In this 2018 review, Valter Longo et al. discuss the current evidence supporting the use of fasting and/or fasting-mimicking diets in cancer therapy.
A fasting-mimicking diet (FMD) is a three- to five-day diet of water, vegetable broths, soups, juices, bars, herbal teas, and supplements. The diet is designed to drive a metabolic response similar to starvation without requiring a water fast. In healthy subjects, the FMD leads to significant reductions in insulin and glucose levels, IGF-1, and leptin, as well as increased adiponectin and ketone levels. A minimum of 48 hours of fasting or FMD is required to achieve clinically meaningful effects, and the FMD allows these effects to be achieved more consistently than true fasting, which involves greater risk and a reduced probability of compliance. In healthy subjects, five-day FMD cycles are well-tolerated; preliminary feasibility studies in self-selected cancer patients suggest they do not induce any significant side effects and may improve quality of life.
An FMD is unlikely to have a significant impact on cancer progression as a sole or primary therapy but may increase the effectiveness of other therapies when delivered simultaneously. The proposed general mechanism for this change is the differential stress response triggered by an FMD (see Figure 1 below). The FMD leads to a variety of metabolic changes (many downstream of the reduced IGF-1 activity it causes) that slow ribosome biogenesis and other proliferative activities within healthy cells, changes that increase cells’ resistance to chemotherapeutic drugs. Cancer cells, due to consistent deficiencies in their metabolic function, are unable to respond in this way and in fact often upregulate a variety of proliferative genes in response to fasting or an FMD. Reduced blood glucose availability also drives cancer cells to shift from aerobic glycolysis (as noted in the Warburg effect) to mitochondrial oxidative phosphorylation, which increases oxidative stress. Taken together, these effects simultaneously increase the impact of chemotherapy and radiotherapy on cancer cells and decrease their impact on healthy cells. Human data showing these effects is limited, but a variety of preclinical mouse studies collectively show that fasting and FMDs can potentiate chemotherapeutic damage and reduce tumor growth in mouse cancer models.
Figure 1
FMDs also may counteract the drawbacks of particular chemotherapeutic agents. For example, mTOR and PI3K inhibitors both lead to hyperglycemia as a side effect, which counteracts their target function (i.e., suppression of metabolic pathways in the cancer cells) and leads to additional systemic damage. An FMD (or any other glucose-suppressing diet, such as a ketogenic diet) can prevent the development of hyperglycemia and increase both the effectiveness and tolerability of these and similar drugs.
The authors also briefly discuss a ketogenic diet and caloric restriction. Chronic caloric restriction, while shown in some studies to reduce cancer risk, has resulted in inconsistent benefits when followed alongside other cancer treatments and carries greater risk of side effects. Ketogenic diets, while inducing much of the same metabolic effects as an FMD, may not deliver the same differential stress response. Additionally, the fasting-and-refeeding cycle unique to the FMD leads to regeneration of immune and bone marrow cells that may be particularly beneficial when delivered in a coordinated fashion alongside chemotherapy (see Fig. 3 below).
Figure 3
Each of these diets may interact well with specific treatments. For example, recent research by Lew Cantley has shown that a ketogenic diet may increase the effectiveness of PI3K inhibitors.
Collectively, the research surrounding the use of fasting-mimicking diets and other similar dietary interventions as a component of cancer treatment, while remaining preliminary, suggests these diets are frequently tolerable and do not reduce the effectiveness of existing cancer treatments. It remains to be seen whether the promising positive evidence in mouse models, along with the compelling mechanistic support, translates consistently to clinical benefits in humans.
Comments on Fasting and Cancer: Molecular Mechanisms and Clinical Applications
One area I'm looking forward to seeing additional research is work similar to that of Cantley et al (noted at the end of the article), where dietary interventions are used alongside more traditional therapies (chemo, radiotherapy, etc.) to increase their effectiveness and reduce harm to the patient. It's very possible that even if the impact of diet is not enough to stop or reverse cancer growth by itself, it can "kick out one leg of the stool" (to use a phrase I've heard elsewhere) and significantly enhance the susceptibility of tumor cells to these therapies. Of course, an enormous amount of research will be needed before we understand whether or not that is the case, but if it's done systematically and with the right level of support it should be a relatively simple hypothesis to test.
Yes. Excited to see research go into that direction!
I the difference in effect found between FMD vs. Keto vs. Caloric Restriction diets with chemo interesting. As well, the possibility of a specific timing cycle to optimize the effects.
It is, especially because the relative effectiveness of different dietary interventions can help us understand the mechanisms by which cancer can be manipulated - and so how we can develop more effective combinatorial therapies in the future.
For example, let's say, as Longo et al argue, fasting has greater benefits than caloric restriction, and that is at least partly related to the greater impact fasting has on IGF-1 levels. That might help us develop diets specifically to maximize IGF-1 suppression, which could have even greater benefits.
The clinical end of this is still a relatively young field, but when we look at the world of opportunities for dietary interventions to directly affect cancer AND to increase the effectiveness of existing cancer therapies, there is much to look forward to.
Fasting and Cancer: Molecular Mechanisms and Clinical Applications
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