Ketogenic Diet

Ketogenic diets are high in fat, moderate in protein and low in carbohydrates, with weak to preliminary evidence of anticancer effects, relief of side effects, and benefits on your body terrainthe internal conditions of your body, including nutritional status, fitness, blood sugar balance, hormone balance, inflammation and more.

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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: metabolism

Inducing ketosis: countering the Warburg effect

Some cancer cells within tumors, as well as tumor-associated cells (such as fibroblasts and macrophages) undergo metabolic changes in response to hypoxia (low oxygen and oxidative stress) of the tumor microenvironment.¹Martinez-Outschoorn U, Sotgia F, Lisanti MP. Tumor microenvironment and metabolic synergy in breast cancers: critical importance of mitochondrial fuels and function. Seminars in Oncology. 2014 Apr;41(2):195-216.

A key alteration of these cells is converting to a complete dependence on glucose for energy generation. These catabolic cells do not have intact mitochondria, and so normal energy production via citric acid cycling and oxidative phosphorylation is not available.

Cells with intact mitochondria can use various metabolic substrates including glucose, fatty acids, glutamine and even ketones to fuel energy production. Catabolic cancer cells and tumor associated stromal cells, on the other hand, lose the ability to make ATP in the mitochondria and instead rely solely upon metabolizing glucose via glycolysis in the cytoplasm to generate ATP.²Schroeder U, Himpe B et al. Decline of lactate in tumor tissue after ketogenic diet: in vivo microdialysis study in patients with head and neck cancer. Nutrition and Cancer. 2013;65(6):843-9. This is called the Warburg effect and is a known attribute of the tumor microenvironment. 

Typical Western diets high in refined carbohydrates provide this glucose substrate as well as promote the insulin pathway, releasing growth factors that are associated with promoting cancer development and progression.³Erickson N, Boscheri A, Linke B, Huebner J. Systematic review: isocaloric ketogenic dietary regimes for cancer patients. Medical Oncology. 2017 May;34(5):72. A ketogenic diet, which severely limits the supply of glucose in favor of ketones, is thought to selectively starve these tumor cells. Evidence suggests that some cancer cells appear less able to metabolize ketones compared with healthy cells.⁴Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells? Trends in Biochemical Sciences. 2016;41(3):211-218; Zhao L, Mao Y, Zhao Y, Cao Y, Chen X. Role of multifaceted regulators in cancer glucose metabolism and their clinical significance. Oncotarget. 2016;7(21):31572-31585; Martinez-Outschoorn UE, Lin Z, Whitaker-Menezes D, Howell A, Sotgia F, Lisanti MP. Ketone body utilization drives tumor growth and metastasis. Cell Cycle. 2012 Nov 1; 11(21): 3964–3971; Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. Journal of General Physiology. 1927;8(6):519-530. 

Of note, while both caloric restriction and a ketogenic diet lower blood glucose and insulin levels, only calorie restriction also lowers fatty acids, and fatty acids may be an important part of anticancer action with some tumors. A mouse study found that only caloric restriction inhibited the growth of select pancreatic tumor allografts in mice. A ketogenic diet alone did not. Further, a higher-fat caloric-restriction diet conferred resistance to the effects of caloric restriction. Altering the fat composition of a ketogenic diet to increase levels of saturated fatty acids in tumors decreased tumor stearoyl-CoA desaturase (SCD) activity to slow tumor growth.⁵Lien EC, Westermark AM et al. Low glycaemic diets alter lipid metabolism to influence tumour growth. Nature. 2021 Nov;599(7884):302-307.

The impact of ketosis on cancer cells does not rely solely on the Warburg effect. The effects of ketosis may induce oxidative stress specific to cancer cells, which may potentiate the effect of chemotherapy and radiation.⁶Zick SM, Snyder D, Abrams DI. Pros and cons of dietary strategies popular among cancer patients. Oncology (Williston Park). 2018 Nov 15;32(11):542-7. 

Reverse Warburg effect: cancer cells adapt

Researchers have proposed the reverse Warburg effect. As tumor-associated cells such as fibroblasts and immune cells struggle under the highly oxidative tumor environment, these cells lose the ability to retain oxidative phosphorylation and, instead, revert to glycolysis for energy production and start to undergo autophagy, a process of self-digestion. The glycolysis and autophagy generate many energy-rich substrates such as fatty acids, lactate, and ketones which these tumor-associated cells release. These substrates are then taken up by growing (anabolic) cancer cells as fuel. 

Experiments show that some tumor cells are able to use lactate and ketones for energy.⁷Schroeder U, Himpe B et al. Decline of lactate in tumor tissue after ketogenic diet: in vivo microdialysis study in patients with head and neck cancer. Nutrition and Cancer. 2013;65(6):843-9; Martinez-Outschoorn UE, Lisanti MP, Sotgia F. Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth. Seminars in Cancer Biology. 2014 Apr;25:47-60; Martinez-Outschoorn UE, Lin Z et al. Ketone body utilization drives tumor growth and metastasis. Cell Cycle. 2012 Nov 1;11(21):3964-71; Maurer GD, Brucker DP et al. Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy. BMC Cancer. 2011 Jul 26;11:315; Seyfried TN, Sanderson TM, El-Abbadi MM, McGowan R, Mukherjee P. Role of glucose and ketone bodies in the metabolic control of experimental brain cancer. British Journal of Cancer 2003;89:1375–82. In this way, tumor-associated cells essentially feed growing cancer cells, the reverse Warburg effect.⁸Bonuccelli G, Tsirigos A et al. Ketones and lactate can actually “fuel” tumor growth, angiogenesis and metastasis: evidence that epithelial cancer cells use oxidative mitochondrial metabolism. Cell Cycle 2010;9:3506–14; Martinez-Outschoorn UE, Prisco M et al. Ketones and lactate increase cancer cell “stemness”, driving recurrence, metastasis and poor clinical outcome in breast cancer: achieving personalized medicine via metabolo-genomics. Cell Cycle 2011;10:1271–86. “In vitro data showed that cancer cells not only adapt to the situation but develop mutations and characteristics of stem cells. One hypothesis is that the [ketogenic] diet puts the tumor under stress and thus selects for resistance and malignancy. In an experiment on mice, the tumors in the diet-treated group initially grew less but later tumor growth accelerated and exceeded that of the control group.”⁹Huebner J, Marienfeld S et al. Counseling patients on cancer diets: a review of the literature and recommendations for clinical practice. Anticancer Research 2014;34:39–48.

Researchers propose that the Warburg and reverse Warburg effects are not totally competitive, but rather reflect the ability of cancer cells to use different metabolic substrates depending upon what is available and what mutations are present.¹⁰Yaojie Fu, Shanshan Liu et al. The reverse Warburg effect is likely to be an Achilles’ heel of cancer that can be exploited for cancer therapy. Oncotarget. 2017 Aug 22; 8(34): 57813–57825; Branco AF, Ferreira A et al. Ketogenic diets: from cancer to mitochondrial diseases and beyond. European Journal of Clinical Investigation. 2016 Mar;46(3):285-98.

The glycolytic pattern is not the only way cancer metabolizes glucose, and therapeutics including the ketogenic diet targeting glycolysis in cancer patients have not always had positive responses.¹¹Yaojie Fu, Shanshan Liu et al. The reverse Warburg effect is likely to be an Achilles’ heel of cancer that can be exploited for cancer therapy. Oncotarget. 2017 Aug 22; 8(34): 57813–57825.

Lower risk of cachexia

Ketogenic diets may have a protein-sparing effect that preserves lean body mass, reducing the risk or severity of cancer cachexia.¹²Zick SM, Snyder D, Abrams DI. Pros and cons of dietary strategies popular among cancer patients. Oncology (Williston Park). 2018 Nov 15;32(11):542-7.