Immune System Regeneration
Ketone therapy offers potential as an immune system booster and as a possible cure for autoimmune disease (multiple sclerosis, diabetes type 1, rheumatoid arthritis, lupus, Hashimoto’s thyroiditis, etc.).
Immune Stem Cell Activation
The immune system involves a host of cells, biological structures, and processes that protect us from disease and ill health caused by microorganisms, parasites, toxic chemicals, and diseased cells (cancer). The workhorse of the immune system is the army of white blood cells that guard and constantly patrol the body, seeking out and destroying foreign invaders and diseased cells. Healthy immune function is vital to the health of the body and is what sweeps harmful substances out of our bodies. Our level of health depends a lot on the efficiency of our immune system. If the immune system is weakened by poor nutrition, physical or emotional stress, excessive exposure to disease-causing microbes and parasites, repeated contact with environmental and industrial toxins, a sedentary lifestyle, and other negative factors, it cannot do its job efficiently, and our health suffers. Infectious illnesses become more frequent and last longer, injuries take more time to heal, symptoms of premature aging develop, and chronic health problems arise. Boosting the efficiency of the immune system can reverse all this.
Therapeutic fasting has long been recognized as a useful tool in bolstering immune function. One of the ways fasting does this is by activating stem cells in the bone marrow to produce more white blood cells, thereby increasing the number of immune cells actively cleansing the body and stimulating repair and healing.
Stem cells are undifferentiated cells, meaning they are not bone cells, blood cells, brain cells, or any of the other specialized cells in the body. Once a cell has taken form, it can never change. A bone cell is a bone cell forever. Like all cells, stem cells contain the DNA, the blueprint, of the entire body, and with that blueprint they can transform into any cell type in the body. Adult stem cells exist throughout the body. They are found in the bone marrow, the brain, blood vessels, muscles, skin, and the liver. They remain in an inactive, nondividing state for years until activated by disease or tissue injury. In the bone marrow, stem cells are the seeds that form red blood cells, platelets, and the many types of white blood cells needed by the immune system.
Valtor Longo, PhD, and his research team at the University of Southern California have been studying the effects of fasting on various parameters of health. Instead of using a water fast, they generally use a very low-calorie, high-fat diet that mimics the effects of fasting, but still allows some calories and nutrients. Like the ketogenic diet, it significantly reduces blood sugar and insulin levels and shifts the body to burning fat and ketones in place of glucose.
Fasting has long been known to prevent and retard cancer growth. However, it hasn’t been used in combination with chemotherapy because of its weight-loss effect and lack of nutrition at a time when the body is in desperate need of nourishment to support immune function. Patients receiving chemotherapy are instructed to increase protein and calorie intake. Chemotherapy itself is very harsh on the body and causes significant collateral damage, including immune suppression by inducing DNA damage and cell death in both peripheral blood and bone marrow (disrupting stem cell development), which often results in long-term impairment to the immune system. Fasting during chemotherapy was believed to be unwise because it would add more stress to the body.
Longo found that short-term fasting before and just after undergoing chemotherapy could greatly reduce the side effects associated with the therapy. He showed that short-term fasting provided complete protection to mice against the side effects of high-dose chemotherapy.1 According to Longo, fasting causes cells to rapidly switch to a protected mode with changes in levels of glucose, IGF-1, protein kinase A (PKA), and many other proteins and molecules, protecting the cells from various toxins, including chemotherapy drugs. In animal research, he found that fasting for 48 hours or longer protects normal, healthy mammalian cells, but not cancer cells from chemotherapy. In a human clinical trial, he had a group of cancer patients go on short fasts before and then soon after undergoing chemotherapy. They were compared with another group of cancer patients who did not fast. The results showed that fasting was not only feasible and safe but caused a reduction in a wide range of reported side effects that included fatigue, weakness, hair loss, headaches, nausea, vomiting, diarrhea, abdominal cramps, mouth sores, dry mouth, short-term memory impairment, and numbness. There was no apparent decline in the effectiveness of the therapy, and it possibly may have improved its efficiency.2
During a fast or calorie restriction, the body cannibalizes itself to some extent, dismantling stored body fat and useless tissues; scientists call this autophagy.3 Body fat is broken down into fatty acids and ketones to provide the energy needs in the absence of glucose. Proteins from old, worn-out tissues, abnormal growths (skin tags, tumors, polyps, cysts, etc.), and scar tissue are broken down into amino acids, some of which are converted into glucose to supplement the energy derived from fat. During starvation or fasting, the body tears down or catabolizes the least important tissues first, preserving vital organs. As a consequence, nonessential tissues and muscles are catabolized in preference to more important tissues. In this manner, useless tissue is removed from the body. Some of the cells that are recycled are old, worn-out red and white blood cells.
“When you starve,” says Longo, “the system tries to save energy, and one of the things it can do to save energy is to recycle a lot of the immune cells that are not needed, especially those that may be damaged. What we started noticing in both our human work and animal work is that the white blood cell count goes down with prolonged fasting. Then when you re-feed, the blood cells come back. So we started thinking, ‘Well, where does it come from?’” What is the source of all of these new white blood cells?
Longo and colleagues began studying this question using what he termed “prolonged fasting,” which he defines as fasting for 48 to 120 hours (2 to 5 days). Their fast was actually a low-protein, high-fat modified fast that was limited to 750 to 1,100 calories per day. “Prolonged fasting forces the body to use stores of glucose, fat, and ketones,” says Longo, “but it also breaks down a significant portion of white blood cells.” Old, worn-out white blood cells are removed from circulation and recycled. “During each cycle of fasting, this depletion of white blood cells induces changes that trigger stem cell–based regeneration of new immune system cells.” Fasting lowers IGF-1 levels, a growth-factor hormone that Longo and others have linked to aging, tumor progression, and cancer risk. It also reduces the enzyme PKA, which needs to shut down in order for stem cells to switch into regenerative mode. “It gives the OK for stem cells to go ahead and begin proliferating and rebuild the entire [immune] system,” explains Longo.
Longo and his team proved that during chemotherapy, fasting can protect blood cells and bone marrow from harm. An immune system that is damaged or weakened by chemotherapy, aging, toxins, drugs, infection, or poor lifestyle choices can be overhauled and revitalized.4
“The body got rid of the parts of the system that might be damaged or old, the inefficient parts, during the fasting,” says Longo. “Now, if you start with a system heavily damaged by chemotherapy or aging, fasting cycles can generate, literally, a new immune system.” Longo recommends prolonged fasting for at least 5 consecutive days once every month to revitalize the immune system. His form of fasting is not a total water fast, but a very calorie-restricted high-fat diet. Longo calls it a fasting-mimicking diet.
The Ketogenic Diet and MCTs
This type of fasting produces the same metabolic changes as a ketogenic diet. A ketogenic diet is a very low-carb, high-fat diet that has proven to have many health benefits. Could a ketogenic diet have the same regenerative effect on the immune system? Researchers at ProMetic Life Sciences, Inc., a leading biopharmaceutical company in Canada, have found that consuming coconut oil derived medium chain triglycerides (MCTs) before chemotherapy also provides protection against the drug’s deleterious side effects. Like fasting, MCT consumption stimulates stem cells in bone marrow to produce white blood cells.5 The researchers claim that consuming a source of MCTs boosts immune cell production and provides extensive protection against hair loss, nausea, anemia, and other chemo side effects, without interfering with the therapeutic action of the treatment. The advantage of using MCTs in place of fasting is that the patients do not have to stop eating or change their diet in any way.
Apparently, there is something both fasting and consuming MCTs have in common that produces these identical effects. What is it? The answer is ketones. When MCTs are consumed, a large portion of them can potentially be converted directly into ketones. Ketones are a form of high-energy fuel that can take the place of glucose or fatty acids in the production of cellular energy. They provide much more energy than these other sources and activate many protective and health-promoting processes in the body, apparently including the conversion of bone marrow stem cells into white blood cells, enhancing immune function. Ketones can be generated by fasting or eating a low-carb calorie-restricted diet (such as Longo’s fasting mimicking diet), by eating coconut oil or MCT oil, or going on a ketogenic diet. Combining coconut oil/MCT oil with a ketogenic diet enhances ketone production. Therefore, a ketogenic diet could be expected to have the same immune-boosting, chemo-protective effect as Longo’s fasting-mimicking diet.
Since ketones can have a similar effect as fasting in promoting immune system regeneration, the ketogenic diet may be useful in treating immune system disorders, including autoimmune diseases, inflammatory diseases, and cancer. Common autoimmune diseases include Hashimoto’s thyroiditis, rheumatoid arthritis, type 1 diabetes, and systemic lupus erythematosus. Valter Longo suggests that short, 5-day fasts repeated monthly over a period of time could be remarkably effective for anyone with an autoimmune condition or whose immune system is deteriorating with age or poor health.
Newspaper columnist Jenni Russell says fasting transformed her life after conventional medicine had failed.6 “I have gone from being an exhausted person with a lifelong and incurable illness, kept alive by four drugs, to a currently healthy and energetic one,” says Russell. This remarkable difference was brought about by fasting.
“I tried fasting because I was desperate,” says Russell. “It’s been two decades since I developed a serious autoimmune condition which has often left me sleeping 12 hours a day and sometimes kept me in bed for months at a time.” Her condition was made worse by chemotherapy to treat cancer 5 years earlier. “I was told after that I could never live without immune-suppressing drugs; when I tried to, I was rushed to the hospital as an emergency admission and spent several days on drips.”
She didn’t like always using steroids, a common immunosuppressant, because of their side effects, even though she had been using them most of her life. She tried an intravenous drug that cost over $25,000 a year, but even that didn’t make her well. In addition, the drug was carcinogenic and had its own side effects. Russell decided she needed an alternative.
That’s when she learned about the fasting research of Valter Longo at USC. Studies on mice showed that intermittent fasting for as little as three days at a time caused their immune systems to regenerate. She figured she had nothing to lose by trying it, so she started her first short fast.
“I lasted two and a half days and thought nothing could come of it. On the fourth day I woke feeling better than I had in years. Since then I have fasted three more times, most recently for four days. It’s no fun. I couldn’t do it while working, or cooking for anyone else. You need to be free to crash out whenever your indignant body complains. You also need distractions to look forward to when you remember, gloomily, that there isn’t a meal ahead: books, films, the company of partners and friends.
“I only do it because the results have been so dramatic. I am off every drug and, for the first time since getting ill, I don’t have to ration my energy and time. I can’t know if it will last, but I have become a quiet evangelist. Fasting, as one doctor said recently, may be the panacea that Western medicine forgot.”
Multiple sclerosis (MS) is a potentially disabling autoimmune disorder that affects the brain and spinal cord. The immune system attacks the protective myelin sheath that covers nerve fibers, causing them to degenerate, disrupting communication between the brain and the rest of the body.
Drug therapy and dietary approaches to treating MS have been generally disappointing. For this reason, stem cell transplants are being investigated as a means to stop the progression of the disease. The treatment works best with younger patients with mild symptoms. The idea behind this approach is that the doctor can use the patients’ own stem cells to reboot the immune system to stop the advance of the disease. But the treatment can be risky because after a specimen of bone marrow is removed, the patient’s immune system has to be completely wiped out before the stem cells are transplanted back into the body. So far, only half of the patients who have received this treatment see any benefit, with a nearly 3 percent fatality rate. This is of concern because MS itself is not life-threatening.7 This is a case where the treatment is riskier than the disease.
Using stem cells to reboot the immune system is not a bad concept, but using transplants is. A far safer and effective approach is to use the body’s own powers of immune system rejuvenation. The fasting-mimicking diet can accomplish the same thing without the health risks.
“We started thinking, if it kills a lot of immune cells and turns on the stem cells, is it possible that maybe it will kill the bad ones and then generate new good ones?” says Longo. The effect would be similar to that of a stem cell transplant, but without the risks. That inspired him to start investigating a fasting-mimicking diet on MS. The results have been encouraging.
His initial study consisted of two parts: an animal trial and a human trial. In the first part of the study, the investigators put a group of mice with chemically induced multiple sclerosis on a fasting-mimicking diet for 3 days at a time, every 7 days for 30 days (3 cycles). A second group of treated mice were put on an unrestricted-calorie ketogenic diet for 30 days. A third group ate a standard diet for comparison. Results showed that both the fasting-mimicking and ketogenic diets reduced disease symptoms in all the mice and “caused complete recovery for 20 percent of the animals.” Complete recovery from MS in 30 days—remarkable!
It is interesting that they included the ketogenic diet in this study. It took the mice 10 days to get into ketosis, suggesting that the diet was only mildly ketogenic. For the first few days, while the mice were becoming fat-adapted, there was not much change in their symptoms, but by the end of the 30 days, the ketogenic diet showed similar effectiveness in reducing symptoms as the fasting-mimicking diet.
In addition to the reduction in symptoms, the researchers reported increased levels of the steroid hormone corticosterone, which is released by the adrenal glands to control metabolism. They also saw a reduction in the inflammation-causing cytokines. They also reported that the diets activated stem cells that resulted in regeneration of the myelin covering on the previously damaged nerve tissues.
“The fasting-mimicking diet kills bad immune cells,” says Longo. “Then, after the mice return to the normal diet, the good immune cells and also the myelin-producing cells are generated, allowing a percentage of mice to reach a disease-free state.”
The second part of the study conducted by a separate group of researchers at Markus Bock at Charité University Hospital in Berlin, checked the safety and potential efficacy of the fasting-mimicking diet and a ketogenic diet on 60 people who had MS.
The participants were divided into three groups. One group with 20 patients was placed on the fasting-mimicking diet for 7 days, then on a Mediterranean diet for 6 months. A second group of 20 patients was placed on a ketogenic diet for 6 months. The third group of 20 patients served as the control and ate their normal diet for 6 months. Those in the fasting-mimicking and ketogenic diets reported significant improvements in their quality of life and their physical and mental health. The researchers concluded that a “fasting-mimicking diet or a chronic ketogenic diet are safe, feasible, and potentially effective in the treatment of relapsing remitting multiple sclerosis patients.”8
An international team of researchers from the US, Canada, and China, not associated with Longo’s group, came to a similar conclusion. They investigated the effects of a ketogenic diet on memory impairment and central nervous system inflammation in mice that had chemically induced multiple sclerosis, just as in Longo’s study. Brain inflammation, memory and learning defects, oxidative stress, and the over-activation of the brain’s immune system were all attenuated by the ketogenic diet, providing further evidence that this type of diet can ease symptoms associated with MS.9
Longo’s team next focused on another autoimmune disease, type 1 diabetes, which affects the insulin-producing beta cells in the pancreas. In type 1 diabetes these cells are unable to produce insulin or produce a normal amount of insulin. It is an inherited condition that is normally identified early in life. Insulin injections are needed to make up for the insulin not produced by the body. In contrast, type 2 diabetes is an acquired condition usually brought on by poor diet and lifestyle choices and develops in adulthood. A type 2 diabetic will produce a normal amount of insulin during the early stages of the disease, but if the condition is not well managed, the disease can damage pancreatic insulin-producing cells. In this case, supplemental insulin would also be needed.
According to Longo, intermittent fasting using a fasting-mimicking diet can replace non-insulin-producing cells with new insulin-producing cells. His research team has regenerated insulin production in the pancreas of mice with late-stage type 1 and type 2 diabetes. They also examined pancreatic cell cultures from human donors and found that, in cells from type 1 diabetic patients, fasting increased insulin production.
In their study they administered high doses of the drug streptozotocin to mice—killing their pancreatic beta cells, producing the equivalent of type 1 diabetes. They also studied mice that had a genetic mutation that caused insulin resistance and type 2 diabetes that eventually stopped insulin production. In both types of diabetes the mice placed on the fasting-mimicking diet for 4 days each week for a period of time regained healthy insulin production, reduced insulin resistance, and demonstrated stable blood glucose levels. The fasting cycles switched on genes that activated pancreatic stem cells to form new insulin-producing beta cells.10
The ketogenic diet was designed specifically to mimic the therapeutic and metabolic effects of fasting. It appears to have the same effect as a modified fast in stimulating bone marrow stem cells and promoting self-renewal of the immune system. It might also do the same for intestinal stem cells, muscle stem cells, neural stem cells, and other stem cells.
The above article is an excerpt from the book Ketone Therapy: The Ketogenic Cleanse and Anti-Aging Diet by Bruce Fife, ND, published by Piccadilly Books, Ltd. 2017.
- Raffaghello, L., et al. Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc Natl Acad Sci USA 2008;105:8215-8220.
- Raffaghello, L., et al. Fasting and differential chemotherapy protection in patients. Cell Cycle 2010;9:4474-4476.
- Starokadomskyy, P. and Dmytruk, K.V. A bird’s-eye view of autophagy. Autophagy 2013;9:1121-1126.
- Cheng, C.W., et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell 2014;14:810-823.
- Medium-chain length fatty acids, glycerides and analogues as neutrophil survival and activation factors. https://patentscope.wipo.int/search/en/detail.jsf?docId=US43454871&redirectedID=true. Accessed 3/2/2017.
- Russell, J. Fasting transformed me after medicine failed. The Times, April 23, 2015.
- Muraro, P.A. et al. JAMA Neurol 2017 Feb 20. doi: 10.1001/jamaneurol.2016.5867.
- Choi, I.Y., et al. Diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms. Cell Rep 2016;15:2136-2146.
- Kim, D.Y., et al. Inflammation-mediated memory dysfunction and effeffects of a ketogenic diet in a murine model of multiple sclerosis. PloS One 7(5): e35476. doi:10.1371/journal.pone.0035476.
- Cheng, C.W., et al. Fasting-mimicking diet promotes Ngn3-driven beta-cell regeneration to reverse diabetes. Cell 2017;168:775-788.