Cyclic Fmd Downregulates Peripheral Blood Immunosuppressive Myeloid Cells While Boosting Activated/cytotoxic Cells
In 38 patients, we used multicolor flow cytometry to investigate the impact of the FMD on the frequency of myeloid and lymphocytic peripheral blood mononuclear cell populations . At the end of five-day FMD, we found a significant decrease of total monocytes and of two highly immunosuppressive monocyte subsets, that is, those lacking HLA-DR expression , acknowledged as monocytic myeloid-derived suppressor cells , and CD14+ cells expressing PD-L1 . The FMD also reduced low-density CD15+ granulocytes, which include polymorphonuclear MDSCs . Interestingly, the observed modifications in myeloid subpopulations were similar in patients undergoing the FMD in combination with ChT or with other standard antitumor therapies .
FMD-induced reduction of myeloid cell subsets was paralleled by an increase of activated CD8+ T cells and cytolytic CD3âCD16+CD56dim natural killer cells , while CD3+ T cells expressing the high-affinity IL2 receptor , which can be associated with Treg activity, were reduced . As in the case of myeloid cells, changes in lymphocytic populations occurred independently of concomitant antitumor therapies , and they were confirmed in a homogeneous subset of 13 patients with TNBC treated with first-line ChT plus FMD , but not in 13 patients with breast cancer treated with ChT alone . Interestingly, the FMD increased CD8+PD-1+CD69+ and CD3âCD16+CD56dim cells in 8 healthy volunteers in a similar way as observed in patients .
Adverse Effects And Safety
Following the Common Terminology Criteria for Adverse Events , 54 to 100% of the participants reported no adverse effects during the FMD cycles . The most common self-reported grade 1 or grade 2 symptoms experienced by the participants were fatigue, weakness, and headaches. No adverse effects of grade 3 or higher were reported. A comprehensive metabolic panel that measured changes in metabolic markers and liver and kidney function showed no negative effects of three cycles of the FMD . In summary, after three cycles of the FMD, subjects reported only some mild and very few moderate side effects.
The Main Benefit Seems To Be To The Immune System
In the first human trial of its kind, scientists showed that a fasting-mimicking diet can work synergistically with conventional therapies in cancer patients, altering their metabolisms and reshaping their immune systems .
What happens when you fast?
Fasting is shaping up to be a powerful addition to clinical practice. It is not a panacea that can fend off virtually every disease, but it can exert a profound effect on the human body. By altering metabolic pathways, periodic fasting can help maintain normal weight, reduce inflammation, lower blood pressure, and beneficially alter the gut microbiome . But what about cancer?
Preclinical studies in mice suggest that fasting and fasting-mimicking diets can work synergistically with anti-cancer treatments, enhancing their activity . FMD is usually defined as low calories, low carbohydrates, low protein. Fasting and FMD reduce glucose, insulin, and insulin-like growth factor 1 levels, thus inhibiting the anabolic processes that help cancer cells grow. Fasting and FMD also alleviate, to a certain extent, the damage incurred by chemotherapy.
Fasting and FMD have also been shown to alter the immune system in particular, by boosting tumor infiltration by CD8+ T cells and reducing the number of immunosuppressive regulatory T cells.
Metabolic changes
This new paper describes the first human clinical trial that investigated the safety and feasibility, as well as the metabolic and immunomodulatory effects, of FMD.
Literature
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Early Study Examines Potential Benefits Of A Fasting
11/22/2021 3:17:57 PM
A severely calorie-restricted, low-carbohydrate, low-protein, 5-day dietary regimen that mimics fasting was shown to be safe and feasible, and it resulted in a decrease of blood glucose and growth factor concentration, a reduction in peripheral blood immunosuppressive cells, and enhanced intratumor T-cell infiltration in patients with cancer receiving standard-of-care therapy, according to a small prospective clinical trial by Vernieri et al published in Cancer Discovery. Phase II/III trials are needed to investigate fasting-mimicking diet antitumor activity and efficacy in combination with standard antineoplastic treatments in these patients, according to researchers.
Preclinical research has found that cyclic fasting or fasting-mimicking diets enhance the activity of antineoplastic treatments by modulating systemic metabolism and boosting antitumor immunity. In this clinical trial, the researchers investigated the safety and biologic effects of cyclic, 5-day fasting-mimicking diets in combination with standard antitumor therapies in patients with various tumor types treated with different standard anticancer therapies.
Study Methodology
Changes In Risk Factors And Metabolic Markers Of Age
After 3 months, 43 subjects from the control arm were crossed over to the FMD intervention. Eleven of these subjects withdrew before completing three FMD cycles . Five of these participants withdrew because of scheduling issues, and two subjects opted to leave the trial for unspecificpersonal reasons. We also excluded four participants based on nonadherence to the FMD protocol. The causes for withdrawal/exclusion were comparable between the arms. Considering both FMD treatment arms, 24 of the 95 participants were excluded or withdrew from the study before completion of the three FMD cycles because of scheduling conflicts , personal issues , or dislike of the diet and/or nonadherence to the dietary protocol . The 25% dropout rate for participants during the FMD is higher than the 10% dropout rate observed during control diet in arm 1, but this is expected considering that subjects in control diet group only dropped out because of scheduling conflicts because they were allowed to remain on their normal diet. Ninety-five subjects completed one cycle, and 71 subjects completed three cycles of the FMD. Compared to the 71 participants who completed the three FMD cycles in arms 1 and 2, the 24 subjects who dropped out were not different in age or BMI but were mostly female .
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Extended Data Fig 9 Fasting Or Fmd Prevents Tamoxifen
ad, Sixeight-week-old female BALB/c mice were treated for 5 weeks with ad libitum diet , tamoxifen , weekly 48-h water-only fasting or FMD , TMX + fasting or TMX + FMD . Mice from all treatment groups were killed at the end of the last fasting/FMD cycle. Uteri were collected, imaged , fixed for histology and subjected to protein lysate generation and RNA extraction. In addition, intra-abdominal fat depots were also isolated. Tff1, Pten and Egr1 mRNA levels in mice uteri were determined by qPCR , and total and phosphorylated AKT , EGR1, PTEN and vinculin in mouse uteri were detected by immunoblotting . For gel source data, see Supplementary Fig. . e, Intra-abdominal fat depots isolated from the mice were imaged. In c, d, data are from biological replicates. P values were determined by two-tailed Students t-test.
Dna Damage: Isolation Of Pbmcs And
PBMCs were isolated using Ficoll-Amidotrizoaat gradient centrifugation according to the standard operating procedure of the Medical Oncology department of LUMC. Isolated PBMCs were carefully resuspended and 3 times washed in PBS . Samples were fixed in 1.5% formaldehyde and permealized in ice-cold pure methanol. Cells were washed 3 times in staining buffer ) and stained for 30min on ice with anti-CD45-PerCP-Cy5.5 , clone 2D1 anti-CD3-PE , anti-CD14-AF700 , anti-CD15-PE CF594 and anti–H2AX-AF488 , followed by another washing step and resuspension in PBS. Per experiment we used 1,000,000 cells or more when available. The cell acquisition was performed immediately after the staining procedure on the flow cytometer and data were analyzed using BD FACS Diva Software version 6.2. The CD45+ cells were gated, after which the CD3+ T-lymphocytes, CD3 non-T cells or CD14+ CD15 monocytes were analyzed for the geomean of -H2AX .
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Research On The Fasting Mimicking Diet
Aside from human studies with the FMD and weight loss, most of the completed research on the fasting-mimicking diet has been done in animals, but that is changing. There is now a human study on FMD and inflammatory bowel disease. Currently, many other projects are in progress looking at the effects of FMD on other health conditions in humans.
Past studies on the FMD show promising results and a step toward similar studies in humans. Currently, the diet is promoted for weight loss and potentially to slow aging. Its ability to help curb particular disease progression or symptoms is still being evaluated, but early findings in animal studies are promising.
Fasting Mimicking Diet May Be Safe Effective As Adjunct To Chemo For Breast Cancer
The findings indicated that a fasting mimicking diet is safe and effective as an adjunct to chemotherapy in women with early breast cancer.
Study results from the phase 2 DIRECT study are the first to indicate that a fasting mimicking diet is safe and effective as an adjunct to chemotherapy in women with early breast cancer.1
The findings, published in Nature Communications, build upon preclinical evidence suggesting that fasting and FMDs prior to chemotherapymay have a beneficial effect on both the efficacy of a wide variety of cancer therapies and on the reduction of the side effects caused by various cancer treatments.
“This revelatory study on the benefits of a plant-based, Fasting Mimicking Diet during chemotherapy may represent a major breakthrough for women undergoing breast cancer treatments,” breast surgeon Kristi Funk, MD, former director of the Breast Center at Cedars-Sinai Medical Center, said in a press release.2″This study supports the concept that FMD creates the metabolic environment that supports chemo’s ability to destroy cancer cells while minimizing the collateral damage to normal cells. With an FMD, you get to eat, so you’re not too hangry, but your cells still respond as if you’re strictly fasting.
The main reason for non-adherence to the FMD was dislike of distinct components of the diet, perhaps induced by chemotherapy, the study authors wrote.
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Fmd Effects Stratified By Baseline Risk Factor Values: A Post Hoc Observational Pre
Age-related physiological changes that lead to increased risk factors occur before diseases can be diagnosed . We used the aggregated FMD data of both study arms and performed a post hoc analysis of the FMD effect on risk factors for CVD and metabolic syndrome, defined as three of five of the following conditions: abdominal obesity, elevated fasting glucose, elevated blood pressure, high serum triglycerides, and low HDL cholesterol . We selected clinically relevant cutoffs and compared normal and at-risk subjects for each risk factor: total cholesterol > 199 mg/dl and LDL cholesterol levels > 130 mg/dl are associated with an increased risk for CVD , a fasting glucose > 99 mg/dl indicates impaired fasting glucose/prediabetes , and triglyceride levels > 100 mg/dl as well as CRP > 1 mg/liter are associated with increased risk for CVD . For serum IGF-1, no clinically relevant risk level has been established, but a number of epidemiological studies have associated IGF-1 levels above 200 ng/ml with various cancers . We therefore compared the effect of FMD cycles on subjects in the highest quartile of IGF-1 expression with that on subjects with IGF-1 levels 225 ng/ml.
The Science Behind Fasting And Cancer
Weight loss is just one benefit of intermittent fasting for a normal healthy adult. Recent animal studies and a few preliminary human trials have shown a decrease in risk for cancer or a decrease in cancer growth rates. These studies indicate this may be due to the following effects from fasting:
- stem cells triggered to regenerate the immune system
- balanced nutritional intake
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Dietary Recommendations For People At High Risk For Cancer
People affected by pathologies may not do the FMD, unless they have the prior approval of their specialized doctor. In the case of serious or relatively serious illnesses , it is important to seek permission and approval from a disease specialist as well as from a dietitian with expertise in the FMD or in therapeutic fasting. The use of the FMD for disease treatment should for the moment be limited to clinical trials unless the doctor determines that there are no viable options and the patient cannot wait until the conclusion of appropriate clinical trials and FDA , and similar agencies in other countries, approval.
Editors Choice In Cancer
Triple-negative breast cancer is one of the most aggressive breast cancers because of its resistance to treatments. However, recentstudies have shown that fasting-mimicking dietswhich include roughly 50 percent fewer calories and reduced proteins and sugars compared to average dietscan slow tumor growth.
Giulia Salvadori, a postdoc at the FIRC Institute of Molecular Oncology in Italy, studied the mechanism behind how fasting affects tumors in biogerontologist Valter Longos lab. Their team experimented with cancer stem cells, both those cultured on nutrient-poor substrates and those in mice given a fasting-type diet. The results showed that lower glucose levels in the nutrient-poor conditions downregulated protein kinase A, an enzyme that promotes cancer cell growth and spread. This resulted in fewer and smaller tumors and longer mouse survival.
The study also examined retrospective data from 81 triple-negative breast cancer patients and found that lower blood glucose levels correlated with higher survival rates, though Longo notes the need for clinical trials to validate the effect. If the combination treatment was also successful in humans, Panda adds, researchers have to make a new drug discovery, but could instead use existing drugs to improve survival.
G. Salvadori et al., Fasting-mimicking diet blocks triple-negative breast cancer and cancer stem cell escape, Cell Metab, 33:224759, 2021.
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Vitamin C And Fasting
A combination of very high intravenous doses of vitamin C and a diet that mimics fasting may be an effective way to treat an aggressive type of cancer, a study in mice suggests. Unlike most cancer therapies, it is unlikely to be toxic for healthy tissue.
In the 1970s, when the Nobel prizewinning chemist Linus Pauling first proposed that high doses of intravenous vitamin C could treat cancer, people dismissed his idea as quackery.
But recent research suggests that he was onto something. A small 2017 clinical trial, for example, found that high doses of vitamin C in combination with radiotherapy and chemotherapy are well-tolerated and may prolong the survival of people with brain cancer.
Larger clinical trials investigating the combination of high dose vitamin C with these conventional cancer therapies are currently underway.
A study in mice now suggests that a diet that mimics the effects of fasting can enhance the ability of vitamin C to treat colorectal cancer while avoiding the need for chemotherapy or radiation therapy.
The research, which appears in
Why Fasting And Vitamin C Work Well In Tandem
The study also provided clues about why previous studies of vitamin C as a potential anticancer therapy showed limited efficacy. By itself, a vitamin C treatment appears to trigger the KRAS-mutated cells to protect cancer cells by increasing levels of ferritin, a protein that binds iron. But by reducing levels of ferritin, the scientists managed to increase vitamin Cs toxicity for the cancer cells. Amid this finding, the scientists also discovered that colorectal cancer patients with high levels of the iron-binding protein have a lower chance of survival.
In this study, we observed how fasting-mimicking diet cycles are able to increase the effect of pharmacological doses of vitamin C against KRAS-mutated cancers, said Maira Di Tano, a study co-author at the IFOM, FIRC Institute of Molecular Oncology in Milan. This occurs through the regulation of the levels of iron and of the molecular mechanisms involved in oxidative stress. The results particularly pointed to a gene that regulates iron levels: heme-oxygenase-1.
The research teams prior studies showed that fasting and a fasting-mimicking diet slow cancers progression and make chemotherapy more effective in tumor cells while protecting normal cells from chemotherapy-associated side effects. The combination enhances the immune systems anti-tumor response in breast cancer and melanoma mouse models.
The study was funded by Associazione Italiana Ricerca sul Cancro grant number 21820 and by NIA/NIH Grant # PO1 AG055369.
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How Can You Eat And Fast At The Same Time
Dr. Longo and his team at the Longevity Institute at The University of Southern California have been working with pathways in the body called nutrient-sensing pathways.
These pathways control something called autophagy-a type of housecleaning of our bodys cells. Autophagy is constantly going on in the body. It is the clean-up crew for all the processes in the cells of our body. Think of it as the garbage truck, taking away unwanted byproducts of cell activity. Every minute of the day cells are working and producing waste in the process. All this work produces junk that needs to be cleaned up. In comes the autophagy crew.
The cells in the body do everything to keep us alive such as breathing and making energy. The more clean-up that happens the better you feel and the less risk there is of health problems occurring in the future. The FMD speeds up autophagy . More autophagy is a good thing. Autophagy helps get rid of bad cells in the body that cause disease and promote aging.
The nutrient-sensing pathways are also involved in epigenetic expression. Epigenetics is how your genes are affected by the environment, i.e., why one person gets a disease but the other person with the same gene does not.
The diet increases cell clean-up
Dr. Longos team created a scientifically formulated diet that increases the housecleaning in your bodys cells. This is the ProLon Fasting Mimicking Diet.
Differential Stress Resistance: Increasing Chemotherapy Tolerability
Fig. 1 â£Differential stress resistance versus differential stress sensitization.
Chemotherapy acts on both cancer cells and normal cells, inducing tumour shrinkage but almost inevitably also causing side effects that can be severe or even life threatening because of the damage to many epithelial and non-epithelial tissues. On the basis of the available preclinical data, fasting or a fasting-mimicking diet could prove useful to separate the effects of chemotherapy, and possibly of newer cancer drugs, on normal versus cancer cells. Owing to the presence of oncogenic mutations that constitutively activate growth-promoting signalling cascades, cancer cells fail to properly adapt to starvation conditions. As a result, many types of cancer cells, but not normal cells, experience functional imbalances, becoming sensitized to toxic agents, including chemotherapy . Conversely, fasting or an FMD initiates an evolutionarily conserved molecular response that makes normal cells but not cancer cells more resistant to stressors, including chemotherapy . The predicted clinical translation of these differential effects of fasting or FMDs on normal versus cancer cells is a reduction in the side effects of cancer treatments, on the one hand, and improved tumour responses, patient progression-free survival and overall survival, on the other.
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