Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.


Fasting and cancer: molecular mechanisms and clinical application


The vulnerability of cancer cells to nutrient deprivation and their dependency on specific metabolites are emerging hallmarks of cancer. Fasting or fasting-mimicking diets (FMDs) lead to wide alterations in growth factors and in metabolite levels, generating environments that can reduce the capability of cancer cells to adapt and survive and thus improving the effects of cancer therapies. In addition, fasting or FMDs increase resistance to chemotherapy in normal but not cancer cells and promote regeneration in normal tissues, which could help prevent detrimental and potentially life-threatening side effects of treatments. While fasting is hardly tolerated by patients, both animal and clinical studies show that cycles of low-calorie FMDs are feasible and overall safe. Several clinical trials evaluating the effect of fasting or FMDs on treatment-emergent adverse events and on efficacy outcomes are ongoing. We propose that the combination of FMDs with chemotherapy, immunotherapy or other treatments represents a potentially promising strategy to increase treatment efficacy, prevent resistance acquisition and reduce side effects.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Differential stress resistance versus differential stress sensitization.
Fig. 2: Mechanisms of fasting or FMD-dependent killing of cancer cells in solid tumours.
Fig. 3: Working hypothesis for the effects of the combination of fasting and/or FMDs with standard therapy in oncology.


  1. 1.

    Lanier, A. P., Bender, T. R., Blot, W. J., Fraumeni, J. F. Jr & Hurlburt, W. B. Cancer incidence in Alaska natives. Int. J. Cancer 18, 409–412 (1976).

    CAS  PubMed  Google Scholar 

  2. 2.

    Henderson, B. E. et al. Cancer incidence in the islands of the Pacific. Natl Cancer Inst. Monogr. 69, 73–81 (1985).

    CAS  PubMed  Google Scholar 

  3. 3.

    Ziegler, R. G. et al. Migration patterns and breast cancer risk in Asian-American women. J. Natl Cancer Inst. 85, 1819–1827 (1993).

    CAS  PubMed  Google Scholar 

  4. 4.

    Le, G. M., Gomez, S. L., Clarke, C. A., Glaser, S. L. & West, D. W. Cancer incidence patterns among Vietnamese in the United States and Ha Noi, Vietnam. Int. J. Cancer 102, 412–417 (2002).

    CAS  PubMed  Google Scholar 

  5. 5.

    Hemminki, K. & Li, X. Cancer risks in second-generation immigrants to Sweden. Int. J. Cancer 99, 229–237 (2002).

    CAS  PubMed  Google Scholar 

  6. 6.

    Kushi, L. H. et al. American Cancer Society guidelines on nutrition and physical activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity. CA Cancer J. Clin. 62, 30–67 (2012).

    PubMed  Google Scholar 

  7. 7.

    Calle, E. E., Rodriguez, C., Walker-Thurmond, K. & Thun, M. J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U. S. adults. N. Engl. J. Med. 348, 1625–1638 (2003).

    PubMed  Google Scholar 

  8. 8.

    Emmons, K. M. & Colditz, G. A. Realizing the potential of cancer prevention - the role of implementation science. N. Engl. J. Med. 376, 986–990 (2017).

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Kerr, J., Anderson, C. & Lippman, S. M. Physical activity, sedentary behaviour, diet, and cancer: an update and emerging new evidence. Lancet Oncol. 18, e457–e471 (2017).

    PubMed  Google Scholar 

  10. 10.

    Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  11. 11.

    Lee, C. et al. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci. Transl Med. 4, 124ra27 (2012).

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Raffaghello, L. et al. Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc. Natl Acad. Sci. USA 105, 8215–8220 (2008).

    CAS  PubMed  Google Scholar 

  13. 13.

    Laviano, A. & Rossi Fanelli, F. Toxicity in chemotherapy—when less is more. N. Engl. J. Med. 366, 2319–2320 (2012).

    CAS  PubMed  Google Scholar 

  14. 14.

    DeVita, V. T. Jr, Eggermont, A. M., Hellman, S. & Kerr, D. J. Clinical cancer research: the past, present and the future. Nat. Rev. Clin. Oncol. 11, 663–669 (2014).

    PubMed  Google Scholar 

  15. 15.

    Jaffee, E. M. et al. Future cancer research priorities in the USA: a Lancet Oncology commission. Lancet Oncol. 18, e653–e706 (2017).

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Cleeland, C. S. et al. Reducing the toxicity of cancer therapy: recognizing needs, taking action. Nat. Rev. Clin. Oncol. 9, 471–478 (2012).

    CAS  PubMed  Google Scholar 

  17. 17.

    Caffa, I. et al. Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition. Oncotarget 6, 11820–11832 (2015).

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Arends, J. et al. ESPEN guidelines on nutrition in cancer patients. Clin. Nutr. 36, 11–48 (2017).

    PubMed  Google Scholar 

  19. 19.

    Arends, J. et al. ESPEN expert group recommendations for action against cancer-related malnutrition. Clin. Nutr. 36, 1187–1196 (2017).

    CAS  PubMed  Google Scholar 

  20. 20.

    Pelt, A. C. (ed.) Glucocorticoids: Effects, Action Mechanisms, and Therapeutic Uses (Nova Science Publishers, Inc. 2011).

  21. 21.

    Khurana, I. Essentials of Medical Physiology (ed. India, E.) (Elsevier, 2008).

  22. 22.

    Brandhorst, S. et al. A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan. Cell Metab. 22, 86–99 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Brennan, A. M. & Mantzoros, C. S. Drug insight: the role of leptin in human physiology and pathophysiology—emerging clinical applications. Nat. Clin. Pract. Endocrinol. Metab. 2, 318–327 (2006).

    CAS  PubMed  Google Scholar 

  24. 24.

    Kubota, N. et al. Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab. 6, 55–68 (2007).

    CAS  PubMed  Google Scholar 

  25. 25.

    Cheng, C. W. et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell 14, 810–823 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Di Biase, S. et al. Fasting regulates EGR1 and protects from glucose- and dexamethasone-dependent sensitization to chemotherapy. PLOS Biol. 15, e2001951 (2017).

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Fabrizio, P. et al. SOD2 functions downstream of Sch9 to extend longevity in yeast. Genetics 163, 35–46 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Fabrizio, P., Pozza, F., Pletcher, S. D., Gendron, C. M. & Longo, V. D. Regulation of longevity and stress resistance by Sch9 in yeast. Science 292, 288–290 (2001).

    CAS  PubMed  Google Scholar 

  29. 29.

    Lee, C. et al. Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index. Cancer Res. 70, 1564–1572 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Levine, M. E. et al. Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Cell Metab. 19, 407–417 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Wei, M. et al. Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9. PLOS Genet. 4, e13 (2008).

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    van der Horst, A. & Burgering, B. M. Stressing the role of FoxO proteins in lifespan and disease. Nat. Rev. Mol. Cell Biol. 8, 440–450 (2007).

    PubMed  Google Scholar 

  33. 33.

    Cheng, Z. et al. Foxo1 integrates insulin signaling with mitochondrial function in the liver. Nat. Med. 15, 1307–1311 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Converso, D. P. et al. HO-1 is located in liver mitochondria and modulates mitochondrial heme content and metabolism. FASEB J. 20, 1236–1238 (2006).

    CAS  PubMed  Google Scholar 

  35. 35.

    Hurley, R. L. et al. Regulation of AMP-activated protein kinase by multisite phosphorylation in response to agents that elevate cellular cAMP. J. Biol. Chem. 281, 36662–36672 (2006).

    CAS  PubMed  Google Scholar 

  36. 36.

    Berasi, S. P. et al. Inhibition of gluconeogenesis through transcriptional activation of EGR1 and DUSP4 by AMP-activated kinase. J. Biol. Chem. 281, 27167–27177 (2006).

    CAS  PubMed  Google Scholar 

  37. 37.

    Chalkiadaki, A. & Guarente, L. The multifaceted functions of sirtuins in cancer. Nat. Rev. Cancer 15, 608–624 (2015).

    CAS  PubMed  Google Scholar 

  38. 38.

    Zhu, Y., Yan, Y., Gius, D. R. & Vassilopoulos, A. Metabolic regulation of Sirtuins upon fasting and the implication for cancer. Curr. Opin. Oncol. 25, 630–636 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Gao, Z. et al. Neurod1 is essential for the survival and maturation of adult-born neurons. Nat. Neurosci. 12, 1090–1092 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Olguin, H. C., Yang, Z., Tapscott, S. J. & Olwin, B. B. Reciprocal inhibition between Pax7 and muscle regulatory factors modulates myogenic cell fate determination. J. Cell Biol. 177, 769–779 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Cheng, C. W. et al. Fasting-mimicking diet promotes Ngn3-driven β-cell regeneration to reverse diabetes. Cell 168, 775–788.e12 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Galluzzi, L., Pietrocola, F., Levine, B. & Kroemer, G. Metabolic control of autophagy. Cell 159, 1263–1276 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Mizushima, N., Yamamoto, A., Matsui, M., Yoshimori, T. & Ohsumi, Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol. Biol. Cell 15, 1101–1111 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Morselli, E. et al. Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death Dis. 1, e10 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Fernandez, A. F. et al. Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice. Nature 558, 136–140 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Rybstein, M. D., Bravo-San Pedro, J. M., Kroemer, G. & Galluzzi, L. The autophagic network and cancer. Nat. Cell Biol. 20, 243–251 (2018).

    CAS  PubMed  Google Scholar 

  47. 47.

    Liang, X. H. et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402, 672–676 (1999).

    CAS  PubMed  Google Scholar 

  48. 48.

    Yue, Z., Jin, S., Yang, C., Levine, A. J. & Heintz, N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl Acad. Sci. USA 100, 15077–15082 (2003).

    CAS  PubMed  Google Scholar 

  49. 49.

    Yang, H. et al. Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell 130, 1095–1107 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Bianchi, G. et al. Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models. Oncotarget 6, 11806–11819 (2015).

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Brandhorst, S., Wei, M., Hwang, S., Morgan, T. E. & Longo, V. D. Short-term calorie and protein restriction provide partial protection from chemotoxicity but do not delay glioma progression. Exp. Gerontol. 48, 1120–1128 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    de Groot, S. et al. The effects of short-term fasting on tolerance to (neo) adjuvant chemotherapy in HER2-negative breast cancer patients: a randomized pilot study. BMC Cancer 15, 652 (2015).

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Dorff, T. B. et al. Safety and feasibility of fasting in combination with platinum-based chemotherapy. BMC Cancer 16, 360 (2016).

    PubMed  PubMed Central  Google Scholar 

  54. 54.

    Lo Re,O. et al. Fasting inhibits hepatic stellate cells activation and potentiates anti-cancer activity of Sorafenib in hepatocellular cancer cells. J. Cell. Physiol. 233, 1202–1212 (2018).

    Google Scholar 

  55. 55.

    Lu, Z. et al. Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation. Nat. Med. 23, 79–90 (2017).

    CAS  PubMed  Google Scholar 

  56. 56.

    Pietrocola, F. et al. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30, 147–160 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Safdie, F. et al. Fasting enhances the response of glioma to chemo- and radiotherapy. PLOS ONE 7, e44603 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Safdie, F. M. et al. Fasting and cancer treatment in humans: a case series report. Aging (Albany NY) 1, 988–1007 (2009).

    Google Scholar 

  59. 59.

    Shi, Y. et al. Starvation-induced activation of ATM/Chk2/p53 signaling sensitizes cancer cells to cisplatin. BMC Cancer 12, 571 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Sun, P. et al. Fasting inhibits colorectal cancer growth by reducing M2 polarization of tumor-associated macrophages. Oncotarget 8, 74649–74660 (2017).

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Bauersfeld, S. P. et al. The effects of short-term fasting on quality of life and tolerance to chemotherapy in patients with breast and ovarian cancer: a randomized cross-over pilot study. BMC Cancer 18, 476 (2018).

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Wei, M. et al. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci. Transl Med. 9, eaai8700 (2017).

    PubMed  Google Scholar 

  63. 63.

    US National Library of Medicine. (2013).

  64. 64.

    US National Library of Medicine. (2013).

  65. 65.

    US National Library of Medicine. (2014).

  66. 66.

    US National Library of Medicine. (2016).

  67. 67.

    US National Library of Medicine. (2017).

  68. 68.

    US National Library of Medicine. (2018).

  69. 69.

    Martin, K., Jackson, C. F., Levy, R. G. & Cooper, P. N. Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database Syst. Rev. 2, CD001903 (2016).

    PubMed  Google Scholar 

  70. 70.

    Oliveira, C. L. P. et al. A nutritional perspective of ketogenic diet in cancer: a narrative review. J. Acad. Nutr. Diet 118, 668–688 (2018).

    PubMed  Google Scholar 

  71. 71.

    Urbain, P. et al. Impact of a 6-week non-energy-restricted ketogenic diet on physical fitness, body composition and biochemical parameters in healthy adults. Nutr. Metab. (Lond.) 14, 17 (2017).

    Google Scholar 

  72. 72.

    Hopkins, B. D. et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560, 499–503 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Abdelwahab, M. G. et al. The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma. PLOS ONE 7, e36197 (2012).

    PubMed  PubMed Central  Google Scholar 

  74. 74.

    Allen, B. G. et al. Ketogenic diets enhance oxidative stress and radio-chemo-therapy responses in lung cancer xenografts. Clin. Cancer Res. 19, 3905–3913 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Aminzadeh-Gohari, S. et al. A ketogenic diet supplemented with medium-chain triglycerides enhances the anti-tumor and anti-angiogenic efficacy of chemotherapy on neuroblastoma xenografts in a CD1-nu mouse model. Oncotarget 8, 64728–64744 (2017).

    PubMed  PubMed Central  Google Scholar 

  76. 76.

    Gluschnaider, U. et al. Long-chain fatty acid analogues suppress breast tumorigenesis and progression. Cancer Res. 74, 6991–7002 (2014).

    CAS  PubMed  Google Scholar 

  77. 77.

    Hao, G. W. et al. Growth of human colon cancer cells in nude mice is delayed by ketogenic diet with or without omega-3 fatty acids and medium-chain triglycerides. Asian Pac. J. Cancer Prev. 16, 2061–2068 (2015).

    PubMed  Google Scholar 

  78. 78.

    Klement, R. J., Champ, C. E., Otto, C. & Kammerer, U. Anti-tumor effects of ketogenic diets in mice: a meta-analysis. PLOS ONE 11, e0155050 (2016).

    PubMed  PubMed Central  Google Scholar 

  79. 79.

    Lussier, D. M. et al. Enhanced immunity in a mouse model of malignant glioma is mediated by a therapeutic ketogenic diet. BMC Cancer 16, 310 (2016).

    PubMed  PubMed Central  Google Scholar 

  80. 80.

    Mavropoulos, J. C. et al. The effects of varying dietary carbohydrate and fat content on survival in a murine LNCaP prostate cancer xenograft model. Cancer Prev. Res. (Phila) 2, 557–565 (2009).

    CAS  Google Scholar 

  81. 81.

    Morscher, R. J. et al. Inhibition of neuroblastoma tumor growth by ketogenic diet and/or calorie restriction in a CD1-nu mouse model. PLOS ONE 10, e0129802 (2015).

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Otto, C. et al. Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides. BMC Cancer 8, 122 (2008).

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Rieger, J. et al. ERGO: a pilot study of ketogenic diet in recurrent glioblastoma. Int. J. Oncol. 44, 1843–1852 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Stemmer, K. et al. FGF21 is not required for glucose homeostasis, ketosis or tumour suppression associated with ketogenic diets in mice. Diabetologia 58, 2414–2423 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Tisdale, M. J., Brennan, R. A. & Fearon, K. C. Reduction of weight loss and tumour size in a cachexia model by a high fat diet. Br. J. Cancer 56, 39–43 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Woolf, E. C. et al. The ketogenic diet alters the hypoxic response and affects expression of proteins associated with angiogenesis, invasive potential and vascular permeability in a mouse glioma model. PLOS ONE 10, e0130357 (2015).

    PubMed  PubMed Central  Google Scholar 

  87. 87.

    Liskiewicz, A. et al. Sciatic nerve regeneration in rats subjected to ketogenic diet. Nutr. Neurosci. 19, 116–124 (2016).

    CAS  PubMed  Google Scholar 

  88. 88.

    Linard, B., Ferrandon, A., Koning, E., Nehlig, A. & Raffo, E. Ketogenic diet exhibits neuroprotective effects in hippocampus but fails to prevent epileptogenesis in the lithium-pilocarpine model of mesial temporal lobe epilepsy in adult rats. Epilepsia 51, 1829–1836 (2010).

    CAS  PubMed  Google Scholar 

  89. 89.

    Berrigan, D., Perkins, S. N., Haines, D. C. & Hursting, S. D. Adult-onset calorie restriction and fasting delay spontaneous tumorigenesis in p53-deficient mice. Carcinogenesis 23, 817–822 (2002).

    CAS  PubMed  Google Scholar 

  90. 90.

    Chen, Y. et al. Effect of intermittent versus chronic calorie restriction on tumor incidence: a systematic review and meta-analysis of animal studies. Sci. Rep. 6, 33739 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Dirx, M. J., Zeegers, M. P., Dagnelie, P. C., van den Bogaard, T. & van den Brandt, P. A. Energy restriction and the risk of spontaneous mammary tumors in mice: a meta-analysis. Int. J. Cancer 106, 766–770 (2003).

    CAS  PubMed  Google Scholar 

  92. 92.

    Engelman, R. W., Day, N. K. & Good, R. A. Calorie intake during mammary development influences cancer risk: lasting inhibition of C3H/HeOu mammary tumorigenesis by peripubertal calorie restriction. Cancer Res. 54, 5724–5730 (1994).

    CAS  PubMed  Google Scholar 

  93. 93.

    Fernandes, G., Chandrasekar, B., Troyer, D. A., Venkatraman, J. T. & Good, R. A. Dietary lipids and calorie restriction affect mammary tumor incidence and gene expression in mouse mammary tumor virus/v-Ha-ras transgenic mice. Proc. Natl Acad. Sci. USA 92, 6494–6498 (1995).

    CAS  PubMed  Google Scholar 

  94. 94.

    Harvey, A. E. et al. Calorie restriction decreases murine and human pancreatic tumor cell growth, nuclear factor-kappaB activation, and inflammation-related gene expression in an insulin-like growth factor-1-dependent manner. PLOS ONE 9, e94151 (2014).

    PubMed  PubMed Central  Google Scholar 

  95. 95.

    Huffman, D. M. et al. Cancer progression in the transgenic adenocarcinoma of mouse prostate mouse is related to energy balance, body mass, and body composition, but not food intake. Cancer Res. 67, 417–424 (2007).

    CAS  PubMed  Google Scholar 

  96. 96.

    Hursting, S. D., Dunlap, S. M., Ford, N. A., Hursting, M. J. & Lashinger, L. M. Calorie restriction and cancer prevention: a mechanistic perspective. Cancer Metab. 1, 10 (2013).

    PubMed  PubMed Central  Google Scholar 

  97. 97.

    Hursting, S. D., Perkins, S. N., Brown, C. C., Haines, D. C. & Phang, J. M. Calorie restriction induces a p53-independent delay of spontaneous carcinogenesis in p53-deficient and wild-type mice. Cancer Res. 57, 2843–2846 (1997).

    CAS  PubMed  Google Scholar 

  98. 98.

    Hursting, S. D., Perkins, S. N. & Phang, J. M. Calorie restriction delays spontaneous tumorigenesis in p53-knockout transgenic mice. Proc. Natl Acad. Sci. USA 91, 7036–7040 (1994).

    CAS  PubMed  Google Scholar 

  99. 99.

    King, J. T., Casas, C. B. & Visscher, M. B. The influence of estrogen on cancer incidence and adrenal changes in ovariectomized mice on calorie restriction. Cancer Res. 9, 436 (1949).

    CAS  PubMed  Google Scholar 

  100. 100.

    Lashinger, L. M. et al. Starving cancer from the outside and inside: separate and combined effects of calorie restriction and autophagy inhibition on Ras-driven tumors. Cancer Metab. 4, 18 (2016).

    PubMed  PubMed Central  Google Scholar 

  101. 101.

    Mai, V. et al. Calorie restriction and diet composition modulate spontaneous intestinal tumorigenesis in Apc(Min) mice through different mechanisms. Cancer Res. 63, 1752–1755 (2003).

    CAS  PubMed  Google Scholar 

  102. 102.

    Olivo-Marston, S. E. et al. Effects of calorie restriction and diet-induced obesity on murine colon carcinogenesis, growth and inflammatory factors, and microRNA expression. PLOS ONE 9, e94765 (2014).

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Rogozina, O. P., Nkhata, K. J., Nagle, E. J., Grande, J. P. & Cleary, M. P. The protective effect of intermittent calorie restriction on mammary tumorigenesis is not compromised by consumption of a high fat diet during refeeding. Breast Cancer Res. Treat. 138, 395–406 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Rossi, E. L. et al. Energy balance modulation impacts epigenetic reprogramming, ERalpha and ERbeta expression, and mammary tumor development in MMTV-neu transgenic mice. Cancer Res. 77, 2500–2511 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Shang, Y. et al. Cancer prevention by adult-onset calorie restriction after infant exposure to ionizing radiation in B6C3F1 male mice. Int. J. Cancer 135, 1038–1047 (2014).

    CAS  PubMed  Google Scholar 

  106. 106.

    Yoshida, K., Inoue, T., Hirabayashi, Y., Nojima, K. & Sado, T. Calorie restriction and spontaneous hepatic tumors in C3H/He mice. J. Nutr. Health Aging 3, 121–126 (1999).

    CAS  PubMed  Google Scholar 

  107. 107.

    Yoshida, K., Inoue, T., Nojima, K., Hirabayashi, Y. & Sado, T. Calorie restriction reduces the incidence of myeloid leukemia induced by a single whole-body radiation in C3H/He mice. Proc. Natl Acad. Sci. USA 94, 2615–2619 (1997).

    CAS  PubMed  Google Scholar 

  108. 108.

    Colman, R. J. et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201–204 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Mattison, J. A. et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489, 318–321 (2012).

    CAS  PubMed  Google Scholar 

  110. 110.

    Maddocks, O. D. et al. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493, 542–546 (2013).

    CAS  PubMed  Google Scholar 

  111. 111.

    Sheen, J. H., Zoncu, R., Kim, D. & Sabatini, D. M. Defective regulation of autophagy upon leucine deprivation reveals a targetable liability of human melanoma cells in vitro and in vivo. Cancer Cell 19, 613–628 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Hens, J. R. et al. Methionine-restricted diet inhibits growth of MCF10AT1-derived mammary tumors by increasing cell cycle inhibitors in athymic nude mice. BMC Cancer 16, 349 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Fontana, L. & Partridge, L. Promoting health and longevity through diet: from model organisms to humans. Cell 161, 106–118 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Holloszy, J. O. & Fontana, L. Caloric restriction in humans. Exp. Gerontol. 42, 709–712 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Dirks, A. J. & Leeuwenburgh, C. Caloric restriction in humans: potential pitfalls and health concerns. Mech. Ageing Dev. 127, 1–7 (2006).

    PubMed  Google Scholar 

  116. 116.

    Das, S. K. et al. Body-composition changes in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE)-2 study: a 2-y randomized controlled trial of calorie restriction in nonobese humans. Am. J. Clin. Nutr. 105, 913–927 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Fontana, L., Weiss, E. P., Villareal, D. T., Klein, S. & Holloszy, J. O. Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell 7, 681–687 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Yilmaz, O. H. et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486, 490–495 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Yousefi, M. et al. Calorie restriction governs intestinal epithelial regeneration through cell-autonomous regulation of mTORC1 in reserve stem cells. Stem Cell Rep. 10, 703–711 (2018).

    CAS  Google Scholar 

  120. 120.

    Jarde, T., Perrier, S., Vasson, M. P. & Caldefie-Chezet, F. Molecular mechanisms of leptin and adiponectin in breast cancer. Eur. J. Cancer 47, 33–43 (2011).

    CAS  PubMed  Google Scholar 

  121. 121.

    Pollak, M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat. Rev. Cancer 12, 159–169 (2012).

    CAS  PubMed  Google Scholar 

  122. 122.

    Newman, J. C. & Verdin, E. Ketone bodies as signaling metabolites. Trends Endocrinol. Metab. 25, 42–52 (2014).

    CAS  PubMed  Google Scholar 

  123. 123.

    Xia, S. et al. Prevention of dietary-fat-fueled ketogenesis attenuates BRAF V600E tumor growth. Cell Metab. 25, 358–373 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Di Biase, S. et al. Fasting-mimicking diet reduces HO-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell 30, 136–146 (2016).

    PubMed  PubMed Central  Google Scholar 

  125. 125.

    Yakar, S. et al. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc. Natl Acad. Sci. USA 96, 7324–7329 (1999).

    CAS  PubMed  Google Scholar 

  126. 126.

    Lin, S. J. et al. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418, 344–348 (2002).

    CAS  PubMed  Google Scholar 

  127. 127.

    Shim, H. S., Wei, M., Brandhorst, S. & Longo, V. D. Starvation promotes REV1 SUMOylation and p53-dependent sensitization of melanoma and breast cancer cells. Cancer Res. 75, 1056–1067 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    D’Aronzo, M. et al. Fasting cycles potentiate the efficacy of gemcitabine treatment in in vitro and in vivo pancreatic cancer models. Oncotarget 6, 18545–18557 (2015).

    PubMed  PubMed Central  Google Scholar 

  129. 129.

    Strickaert, A. et al. Cancer heterogeneity is not compatible with one unique cancer cell metabolic map. Oncogene 36, 2637–2642 (2017).

    CAS  PubMed  Google Scholar 

  130. 130.

    Chan, L. N. et al. Metabolic gatekeeper function of B-lymphoid transcription factors. Nature 542, 479–483 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Chen, G. G. et al. Heme oxygenase-1 protects against apoptosis induced by tumor necrosis factor-alpha and cycloheximide in papillary thyroid carcinoma cells. J. Cell. Biochem. 92, 1246–1256 (2004).

    CAS  PubMed  Google Scholar 

  132. 132.

    Postow, M. A., Callahan, M. K. & Wolchok, J. D. Immune checkpoint blockade in cancer therapy. J. Clin. Oncol. 33, 1974–1982 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Galluzzi, L., Buque, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell 28, 690–714 (2015).

    CAS  PubMed  Google Scholar 

  134. 134.

    Stafford, P. et al. The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma. Nutr. Metab. (Lond.) 7, 74 (2010).

    Google Scholar 

  135. 135.

    Morscher, R. J. et al. Combination of metronomic cyclophosphamide and dietary intervention inhibits neuroblastoma growth in a CD1-nu mouse model. Oncotarget 7, 17060–17073 (2016).

    PubMed  PubMed Central  Google Scholar 

  136. 136.

    Shields, B. A., Engelman, R. W., Fukaura, Y., Good, R. A. & Day, N. K. Calorie restriction suppresses subgenomic mink cytopathic focus-forming murine leukemia virus transcription and frequency of genomic expression while impairing lymphoma formation. Proc. Natl Acad. Sci. USA 88, 11138–11142 (1991).

    CAS  PubMed  Google Scholar 

  137. 137.

    Stewart, J. W. et al. Prevention of mouse skin tumor promotion by dietary energy restriction requires an intact adrenal gland and glucocorticoid supplementation restores inhibition. Carcinogenesis 26, 1077–1084 (2005).

    CAS  PubMed  Google Scholar 

  138. 138.

    Yoshida, K. et al. Radiation-induced myeloid leukemia in mice under calorie restriction. Leukemia 11 (Suppl. 3), 410–412 (1997).

    PubMed  Google Scholar 

  139. 139.

    Pugh, T. D., Oberley, T. D. & Weindruch, R. Dietary intervention at middle age: caloric restriction but not dehydroepiandrosterone sulfate increases lifespan and lifetime cancer incidence in mice. Cancer Res. 59, 1642–1648 (1999).

    CAS  PubMed  Google Scholar 

  140. 140.

    Al-Wahab, Z. et al. Dietary energy balance modulates ovarian cancer progression and metastasis. Oncotarget 5, 6063–6075 (2014).

    PubMed  PubMed Central  Google Scholar 

  141. 141.

    Galet, C. et al. Effects of calorie restriction and IGF-1 receptor blockade on the progression of 22Rv1 prostate cancer xenografts. Int. J. Mol. Sci. 14, 13782–13795 (2013).

    PubMed  PubMed Central  Google Scholar 

  142. 142.

    Fontana, L. & Klein, S. Aging, adiposity, and calorie restriction. JAMA 297, 986–994 (2007).

    CAS  PubMed  Google Scholar 

  143. 143.

    Paoli, A., Rubini, A., Volek, J. S. & Grimaldi, K. A. Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur. J. Clin. Nutr. 67, 789–796 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Willcox, B. J. et al. Caloric restriction, the traditional Okinawan diet, and healthy aging: the diet of the world’s longest-lived people and its potential impact on morbidity and life span. Ann. NY Acad. Sci. 1114, 434–455 (2007).

    CAS  PubMed  Google Scholar 

  145. 145.

    Descamps, O., Riondel, J., Ducros, V. & Roussel, A. M. Mitochondrial production of reactive oxygen species and incidence of age-associated lymphoma in OF1 mice: effect of alternate-day fasting. Mech. Ageing Dev. 126, 1185–1191 (2005).

    CAS  PubMed  Google Scholar 

  146. 146.

    Arezzo di Trifiletti, A. et al. Comparison of the performance of four different tools in diagnosing disease-associated anorexia and their relationship with nutritional, functional and clinical outcome measures in hospitalized patients. Clin. Nutr. 32, 527–532 (2013).

    PubMed  Google Scholar 

  147. 147.

    Kilgour, R. D. et al. Handgrip strength predicts survival and is associated with markers of clinical and functional outcomes in advanced cancer patients. Support Care Cancer 21, 3261–3270 (2013).

    CAS  PubMed  Google Scholar 

  148. 148.

    Muscaritoli, M. et al. Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) “cachexia-anorexia in chronic wasting diseases” and “nutrition in geriatrics”. Clin. Nutr. 29, 154–159 (2010).

    CAS  PubMed  Google Scholar 

  149. 149.

    Mourtzakis, M. et al. A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care. Appl. Physiol. Nutr. Metab. 33, 997–1006 (2008).

    PubMed  Google Scholar 

  150. 150.

    Prado, C. M., Birdsell, L. A. & Baracos, V. E. The emerging role of computerized tomography in assessing cancer cachexia. Curr. Opin. Support. Palliat. Care 3, 269–275 (2009).

    Google Scholar 

  151. 151.

    Laconi, E. et al. The enhancing effect of fasting/refeeding on the growth of nodules selectable by the resistant hepatocyte model in rat liver. Carcinogenesis 16, 1865–1869 (1995).

    CAS  PubMed  Google Scholar 

  152. 152.

    Premoselli, F., Sesca, E., Binasco, V., Caderni, G. & Tessitore, L. Fasting/re-feeding before initiation enhances the growth of aberrant crypt foci induced by azoxymethane in rat colon and rectum. Int. J. Cancer 77, 286–294 (1998).

    CAS  PubMed  Google Scholar 

  153. 153.

    Choi, I. Y. et al. A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms. Cell Rep. 15, 2136–2146 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


This work was supported in part by the Associazione Italiana per la Ricerca sul Cancro (AIRC) (IG#17736 to A.N. and IG#17605 to V.D.L.), the Seventh Framework Program ATHERO-B-CELL (#602114 to A.N.), the Fondazione Umberto Veronesi (to A.N. and V.D.L.), the Italian Ministry of Health (GR-2011-02347192 to A.N.), the 5 × 1000 2014 Funds to the Istituto di Ricovero e Cura a Carattere Scientifico per l’Oncologia (IRCCS) Ospedale Policlinico San Martino (to A.N.), the BC161452 and BC161452P1 grants of the Breast Cancer Research Program (US Department of Defense) (to V.D.L. and to A.N., respectively) and the US National Institute on Aging–National Institutes of Health (NIA–NIH) grants AG034906 and AG20642 (to V.D.L.).

Reviewer information

Nature Reviews Cancer thanks O. Yilmaz, C. C. Zhang and the anonymous reviewer for their contribution to the peer review of this work.

Author information




V.D.L. substantially contributed to discussion of content, wrote the manuscript and reviewed and/or edited it before submission. A.N. researched data for the manuscript, substantially contributed to discussion of content and wrote the manuscript. I.C. and S.C. researched data for the manuscript and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Valter D. Longo.

Ethics declarations

Competing interests

A.N. and I.C. are inventors on three patents of methods for treating cancer by fasting-mimicking diets that are currently under negotiation with L-Nutra Inc. V.D.L. is the founder of L-Nutra Inc.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nencioni, A., Caffa, I., Cortellino, S. et al. Fasting and cancer: molecular mechanisms and clinical application. Nat Rev Cancer 18, 707–719 (2018).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing