Tumors, Cancer can be prevented and treated by Intermittent Fasting and Caloric Restriction.

Scientific evidence:

Energy restriction and the prevention of breast cancer. Harvie M, Howell A. Proc Nutr Soc. 2012 May;71(2):263-75. Epub 2012 Mar 14. Nightingale Centre, University Hospital of South Manchester, Manchester M23 9LT, UK.

Energy restriction (ER) to control weight is a potential strategy for breast cancer prevention. The protective effects of habitual continuous energy restriction (CER) and weight loss on breast tumour formation have been conclusively demonstrated in animal studies over the past 100 years, and more recently in women using data from observational studies and bariatric surgery. Intermittent energy restriction (IER) and intermittent fasting (IF) are possible alternative preventative approaches which may be easier for individuals to undertake and possibly more effective than standard CER. Here, we summarise the available data on CER, IER and IF with special emphasis on their potential for breast cancer prevention. In animals, IER is superior or equivalent to CER with the exception of carcinogen-induced tumour models when initiated soon after carcinogen exposure. There are no human data on IER and breast cancer risk, but three studies demonstrated IER and CER to be equivalent for weight loss. IF regimens also reduce mammary tumour formation in animal models and also led to weight loss in human subjects, but have not been directly compared with CER. Animal and some human data suggest that both IER and IF may differ mechanistically compared with CER and may bring about greater reduction in hepatic and visceral fat stores, insulin-like growth factor 1 (IGF-1) levels and cell proliferation, and increased insulin sensitivity and adiponectin levels. Although IER and IF were first studied 65 years ago, we conclude that further studies are required to assess their values compared with CER.

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Calories and carcinogenesis: lessons learned from 30 years of calorie restriction research. Hursting SD, Smith SM, Lashinger LM, Harvey AE, Perkins SN. Carcinogenesis. 2010 Jan;31(1):83-9. Epub 2009 Dec 7. Department of Nutritional Sciences, The University of Texas at Austin, 103 West 24th Street, Austin, TX 78712, USA.

Calorie restriction (CR) is arguably the most potent, broadly acting dietary regimen for suppressing the carcinogenesis process, and many of the key studies in this field have been published in Carcinogenesis. Translation of the knowledge gained from CR research in animal models to cancer prevention strategies in humans is urgently needed given the worldwide obesity epidemic and the established link between obesity and increased risk of many cancers. This review synthesizes the evidence on key biological mechanisms underlying many of the beneficial effects of CR, with particular emphasis on the impact of CR on growth factor signaling pathways and inflammatory processes and on the emerging development of pharmacological mimetics of CR. These approaches will facilitate the translation of CR research into effective strategies for cancer prevention in humans.

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Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends Pharmacol Sci. 2010 Feb;31(2):89-98. Epub 2010 Jan 25. Longo VD, Fontana L. The Andrus Gerontology Center, University of Southern California, Los Angeles, CA, USA.

An important discovery of recent years has been that lifestyle and environmental factors affect cancer initiation, promotion and progression, suggesting that many malignancies are preventable. Epidemiological studies strongly suggest that excessive adiposity, decreased physical activity, and unhealthy diets are key players in the pathogenesis and prognosis of many common cancers. In addition, calorie restriction (CR), without malnutrition, has been shown to be broadly effective in cancer prevention in laboratory strains of rodents. Adult-onset moderate CR also reduces cancer incidence by 50% in monkeys. Whether the antitumorigenic effects of CR will apply to humans is unknown, but CR results in a consistent reduction in circulating levels of growth factors, anabolic hormones, inflammatory cytokines and oxidative stress markers associated with various malignancies. Here, we discuss the link between nutritional interventions and cancer prevention with focus on the mechanisms that might be responsible for these effects in simple systems and mammals with a view to developing chemoprevention agents.

Lung cancer:

ScienceDaily (Dec. 26, 2009) — Going back for a second dessert after your holiday meal might not be the best strategy for living a long, cancer-free life say researchers from the University of Alabama at Birmingham. That’s because they’ve shown exactly how restricted calorie diets — specifically in the form of restricted glucose — help human cells live longer. This discovery, published online in The FASEB Journal, could help lead to drugs and treatments that slow human aging and prevent cancer. “Our hope is that the discovery that reduced calories extends the lifespan of normal human cells will lead to further discoveries of the causes for these effects in different cell types and facilitate the development of novel approaches to extend the lifespan of humans,” said Trygve Tollefsbol, Ph.D., a researcher involved in the work from the Center for Aging and Comprehensive Cancer Center at the University of Alabama at Birmingham. “We would also hope for these studies to lead to improved prevention of cancer as well as many other age-related diseases through controlling calorie intake of specific cell types.” To make this discovery, Tollefsbol and colleagues used normal human lung cells and precancerous human lung cells that were at the beginning stages of cancer formation. Both sets of cells were grown in the laboratory and received either normal or reduced levels of glucose (sugar). As the cells grew over a period of a few weeks, the researchers monitored their ability to divide, and kept track of how many cells survived over this period. They found that the normal cells lived longer, and many of the precancerous cells died, when given less glucose. Gene activity was also measured under these same conditions. The reduced glucose caused normal cells to have a higher activity of the gene that dictates the level of telomerase, an enzyme that extends their lifespan and lower activity of a gene (p16) that slows their growth. Epigenetic effects (effects not due to gene mutations) were found to be a major cause in changing the activity of these genes as they reacted to decreased glucose levels. Western science is on the cusp of developing a pharmaceutical fountain of youth” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “This study confirms that we are on the path to persuading human cells to let us to live longer, and perhaps cancer-free, lives.”

Intermittent Fasting May Boost Chemo Therapy By Weakening Cancer Cells
Fasting was as effective as chemotherapy in delaying growth of specific tumors in mice and boosted the effectiveness of chemotherapy on melanoma, glioma, and breast cancer cells. And fasting plus chemotherapy, but neither treatment on its own, resulted in long-term cancer-free survival in mice with neuroblastoma, according to a study published online in Science Translational Medicine.

In animals at least, the study suggests that cancer cells are less resilient when attacked by chemo accompanied by cycles of fasting. Even fasting on its own appears to treat many cancers tested in animals, including those derived from human cells. The study shows that five out of eight cancer types in mice responded to fasting alone: it slowed the growth and spread and of tumors. Longo, who is professor of gerontology and biological sciences at the USC Davis School of Gerontology and the USC Dornsife College of Letters, Arts and Sciences, said that without exception “the combination of fasting cycles plus chemotherapy was either more or much more effective than chemo alone”.

He and his colleagues found, for example, that repeated cycles of fasting with chemotherapy cured 1 in 5 mice with a highly aggressive form of children’s neuroendocrine cancer, and 40% of mice with a less severe form. In either case, no mice survived when treated only with chemo. For their study, in which they used used cancer cells and mice, Longo and colleagues found that for all the cancers they tested, fasting combined with chemotherapy improved survival, slowed tumor growth and/or limited the spread of tumors. They found that fasting without chemotherapy, slowed the growth of breast cancer, melanoma, glioma and human neuroblastoma. In several cases, fasting was as effective as chemotherapy.

They also found that fasting prolonged survival in mice with human ovarian cancer. To try and find out how fasting has an effect on cancer cells Longo and colleagues studied one type of breast cancer in detail. When normal cells are starved of nutrients, they go into a dormant state, rather like hibernation.

They saw what Longo describes as a “cascade of events” that results in damaging free radicals that destroy cancer cells by breaking down their DNA.
Perhaps a way to beat cancer cells is not to try and find drugs that selectively destroy them, but to “confuse them by generating extreme environments, such as fasting that only normal cells can quickly respond to”, said Longo. He also cautioned that for the time being, because they don’t know whether this approach is effective in humans, it should be “off limits to patients”. But that doesn’t mean patients shouldn’t go to their oncologist and ask: “What about fasting with chemotherapy or without if chemotherapy was not recommended or considered?”

Funds from the National Institutes of Health, the Bakewell Foundation, The V Foundation for Cancer Research, the Norris cancer center, the Italian Association for Cancer Research and the Italian Foundation for Cancer Research helped pay for the study.Calorie Restricted Diet Prevents Pancreatic Inflammation And Cancer. Study Suggests ScienceDaily (Apr. 17, 2008)

Prevention of weight gain with a restricted calorie diet sharply reduced the development of pancreatic lesions that lead to cancer in preclinical research reported April 15 by researchers from The University of Texas at Austin and The University of Texas M. D. Anderson Cancer Center at the American Association for Cancer Research annual meeting. The research sheds light on the connection between obesity, calorie intake and pancreatic cancer by comparing a calorie restricted diet, an overweight diet and an obesity-inducing diet in a strain of mice that spontaneously develops pancreatic lesions that lead to cancer. “Obesity is a known risk factor for pancreatic cancer, but the mechanism underlying that relationship is unknown,” said senior author Stephen D. Hursting, Ph.D., professor in M. D. Anderson’s Department of Carcinogenesis and Chair of the Division of Nutritional Sciences at the University of Texas. “Our findings indicate that calorie restriction hinders development of pancreatic cancer, which could have implications for prevention and treatment of pancreatic tumors caused by chronic inflammation and obesity.” The group’s analysis points to a connection between calorie intake and a protein called Insulin-like Growth Factor (IGF) -1, with obesity increasing and calorie restriction decreasing levels of IGF-1. IGF-1 is an important growth factor known to stimulate the growth of many types of cancer cells. Inflammatory signaling proteins also were found to be reduced in the blood of the calorie-restricted mice.

“Mice on the heavier diets had significantly more lesions and larger lesions than those on the restricted calorie diet,” said first author Laura Lashinger, Ph.D., a post-doctoral fellow in Hursting’s laboratory. The strain of mice, developed by Susan Fischer, professor in M. D. Anderson’s Department of Carcinogenesis, spontaneously develops lesions associated with pancreatitis – inflammation of the pancreas. These lesions develop into pancreatic cancer and virtually all of these mice die within six to eight months. The researchers fed the calorie restricted group a diet that was 30 percent lower in calories than that consumed by the overweight group and 50 percent lower than the obese group. Only 7.5 percent of mice on the calorie-restricted diet developed pancreatic lesions at the end of the experiment, and these lesions were so small that none exhibited symptoms of illness. For mice on the overweight diet, 45 percent developed lesions, as did 57.5 percent of those on the obesity-inducing diet. Lesions were also much larger in the overweight and obese mice than the calorie restricted mice. While calorie restriction has been shown to have an anti-cancer effect in multiple species and for a variety of tumor types, its impact had not been well-studied in a model of pancreatic cancer. Pancreatic cancer is the fourth leading cause of cancer death and remains mostly intractable to existing treatments. The decline in blood levels of inflammatory proteins in the calorie restricted mice makes sense, Lashinger notes, because fat tissue is a major source of inflammatory factors such as cytokines.

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Modified alternate-day fasting regimens reduce cell proliferation rates to a similar extent as daily calorie restriction in mice. FASEB J. 2008 Jun;22(6):2090-6. Epub 2008 Jan 9. Varady KA, Roohk DJ, McEvoy-Hein BK, Gaylinn BD, Thorner MO, Hellerstein MK. Department of Nutritional Sciences and Toxicology, University of California at Berkeley, Morgan Hall, Rm. 308, Berkeley, California, 94720-3104, USA.

Calorie restriction (CR) and alternate-day fasting (ADF) reduce cancer risk and reduce cell proliferation rates. Whether modified ADF regimens (i.e., allowing a portion of energy needs to be consumed on the fast day) work, as well as true ADF or CR to reduce global cell proliferation rates, remains unresolved. Here, we measured the effects of true ADF, modified ADF, and daily CR on cell proliferation rates in mice. Thirty female C57BL/6J mice were randomized to one of five interventions for 4 wk: 1) CR-25% (25% reduction in daily energy intake), 2) ADF-75% (75% reduction on fast day), 3) ADF-85% (85% reduction on fast day), 4) ADF-100% (100% reduction on fast day), and 5) control (ad libitum intake). Body weights of the ADF groups did not differ from controls, whereas the CR-25% group weighed less than all other groups posttreatment. Epidermal cell proliferation decreased (P<0.01) by 29, 20, and 31% in the CR-25%, ADF-85% and ADF-100% groups, respectively, relative to controls. Proliferation rates of splenic T cells were reduced (P<0.01) by 37, 32, and 31% in the CR-25%, ADF-85%, and ADF-100% groups, respectively, and mammary epithelial cell proliferation was 70, 65, and 62% lower (P<0.01), compared with controls. Insulin-like growth factor-1 levels were reduced (P<0.05) in the CR-25% and ADF-100% groups only. In summary, modified ADF, allowing the consumption of 15% of energy needs on the restricted intake day, decreases global cell proliferation similarly as true ADF and daily CR without reducing body weight.
A restricted-calorie diet inhibited the development of pre-cancerous growths in a mouse model of skin cancer. (Source: chinaview.cn April 14)

Calorie restriction is reducing the activation of two signaling pathways known to contribute to cancer growth and development, a new study by U.S. researchers has shown. A restricted-calorie diet inhibited the development of pre-cancerous growths in a mouse model of skin cancer, reducing the activation of two signaling pathways known to contribute to cancer growth and development, a new study by U.S. researchers has shown. An obesity-inducing diet, by contrast, activated those pathways, a research team from the University of Texas’ Anderson Cancer Center reported at the American Association for Cancer Research annual meeting Monday. “These results, while tested in a mouse model of skin cancer, are broadly applicable to epithelial cancers in other tissues,” said the report’s senior author John DiGiovanni. Cancers of the epithelium — the tissue that lines the surfaces and cavities of the body’s organs — comprise 80 percent of all cancers. Calorie restriction and obesity directly affect activation of the cell surface receptors epidermal growth factor (EGFR) and insulin-like growth factor (IGF-1R). These receptors then affect signaling in downstream molecular pathways such as Akt and mTOR. Calorie restriction or negative energy balance inhibits this signaling, while obesity or positive energy balance enhances signaling through these pathways, leading to cell growth, proliferation and survival. Dietary energy balance refers to the relationship between caloric intake and energy expenditure. Previous research, both experimental and epidemiological, suggests that chronic positive energy balance, which can lead to obesity, increases the risk of developing a variety of cancers, while negative balance often decreases risk. “These new findings provide the basis for future translational studies targeting Akt/mTOR pathways through combinations of lifestyle and pharmacologic approaches to prevent and control obesity-related epithelial cancers in humans,” DiGiovanni said.

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Intermittent calorie restriction delays prostate tumor detection and increases survival time in TRAMP mice. Nutr Cancer. 2009;61(2):265-75. Bonorden MJ, Rogozina OP, Kluczny CM, Grossmann ME, Grambsch PL, Grande JP, Perkins S, Lokshin A, Cleary MP. Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA.

Prostate cancer is the most frequently diagnosed cancer in men. Whereas chronic calorie restriction (CCR) delays prostate tumorigenesis in some rodent models, the impact of intermittent caloric restriction (ICR) has not been determined. Here,transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were used to compare how ICR and CCR affected prostate cancer development. TRAMP mice were assigned to ad libitum (AL), ICR (2 wk 50% AL consumption followed by 2 wk pair feeding to AL consumption), and CCR (25% AL consumption) groups at 7 wk of age and followed until disease burden necessitated euthanasia or mice reached terminal endpoints (48 or 50 wk of age). Body weights fluctuated in response to calorie intake (P < 0.0001). ICR mice were older at tumor detection than AL (P = 0.0066) and CCR (P = 0.0416) mice. There was no difference for age of tumor detection between AL and CCR mice (P = 0.3960). Similar results were found for survival. Serum leptin, adiponectin, insulin, and IGF-I were all significantly different among the groups. These results indicate that the way in which calories are restricted impacts both time to tumor detection and survival in TRAMP mice, with ICR providing greater protective effect compared to CCR.

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Pi-class glutathione-S-transferase-positive hepatocytes in aging B6C3F1 mice undergo apoptosis induced by dietary restriction. Am J Pathol. 1996 Nov;149(5):1585-91. Muskhelishvili L, Turturro A, Hart RW, James SJ. Division of Nutritional Toxicology, FDA-National Center for Toxicological Research, Jefferson, Arkansas, USA.

Liver sections from aging ad libitum-fed and diet-restricted B6C3F1 male mice were evaluated immunohistochemically for pi-class glutathione S-transferase (GST-II). GST-II immunostaining of hepatocytes was diffuse and occurred in periportal regions of hepatic acinus, whereas perivenous areas were weakly stained or were stain-free. Expression of GST-II was significantly diminished in diet-restricted mice in all age groups and was associated with a marked decrease in liver tumor development. As most spontaneous liver tumors were GST-II positive, it can be speculated that they developed from GST-II positive initiated hepatocytes. To determine whether dietary restriction induces apoptosis in GST-II-positive hepatocytes, 24-month-old ad libitum-fed mice were introduced to 40% diet restriction. After 1 week of diet restriction, a decrease in GST-II expression was associated with a threefold increase in the frequency of apoptotic bodies as detected by terminal deoxynucleotidyl transferase-mediated d-UTP nick end labeling of DNA fragments. A two-step immunohistochemical procedure revealed that approximately 70% of apoptotic bodies were GST-II positive. These results suggest that spontaneous, potentially preneoplastic hepatocytes in tumor-prone B6C3F1 mice are eliminated by apoptosis with dietary restriction.

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Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans. Cancer Invest. 1988;6(6):677-80. Siegel I, Liu TL, Nepomuceno N, Gleicher N. Department of Obstetrics and Gynecology, Mount Sinai Hospital Medical Center, Chicago

We studied the effects of short-term dietary restriction on the survival of 3-4-month-old tumor-free and tumor-bearing Fisher rats. The diet-restricted food regimen consisted of alternate day ad libitum feeding followed by alternate day fasting. Diet-unrestricted control rats were fed ad libitum daily. Six tumor-free rats on the diet-restricted regimen compensated for the dietary restriction by an increase in food consumption during the alternate feeding days, and lost an average of only 2-3% of their weight in 13 days. Six tumor-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 24 rats were inoculated intraperitoneally with 15 million Mat 13762 ascites tumor cells. 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 tumor inoculation (p less than 0.005). Twelve of 24 (50%) diet-restricted tumor-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, the survival of tumor-bearing rats was enhanced by short-term relatively mild dietary restrictions. We suggest that relatively mild dietary restrictions should be included in clinical trials designed to inhibit cancer growth and enhance the survival of human cancer patients.Caloric restriction has documented beneficial effects on numerous diseases including cancer, yet the mechanism(s) that accounts for these wide ranging benefits is unknown. Part of the difficulty in defining mechanisms has been the long-term nature of experimental protocols in which these beneficial effects have been observed and the inherent difficulty of investigating mechanisms in such studies. The experiments reported were designed: (1) to determine if caloric restriction would inhibit mammary carcinogenesis in a model for this disease process that is 35 days in duration; (2) to determine if progression from pre-malignant to malignant stages of mammary carcinogenesis was affected by caloric restriction; and (3) to explore whether the effects of caloric restriction were associated with changes in adrenal function. Mammary carcinogenesis was induced in female Sprague-Dawley rats by the i.p. administration of 1-methyl-1-nitrosourea (50 mg/kg body weight) at 21 days of age. Rats were randomized to one of four dietary treatment groups: ad libitum fed, or restriction of food intake to 90, 80 or 60% of the ad libitum intake. Rats were palpated for detection of mammary tumors and all mammary lesions excised at necropsy were histologically classified. Twenty-four-hour collections of urine were obtained at weekly intervals throughout the 35-day experiment. Urine was assayed for corticosterone by direct radioimmunoassay. Caloric restriction resulted in both a dose dependent prolongation of latency to palpable carcinomas (P < 0.01) and a reduction in final incidence of mammary cancer; the dose response was linear (P < 0.05). The percentage of pre-malignant mammary lesions in a group increased with increasing degree of caloric restriction, whereas the percentage of carcinomas decreased (P < 0.05). The level of cortical steroid increased linearly with increasing caloric restriction (P < 0.01) an effect that was not attenuated over time. Poisson regression analyses with the number of cancers per rat as the dependent variable, level of caloric restriction as the independent variable and urinary cortical steroid excretion as a co-variate were performed. These analyses indicated that the variation in cancers per rat, irrespective of the treatment group to which an animal was assigned, could be accounted for by urinary cortical steroid excretion (P<0.05); i.e. urinary cortical steroid excretion was an independent predictor of an animal’s carcinogenic response. The data reported in this study support the use of a short term model to study the mechanism(s) by which caloric restriction inhibits mammary carcinogenesis and point to both a stage in the disease process, the conversion of pre-malignant to malignant cells, and a target tissue (adrenal gland) and chemical species (adrenal cortical steroid) that may be involved in mediating the protective effects of energy restriction. These data indicate the feasibility of identifying a chemical basis for the protective effect of caloric restriction that is independent of energy restriction per se and this, in turn, indicates that it may be possible to circumvent the practical problem of implementing a program of chronic energy restriction in human populations, yet still achieve the wide-ranging health benefits of such a program.

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The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr. 1986 Apr;116(4):641-54. Weindruch R, Walford RL, Fligiel S, Guthrie D.

We sought to clarify the impact of dietary restriction (undernutrition without malnutrition) on aging. Female mice from a long-lived strain were fed after weaning in one of six ways: group 1) a nonpurified diet ad libitum; 2) 85 kcal/wk of a purified diet (approximately 25% restriction); 3) 50 kcal/wk of a restricted purified diet enriched in protein, vitamin and mineral content to provide nearly equal intakes of these essentials as in group 2 (approximately 55% restriction); 4) as per group 3, but also restricted before weaning; 5) 50 kcal/wk of a vitamin- and mineral-enriched diet but with protein intake gradually reduced over the life span; 6) 40 kcal/wk of the diet fed to groups 3 and 4 (approximately 65% restriction). Mice from groups 3-6 exhibited mean and maximal life spans 35-65% greater than for group 1 and 20-40% greater than for group 2. Mice from group 6 lived longest of all. The longest lived 10% of mice from group 6 averaged 53.0 mo which, to our knowledge, exceeds reported values for any mice of any strain. Beneficial influences on tumor patterns and on declines with age in T-lymphocyte proliferation were most striking in group 6. Significant positive correlations between adult body weight and longevity occurred in groups 3-5 suggesting that increased metabolic efficiency may be related to longevity in restricted mice. Mice from groups 3-6 ate approximately 30% more calories per gram of mouse over the life span than did mice from group 2. These findings show the profound anti-aging effects of dietary restriction and provide new information for optimizing restriction regimes.

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Caloric restriction and insulin-like growth factors in aging and cancer. Horm Metab Res. 2003 Nov-Dec;35(11-12):705-11. Sell Ch. Lankenau Institute for Medical Research, Wynnewood, PA 19096.

This review examines the influence of a reduction in caloric intake on cancer and longevity. Data indicating that rodents subjected to caloric restriction display lower tumor incidence, reduced susceptibility to carcinogens and extended lifespan is analyzed. The potential role of the growth hormone/insulin-like growth factor type 1 (IGF-I) axis in this effect is discussed as is the evidence that a reduction in growth hormone and/or IGF-I leads to a reduction in spontaneous tumors and susceptibility to carcinogens.

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Diet, cancer and aging in DNA mismatch repair deficient mice. Carcinogenesis. 2002 Nov;23(11):1807-10. Tsao JL, Dudley S, Kwok B, Nickel AE, Laird PW, Siegmund KD, Liskay RM, Shibata D. Department of Pathology, Molecular Biology and Surgery, Norris Cancer Center, University of Southern California School of Medicine, Los Angeles, CA 90033, USA.

Diet is an important risk factor for many cancers. High fat/low calcium (HFLC) diets are associated with increased tumorigenesis, whereas caloric restriction (CR) reproducibly increases lifespan and decreases tumors. Mutations are involved in aging and cancer, and different diets may alter mutagenesis. However, a number of repair pathways normally counteract mutations by correcting errors before they can be fixed in the genome. To further understand interactions between diet, aging and cancer, mice deficient in a major repair pathway called DNA mismatch repair (MMR) were fed HFLC, CR or control diets. Mlh1 deficient mice are prone to lymphomas and intestinal adenomas and carcinomas. No significant changes in adenocarcinoma or lymphoma incidence were observed with HFLC or CR diets. Significantly more (2.2-fold) adenomas occurred with HFLC diets although adenoma numbers were unchanged with CR. Only a small increase in lifespan (116% of control) was achieved with CR. In addition, levels of microsatellite mutations in the small and large intestines were unchanged with the different diets. Our studies indicate that MMR deficiency may be epistatic to certain otherwise strong environmental influences on carcinogenesis or aging.

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Caloric restriction and cancer. J Nutr Sci Vitaminol (Tokyo). 2001 Feb;47(1):13-9. Kritchevsky D. The Wistar Institute, Philadelphia, PA 19104

In 1909 Moreschi observed that tumors transplanted into underfed mice did not grow as well as those transplanted into mice fed ad libitum. His finding stimulated a decade of research which showed that caloric restriction also affected negatively the growth of spontaneous tumors. Between 1920 and 1940 little work was done in this area, possibly because of limiting methodology. In the 1940s the laboratories of Tannenbaum (Chicago) and Baumann (Wisconsin) were able to design studies using defined diets and showed that the observed effect was due to caloric content of the diet independently of the source of calories. After another active decade research activity in the calorie-cancer area declined until it was reborn in the 1980s. By the 1980s knowledge of physiology and molecular biology had advanced enough to allow investigators to probe mechanisms underlying the calorie-cancer phenomenon. We now know that caloric expenditure (as work or exercise) will lead to reduced risk. Energy restriction enhances DNA repair and moderates oxidative damage to DNA. Energy restriction reduces oncogene expression as well. Over a half century ago, Boutwell noted that energy restriction in female rats resulted in adrenal hypertrophy and reduced weight of ovaries and uterus. He suggested that energy restriction resulted in “pseudohypophysectomy”. We now know that adrenalectomy can negate the effects of caloric restriction. Caloric restriction also affects insulin metabolism and may influence gene expression. These recent observations should help us understand some of the basic mechanisms involved in establishment and proliferation of tumors.

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Nutrition, cancer, and aging. Ann N Y Acad Sci. 1998 Nov 20;854:371-7. Dreosti IE. CSIRO Division of Human Nutrition, Adelaide, South Australia.

The parallel increase in cancer risk with advancing age is well recognized, and several pathophysiological mechanisms common to both conditions have been proposed to explain this interrelationship. The importance of nutrition, both in delaying the aging process and in protecting against cancer is also well recognized, and it is therefore of interest to compare the relative impact several of the more widely studied dietary manipulations may have on each of these conditions. For example, caloric restriction, which putatively reduce oxidative stress and effectively increases life span in animals also seems to reduce the incidence of many cancers, possibly due to diminished mitogenesis. Likewise, oxidative damage to DNA appears to be common to both processes but may be more important in the mitochondria with respect to aging and in the nucleus in relation to cancer. Inadequate dietary folate and impaired DNA methylation status are closely associated with increased cancer risk, and recently defective somatic cell methylation and accumulated genetic instability have been proposed as key mechanisms contributing to senescence. Several other well-established anticancer dietary strategies, which include increased fiber intake and the consumption of more fruits and vegetables, have not been studied extensively in relation to aging, although many of the phytochemicals considered important as chemopreventive agents for cancer may well contribute to delaying the aging process. Although not directly related to nutrition, but nevertheless highly relevant, is the question of physical activity, which has been strongly linked to a reduction in risk of some cancers. Although less is known with respect to exercise and biological markers of aging, physical activity does appear to retard the age-related decline in the muscle strength and in the bone density.

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Effect of caloric restriction on age-associated cancers. Exp Gerontol. 1992 Sep-Dec;27(5-6):575-81. Weindruch R. Department of Medicine, University of Wisconsin-Madison 53706.

Caloric restriction (CR) without malnutrition in mice and rats reduces the incidence of spontaneous tumors and delays their appearance while increasing maximum life span. These results depend largely on CR per se, and not on low intakes of fat or other nutrients. Although most studies have tested CR imposed early in life, CR started in midadulthood also retards cancer and aging. The way(s) by which CR impedes cancers remain unclear, but possibilities include less cellular oxidative damage, retarded immunologic aging, hormonal changes, less energy available for cell proliferation, reduced exposure to dietary carcinogens and promoters, enhanced DNA repair, and less carcinogen activation. Far less is known about the relationship between caloric intake and cancer incidence in humans; however, recent findings suggest a positive association for certain cancers.

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The role of calories and caloric restriction in carcinogenesis. Hematol Oncol Clin North Am. 1991 Feb;5(1):79-89. Weindruch R, Albanes D, Kritchevsky D. Department of Medicine, Universityof Wisconsin, Madison.

Studies in mice and rats show that caloric restriction (CR) without malnutrition lowers the incidence of most spontaneous and induced tumors and delays their onsets. The maximum life spans of rodents and other experimental animals (e.g., fish spiders, water fleas) are extended by CR. The molecular events that underlie these outcomes remain unelucidated. Although epidemiologic studies have not usually examined the relationship between caloric intake and cancer incidence, recent findings suggest a positive association for certain cancers such as colorectal, breast, and stomach. It is apparent that future studies of diet and cancer in humans must seriously assess the role of calories and energy balance as well as their interaction with the effects of specific nutrients

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 Dietary restriction, tumors, and aging in rodents.  National Institute on Aging, Biomedical Research and Clinical Medicine Program Bethesda, MD 20892.  J Gerontol. 1989 Nov;44(6):67-71. Weindruch R.

A chronic 30-50% restriction of dietary energy intake (but without malnutrition) typically and strongly lowers the incidence of most spontaneous and induced tumors, delays their onsets, and extends maximum life span in rodents. When compared to normally fed controls, animals fed these dietary restriction (DR) regimens show decreased rates of change for most (but not all) age-sensitive biologic indexes studied to date. DR’s impact on chemically induced tumors appears to depend more on energy than on fat restriction, and result from less promotion (and not less initiation). The molecular and cellular events underlying these various outcomes of DR are unclear. Viable explanations include less cellular oxidative damage, a retardation in the age-related changes in the immune system, hormonal changes, less exposure to dietary carcinogens and promoters, less energy for tumor growth, less carcinogen activation, and better DNA repair. New findings are consistent with the notion that DR reduces cellular damage mediated by active oxygen. A lower production or higher detoxification rate of active oxygen species, which damages molecules and promotes tumor growth, could explain DR’s effects on aging and tumors.

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Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. Science. 1982 Mar 12;215(4538):1415-8. Weindruch R, Walford RL.

Lifelong dietary restriction beginning at 3 to 6 weeks of age in rodents is known to decelerate the rate of aging, increase mean and maximum life-spans, and inhibit the occurrence of many spontaneous cancers. Little is known about the effects of dietary restriction started in middle age. In the experiments now reported the food intake of 12- to 13-month-old mice of two long-lived strains was restricted by using nutrient-enriched diets in accordance with the concept of “undernutrition without malnutrition.” The mice on the restricted diet averaged 10 to 20 percent increases in mean and maximum survival times compared to the control mice. Spontaneous lymphoma was inhibited by the food restriction.

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Caloric intake, body weight, and cancer: a review. Nutr Cancer. 1987;9(4):199-217. Albanes D.

The literature is reviewed for evidence concerning the relation between caloric intake, body weight, and cancer. Convincing experimental data regarding caloric intake and benign and malignant tumor incidence have been available since the 1940s and demonstrate that caloric restriction significantly reduces tumor incidence for a variety of tumor types in several animal models. Some epidemiological investigations provide evidence for a positive calorie-cancer association in humans, although it is difficult (in these studies) to separate the effects of calories per se from those of dietary fat. A larger number of investigations have evaluated body weight alone, and high relative body weight or high caloric intake has been associated with increased risk of cancer of the breast, colon, rectum, prostate, endometrium, kidney, cervix, ovary, thyroid, and gallbladder. In contrast, lung, bladder, and stomach cancers appear to be inversely associated with body weight, and some prospective studies of men demonstrate greater total cancer mortality among lean individuals. However, in their analyses, few of these latter investigations considered the effects of cigarette smoking, antecedent illness, or competing causes of death. While the relations between caloric intake, other dietary macronutrients (e.g., fat), and body weight are complex and require further investigation, a complete review of the data suggests that reducing caloric intake and relative body weight may lead to a considerable decrease in cancer risk in humans.

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Caloric restriction perturbs the pituitary-ovarian axis and inhibits mouse mammary tumor virus production in a high-spontaneous-mammary-tumor-incidence mouse strain (C3H/SHN). Mech Ageing Dev. 1989 Aug;49(2):93-104. Koizumi A, Masuda H, Wada Y, Tsukada M, Kawamura K, Kamiyama S, Walford RL. Department of Hygiene, Akita University School of Medicine.

Dietary restriction (DR) retards aging and extends maximum life span. It is also known to decrease the incidence of hormone-dependent tumors. In the present investigation, we focussed primarily on the influence of DR on the pituitary-ovarian axis, and subsequently on gene expression of the mouse mammary tumor virus. F1 females from the mating of SHN female and C3H male mice were used in this study, since these hybrids display a very high incidence of mouse mammary tumors. The mice weaned at 3 weeks were raised on either a calorically-restricted diet (DR: 50 kcal/week; N = 5) or on a control diet (C: 95 kcal/week N = 5) for 5 weeks. Three C57BL/6J Jcl ad libitum-fed female mice, 8 weeks of age, were used as reference animals since this strain has a very low incidence of mammary tumors. The mean cellular contents of prolactin (PRL) and growth hormone (GH) in the pituitary, as determined by immunohistochemistry, were found to be reduced in mice raised on the DR diet. The decrease in the mean cellular content of PRL (50% of the mean control value) was accompanied by a decrease in the number of lactotrophs (17% of the mean value of control diet mice). However, the decrease in cellular content of GH (53% of the mean control value) was not accompanied by a decrease in the number of somatotrophs (no. of somatotrophs in DR = 103% of mean control value). Histologically, ovaries from DR mice showed many growing and atretic follicles, with few corpora lutea. In contrast, both control-diet and reference (C57BL/6J Jcl) mice showed two or three corpora lutea per ovarian section. In accordance with this finding, DR mice had not established stable estrus cycles by 8 weeks of age, in contrast to both control-diet and reference mice. Since caloric restriction has been shown to decrease mammary tumor virus (MMTV) gene expression, MMTV production was investigated by electron microscopy to confirm the validity of our experimental conditions. In DR or reference C57BL/6J Jcl mice, MMTV particles were rarely found in the mammary gland samples, but were always found in samples from control mice. The development of mammary glands, as indicated by the number of villi or the development of the rough endoplasmic reticulum, was delayed in DR mice. Thus, it was concluded that caloric restriction decreases the number of lactrotrophs, inhibits ovulation and delays mammary gland development. This immature status is considered to be due to perturbations in the pituitary-ovarian axis by caloric restriction.

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Diet and carcinogenesis. Carcinogenesis. 1993 Nov;14(11):2205-17. Rogers AE, Zeisel SH, Groopman J. Boston University Schoolof Medicine, Department of Pathology, MA 02116.

In summary there is a wealth of information on dietary and nutritional effects on carcinogenesis in laboratory rodents. Experimental studies based on epidemiological evidence, earlier experimental studies and known or predicted cellular,biochemical and molecular effects of nutrients have produced clear evidence that carcinogenesis in laboratory rodents is influenced by dietary intake of calories, fat, lipotropes (choline, methionine), vitamin A and related retinoids, Se, calcium, zinc, fiber, ethanol and a large number of non-nutrient components of foods. For these substances or groups of substances mechanistic hypotheses supported by experimental data and are leading to further research. The information provided will contribute to understanding of basic processes in carcinogenesis as well as of the specific interactions studied, and should contribute to significant advances in preventive medicine. Restriction of caloric intake of rodents by amounts > 10% over a significant portion of their lifetime reduces tumorigenesis. That level of restriction reduces the rate of growth and maturation, and most experiments in this area employ greater restrictions that virtually abolish growth from a young age. Therefore, the observations are of interest in mechanistic studies, but their applicability to preventive medicine requires better definition of the degree and duration of restriction required for a significant effect and the age at which it must be imposed. Restriction of total fat intake and modifications to increase the intake of omega-3 fats have a reasonably consistent effect on tumorigenesis in rodents but a much less consistently demonstrable effect in humans. Again, the observations in rodents are providing a major stimulus to mechanistic studies. The lipotropes are extremely valuable as tools for investigating mechanisms of carcinogenesis in rodents. Their importance in the epidemiology of human cancer has yet to be demonstrated clearly and is a subject of research at present. The naturally occurring vitamins and minerals, as well as fiber, derive their importance in this context from investigations to explain the consistent epidemiological demonstrations of reduction of tumor risk with increased consumption of fruits and vegetables. The activity of the isolated nutrients as anticarcinogens in rodents has generally not matched the activity expected from epidemiological studies. The anticarcinogenic activity of many of the non-nutrient components of fruits and vegetables is remarkable in particular models, however, as is the activity of natural and synthetic retinoids. At present the results must be interpreted to indicate an important effect of combinations of the whole foods with identification of particular nutrients or non-nutrients in specific cases.

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Prevention of cancer: restriction of nutritional energy intake (joules). Comp Biochem Physiol A. 1988;91(2):209-20. Hocman G. Research Institute of Preventive Medicine, Bratislava

The reduction of nutritional energy intake (joules) often reduces the incidence of both spontaneous and induced cancers in humans and experimental animals in an approximately dose-dependent manner. 2. To achieve the best preventive effect, the reduction of dietary intake should begin well before the carcinogen insult, should be intense enough (lowering the intake of joules by at least approx. 25-30%) and should last a long time, preferably even life-long. 3. This preventive effect depends upon the strain, sex and age of animals, the kind of carcinogenic insult and also the susceptibility of the target tissue. 4. The mechanism by which the dietary restriction may exert its protective action may involve changes in the hormonal equilibria, influences upon the immuno-surveillance, changes of activities of enzymes involved in carcinogen metabolism and other factors. 5. Since over-eating and the resulting obesity constitutes a pronounced risk factor for the incidence of cancer and other diseases, lowering the nutritional energy intake represents today the simplest, cheapest and most effective way to prevent cancer in the general population.

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Intermittent Fasting Can Reduce Cancer Risk and Prolong Life Span. By University of California, Berkeley.

A new study has shown that healthy mice given only 5 percent fewer calories than mice allowed to eat freely experienced a significant reduction in cell proliferation in several tissues, considered an indicator for cancer risk. The key was that the mice eating 5 percent fewer calories were fed intermittently, or three days a week. What is encouraging about the findings is that the reduction in cell proliferation from that intermittent feeding regimen was only slightly less than that of a more severe 33 percent reduction in calories. Until now, scientists have been certain only of a link between a more substantial calorie reduction and a reduction in the rate of cell proliferation. “Cell proliferation is really the key to the modern epidemic of cancer,” said Marc Hellerstein, professor of human nutrition in the Department of Nutritional Sciences and Toxicology at UC Berkeley’s College of Natural Resources. Hellerstein is principal investigator of the study. Cancer is essentially the uncontrolled division of cells, and its development typically requires the presence of multiple mutations. “Normally, a cell will try to fix any damage that has occurred to its DNA,” said Hellerstein, “But, if it divides before it has a chance to fix the damage, then that damage becomes memorialized as a mutation in the offspring cells. Slowing down the rate of cell proliferation essentially buys time for the cells to repair genetic damage.” Cell proliferation contributes to carcinogenesis in a number of other ways, as well, collectively termed “cancer promotion.” Studies over the past 70 years have established that substantial calorie reduction – up to 50 percent in some studies – not only can reduce the rate of cell proliferation, it can extend the maximum life span of a variety of organisms, including rats, flies, worms and yeast. The results can be dramatic, with 30 to 70 percent increases in life span reported in the studies.”Significant caloric restriction is the one and only thing that has been scientifically proven to extend life span,” said Hellerstein, who has a joint appointment at UC San Francisco. He noted that while exercise and good nutrition can prevent premature death by disease, they have not been shown to extend a maximum life span. Cutting calories has also been shown to reduce the development of cancer, enhance insulin sensitivity and lower the risk of heart disease.Yet, as remarkable as those studies may be, their applicability to a human diet is clearly limited. The researchers refer to an old joke that goes along with the findings on caloric restriction: “It’s not that you’re living longer, it just feels that way.” No doubt, one would be hard pressed to find people willing to embark on what amounts to a lifetime of food deprivation, so the prospect of a more viable intermittent-feeding pattern is appealing. “What we found is that it may not be necessary to severely restrict calories to reap some of those health benefits,” said Elaine Hsieh, a UC Berkeley Ph.D. student in molecular and biochemical nutrition and lead author of the study. “Cutting just a few calories overall but feeding intermittently may be a more feasible eating pattern for some people to maintain.” The researchers conducted several trials with a control group of mice that ate “ad lib,” or freely. They compared the control group with mice that ate 5 percent fewer calories but were fed three times a week with mice that were given 33 percent fewer calories. Trial periods ranged from two weeks to three months. As expected, the researchers found that mice on the 33 percent reduced calorie diet exhibited significantly decreased prolife ration rates for skin, breast and T (lymphocyte) cells. The greatest effect was seen after one month on the regimen, when proliferation of skin cells registered only 61 percent of that for mice fed freely. The surprising finding came with the results of the more modest 5 percent reduced calorie diet that was fed intermittently. Mice in this group had skin cell division rates that were 81 percent of those for mice fed freely. In all cases, division rates for breast cells were reduced the most. Mice with the lowest calorie diet had breast cell proliferation results that were only 11 percent of those for the control group mice, and mice fed intermittently had results that were 37 percent of those for the control group. The researchers said this may be partly related to the reduction in estrogen, which stimulates breast cell division. Tests revealed that the estrus cycle stopped for mice on the lowest calorie diet. The mice fed intermittently, on the other hand, continued to cycle regularly. Results of the refeeding trials indicated that any weight lost during the calorie restriction period was regained once a normal feeding pattern was resumed. “Overall, we found that the effects of the diet regimens were rapid and reversible, with cell division rates and weight going back to normal after refeeding,” said Hsieh. “Although it’s too early to say whether similar results would be seen in humans, this study at least provides some hope that another option to severe calorie reduction exists.”

“A five percent reduction in calories would be the equivalent of reducing about 100 calories a day in a human diet,” said Hellerstein. In other words, for the mice, intermittent feeding seemed to provide similar gain with a bit less pain than a more restrictive diet. Hellerstein noted that animals in the wild regularly go through cycles of too much and too little food, though not by choice. Major predators, such as lions, may go days without eating and then binge when they make a successful kill. “It may be normal to have periods where we are not eating,” said Hellerstein. “But in domestic life, there generally is continuous access to food.” It goes without saying, however, that there is more to changes in eating patterns, such as fasting, than just the physical effects. Both scientific and anecdotal evidence indicates that eating also can impact one’s mental state and emotions. A recent pilot study of 16 non-obese adults by researchers at the Pennington Biomedical Research Center in Louisiana found that eating only every other day was feasible when the participants successfully followed an alternate-day fasting regimen for three weeks. However, the people also reported feeling hungry and irritable on their fasting days. The authors of the pilot study said that adding a small meal, fulfilling no more than 20 percent of the day’s caloric needs, might just take the edge off and make the feeding pattern more palatable. Notably, the UC Berkeley study is the first to actually quantify the effects of calorie manipulation on cell division. The researchers did so by using heavy water, which is chemically identical to regular water but is about 10 percent heavier because of an extra neutron. Hellerstein’s laboratory pioneered the use of heavy water as a biological marker for cell proliferation. Because heavy water is incorporated into the DNA of new cells, researchers can compare the mass of DNA from tissues in experimental animals to tissues from control animals. They would know that any differences in DNA mass would be attributed to new cells.”The significance of this labeling is that it allows researchers to accurately gauge the effects of relatively small changes in diet, such as a five percent reduction in caloric intake,” said Hellerstein.