The beneficial effects of prolonged fasting — fasting that lasts 48–120 hours — have been known for several years. One of these effects is the enhancement of the cellular resistance to toxins in both experimental animals and humans. A recent study (Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression) published in the journal Cell Stem Cell (June 5, 2014), shows that cycles of prolonged fasting protect against damage to the immune system and induces its regeneration, shifting hematopoietic stem cells from an inactive state to a state of self-renewal.
Stem cells are cells that have the ability to divide and develop into many different cell types in the body during early life and growth. Stem cells may also help repair the body by dividing to replenish cells that are damaged by disease, injury, or normal wear. When a stem cell divides, each new cell has the potential either to remain a stem cell or to become another type of cell with a more specialized function, such as a nerve cell, a skin cell, or a red blood cell.
Hematopoietic stem cells form all red cells, the white cells of the immune system, and others. They are ultimately responsible for the constant renewal of blood — the production of billions of new red and white cells each day. The study shows that, during prolonged fasting, the number of hematopoietic stem cells increases, while the number of the normally much more abundant white blood cells — which are the immune cells — decreases. Such decrease occurs because older and damaged immune cells die. Eventually, the stem cells generate new, healthy white blood cells. In mice treated with chemotherapy (which results in immunosuppression) or in old mice, cycles of fasting reverse the immunosuppression and immunosenescence, respectively. Cycles of fasting consist of periods of no food for two to four days at a time over the course of six months.
During each cycle of fasting, the depletion of white blood cells induces changes that trigger stem cell-based regeneration of new immune system cells. In particular, prolonged fasting reduces the enzyme PKA and also lowers the levels of IGF-1, a growth-factor hormone linked to aging, tumor progression and cancer risk.
Valter Longo, one of the researchers involved in the study, said in a press release “PKA is the key gene that needs to shut down in order for these stem cells to switch into regenerative mode. It gives the ‘okay’ for stem cells to go ahead and begin proliferating and rebuild the entire system. The good news is that the body got rid of the parts of the system that might be damaged or old, the inefficient parts, during the fasting. Now, if you start with a system heavily damaged by chemotherapy or aging, fasting cycles can generate, literally, a new immune system.”
Prolonged fasting also protected against toxicity in a pilot clinical trial in which a small group of patients fasted for a 72-hour period prior to chemotherapy. Tanya Dorff, another researcher involved in the study, said in the press release “While chemotherapy saves lives, it causes significant collateral damage to the immune system. The results of this study suggest that fasting may mitigate some of the harmful effects of chemotherapy. More clinical studies are needed, and any such dietary intervention should be undertaken only under the guidance of a physician.”
This article is a good insight especially for those who practice fasting for religious reasons. From reading this article, I can somewhat correlate fasting with undergoing a cleansing of the body and regeneration of immune system cells. Fasting and starving are often used interchangeably but I think it’s important to note the differences between starvation which is characterized as a chronic ie long term nutritional insufficiency and fasting which is short term. Fasting is also beneficial because unlike starvation most of the organs do not gradually decrease in size which shows the body’s ability to survive under conditions such as lack of food. It has also been shown that during fasting, inflammation is reduced but according to Fasting: Molecular Mechanisms and Clinical Applications it has been proven that unless that person immediately follows a vegetarian diet, the inflammation will return. I think an important future study is to look into how an individual’s body recovers from the fasting period and if there are any damages to other bodily functions as a result of undergoing fasting.
In response to your inquiry whether fasting can cause damage to bodily function, depends on whether the individual immune system is compromised or healthy or have an illness or not such as diabetes. The body uses glucose for fuel. Once that supply is depleted like what happens during fasting then it depends on amino acids from protein into glucose to supply brain with energy. The fat that is stored then turns into ketones to supply brain fuel… The body is basically eating away at itself. During cases of long-term fasting, the body determines that it is undergoing starvation. According to Owen et al. (1979) the metabolic profile is set to conserve protein and supply greater quantities of fuel, therefore using fatty acids for fuel. This is harmful to the body in the case of diabetes. According to the Mayo clinic, a person with diabetes who has a high level of ketone production in the blood causes the blood to become acidic and have no access to insulin (Mayo Clinic, 2014.) This acidity in the blood can lead to loss of consciousness, confusion, and altered mental status and if left untreated can become fatal into a coma.
Refrences:
Diabetic ketoacidosis. (2014) Retrieved from the web December 8, 2014 from http://www.mayoclinic.org/diseases-conditions/diabetic-ketoacidosis/basics/definition/con-20026470
Owen O.E., Reichard G.A. Jr, Patel M.S., Boden G..(1979) Energy Metabolism in feasting and fasting. Adv. Exp Med Biol. 111:169-88.
At first I was skeptical about why would fasting have to be immediately followed by a vegetarian diet until I read more of the article and read IU’s response to the original comment. It makes sense that protein restriction (PR) would force the body into a fasting state that utilizes glucose or stored fat but what mechanism actually improves immunity and resistance? A more recent study carries on the original article’s research to determine that the TSC complex is required in during PR to help with increasing insulin sensitivity and increase resistance to ischemic injury in hepatic cells. This implicates the TSC into allowing for increased utilization of glucose as well as strengthening the body to injury. This could be a reaction to evolutionary factors that made the human body become more efficient when resources were scarce. The added effect of resistance to injury is even more interesting in the fact that the body now uses resources to prevent injury. Further research into how and what signaling pathway that increases this resistance may help clinical patients strengthen their bodies before surgery.
It seems like that fasting had a broader research area because it linked to many biological metabolism phenomenon. One of the most research area is the connection between fasting and the lifespan. Although the research in this blog is about the regeneration of hematopoietic stem cell, I think such self-renew represent another type of prolongation of lifespan, because longevity means your organs are well as new as you were young. Previews review showed that from yeast to human, Dietary restriction (DR) increase lifespan in model organisms.
For example, In S. cerevisiae (yeast), starvation implemented by switching the cells from medium containing nutrients to water, will extend reproductive period and decrease DNA mutation and damage. Because yeast heavily rely on Tor-Sch9 and AC-PKA pathways, the two pathways can regulate life span by increasing cellular protection independently of their effect on extracellular carbon sources. In mice, mutations that cause decreased IGF-I receptor expression extends life span by 33% in female, and disruption of PKA or downstream of adenylyl cyclase, also causes life span extension. Fasting will protect mice in part by reducing serum IGF-I signaling. Similar fasting experiment which lead to the decrease of IGF-I or PKA can be seen in primate. Based on these previous research, some particular cells as hematopoietic stem cells may increase the renewal ability by reducing IGF-I/PKA.
This comment correlating fasting to extended lifespan reminded me of a discussion I had regarding caloric restriction linked to increased lifespan and anti-aging effects, in organisms ranging from yeast to Rhesus monkeys. Interestingly, the caloric restriction diet affects the same PKA pathway as fasting more specifically, the Ras/cAMP/PKA/Rim15/Msn2/4 pathway. A study by Wei et al. (2008) shows that the presence of Rim15 protein, a product downstream of Ras/PKA, was required to see the longevity effects in yeast from a caloric restriction diet, in that yeast deficient in this gene did not see as strong of longevity effects from the diet. This leads me to speculate that Rim15, among “other yet to be identified factors” may also be necessary to see the beneficial effects of fasting. Additionally, if the pathways affected by fasting are the same as those affected by a caloric restriction diet, I wonder if the caloric restriction diet is an overall better means to obtain the same health and wellness benefits seen with fasting. Abrupt changes in caloric intake through fasting may have detrimental effects on the body such as headaches, dizziness, irregular heart rate, and low blood pressure, whereas a continued lifestyle of caloric restriction causes less stress on the body while still achieving the health benefits.
As you said, like Rim15, there are some extra typical factors which related to fasting in particular species.
In C. elegans, Pha-4 together with the co-factor SMK-1, and SKN-1, are required for the response to dietary restriction. These three factors play a key role in metabolic homeostasis and induce the Phase II detoxification pathway, which directly increase lifespan. Fasting activity increased the expression of Pha-4, SMK-1 and SKN-1, thus increase lifespan.
In Drosophila, TOR and IIS are another important factors which related to the extension of lifespan. When increasing the food take, TOR can protect Drosophila against the shortening of lifespan. Meanwhile, reduced IIS plays a role in the response of lifespan to dietary restriction. Although this discussion is not about the relationship between fasting and immunological process, but it is very interesting to see the connection between fasting and the extension of lifespan.
That’s an interesting insight on how fasting can affect other parts of the body, it truly does span not only the immune system but the over life-span and health-span of individuals. I found an article that mentions how intermittent fasting as well as caloric restriction, that JLH mentioned above, can also have positive effects on brain aging and can help in the prevention of neurodegenerative diseases. Brain disorders due to aging have always been prominent, along with cancer and cardiovascular diseases. The bottom line always leads to questioning, how can we prevent and treat these diseases. The study review Caloric restriction and intermittent fasting: Two potential diets for successful brain aging shows that caloric restriction and fasting can positively affect the cellular stress response a well as protects neurons that can lead to brain aging due to environmental and genetic factors. Fasting and caloric restriction can be affiliated with pathways that increase protein production of chaperones, neurotrophic factors and antioxidant enzymes that have been known to help with diseases and stress factors. With this said, is fasting and caloric intake both needed for a healthier life, or can we really determine whether one is ultimately better than the other. It seems there are never ending factors such as age, health, efficiency of our immune system and even what kind of microbiota we have in our bodies, that can play a role in how well fasting or caloric restriction can affect each of us individually.
Intermittent fasting (IF) is a current diet trend that definitely has its pros and cons. As you have listed the many pros of intermittent fasting, there are some additional pros and cons aside from the ones already mentioned. One of the cons that I wanted to discuss is that likelihood of causing adrenal stress to the body. This study indicated that short term diet change can have an affect on circadian rhythms and cause hormonal imbalance. Effects on memory was also discussed in this particular study. It seems that IF has pros and cons that are almost equally weighed. Is this type of fasting only beneficial short term rather than over an extended period of time?
Hi Amina,
It’s interesting that you mention the cellular stress response because, for the longest time, we have thought that the resulting damage to cells from cellular stress was due to, at least in part, increased production reactive oxygen species (ROS) as a byproduct of metabolism. In fact, the entire free radical theory of aging is based on the premise that ROS cause undo harm to cellular structures thus leading to premature aging (this is also the reason for the boost in sales of “antioxidants”); however, in a perspective, published in the Journal of Medical Hypothesis from the School of Medicine at the University of Alabama, investigators found that an augmentation of ROS may actually precipitate most of the beneficial cellular alterations seen as a result of intermittent fasting and caloric restriction including those involving the immune system and inflammation. Specifically, ROS have been shown to generate crucial derivatives of certain prostaglandins that exert anti-inflammatory effects on macrophages. While the exact signal transduction pathway involved has not been elucidated, the authors propose this as an area of important research especially with the rise in atherosclerosis and heart disease.
I found an interesting article in which researchers conducted a trial to identify how fasting exactly affects our immune system host defenses in a negative or positive manner. These researchers wanted to examine if fasting has a uniform effect on the immune system, or if only parts of the immune system are affected. These researchers found a direct correlation between acute nutritional deprivation from fasting and the performance level of our immune system cells. The study was conducted with 15 obese subjects that fasted 14 days prior to the beginning of the trial. Immune system cell levels were measured both before and after the completion of the trial.
Researchers found an increase in both monocyte activity and natural killer cell activity. Killing by monocytic cells increased in 12 out of patients, while natural killer cell activity increased by 24% in 13 of the patients. In addition, researchers also saw an increase in immunoglobulin G, A, and M in serum concentrations of the subjects. The concentration of neutrophils, B cells, and T cells did not demonstrate a significant change before/after the 14-day fasting period.
These conclusions support the idea that fasting doesn’t have a uniform negative/positive effect on our immune system. I think an important point to address is if different forms of fasting has different effects on our immune system.
Reference:
Adibi, Siamak A., Stanko, Ronald T., Wing, Edward J., Winkelstein, Alan. (1983). Fasting-enhanced immune effector mechanisms in obese subjects. The American Journal of Medicine. 75(1): 91-96.
Fasting has been seen to improve the immune system through regenerating new immune cells to rid the body of old and damaged cells. Certain studies have also demonstrated that diets rich in vegetables and fruits also have an influence in the immune system, although mechanisms are still unable to be clearly understood. Fasting has the potential ability to regenerate a new immune system after it has been damaged or destroyed from aging or chemotherapy, and this process could possibly be enhanced by practicing a healthy diet following the period of caloric restriction. Studying dietary effects on the components of the immune system can prove to be very challenging for researchers, but more information becomes available due to the importance in understanding this. One study displayed that polyphenols, which are compounds found in fruits, vegetables and teas, have an effect on dendritic cell differentiation and maturation, which would be important to the inflammatory response. After a new immune system is created from fasting, the responses of this system need to be strictly regulated by dendritic cells. Another study suggests that polyphenols obtained from the diet can stimulate transcription of antioxidants as well as defense detoxification systems, which would also be important in strengthening the immune system. I think that combining the information available of both fasting and diet could have the potential to create effective immune systems in patients treated with chemotherapy.
Regulation of dendritic cell function by dietary polyphenols:
http://www-tandfonline-com.ezproxy.gsu.edu/doi/pdf/10.1080/10408398.2012.713046
Novel mechanisms of natural antioxidant compounds in biological systems: involvement of glutathione and glutathione-related enzymes
http://www.jnutbio.com/article/S0955-2863(05)00152-X/abstract
I am curious about other effects that fasting could have based on the age of the person undergoing this fasting and feeding process. For example, do the benefits outweigh the complications that could arise in an elderly person attempting fasting? A study on fasting and refeeding in young adults and the elderly was conducted that found elderly might have a reduction in immune function when undergoing this type of fasting. Elderly subjects exhibited a lowered T lymphocyte count. The researchers propose that this is due to aging of the thymus inhibiting the maturation of T cells. I would also consider the impact of malnutrition on children undergoing fasting and feeding. I would propose that the only group of people who would greatly benefit from fasting without negative effects would be healthy adults.
I agree with what you have said that elderly people and young children can have adverse health effects due to fasting. While researching the effects of fasting, I found a paper that tested glucose levels of pregnant women during the fasting month of Ramadan. A cross sectional study was performed on a 150 women from the United Arab Emirates, (76 during Ramadan and 74 after Ramadan), with normal pregnancies at a gestational age of 20-36 weeks. Glucose levels were measuring using the 1-hour postprandial glucose test before and 1-hour after a meal. Glucose levels were significantly higher in pregnant women after their meal than in non-pregnant women. In the 3rd trimester, pregnant women in general have an insulin level 50% higher than that of non-pregnant women thus resulting in a low glucose level during pregnancy. The researchers found during the month of Ramadan there was a higher rate of fetal loss, low birth weight and an increased frequency of neonate special care admission. This could be due to pregnant women restricting their diet which can lead to a higher risk of gestational diabetes mellitus and induction of labor as well as increases in her levels of corticotrophin-releasing factor, epinephrine, norepinephrine, and insulin secretions.
Reference:
Al Ketbi, Latifa Mohammad Baynouna, et al. “Diet Restriction In Ramadan And The Effect Of Fasting On Glucose Levels In Pregnancy.” BMC Research Notes 7.1 (2014): 2-11. Academic Search Complete. Web. 10 Dec. 2014.
What I find interesting about this article is the study on chemotherapy and fasting in mice. I wonder if this could be applied to cancer patients undergoing chemotherapy. Many of these patients that undergo chemotherapy suffer from nausea or loss of appetite after receiving treatment. This article makes me believe that maybe this side effect is maybe in part the body’s way to induce fasting in order to cause this regenerative process to occur. These patients experience so much nausea that a lot of times they do go without eating anything (unintentional fasting) for periods of time so maybe the body is undergoing this process. Also, since PKA plays a huge role in this process (its inhibition), I think therapeutic cancer studies should be focusing on strategies to inhibit PKA so that this process can occur even without fasting.
There’s actually been a study done back in 2010 Fasting and differential chemotherapy protection in patients where 10 patients were found to have decreased side effects from chemotherapy when their treatment was combined with a fasting cycle. So it is definitely something that can be done intentionally to withstand the effects of chemo. But it probably depends on how certain cancer patients can have efficiency like this, there are many factors in determining the right candidate since it won’t apply to everyone, especially seeing as only 10 patients could be tested there.
Another study done by a common researcher Fasting Cycles Retard Growth of Tumors and Sensitize a Range of Cancer Cell Types to Chemotherapy showed fasting to have impeded progression of tumor growth and helped in being effective against melanoma, glioma and breast cancer cells when combined with chemotherapy drugs. It was found that in 4T1 breast cancer cells, fasting and chemo lead to increased phosphorylation of stress-sensitizing Akt and S6 kinases, DNA damage and apoptosis. Therefore, fasting and chemo could potentially treat a wide range of cancers and someday replace certain chemotherapy treatment drugs for certain tumors. Though the mouse models did show long-term cancer survival when fasting and chemotherapy were performed, it is a speculation on whether this would be as effective when applied to humans someday.
This article actually is very impressing and surprising to me. The traditional culture of China also have fasting as a way to gain health. The theory behind fasting in old Chinese tradition is to remove toxins within bodies because it is inevitable to ingest chemicals that might be harmful to human body from daily meals. The whole process is usually around 1 week. The first 2-3 days are used to gradually decrease the food intake and the next 2-3 days are without food, but water is necessary. The last 2-3 days are used to gradually recover normal meal. Scientifically, studies have done showing that fasting could help increase the activity of NK cells and cytotoxic cells while the number of lymphocytes remain unchanged. The mechanism behind the increase of activity might be the process of hematopoietic stem cells differentiation initiated by fasting, which is the topic of the article.
Mr. Chen, your post inspired me to look more into the Chinese tradition of fasting that you mentioned. I have been looking into different forms of alternative medicine to better my health. After some research, I found a few articles that explained the benefits of Chinese fasting, referred to as Pi Gu. PiGu is a form of fasting that relies mainly on meditation. “According to [Traditional Chinese medicine], most disease is caused from intake of food through the mouth. This includes diet, virus, germ, and food pollution.” (Fredericks) Pi Gu has been used to reduce the side effects of stomach ulcers, diabetes, gallstones, and other illnesses within the body.
To tie this back to your comment and the article, I wonder why there has not been any research done to prove the efficiency of Pi Gu fasting. “In China, no one can explain how Pi Gu works. Science has a hard time understanding the effectiveness of Pi Gu…” If this form of fasting really regenerates the immune system, I would set up a study with 50 people that practice Pi Gu fasting, 50 people that fast according to other theories, and 50 people that do not fast at all (a control group) and observe how quick their immune cells respond to an extracellular pathogen. Also, the levels of PKA (and IGF-1) should be studied in the same groups of people to determine if Pi Gu reduces really reduces cancer risks, and tumor progression.
I really like this research idea of yours because it can show how fasting effects the immune system. However, for the 50 people that will be fasting according to other theories seems a bit vague. In my opinion what you are trying to carry out is something similar to a clinical trial. The US Department of Veterans Affairs defines a clinical trial to be a type of research to see the effectiveness of a type of medical device or therapy. The experimental groups are well established and in your case compared to a control group. However, in your case of the 50 people that are going to be fasting according to other theories should be more specific. There are multiple ways of fasting and for a good study to be carried out; the experimental groups should directly state exactly what type of fasting they would be doing. Overall, I think this is a great approach to really see how different techniques of fasting really affect the levels of PKA and the generation of new immune cells.
http://www.va.gov/ORO/Basic_Research_Requirements.asp
Thank you for your thoughtful insights.