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Intermittent Fasting and Health

Date post: 18-Oct-2015
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By Mark P. Mattson, Ph.D.Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD.
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    Intermittent Fasting and HealthIntermittent Fasting and Health By Mark P. Mattson, Ph.D.By Mark P. Mattson, Ph.D.

    The results of recent research refute the notion that eating many small meals throughout the day is healthier than skipping meals.

    Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD.

    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.



    Intermittent Fasting and Health | Mark P. Mattson, Ph.D.

    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.

    Intermittent fasting (IF) can be defined as going 16-36 hours with little or no food periodically, typically 1-3 times each week. The three IF diets that are currently the most popular are:

    Variations of Intermittent FastingVariations of Intermittent Fasting

    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;

    alternate day fasting in which the person alternates between normal eating and 600 calorie days3 and

    time-restricted eating in which food is consumed only during a 4-8 hour time period every day4.


  • A valuable feature of studies of laboratory animals such as rats and mice is that experiments can be performed under tightly controlled conditions. In contrast to human studies, in animal studies there are no problems with compliance with an IF diet (the animals have no choice), and there is little or no variability among individuals in their genetics or lifestyle. Research on animal models of human diseases has been critical for the development of effective treatments for patients. This is true for cancers, cardiovascular disease, diabetes, many different infectious agents, and some neurological disorders including depression and multiple sclerosis. However, the most common treatments for these diseases can have prominent side effects, and may themselves pose a considerable risk of death. In contrast, IF poses little or no risk as an intervention for the primary prevention and/or treatment of many diseases.


    Intermittent Fasting and Health | Mark P. Mattson, Ph.D.

    Studies of laboratory animals and humans have shown clear improvements of a wide range of health indicators including:

    Studies of laboratory animals and humans have shown clear improvements of a wide range of health indicators including:

    1) reduced blood pressure and resting heart rate, and increased heart rate variability (changes similar to those of endurance exercise training)5

    2) reduced blood glucose and insulin levels, and an associated increase in insulin sensitivity (changes that protect against diabetes)6-8

    3) reduced abdominal fat with maintenance of muscle mass7, 9

    4) reduced levels of inflammation and oxidative stress (which may protect against conditions such as asthma and autoimmune disorders)10, 11

    5) improved mood and cognitive function12

    Animal Studies Show that IF is a Powerful Protector Against DiseasesAnimal Studies Show that IF is a Powerful Protector Against Diseases

    Intermittent Fasting Improves Many Aspects of HealthIntermittent Fasting Improves Many Aspects of Health


  • 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.


    Intermittent Fasting and Health | Mark P. Mattson, Ph.D.

    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 hippocampalneurons 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.



    Intermittent Fasting and Health | Mark P. Mattson, Ph.D.

    The liver is the major source of energy for the body when regular meals are consumed. Glucose in foods and drinks is transferred from the intestines into the blood, and is then taken up by liver cells which retain glucose in a storage form called glycogen. Between meals glucose is released from glycogen stores and enters the blood, where it is distributed to cells throughout the body and brain to provide the energy required to sustain their function. However, the liver stores only enough glucose to last for 10-12 hours after a meal. Therefore, fasting for more than 12 hours results in a shift in energy metabolism such that fats become the major source of fuel. Studies in human subjects have shown that IF is more effective than low calorie diets (eating regular meals, but reducing the size of each meal) in reducing abdominal fat and retaining muscle mass7. Moreover, a recent study showed that when mice are fed high fat food that normally makes them obese, when they are allowed to eat the food only during an 8 hour time period each day, they do not become obese26. Because Americans usually spread out their 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.

    IF Promotes Fat Burning and the Production of Beneficial KetonesIF Promotes Fat Burning and the Production of Beneficial Ketones



    Intermittent Fasting and Health | Mark P. Mattson, Ph.D.

    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-hydroxbutyrateand acetoacetate. The ketonesare then released into the blood and distributed throughout the body and brain where they are used as energy source by cells. Upon entering cells, ketonebodies can be metabolized to acetyl CoA which then enters the citric acid cycle resulting in the generation of ATP. Ketonesprovide 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 ketonescan 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 ketonesthemselves. For example, ketogenicdiets 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 ketoneester 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 ketonebodies in the calming/antidepressant effects of IF and exercise.



    Intermittent Fasting and Health | Mark P. Mattson, Ph.D.

    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.

    One benefit of IF diets for overweight people is that they lose weight. However, the beneficial effects of IF on health and protection against diseases go beyond simply reducing overall calorie intake. The fact that IF can protect neurons in the brain against a wide range of severe stressors (epileptic seizures, stroke, neurotoxins, oxidative stress, amyloid, and others) suggests that IF may itself be a mild stress that stimulates cells to enhance their ability to cope with more severe stress and resist injury and disease32. This possibility is consistent with the well-established concept of hormesis, in which exposure of an organism to a low level of a toxin or other type of stress bolsters their ability to withstand a more severe stress33. To test the hormesis hypothesis of the health benefits of IF, we performed experiments in mice to determine the effects of IF on the levels of various molecules known to be involved in adaptive stress responses and cellular resiliency. We found that IF results in increased amounts of neurotrophicfactors, protein chaperones and antioxidant enzymes in the brain11. These effects of IF are likely very important for optimal brain health. Indeed, one of the neurotrophic factors that is increased by IF (brain-derived neurotrophic factor or BDNF) is known to enhance learning and memory and can even stimulate the production of new neurons from stem cells in the brain34. Moreover, by increasing levels of antioxidant enzymes and protein chaperones, IF can protect brain cells against free radicals and the accumulation of damaged proteins, both of which are implicated in Alzheimers and Parkinsons diseases.

    IF is a Challenge that Strengthens CellsIF is a Challenge that Strengthens Cells

    IF can also reduce inflammation. In a study of mice, IF decreased levels of inflammation in the brain by inhibiting the production of interleukin-1b, interleukin-6 and tumor necrosis factor11. IF also increases levels of adiponectin, a hormone that is believed to suppress inflammation and that may thereby reduce tissue damage caused by injury or inflammatory diseases35. The elevation of adiponectin levels in mice on an IF diet has been associated with protection of heart cells against ischemic damage in an animal model of myocardial infarction36.


  • While the scientific evidence conclusively shows that IF is good for health, particularly in individuals who are overweight, health care providers rarely or never prescribe IF diets to their patients.

    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,


    Intermittent Fasting and Health | Mark P. Mattson, Ph.D.

    The Effects of IF on the Brain and Body Make Sense When Viewed in the Light of EvolutionThe Effects of IF on the Brain and Body Make Sense When Viewed in the Light of Evolution

    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.

    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.

    Barriers to the Implementation of IF Prescriptions Barriers to the Implementation of IF Prescriptions



    Intermittent Fasting and Health | Mark P. Mattson, Ph.D.

    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.

    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.

    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.



    Intermittent Fasting and Health | Mark P. Mattson, Ph.D.

    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 membersand 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.



    About the Author Mark P. Mattson, Ph.D.Dr. Mattson is currently Chief of the Laboratory of Neurosciences at the National Institute on Aging (NIA) in Baltimore, and is also a Professor in the Department of Neuroscience at Johns Hopkins University School of Medicine. After receiving his PhD degree from the University of Iowa, Dr. Mattson completed a postdoctoral fellowship in Developmental Neuroscience at Colorado State University. He then joined the

    University of Kentucky College of Medicine where he was a Professor at the Sanders-Brown Center on Aging. He moved to the NIA in 2000, where he leads a multi-faceted research team that applies cutting-edge technologies in research aimed at understanding molecular and cellular mechanisms of brain aging and the pathogenesis of neurodegenerative disorders. He has trained more than 80 postdoctoral and predoctoral scientists, and has made major contributions to the education of undergraduate, graduate and medical students.

    Dr. Mattson is considered a leader in the area of cellular and molecular mechanisms underlying neuronal plasticity and neurodegenerative disorders, and has made major contributions to understanding how dietary energy intake affects the brain, and to the development of interventions for Alzheimers disease, Parkinsons disease, amyotrophic lateral sclerosis and stroke. Dr. Mattsons research on intermittent fasting in animals and humans led to the current popular interest in such diets.

    Dr. Mattson has published more than 500 original research articles and numerous review articles in leading journals, and has edited 10 books in the areas of neuronal signal transduction, cellular stress responses, hormesisand aging. Dr. Mattson has received many awards including the Metropolitan Life Foundation Medical Research Award, the Alzheimers Association Zenith Award, the Santiago Grisolia Chair Prize and the Tovi Comet-WalersteinScience Award. He was elected a Fellow of the American Association for the Advancement of Science in 2011. He is Editor-in-Chief of Ageing Research Reviews and NeuroMolecular Medicine.

    A description of Dr. Mattsons research program, which is funded by the National Institute on Aging Intramural Research Program, can be found at: http://www.irp.nia.nih.gov/branches/lns/mcnu.htm

    Click here for more information on Dr. Mattson and his contributions to science: http://en.wikipedia.org/wiki/Mark_Mattson

    Intermittent Fasting and Health | Mark P. Mattson, Ph.D.



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    271 pp.4. Zinczenko D, Moore P. The 8 Hour Diet. 2013; Rodale Inc., New York, New York. 266 pp.5. Wan R, Camandola S, Mattson MP. Intermittent food deprivation improves cardiovascular and

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    11. Arumugam, T.V., Phillips, T.M., Cheng, A., Morrell, C.H., Mattson, M.P. and Wan, R. Age and energy intake interact to modify cell stress pathways and stroke outcome. Ann. Neurol. 2010; 67:41-52.

    12. Mattson MP. Energy intake and exercise as determinants of brain health and vulnerability to injury and disease. Cell Metab. 2012; 16:706-722.

    13. Varady KA, Roohk DJ, Hellerstein MK. Dose effects of modified alternate-day fasting regimens on in vivo cell proliferation and plasma insulin-like growth factor-1 in mice. J Appl Physiol. 2007; 103:547-551.

    14. Lee C, Raffaghello L, Brandhorst S, Safdie FM, Bianchi G, Martin-Montalvo A, Pistoia V, Wei M, Hwang S, Merlino A, Emionite L, de Cabo R, Longo VD. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med. 2012; 4(124):124ra27.

    15. Duan W, Guo Z, Jiang H, Ware M, Mattson MP. Reversal of behavioral and metabolic abnormalities, and insulin resistance syndrome, by dietary restriction in mice deficient in brain-derived neurotrophic factor. Endocrinology 2003; 144:2446-2453.

    16. Ahmet I, Wan R, Mattson MP, Lakatta EG, Talan M. Cardioprotection by intermittent fasting in rats.Circulation 2005; 112:3115-3121.

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    18. Yu ZF, Mattson MP. Dietary restriction and 2-deoxyglucose administration reduce focal ischemic brain damage and improve behavioral outcome: evidence for a preconditioning mechanism. J Neurosci Res. 1999; 57:830-839.

    19. Plunet WT, Streijger F, Lam CK, Lee JH, Liu J, Tetzlaff W. Dietary restriction started after spinal cord injury improves functional recovery. Exp Neurol. 2008; 213:28-35.

    20. Davis LM, Pauly JR, Readnower RD, Rho JM, Sullivan PG. Fasting is neuroprotective following traumatic brain injury. J Neurosci Res. 2008; 86:1812-1822.

    Intermittent Fasting and Health | Mark P. Mattson, Ph.D.




    HIntermittent Fasting and Health | Mark P. Mattson, Ph.D.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 huntingtinmutant 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 ketogenicdiet, and ketone bodies. Brain Res Rev. 2009; 59:293-315.

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    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.

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