Fasting or Calorie Restriction

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This section does not replicate the other information on this topic but provides additional details or context most relevant to professionals.

Modes of action

Fasting acts by upsetting nutrition to cancer cells. “The vulnerability of cancer cells to nutrient deprivation and their dependency on specific metabolites are emerging hallmarks of cancer.”¹Nencioni A, Caffa I, Cortellino S, Longo VD. Fasting and cancer: molecular mechanisms and clinical application. Nature Reviews. Cancer. 2018;18(11):707–719.

• “A calorically restricted diet reduced the availability of fatty acids, and this was linked to a slowdown in tumor growth.”²How Does Diet Affect the Growth of Tumors? based on Lien EC, Westermark AM et al. Low glycaemic diets alter lipid metabolism to influence tumour growth. Nature. 2021 Nov;599(7884):302-307.
• Fasting and fasting-mimicking diets (FMDs) “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.”³Buono R, Longo VD. Starvation, stress resistance, and cancer. Trends in Endocrinology and Metabolism. 2018;29(4):271–280.
• Fasting promotes reduced levels of glucose and IGF-1.⁴Brandhorst S. Longo VD. Fasting and caloric restriction in cancer prevention and treatment. Recent Results Cancer Research. 2016;207:241-66.
• Fasting is one approach to alter aberrant metabolism, which was once seen just as an epiphenomenon of oncogenic reprogramming but plays a key role in oncogenesis with the power to control both genetic and epigenetic events in cells.⁵Hirschey MD, DeBerardinis RJ et al; Target Validation Team. Dysregulated metabolism contributes to oncogenesis. Seminars in Cancer Biology. 2015 Dec;35 Suppl:S129-S150.

Fasting may also have other more diffuse metabolic effects.

• “Fasting suppressed M2 polarization of tumor-associated macrophages to inhibit tumor growth through decreasing the level of adenosine in the tumor microenvironment.”⁶Sun P, Wang H et al. Fasting inhibits colorectal cancer growth by reducing M2 polarization of tumor-associated macrophages. Oncotarget. 2017;8(43):74649–74660. 
• Fasting plays a “role in adaptive cellular responses that reduce oxidative damage and inflammation, optimize energy metabolism and bolster cellular protection.”⁷Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applications. Cell Metabolism. 2014 Feb 4;19(2):181-92.
• “Prolonged fasting reduces circulating IGF-1 levels and PKA activity in various cell populations.”⁸Cheng CW, Adams Gregor B et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell. 2014;14:810–823.
• Calorie restriction “results in a consistent reduction in circulating levels of growth factors, anabolic hormones, inflammatory cytokines and oxidative stress markers associated with various malignancies.”⁹Longo VD, Fontana L. Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends in Pharmacological Sciences. 2010 Feb;31(2):89-98.
• “The PI3K pathway is a major determinant of the sensitivity of tumours to DR [dietary restriction] and activating mutations in the pathway may influence the response of cancers to DR-mimetic therapies.”¹⁰Kalaany NY, Sabatini DM. Tumours with PI3K activation are resistant to dietary restriction. Nature. 2009 Apr 9;458(7239):725-31.

A range of mechanisms have been proposed for the role of fasting and calorie restriction on extending life. None of these proposed mechanisms so far are entirely supported by evidence.¹¹Masoro EJ. Overview of caloric restriction and ageing. Mechanisms of Ageing and Development. 2005 Sep;126(9):913-22.

Preclinical evidence

Noteworthy preclinical evidence is summarized here. Clinical evidence is described in How can fasting or calorie restriction help you? What the research says ›

Improving treatment outcomes

Cancer as a whole

Survival

• Reducing glucose and IGF-1 promotes cancer-free survival among animal models.¹²Buono R, Longo VD. Starvation, stress resistance, and cancer. Trends in Endocrinology and Metabolism. 2018;29(4):271–280.

Enhancing anticancer therapies

• Fasting or fasting-mimicking diets “increase resistance to chemotherapy in normal but not cancer cells and promote regeneration in normal tissues.”¹³Nencioni A, Caffa I, Cortellino S, Longo VD. Fasting and cancer: molecular mechanisms and clinical application. Nature Reviews. Cancer. 2018;18(11):707–719.
• Fasting (short-term starvation) protects healthy cells but not cancer cells against chemotherapy.¹⁴Raffaghello L, Lee C, Safdie FM, et al. Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(24):8215–8220.
• Fasting enhances the anticancer effects of vitamin C, “an effect further potentiated by chemotherapy.”¹⁵Di Tano M, Raucci F et al. Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers. Nature Communications. 2020;11(1):2332.

Brain cancer

• Dietary caloric restriction had “antiangiogenic and proapoptotic effects in the three distinct brain tumor models.”¹⁶Mukherjee P, Abate LE, Seyfried TN. Antiangiogenic and proapoptotic effects of dietary restriction on experimental mouse and human brain tumors. Clinical Cancer Research. 2004;10:5622–5629.
• Calorie restriction led to less tumor growth and invasion in mice with glioblastoma multiforme.¹⁷Shelton LM, Huysentruyt LC, Mukherjee P, Seyfried TN. Calorie restriction as an anti-invasive therapy for malignant brain cancer in the VM mouse. ASN Neuro. 2010;2:171–176.

Breast cancer

• “A fasting-mimicking diet (FMD) increases the levels of bone marrow common lymphoid progenitor cells (CLP) and cytotoxic CD8⁺ tumor-infiltrating lymphocytes (TILs), leading to a major delay in breast cancer and melanoma progression.”¹⁸Di Biase S, Lee C et al. Fasting-mimicking diet reduces HO-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell. 2016 Jul 11;30(1):136-146.

Colorectal cancer

• “Glucose starvation potentiated the efficacy of MeV-mediated cell killing in CRC cells.”¹⁹Scheubeck G, Berchtold S et al. Starvation-induced differential virotherapy using an oncolytic measles vaccine virus. Viruses. 2019;11(7):614.
• “Alternate day fasting for 2 weeks inhibited the tumor growth of mice without causing a reduction of body weight.”²⁰Sun P, Wang H, He Z, et al. Fasting inhibits colorectal cancer growth by reducing M2 polarization of tumor-associated macrophages. Oncotarget. 2017;8(43):74649–74660.
• “Transcriptional changes after PBF [preconditioning by fasting] to irinotecan treatment showed an improved protective stress response in healthy liver but not in tumor tissue, including changes in irinotecan metabolism.”²¹Jongbloed F, Huisman SA, van Steeg H, et al. The transcriptomic response to irinotecan in colon carcinoma bearing mice preconditioned by fasting. Oncotarget. 2019;10(22):2224–2234.

Melanoma

• “A fasting-mimicking diet (FMD) increases the levels of bone marrow common lymphoid progenitor cells (CLP) and cytotoxic CD8⁺ tumor-infiltrating lymphocytes (TILs), leading to a major delay in breast cancer and melanoma progression.”²²Di Biase S, Lee C et al. Fasting-mimicking diet reduces HO-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell. 2016 Jul 11;30(1):136-146.

Prostate cancer

• Intermittent fasting (intermittent caloric restriction) providing greater protective effect compared to chronic calorie restriction in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice.²³Bonorden MJ, Rogozina OP, Kluczny CM, Grossmann ME, Grambsch PL, Grande JP, et al. Intermittent calorie restriction delays prostate tumor detection and increases survival time in TRAMP mice. Nutrition and Cancer. 2009;61:265–275.

Optimizing body terrain

• Serum from fasting men decreased IGF-I levels and increased IGFBP-1 levels in LNCaP cells²⁴Ngo TH, Barnard RJ, Tymchuk CN, Cohen P, Aronson WJ. Effect of diet and exercise on serum insulin, IGF-I, and IGFBP-1 levels and growth of LNCaP cells in vitro (United States). Cancer Causes & Control. 2002;13(10):929–935.

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