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Animal studies suggest that intermittent fasting (IF or periodic short fasts of 16-36 hours) can promote optimal health and protect against a broad range of chronic maladies including diabetes, cancers, cardiovascular disease and neurodegenerative brain disorders. Moreover, IF can reduce cellular damage and improve functional outcome in animal models of stroke, epilepsy and trauma. Studies of overweight human subjects show that IF diets promote loss of abdominal fat with retention of lean mass, and can be effective in preventing and treating diabetes, cardiovascular disease, cancers and inflammatory disorders such as asthma.
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD.
The results of recent research refute the notion that eating many small meals throughout the day is healthier than skipping meals.
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Our research suggests that IF promotes health by imposing a mild transient challenge to the brain and body, which stimulates cells in ways that improve their function and protects them against injury and disease. From an evolutionary perspective, eating three meals plus snacks is not normal. Humans are designed for IF diets and, based on evidence described and referenced below, a return to such eating patterns may go a long way towards squelching the current epidemics of obesity, diabetes and the many diseases associated with these conditions.
the 5:2 diet in which one eats normally 5 days each week, and
eats no more than 600 calories 2 days each week1, 2;
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The most commonly used IF diet for animal studies is alternate day fasting where the animals go 24 hours with no food (and free access to water) every other day6. This IF diet inhibits the formation and growth of tumors and reduces IGF-1 levels in rodents, indicating a potential for IF in cancer risk reduction and cancer treatment13, 14. IF counteracts diabetes and obesity by reducing overall energy intake, by increasing insulin sensitivity, and by promoting fat oxidation8, 15. Rats maintained on an IF diet exhibit improvements in multiple risk factors for cardiovascular disease, including reductions in levels of circulating triglycerides and cholesterol and a reduction in both diastolic and systolic blood pressure5, 8. Moreover, IF protects the heart against ischemic damage in a rat model of myocardial infarction16.
The first two neurological disorders that IF was found to counteract in animal models were epileptic seizures and ischemic stroke. In a rat model, severe epileptic seizures cause damage to neurons in the hippocampus, a brain region critical for learning and memory. However, many hippocampal neurons in rats maintained on an IF diet were not damaged by the seizures, and learning and memory ability was preserved17. Stroke is a major cause of death and disability worldwide. In both rat18 and mouse11 stroke models, IF protected neurons from dying and also improved functional outcome. IF can also improve recovery from spinal cord injury and traumatic brain injury in animal models19, 20.
IF can protect neurons against dysfunction and degeneration in animal models of several different neurological disorders. In a transgenic mouse model of Alzheimers disease, IF ameliorates learning and memory deficits21. In a model of Parkinsons disease in which mice are exposed to a neurotoxin, IF reduced degeneration of dopaminergic neurons and lessened motor impairment22. In a mouse model of an inherited form of Parkinsons disease, IF reversed neurological symptoms23. Huntingtons disease is a fatal inherited disorder that involves the degeneration of neurons in a region of the brain called the striatum that controls body movements. In mice engineered with the defective human gene that causes Huntingtons disease, IF reduces brain damage and associated symptoms24. While remarkably beneficial in animal models of Alzheimers, Parkinsons and Huntingtons diseases, IF may not be a panacea for all neurodegenerative disorders. IF did not delay the onset of symptoms, and hastened the progression of the disease in a mouse model of amyotrophic lateral sclerosis (ALS)25. The reason for the failure of IF to benefit ALS mice may be the result of an impaired ability of the spinal cord motor neurons affected in ALS to respond to IF.
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consumption of food and caloric beverages throughout most of their waking hours, they might improve their health by simply restricting the time period during which they eat to 8 hours or less each day.
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During IF, fats are broken down (lipolysis), and fatty acids are released into the blood and transported into liver cells, where they are converted to ketone bodies in a process involving beta-oxidation to produce acetyl CoA. This is then used in the synthesis of the ketones beta-hydroxbutyrate and acetoacetate. The ketones are then released into the blood and distributed throughout the body and brain where they are used as energy source by cells. Upon entering cells, ketone bodies can be metabolized to acetyl CoA which then enters the citric acid cycle resulting in the generation of ATP. Ketones provide a critical source of energy for heart and muscle cells and neurons during fasting. For example, in the fed state glucose provides nearly 100% of the energy for neurons, whereas during prolonged fasting ketones can provide more than 70% of the energy for neurons27. Ketones are also produced during prolonged endurance exercise, another situation in which liver glycogen stores are depleted, and so heart, brain and muscle cells are dependent upon the ketones to support their high energy demand.
Beneficial effects of ketones bodies on the brain and heart have been established in studies in which animals have been fed ketogenic diets or treated with ketones themselves. For example, ketogenic diets protected brain cells and improved functional outcome in animal models of stroke28 and myocardial infarction29. Ketogenic diets are also beneficial in mouse models of ALS30. In a recent study we supplemented the diet of 3xTgAD mice (an animal model of Alzheimers disease) with a ketone ester that is an immediate precursor to the major ketone body produced by the body during fasting. We found that the ketone ester treatment improved the cognitive function of the 3xTgAD mice and lessened the accumulation of amyloid in their brains31. Interestingly, mice given the ketone ester exhibited lower levels of anxiety, which suggests a role for ketone bodies in the calming/antidepressant effects of IF and exercise.
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The potential value of supplementation with ketone bodies or ketone esters is that they avoid the down side of typical ketogenic diets which contain saturated fats and cholesterol that are bad for the cardiovascular system.
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While more research is required to understand the exact ways in which IF reduces inflammation, it is likely that they are similar to how exercise reduces inflammation37; they both are mild energetic challenges that inhibit the activity of inflammatory immune cells including macrophages and lymphocytes.
The Effects of IF on the Brain and Body Make Sense When Viewed in the Light of Evolution
As the result of our evolutionary history, we humans are mostly the same as other animals, except for the superior information processing and transfer capabilities of our larger brains. Ironically, our brain power has led to rapid changes in our living environments in ways that have rendered many people in modern societies unchallenged, such that they do not have to work for food, nor expend energy in their occupations12. From an evolutionary perspective, IF is normal and eating 3 meals a day plus snacks is abnormal. Going without food for most of the day or even for several days is a challenge that we are very capable of meeting. Similarly, humans are capable of quite remarkable amounts of physical activity,
particularly endurance running, which has been an important factor in their evolution38. Challenges such as IF and exercise are not only tolerable, but we thrive on them because they make our cells and organs stronger, and more likely to recover from injuries and illnesses.
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Why? Sadly, the reason for this lack of effort by primary care physicians is that no one profits from IF prescriptions. The processed food and agriculture industries collaborate to produce and market high energy-density foods that include chemical additives that are addictive39. Moreover, they have targeted the most vulnerable groups in our society including children and the poor, as is clear from the obesity epidemic in these populations40. Drugs are promoted by pharmaceutical companies with their implicit mantra: dont worry about getting a disease, we have a pill you can take for that.
Most Americans have taken the bait and are hooked, including physicians41. Primary care physicians often opine that patients cannot comply with IF diets, even though the scientific evidence suggests otherwise. Specialists (cardiologists, pulmonologists, orthopedists, etc.) will retort that it is not their job to tackle the underlying cause (a couch potato lifestyle) of their patients condition (coronary artery disease, asthma, joint degeneration, etc.); instead, they dispense drugs and wield scalpels because that is what they were trained to do.
Indeed, medical school students are not taught about the profound health benefits of IF and exercise, and there has been no attempt to implement prescriptions for IF diets in clinical practice.
Based on recent clinical trials7, 9, 10 and thousands of individual examples documented in blogs, patients very often can and will comply with IF prescriptions if they are given a specific plan for the diet and for monitoring their progress. For example, a middle-age overweight patient who has hypertension and is developing diabetes could be give a prescription that includes a 5:2 IF diet and thrice-weekly exercise. The physician and/or an assistant would then keep in touch with, and be a cheerleader for, the patient via text messaging or social media with the purpose of guiding them through the 1 2 month period that is often required for a person to adjust to and prefer the IF eating pattern.
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The problem in implementing IF prescriptions is not that patients will not comply; instead, the problem lies with the health care industry which lacks motivation to prescribe IF. Americans spend more money on health care than any other country, and yet our health outcomes are worse than most other industrialized countries because we do not emphasize prevention and treatments such as IF, that address the underlying cause of the most common chronic diseases, namely, overeating and a sedentary lifestyle.
The good news is that everyone who reads this article can improve their health and reduce their risk for many diseases, while at the same time saving money. They can encourage their family members and friends to do the same. For example, someone on the 5:2 diet will accrue the many health benefits described above and will also spend 20% less on food. Changing ones diet from processed foods comprised mainly of unhealthy fats and sugars, to diets with whole grains, fruits, vegetables, nuts and healthy meats will also be important, and might be enabled by IF diets. The why and how of IF diets have been elaborated upon in several books published within the past several years1-4. Research on IF in human subjects is accelerating and, notwithstanding the many barriers to incorporation of IF into health care practice, there is reason to be optimistic that IF eating patterns will become the norm for many people throughout the world.
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References
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21. Halagappa VK, Guo Z, Pearson M, Matsuoka Y, Cutler RG, Laferla FM, Mattson MP. Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer's disease. Neurobiol Dis. 2007; 26:212-220. 22. Duan W, Mattson MP. Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson's disease. J Neurosci Res. 1999; 57:195-206. 23. Griffioen KJ, Rothman SM, Ladenheim B, Wan R, Vranis N, Hutchison E, Okun E, Cadet JL, Mattson MP. Dietary energy intake modifies brainstem autonomic dysfunction caused by mutant synuclein. Neurobiol Aging 2013; 34:928-935. 24. Duan W, Guo Z, Jiang H, Ware M, Li XJ, Mattson MP. Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proc Natl Acad Sci USA 2003; 100:2911-2916. 25. Pedersen WA, Mattson MP. No benefit of dietary restriction on disease onset or progression in amyotrophic lateral sclerosis Cu/Zn-superoxide dismutase mutant mice. Brain Res. 1999; 833:117-120. 26. Hatori M, Vollmers C, Zarrinpar A, Ditacchio L, Bushong EA, Gill S, Leblanc M, Chaix A, Joens M, Fitzpatrick JA, Ellisman MH, Panda S. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab. 2012; 15:848-860. 27. Maalouf M, Rho JM, Mattson MP. The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev. 2009; 59:293-315. 28. Puchowicz MA, Zechel JL, Valerio J, Emancipator DS, Xu K, Pundik S, LaManna JC, Lust WD. Neuroprotection in diet-induced ketotic rat brain after focal ischemia. J Cereb Blood Flow Metab. 2008; 28:1907-1916. 29. Al-Zaid NS, Dashti HM, Mathew TC, Juggi JS. Low carbohydrate ketogenic diet enhances cardiac tolerance to global ischaemia. Acta Cardiol. 2007; 62:381-389. 30. Dupuis L, Oudart H, Ren F, Gonzalez de Aguilar JL, Loeffler JP. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci U S A. 2004; 101:11159-11164. 31. Kashiwaya Y, Bergman C, Lee JH, Wan R, King MT, Mughal MR, Okun E, Clarke K, Mattson MP, Veech RL. A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer's disease. Neurobiol Aging. 2013; 34:1530-1539. 32. Stranahan AM, Mattson MP. Recruiting adaptive cellular stress responses for successful brain ageing. Nat Rev Neurosci. 2012; 13:209-216. 33. Calabrese V, Cornelius C, Dinkova-Kostova AT, Calabrese EJ, Mattson MP. Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders. Antioxid Redox Signal. 2010; 13:1763-1811. 34. Rothman SM, Mattson MP. Activity-dependent, stress-responsive BDNF signaling and the quest for optimal brain health and resilience throughout the lifespan. Neuroscience 2013; 239:228-240. 35. Lago F, Dieguez C, Gmez-Reino J, Gualillo O. Adipokines as emerging mediators of immune response and inflammation. Nat Clin Pract Rheumatol. 2007; 3:716-724. 36. Wan R, Ahmet I, Brown M, Cheng A, Kamimura N, Talan M, Mattson MP. Cardioprotective effect of intermittent fasting is associated with an elevation of adiponectin levels in rats. J Nutr Biochem. 2010; 21:413-417. 37. Perandini LA, de S-Pinto AL, Roschel H, Benatti FB, Lima FR, Bonf E, Gualano B. Exercise as a therapeutic tool to counteract inflammation and clinical symptoms in autoimmune rheumatic diseases. Autoimmun Rev. 2012; 12:218-224. 38. Mattson MP. Evolutionary aspects of human exercise - born to run purposefully. Ageing Res Rev. 2012; 11:347-352. 39. Garber AK, Lustig RH. Is fast food addictive? Curr Drug Abuse Rev. 2011; 4:146-162. 40. Keller SK, Schulz PJ. Distorted food pyramid in kids programmes: a content analysis of television advertising watched in Switzerland. Eur J Public Health. 2011; 21:300-305. 41. Tonelli MR. Conflict of interest in clinical practice. Chest 2007; 132:664-670.
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