Fasting and Time Restricted Eating

How to Eat Healthy – Fasting and Time-Restricted Eating

We focus on the content of our plate, but what about the timing of when we eat? Many people start eating within an hour from waking up and cannot live without their bedtime snack. Days are filled with meal, snack, meal, snack, snack, meal, snack… But have you ever thought:

• Is it more important what you eat or what you do not eat?
• Is it more important how much you eat or how often?
• Is it more important when you are eating or when you are not eating?

Good questions, right?

 

There is an important factor for our health and immune system strength that has been forgotten since food has become widely available, everywhere, all the time. The power of not eating. The immense benefits of fasting! As stated by Dr Thomas Lodi, founder of An Oasis of Healing, “fasting is the most universal, logical, and instinctive method of healing.”

 

What animal studies show and corroborated by the observation of modern societies, is that overconsumption of food several times a day (most people eat at least 3 to 5 times daily), especially when coupled with sedentary behaviors, such as lack of movement and desk jobs, often leads to metabolic morbidities¹. These metabolic morbidities are pervasive in today’s society, things like insulin resistance, excessive accumulation of visceral fat, dyslipidemia, high blood pressure, that often lead to chronic illnesses like cancer and metabolic syndrome.

Fasting seems a foreign concept for many. Especially if you are new to healthy eating and building longevity habits. But fasting has been part of human existence and experience since ancient times, even in many religious practices, and probably played a very significant role in our survival throughout time.  Why is that? Because humans had to adapt to not having food all the time. Refrigerators and packaged foods were not available back in the day. As Mattson et al. explains “animals, including humans, evolved in environments where food was relatively scarce, they developed numerous adaptations that enabled them to function at a high level, both physically and cognitively, when in a food-deprived/fasted state¹.” This means that evolutionarily our bodies, brains, metabolism and performance evolved to achieve mastery of function during fasting periods.

What does “Fasting” mean?

Fasting is “to eat no food for a period of time”, at least 24h. However, the term has been generalized and its use applied more broadly. Nowadays it’s common to consider intermittent fasting (IF) as “eating patterns in which individuals go extended time periods (e.g., 16-48h) with little or no energy intake, with intervening periods of normal food intake, on a recurring basis.” This type of IF can also be termed time-restricted eating or feeding. And fasting or periodic fasting (PF) can be used for periods of fasting lasting from 2 to as many as 21 or more days¹.

Intermittent fasting as defined by the authors of a 2019 New England Journal of Medicine review is “a period of food restriction sufficient to clear liver glycogen stores and dramatically suppress glucose, insulin, and amino acid uptake by cells^2”. The authors go on to explain that during fasting, fatty acids are released into circulation and taken up by liver cells, which produce ketone bodies to be used as fuel by other cells. These changes result in a cascade of systemic and cellular responses related to the suppression of insulin and IGF, energy depletion in cells, and the regulatory impact of ketone bodies. As mentioned before, eating patterns that induce this change include complete abstention from food for one or more days (such as alternate-day fasting and 5:2 fasting – eat for 5 days, fast for 2), time-restricted eating (where food is only eaten during a limited number of hours each day, for example within a 6h window) and near-fasting regimens (where daily caloric intake is restricted to 500-700 calories)².

Is Fasting Beneficial?

The benefits of fasting were praised, more than 500 years ago, by Paracelsus, considered the “father of toxicology”. Scientific research is now corroborating the intuitive interpretation of the beneficial effects of fasting, derived from human adaptation, physiology and behavior. As Mattson et al. described it “during evolution, individuals whose brains and bodies functioned well in a fasted state were successful in acquiring food, enabling their survival and reproduction³.”

Evidence is accumulating that fasting or time-restricted eating can trigger a metabolic switch from glucose-based to ketone-based energy, with increased resistance of cells, tissues and organs to stress, increased longevity, and a decreased incidence of diseases often associated with aging and sedentary or overindulgent lifestyles, including cancer and obesity^1,2.

The authors of the 2019 comprehensive review mentioned above, summarized the impact of intermittent fasting at both a cellular and an organ/body system level. Rafael de Cabo and Mark P. Mattson described how intermittent fasting downregulates pathways related to cellular metabolism, insulin, IGF-1, and amino acid signaling. Those changes activate cellular repair, maintenance processes, stress resistance, and mitochondrial biogenesis, which in turn support repair of cellular damage and cell survival. The subsequent refeeding process also has beneficial effects by upregulating biogenesis and growth².

Laboratory studies using rodents had already shown that intermittent fasting (IF) improved numerous physiological indicators of health namely: “reduced levels of insulin and leptin with parallel increases in insulin and leptin sensitivity; reduced body fat; elevated ketone levels; reduced resting heart rate and blood pressure, and increased heart rate variability (resulting from increased parasympathetic tone); reduced inflammation; increased resistance of the brain and heart to stress (e.g., reduced tissue damage and improved functional outcome in models of stroke and myocardial infarction); and resistance to diabetes¹” and improved cardiovascular and neuroendocrine response to stress⁴. In animal models, IF was also shown to delay the onset and slow the progression of neuronal dysfunction and degeneration of Alzheimer’s, Parkinson’s and Huntington’s diseases¹.

Similar findings are being reported in primates under calorie restriction (CR) or IF resulting in lower incidence of diabetes, cancer, cardiovascular disease, and brain atrophy⁵. Studies demonstrated an improved metabolic profile and lower oxidative stress associated with CR⁶, which indicates that such dietary regimens may contribute to delay the onset of disease and mortality and slow aging in primates. ^5,7,8. In a 2017 comparison of two studies with contradictory findings in terms of survival outcomes, the authors concluded that caloric restriction improves health and survival in Rhesus monkeys⁷.

A plethora of recent studies have been corroborating the benefits and mechanisms by which IF and/ or CR, improve health and counteract disease processes. Some Benefits of Fasting Regimens:

Cellular and Molecular Level

• Activation of adaptive cellular stress response signaling pathways that enhance mitochondrial health, DNA repair and autophagy and promotion of stem cell-based regeneration as well as long-lasting metabolic effects¹.
• Reduce oxidative damage and increase cellular stress resistance, bolster cellular protection and decrease inflammation^{9,10,11,12,13,14,15}.
• Cycles of fasting and re-feeding have been shown to promote hematopoietic stem cell activation and regeneration of immune cell6¹⁶.

Chronic Disorders

• Contribute to weight loss and improve risk markers for cancer, diabetes and cardiovascular disease: reduce fasting insulin, insulin resistance, leptin, the leptin: adiponectin ratio, free androgen index, inflammatory markers, lipids, blood pressure, and increase in sex hormone-binding globulin, insulin-like growth factor-binding protein 1 and 2¹⁷.
• Protect against the metabolic syndrome and associated disorders and help reduce obesity, hypertension, asthma, and rheumatoid arthritis^1,12.
• Shown to ameliorate pathology in various mouse autoimmunity models. May contribute to alleviate and possibly reverse a variety of autoimmune disorders as well as immunosenescence by killing old and damaged cells and replacing them with young and functional ones^15,16.

Aging, health and life span

• May retard the aging process in humans (reduces aging-associated biomarkers), diminish risk factors for age-related cardiovascular and metabolic diseases, increase healthy life and prolong lifespan^10,11,18,19.
• Optimize physiological function and energy metabolism, enhance performance, and slow aging and disease processes^12,20.

Cardiovascular System

• Improve cardiometabolic health: improve risk factors for cardiovascular and metabolic disease such as visceral adipose tissue mass, ectopic lipid accumulation, blood pressure, and lipid profile, and associated decrease in CHD/ CVD risk^18,21,22,23.

Cerebrovascular System

• Improve brain function. Positively impact brain aging and possible neurodegeneration. Promote neuroplasticity and resistance of the brain to injury and disease. May improve cognition and memory^{23,24,25,26,27}.

Microbiota

• Fasting can positively modulate gut microbiota. Slow down compositional age-microbiota changes with an enrichment of beneficial bacteria, which may positively influence host metabolism, immunity, gut barrier, and brain functions. These effects on microbiota may delay the onset of disease and prolong health span and lifespan^16,28.

Fasting and Cancer

Studies show that fasting regimens and calorie restriction without malnutrition are the most potent and reproducible physiological interventions for increasing lifespan and protecting against cancer in mammals. These regimens reduce the levels of a number of anabolic hormones, growth factors and inflammatory cytokines, reduce oxidative stress and cell proliferation and enhance autophagy and several DNA repair processes^29,30,31. Fasting upregulates intracellular cleansing, triggering autophagy (cellular self-digestion). Autophagy is the only way for cells to repair their structures and healthy cell structures result in an anti-cancer environment.

In an article published in 2018, the authors Roberta Buono and Valter Longo, were able to highlight the relationship between “Starvation, Stress Resistance, and Cancer” ³²:

• Cancer cells are characterized by dysregulation in signal transduction and metabolic pathways, leading to increased glucose uptake, altered mitochondrial function, and the evasion of antigrowth signals.
• Fasting and fasting-mimicking diets provide a particularly promising intervention to promote differential effects in normal and malignant cells. These effects are caused in part by the reduction in IGF-1, insulin, and glucose and the increase in IGFBP1 and ketone bodies, which generate conditions that force cancer cells to rely more on metabolites and factors that are limited in the blood, thus resulting in cell death.

A great review of the potential role of intermittent fasting (IF) in tumors was published in 2021, evidencing new research showing how IF can alter the energy metabolism of tumor cells, thereby inhibiting tumor growth and improving antitumor immune responses. Fasting can also increase cancer sensitivity to chemotherapy and radiotherapy and reduce the side effects of these traditional anticancer treatments. However, the authors of this study reveal some concerns in how IF can affect tumorigenesis, increase immune responses, and alter the energy metabolism of tumor patients. They also point to the lack of research related to tumor immunotherapy and gene therapy, highlighting the necessity for further, more detailed studies³³. Most researchers agree that IF may have many beneficial effects in cancer treatment, however the application of this nutritional intervention in cancer patients must be rigorous and account for many variables (such as malnourishment, cachexia, weakened immune systems, susceptibility to infections) and possible negative effects, such as aggravating malnutrition or other cancer treatment related adverse reactions³³.

Some possible beneficial effects of fasting regimens on cancer:

• Positive effect in inducing an anticancer immune response and promote the T cell-dependent killing of cancer cells^16,41.
• Ability to decrease the incidence of spontaneous tumors and slow the growth of primary tumors. Animal models also show that it may have an effect on distant metastases ^42,43.
• May enhance the efficiency of tumor cell killing by chemotherapeutic drugs and ameliorate side effects caused by chemotherapy. This means a double positive influence, by improving the efficacy of anticancer therapies and reducing the side effects of cytotoxic treatments and other treatment-related symptoms^{33,41,42,43,44,45}.
• Promote differential effects in normal and malignant cells, protecting healthy cells and resulting in cancer cell death³².
• Possible adjuvant to immunotherapies, where more research needs to be conducted⁴⁸.

Although more clinical experiments in humans are needed, metabolic-based therapies, such as intermittent fasting and caloric restriction, seem to play a crucial role, today and in the near future, in cancer prevention, protection and treatment ^{34,35,36,37,38,39,40}.

Knowing how different fasting regimens may benefit your health and counteract disease, contributing at the same time to delayed aging, increased longevity and protection from cancer, are you willing to give it a try?

References

1. Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017 Oct;39:46-58. doi: 10.1016/j.arr.2016.10.005. Epub 2016 Oct 31. PMID: 27810402; PMCID: PMC5411330.
2. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. N Engl J Med. 2019 Dec 26;381(26):2541-2551. doi: 10.1056/NEJMra1905136. Erratum in: N Engl J Med. 2020 Jan 16;382(3):298. Erratum in: N Engl J Med. 2020 Mar 5;382(10):978. PMID: 31881139.
3. Mattson MP, Moehl K, Ghena N, Schmaedick M, Cheng A. Intermittent metabolic switching, neuroplasticity and brain health. Nat Rev Neurosci. 2018 Feb;19(2):63-80. doi: 10.1038/nrn.2017.156. Epub 2018 Jan 11. Erratum in: Nat Rev Neurosci. 2020 Aug;21(8):445. PMID: 29321682; PMCID: PMC5913738.
4. Wan R, Camandola S, Mattson MP. Intermittent food deprivation improves cardiovascular and neuroendocrine responses to stress in rats. J Nutr. 2003 Jun;133(6):1921-9. doi: 10.1093/jn/133.6.1921. PMID: 12771340.
5. Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. 2009 Jul 10;325(5937):201-4. doi: 10.1126/science.1173635. PMID: 19590001; PMCID: PMC2812811.
6. Mattison JA, Roth GS, Beasley TM, et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature. 2012;489(7415):318-321. doi:10.1038/nature11432
7. Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth GS, Ingram DK, Weindruch R, de Cabo R, Anderson RM. Caloric restriction improves health and survival of rhesus monkeys. Nat Commun. 2017 Jan 17;8:14063. doi: 10.1038/ncomms14063. PMID: 28094793; PMCID: PMC5247583.
8. Noni L. Bodkin, Theresa M. Alexander, Heidi K. Ortmeyer, Elizabeth Johnson, Barbara C. Hansen, Mortality and Morbidity in Laboratory-maintained Rhesus Monkeys and Effects of Long-term Dietary Restriction, The Journals of Gerontology: Series A, Volume 58, Issue 3, March 2003, Pages B212–B219, https://doi.org/10.1093/gerona/58.3.B212
9. Mattson MP, Wan R. Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems. J Nutr Biochem. 2005 Mar;16(3):129-37. doi: 10.1016/j.jnutbio.2004.12.007. PMID: 15741046.
10. Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science. 1996 Jul 5;273(5271):59-63. doi: 10.1126/science.273.5271.59. PMID: 8658196; PMCID: PMC2987625.
11. Weindruch R, Sohal RS. Seminars in medicine of the Beth Israel Deaconess Medical Center. Caloric intake and aging. N Engl J Med. 1997 Oct 2;337(14):986-94. doi: 10.1056/NEJM199710023371407. PMID: 9309105; PMCID: PMC2851235.
12. Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applications. Cell Metab. 2014 Feb 4;19(2):181-92. doi: 10.1016/j.cmet.2013.12.008. Epub 2014 Jan 16. PMID: 24440038; PMCID: PMC3946160.
13. Johnson JB, Summer W, Cutler RG, Martin B, Hyun DH, Dixit VD, Pearson M, Nassar M, Telljohann R, Maudsley S, Carlson O, John S, Laub DR, Mattson MP. Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma. Free Radic Biol Med. 2007 Mar 1;42(5):665-74. doi: 10.1016/j.freeradbiomed.2006.12.005. Epub 2006 Dec 14. Erratum in: Free Radic Biol Med. 2007 Nov 1;43(9):1348. Tellejohan, Richard [corrected to Telljohann, Richard]. PMID: 17291990; PMCID: PMC1859864.
14. Faris MA, Kacimi S, Al-Kurd RA, Fararjeh MA, Bustanji YK, Mohammad MK, Salem ML. Intermittent fasting during Ramadan attenuates proinflammatory cytokines and immune cells in healthy subjects. Nutr Res. 2012 Dec;32(12):947-55. doi: 10.1016/j.nutres.2012.06.021. Epub 2012 Oct 4. PMID: 23244540.
15. Choi IY, Lee C, Longo VD. Nutrition and fasting mimicking diets in the prevention and treatment of autoimmune diseases and immunosenescence. Mol Cell Endocrinol. 2017 Nov 5;455:4-12. doi: 10.1016/j.mce.2017.01.042. Epub 2017 Jan 28. PMID: 28137612; PMCID: PMC5862044.
16. Buono R, Longo VD. When Fasting Gets Tough, the Tough Immune Cells Get Going-or Die. Cell. 2019 Aug 22;178(5):1038-1040. doi: 10.1016/j.cell.2019.07.052. PMID: 31442398; PMCID: PMC7474734.
17. Harvie MN, Pegington M, Mattson MP, Frystyk J, Dillon B, Evans G, Cuzick J, Jebb SA, Martin B, Cutler RG, Son TG, Maudsley S, Carlson OD, Egan JM, Flyvbjerg A, Howell A. The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women. Int J Obes (Lond). 2011 May;35(5):714-27. doi: 10.1038/ijo.2010.171. Epub 2010 Oct 5. PMID: 20921964; PMCID: PMC3017674.
18. Most J, Gilmore LA, Smith SR, Han H, Ravussin E, Redman LM. Significant improvement in cardiometabolic health in healthy nonobese individuals during caloric restriction-induced weight loss and weight loss maintenance. Am J Physiol Endocrinol Metab. 2018 Apr 1;314(4):E396-E405. doi: 10.1152/ajpendo.00261.2017. Epub 2017 Dec 12. PMID: 29351490; PMCID: PMC5966756.
19. Ravussin E, Redman LM, Rochon J, Das SK, Fontana L, Kraus WE, Romashkan S, Williamson DA, Meydani SN, Villareal DT, Smith SR, Stein RI, Scott TM, Stewart TM, Saltzman E, Klein S, Bhapkar M, Martin CK, Gilhooly CH, Holloszy JO, Hadley EC, Roberts SB; CALERIE Study Group. A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity. J Gerontol A Biol Sci Med Sci. 2015 Sep;70(9):1097-104. doi: 10.1093/gerona/glv057. Epub 2015 Jul 17. Erratum in: J Gerontol A Biol Sci Med Sci. 2016 Jun;71(6):839-40. PMID: 26187233; PMCID: PMC4841173.
20. Anton SD, Moehl K, Donahoo WT, Marosi K, Lee SA, Mainous AG 3rd, Leeuwenburgh C, Mattson MP. Flipping the Metabolic Switch: Understanding and Applying the Health Benefits of Fasting. Obesity (Silver Spring). 2018 Feb;26(2):254-268. doi: 10.1002/oby.22065. Epub 2017 Oct 31. PMID: 29086496; PMCID: PMC5783752.
21. Kroeger, C.M., Klempel, M.C., Bhutani, S. et al. Improvement in coronary heart disease risk factors during an intermittent fasting/calorie restriction regimen: Relationship to adipokine modulations. Nutr Metab (Lond) 9, 98 (2012). https://doi.org/10.1186/1743-7075-9-98
22. Fontana L, Meyer TE, Klein S, Holloszy JO. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6659-63. doi: 10.1073/pnas.0308291101. Epub 2004 Apr 19. PMID: 15096581; PMCID: PMC404101.
23. Mattson MP, Wan R. Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems. J Nutr Biochem. 2005 Mar;16(3):129-37. doi: 10.1016/j.jnutbio.2004.12.007. PMID: 15741046.
24. Leclerc E, Trevizol AP, Grigolon RB, Subramaniapillai M, McIntyre RS, Brietzke E, Mansur RB. The effect of caloric restriction on working memory in healthy non-obese adults. CNS Spectr. 2020 Feb;25(1):2-8. doi: 10.1017/S1092852918001566. PMID: 30968820.
25. Witte AV, Fobker M, Gellner R, Knecht S, Flöel A. Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1255-60. doi: 10.1073/pnas.0808587106. Epub 2009 Jan 26. PMID: 19171901; PMCID: PMC2633586.
26. Mattson MP, Moehl K, Ghena N, Schmaedick M, Cheng A. Intermittent metabolic switching, neuroplasticity and brain health. Nat Rev Neurosci. 2018 Feb;19(2):63-80. doi: 10.1038/nrn.2017.156. Epub 2018 Jan 11. Erratum in: Nat Rev Neurosci. 2020 Aug;21(8):445. PMID: 29321682; PMCID: PMC5913738.
27. Wahl D, Coogan SC, Solon-Biet SM, de Cabo R, Haran JB, Raubenheimer D, Cogger VC, Mattson MP, Simpson SJ, Le Couteur DG. Cognitive and behavioral evaluation of nutritional interventions in rodent models of brain aging and dementia. Clin Interv Aging. 2017 Sep 8;12:1419-1428. doi: 10.2147/CIA.S145247. PMID: 28932108; PMCID: PMC5598548.
28. Rinninella E, Cintoni M, Raoul P, Ianiro G, Laterza L, Lopetuso LR, Ponziani FR, Gasbarrini A, Mele MC. Gut Microbiota during Dietary Restrictions: New Insights in Non-Communicable Diseases. Microorganisms. 2020 Jul 28;8(8):1140. doi: 10.3390/microorganisms8081140. PMID: 32731505; PMCID: PMC7465033.
29. Hursting SD, Lavigne JA, Berrigan D, Perkins SN, Barrett JC. Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans. Annu Rev Med. 2003;54:131-52. doi: 10.1146/annurev.med.54.101601.152156. Epub 2001 Dec 3. PMID: 12525670.
30. Fontana L, Klein S. Aging, adiposity, and calorie restriction. JAMA. 2007 Mar 7;297(9):986-94. doi: 10.1001/jama.297.9.986. PMID: 17341713.
31. Longo VD, Fontana L. Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends Pharmacol Sci. 2010 Feb;31(2):89-98. doi: 10.1016/j.tips.2009.11.004. Epub 2010 Jan 25. PMID: 20097433; PMCID: PMC2829867.
32. Buono R, Longo VD. Starvation, Stress Resistance, and Cancer. Trends Endocrinol Metab. 2018 Apr;29(4):271-280. doi: 10.1016/j.tem.2018.01.008. Epub 2018 Feb 17. PMID: 29463451; PMCID: PMC7477630.
33. Zhao X, Yang J, Huang R, Guo M, Zhou Y, Xu L. The role and its mechanism of intermittent fasting in tumors: friend or foe? Cancer Biol Med. 2021 Feb 15;18(1):63-73. doi: 10.20892/j.issn.2095-3941.2020.0250. PMID: 33628585; PMCID: PMC7877171.
34. Harvie M, Howell A. Energy balance adiposity and breast cancer – energy restriction strategies for breast cancer prevention. Obes Rev. 2006 Feb;7(1):33-47. doi: 10.1111/j.1467-789X.2006.00207.x. PMID: 16436101.
35. Harvie M, Howell A. Energy restriction and the prevention of breast cancer. Proc Nutr Soc. 2012 May;71(2):263-75. doi: 10.1017/S0029665112000195. Epub 2012 Mar 14. Erratum in: Proc Nutr Soc. 2012 Aug;71(3):433. PMID: 22414375.
36. Pearson KJ, Lewis KN, Price NL, Chang JW, Perez E, Cascajo MV, Tamashiro KL, Poosala S, Csiszar A, Ungvari Z, Kensler TW, Yamamoto M, Egan JM, Longo DL, Ingram DK, Navas P, de Cabo R. Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction. Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2325-30. doi: 10.1073/pnas.0712162105. Epub 2008 Feb 19. PMID: 18287083; PMCID: PMC2268135.
37. de Roon M, May AM, McTiernan A, Scholten RJPM, Peeters PHM, Friedenreich CM, Monninkhof EM. Effect of exercise and/or reduced calorie dietary interventions on breast cancer-related endogenous sex hormones in healthy postmenopausal women. Breast Cancer Res. 2018 Aug 2;20(1):81. doi: 10.1186/s13058-018-1009-8. PMID: 30071893; PMCID: PMC6090977.
38. Howell A, Chapman M, Harvie M. Energy restriction for breast cancer prevention. Recent Results Cancer Res. 2009;181:97-111. doi: 10.1007/978-3-540-69297-3_11. PMID: 19213562.
39. Steinbach G, Heymsfield S, Olansen NE, Tighe A, Holt PR. Effect of caloric restriction on colonic proliferation in obese persons: implications for colon cancer prevention. Cancer Res. 1994 Mar 1;54(5):1194-7. PMID: 8118805.
40. Eslami S, Barzgari Z, Saliani N, Saeedi N, Barzegari A. Annual fasting; the early calories restriction for cancer prevention. Bioimpacts. 2012;2(4):213-5. doi: 10.5681/bi.2012.028. Epub 2012 Dec 21. PMID: 23678462; PMCID: PMC3648937.
41. Meynet O, Ricci JE. Caloric restriction and cancer: molecular mechanisms and clinical implications. Trends Mol Med. 2014 Aug;20(8):419-27. doi: 10.1016/j.molmed.2014.05.001. Epub 2014 Jun 8. PMID: 24916302.
42. Lv M, Zhu X, Wang H, Wang F, Guan W. Roles of caloric restriction, ketogenic diet and intermittent fasting during initiation, progression and metastasis of cancer in animal models: a systematic review and meta-analysis. PLoS One. 2014 Dec 11;9(12):e115147. doi: 10.1371/journal.pone.0115147. PMID: 25502434; PMCID: PMC4263749.
43. Simone BA, Champ CE, Rosenberg AL, Berger AC, Monti DA, Dicker AP, Simone NL. Selectively starving cancer cells through dietary manipulation: methods and clinical implications. Future Oncol. 2013 Jul;9(7):959-76. doi: 10.2217/fon.13.31. PMID: 23837760.
44. Safdie FM, Dorff T, Quinn D, Fontana L, Wei M, Lee C, Cohen P, Longo VD. Fasting and cancer treatment in humans: A case series report. Aging (Albany NY). 2009 Dec 31;1(12):988-1007. doi: 10.18632/aging.100114. PMID: 20157582; PMCID: PMC2815756.
45. Klement RJ, Champ CE. Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R’s through dietary manipulation. Cancer Metastasis Rev. 2014 Mar;33(1):217-29. doi: 10.1007/s10555-014-9495-3. PMID: 24436017; PMCID: PMC3988521.
46. Lee C, Raffaghello L, Brandhorst S, Safdie FM, Bianchi G, Martin-Montalvo A, Pistoia V, Wei M, Hwang S, Merlino A, Emionite L, de Cabo R, Longo VD. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med. 2012 Mar 7;4(124):124ra27. doi: 10.1126/scitranslmed.3003293. Epub 2012 Feb 8. PMID: 22323820; PMCID: PMC3608686.
47. O’Flanagan CH, Smith LA, McDonell SB, Hursting SD. When less may be more: calorie restriction and response to cancer therapy. BMC Med. 2017 May 24;15(1):106. doi: 10.1186/s12916-017-0873-x. PMID: 28539118; PMCID: PMC5442682.
48. Eriau E, Paillet J, Kroemer G, Pol JG. Metabolic Reprogramming by Reduced Calorie Intake or Pharmacological Caloric Restriction Mimetics for Improved Cancer Immunotherapy. Cancers (Basel). 2021 Mar 12;13(6):1260. doi: 10.3390/cancers13061260. PMID: 33809187; PMCID: PMC7999281.