Caloric restriction and fasting

Fasting has been practiced for millennia, but only recently studies have shed light on its role in adaptive cellular responses that reduce oxidative damage and inflammation, optimize energy metabolism and bolster cellular protection. In lower eukaryotes, chronic fasting extends longevity in part by reprogramming metabolic and stress resistance pathways. In rodents intermittent or periodic fasting protects against diabetes, cancers, heart disease and neurodegeneration, while in humans it helps reduce obesity, hypertension, asthma, and rheumatoid arthritis. Thus, fasting has the potential to delay aging and help prevent and treat diseases.

Caloric restriction and fasting have deep roots in naturopathic medicine. In the past decade, there has been a resurgence of interest in fasting for many health reasons including cancer treatment, with new research fuelling more acceptance throughout medicine. This talk will summarize our current understanding of the mechanisms behind fasting, the available human research and the practical use of fasting in practice, both as an adjunct to chemotherapy and for cancer prevention.

The problem with western diets:

• Too many calories, too many carbs and no break from the constant overfeeding.
• We are running our engines too richly.
• We are genetically programmed for short periods of starvation.
• If we ate 30% less than we currently do in society, we'd see a decrease in the chronic diseases most associated with western lifestyles (cancer, heart disease, diabetes, stroke), as well as an increase in lifespan.

Brief History of Fasting

• We see fasting practiced in many cultures and religions for health reasons, including Buddhism, Christianity, Islam, Judaism, Taoism, and Hinduism.
• Animals fast when sick. Is there wisdom in nature?
• Naturopaths have long used fasting as a therapeutic tool. Detox has been our main rationale.
• Achieve clinically relevant results and help people feel better.
• I have been fasting periodically for the last decade, for usually up to a week at a time.

Health and Disease

• Diabetes: Generally, we observe an improvement in insulin resistance and haemoglobin A1C, along with positive effects on body weight.
• Hypertension: In a study of 174 patients who were water-fasted for 10 days, participants saw an average drop in blood pressure of 37/13mmHg. In addition, all participants discontinued their hypertension medications

Caloric restriction

Caloric restriction(CR) appears to be effective regardless of age, gender, ethnicity, weight, body mass index (BMI) or a diagnosis of metabolic syndrome or type 2 diabetes, but the greatest benefit is usually observed in the sickest subjects and BP may continue to improve during the refeeding period. Exercise enhances the effects of CR only in hypertensive subjects. There is as yet no consensus on the mechanism of effect of CR and it may be multifactorial. Several studies have suggested that improvement in BP is related to improvement in insulin sensitivity, as well as increased nitric oxide production through improved endothelial function. In addition, CR is known to induce SIRT1, a nutrient sensor, which is linked to a number of beneficial effects in the body. Fasting has been shown to maintain HDL while lowering triglycerides and LDL.

Fasting and Cancer Physiology

The PI3K/AKT signaling pathway is a key regulator of normal cellular processes involved in cell growth, proliferation, metabolism, motility, survival, and apoptosis. Aberrant activation of the PI3K/AKT pathway promotes the survival and proliferation of tumor cells.
Aberrant activation of The PI3K/AKT signaling pathway is commonly observed in most cancers.  Increased activity of this pathway is often associated with tumor progression and resistance to cancer therapies.  Activation of this pathway can be caused by chemotherapy and targeted therapies and creates treatment resistance to these very same therapies in multiple tumor types

Fasting alongside Chemotherapy

• We can down regulate healthy cellular metabolism, putting healthy cells in a more protected state from chemotherapy, which attacks rapidly dividing cells.
• Cancer cells cannot down regulate their metabolism and get stressed by the lack of glucose.

Recent Research

1. https://bmccancer.biomedcentral.com/articles/10.1186/s12885-018-4353-2 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: STF during chemotherapy is well tolerated and appears to improve QOL and fatigue during chemotherapy. April 2018
2. https://www.embopress.org/doi/full/10.15252/embj.201899815 Periodic fasting starves cisplatinresistant cancers to death. Most recent publication by Walter Longo, noting that chemo resistant cancer cells are more vulnerable to anti-cancer effects of fasting. Of note, He proposes that dependence of cancer on glutamine that develops becomes an Achilles' heel.

Safety and Contraindications

• Frail and/or underweight patients
• Patients at risk for malnutrition
• Patients with widely metastatic disease
• Patients with abnormal liver function tests
• Other metabolic scenarios like DM1 and hypoglycaemia

References:

Saleh AD, Simone BA, Palazzo J, et al. Caloric restriction augments radiation efficacy in breast cancer. Cell Cycle. 2013;12(12):1955-1963.

Simone BA, Dan T, Palagani A, et al. Caloric restriction coupled with radiation decreases metastatic burden in triple negative breast cancer. Cell Cycle. 2016:15(17):2265-2274.

Brandhorst S, Harputlugil E, Mitchell JR, Longo VD. Protective effects of short-term dietary restriction in surgical stress and chemotherapy. Ageing Res Rev. 2017;39:68-77.

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

Raffaghello L, Lee C, Safdie FM, et al. Starvation-dependent differential stress resistanceprotects normal but not cancer cells against high-dose chemotherapy. Proc Natl Acad Sci U S A. 2008;105(24):8215-8220.

Arnaldez FI, Helman LJ. Targeting the insulin growth factor receptor 1. Hematol Oncol Clin North Am. 2012;26(3):527-542.

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

Bauersfeld SP, Kessler CS, Wischnewsky M, 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. 2018;18(1):476

Dorff TB, Groshen S, Garcia A, et al. Safety and feasibility of fasting in combination with platinum-based chemotherapy. BMC Cancer. 2016;16:360.

Cheng CW, Adams GB, Perin L, et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell. 2014;14(6):810-823.