Endnotes Chapters 21,22,23

Chapter 21
1 B. N. Ames and P. Wakimoto. 2002. “Are vitamin and mineral deficiencies a major cancer risk?” Nat Rev Cancer. Sep;2(9): 694–704.
2 J. E. DaVanzo et al. 2003. “A study of the cost effects of daily multivitamins for older adults.” The Lewin Group, Inc., Oct 8.
3 T. S. Church et al. 2003. “Reduction of C-Reactive Protein Levels Through Use of a Multivitamin.” Am J Med. Dec 15;115(9): 702–707.
4 D. Salisbury. 2004. “Chemists develop antioxidants 100 times more effective than vitamin E.” Exploration, Jan. 16;
5 K. Dean. “Breathing new life into medicine.” Wired News, July 16, 2003;
6 C. Lok. “Smarter drugs.” MIT Technology Review, March 2004;
7 K. Philipkoski. “Souped-up rice goes against the grain.” Wired News, June 5, 2003;,1286,59117,00.html.
8 D. Shintani and D. DellaPenna. 1998. “Elevating the Vitamin E Content of Plants Through Metabolic Engineering.” Science. Dec 11;282: 5396.
9 I. Ajjawi and D. Shintani. 2004. “Engineered plants with elevated vitamin E: a nutraceutical success story.” Trends in Biotechnology. Mar;22(3): 104–107.
10 K. Kleiner. “Biotech researchers create safer soybeans.”, September 2002;
11 AP News Service. “Scientists foresee genetically engineered healthier steak.” February 2, 2004;; S. M. Kitessa et al. 2004. “Supplementation of grazing dairy cows with rumen-protected tuna oil enriches milk fat with n-3 fatty acids without affecting milk production or sensory characteristics.” Br J Nutr. Feb;91(2): 271–278.
12 B. Demmig-Adams and W. Adams III. 2002. “Antioxidants in photosynthesis and human nutrition.” Science. Dec 13;298: 2149–2153; I. Raskin et al. 2002. “Plants and human health in the twenty-first century.” Trends in Biotechnology. 20(12): 522–531.
13 Ibid, p. 2153.
14 The antioxidant enzymes don’t have to commit suicide (hara-kiri) when they give up one of their electrons; rather, they can work together as a team. For example, when a molecule of vitamin E gives up an electron to quench a free radical, a molecule of vitamin C often comes along and gives up one of its electrons to restore the vitamin E molecule, and then a glutathione molecule gives one of its electrons to vitamin E.
15 Swiss Institute of Bioinformatics. ENZYME. Enzyme nomenclature database. Release 27.0, October 2001, updates up to 1 Feb 2002; (accessed February 2, 2002).
16 This seminal article by Bruce Ames provides a scientific basis for the use of high-dose vitamin therapy in the treatment of numerous diseases. B. N. Ames, I. Elson-Schwab, and E. A. Silver. 2002. “High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(m)): relevance to genetic disease and polymorphisms.” Am J Clin Nutr. Apr;75(4): 616–658.
17 Ibid., p. 1.
18 Much of our DNA does not encode any proteins, so this number of mutations is not quite as worrisome as it first appears. Cells can repair some of the changes to DNA; changes that cannot be repaired are called mutations. Mutations are particularly common when cells divide because the DNA must be replicated at that time. See T. Beardsley. “Mutations galore: humans have high mutation rates. But why worry?” Sci Am. April 1999;
“Repeated sequences that do not code for proteins (‘junk DNA’) make up approximately 98 percent of the human genome. This so-called junk DNA is not junk as it plays a critical role in gene expression. Repetitive sequences shed light on chromosome structure and dynamics. Over time, these repeats reshape the genome by rearranging it, thereby creating entirely new genes or modifying and reshuffling existing genes . . . ”
“Humans share most of the same protein families with worms, flies, and plants, but the number of
gene family members has expanded in humans, especially in proteins involved in development and immunity. The human genome has a much greater portion (50%) of repeat sequences than the mustard weed (11%), the worm (7%), and the fly (3%).” Human Genome Project Sequence Analysis;
Humans have between 30,000 to 35,000 genes, and there are about 1.4 million locations where small changes can occur on a gene. The laboratory mouse has 30,000 genes.
19 Favism is a disease in which red blood cells are destroyed after eating fava beans, a common broad bean in the Mediterranean region.
20 A search on the National Library of Medicine Web site for the keyword antioxidant revealed over 89,000 references. A search for vitamin C came up with 22,000 articles.
21 The New England Journal of Medicine suggests that it is reasonable for most adults to take a multivitamin supplement at the RDA level, with the possibility of higher levels of folic acid, vitamins B6, B12 and D, depending on risk of cardiovascular disease and bone loss. W. C. Willett and M. J. Stampfer. 2001. “Clinical practice. What vitamins should I be taking, doctor?” N Engl J Med. Dec 20;345 (25):1819–1824.
In the JAMA article, the authors admit, “Most people do not consume an optimal amount of all vitamins by diet alone.” R. H. Fletcher and K. M. Fairfield. 2002. “Vitamins for chronic disease prevention in adults: clinical applications.” JAMA. Jun 19;287(23): 3127–3129.
22 IOM (Institute of Medicine). 2000. “Dietary Reference Intakes. Applications in Dietary Assessment. A Report of the Subcommittee on Interpretation and Uses of Dietary Reference Intakes and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Food and Nutrition Board.” National Academy Press: Washington, D.C.
23 For reasons of space, only a brief summary of each nutrient is included. For additional information, see S. Lieberman and N. Bruning. 1997. The Real Vitamin and Mineral Book. Garden City Park, New York: Avery Publishing Group; R. Atkins. 1998. Dr. Atkins’ Vita-Nutrient Solution. New York: Simon and Schuster.
24 In a study published in the New England Journal of Medicine in 1998, Melissa K. Thomas, M.D., Ph.D., of Boston’s Massachusetts General Hospital, reported that blood levels of vitamin D were deficient in 57 percent of hospitalized patients, and 22 percent were severely deficient.
25 R. P. Heaney. 2003. “Long-latency deficiency disease: insights from calcium and vitamin D.” Am J Clin Nutr. Nov;78(5): 912–919.
26 R. P. Heaney et al. 2003. “Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol.” Am J Clin Nutr. Jan;77(1): 204–10.
27 G. A. Plotnikoff and J. M. Quigley. 2003. “Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain.” Mayo Clin Proc. Dec;78(12): 1463–1470.
28 The results of one of the largest studies ever performed involving vitamin E were published in the New England Journal of Medicine in 1993. In this study, 87,000 female nurses and 40,000 male health professionals were followed for eight years during which time they regularly filled out questionnaires about their lifestyles and diets. Those who consumed at least 100 IU of vitamin E as a supplement for at least two years had a 36 percent lower risk of major coronary disease than did those with the lowest intake.
29 A recent book by T. E. Levy, M.D., J.D. Vitamin C, Infectious Diseases, & Toxins, Xlibris Corp. 2002, contains over 1,200 scientific references regarding the safety and efficacy of vitamin C.
30 G. J. Fosmire. 1990. “Zinc toxicity.” Am J Clin Nutr. Feb;51(2): 225–227.
31 H. R. Casdorph and M. Walker. 1995. Toxic Metal Syndrome. Garden City Park, New York: Avery Publishing, pp. 75–127.
32 F. L. Crane. 2001. “Biochemical functions of coenzyme Q10.” J Am Coll Nutr. Dec;20(6): 591–598.
33 O. Portakal et al. 2000. “Coenzyme Q10 concentrations and antioxidant status in tissues of breast cancer patients.” Clin Biochem. Jun;33(4): 279–284.
34 “CoQ10 functions as an electron carrier in the mitochondrial respiratory chain as well as serving as an important intracellular antioxidant. Lowered blood and tissue concentrations of CoQ10 have been reported in a number of diseases, although whether this deficiency is the cause or an effect of the disease remains largely unresolved.” I. P. Hargreaves. 2003. “Ubiquinone: cholesterol’s reclusive cousin.” Ann Clin Biochem. May;40(Pt 3): 207–218. This study also suggests that more work needs to be done to identify CoQ10’s role: “Although a number of studies have reported clinical improvement in congestive heart failure patients after CoQ10 supplementation to standard therapy, concerns about the design of these studies coupled to the small number of patients involved have limited their acceptance.” According to one review of the literature, CoQ10’s low toxicity warrants its use even before the additional clinical trials are completed. B. Sarter. 2002. “Coenzyme Q10 and cardiovascular disease: a review.” J Cardiovasc Nurs. Jul;16(4): 9–20. Also see S. Greenberg and W. H. Frishman. 1990. “Co-enzyme Q10: a new drug for cardiovascular disease.” J Clin Pharmacol. Jul;30(7): 596–608.
35 Selective toxicity of GSPE toward breast, lung, and gastric adenocarcinoma has been noted. See D. Bagchi et al. 2002. “Cellular protection with proanthocyanidins derived from grape seeds.” Ann NY Acad Sci. May;957: 260–270.
36 Ibid.
37 See S. Lamm. 1997. Younger At Last. New York: Pocket Books, pp. 132–150.
38 H. Moini, L. Packer, and N. E. Saris. 2002. “Antioxidant and prooxidant activities of alpha-lipoic acid and dihydrolipoic acid.” Toxicol Appl Pharmacol. Jul 1;182(1): 84–90.
39 One study pointed to the beneficial effects of alpha-lipoic acid mimicking insulin D. Konrad et al. 2001. “The antihyperglycemic drug alpha-lipoic acid stimulated glucose uptake via both GLUT4 translocation and GLUT4 activation.” Diabetes. 50: 1464–1471. Another study investigating LA’s cellular mechanism of action pointed out that alpha-lipoic acid “directly activates lipid, tyrosine and serine/threonine kinases in target cells, which could lead to the stimulation of glucose uptake . . .” Of particular note, according to this study, “these properties are unique among all agents currently used to lower glycaemia in animals and humans with diabetes.” K. Yaworsky et al. 2000. “Engagement of the insulin-sensitive pathway in the stimulation of the glucose transport by alpha-lipoic acid in 3T3-L1 adipocytes.” Diabetologia. Mar 1;43(3): 294–303. See also A. El Midaoui and J. de Champlain. 2002. “Prevention of hypertension, insulin resistance, and oxidative stress by alpha-lipoic acid.” Hypertension. Feb;39(2): 303–307.
40 A. M. Wang et al. 2000. “Use of carnosine as a natural anti-senescence drug for human beings.” Biochemistry (Mosc). Jul;65(7): 869–871; C. Brownson and A. R. Hipkiss. 2000. “Carnosine reacts with a glycated protein.” Free Radic Biol Med. May 15;28(10): 1564–1570.
41 Even more important is that the French don’t overeat. The portions are smaller in France than in the U.S., and only 7 percent of the French are obese. They don’t snack in between meals and are very slim as a result. See “Secrets of slim French revealed.” BBC News, August 22, 2003;
42 Researchers are still trying to figure out the mechanism by which resveratrol acts. See, for example, A. Sgambato et al. 2001. “Resveratrol, a natural phenolic compound, inhibits cell proliferation and prevents oxidative DNA damage.” Mutat Res. Sep 20;496(1–2): 171–180; S. Bastianetto, W. H. Zheng, and R. Quirion. 2000. “Neuroprotective abilities of resveratrol and other red wine constituents against nitric oxide-related toxicity in cultured hippocampal neurons.” Br J Pharmacol. Oct;131(4): 711–720.
43 Green vegetables have the highest concentrations of both lutein and zeaxanthin; while yellow-orange fruits and vegetables, except for butternut squash, have “a much lower level of lutein in comparison to greens but contained a higher concentration of zeaxanthin.” J. M. Humphries and F. Khachik. 2003. “Distribution of lutein, zeaxanthin, and related geometrical isomers in fruit, vegetables, wheat, and pasta products.” J Agric Food Chem. Feb 26;51(5): 1322–1327. See also E. L. Snellen et al. 2002. “Neovascular age-related macular degeneration and its relationship to antioxidant intake.” Acta Ophthalmol Scand. Aug; 80(4): 368–371.
44 J. A. Mares-Perlman et al. 2001. “Lutein and zeaxanthin in the diet and serum and their relation to age-related maculopathy in the third national health and nutrition examination survey.” Am J Epidemiol. Mar 1;153(5): 424–432.
45 R. S. Lord et al. 2002. “Estrogen metabolism and the diet-cancer connection: rationale for assessing the ratio of urinary hydroxylated estrogen metabolites.” Altern Med Rev. Apr;7(2): 112–129.
46 Another mechanism of controlling estrogen risk is by facilitating the conversion of the more powerful (and carcinogenic) estradiol into estrone. Soy products contain genistein, a phytonutrient that assists in this conversion. See R. W. Brueggemeier et al. 2001. “Effects of phytoestrogens and synthetic combinatorial libraries on aromatase, estrogen biosynthesis, and metabolism.” Ann NY Acad Sci. Dec;948: 51–66.
47 M. S. Brignall. 2001. “Prevention and treatment of cancer with indole-3-carbinol.” Altern Med Rev. Dec;6(6): 580–589.
48 E. Giovannucci et al.1995. “Intake of carotenoids and retinol in relation to risk of prostate cancer.” J Natl Cancer Inst. 87 (23): 1767–1776.
49 J. K. Rossinow et al. 2003. “Effects of lycopene and vitamin E on gamma-irradiated prostate cancer cells.” Int J Radiat Oncol Biol Phys. Oct 1;57(2 Suppl): S348–349; E. Giovannucci et al. 2002. “A prospective study of tomato products, lycopene, and prostate cancer risk.” J Natl Cancer Inst. Mar 6;94(5): 391–398.
50 T. Wilt, A. Ishani, and R. MacDonald. 2002. “Serenoa repens for benign prostatic hyperplasia.” Cochrane Database Syst Rev. (3): CD001423; F. Debruyne et al. 2002. “Comparison of a phytotherapeutic agent (Permixon) with an alpha-blocker (Tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study.” Eur Urol. May;41(5): 497–506.
51 According to one study, “F(2)-isoprostanes are recently described prostaglandin F isomers produced by cyclooxygenase-independent free radical peroxidation of arachidonic acid. Their quantification in plasma and urine is a sensitive and specific indicator of lipid peroxidation and, hence, of oxidative stress in vivo.” Dietary supplementation for 14 days with garlic extract “reduced plasma and urine concentrations of 8-iso-PGF(2 alpha) by 29% and 37% in nonsmokers and by 35% and 48% in smokers. Fourteen days after cessation of dietary supplementation, plasma and urine concentrations of 8-iso-PGF(2 alpha) returned to values not different from those before ingestion of AGE in both groups.” S. A. Dillon et al. 2002. “Dietary supplementation with aged garlic extract reduces plasma and urine concentrations of 8-iso-prostaglandin F(2 alpha) in smoking and nonsmoking men and women.” J Nutr. Feb;132(2): 168–171. See also A. Mohamadi and S. T. Jarrell. 2000. “Effects of wild versus cultivated garlic on blood pressure and other parameters in hypertensive rats.” Heart Dis. Jan–Feb;2(1): 3–9.
52 C. Borek. 2001. “Antioxidant health effects of aged garlic extract.” J Nutr. Mar;131(3s): 1010S–5S.
53 Institute of Medicine, Food and Nutrition Board. 2000. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. National Academies Press: Washington, D.C. See also
54 E. Anngard. 1994. “Nitric Oxide: Mediator, Murderer, and Medicine.” Lancet. 343: 1199–1207.
55 As a naturally occurring amino acid, side effects from arginine are rare. It should, however, be avoided by individuals with a history of herpes outbreaks or cancer. The herpes virus has an affinity for arginine and can be stimulated into reactivation when arginine is taken in large amounts. Blood sugar levels can be raised by arginine, so caution should be used in cases of diabetes.

Chapter 22
1 Improved physical fitness is a “pressing” need for Americans because regular physical activity reduces the morbidity, mortality, and costs associated with chronic illness, according to the 2002 U.S. Department of Health and Human Services report “Physical Activity Fundamental to Preventing Disease.” This report highlighted a 1993 study, which claims that “14 percent of all deaths in the United States were attributed to activity patterns and diet.” (J. M. McGinnis and W. H. Foege. 1993. “Actual causes of death in the United States.” JAMA. 270(18): 207–212.)
Research summarized in Physical Activity and Health: A Report of the Surgeon General (1996) emphasized that virtually everyone would benefit from physical exercise (U.S. Department of Health and Human Services. Atlanta, Georgia: Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion).
Another landmark report and goal-setting document is Healthy People 2010, chapter 22: “Physical Activity and Fitness” ( According to this report, “The 1990s brought a historic new perspective to exercise, fitness and physical activity by shifting the focus from intensive exercise to a broader range of health-enhancing physical activities.” The report goes on to say: “On average, physically active people outlive those who are inactive. Regular physical activity also helps to maintain the functional independence of older adults and enhances the quality of life for people of all ages . . . The role of physical activity in preventing coronary heart disease (CHD) is of particular importance, given that CHD is the leading cause of death and disability in the United States. Physically inactive people are almost twice as likely to develop CHD as persons who engage in regular physical activity.”
Because “physical inactivity characterizes most Americans” and “exertion has been systematically engineered out of most occupations and lifestyles,” experts from a National Institutes of Health (NIH) panel produced a consensus statement in 1995 on physical activity and cardiovascular health (NIH Consensus Statement, 13(3), Dec 18–20). They emphasized the importance of a “coordinated national campaign involving a consortium of collaborating health organizations to encourage regular health activity.” Healthy People 2010 embodies that recommendation.
For a summary of landmark reports on fitness, statistics, and other resources, see the Web site of the National Coalition for Promoting Physical Activity,
2 S. N. Blair et al. 1989. “Physical fitness and all-cause mortality.” JAMA. Nov;262: 2395–2401.
3 C. D. Lee, S. N. Blair, and A. S. Jackson. 1999. “Cardiorespiratory fitness, body composition, and all-cause and cardiovascular disease mortality in men.” Am J Clin Nutr. Mar;69(3): 373–380.
4 S. N. Blair et al. 1996. “Influences of cardiorespiratory fitness and other precursors on cardiovascular disease and all-cause mortality in men and women.” JAMA. Jul 17;276(3): 205–210.
5 I. M. Lee. 2003. “Physical activity in women: how much is good enough?” JAMA. Sept 10;290(10): 1377–1378.
6 Exercise is one of the “cornerstones” of treatment for raised levels of triglycerides. M. J. Malloy and J. P. Kane. 2001. “A risk factor for atherosclerosis: triglyceride-rich lipoproteins.” Adv Intern Med. 47: 111–136. See also A. H. Liem, J. W. Jukema, and D. J. van Veldhuisen. 2003. “Secondary prevention in coronary heart disease patients with low HDL: what options do we have?” Int J Cardiol. Jul;90(1): 15–21; P. A. Metcalf et al. 2001. “Factors associated with changes in serum total cholesterol levels over 7 years in middle-aged New Zealand men and women: a prospective study.” Nutr Metab Cardiovasc Dis. Oct;11(5): 298–305.
7 American College of Sports Medicine, Fit Society Page: Exercise for Health, Winter 2003 (, page 5. Also see Mayo Clinic, “How
to measure exercise intensity,”
8 The AHA identifies the zone as 50–75 percent of maximum heart rate and suggests that, when you start exercising, you aim at the lower end of that zone. “Target Heart Rates,”
presenter.jhtml?identifier54736. Other sources, such as the Mayo Clinic, use American College of Sports Medicine (ACSM) guidelines to define 75–85 percent target heart rates. The Mayo Clinic site notes that target heart rates are “a rough guideline that is less reliable as you grow older.” “How to measure exercise intensity,”
9 G. F. Fletcher et al. 1996. “Statement on exercise: benefits and recommendations for physical activity programs for all Americans.” Circulation. 94: 857–862; American Council on Exercise (ACE), “Who
should have an exercise stress test and how safe is such a test?” (
fitbits_display.cfm?itemid5283); D. H. Mahler. 1995. American College of Sports Medicine Guidelines for Exercise Testing and Prescription. 5th ed. Baltimore, Maryland: Williams & Wilkins, p. 373.
10 See, for example, “Who needs cardiac evaluation?” Johns Hopkins Health After 50, April 2001;; Your Heart Health Record Web site, Bristol-Myers Squibb Medical Imaging, Inc.;
11 J. Torr. “Biotech a healthy market for chips.” Computerworld, August 15, 2003; www.computerworld.
12 S. Shoham et al. 2001. “Motor-cortical activity in tetraplegics.” Nature. 413: 793. For the University of Utah news release, see “An early step toward helping the paralyzed walk.” October 24, 2001;
13 R. A. Freitas Jr. “Say Ah.”; R. A. Freitas Jr. Nanomedicine, Volumes I and IIA. Austin, Texas: Landes Bioscience. Excerpts from volume 1 available on at
14 “Stretching lengthens muscles and tendons, and thereby improves flexibility. Longer muscles can generate more force around joints, helping a person jump higher, lift heavier weights, run faster, and throw farther . . . There is scant evidence that stretching prevents injuries or delayed-onset muscle soreness, which is caused by muscle fiber damage.” S. Jonas. “Preventing injury,” chapter 6, “Exercise and Fitness.” The Merck Manual, 2nd Home Edition;
15 M. C. Escher is a 20th-century artist known for his paradoxical paintings and drawings. One of Escher’s most famous drawings shows people walking uphill on four connected stairways in which the last stairway leads back to the first stairway, an apparent impossibility.
16 M. Hargrave et al. 2003. “Subtalar pronation does not influence impact forces or rate of loading during a single-leg landing.” J Athletic Training. Mar;38(1): 18–23.
17 “Runners report average yearly injury rates from 24% to 68%, of which 2% to 11% involve the hip or pelvis.” K. H. Browning. “Hip and pelvis injuries in runners.” Physician & Sports Med. Jan;29(1);, referring to W. van Mechelen. 1992. “Running injuries: a review of the epidemiological literature.” Sports Med. 14(5): 320–335.
According to Browning, “among athletes, females have been reported to be at 1.5 to 3.5 times greater risk of stress fractures than are males. Recent prospective studies suggest that the difference is not related to athletes’ sex per se, but to factors such as amenorrhea, bone density, and diet.”
18 J. Hartgerink, S. Stupp, and E. Beniash. 2001. “Self-Assembling Materials: Coated Nanofibers Copy What’s Bred in the Bone,” Science. 294: 1635–1637;
19 A. H. Goldfarb and A. Z. Jamurtas. 1997. “Beta-endorphin response to exercise: an update.” Sports Med. Jul 1;24(1): 8–16; D. V. Taylor et al. 1994. “Acidosis stimulates beta-endorphin release during exercise.” J Appl Physiol. 77(4): 1913–1918. See also “Understanding endorphins,”,
20 American College of Sports Medicine Fit Society Page. “Resistance Training.” Fall 2002.
21 Ibid., p. 4.
22 National Association for Fitness Certification, “Weight training basics,”
23 “Weight training: How and why,” OhioHealth,
24 American College of Sports Medicine Fit Society Page. “Enhancing your flexibility,” p. 5. Spring 2002.
25 Ibid.
26 “A low-fat diet combined with sufficient exercise may be the one-two punch needed to improve blood cholesterol levels for many persons who have had trouble doing so,” according to a Stanford online report on a 1998 study conducted at the Stanford Center for Research in Disease Prevention ( Marcia Stefanick, the lead author in the study, pointed to the issues facing doctors in an interview for this article. “If you just reduce dietary fat to lose weight without exercising, you often reduce good cholesterol along with the bad, canceling out the benefits.” She went on to say, “The challenge [with adding exercise] is not to think you can get away with eating more just because you started exercising.” You will not burn off the calories you eat from a cookie by running or walking a mile, for example. See M. L. Stefanick et al. 1998. “Effects of diet and exercise in men and postmenopausal women with low levels of HDL cholesterol and high levels of LDL cholesterol.” N Engl J Med. Jul 2;339(1): 12–20; T. R. Thomas et al. 2002. “Exercise training does not reduce hyperlipidemia in pigs fed a high-fat diet.” Metabolism. Dec;51(12): 1587–1595.

Chapter 23
1 H. Malmros. 1950. “The relation of nutrition to health: a statistical study of the effect of the war-time on arteriosclerosis, cardiosclerosis, tuberculosis, and diabetes.” Acta Medica Scandinavia. 246(Suppl): 141–149. Despite its title, this article is surprisingly nontechnical. The dramatic effect of food rationing on heart disease in several European countries during World War II is presented in standard prose and charts.
A. Keys. 1975. “Coronary heart disease: the global picture.” Atherosclerosis. 22: 153–154. A comprehensive overview on coronary heart disease by the author of the eminent Seven Countries Study, this article cites extensive evidence from around the world, including studies of global peoples; the effects of wartime; social class and occupation; the impact of exercise, stress, and personality type; the role of risk factors, dietary factors, and genetics; and a discussion on the prevention of coronary heart disease.
R. G. Wilkinson. 1996. Unhealthy Societies: The Afflictions of Inequality. London: Routledge. In this book, Wilkinson posits a connection between income inequality and mortality. He also claims that life expectancy at birth in England and Wales increased by 6.5 and 6.6 years, respectively, for men and women from 1911–1921, compared with 2.4 and 2.3 years, respectively, from 1921–1931 and 1.5 and 1.2, respectively, for 1931–1940. A similar jump (7.0 and 6.5) was noted for 1940–1951.
2 This trend has been noticed in many countries. In Australia, for example, “suicide rates were higher during periods of draught and lower during WWII.” (“More suicides under Conservative rule.” BBC News, September 18, 2002;
In Croatia, “in the areas directly affected by war, the suicide rate was significantly lower than in other areas during the study period 1993–1998.” (M. Grubisic-Ilic et al. 2002. “Epidemiological study of suicide in the Republic of Croatia.” Eur Psych. Sep 1;17(5): 259–264.) In Jaffna, Sri Lanka, between 1980 and 1989, “there was a marked drop in the suicide rate during the war” (D. J. Somasundarum and S. Rajadurai. “War and suicide in northern Sri Lanka.” Acta Psychiatr Scand. Jan 1;91(1): 1–4.)
3 Stress may lengthen the time triglycerides stay in the blood. “If a person has a high-fat snack or meal during a time of stress, that fat is going to be circulating in the blood for a longer period of time. That means it may be more likely to be deposited in the arteries where it can contribute to heart disease.” C. M. Stoney. 2002. Quoted in “Stress causes heart-damaging fats to stay in blood longer.” Ohio State Research ( C. M. Stoney et al. 2002. “Acute psychological stress reduces plasma triglyceride clearance.” Psychophysiology. Jan;39(1): 80–85.
4 A. M. Tacon. 2003. “Meditation as a complementary therapy in cancer.” Fam Community Health. Jan–Mar;26(1): 64–73; M. J. Kreitzer and M. Snyder. 2002. “Healing the heart: integrating complementary therapies and healing practices into the care of cardiovascular patients.” Prog Cardiovasc Nurs. Spring;17(2): 73–80.
5 A. Elkin. 1999. Stress Management for Dummies. New York: Wiley Publishing, Inc.; S. S. Nussey and S. A. Whitehead, eds. 2001. “Catecholamine synthesis and secretion.” Endocrinology: An Integrated
Approach. BIOS Scientific Publishers, Ltd. Online table of contents:
bv.fcgi?call5bv.View..ShowTOC&rid5endocrin.TOC&depth51; N. Schneiderman. “Behavior, Autonomic Function, and Animal Models of Cardiovascular Pathology,” in T. M. Dembroski, T. H. Schmidt, and G. Blümchen, eds. 1983. Biobehavioral Bases of Coronary Heart Disease. Basel, Switzerland: Karger, pp. 304–364, 317–322; R. M. Sapolsky. 1990. “Stress in the Wild.” Sci Amer. Jan: 116–124; R. Williams. 1989. The Trusting Heart. New York: Times Books, pp. 75–82.
6 “When demands are physical, as they often were in earlier times, the hormones and fats released during the stress response are rapidly delivered to the muscles by the increased heart rate and blood pressure . . . Meeting mental demands requires lower, but ongoing, levels of stress hormones and fatty fuels . . . When the work to be done is mental, the hormones and fats that have been mobilized for action are not used up. The unnecessarily high heart rate and blood pressure set up a condition of increased turbulence in the bloodstream, which in turn increases the tension on the walls of the arteries.” M. Burg. “Stress, behavior, and heart disease.” Chapter 8, p. 97, in B. Zaret et al., eds. 1992. Yale University School of Medicine Heart Book;
7 R. Misslin. 2003. “The defense system of fear: behavior and neurocircuitry.” Clin Neurophysiol. April;33(2): 55–66.
8 Story provided by Joel Miller, M.D.
9 M. Burg, pp. 99–104; I. Kawachi et al. 1998. “Prospective study of a self-report Type A scale and risk of coronary heart disease.” Circulation. 98: 405.
According to the Kawachi study, one of the reasons is the difference in results gathered by self-report questionnaires versus structured interview approach (VCE). The authors suggest that the former are less likely to capture some aspects of hostile behavior, such as hurried speech and hostile facial expressions. Another reason is that perhaps the questionnaires don’t cover some components of the complex. Different questionnaires emphasize different things. The Kawachi study used the MMPI-2 Type A Scale, which incorporates a broader range of components. The study used a cohort of 2280 community-dwelling men from Boston, ages 21–80, at the start. The MMPI-2 was administered by mail in 1986 and participants were followed up for an average of seven years. Higher type A scores were associated with higher average body mass index, more frequent history of heart disease, more smoking, more alcohol consumption. “The MMPI-2 Type A Scale provides a global score based on 3 apparently critical aspects of TAB: time urgency, competitiveness, and hostility. It may be the confluence of these behavior styles, rather than one aspect alone, that increases risk of CHD.”
A much-cited study on type A personality and heart disease risk is T. M. Dembroski et al. 1989. “Components of hostility as predictors of sudden death and myocardial infraction in the Multiple Risk Factor Intervention Trial.” Psychosom Med. 54(5): 514–522.
T. Hallman. 2001. “Psychosocial risk factors for coronary heart disease, their importance compared with other risk factors and gender differences in sensitivity.” J Cardiovasc Risk. Feb;8(1): 39–49.
The Hallman study showed that women were more sensitive than men with respect to psychosocial risk factors for CHD.
E. R. Greenglass and J. Julkunen. 1991. “Cook-Medley hostility, anger, and the Type A behavior pattern in Finland.” Psychol Rep. Jun;68(3 Pt 2): 1059–1066. This study supports the points made by Kawachi by pointing to the importance of “specifying the kind of hostility” measured by the scale used, in this case, the Cook-Medley scale. The study looked at 219 university students. When they used a “subscale” measuring cynical distrust, they found a positive correlation between cynicism and CHD.
The following study was also aimed at figuring out what hostility components were important: Y. Gidron and K. Davidson. 1996. “Development and preliminary testing of a brief intervention for modifying CHD-predictive hostility components.” J Behav Med. Jun;19(3): 203–220.
The presence of depression can alter the association between hostility and CHD but not reduce the risk of the patient. See N. Ravaja, T. Kauppinen, and L. Keltikangas-Jarvinen. 2000. “Relationships between hostility and physiological coronary heart disease risk factors in young adults: the moderating influence of depressive tendencies.” Psychol Med. Mar;30(2): 381–393. “Despite the established risk factor status of hostility, lack of anger and hostility, when combined with high depressive tendencies, may represent the most severe exhaustion where the individual has given up. Disregard of this fact may explain some null findings in the research on hostility and CHD risk.”
G. E. Miller et al. 2003. “Cynical hostility, depressive symptoms, and the expression of inflammatory risk markers for coronary heart disease.” J Behav Med. Dec;26(6): 501–515. This study emphasizes the importance of looking at both the “independent and interactive relationships among psychosocial characteristics involved in disease.” The study looked at 100 adults regarding hostility and depressive symptoms. The study discusses how these factors operate together to influence coronary heart disease.
J. E. Gallacher et al. 2003. “Is type A behavior really a trigger for coronary heart disease events?” Pyschosom Med. May–Jun;65(3): 339–346. This study provides another perspective on the role of the type A personality. The study looked at 2,394 men aged 50–64: “The data show Type A is a strong predictor of when incident coronary heart disease (or coronary event) will occur rather than if it will occur. These findings suggest that Type A increases exposure to potential triggers, rather than materially affecting the process of atherosclerosis.”
10 M. Burg, pp. 99–104; R. B. Williams Jr. 1987. “Psychological factors in coronary artery disease: epidemiologic evidence.” Circulation. Jul;76(Suppl I): 1117–1123.
11 I. Kawachi et al. 1998. “Prospective study of a self-report Type A scale and risk of coronary heart disease.” Circulation. Aug 4;98(5): 405; see also J. E. Muller et al. 1997. “Mechanisms precipitating acute cardiac events.” Circulation. Nov 4;96(9): 3233–3239.
12 J. C. Barefoot et al. 1989. “The Cook-Medley hostility scale: item content and ability to predict survival.” Psychosom Med. Jan–Feb;51(1): 46–57.
13 J. C. Barefoot et al. 1983. “Hostility, CHD incidence, and total mortality: a twenty-five-year follow-up study of 255 physicians.” Psychosom Med. Mar;45(1): 59–63.
14 J. C. Barefoot et al. 1987. “Suspiciousness, health and mortality: a follow-up study of five hundred older adults.” Psychosom Med. Sep–Oct;49(5): 450–457.
15 S. Segerstrom et al. 1998. “Optimism is associated with mood, coping, and immune change in response to stress.” J Pers Soc Psych. Jun;74(6): 1646–1655; M. F. Scheier and C. S. Carver. 1987. “Dispositional optimism and physical well-being: the influence of generalized outcome expectancies on health.” J Pers. Jun;55(2): 169–210.
16 S. E. Taylor et al. 2000. “Behavioral responses to stress in females: tend-and-befriend, not fight-or-flight.” Psych Rev. Jul;107(3): 411–429.
17 M. Friedman and D. Ulmer. 1984. Treating Type A Behavior and Your Heart. New York: Alfred A. Knopf, pp. 175–237.
18 Data from: T. H. Holmes and R. H. Rahe. 1967. “The social readjustment rating scale.” J Psychosom Res. Aug;11(2): 227–237. Also see Holmes Rahe Social Readjustment Rating Scale;
19 Per 2002 CDC statistics, “smoking costs Americans over $157 billion annually in medical care.” Of the 442,398 deaths per year in the U.S. from smoking-related causes, 33.5 percent are cardiovascular-related. 2003 Heart Disease and Stroke Statistical Update, American Heart Association (
presenter.jhtml?identifier53000090), p. 26. Approximately a quarter of U.S. men and women smoke (p. 25).
20 “Number of deaths and age-adjusted death rates per 100,000 population for categories of alcohol-related (A-R) mortality, United States and States, 1979–1996.” National Institute on Alcohol Abuse and Alcoholism ( The total number of deaths attributable to
A-R mortality was 110,000 in 1996, and is only provided to 1996. However, each of the components of this death rate, such as cirrhosis of the liver, has remained stable since this time, having increased by less than 10 percent. Thus it remains the case that over 100,000 deaths in the U.S. are attributable to A-R mortality.
21 U.S. Department of Health and Human Services, Centers for Disease Control. 1990. “Alcohol-related mortality and years of potential life lost: United States, 1987.” Morbidity and Mortality Weekly Report. Mar;39(11): 173–178;
U.S. Department of Health and Human Services. Tenth Special Report to the U.S. Congress on Alcohol and Health from the Secretary of Health and Human Services, June 2000;
22 E. B. Rimm et al. 1991. “Prospective study of alcohol consumption and risk of coronary heart disease in men.” Lancet. Aug;338: 464–468.
23 In 2000, Americans consumed 17.3 gallons of coffee per capita. U.S. Department of Agriculture, Foreign Agricultural Service (data from Davenport & Company LLC). By some popular reports, 80 percent of Americans drink coffee every day. P. McMahon. “‘Cause coffees’ produce a cup with an agenda.” USA Today, July 25, 2001.
24 M. J. Klag et al. 2002. “Coffee intake and risk of hypertension.” Arch Int Med. Mar 25;162: 657–662.
25 “Caffeine is well known to promote anxious behavior in humans and animal models . . .” M. El Yacoubi et al. 2000. “The anxiogenic-like effect of caffeine in two experimental procedures measuring anxiety in the mouse isn’t shared by selective A(2A) adenosine receptor antagonists.” Psychopharmacol (Berl). Feb;148(2): 153–163; J. P. Boulenger et al. 1984. “Increased sensitivity to caffeine in patients with panic disorders.” Arch Gen Psych. Nov;41: 1067–1071.
26 S. M. Wolfe et al. 1988. Worst Pills, Best Pills. Washington, D.C.: Public Citizen Health Research Group, p. 145; C. R. H. Newton. “Benzodiazepine abuse” (
27 T. Thiele et al. 1998. “Ethanol consumption and resistance are inversely related to neuropeptide Y levels.” Nature. 396: 366–369; M. Cockerill. 1998. “Low levels of brain chemical drives mice to drink.” Br Med J. Dec(317): 1544B.
28 George F. Koob has written hundreds of articles on the topic of drug addiction.
S. B. Caine and G. F. Koob. 1993. “Modulation of cocaine self-administration in the rat through D-3 dopamine receptors.” Science. 260: 1814–1816; G. F. Koob et al. 1994. “Corticotropin releasing factor, stress and behavior.” Seminars in the Neurosciences. 6: 221–229; P. Hyytia and G. F. Koob. 1995. “GABAA receptor antagonism in the extended amygdala decreases ethanol self-administration in rats.” European Journal of Pharmacology. 283: 151–159; G. Schulteis, A. Markou, M. Cole, and G. F. Koob, 1995. “Decreased brain reward produced by ethanol withdrawal.” Proc Natl Acad Sci USA. 92: 5880–5884; G. F. Koob. 1996. “Hedonic valence, dopamine, and motivation.” Molecular Psychiatry. 1: 186–189; G. F. Koob. 1996. “Drug addiction: The yin and yang of hedonic homeostasis.” Neuron. 16: 893–896; M. Spina et al. 1996. “Appetite-suppressing effects of urocortin, a CRF-related neuropeptide.” Science. 273: 1561–1564; D. A. Finn, R. H. Purdy, and G. F. Koob. “Animal models of anxiety and stress-induced behavior: effects of neuroactive steroids.” In S. S. Smith, ed. 2004. Neurosteroid Effects in the Central Nervous System: The Role of the GABA-A Receptor. Boca Raton, Florida: CRC Press, pp. 317–338; P. J. Kenny, I. Polis, G. F. Koob, and A. Markou. 2003. “Low dose cocaine self-administration transiently increases but high dose cocaine persistently decreases brain reward function in rats.” European Journal of Neuroscience. 17: 191–195; G. F. Koob. 2003. “Neuroadaptive mechanisms of addiction: studies on the extended amygdala.” European Neuropsychopharmacology. 13: 442–452; G. F. Koob. “Drug reward and addiction.” In L. R. Squire, F. E. Bloom, S. K. McConnell, J. L. Roberts, N. C. Spitzer, and M. J. Zigmond, eds. 2003. Fundamental Neuroscience, 2nd edition. San Diego: Academic Press, pp. 1127–1143; G. F. Koob, A. J. Roberts, B. L. Kieffer, C. J. Heyser, S. N. Katner, R. Ciccocioppo, and F. Weiss. “Animal models of motivation for drinking in rodents with a focus on opioid receptor neuropharmacology.” In M. Galanter, ed. 2003. Research on Alcoholism Treatment (series title: Recent Developments in Alcoholism, vol. 16). New York: Plenum Press, pp. 263–281; G. F. Koob and L. Pulvirenti. “Drug addiction and loss of control: focus on motivation in an allostatic perspective.” In M. Massotti and L. Pulvirenti, eds. 2003. Neuroscience of Drug Addiction: Focus on Neural Plasticity (series title: Rapporti ISTISAN 03/7). Rome: Instituto Superiore di Sanita, pp. 39–48.
29 T. Phillips et al. 1998. “Alcohol preference and sensitivity are markedly reduced in mice lacking dopamine D2 receptors.” Nature Neuroscience. Nov 1(1): 610–615.
30 University of California. Berkeley Wellness Letter 5.7 (Apr 1989).
31 S. Higgens and J. Katz. 1998. Cocaine Abuse: Behavior, Pharmacology, and Clinical Applications. New York: Academic Press; T. Madge. 2004. White Mischief: A Cultural History of Cocaine. New York: Thunder’s Mouth Press; C. Reinarman and H. G. Levine, eds. 1997. Crack in America: Demon Drugs and Social Justice. Berkeley: University of California Press; S. Ali, ed. 2000. The Neurochemistry of Drugs of Abuse: Cocaine, Ibogaine, and Substituted Amphetamines. New York: New York Academy of Sciences; E. V. Nunes and J. S. Rosecan. “Human neurobiology of cocaine.” In H. I. Spitz and J. S. Rosecan, eds. 1987. Cocaine Abuse: New Directions in Treatment and Research. New York: Brunner/Mazel Publishers, pp. 48–97; S. Shiffman and T. A. Wills, eds. 1985. Coping and Substance Use. San Diego: Academic Press, pp. 41–42.
32 2003 Heart Disease and Stroke Statistical Update, American Heart Association;
presenter.jhtml?identifier53000090, p. 25.
33 “Projections of DSM-III alcohol abuse and alcohol dependence for the U.S. population aged
18 and older, 1990, 1995, 2000.” National Institute on Alcohol Abuse and Alcoholism; “An estimated 20 to 40 percent of patients in large urban hospitals are there because of illnesses that have been caused or made worse by their drinking . . . [O]ne in four children under the age of 18 lives in a household with one or more family members who are alcohol dependent . . .” U.S. Department of Health and Human Services, Tenth Special Report to the U.S. Congress on Alcohol and Health from the Secretary of Health and Human Services, June 2000;, p. ix.
34 Researchers are still debating whether caffeine is addictive.
According to one study, “[the] data correlate well with the known sensitivity of locomotion, mood and sleep to low doses of caffeine. They also show that low doses of caffeine which reflect the usual human level of consumption fail to activate reward circuits in the brain and thus provide functional evidence of the very low addictive potential of caffeine.” A. Nehlig and S. Boyet. 2000. “Dose-response study of caffeine effects on cerebral functional activity with a specific focus on dependence.” Brain Res. Mar 6;858(1): 71–77.
Another study claims “caffeine is an addictive psychoactive substance. Similar to previous findings with other licit and illicit psychoactive drugs, individual differences in caffeine use, intoxication, tolerance, and withdrawal are substantially influenced by genetic factors.” K. Kendler and C. Prescott. 1999. “Caffeine intake, tolerance, and withdrawal in women: a population-based twin study.” Am J Psych. Feb;156: 223–228.
35 Department of Health and Human Services, 2001 National Household Survey on Drug Abuse: Volume 1. Summary of National Findings (, chapter 2, p. 11 and chapter 7, p. 2. An estimated 123,000 Americans used heroin in 2001; 1.7 million, cocaine; and 406,000, crack. A “current user” is defined as someone who has used the drug in the month prior to the survey.
36 Two-thirds of U.S. adults report relying on the weekends to catch up on sleep. National Sleep Foundation. “Sleep in America” Poll, March 2002.
According to one recent study, “[s]leep debt has a harmful impact on carbohydrate metabolism and endocrine function. The effects are similar to those seen in normal aging and, therefore, sleep debt may increase the severity of age-related chronic disorders.” K. Spiegel et al. 1999. “Impact of sleep debt on metabolic and endocrine function.” Lancet. Oct 23;354(9188): 1435–1439.
37 Acknowledgments to Dr. Joel Miller who contributed his ideas to this list.
38 H. Benson et al. 1974. “The relaxation response.” Psychiatry. Feb;37: 37–46; H. Benson et al. 1975. “The relaxation response: psychophysiologic aspects and clinical applications.” Int J Psych Med. 6: 87–98.
See also Benson’s more recent book: The Wellness Book: The Comprehensive Guide to Maintaining Health and Treating Stress-Related Illness and Timeless Healing. 1993. New York: Scribner.
Some other recent studies include:
B. H. Chang et al. 2004. “Relaxation response for Veterans Affairs patients with congestive heart failure: results from a qualitative study within a clinical trial.” Prev Cardiol. Spring;7(2): 64–70. This study suggested value of RR in congestive heart failure health care (with both physical and emotional changes seen.)
R. Bonadonna. 2003. “Meditation’s impact on chronic illness.” Holist Nurs Pract. Nov–Dec;17(6): 309–319. This is an overview of different types of techniques for “mindfulness” and their role in a clinical setting.
T. Esch, G. L. Fricchione, and G. B. Stefano. 2003. “The therapeutic use of the relaxation response in stress-related diseases.” Med Sci Monit. Feb;9(2): RA23–34. This study points to the therapeutic uses of RR techniques, particularly in mild or early disease states when “a high degree of biological and physiological flexibility may still be possible.” Interesting connection to nitric oxide production.
G. D. Jacobs. 2001. “Clinical applications of the relaxation response and mind-body interventions.” J Altern Complement Med. 7(Suppl 1): S93–101. This study refers to the “several hundred peer-reviewed studies in the past 20 years” that have shown that “the relaxation response and mind-body interventions are clinically effective in the treatment of many health problems that are caused or made worse by stress.” It suggests that these techniques are very effective when combined with standard medical care.
C. L. Mandle et al. 1996. “The efficacy of relaxation response interventions with adult patients: a review of the literature.” J Cardiovasc Nurs. Apr;10(3): 4–26. This study reviewed 37 studies of the efficacy of RR interventions with adult patients. “Consistencies in the results suggest the effectiveness of the relaxation response in reducing hypertension, insomnia, anxiety, pain, and medication use across multiple populations, diagnostic categories, and settings.”
39 H. Benson et al. 1974. “Decreased blood pressure in borderline hypertensive subjects who practiced meditation.” J Chron Dis. 27: 163–89.
40 C. N. Alexander et al. 1989. “Transcendental meditation, mindfulness, and longevity: an experimental study with the elderly.” J Pers Soc Psych. Dec;57: 950–964.
41 H. Benson with M. Z. Klipper. 1975 [2000]. The Relaxation Response. New York: William Morrow, pp. 23–25, 68–74.
42 J. Kabat-Zinn. 1990. Full Catastrophe Living: Using the Wisdom of Your Body and Mind to Face Stress, Pain, and Illness. New York: Delacorte Press; J. Kabat-Zinn. 1995. Wherever You Go, There You Are: Mindfulness Meditation in Everyday Life. New York: Hyperion.
43 Biofeedback is being proposed for a variety of health issues, such as urinary incontinence (N. M. Shinopulos and J. Jacobson. 1999. “Relationship between health promotion lifestyle profiles and patient outcomes of biofeedback therapy for urinary incontinence.” Urol Nurs. Dec;19(4): 249–253) and cutaneous problems (P. D. Shenefelt. 2003. “Biofeedback, cognitive-behavioral methods, and hypnosis in dermatology: Is it all in your mind?” Dermatol Ther. Jun;16(2): 114–122). See also D. Shapiro and R. S. Surwit. “Biofeedback.” In O. F. Pomerleau and J. P. Brady, eds. Behavioral Medicine: Theory and Practice. Baltimore: Wilkins & Williams.
44 Although Benson derived his technique largely from transcendental meditation (TM), proponents of TM point out that Benson’s technique isn’t the same as TM and differs from it in subtle but important ways. There has been extensive research reported on the health benefits of TM, which includes papers in over 100 referenced journals. A summary of this research and a complete listing of references is contained in D. Orme-Johnson and C. N. Alexander, “Summary of research on the transcendental meditation and TM-Sidhi program,” available from TM centers.
For information on TM, visit and for centers that teach transcendental meditation in your area, visit or call 1-888-432-7686. Online courses are also available from the Maharishi Open University (
45 Benson with Klipper, pp. 158–166. See note 41 on page 441.

Chapters: 1-5, 6-10, 11-15, 16-20,

Fantastic Voyage: Live Long Enough to Live Forever by Ray Kurzweil and Terry Grossman M.D. Rodale: 11/2004 ISBN#1-57954-954-3