Calorie Restriction as an Adjuvant Cancer Treatment

Calorie restriction and intermittent fasting have been extensively studied in the context of aging, and most of the age-slowing interventions so far tested in animal studies are derived in some way from a knowledge of the stress response mechanisms triggered by a lowered calorie intake. The long term effects of calorie restriction and fasting in short-lived species are quite different from those in long-lived species: only the short-lived species exhibit a meaningful extension of life span, as much as 40% in mice. Yet the short-term effects on metabolism and cellular mechanisms are very similar. The beneficial response to periods of low nutrient availability evolved very early in the development of life, likely because it increases the chance of living to replicate in the next period of abundance.

The short-term effects of calorie restriction are beneficial to normal cells, but harmful to cancer cells. Calorie restriction upregulates cell maintenance mechanisms likely to cause cancer cells to self-destruct. This is now well known, demonstrated in animal models and human trials. In recent years researchers have put considerable effort into codifying and quantifying fasting and fasting mimicking diets in the context of cancer treatment. Similarly, there is considerable interest in the application to cancer treatment of calorie restriction mimetic drugs, those that induce some fraction of the response to lowered calorie intake. An example is the class of mTOR inhibitors, known to slow aging and lower cancer incidence in mice.

Metabolic Reprogramming by Reduced Calorie Intake or Pharmacological Caloric Restriction Mimetics for Improved Cancer Immunotherapy

Fasting and caloric restriction (CR) were shown in non-human primates to reduce the incidence of not only cancer but also metabolic diseases, arteriosclerosis, and neurodegeneration - thus extending the healthspan. Furthermore, fasting and CR were shown in yeast, plants, worms, flies, and rodents to prolong lifespan and reduce the incidence of a wide array of age-associated pathologies, notably malignant diseases. Fasting-mimicking-diets (FMDs) reproduce the effects of fasting while maintaining a food supply, yet with a limited number of calories and a particular macronutrient composition, frequently poor in proteins, enriched in unsaturated fats, and with low to moderate proportions of carbohydrates. FMDs were shown in pilot trials to reduce risk factors associated with aging, diabetes, cardiovascular disease, and cancer, without major adverse effects. In this review, when indistinctively referring to fasting, CR, and/or their mimetics, we will use the term "energy reduction" (ER).

It has been known for more than a decade that starvation protects normal but not transformed cells against chemotherapeutics and oxidative damage, in yeasts, cell cultures, and mice. This effect has been observed in several malignancies such as colon carcinomas, melanomas, gliomas, and breast cancers. Such phenomenon has been dubbed "differential stress resistance" (DSR; sometimes referred to as "differential stress sensitization"). DSR likely originates from the independence of malignant cells from growth signals and their insensitivity to anti-growth signals. These characteristics result from oncogenic gain-of-function mutations affecting the activity of AKT, mechanistic target of rapamycin (mTOR), RAS, and other pro-proliferative signaling factors, and/or of loss-of-function mutations in genes encoding tumor suppressors such as TP53. Consequently, cancer cells are unable to adapt to the lack of nutrients and maintain a sustained proliferation. On the contrary, normal cells switch to a maintenance program conferring resistance to stress.

One of the knock-on effects of ER is autophagy induction, which is triggered in response to cellular stress such as DNA damage, endoplasmic reticulum or mitochondrial stress, oxidative or metabolic stress. In cancer cells, autophagic activity helps to survive in the hypoxic and nutrient-deprived tumor microenvironment and has also been described as a drug resistance mechanism. Somewhat counter-intuitively, this knock-on autophagy induction is not detrimental to the general antitumoral effect of ER and helps explain DSR. As we have seen, cancer cells are more sensitive to metabolic stresses and, as we know, they are also more sensitive to genotoxic stress than most somatic cells. Thus, the concomitant amplification of these two stresses thanks to ER and chemotherapy can prove fatal to malignant cells, whereas ER-induced autophagy probably contributes to its observed protective effect against chemotherapy in healthy cells.

DSR is thus mediated in part by the different metabolic requirements of cancer and healthy cells, but also - and perhaps chiefly - by the cellular effects of ER, especially as it pertains to autophagy. We have known for a few years that autophagy promotes (i) cancer cell immunogenicity, (ii) tumor-bed immune infiltration, and (iii) depletion of tumor-infiltrating regulatory T cells, especially when autophagy is induced at the same time as immunogenic cell death (ICD)-inducing agents are administered. This points towards an immune mechanism that explains the capacity of ER to prevent - and probably even to treat - cancer. This has led us and others to propose ER as an adjuvant to immunotherapy, especially as ER is relatively well tolerated.

Comments

I think that even during 70s and 80s there were some experimental studies that showed that for some cancer types you can get amazing result up to complete remission with fasting alone. (that usually happens after many weeks of fasting , though) However, there are other cancers that don't respond that well. What was interesting is that you can get tumor reduction (at least in size) during the fasting period but once the fast is broken if the tumor is not killed it comes back with a vengeance. However, for some hopeless forms of cancer where there is radiotherapy just to buy a few months of prolonged suffering it might actually work better.

Of course, YMMV. So despite this being quite an old subject is deserves more studies. I have seen in some fasting forums where some incurable diseases are kept at very long remission. No peer reviewed studies i can cite, though. Logically type II diabetes melitus should be absolutely if not curable at least manageable by fasting.

Caveat: My personal experience is much less dramatic. after 22 days, i got rid of my back pain for many years, seems the skin got better with better collagen. Of course, I was lucky enough not to have any major or serious disease (knock on wood)

Posted by: Cuberat at April 19th, 2021 4:10 PM

Cancer is an age-related disease and aging is inextricably linked to metabolism. Otto Warburg was first to suggest starving cancer would suppress or kill neoplasticism cells. There is support for this as cancer cells do not utilize beta oxidation for energy but rather aerobic glycolysis. Suppressing glycolytic intermediates will slow cancer but will not cure it. It should be noted that insulin potentiation was not effective in treating cancer. It's questionable how effective this approach would be in most patients, but it's worth a try. So, prevention by slowing metabolism will decrease incidence of age-related disease like cancer. Focusing on treating and understanding aging would be a more useful goal, if we want to decrease diseases associated with advanced age.

Posted by: Dr. Mark Obrenovich at April 25th, 2021 9:33 PM

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