Dietary restriction
Introduction. Dietary restriction influences aging and disease by modulation of biological and pathological processes. Dietary restriction retards age-related functional deterioration and the onset or progression of age-related diseases, prolongs mean and maximum lifespans, and improves overall health [5333]. Szilard [5632] in 1959 proposed the hypothesis that the accumulation of DNA damage was a basic mechanism in the aging process and that cancer may result from faulty DNA repair [5627]. MaCay in the 1930s demonstrated a significant increase in lifespan in weanling rats on a severely restricted diet [801, 5630], an observation that was later extended to adult rodents on less restricted diets [803, 5625-5626, 5631]. These benefits include decreased tumorigenesis [5310, 5330], enhanced antioxidant enzyme defenses [5319], enhanced immune defenses [5302, 5316] and reduced total serum cholesterol [5324, 5328]. Tannenbaum [861] in the 1940s concluded from his studies with benzo(a)pyrene-induced skin tumors that dietary restriction exerted its main anticarcinogenic effect on promotion of carcinogenesis.

Body Weight. The relationship of body weight and mortality, particularly with respect to optimal weight for longevity, is of great interest. Many studies have examined the relationship between weight loss or weight fluctuation with respect to mortality from all causes [19753-19765, 19794]. The nature of this relationship between body weight and mortality may exhibit several associations: an inverse association [19781], a J-shaped association [19768-19770, 19772-19774], a U-shaped association [19775-19776], or no association [19768-19771]. The lowest mortality rate was observed among women who weighed at least 15 percent less than the US average for women of similar age and among whose weight had been stable since early adulthood [19766]. Weight loss and weight fluctuation were less related to death among healthy men who had never smoked [19752].

Obesity, defined as being 20 percent or more over optimal weight for height, age and gender, is associated with several serious and common adverse health outcomes, placing a severe burden on the US health care system [6395-6396, 11181-11182, 12737-12738]. Cholesterol levels are currently dropping in the US while calorie intake is increasing [19792-19793]. The result has been a continuing increase in body weight and obesity in the US. Obesity is an alarming epidemic [19783, 19785] that is clearly associated with increased mortality [19767], particularly from diabetes, cardiovascular disease [639, 19767, 19782] and cancer [19767].

Obesity is classified according to the size and number of fat cells [6400]. In the hyperplastic type of obesity, fat cells actively proliferate during gestation to 1 year after birth and again during puberty. In the hypertrophic type, fat cells are normal in number but enlarge in size during adulthood. Most highly obese individuals exhibit both hyperplasia and hypertrophy of fat cells [6399]. The incidences of diabetes mellitus, hyperlipidemia, hypertension and heart disease are higher in those with abdominal visceral obesity than in those with peripheral or subcutaneous obesity [6401]. Excess fat, expressed as obesity is unhealthy. However, fat in proper amount and distribution within the body does serve beneficial functions. Fat is the body's reserve of energy. Fat beneath the skin provides insulation and suppresses heat loss. Fat supports and protects the internal organs, including the eye and kidneys [17997].
Table 5-1: Body composition of percent body water, percent body fat and percent lean mass can be estimated within +/- 3 percent using a simple method that measures electrical impedance with external electrodes. This table provides normal ranges of percent fat in both genders as a function of age. 
Obesity is associated with increased levels of serum lipids [2549, 11185-11186] and increased liver size, fatty infiltration of liver and hepatocyte necrosis [11182-11184]. The hepatic clearance and metabolism of xenobiotics may be altered in obese people [11187]. Numerous studies have been carried out in the genetically obese Zucker rat [11188-11191] and in genetically normal, obese overfed rodents [11179, 11192-11194]. The Zucker rat has a reduced level of growth hormone and testosterone [11195-11196] which alters levels of P450 enzymes [11197]. The overfed obese rat has normal hormone levels [11194] but high levels of serum lipids [11193]. The obese overfed rat model is most similar to humans with respect to pharmacokinetic and physiologic changes [11194].

The benefits of a decreased body weight include reduced risks of cancer, hypertension, cardiovascular disease, stroke, adult-onset diabetes, hiatal hernia and reflux disease, oligospermia, amenorrhea, hypoxemia, sleep apnea and gallbladder disease [12738, 18010-18013, 18018]. The economic cost of obesity in 1986 was estimated to be at least $39 billion [12739]. Obesity cost the nation about 70 billion dollars in 1990 [19876]. From 1988 to 1991, > 25 percent of all American adults 20 years of age or older were considered to be obese [11180]. Harris polls have found a steady increase in body weight: 58 percent of Americans were overweight in 1983, 64 percent in 1990 and 69 percent in 1994. The mean body weight of adult Americans increased 3.6 kg from 1976 to 1991 [17281, 19786]. Metropolitan Life found that 10 percent of Americans are at least 30 percent overweight [19787]. Obesity among the nation's youth is increasing faster than among adults [12736]. Obesity in US teens, aged 12-19, has risen from 15 percent in 1980 to 31 percent in 1991.
Table 5-2: Age-adjusted prevalence of overweight for the US population 20 years of age and older [12736].
Obesity is also difficult to treat and is resistant to intervention strategies [12740]. There is a well documented discrimination against obese people, with important social and economic consequences. A significant positive relationship was found between psychiatric problems and binge eating [17985]. The obese have higher levels of anxiety, depression and a lower self-esteem [17986]. Upper body fat was associated with higher levels of anger, anxiety, and depression and lower levels of social support [17987-17996]. In a 7-year follow-up study of females aged 16 to 24 years, obese females were less likely to have been married and had less schooling, lower incomes, and higher rates of household poverty than females with other chronic medical conditions [17282]. There is no national commitment to obesity as a public health problem.

Glucose, the primary source of energy in the body, contains 4.1 calories per gram. Protein also contains about 4.1 calories per gram, while each gram of fat contains 9.3 calories [18000]. You must burn an excess of 3,500 calories, or 500 calories per day, to lose one pound a week [19876].

The incidences of obesity and diabetes among the Pima Indians of Arizona are 80 percent and 50 percent, respectively. This high incidence of obesity is thought to be due to the presence of a "thrifty" gene that provided a survival advantage over the centuries to Indians during periods of famine. However, the incidence of obesity and diabetes among Pima Indians in Mexico is no different than other racial populations in Mexico. The difference between Arizona and Mexico Pima Indians is in their lifestyles. Exposure to diabetogenic lifestyle factors in Arizona Pima Indians have progressively increased over the past 80 years [19840]. The Arizona Indians live a sedentary life with a typical high fat western diet, while the Indians of Mexico are much more active with low fat diets comprised mostly of beans and corn tortillas. Among the Pima Indians of Peru, obesity along with diabetes does not contribute substantially to cardiovascular disease [6398]. Sumo wrestlers are very heavy due to subcutaneous fat cell hypertrophy. Yet their plasma glucose and triglyercides are normal and plasma cholesterol is low compared with normal weight subjects. This is probably due to the intense exercise routine and developed musculature of Sumo wrestlers [6395]. However, cardiovascular disease mortality in former sumo wrestlers is high.

Weight control can be maintained by (1) minimizing eating between meals; (2) eating more raw fruits and vegetables; (3) increasing water intake [17984, 18015-18017].

Caloric Restriction. Caloric restriction is the most powerful and diversified strategy in the field of experimental gerontology [798, 5715-5716, 5723]. Other than in Mediterranean regions [11655], reduction of dietary fat to 30-35 percent or less of total dietary calories is thought to decrease coronary heart disease and cancer incidence at several anatomic sites [11648, 11653]. Women over 40 percent above desirable weight have a 55 percent greater mortality from cancer than those of normal body weight. Similarly, obese men have a 33 percent increased risk of fatal cancer [2431]. Forty percent of women and 25 percent of men in the US are trying to lose weight at any particular time. A summary of 43 studies by NIH concluded that it is more unhealthy to be overweight than yo-yo through chronic dieting. The studies also shows that dieting alone is not the most healthy method to help control weight.

Dietary caloric intake plays an important role in the rate of DNA damage, including oncogene expression [4279-4280, 5211]. mRNA expression levels of oncogenes are significantly reduced in rodents on restricted caloric diets [2426]. Transgenic mice with both alleles of the p53 tumor suppressor gene (most observed genetic mutation in human cancer) knocked out by gene targeting provides a valuable tool to study calorie restriction on tumorigenesis [17738]. A diet restricted to 60 percent of ad libitum calories increased the median lifespan of p53-knockout mice by over 50 percent while delaying tumor appearance [13393].

Reduced calorie intake to levels of 20-40 percent less than ad libitum intake extends the latency to onset and reduces the incidence of cancer and autoimmune diseases in rodents and prolongs lifespan in many mammalian species [795-800, 803, 4268, 5719-5720, 6708-6711]. However, restricting fat and mineral components without restricting calories does not significantly affect survival time [5718]. Decreases, ranging from 30 to 100 percent, for common inflammatory, proliferative and neoplastic diseases were found in rats on a restricted caloric diet as compared to an ad libitum diet [797, 802, 804-807, 818-823]. Maximum survival in male F344 rats increased from about 950 days for rats fed ad libitum to about 1350 days for rats fed a restricted diet [801]. A study of 650 Charles River male rats found a 50 percent increase in maximum survival (from 1000 days in ad libitum rats to 1500 days in restricted diet rats) following diet restriction [802]. A restricted diet (60 percent of ad libitum starting at six weeks of age) in male Wistar rats increased the median life span over ad libitum fed animals by 51 percent [803]. In another study of male F344 rats, the mean survival time of diet restricted rats was greater than the longest living ad libitum rat [804]. Caloric restriction of complex carbohydrates may have undesirable effects [5205-5206, 5224].

Protein Restriction. Dietary restriction of protein decreases cellular protein synthesis and can extend lifespan provided a balanced level of essential amino acids is present in the diet. mRNA levels for a number of proteins in rat liver were depressed by about 40 percent after three days on a protein-free diet, with mRNA levels returning to normal after 3 days of feeding a high protein diet [5307]. Hepatic microsomal mixed function oxidase, epoxide hydrase and benzo(a)pyrene monooxygenase activities are decreased by protein restriction [5296, 5303, 5313], resulting in less metabolite covalent binding to DNA [5314, 5317, 5321]. Two main vegetable foods - corn and cassava - are deficient in amino acids. Corn lacks tryptophan and cassava methionine. Restriction of the amino acids tryptophan or methionine extends the lifespan of rats [5212, 5215].

Replacing dietary casein with soy protein improved median lifespan of rats about 15 percent due to suppression of the progression of chronic nephropathy [5721]. A high protein diet enhanced preneoplastic lesion development, while a low protein diet caused a disappearance of the lesions [5203]. Protein restriction exerts its strongest influence on lesion growth long after the genetic damage had occurred [5334]. High protein consumption enhanced carcinogen-induced mammary carcinogenesis [5310-5312]. Protein fermentation products do not play a role in colon cancer promotion [18608]. The FAO/WHO group [5335] recommended a dietary protein intake of 6-8 percent of calories, while the USDA suggests 14-18 percent of total energy intake to be derived from protein [5297-5299]. Nitrogen balance in rats is achieved with only 4-5 percent protein [5322]. The low protein content (6-7 percent of calories) of the diet in China may be associated with a smaller stature and a reduced risk of several types of cancer, coronary heart disease and several other degenerative diseases [5304].
Table 5-3: Protein content of select foods [10845].
DNA Repair. The antioxidant action of dietary restriction produces strong indications supporting the hypothesis that age-related oxidative damage to the subcellular membranes and the deterioration of cytoplasmic protective components are inhibited by dietary restriction [4282, 5202, 5332, 5372]. Food restriction inhibits free radical formation by changes in fatty acid composition of subcellular components [826]. This strengthens the notion that dietary caloric restriction promotes an antiradical action, protecting DNA from oxidant injury [827-829].

DNA repair shows a decline with increasing age [832]. Stimulation of DNA repair by caloric restriction may be responsible for suppression of diseases associated with obesity and aging [830-831, 5624]. DNA repair in rodent kidney, liver, skin, spleen and lung cells following exposure to UV radiation was significantly increased in animals on a 50-75 percent caloric restricted diet [832-834, 5367, 5370]. Dietary restriction significantly inhibited by 20-78 percent the expression of DNA damage in otherwise untreated rodents, when expressed as mutations at the hypoxanthine phosphoribosyl transferase locus [5633] or oxidative damage to DNA resulting in the production of 5-hydroxymethyluracil [5305, 5628]. Oxidative DNA damage in leukocytes, as measured by the molar ratio of 5-hydroxymethyluracil /104 thymine residues, was significantly decreased in women on a low fat diet [5336, 5344]. However, dietary restriction did not significantly lower single strand DNA breaks in mice [5629]. Caloric restriction may also reduce oncogene expression [2426].

Immune System. Food restriction appears to reverse or slow some immunological alterations [797-798, 803, 836-838]. Food restriction delays the progression of immune deficiency with aging and suppresses the rise in associated chronic diseases [5302, 5316, 5325]. Genetic obesity in mice largely eliminates the immunopotentiating effects of food restriction [16751]. A higher interleukin-2 (IL-2) production and increase in the number of HA IL-2 receptors in T cells is seen in food restricted rats [835]. The decline in immune response during aging may be closely associated with age- related alterations in lymphoid cell fatty acids. In mice, reduction in dietary calories delays and/or inhibits cell proliferation in the spleen and lymph nodes [798, 5325, 6717, 6728-6729], and inhibits a variety of diseases, including systemic amyloidosis [6711], systemic lupus erythematosis-like syndrome [6712-6713], breast tumors [5378, 5386, 6714-6717], nephrosis [6718], lymphoproliferative syndrome [6719-6720] and thymic lymphosarcoma [6721].

Lectin-induced lymphocyte proliferation, induced natural killer (NK) cell activity, production and responsiveness to interleukin 2 and induced T lymphocyte killing of tumor cells are all enhanced by dietary caloric restriction in mice [798, 6325, 6726, 6728-6729]. The cellular immune response is usually impaired in cancer patients, especially in those with metastatic disease [6731-6732]. The immune system is further inhibited by chemotherapy and radiotherapy. Dietary and biological modifiers, such as caloric restriction, vitamins, interferons and plant extracts, that could favorably modulate the immune system or preserve existing immune function, may prove of benefit to cancer patients [1247, 6733-6737].

Neuroendocrine Effects. Many cancers arise out of a background of an obesity-related, disturbed physiological status and/or hormone-mediated, regenerative hyperplasia [839, 843-847]. Food restriction may act on the neuroendocrine system of rodents to decrease glucocorticoid secretion by the adrenal cortex and insulin secretion from the pancreas, thereby decreasing plasma glucose levels as compared to those seen in ad libitum fed rodents [797, 839, 8281, 8285-8287]. The age-related decrease in binding affinity of insulin and glucagon receptors is attenuated by caloric restriction [5506-5507, 5513]. Serum parathyroid hormone levels increase to significantly higher levels in aging rats compared to aging rats on a restricted diet [5722]. The onset of reproductive senescence is delayed in mice by caloric restriction [6708, 6723-6725]. Fat restriction dramatically increases the permeability of the skin to hydrocortisone, and probably to lipophilic toxicants [5207].

Xenobiotic Metabolism. Dietary restriction alters the way in which xenobiotics are detoxified or metabolically activated [8, 854, 856-857, 5191, 5193, 5204, 5208, 5217-5218, 5533, 5537-5538, 5553]. In rats, xenobiotic and steroid metabolism involving enzyme system isoforms are age- and gender- dependent [5528-5529, 5546, 5549, 5554, 5568]. Xenobiotics induce their responsive isoforms by initially binding to intracellular receptor proteins that are analogous to those found for steroid hormones [5536, 5558, 5567]. The xenobiotic-receptor complexes cause transcription of the related isoforms by binding to specific DNA sequences that are functionally linked to the coding regions of the isoform genes [5524]. Enzyme metabolizing systems are usually decreased by low protein or high carbohydrate diets, and increased by high unsaturated fat diets [5553, 5562, 5571]. Diets deficient in vitamin A [5533, 5537-5538, 5553], riboflavin [5533] or iron [5534] may depress P450 isoforms. Fasting, vitamin E, ascorbic acid, thiamine or selenium each influence the induction of various P450 isoforms [5557, 5569, 5573, 5575].

Aflatoxin B1-induced mutagenic and carcinogenic activities are modified by nutritional factors such as fat [5621], protein [5614], essential vitamins [4036], minerals [5615] and total caloric intake in food [5620]. Caloric restriction inhibited the conversion into reactive metabolites and binding of chemical hepatocarcinogens, such as aflatoxin B1 and 2-acetylaminofluorene to liver DNA [5525-5526, 5561, 5613]. Hepatic glutathione S-transferase activity towards 1-chloro-2, 4-dinitrobenzene was significantly higher in lean mice than in obese mice; obese mice, irrespectively of their genotype, were deficient in this enzyme [5711-5714]. Human cytochrome P450 related N-demethylation of erythromycin declined significantly (more in females than in males) with increase in body weight [5543]. Protein restriction and caloric restriction decreased oxazepam clearance [5541]. Dietary restriction in rats did not significantly change hepatotoxic or nephrotoxic effects of phenobarbitol, clofibrate or cyclosporin A in either gender [10272].

Carcinogenesis. Cell division is critical to converting DNA lesions to mutations and eventually to cancer formation, whether agents causing increased cell division are genotoxic or nongenotoxic [4276, 5300-5301, 5306]. Cohen and Ellwein [840] have argued that increased cell proliferation predisposes to mutagenesis and subsequent carcinogenesis. Thus, simple caloric restriction may reduce the risk of cancer by inhibiting inflammation and cell proliferation [805, 841-842, 849, 5619]. Caloric restriction stabilizes or reduces cell proliferation in vivo [848-849, 5654, 5657]. Caloric restriction reduces apoptosis [5653], while long-chain fatty acids have the opposite action [5652]. Caloric restriction significantly reduced colon epithelial cell proliferation in young and old rats [851-852] and lowered carcinogen-induced increased cell proliferation in the colon [853]. A three day fast decreased epithelial cell proliferation of the rat colon by 70 percent [850].

Caloric restriction without essential nutrient deficiency retards aging [8280-8283, 8285, 8288, 8296-8297]. Caloric restriction in laboratory animals results in an increased lifespan, decreased proliferation rate, decreased severity of nonneoplastic diseases, extended time-to-tumor, and decreased incidence of tumors of spontaneous and chemically induced tumorigenesis [797-798, 857-859, 5323, 5551, 5616-5618, 5620, 5622-5623, 5525-5526, 9937-9940]. Studies at the turn of this century noted growth retardation of implanted sarcomas in underfed mice [816-817]. A prospective study of 750,000 men and women has shown higher mortality rates for cancer in several organs for overweight as compared to normal weight men and women [2424]. Overall, there was a close relationship between the amount of food eaten, obesity and tumor development [5851-5854]. Decreased cellular proliferation and transformation, depressed oncogene expression and mutation and decreased tumor suppressor gene, an increased oncogene methylation, and enhanced DNA repair capacity are all hallmarks of caloric restriction in animals [2426, 5211, 5650-5651, 5655-5656, 5658, 6727].

A dose-related increase in tumor incidence was seen in rodents as dietary fat intake increased from 10 percent to 40 percent of calories [8284-8285, 8288, 8298]. Caloric restriction inhibited spontaneous and chemically-induced carcinogenesis for a variety of chemical carcinogens at different sites, including mammary gland [5616], lung [9911, 18605], bone marrow [9907, 9910], lymph nodes [6726] colon [5616-5617, 9915], intestine [857], pancreas [858] and liver [5618, 5620]. Caloric restriction reduced the incidence of leukemia and lymphoma in mice [10924-10925]. Caloric restriction retarded the onset but not the progression of leukemia in F344 rats [9940]. Food restriction inhibited induced tumorigenesis from aflatoxin B1, benzo(a)pyrene, 7,12-dimethylbenz (a)anthracene and 3-methylcholanthrene [5177, 5200, 5225]. A restricted diet significantly reduced the number of small intestine tumors in rats treated with methylazoxymethanol [857] and the number of pancreatic tumors induced by azoserine [858] as compared to tumor incidence seen in rats fed ad libitum. A low fat diet and reduced calories in the diet completely inhibited methylcholanthrene- induced skin tumors in mice as compared to a 54 percent incidence in mice fed ad libitum [859]. Caloric restriction completely inhibited 7,12-dimethylbenz(a)anthracene-induced mammary tumors in Sprague Dawley rats as compared to an incidence of 60 percent in ad libitum fed rats [860].
Table 5-4: Significant physiological effects of food (caloric, fat) restriction. 
Vegetarians. Vegetarian-type diets are associated with a decreased incidence of untimely death from cancer and cardiovascular diseases [18328, 18331]. Vegetarians eat no food of animal origin, while lactovegetarians consume dairy products and lacto-ovovegetarians consume diary products and eggs. Abstinence from the use of tobacco, alcohol and caffeine often is associated with vegetarianism [10837-10841]. Vegetarians consume less calories but more fiber and complex carbohydrates than omnivores [10842-10843]. The recommended daily amount of protein for a 128 pound women consuming a 2,000 calorie diet is 44 grams [10845]. The intake of a variety of high-protein plant foods, such as grains, seeds, nuts and legumes provides sufficient levels of essential amino acids even for pregnant and lactating women [10837, 10842, 10844]. Only about 2 percent of the US population call themselves vegetarians [10836, 10869].

Vegetarians with a wide variety of foods in their diet have adequate or better intake of most vitamins than omnivores [10837, 10842, 10844, 10846, 10848, 10851]. Vegetarians have a higher plasma -tocopherol/cholesterol ratio than omnivores [10847]. The use of tobacco, alcohol and certain drugs may cause a vitamin B12 deficiency in vegetarians and omnivores [10849]. The use of vitamin D-fortified milk may be necessary to overcome vitamin D deficiency in some vegetarians [10837, 10842]. A vegetarian diet usually contains adequate iron and zinc [10844, 10846, 10850]. Vegetarians may have lower serum ferritin levels than omnivores, but it does not result in more frequent anemia [10852]. Vegetarians consistently have a lower body weight than omnivores [10838-10840, 10842, 10844, 10853]. Vegetarians have lower sodium intake and higher potassium intake in their diet [10839-10840]. Potassium supplementation of vegetarians has little, if any, effect on blood pressure [10854-10855]. The 1995 US government advisory panel's new recommendations for healthy eating has recognized vegetarians for the first time. The report revises the 1990 edition and recommends that vegetarians, especially children, supplement their diet with vitamin D, calcium, zinc, iron and B vitamins. Long-term vegetarians may experiencing vitamin B12 deficiency resulting in mild stage anemia related to megaloblastic anemia [18611]. Vegetarians experience significantly less cancer, heart disease, gallstones, diabetes and osteoporosis than omnivores [149-150, 792-794, 1211, 1213, 1578, 1632-1633, 1639, 1987, 2328, 3407, 4149, 6989, 10860, 10863-10865]. Cancer risk for male vegetarians was about 50 percent less and 25 percent less for female vegetarians compared to meat eaters.

Abstinence. Cancer incidence and mortality is low in nonsmokers and in religious groups whose lifestyles are characterized by abstinence in use of alcoholic beverages and tobacco. These include groups such as Mormons and Seventh Day Adventists [149, 163]. Cancer of the mouth, pharynx, larynx, esophagus, lung, bladder and cervix are significantly reduced in Seventh Day Adventists [159-162]. Meat consumption by itself was not a risk factor for cancer of the colon, breast or prostate in Seventh Day Adventists [10862]. Sister chromatid exchanges in lymphocytes of Seventh Day Adventists were significantly lower than in the general population [17816-17817]. Cancer mortality in smoking-sensitive tissues in populations of nonsmokers in California was reduced by 42 percent and the mortality from all cancers was reduced by 32 percent from cancer incidences seen in the general California population [164]. Cancers at all sites in nonsmoking males was 47 percent of that seen in smokers and 64-71 percent of that seen in the general population [165-168]. A study of 200 people in England over the age of 90, where women outnumber men by four to one, cited moderation as the main reason for longevity [1653].
Table 5-5: Cancer mortality among low risk male populations. 
Exercise. About 60 percent of Americans can be classified as sedentary. This is largely due to the fact that mostly everything is automated and convenient. Little energy is spent each day by most persons unless one goes out of their way to exercise. Physical exercise and training increase aerobic capacity and inhibit the appearance and progression of many diseases and disabilities including cancer [14805, 14810-14812, 15543]. NK cell concentration and activity are increased immediately after rigorous physical exercise [14849-14859], which is followed by a decrease in NK cells to below normal levels several hours after ending exercise [14849, 14852, 14860]. Slower, prolonged aerobic exercise increases the cytotoxicity of NK cells [1013, 14857, 14861-14863]. Caloric restriction and exercise both retard the decline in hepatobiliary function associated with aging [15389-15398]. Seven weeks of bodybuilding increases plasma testosterone, lean body mass and strength [17771].

A 26 year study of 17,321 male Harvard alumni who graduated between 1924 and 1954 found that vigorous exercise burning at least 1500 calories per week was associated with significantly lower mortality. Vigorous exercise is equivalent to walking briskly 4 to 5 mph for a least 45 minutes a day, five days per week, or jogging, at least an hour three times a week. Men who were considered unfit by treadmill test had a mortality rate over a five year study period that was about 70 percent greater than those who were considered fit. Men who improved from unfit to fit exhibited a reduction in mortality risk from all causes of 44 percent. For each minute increase in maximal treadmill time between examinations, there was a corresponding 7.9 percent decrease in risk of mortality [17062]. Long-distance running or comparable aerobic exercise are associated with improved quality of life, lower death rates and preservation of good physiological and physical function in the latter years of life.

Aerobic exercise significantly increases muscle demand for oxygen but only to the extent that the body is able to meet the demand. Anaerobic exercise uses a different set of enzymes to obtain energy from the body. High-intensity exercise is anaerobic and can be performed only for a short period of time. Waste products of anaerobic exercise are acidic, causing fatigue when they accumulate in the muscle.

Table 5-6: Examples of different exercises and calories per hour expenditured for a 150 pound person. 
Exercise influences xenobiotic metabolism [15547-15548]. Exercise reduced chemically-induced mammary and pancreatic tumors [2423] and colon tumors in rats [1191]. Treadmill exercise decreased azoxymethane-induced intestinal tumors in rats fed a high coconut oil diet [19021]. Volunteer wheel-running exercise inhibited pancreatic carcinogenesis in rats [15541]. Exercise inhibited 3'-methyl-4-dimethylaminoazobenzene-induced hepatomas in male rats, that was also associated with an increase in serum alkaline phosphatase and a decrease in serum -glutamyl-transpeptidase [5847]. Other studies demonstrated a reduction in benzidine-induced hepatomas in mice [5855-5856] and of spontaneous hepatomas in mice [5850] due to exercise.

Moderate exercise in rats caused a reduction in food intake and a decreased pancreatic carcinogenesis while intense exercise increased carcinogenesis [15533]. Increased duration of exercise tends to promote 1-methyl-1-nitrosourea-induced mammary carcinogenesis in rats, while moderate exercise is inhibitory [15542, 15546, 15549-15550]. Both the intensity and duration of exercise influence the development of experimentally induced breast cancer [15542]. Heavy exercise in one epidemiological study tended to increase mortality from cancer of the lung, pancreas and colorectum, compared to moderate exercisers [15537]. A U-shaped mortality curve for pancreatic and colorectal cancer with increased exercise was found for a population of longshoreman [15540].

Ewing in 1911 found that cancer was much more likely to occur in sedentary higher socioeconomic classes than in the "poor and over-worked" [17104]. The pioneering studies of Sivertsen and Dahlstrom in 1921 showed an inverse relationship between physical activity and cancer mortality in Minnesota residents [1180-1181]. Numerous studies since then have shown that increased physical activity is associated with a decreased risk of cancer in several organs [1183-1184, 1299, 1301, 2196, 3662, 5945, 15537-15540]. This relationship has been the subject of several reviews [5848-5849, 5857]. Occupational or recreational exercise suppresses the development of cancer, particularly in the colon and prostate of males and the breast and reproductive organs of females [1299, 1301-1302, 2195-2198, 3664]. One study failed to confirm the association [3666]. Former athletes were found to have a lower relative risk of breast cancer than non-athletes [15544]. Other studies failed to detect an association between participation in college athletes and breast cancer in women [15545]. A decrease in deaths from cancer was found for those who exercised moderately, compared to nonexercisers.

Several studies have shown that increased physical activity is particularly associated with a reduced risk of colon cancer [1182-1184, 1188-1189, 1300, 2195, 2198]. Two cohort and two case-control studies in Sweden showed an inhibitory action of modest physical exercise on risk of colon cancer [201]. Vigorous occupational activity has been shown to reduce the risk of colon cancer in men [1301, 2197]. An inverse association with increasing exercise and colon cancer was found with running or cycling for half an hour continuously at least once a week (RR = 0.46) compared with the control group [1192]. Possible mechanisms for exercise-related decreased risk of colon cancer include: (1) Decreased intestinal transit time reducing contact between colonic mucosa and potential carcinogens; (2) exercise-related increase in plasma prostaglandin F2 which strongly inhibited the growth of chemically-induced colon cancer in rats and human tumors propagated as xenografts [1185] and (3) exercise increased levels of several antioxidants in the blood which may have a protective effect on colon cancer formation [1186-1187]. Physical activity during early adulthood may not confer the same protective effect on colon cancer risk as recent consistent physical activity during older age [16625].

Regular exercise enhances antioxidant levels and protects against lipid peroxidation [13044, 13047, 13062, 13066]. Vitamin E deficiency in animals during exercise is associated with lipid peroxidation [13060, 13084], while vitamin E supplementation reduced lipid peroxidation in exercised animals [13055, 13057, 13061]. An increase level of vitamin C content in blood lymphocytes is found in trained persons [13062-13063], and for several days following strenuous exercise [13062-13063]. Plasma uric acid is increased with most forms of exercise [13064-13065]. Athletes also have a higher erythrocyte vitamin E content [13062].

The message for exercise is made stronger with a reminder that one should try to maintain body weight by balancing what you eat with physical activity. There is a controversy about how much exercise and how strenuous that exercise provides the greatest health benefits [18163]. The US Centers for Disease Control and Prevention and the American College of Sports Medicine concluded that "every US adult should accumulate 30 minutes or more of moderate-intensity physical activity on most, preferably all, days of the week". Vigorous exercise may mean running about 15 miles a week at about 10-minute per mile pace or faster. The risks of heart disease decreases linearly as mileage increases up to 50 miles per week. Thus, more is better up to a weekly total of 50 miles. No one has adequate data after that distance.

An exercise program may have beneficial results in patients with cancer. Cancer patients, successfully treated for cancer, who maintained a program of vigorous physical exercise after diagnosis, typically had slim, muscular builds [17107]. Tumor weight in mice bearing a transplanted tumor was reduced by 30 percent when they were exercised [2434]. An extract from fatigued (exercised) muscle from mice decreased tumor growth in mice given transplanted cancer cells. In a few mice, the tumor disappeared [17105-17106]. The voluntary use of an exercise wheel significantly reduced the growth of human breast carcinomas maintained in athymic nude mice [18606].

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