Benefits and Risks of Fasts & Caloric Restriction: Mechanisms and Application

 

FASTING

 

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Rhonda…rogan

Researchers at MIT, the Duke University School of Medicine and the Whitehead Institute for Biomedical Research in Cambridge recently published a short article in Cell Stem Cell revealing that part of this puzzle may be fatty acid oxidation inside of our mitochondria. Omer H. Yilmaz and colleagues found that a 24-hour fast in mice induces fat breakdown in intestinal stem and progenitor cells. This fatty acid oxidation appears to in turn improve the function of stem cells, even in aged mice.

Volume 22, Issue 5, 3 May 2018, Pages 769-778.e4

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Short Article

Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging

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Maria M.Mihaylova1231112Chia-WeiCheng2312Amanda Q.Cao1231113SuryaTripathi213Miyeko D.Mana23Khristian E.Bauer-Rowe23MontherAbu-Remaileh12311LauraClavain12311AysegulErdemir210Caroline A.Lewis1ElizavetaFreinkman1Audrey S.Dickey4Albert R.La Spada4YanmeiHuang1George W.Bell1VikramDeshpande5PeterCarmeliet67PekkaKatajisto89…Ömer H.Yilmaz2351415

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https://doi.org/10.1016/j.stem.2018.04.001

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Referred to by

Derek A.G. Barisas, Thaddeus S. Stappenbeck

Intestinal Stem Cells Live Off the Fat of the Land

Cell Stem Cell, Volume 22, Issue 5, 3 May 2018, Pages 611-612

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Highlights

Fasting induces fatty acid oxidation (FAO) in intestinal stem and progenitor cells

Aging reduces ISC numbers and function, correlating with decreased FAO

PPAR/CPT1a-mediated FAO augments ISC function in aging and during regeneration

PPARδ agonists boost and restore ISC and progenitor function in young and old age

Summary

Diet has a profound effect on tissue regeneration in diverse organisms, and low caloric states such as intermittent fasting have beneficial effects on organismal health and age-associated loss of tissue function. The role of adult stem and progenitor cells in responding to short-term fasting and whether such responses improve regeneration are not well studied. Here we show that a 24 hr fast augments intestinal stem cell (ISC) function in young and aged mice by inducing a fatty acid oxidation (FAO) program and that pharmacological activation of this program mimics many effects of fasting.

Acute genetic disruption of Cpt1a, the rate-limiting enzyme in FAO, abrogates ISC-enhancing effects of fasting, but long-term Cpt1a deletion decreases ISC numbers and function, implicating a role for FAO in ISC maintenance.

These findings highlight a role for FAO in mediating pro-regenerative effects of fasting in intestinal biology, and they may represent a viable strategy for enhancing intestinal regeneration.

Graphical Abstract

Mechanism cellular

But researchers have yet to nail down the cellular mechanisms of how caloric restriction or fasting interventions lead to tissue regeneration, particularly through stem cell activity. To answer this outstanding question, Yilmaz and colleagues fasted mice for 24 hours to study how the fasted state impacts intestinal stem cells. They found that a single fast augments intestinal stem cell function in both young and aged mice, by boosting fat metabolism. It appears that using fats for energy preserves the health and function of intestinal stem cells, and that the ability to break down and use fats for energy is impaired in older individuals — unless they fast.

“Acute fasting regimens have pro-longevity and regenerative effects in diverse species, and they may represent a dietary approach to enhance aged stem cell activity in tissues.” — Cell Stem Cell, 2018

“Our results were quite surprising — a single 24-hour fast dramatically improved the function of stem cells regardless of age,” Yilmaz said. “We saw an improvement in stem cell function in young mice that were fasted, but more importantly a dramatic improvement in stem cell function in aged mice that were fasted.”

Yilmaz and colleagues also found that if they damaged the intestines of mice, the fasted mice’s intestines recovered much more quickly than mice fed ad libitum.

Discussion

Keto diets have been used clinically to treat patients with seizures and related disorders for decades. Improvements in neurological symptoms that accompany keto diets and intermittent fasting have been associated with ketone bodies produced during the metabolism of fats and their use as an energy source in the brain. But it’s not clear exactly how fatty acid oxidation contributes to rejuvenation in other tissues in response to fasting.

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Fasting has also been associated with cellular turnover through autophagy or the dying off of aged, senescent cells that are damaged and can no longer divide. By selectively targeting senescent cells, fasting may improve tissue function such as that seen in the fasted mice’s intestines. However, Yilmaz says, a 24-hour fast for a mouse is short in the grand scheme of things. It’s unlikely that the observed improvement inintestinal tissue and stem cell function within that time frame would be primarily due to a clearing out of damaged, pro-inflammatory senescent cells.

“We think we are improving the quality of the existing stem cells, rather than generating new stem cells under these conditions,” Yilmaz said. “But with these types of interventions, there’s never one simple answer. Autophagy or the clearing out of senescent stem cells could be contributing to this improvement. However, we didn’t see any significant increase in cell death of intestinal stem cells in our fasted mice.”

If, as Yilmaz suspects, fasting is able to improve the function of existing intestinal stem cells in mice through fat metabolism, then the mitochondria in these cells, the “energy powerhouses” responsible for producing cellular energy, are key players. Fat metabolism occurs in mitochondria, where fat that enters the cell is immediately shuttled for breakdown and “burning.” Impaired energy production as a result of aging and dysfunctional mitochondria might be a reason why human brains are susceptible to age-related diseases — and why fasting and fatty acid oxidation have been associated with cognitive improvements

PS

For example, fasting is contraindicated for Type 1 diabetics, pregnant women, and other individuals suffering from malnutrition or muscle wasting. Yilmaz is investigating whether some of the metabolic benefits of fasting might be activated synthetically, or with drugs that drive fatty acid oxidation.

Ketone supplementation, on the other hand, may be tricky. Most ketones supplements are likely to be unstable in the bloodstream, Yilmaz says. If you take ketones artificially, you’ll probably end up peeing most of them out within a short period, he says. We likely need more research in this area to justify ketone supplementation as an alternative to or driving of fasting benefits. The drug Yilmaz used to reproduce the metabolic health and intestinal tissue function benefits of fasting in mice actually turns on or activates genes that ultimately help break down fat. However, there ar

 

Mech

 

  • AMPK and DR maintain mitochondrial network homeostasis with age

    Mitochondrial fusion and fission are required for DR- and AMPK-mediated longevity

    Preserving mitochondrial homeostasis increases lifespan via fatty acid oxidation

    These longevity pathways require coordination between mitochondria and peroxisomes

Summary

Mitochondrial network remodeling between fused and fragmented states facilitates mitophagy, interaction with other organelles, and metabolic flexibility. Aging is associated with a loss of mitochondrial network homeostasis, but cellular processes causally linking these changes to organismal senescence remain unclear. Here, we show that AMP-activated protein kinase (AMPK) and dietary restriction (DR) promote longevity in C. elegans via maintaining mitochondrial network homeostasis and functional coordination with peroxisomes to increase fatty acid oxidation (FAO). Inhibiting fusion or fission specifically blocks AMPK- and DR-mediated longevity. Strikingly, however, preserving mitochondrial network homeostasis during aging by co-inhibition of fusion and fission is sufficient itself to increase lifespan, while dynamic network remodeling is required for intermittent fasting-mediated longevity. Finally, we show that increasing lifespan via maintaining mitochondrial network homeostasis requires FAO and peroxisomal function. Together, these data demonstrate that mechanisms that promote mitochondrial homeostasis and plasticity can be targeted to promote healthy aging.

https://www.cell.com/cell-metabolism/fulltext/S1550-4131%2817%2930612-5

 

 

 

In humans, depending upon their level of physical activity, 12 to 24 hours of fasting typically results in a 20% or greater decrease in serum glucose and depletion of the hepatic glycogen, accompanied by a switch to a metabolic mode in which non-hepatic glucose, fat-derived ketone bodies and free fatty acids are used as energy sources (Figures 2 and

and3).

3). 

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Introduction

In humans, fasting is achieved by ingesting no or minimal amounts of food and caloric beverages for periods that typically range from 12 hours to three weeks. Many religious groups incorporate periods of fasting into their rituals including Muslims who fast from dawn until dusk during the month of Ramadan, and Christians, Jews, Buddhists and Hindus who traditionally fast on designated days of the week or calendar year. In many clinics, patients are now monitored by physicians while undergoing water only or very low calorie (less than 200 kcal/day) fasting periods lasting from 1 week or longer for weight management, and for disease prevention and treatment. Fasting is distinct from caloric restriction (CR) in which the daily caloric intake is reduced chronically by 20–40%, but meal frequency is maintained. Starvation is instead a chronic nutritional insufficiency that is commonly used as a substitute for the word fasting, particularly in lower eukaryotes, but that is also used to define extreme forms of fasting, which can result in degeneration and death. 

We now know that fasting results in ketogenesis, promotes potent changes in metabolic pathways and cellular processes such as stress resistance, lipolysis and autophagy, and can have medical applications that in some cases are as effective as those of approved drugs such as the dampening of seizures and seizure-associated brain damage and the amelioration of rheumatoid arthritis (Bruce-Keller et al., 1999; Hartman et al., 2012; Muller et al., 2001). 

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In humans, depending upon their level of physical activity, 12 to 24 hours of fasting typically results in a 20% or greater decrease in serum glucose and depletion of the hepatic glycogen, accompanied by a switch to a metabolic mode in which non-hepatic glucose, fat-derived ketone bodies and free fatty acids are used as energy sources (Figures 2 and

and3).

3). 

Whereas most tissues can utilize fatty acids for energy, during prolonged periods of fasting, the brain relies on the ketone bodies β-hydroxybutyrate and acetoacetate in addition to glucose for energy consumption (Figure 3B). Ketone bodies are produced in hepatocytes from the acetyl-CoA generated from β oxidation of fatty acids released into the bloodstream by adipocytes, and also by the conversion of ketogenic amino acids. After hepatic glycogen depletion, ketone bodies, fat-derived glycerol, and amino acids account for the gluconeogenesis-dependent generation of approximately 80 grams/day of glucose, which is mostly utilized by the brain. Depending on body weight and composition, the ketone bodies, free fatty acids and gluconeogenesis allow the majority of human beings to survive 30 or more days in the absence of any food and allow certain species, such as king penguins, to survive for over 5 months without food (Eichhorn et al., 2011) (Figure 3C).

 In humans, during prolonged fasting, the plasma levels of 3-β-hydroxybutyrate are about 5 times those of free fatty acids and acetoacetic acid (Figure 3A and 3B). The brain and other organs utilize ketone bodies in a process termed ketolysis, in which acetoacetic acid and 3-β-hydroxybutyrate are converted into acetoacetyl-CoA and then acetyl-CoA. These metabolic adaptations to fasting in mammals are reminiscent of those described earlier for E. coli and yeast, in which acetic acid accumulates in response to food deprivation (Gonidakis et al., 2010; Longo et al., 2012). In yeast, 

 

The most extensively investigated IF method in animal studies of aging has been alternate day fasting (food is withdrawn for 24 hours on alternate days, with water provided ad libitum) (Varady and Hellerstein, 2007). The magnitude of the effects of alternate day fasting on longevity in rodents depends upon the species and age at regimen initiation, and can range from a negative effect to as much as an 80% lifespan extension (Arum et al., 2009; Goodrick et al., 1990). IF every other day extended the lifespan of rats more than fasting every 3rd or 4th day (Carlson and Hoelzel, 1946). Fasting for 24 hours twice weekly throughout adult life resulted in a significant increase in lifespan of black-hooded rats (Kendrick, 1973). In rats, the combination of alternate day fasting and treadmill exercise resulted in greater maintenance of muscle mass than did IF or exercise alone (Sakamoto and Grunewald, 1987). Interestingly, when rats were maintained for 10 weeks on a PF diet in which they fasted 3 consecutive days each week, they were less prone to hypoglycemia during 2 hours of strenuous swimming exercise as a result of their accumulation of larger intramuscular stores of glycogen and triglycerides (Favier and Koubi, 1988). Several major physiological responses to fasting are similar to those caused by regular aerobic exercise including increased insulin sensitivity and cellular stress resistance, reduced resting blood pressure and heart rate, and increased heart rate variability as a result of increased parasympathetic tone (Figure 2) (Anson et al., 2003; Mager et al., 2006; Wan et al., 2003). Emerging findings suggest that exercise and IF retard aging and some age-related diseases by shared mechanisms involving improved cellular stress adaptation (Stranahan and Mattson, 2012)

 

Cancer

Fasting and cancer

Fasting can have positive effects in cancer prevention and treatment. In mice, alternate day fasting caused a major reduction in the incidence of lymphomas (Descamps et al., 2005) and fasting for 1 day per week delayed spontaneous tumorigenesis in p53-deficient mice (Berrigan et al., 2002). However, the major decrease in glucose, insulin and IGF-1 caused by fasting, which is accompanied by cell death and/or atrophy in a wide range of tissues and organs including the liver and kidneys, is followed by a period of abnormally high cellular proliferation in these tissues driven in part by the replenishment of growth factors during refeeding. 

When combined with carcinogens during refeeding, this increased proliferative activity can actually increase carcinogenesis and/or pre-cancerous lesions in tissues including liver and colon (Tessitore et al., 1996). Although these studies underline the need for an in depth understanding of its mechanisms of action, fasting is expected to have cancer preventive effects as indicated by the studies above and by the findings that multiple cycles of periodic fasting can be as effective as toxic chemotherapy in the treatment of some cancers in mice (Lee et al., 2012).

In the treatment of cancer, fasting has been shown to have more consistent and positive effects. PF for 2–3 days was shown to protect mice from a variety of chemotherapy drugs, an effect called differential stress resistance (DSR) to reflect the inability of cancer cells to become protected based on the role of oncogenes in negatively regulating stress resistance, thus rendering cancer cells, by definition, unable to become protected in response to fasting conditions (Figure 5) (Raffaghello et al., 2008). PF also causes a major sensitization of various cancer cells to chemo-treatment, since it fosters an extreme environment in combination with the stress conditions caused by chemotherapy. In contrast to the protected state entered by normal cells during fasting, cancer cells are unable to adapt, a phenomenon called differential stress sensitization (DSS), based on the notion that most mutations are deleterious and that the many mutations accumulated in cancer cells promote growth under standard conditions but render them much less effective in adapting to extreme environments (Lee et al., 2012). In mouse models of metastatic tumors, combinations of fasting and chemotherapy that cause DSR and DSS, result in 20 to 60% cancer-free survival compared to the same levels of chemotherapy or fasting alone, which are not sufficient to cause any cancer-free survival (Lee et al., 2012; Shi et al., 2012). Thus, the idea that cancer could be treated with weeks of fasting alone, made popular decades ago, may be only partially true, at least for some type of cancers, but is expected to be ineffective for other types of cancers. The efficacy of long-term fasting alone (2 weeks or longer) in cancer treatment will need to be tested in carefully designed clinical trials in which side effects including malnourishment and possibly a weakened immune system and increased susceptibility to certain infections are carefully monitored. By contrast, animal data from multiple laboratories indicate that the combination of fasting cycles with chemotherapy is highly and consistently effective in enhancing chemotherapeutic index and has high translation potential. A number of ongoing trials should soon begin to determine the efficacy of fasting in enhancing cancer treatment in the clinic.

 

 

Fasting and Senescence

 

Fasting, aging, and disease in humans

Fasting and factors implicated in aging

Clinical and epidemiological data are consistent wit h an ability of fasting to retard the aging process and associated diseases. Major factors implicated in aging whose generation are accelerated by gluttonous lifestyles and slowed by energy restriction in humans include: 1) oxidative damage to proteins, DNA and lipids; 2) inflammation; 3) accumulation of dysfunctional proteins and organelles; and 4) elevated glucose, insulin and IGF-I, although IGF-1decreases with aging and its severe deficiency can be associated with certain pathologies (Bishop et al., 2010; Fontana and Klein, 2007). Serum markers of oxidative damage and inflammation as well as clinical symptoms are reduced over a period of 2–4 weeks in asthma patients maintained on an alternate day fasting diet (Johnson et al., 2007). Similarly, when on a 2 days/week fasting diet overweight women at risk for breast cancer exhibited reduced oxidative stress and inflammation (Harvie et al., 2011) and elderly men exhibited reductions in body weight and body fat, and improved mood (Teng et al., 2011). Additional effects of fasting in human cells that can be considered as potentially ‘anti-aging’ are inhibition the mTOR pathway, stimulation of autophagy and ketogenesis (Harvie et al., 2011; Sengupta et al., 2010).

Among the major effects of fasting relevant to aging and diseases are changes in the levels of IGF-1, IGFBP1, glucose, and insulin. Fasting for 3 or more days causes a 30% or more decrease in circulating insulin and glucose, as well as rapid decline in the levels of insulin-like growth factor 1 (IGF-1), the major growth factor in mammals, which together with insulin is associated with accelerated aging and cancer (Fontana et al., 2010). In humans, five days of fasting causes an over 60% decrease in IGF-1and a 5-fold or higher increase in one of the principal IGF-1-inhibiting proteins: IGFBP1 (Thissen et al., 1994a). This effect of fasting on IGF-1is mostly due to protein restriction, and particularly to the restriction of essential amino acids, but is also supported by calorie restriction since the decrease in insulin levels during fasting promotes reduction in IGF-1(Thissen et al., 1994a). Notably, in humans, chronic calorie restriction does not lead to a decrease in IGF-1unless combined with protein restriction (Fontana et al., 2008).

KEY PROTINE

IF can be achieved in with a minimal decrease in overall calorie intake if the refeeding period in which subjects overeat is considered. Thus, fasting cycles provide a much more feasible strategy to achieve the beneficial effects of CR, and possibly stronger effects, without the burden of chronic underfeeding and some of the potentially adverse effects associated with weight loss or very low BMIs. In fact, subjects who are moderately overweight (BMI of 25–30) in later life can have reduced overall mortality risk compared to subjects of normal weight (Flegal et al., 2013). Although these results may be affected by the presence of many existing or developing pathologies in the low weight control group, they underline the necessity to differentiate between young individuals and elderly individuals who may use CR or fasting to reduce weight or delay aging. Although extreme dietary interventions during old age may continue to protect from age-related diseases, they could have detrimental effects on the immune system and the ability to respond to certain infectious diseases, wounds and other challenges (Kristan, 2008; Reed et al., 1996). However, IF or PF designed to avoid weight loss and maximize nourishment have the potential to have beneficial effects on infectious diseases, wounds and other insults even in the very old. Nourishment of subjects can be achieved by complementing IF or PF with micro- and macro Studies to test the effect of IF or PF regimens on markers of aging, cancer, cognition and obesity are in progress (V. Longo and M. Mattson).

 

 

 

 

Mechanisms of fasting

The scientists used C. elegans (nematode worms), which live just two weeks and thus enable the study of aging in real time in the lab. Mitochondrial networks inside cells typically toggle between fused and fragmented states. The researchers found that restricting the worms’ diet, or mimicking dietary restriction through genetic manipulation of an energy-sensing protein called AMP-activated protein kinase (AMPK), maintained the mitochondrial networks in a fused or “youthful” state. In addition, they found that these youthful networks increased lifespan by communicating with organelles called peroxisomes to modulate fat metabolism.

Harvard study shows how intermittent fasting and manipulating mitochondrial networks may increase lifespan

BY Karen Feldscher

Harvard Chan School Communications

DATENovember 3, 2017

TRENDING

Manipulating mitochondrial networks inside cells — either by dietary restriction or by genetic manipulation that mimics it — may increase lifespan and promote health, according to new research from Harvard T.H. Chan School of Public Health.

The study, published Oct. 26 online in Cell Metabolism, sheds light on the basic biology involved in cells’ declining ability to process energy over time, which leads to aging and age-related disease, and how interventions such as periods of fasting might promote healthy aging.

Mitochondria — the energy-producing structures in cells — exist in networks that dynamically change shape according to energy demand. Their capacity to do so declines with age, but the impact this has on metabolism and cellular function was previously unclear. In this study, the researchers showed a causal link between dynamic changes in the shapes of mitochondrial networks and longevity.

 

 

 

Long-term fasting can take several different forms. The most extreme is a “dry fast,” consuming nothing at all (food or water). This is definitely not advisable, as it’s very dangerous to go for more than a day or so without drinking. Water fasting means drinking only water, but consuming no calories during the fast. Another technique is juice fasting, or consuming only fruit and vegetable juices. Some people also fast on broth, or extremely low-calorie protein mixes.

Juice fasting and bone broth fasting aren’t truly fasts, since they do involve some intake of calories and nutrients. And protein fasts can be downright dangerous, since humans just weren’t built to live on protein with no accompanying fat. This article focuses on water fasting: the benefits, the drawbacks, and precautions to take if you do decide to start a longer fast.

Long Fasts and Weight Loss

The most obvious and best-researched benefits of longer fasts are for weight loss: if you’re not eating anything, weight will drop off your body fairly quickly. During the first 24 hours or so, you go through all the glycogen in your liver. After that, your body needs to run on what it has stored, either protein or fat.

For the first few days, weight loss averages around 1-2 pounds a day, both because you’re shedding water weight and because you’re using more protein. But consuming protein for fuel is risky, because it means breaking down muscles – not only your biceps, but also more essential muscles like your heart. This makes fat by far a preferential energy source, so after a few days, your body turns to its stored fat reserves for energy (ketosis). Since fat is more energy-dense per pound than protein, weight loss during this phase slows down to a more reasonable but still rapid pace of a little over 1 pound every 2 days.

Essentially, then, a long fast is a way of staying in ketosis for an extended period of time, but forcing your body to rely entirely on its own fat stores instead of dietary fat intake. Being in ketosis makes for fairly easy weight loss, since it suppresses hunger (once you get through the first few days, which are always rough). Fasting also allows you to completely get your mind off food, instead of always thinking about what you’re going to eat next and worrying about whether or not you’re eating too much.

Long fasting is an effective way to lose a lot of weight quickly, but with a significant caveat: many people proceed to gain it all back again, because they just go back to their old obesogenic diet right afterwards. Like any other “crash diet,” fasting will help you lose weight, but won’t help you keep it off unless you also make a long-term change in your diet after the fast is over. One study in obese patients who lost weight during 2 weeks of fasting found that 50% of their 46 patients either did not respond to the hospital’s attempts to contact them (which the researchers took as a sign they’d regained the weight) or responded saying they’d regained all the lost weight after 2 years.

Long Fasts: Other Benefits

In addition to weight loss, fasting also promotes autophagy, which is like a “spring cleaning” for your cells. Since your body is essentially eating itself, it has a chance to get rid of any junk or waste material that may have built up, and repair the damage of oxidative stress. This is one of the biggest benefits of fasting even for people who are already at a healthy weight, since it has powerful anti-aging and muscle-building properties.

One study also found that an extended fast (10 days on average) was beneficial to patients with hypertension, also noting that even though the patients didn’t embark on the fast to lose weight, all of them did – average weight loss was around 15 pounds. Longer term fasting (up to 5 days) may also have some benefits for chemotherapy patients.

Another benefit of extended fasting is purely mental: for many fasters, it’s a way to “re-set” their relationship with food, break free from patterns of emotional eating, or start fresh at the end of the fast. Fasting is part of many religious and spiritual practices because of its value for meditation and mindfulness. Bear in mind that this doesn’t happen automatically: it requires a high level of self-awareness and effort on the part of the faster. It’s a very useful tool, but it’s not a miracle cure.

Long Fasts: Dangers and Drawbacks

The ultimate risk of fasting, of course, is death by starvation; this doesn’t usually happen to people fasting for medical reasons, but taking anything to extremes is perilous. In Ireland in 1981, for example, 10 political prisoners starved themselves to death in a hunger strike against the British government, fasting between 46 and 73 days before they died.

Even fasts of a few weeks or less can have dangerous consequences. Fasting puts two different types of stress on your heart. First, it cannibalizes cardiac muscle for fuel. The human body does everything it can to conserve muscle during a fast, but inevitably some muscle will be sacrificed at the beginning of the fast. After a few days, the body switches over to using fat, but researchers have discovered that protein (muscle) utilization actually increases again later on, even though fat stores are still available. This protein includes the muscle in your heart: weaken this too much, and heart failure will result.

Strict water fasting is also a risk for heart failure because during a fast, the body’s intracellular stores of minerals vital for cardiac function, like magnesium and potassium, are depleted, even though serum levels remain normal. The results of this cardiac muscle loss and mineral deprivation can be tragic. During the 1950s and 60s, fasting was used as an experimental treatment for obesity, and several patients died (many from heart failure). Other reports of people dying during long fasts include more cases of heart failure. More recently, in 2010, a woman in Florida died after 21 days of fasting.

Other fasters die of infectious diseases that they simply don’t have the energy to fight off without adequate nutrition. In 1978, for example, a man named William Carlton died of pneumonia at a fasting center after fasting for 29 days in an attempt to cure his ulcerative colitis. He was 49 years old, and in normal health other than the colitis. Worldwide, infectious diseases are actually the most common cause of death among starving people, because an immune system weakened by malnutrition tends to give in before heart problems start to show. This is particularly common among children who go on (or are forced to go on) long fasts.

Of course, many people also fast safely, but it’s worth noting that fasting isn’t a risk-free experiment. Less serious drawbacks also include intense mood swings, low energy, and irritability. Fasting lowers blood pressure, so you may feel weak, dizzy, or nauseous during the fast. It raises levels of the stress hormones norepinephrine and cortisol, probably an adaptation to give you more energy for finding food, but not beneficial for optimum health.

 

Another potential downside of long-term fasting is the rate of detox.

 

In Ireland in 1981, for example, 10 political prisoners starved themselves to death in a hunger strike against the British government, fasting between 46 and 73 days before they died.

Even fasts of a few weeks or less can have dangerous consequences. Fasting puts two different types of stress on your heart. First, it cannibalizes cardiac muscle for fuel. The human body does everything it can to conserve muscle during a fast, but inevitably some muscle will be sacrificed at the beginning of the fast. After a few days, the body switches over to using fat, but researchers have discovered that protein (muscle) utilization actually increases again later on, even though fat stores are still available. This protein includes the muscle in your heart: weaken this too much, and heart failure will result.

Strict water fasting is also a risk for heart failure because during a fast, the body’s intracellular stores of minerals vital for cardiac function, like magnesium and potassium, are depleted, even though serum levels remain normal. The results of this cardiac muscle loss and mineral deprivation can be tragic. During the 1950s and 60s, fasting was used as an experimental treatment for obesity, and several patients died (many from heart failure). Other reports of people dying during long fasts include more cases of heart failure. More recently, in 2010, a woman in Florida died after 21 days of fasting.

Other fasters die of infectious diseases that they simply don’t have the energy to fight off without adequate nutrition. In 1978, for example, a man named William Carlton died of pneumonia at a fasting center after fasting for 29 days in an attempt to cure his ulcerative colitis. He was 49 years old, and in normal health other than the colitis. Worldwide, infectious diseases are actually the most common cause of death among starving people, because an immune system weakened by malnutrition tends to give in before heart problems start to show. This is particularly common among children who go on (or are forced to go on) long fasts.

Of course, many people also fast safely, but it’s worth noting that fasting isn’t a risk-free experiment. Less serious drawbacks also include intense mood swings, low energy, and irritability. Fasting lowers blood pressure, so you may feel weak, dizzy, or nauseous during the fast. It raises levels of the stress hormones norepinephrine and cortisol, probably an adaptation to give you more energy for finding food, but not beneficial for optimum health.

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Another potential downside of long-term fasting is the rate of detox. Fat is your body’s storage organ for everything, including any toxins that may have accumulated over the years. When you lose weight, all these toxins have to be removed through your bloodstream, which can be extremely uncomfortable. During fasting, these symptoms are even more pronounced, since the rate of fat burning is so rapid – many people feel nauseous, sick, or otherwise unwell.

Detox is sometimes a necessary evil, but when you’re thinking about the potential dangers of long-term fasting, make sure not to get taken in by fanatical advocates who claim that everything is just another detox symptom. Sometimes it’s actually a symptom of a bigger problem, not just detox, and even rapid detox can be unhealthy in itself.

There’s also a darker side to the mental health benefits of fasting. For eating disordered people, fasting can quickly turn into another form of abuse (punishment for eating too much or anything “wrong.”) Because fasting is often accompanied by a strange kind of energy, it’s possible to get addicted to it, and ignore physical danger in pursuit of that “fasting high.” This is just as dangerous as any other form of chronic malnutrition and starvation.

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Long Fasts: Case Reports

In humans, most of the studies on fasting have dealt with religious fasts, which are more like intermittent fasting (for example, during the month of Ramadan, observant Muslims may not eat or drink while the sun is up, but observers commonly do eat dinner after sundown, and sometimes a small “breakfast” before sunrise as well. These studies tell us a lot about the benefits of intermittent fasting, but not much about long-term water fasts. There haven’t been a lot of high-quality studies on long-term water fasting, since mainstream medicine regards it as very dangerous. There are a few case studies which are interesting, but difficult to draw conclusions from:

One study tracked an anonymous monk who undertook a 40-day fast, with no caloric intake at all except from taking communion, which the researchers estimated at 60 calories per day. After thoroughly measuring every baseline of health before the man started fasting, the researchers took daily and weekly measurements until day 36. During this time, the man:

  • Lost around 34.5 pounds
  • Developed symptoms of severe hypotension (blood pressure that’s lower than normal), to the point where he needed almost half an hour just to stand up in the morning.
  • Showed no major changes in serum potassium, magnesium, calcium, or phosphorous (although this isn’t a sign of mineral sufficiency; see the section on breaking the fast and refeeding syndrome below)
  • Showed a slight rise in serum zinc
  • Showed increased levels of uric acid for the first two weeks. Uric acid stabilized in the third week, and then normalized after that.

The man had originally planned to fast for 40 days, but stopped on day 36, when “profound weakness and symptoms of postural hypotension interfered with his daily activities in the monastery.”

One reporter from Harper’s Magazine lost 30 pounds on a 17-day fast, and suggested that fasting is so denigrated as a cure for chronic disease because it’s just not profitable for drug companies. His article also detailed the case of a suicidal doctor after the Civil War who tried to starve himself to death, only to find that the longer he fasted, the better he felt.

An extremely obese man in Scotland lost 276 pounds on a 382-day fast, while taking supplemental vitamins and minerals. A rarity among extreme weight loss patients, he actually kept the weight off once the fast was over.

One follower of the Perfect Health Diet fasted for 30 days, and reported that his migraines were cured at the end of the fast. However, he later discovered that just eating a ketogenic diet would have the same effect.

Perhaps most usefully to anyone considering a long fast, a blogger named Celestine Chua fasted for 21 days and kept an astonishingly detailed record of her physical and emotional reactions. Although she experienced severe mental and physical “detox,” she reported being glad that she’d fasted, and having a better relationship with food afterwards.

All these reports are biased, of course, because people who try a fast and fail are much less likely to write publicly about it. But they are interesting resources, and we’re not likely to get a randomized, controlled clinical study any time soon, so they’re the best we have for now.

Long Fasts vs. Shorter Fasts

With any dietary intervention, you want to get the most gain for the least amount of pain. Especially considering that the benefits of intermittent fasting (as opposed to longer fasts) are so well attested, it’s worth a look to see if shorter fasts aren’t a better idea overall.

So are long or short fasts superior? The answer is that it depends on why you’re fasting. You can get the physical benefits of longer fasts just as easily from intermittent fasting, or even from not fasting at all. Ketosis, for example, doesn’t require any calorie restriction, only carbohydrate restriction. Since a ketogenic diet includes all the vitamins and nutrients your body needs to keep functioning, it’s much less dangerous and easier to just eat ketogenic meals than to enter ketosis by fasting.

Autophagy is also achievable through intermittent fasting just as easily as longer fasts. Autophagy begins when liver glycogen is depleted, around 12-16 hours into a fast. The rate of autophagy peaks there, and then drops after about 2 days. If your goal is a “spring cleaning” for your cells, intermittent fasting may be even more effective, since you spend more time in the “early fasting” period when autophagy is at its peak.

Long fasts also lose points for the social aspect – it’s easy to plan family meals around an 8-hour feeding window, but much more difficult to stay engaged in a healthy social life if you’re avoiding food altogether.

Intermittent fasting also reduces many of the drawbacks of long fast. There’s typically no loss of lean tissue (muscle), since people who IF eat plenty of protein, just at different times. Intermittent fasting allows you to keep working out, while exercising during long fasts will just cause more muscle loss. There’s much less risk of malnutrition, heart failure, and infectious complications with intermittent fasting – from a physical perspective, it’s hard to see how anyone would prefer an extended water fast.

On the other hand, there are some emotional and psychological benefits of longer fasts that intermittent fasting just doesn’t provide. A 2 or 3 week fast can be a springboard for a radical change in dietary habits – fasters report that abstaining from food completely gave them a valuable chance to re-evaluate their eating habits. For example, even emotional eating of ketogenic or otherwise healthy foods doesn’t break you out of the cycle of eating to deal with uncomfortable feelings. A total fast forces you to find other ways of handling these emotions. This can make a fast very difficult, but also very rewarding for people who can stick it out.

On the whole, intermittent fasting is superior for physical health (the same gain with less risk), but longer fasting may be superior for emotional, psychological, or spiritual reasons.

Long Fasts: Precautions

If you do decide to embark on a long fast, some common-sense precautions can prevent prevent a disappointing failure – or worse, a trip to the emergency room. Some people simply shouldn’t practice extended fasts, period:

  • Young children are still growing rapidly and need adequate nutrition at every stage to make sure their bodies develop properly
  • Very elderly people often don’t have the physical resources to fast safely.
  • People who are seriously ill, or people with chronic heart or kidney conditions, shouldn’t fast since their bodies may not be able to withstand the stress of fasting.
  • Women who are pregnant, or trying to get pregnant, should eat plenty of nutrient-dense food, because a well-fed state is essential for healthy reproduction.

If you’re not in any of these groups, make sure to do your own research and have a plan beforehand. Read up on other people’s experiences with long fasts, so you understand what you’re getting into. Think about your physical and emotional relationship with food – what do you think will be the difficulties of fasting for you, and how will you overcome them? Are there any specific issues that you want to meditate on or work through while you’re fasting?

A useful fasting plan should also include a plan for dealing with other people during your fast. Unless you live alone, chances are good that someone will notice and be concerned. How will you reassure them that you’re not anorexic or starving yourself? What if you have to participate in a business lunch or another work meeting involving food?

Also, make a backup plan while you’re well-fed and healthy for what you’ll do if the fast isn’t going well. During a long fast, it’s normal to experience crazy emotional highs and lows; this can prevent you from making a rational decision about whether or not you want to continue. Write down your criteria for what will make you stop the fast (“I will stop fasting if my blood pressure drops below _____________” or “I will stop fasting if I lose __________ pounds” or whatever it might be for you) and stick to them during your fast.

An even better option is to find someone to supervise your fast. If at all possible, it’s wise to fast under the care of a doctor, but this isn’t always an option, since most mainstream doctors have a knee-jerk negative reaction towards fasting. Even a close friend with no medical training can help provide some valuable perspective on how the fast is going. Fasting centers are another option, but these also aren’t without their problems: some of the fasting experts who run them have been implicated in very sketchy practices, and it’s crucial to do a lot of research before entrusting yourself to them.

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During your fast, make sure to drink plenty of water to avoid dehydration, and take supplemental electrolytes: sodium, potassium, calcium, phosphate, and magnesium. Your body needs these minerals to balance fluid levels, and supplementing also prevents one of the chief dangers of fasting: refeeding syndrome (see the section on breaking your fast below). Normally, you get those minerals from your food; since you’re continuing to drink water without eating anything, you need them from an alternate source during your fast. You can buy “electrolyte water” (make sure you don’t get sports drinks full of artificial flavorings, though), make your own with water, lemon, and a pinch of salt, or take supplements.

While you’re in the midst of a fast, don’t try to work out at all – this will just cause your body to lose more muscle than necessary. The closer you can get to bed rest, the better. Read, journal, meditate, sleep, listen to music, or talk to people you love. Many people take time off work to concentrate on their fast. Keeping a slow-paced and thoughtful environment will help you really get the most of the psychological and spiritual benefits of fasting.

Breaking a Fast

Breaking the fast correctly is one of the most important ways to prevent any negative consequences. Introducing too much food too rapidly can lead to a fatal condition called refeeding syndrome. A sudden shift from ketosis (fat-adapted metabolism) to carbohydrate-based foods causes your body to release a flood of insulin to digest all those carbs, a process that requires large amounts of phosphate, potassium, magnesium, and several vitamins, especially thiamine (Vitamin B1). If you’ve been fasting for any length of time, though, these nutrients are severely depleted, so suddenly needing a lot of them leads to serious acute deficiencies, causing heart failure, hypotension, and sudden death.

A set of guidelines from Scarborough Hospital in the UK for avoiding refeeding syndrome include:

  • Start slow: 10 calories/kilogram of body weight per day (or 5 calories/kilogram if you’ve been fasting longer than 15 days), with a daily increase of 5 calories/kilogram.
  • Supplement with thiamine and other B vitamins 30 minutes before breaking the fast (the guidelines are meant for hospitals and suggest an IV; another article gives an appropriate dose as 50-250mg).
  • Supplement with phosphorous, potassium, magnesium, and sodium before breaking the fast.

Additional guidelines include:

  • Supplement with electrolytes during the fast, as discussed above.
  • Break your fast with bone broth or diluted fruit juice, both rich in electrolytes. Squeeze your own juice, or if you buy some at the store, make sure it’s pure juice, with no sugar or other nasty additives involved.
  • The longer you fast, the longer you’ll need to spend breaking the fast; for anything longer than a week, plan on spending several days slowly reintroducing your body to solid foods.

Eat small portions, more often, and eat slowly. As your body starts to get more used to food again, pureed soups (like sweet potato lime soup, cream of tomato soup, or butternut squash soup) are a good transition food. Avocados are soft and easy to digest, and a good source of healthy fats. A bone broth soup with egg yolks and some well-cooked vegetables is loaded with nutrients, fat, and protein. Fruit is often recommended as a transition food, but this isn’t a great idea because the fructose can be hard on your gut.

As you slowly work your way up to eating normally, make sure to re-introduce foods slowly and carefully. If you’ve never done an elimination diet before, this is a great opportunity to do so: try testing nightshades, nuts, or FODMAPs separately to see whether or not you have any reaction to them.

The Upshot

Long-term fasting is definitely an intriguing idea. Humans certainly have the ability to endure long periods of famine, but that doesn’t mean it’s healthy. So far, there’s some substantial evidence showing benefits for weight loss, but whether this weight loss is actually sustainable in the long term remains to be proven. And in most cases, you can get all the physical benefits of long-term fasting from intermittent fasting or even just a ketogenic diet, without all the attendant risks of completely abstaining from food for several weeks at a time. So for purely physical health reasons, longer fasts aren’t great because they have increased dangers without any increased benefits.

For the vast majority of people, it’s a much better idea to use intermittent fasting or alternate-day fasting (24 hours of feeding followed by 24 hours of fasting) and perhaps a ketogenic diet to reap the physical benefits of food restriction, without the very real dangers of longer fasts.  For mental health and spiritual practice, on the other hand, longer fasts do have some advantages over intermittent fasting. Whether the benefits outweigh the risks is a decision everyone has to make individually – don’t take the dangers lightly, and make sure to do your own research before you make your choice.

 

Conclusion

Conclusions and Recommendations

Based on the existing evidence from animal and human studies described, we conclude that there is great potential for lifestyles that incorporate periodic fasting during adult life to promote optimal health and reduce the risk of many chronic diseases, particularly for those who are overweight and sedentary. Animal studies have documented robust and replicable effects of fasting on health indicators including greater insulin sensitivity, and reduced levels of blood pressure, body fat, IGF-I, insulin, glucose, atherogenic lipids and inflammation. Fasting regimens can ameliorate disease processes and improve functional outcome in animal models of disorders that include myocardial infarction, diabetes, stroke, AD and PD. One general mechanism of action of fasting is that it triggers adaptive cellular stress responses, which result in an enhanced ability to cope with more severe stress and counteract disease processes. In addition, by protecting cells from DNA damage, suppressing cell growth and enhancing apoptosis of damaged cells, fasting could retard and/or prevent the formation and growth of cancers.

However, studies of fasting regimens have not been performed in children, the very old and underweight individuals, and it is possible that IF and PF would be harmful to these populations. Fasting periods lasting longer than 24 hours and particularly those lasting 3 or more days should be done under the supervision of a physician and preferably in a clinic. IF- and PF-based approaches towards combating the current epidemics of overweight, diabetes and related diseases should be pursued in human research studies and medical treatment plans. Several variations of potential ‘fasting prescriptions’ that have been adopted for overweight subjects revolve around the common theme of abstaining from food and caloric beverages for at least 12 – 24 hours on one or more days each week or month, depending on the length, combined with regular exercise. For those who are overweight, physicians could ask their patients to choose a fasting-based intervention that they believe they could comply with based upon their daily and weekly schedules. Examples include the ‘5:2’ IF diet (Harvie et al., 2011), the alternate day modified fasting diet (Johnson et al., 2007; Varady et al., 2009), a 4–5 day fast or low calorie but high nourishment fasting mimicking diets once every 1–3 months followed by the skipping of one major meal every day if needed (V. Longo, clinical trial in progress). One of the concerns with unbalanced alternating diets such as those in which low calorie intake is only observed for 2 days a week are the potential effects on circadian rhythm and the endocrine and gastrointestinal systems, which are known to be influenced by eating habits. During the first 4 – 6 weeks of implementation of the fasting regimen, a physician or registered dietitian should be in regular contact with the patient to monitor their progress and to provide advice and supervision.

Fasting regimens could also be tailored for specific diseases as stand-alone or adjunct therapies. Results of initial trials of IF (fasting 2 days per week or every other day) in human subjects suggest that there is a critical transition period of 3 – 6 weeks during which time the brain and body adapt to the new eating pattern and mood is enhanced (Harvie et al., 2011; Johnson et al., 2007). Though speculative, it is likely that during the latter transition period brain neurochemistry changes so that the ‘addiction’ to regular consumption of food throughout the day is overcome. Notably, the various fasting approaches are likely to have limited efficacy particularly on aging and conditions other than obesity unless combined with diets such as the moderate calorie intake and mostly plant-based Mediterranean or Okinawa low protein diets (0.8 g protein/Kg of body weight), consistently associated with health and longevity.

In the future, it will be important to combine epidemiological data, studies of long-lived populations and their diets, results from model organisms connecting specific dietary components to pro-aging and pro-disease factors, with data from studies on fasting regimens in humans, to design large clinical studies that integrate fasting with diets recognized as protective and enjoyable. A better understanding of the molecular mechanisms by which fasting affects various cell types and organ systems should lead to the development of novel prophylactic and therapeutic interventions for a wide range of disorders.

 

 

 

 

Mech Ageing Dev. 2018 Nov 3;176:19-23. doi: 10.1016/j.mad.2018.10.005. [Epub ahead of print]

Caloric restriction and cellular senescence.

Fontana L1, Nehme J2, Demaria M3.

Author information

Abstract

Cellular senescence is a state of irreversible growth arrest characterized by hypertrophy and secretion of various bioactive molecules, a phenomenon defined the Senescence-Associated Secretory Phenotype (SASP). Senescent cells are implicated in a number of biological functions, from embryogenesis to aging. Significantly, excessive accumulation of senescent cells is associated to a decline of regenerative capacity and chronic inflammation. In accordance, the removal of senescent cells is sufficient to delay several pathologies and promote healthspan. Calorie restriction (CR) without malnutrition is currently the most effective non-genetic intervention to delay aging phenotypes. Recently, we have shown that CR can prevent accumulation of senescent cells in both mice and humans.

Mech Ageing Dev. 2018 Nov 3;176:19-23. doi: 10.1016/j.mad.2018.10.005. [Epub ahead of print]

Caloric restriction and cellular senescence.

Fontana L1, Nehme J2, Demaria M3.

Author information

 

 

 

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