LM et al. Am J Clin Nutr. 2003 Sep; 78(3): 383-90

Am J Clin Nutr. 2003 Sep;78(3):383-90. Links
Comment in:
Am J Clin Nutr. 2003 Sep;78(3):357-8.

Associations of whole-grain, refined-grain, and fruit and vegetable consumption with
risks of all-cause mortality and incident coronary artery disease and ischemic stroke:
the Atherosclerosis Risk in Communities (ARIC) Study.
Steffen LM,
Jacobs DR Jr,
Stevens J,
Shahar E,
Carithers T,
Folsom AR.
Division of Epidemiology, University of Minnesota School of Public Health, Minneapolis,
55454, USA. steffen@epi.umn.edu
BACKGROUND: Recent epidemiologic study results showed that subjects who had high
intakes of whole-grain foods had lower risks of death and heart disease than did subjects who
had low intakes. However, the findings were inconsistent for fruit and vegetable intake.
OBJECTIVE: The relations of whole-grain, refined-grain, and fruit and vegetable intakes with
the risk of total mortality and the incidence of coronary artery disease (CAD) and ischemic
stroke were studied in the Atherosclerosis Risk in Communities (ARIC) cohort (baseline: age
45-64 y, n = 15,792). DESIGN: Proportional hazards regression analyses were used to assess
the relations of whole-grain, refined-grain, and fruit and vegetable intakes with the risk of
death and the incidence of CAD and ischemic stroke, with adjustment for age, sex, ethnicity,

energy intake, and cardiovascular disease risk factors. Dietary intakes were assessed by using
a food-frequency questionnaire. RESULTS: Over an 11-y follow-up period, whole-grain
intake was inversely associated with total mortality and incident CAD. The relative hazards of
death for quintiles 2-5 of fruit and vegetable intake were 1.08 (95% CI: 0.88, 1.33), 0.94
(0.75, 1.17), 0.87 (0.68, 1.10), and 0.78 (0.61, 1.01), respectively; P for trend = 0.02. An
inverse association between fruit and vegetable intake and CAD was observed among African
Americans but not among whites (P for interaction = 0.01). The risk of ischemic stroke was
not significantly related to whole-grain, refined-grain, or fruit and vegetable consumption.
CONCLUSION: These observational findings suggest a beneficial effect of whole-grain and
fruit and vegetable consumption on the risks of total mortality and incident CAD but not on
the risk of ischemic stroke.

Fruit & vegetable intake => ↓ risk of
hypertension
Upper quintiles
Lowest
Relative risk quintile
(adjusted Fruit
prevalence 1 Vegetable consumption
1
odds ratio) 0.8 consumption Fruit &
n = 4393 vegetable
0.6
0.68 consumption
0.58 (95 % CI:
0.4
(95 % CI: 0.43- 1.09) 0.23
0.2 0.36-0.91) (95 % CI:
0.43- 1.09)
0
P = 0.01 P = 0.10 P = 0.001

In a Mediterranean population with an elevated fat consumption (37 % of diet), a high
fruit & vegetable intake is inversely associated with BP levels
Alonso A et al. Br J Nutr. 2004;92(2):311-9

Br J Nutr. 2004 Aug;92(2):311-9. Links

Fruit and vegetable consumption is inversely associated with blood pressure in a
Mediterranean population with a high vegetable-fat intake: the Seguimiento
Universidad de Navarra (SUN) Study.
Alonso A,
de la Fuente C,
Martin-Arnau AM,
de Irala J,
Martinez JA,
Martinez-Gonzalez MA.
Department of Epidemiology and Public Health, University of Navarra, Pamplona, Spain.
There is evidence that a diet rich in fruit and vegetables reduces blood pressure (BP).
Characteristically, the Mediterranean diet is rich in plant-derived foods and also in fat, but
studies conducted in Mediterranean countries to relate diet to BP are scarce. We studied the
association between fruit and vegetable consumption and BP in a cross-sectional analysis of
4393 participants in the Seguimiento Universidad de Navarra (SUN) Study, an ongoing
dynamic cohort study in Spain. Diet was measured using a food-frequency questionnaire

previously validated in Spain. Fat represented more than 37 % total energy intake. Subjects
were considered to have undiagnosed hypertension if they reported systolic BP > or = 140
mmHg or diastolic BP > or = 90 mmHg, and not a medical diagnosis of hypertension. The
adjusted prevalence odds ratio of undiagnosed hypertension (upper v. lowest quintile) was
0.58 (95 % CI 0.36, 0.91; P for trend 0.01) for vegetable consumption and 0.68 (95 % CI
0.43, 1.09; P for trend 0.10) for fruit consumption. Comparing those in the highest quintile of
both fruit and vegetable consumption with those in the lowest quintile of both food groups,
the prevalence odds ratio was 0.23 (95 % CI 0.10, 0.55; P = 0.001), after adjusting for risk
factors for hypertension and other dietary exposures. In a Mediterranean population with an
elevated fat consumption, a high fruit and vegetable intake is inversely associated with BP
levels.

↑ Fruit & vegetable intake => ↓
cardiovascular and all cause mortality
FRUIT & VEGETABLE INTAKE ≥ 3x/day
Relative risk of
disease or death
Ischemic Cardiovascular
<1x/day heart disease All cause
Stroke
Stroke disease disease mortality
incidence
mortality mortality mortality
1 - 15%
- 27%
0.8 - 42% - 24% - 27%

0.6

0.4 0.73 0.58 0.76 0.73 0.85
0.2

0
n = 9608 adults aged 25-74 yr (average 19-yr follow-up) P = 0.02
An inverse association of fruit & vegetable intake with the risk of cardiovascular disease &
all-cause mortality was observed in the general US population.
Bazzano LA et al. Am J Clin Nutr. 2002 Jul; 76(1): 93-9

Am J Clin Nutr. 2002 Jul;76(1):93-9. Links
Comment in:
Am J Clin Nutr. 2002 Jul;76(1):1-2.

Fruit and vegetable intake and risk of cardiovascular disease in US adults: the first
National Health and Nutrition Examination Survey Epidemiologic Follow-up Study.
Bazzano LA,
He J,
Ogden LG,
Loria CM,
Vupputuri S,
Myers L,
Whelton PK.
Department of Epidemiology, Tulane University School of Public Health and Tropical
Medicine, New Orleans, LA 70112, USA.
BACKGROUND: Epidemiologic studies report inconsistent findings on the association of
fruit and vegetable intake with the risk of cardiovascular disease. OBJECTIVE: The objective
was to examine the relation between fruit and vegetable intake and the risk of cardiovascular

disease. DESIGN: We studied 9608 adults aged 25-74 y participating in the first National
Health and Nutrition Examination Survey Epidemiologic Follow-up Study and free of
cardiovascular disease at the time of their baseline examination between 1971 and 1975. Fruit
and vegetable intake at baseline was measured with a food-frequency questionnaire. The
incidence of and mortality from cardiovascular disease were obtained from medical records
and death certificates. RESULTS: Over an average of 19 y, 888 strokes (218 fatal), 1786
ischemic heart disease events (639 fatal), 1145 cardiovascular disease deaths, and 2530 all-
cause deaths were documented. Consuming fruit and vegetables > or = 3 times/d compared
with <1 time/d was associated with a 27% lower stroke incidence [relative risk (RR): 0.73;
95% CI: 0.57, 0.95; P for trend = 0.01), a 42% lower stroke mortality (0.58; 0.33, 1.02; P for
trend = 0.05), a 24% lower ischemic heart disease mortality (0.76; 0.56, 1.03; P for trend =
0.07), a 27% lower cardiovascular disease mortality (0.73; 0.58, 0.92; P for trend = 0.008),
and a 15% lower all-cause mortality (0.85; 0.72, 1.00; P for trend = 0.02) after adjustment for
established cardiovascular disease risk factors. CONCLUSION: We showed an inverse
association of fruit and vegetable intake with the risk of cardiovascular disease and all-cause
mortality in the general US population.

↑ Fruit & vegetable intake => ↓ cancer mortality
Overall cancer mortality Liver Stomach &
cancer lung cancer
(Almost) daily (Almost) daily green-
Relative risk Mean
of dying FRUIT intake yellow VEGETABLE (Amost) daily
Risk
from cancer FRUIT intake
- 12 % - 8 % intake
1 - 20%
- 25%
0.8
0.6 1.0 0.88 0.92 0.75 0.8
0.4 95%CI
= 0.80 0.94- 0.60- 0.65-
0.2
-0,96) 1,01) 0,95) 0.98)
0
P < 0.05 P < 0.05 P < 0.05 P < 0.05
38 540 men & women who were atomic-bomb survivors in Hiroshima & Nagasaki, Japan, were
followed-up for cancer deaths until March 1998, during which time 3136 cancer deaths were
identified.
Daily consumption of fruit & vegetables reduces the mortality from total cancer, &
specifically cancers of stomach, liver, & lung. Not statist. sign. associations were found w/
oesophageal cancer, but none w/ breast & colorectal cancer.
Sauvaget C et al. Br J Cancer. 2003; 88(5): 689-94

Br J Cancer. 2003 Mar 10;88(5):689-94. Links

Vegetables and fruit intake and cancer mortality in the Hiroshima/Nagasaki Life Span
Study.
Sauvaget C,
Nagano J,
Hayashi M,
Spencer E,
Shimizu Y,
Allen N.
Department of Epidemiology, Radiation Effects Research Foundation, Minami-ku,
Hiroshima, Japan. sauvaget@rerf.jp

The association between green-yellow vegetables and fruit consumption and risk of cancer
death was investigated in a prospective study of 38 540 men and women who were atomic-
bomb survivors in Hiroshima and Nagasaki, Japan. Study participants completed a dietary
questionnaire in 1980-1981 and were followed-up for cancer deaths until March 1998, during
which time 3136 cancer deaths were identified. Daily or almost daily fruit consumption was
associated with a significant 12% reduction in total cancer mortality (RR=0.88; 95% CI, 0.80-
0.96 for daily intake compared with intake once per week or less). Daily or almost daily
green-yellow vegetables consumption was associated with a marginally significant 8%
reduction in total cancer mortality (0.92; 0.94-1.01). Green-yellow vegetables consumption
was associated with a significant reduction in liver cancer mortality (0.75; 0.60-0.95). Fruit
consumption was associated with a significantly reduced risk of stomach cancer and lung
cancer mortality (0.80; 0.65-0.98). Green-yellow vegetables and fruit consumption was
associated with a reduction in oesophageal cancer, but these associations were not statistically
significant. Neither green-yellow vegetables nor fruit consumption was associated with
colorectal cancer or breast cancer mortality. These results support the evidence that daily
consumption of fruit and vegetables reduces the risk of total cancer, and specifically cancers
of the stomach, liver, and lung.

Coffee + Alcohol + smoking => ↑ risk of
pancreatic cancer Smoking
+ Alcohol
+ Coffee
Pancreatic 30
Alcohol
Cancer
+ Coffee 26.3
20
(Relative
Risk)
10 13.9
1

0
p = 0.02 p = 0.13

n = 29 cases + pancreatic cancer & 29 controls
The combination of 2 to 3 risk factors increases considerably the risk of pancreatic cancer.
Considered independently, only alcohol & coffee consumption were found to be sign.
assoc. + pancreas cancer
Pfeffer F et al. Rev Invest Clin. 1989 Jul-Sep;41(3):205-8

Rev Invest Clin. 1989 Jul-Sep;41(3):205-8. Links
[Smoking, consumption of alcoholic beverages and coffee as factors associated with the
development of cancer of the pancreas]
[Article in Spanish]
Pfeffer F,
Avilas Rosas H,
Vargas F,
Villalobos JJ.
The purpose of this study was to evaluate retrospectively the role of alcohol intake, smoking
and coffee consumption as risk factors in the development of cancer of the pancreas. Twenty
nine cases with pancreatic cancer and 29 controls matched by sex, socioeconomic status and
age were evaluated. Information on alcohol, tobacco and coffee consumption was obtained by

specially designed questionnaires. Odds ratios were calculated and analyzed by chi square
testing. The combination of the 3 factors gave an odds ratio of 26.3, whereas alcohol and
coffee consumption gave an odds ratio of 13.9. Considered independently, only alcohol and
coffee consumption were found to be significantly associated with cancer of the pancreas.

Alcohol => ↑ risk of breast cancer
Follow-up:
Daily initial
daily alcohol
alcohol
consumption of of 24 g
2
24 g (2 drinks) continues

1.5 Non
drinkers
1 1,7
1,4
(95% CI,
(95% CI, 1.4-2.2)
0.5 1.0-1.8)

0
Risk of breast cancer in daily alcohol drinkers & non-drinkers

Longnecker MP et al. JAMA. 1988 Aug 5;260(5):652-6

JAMA. 1988 Aug 5;260(5):652-6. Links
A meta-analysis of alcohol consumption in relation to risk of breast cancer.
Longnecker MP,
Berlin JA,
Orza MJ,
Chalmers TC.
Department of Epidemiology, Harvard School of Public Health, Boston, MA.
Epidemiologic findings regarding the relation between alcohol consumption and risk of breast
cancer have been inconsistent. We performed a meta-analysis (a quantitative review) of the
available data. To evaluate whether there was a dose-response relation between alcohol
consumption and risk of breast cancer, we fitted mathematical models to the pooled data.
There was strong evidence to support a dose-response relation in both the case-control and
follow-up epidemiologic data. Using the dose-response curves that we calculated, the risk of
breast cancer at an alcohol intake of 24 g (1 oz) of absolute alcohol daily (about two drinks
daily) relative to nondrinkers was 1.4 (95% confidence interval, 1.0 to 1.8) in the case-control
data and was 1.7 (95% confidence interval, 1.4 to 2.2) in the follow-up data. We interpret
these findings not as proof of causality, but as strongly supportive of an association between
alcohol consumption and risk of breast cancer.

Alcohol => ↑ risk of Prostate cancer
Alcoholusers
Prostate >96
cancer 22-96 grams
risk <22 grams grams
4 +210%
(Rel. Risk) alcohol +160 %
3 per week
3.1
large-scale 2 Nonusers +10 % 2.6
Iowa Cohort
study; 1
110 (?) cases 1.1
0
NS p< 0.05 p< 0.05

Increased risk of prostate cancer in alcohol consumers

Putnam SD et al. Ann Epidemiol. 2000 Aug;10(6):361-9

Ann Epidemiol. 2000 Aug;10(6):361-9. Links

Lifestyle and anthropometric risk factors for prostate cancer in a cohort of Iowa men.
Putnam SD,
Cerhan JR,
Parker AS,
Bianchi GD,
Wallace RB,
Cantor KP,
Lynch CF.
Department of Preventive Medicine and Environment Health, University of Iowa, College of
Medicine, Iowa City, IA, USA.
PURPOSE: Several lines of evidence suggest that prostate cancer has a hormonal etiology.
We evaluated factors known to modulate the endocrine system, including alcohol and tobacco
use, physical activity, and obesity as risk factors for prostate cancer. METHODS: Cancer-free
controls who participated in a population-based case-control study from 1986-1989 (81%
response rate) were followed through 1995 for cancer incidence by linkage to the Iowa
Cancer Registry; 101 incident prostate cancers were identified. RESULTS: Compared with
non-users of alcohol, men who consumed <22 grams alcohol per week (relative risk [RR] =
1.1; 95% Confidence Interval [CI] 0.6-2.1), 22-96 grams alcohol per week (RR = 2.6; 95% CI
1.4-4. 6) and >96 grams alcohol per week (RR = 3.1; 95% CI 1.5-6.3) were at increased risk
of prostate cancer after adjustment for age, family history of prostate cancer, body mass
index, total energy, and intake of carbohydrate, linoleic acid, lycopene, retinol, and red meat
(p for trend < 0.0001). The respective RRs were similar when assessing type of alcohol
consumed (beer, wine or liquor) or when well-differentiated, localized tumors were excluded.
Body mass index was only weakly and positively associated with prostate cancer after
adjustment for age, but this association strengthened after multivariate adjustment and
exclusion of well-differentiated, localized tumors. For the latter tumors, men with a BMI of
24.1-26.6 kg/m(2) and >26.6 kg/m(2) were at elevated risk compared to men with a BMI
<24.1 kg/m(2). Tobacco use (cigarettes, cigar/pipe, chewing tobacco and snuff use), height,
weight, and both leisure and occupational physical activity were not associated with risk of

prostate cancer in this cohort. CONCLUSIONS: These data suggest that in white men obesity
is a risk factor for more clinically significant prostate cancer and confirm limited previous
reports showing that alcohol consumption is positively associated with prostate cancer and
that this risk is not limited to any specific type of alcohol.

Mediterranean diet => mortality

Alonso A, Martinez-Gonzalez MA. JAMA. 2005 Feb 9;293(6):674

JAMA. 2005 Feb 9;293(6):674; author reply 674-5. Links
Comment on:
JAMA. 2004 Sep 22;292(12):1433-9.

Mediterranean diet, lifestyle factors, and mortality.
Alonso A,
Martinez-Gonzalez MA.

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