The fasting mimicking diet (FMD) is gaining recognition as a promising approach in cancer research, showing potential in slowing down tumor growth, reducing chemotherapy-related side effects, and improving quality of life. This article explores the mechanisms behind FMD, its effects on cancer biology and treatment, and the current research landscape.
Understanding the Fasting Mimicking Diet
The FMD is a dietary intervention designed to mimic the physiological effects of fasting while still providing essential nutrients and calories. This allows individuals to attain fasting-like effects without the challenges and potential risks associated with complete fasting, such as water-only fasts or intermittent fasting on a few nonconsecutive days per week. FMD plans typically include a variety of plant-based foods formulated to satisfy taste buds while adhering to specific macronutrient and calorie guidelines. A common FMD protocol involves a restriction on Day 1 with further caloric restriction on the following days, often ranging between 700 and 200 kcal/day. For example, one study applied a regimen of 600 kcal on Day 1, followed by up to 300 kcal on Days 2-5.
FMD and its mechanisms
Prolonged fasting and low-calorie FMDs have a major impact on the regulation and renewal of the immune system. The metabolic and physiologic changes that result from prolonged fasting promote hematopoietic stem cell (HSC) enrichment in the bone marrow and lead to lymphoid and myeloid population migration from the peripheral blood to the bone marrow. In this favorable environment, fasting rejuvenates HSC, improves memory T cell function and strengthens the immune responses by stimulating autophagy or apoptosis, which can remove damaged organelles, molecules and cells. Fasting can reduce monocytes proinflammatory activity by shifting their metabolism from glycolysis to oxidative phosphorylation (OXPHOS). These effects of fasting on the immune system are mediated, in part, by the modulation of the IGF-1-PKA nutrient sensing pathway. Alternating fasting/FMD cycles with normal nutrition can also reverse or ameliorate autoimmune diseases including multiple sclerosis and inflammatory bowel disease in mouse models by reducing inflammation, removing autoimmune cells, and increasing hematopoietic stem cells, which generate differentiated immune cells from progenitor/stem cells.
Effects on Cancer Biology
FMDs have demonstrated several effects on cancer biology. These diets can stabilize p53, a tumor suppressor protein, resulting in proliferation arrest of cancer cells. Additionally, FMDs can protect normal cells from the DNA-damaging effects of chemotherapy. Studies have shown that FMDs can influence the tumor microenvironment, potentially favoring the priming of T cells by recruiting dendritic cells into the tumor bed, reducing the percentage of immunosuppressive M-MDSC, and promoting the cytolytic activity of NK cells.
FMD and Cancer Treatment
Chemotherapy
Research suggests that FMDs can enhance the effectiveness of antineoplastic treatments. Patients undergoing chemotherapy with STF (short-term fasting) have reported better tolerance to chemotherapy. Some studies implemented STF for 48-140 hours prior to and/or 5-56 hours following chemotherapy. A study by de Groot et al. (2015) found that patients undergoing chemotherapy with STF had significantly higher quality of life compared to those not on STF.
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Targeted Therapies
FMDs are also being investigated in combination with targeted therapies, including tyrosine kinase inhibitors (TKIs). These therapies often have pharmacokinetic variability, and some should be administered with food. Dietary changes could be clinically relevant and need to be carefully considered.
Immunotherapy
In recent years, periodic cycles of fasting or FMDs have emerged as effective in potentiating the anti-cancer effects of chemotherapy, hormone therapy, and kinase inhibitors against cancer cells while reducing side effects in mice. More recent work indicates that fasting can also potentiate immunotherapy against lung cancer and breast cancer in agreement with the role of fasting/FMD in combination with chemotherapy in increasing the T cell-dependent attack of breast cancer and melanoma cells.
Clinical Studies and Trials
Several clinical trials have assessed the safety and efficacy of FMD in cancer patients. A pilot study by Zorn et al. (2020) found that modified STF (mSTF) was safe and feasible. Valdemarin et al. (2021) also reported that FMD was largely safe with only mild side effects. These studies often involve patients receiving periodic FMD cycles alongside their active medical treatment.
Safety and Feasibility
The FMD has generally been shown to be safe and feasible in clinical trials, with mostly mild side effects reported. Vernieri et al. observed that fat-free mass increased, while fat mass decreased in patients undergoing FMD. However, concerns have been raised regarding the potential for FMD-related adverse events. A study noted that grade 2-4 side effects can occur more frequently in patients using the FMD.
Challenges and Considerations
Compliance is a major issue regarding FMD use in combination with chemotherapy. Differences in FMD composition and patient management across studies can lead to variable outcomes. It is crucial to demonstrate high FMD compliance, which can be achieved with dietician support. Factors such as the type and stage of malignancies, duration of fasting, and individual patient response to chemotherapy can influence adherence.
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The Longevity Diet
Although the Longevity Diet can be generally applied for cancer prevention, it has the potential to be especially beneficial for people with certain genetic mutations-such as the BRCA genes-which put them at a greatly increased risk of cancer. Prophylactic mastectomies and other surgical procedures can reduce the incidence of genetically induced cancers, but nutrition and fasting mimicking diet may also help. Dietary interventions additionally have the potential to reduce the chance of recurrence in previously diagnosed patients whose cancer is in remission.
People affected by pathologies may not do the fasting mimicking diet, unless they have the prior approval of their specialized doctor. In the case of serious or relatively serious illnesses (cancer, diabetes, or cardiovascular, autoimmune, or neurodegenerative diseases), it is important to seek permission and approval from a disease specialist as well as from a dietitian with expertise in the fasting mimicking diet or in therapeutic fasting.
- Reduce sugars to very low levels. Also minimize the consumption of pasta and breads.
- Undergo a five-day fasting mimicking diet every one-to-three months, depending on your weight and health status (every three-to-six months if you are very healthy, with ideal weight and abdominal fat; once a month if you are overweight or obese and at high risk for cancer). In mouse studies, the fasting mimicking diet was as effective as chemotherapy.
- Nourish yourself with essential fatty acids (omega-3 and omega-6), vitamins, and minerals from a variety of vegetables (broccoli, carrots, green peppers, tomatoes, garbanzo beans, lentils, peas, black beans, etc.) and fish (salmon, anchovies). Your immune system is one of the major defenses against cancer.
- Discuss with your oncologist the option of taking 6 grams of vitamin C or Ester-C® daily for a few weeks every six months. Multiple studies have demonstrated vitamin C to possess cancer-fighting properties, although its effectiveness in preventing cancer is controversial. Taken at this level for a few weeks every six months, vitamin C is not known to have major side effects.
Immune Checkpoint Inhibitors (ICIs) and FMDs
Immune checkpoint inhibitors (ICIs) boost anti-tumor immune response by mitigating the self-tolerance mechanism of the immune cells, which is hijacked by tumor cells. The clinical application of ICI has profoundly improved prognosis and life expectancy in metastatic cancer patients suffering from melanoma, non-small-cell lung, and kidney cancer, representing a paradigm shift in cancer therapy.
Immunotherapy is based on the role of cell-surface receptors and ligands accessory to the T-cell receptor in inhibiting cell-mediated immune response. The first monoclonal antibodies targeting this inhibitory axis were developed against the immune checkpoint PD-1 (programmed death-1), its ligand PD-L1 (programmed death ligand-1) and CTLA-4 (cytotoxic T lymphocyte antigen-4). They were first tested in the treatment of melanoma and then applied to the treatment of other cancers characterized by poor prognosis.
Although ICIs therapy has improved the survival of many cancer patients, the percentage of patients responding remains low. In order to improve efficacy and patient response rates, new therapeutic strategies combining ICIs with adjuvants that augment immune-dependent attack of cancer cells are needed. For example, targeting alternative pathways such as the co-stimulatory molecules OX40, 4-1BB, glucocorticoid-induced TNFR-related protein (GITR) has proven to enhance T-cell mediated immunity in preclinical model, although no clinical studies have confirmed the efficacy of such treatments in humans.
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However, ICIs also cause side effects which are uniquely associated with an increase in autoimmunity due to alteration of self-tolerance. A recent study found that 3.5% of patients initiating ICI experience adverse events requiring hospitalization and immunosuppression. Immune-related adverse events (IRAEs) can affect colon, lungs, liver, skin, pituitary, thyroid, and heart. Although cardiotoxicity accounts for <1% of IRAEs, the onset of such complications, such as myocarditis, arrhythmia, pericarditis and vasculitis results in death in 50% of cases.
Cardiovascular immune-related adverse events include myocarditis, pericardial disease, vasculitis, Takotsubo syndrome, destabilization of atherosclerotic lesions, venous thromboembolism, and conduction abnormalities. ICI-associated myocarditis results from inflammation of the conduction system due to infiltration of T cells and macrophages. Under physiological conditions, the cardiac lymphocyte infiltrate is limited and the macrophages and dendritic cells resident in the heart control the expression of the immune checkpoint proteins in order to maintain homeostasis. Thus, inhibiting the immune checkpoint pathway could lead to adverse outcomes, by promoting the recruitment of lymphocytes and macrophages and triggering an inflammatory response.
Indeed, in genetically modified mice, deletion of CTLA4 leads to massive lymphoproliferative disease and diffuse lymphocyte infiltration in almost all organs, including the heart. In contrast the deletion of Pdcd1 (encoding PD-1) in Balb/c mice causes cardiomyopathy due to the development of autoantibodies against troponin I. On the other hand, activation of OX40 with agonistic antibodies stimulates the release of proinflammatory cytokines (IL6, TNFα, IFNγ) by activated T lymphocytes and antigen-presenting cells (APCs) thus causing a systemic inflammatory response syndrome. Thus, it is important to develop new strategies capable of increasing the anticancer efficacy of immunotherapy while preventing unwanted side effects.
Notably, fasting/FMD cycles promotes immune cell infiltration and delays tumor growth in both breast cancer and melanoma cells, raising the possibility that it could enhance the efficacy of immunotherapy without increasing side effects.
Specific Studies and Results
FMD and Anti-PD-1/Anti-CTLA-4 Combination Therapy
One study tested FMD cycles lasting 4 days in combination with immunotherapy directed against the immune checkpoints PD-1 and CTLA4. The combined anti-PD-1/anti-CTLA4 therapy only caused a trend for delayed growth of B16F10 tumors compared to the untreated groups. One cycle of FMD also was not sufficient to slow tumor growth in either the control or immunotherapy groups compared with the ad libitum (AL) diet. However, the analysis of the immune infiltrate 10 days after refeeding, shows that ICIs therapy alone increases the levels of cytotoxic CD8+CD44+GzmB+ lymphocytes, effector memory CD8+CD44+CD62L− T cells, and cytotoxic CD45+Nkp46+GzmB+ NK cells independently of the diet.
FMD and Anti-OX40/Anti-PD-L1 Therapy
Another study tested whether two cycles of FMD enhances the efficacy of another immunotherapy treatment in melanoma by combining antagonist antibody against immune checkpoint PD-L1 and agonist antibody against costimulatory molecule OX40. Whereas anti-OX40/anti-PD-L1 therapy had no effect on melanoma growth, two cycles of FMD plus anti-OX40/anti-PD-L1 caused a strong delay of tumor progression, although most of the effect appears to be caused by the dietary intervention since FMD plus anti-OX40/anti-PD-L1 only caused a non significant trend for improved anti-cancer effects compared to FMD alone.
Mice treated with the combination of ICIs and FMD showed only a trend for increased accumulation of cytotoxic NK cells (CD45+Nkp46+GzmB+) inside the tumor and increased expression of CD127 by CD8+CD44+ effector T cell compared to ICI alone. Regarding the innate immune system, FMD alone increases the percentage of dendritic cells (CD11c+ MHCII+) and macrophages (CD45+ CD11b+ F4/80high), an effect reversed by ICI drugs. Both FMD, anti-OX40/anti-PD-L1 treatment and their combinations reduce the percentage of the immunosuppressive M-MDSC (CD11b+Ly6Chigh) in the tumor bed compared to the standard diet group, whereas PMN-MDSC (CD11b+Ly6ClowLy6Ghigh) display a trend for enrichment only in the AL group treated with ICIs.