Monday, June 24, 2019

Intermittent fasting and the Ketogenic Diet


Intermittent Fasting and the Ketogenic Diet:
Trendy Fads or Weight Management Revolutions?

The prevalence of obesity was 39.8% and affected about 93.3 million of US adults in 2015~2016.1 Recent studies have shown that even modest weight loss can have significant health benefits, providing more direction for practitioners to help their patients take steps to shed the pounds.2
The weight-loss industry is an approximately $72 billion juggernaut,3 denoted by rising and falling diet and exercise trends. Two trends in particular are gaining in popularity: the ketogenic diet and intermittent fasting. 

What’s So Special About Medium-Chain Triglycerides (MCTs)?


Before diving into the what, the how, and the why on MCTs, let’s cover some background for better understanding. Ketosis is a natural metabolic state of the body defined by increases in the primary ketone body, beta-hydroxybutyrate (BHB), to levels above 0.5 mmol/L. At these raised levels, the body transitions away from using glucose for fuel and toward using ketones and free fatty acids for energy. Entering a state of ketosis can be achieved by fasting, calorie restriction, and/or consuming a ketogenic diet.1 BHB can also be elevated temporarily through supplementation by exogenous ketones1—which is a fancy way to say using ketone supplements. Today, exogenous ketones are commonly found on the market as ketone salts(ketone body bound to a mineral salt or amino acid) or ketone esters (ketone body bound to a ketogenic precursor via an ester bond).1
Interestingly, MCTs, even though not produced outside the body, act similarly to exogenous ketones in that they can help elevate blood ketone levels without restriction of carbohydrates and protein to the extent that the classical ketogenic diet (i.e. 4 parts fat to 1 part protein and carbohydrates) does.2 That is what makes them pretty special!  

What are MCTs?

MCTs are fat molecules that contain a glycerol backbone attached to three medium-chain fatty acids that may be 6 carbons (C6 or caproic acid), 8 carbons (C8 or caprylic acid), 10 carbons (C10 or capric acid), or 12 carbons (C12 or lauric acid) in length. Based on taste, accessibility, and the way they are digested, the MCTs you find on the shelves of your health food store are predominantly C8 and C10. In addition, C8 is the most ketogenic of the MCTs, with C10 following close behind.3 However, C6 is known to cause digestive issues, and C12 is digested more like long-chain fatty acids.4 Long-chain fatty acids range from 14-22 carbons in length and are the predominant fatty acids found in the diet. Short-chain fatty acids are any fatty acid less than 6 carbons in length and are not commonly consumed in the diet; rather, they are primarily produced by the gut microbiome during the fermentation of insoluble fiber.5
Fun fact: One of the primary short-chain fatty acids produced in the gut is butyrate, a molecule that is structurally similar to the ketone body beta-hydroxybutyrate, and can contribute to ketogenesis.6 Learn more about fiber and the ketogenic diet here.

How are MCTs digested differently from other dietary fats?

The length of fatty acids dictates how the body digests and utilizes the fats consumed. Medium-chain fatty acids are unique in that they are absorbed directly into the bloodstream through the hepatic portal circulation and transported to the liver. A lot more work goes into the digestion of long-chain fatty acids, as they require pancreatic enzymes and bile acids for their breakdown, are further packaged into chylomicrons, and are finally delivered to the liver via lymphatic and vascular circulation to be oxidized for energy or stored in adipose tissue. Thus, MCTs are metabolized and utilized much more rapidly than other fatty acid types.3

MCTs to ketones—using MCTs with the ketogenic diet 

In order to use fats for fuel, fatty acids must enter the mitochondria of our liver cells, since this is where the bulk of our cellular energy (ATP) is made. Normally, fatty acids require the help of L-carnitine for entry into the mitochondria; however, MCTs do not require L-carnitine, and as a result their entry into the mitochondria is much more rapid than other fatty acids. Inside the mitochondria, free fatty acids quickly generate acetyl-CoA via beta-oxidation, which go on to make what we are all after: ketone bodies! This rapid assimilation and conversion to ketones makes MCTs much more likely to be used as energy than to be stored as fat. 
Due to their ketogenic properties, incorporating MCTs into the ketogenic diet can allow you to be more liberal with protein and nonsugar/nonstarch carbohydrates (e.g. fibrous vegetables) to sustain nutritional ketosis (i.e. BHB > 0.5 mM).   


Figure 1. MCTs to Ketone Bodies: Medium-chain fatty acids can freely cross the inner mitochondrial membrane (compared with other types of fatty acids, which can enter in a more regulated manner). This more rapid absorption into the inner mitochondrial space quickly increases acetyl-CoA and ketone body formation. 
MCFA=medium-chain fatty acids; OM=outer membrane; IM=inner membrane

Sources of MCTs

Whole-food sources of MCTs are found primarily in coconut oil and palm oil and small amounts in butter or ghee.7 However, they are only found in minute fractions, and the predominant type of MCT in all examples is lauric acid (C12).8 As mentioned previously, the ketogenic properties of MCTs are primarily in response to the smaller length C8 and C10 MCTs.9 This is where concentrated MCT oils and powders shine. Concentrated MCT oil and powder have become widely available as the popularity of this supplement has grown. These oils come from natural sources such as coconut and palm fruits, which adds to their appeal as being a natural supplement. There are many ways to consume MCTs, and in addition to their many benefits, they can even make foods taste more delicious!   
Resources:
  1. Evans M et al. J Physiol. 2017;595(9):2857-2871.
  2. Harvey CJDC et al. PeerJ. 2018;6:e4488. 
  3. Cunnane S et al. Front Mol Neurosci. 2016;9:53. 
  4. A C Bach et al. Am J Clin Nutr. 1982;36(5):950–962.
  5. Tan J et al. Advances in Immunology. 2014;121:91-119. 
  6. St-Pierre V et al. J Functional Foods. 2017;32:170-275.
  7. Nagao K et al. Pharmacological Research. 2010;61:208-212. 
  8. Kinsella R et al. Physiology & Behavior. 2017;179:422-426.
  9. Khabbush A et al. Epilepsia. 2017;58(8):1423-1429. 

5 Common Mistakes People Make with Intermittent Fasting


Intermittent fasting is a hot topic these days. This type of eating pattern involves an “eating window” and a “fasting window,” rather than a style of eating that pertains to food groups or macronutrients. The length of each window can differ depending on the style you choose to adopt. 
Fasting, documented throughout history for its benefits, has been adopted all around the world and is now accepted as a way to support human health. Some published data reports benefits of intermittent fasting such as weight loss, improved mental clarity, improved metabolism, better glucose regulation, and the potential to slow natural aging conditions, among others.1
The most common forms of intermittent fasting are: 
  • Daily intermittent fasting: eating within a 4-10-hour window and fasting for 14-20 hours
  • 24-hour fast: fasting for 24 hours, typically 1-2 times a week  
  • 5:2 protocol: restricting calories to 20-25% of your usual intake for two nonconsecutive days in a 7-day time frame and consuming calories as per usual for the other 5 days 

Regardless of the intermittent fasting form people choose, they tend to make the same five common mistakes:

1. Not eating the suggested foods 

This is by far the biggest mistake you can make when trying to implement an intermittent fasting schedule into your life. In order to fast successfully, you generally need to be able to control your appetite for a long stretch of time (~12-24 hours). Food choices will make this practice easy or hard, and you don’t want this to be hard! Metabolism works like a hybrid car: For fuel you can either burn glucose or fats and the byproducts of fat metabolism, ketones.

A carbohydrate reliance can make fasting difficult because our blood glucose is constantly fluctuating, and in turn our appetite is constantly fluctuating. An easy way to fast is to follow a low-carbohydrate diet where the focus is on quality proteins and fats. This way you are satiated for longer periods of time and allow for the metabolic flexibility to tap into fat stores for fuel during the fasting window. You may even end up going in and out of ketosis without even trying, just by virtue of the diet and the long periods of time between meals. The satiety factor of a low-carbohydrate diet can work in your favor during the fasting window.    

2. Not being prepared 

Intermittent fasting goes against society’s “normal” eating patterns. If you participate in daily intermittent fasting, you are probably eating at odd times of the day, breakfast at 11 AM or dinner at 4 PM, for example. If you work a standard 9-5 job, this can be challenging, but all it takes is a little preparation. Instead of eating breakfast at home, pack your meal to eat later, and the same goes for trying to eat dinner earlier. When you fail to prepare for your eating window, you might end up gravitating toward poor food choices when it’s “time to eat” or get stuck eating late into the evening. 

3. Not eating enough calories 

Although intermittent fasting is typically used as a strategy to inadvertently reduce overall caloric intake, restricting calories too much could have certain negative consequences. This is most pronounced in athletes and women. For athletes, activity level and goals should be taken into consideration when choosing an intermittent fasting protocol to support and enhance performance, muscle growth, and recovery. If you struggle to consume enough calories in your allotted “eating window,” consider extending your window to support your goals and optimize your health. 

4. Restricting all day and binging at night 

Have you ever gone an entire day without eating, only to come home later and clean out the entire pantry, fridge, and everything in between? Waiting until the end of the day to consume all, or the majority, of daily calories can work for some people but in others may trigger binge eating. This could lead to consuming more food than you normally would have, had you spread your meals throughout the day. In addition, overeating in the evening, and too close to bedtime, can result in poor sleep and disruption of circadian rhythms. You may wake up not feeling your best by eating in this way, and the whole reason for intermittent fasting is to feel better! Shifting the eating window to earlier hours of the day, for example 11 AM to 7 PM, may prevent overeating or binging into the late hours of the night.          

5. Making exceptions for what you consume outside your “eating window”  

This is a very common mistake and is actually quite controversial. To make things simple, anything with calories, and therefore energy, “breaks a fast.” This means no butter in your coffee and no glass of wine before bed. We hate to break it to you, but a true fast includes water only. With that said, if you are intermittently fasting for weight loss, herbal tea and black coffee are okay to consume outside your eating window, as they do not contribute to overall calorie intake. It is in your best interest to avoid zero-calorie sweetened beverages as well, since certain sweeteners, calorie-free or not, can actually trigger an insulin response and negate many of the benefits of fasting.2    
Reference:
  1. Mattson MP et al. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017;39:46–58. 
  2. Pepino MY et al. Sucralose affects glycemic and hormonal responses to an oral glucose load. Diabetes Care. 2013;36(9):2530-2535.

4 Common Types of Intermittent Fasting


By Annalouise O’Connor, PhD, RD
Intermittent fasting is a dieting style growing rapidly in popularity. We sat down with Annalouise O’Connor, PhD, RD to learn more about this eating option. 

Q: What is the difference between traditional dieting and intermittent fasting?

When people go on a traditional diet, their primary focus is on what they eat and how to cut calories every day until their weight loss goal is met. Intermittent fasting differs in that the primary focus is on when you eat. Intermittent fasting focuses on the food timing pattern and builds in clear fasting windows of at least 12 consecutive hours. 
Another difference lies in the potential benefits and how they are discussed. When we think “diet,” we generally think weight loss. But the benefits of intermittent fasting are thought of more broadly than this. Many studies have shown us that intermittent fasting leads to successful weight management, but there are examples of benefit beyond or independent of weight loss, making these protocols relevant to a broader group of people.1,2

Q: Why do you think there is so much interest in intermittent fasting? 

Intermittent fasting protocols firstly provide another layer of personalization, helping people meet their individual health goals, beyond focusing on what they eat. 
Intermittent fasting also applies what we are learning about the body’s need to repair and renew each day and the link to its circadian rhythms. If these circadian rhythms (processes that the body follows over 24 hours), become dampened or irregular, it can spell trouble for weight management, glucose control, and mood.3 Introducing short periods of fasting within a 24-hour period can help reset these circadian patterns and provide the body with a break from digesting food and storing nutrients to focus on critical repair activities.1
With no incoming nutrients, the body must dip into stored energy during these times of fasting and shifts from preferring glucose as an energy source to using fat or ketone bodies (an energy source made from fat)—a shift described as “flipping the metabolic switch,” which is proposed to underlie many of the health benefits of intermittent fasting.1 For someone having three meals and snacks throughout the day and into the evening, this may rarely happen. Intermittent fasting can help to “flip this metabolic switch” and provide the body with the time it needs to engage in repair. 

Q: I understand there are four common intermittent fasting protocols. Can you take us through each one?

One popular protocol is time-restricted feeding (TRF), which sets the eating window to anywhere from 4-12 hours per day. A typical protocol is 16:8, which basically means all food is eaten during an 8-hour eating window. This is followed by a 16-hour fast (water or zero-calorie beverages only). This protocol applies our learning on how the feeding-fasting cycle can help to keep circadian rhythms regular.
Another well-studied protocol is alternate-day fasting (ADF). This involves a fast of at least 24 hours alternating with a nonfasting day, which is not restricted. This fasting period allows the body to dip into its stored energy and take a break from digestion in order to focus on repair.
An evolution of the ADF protocol is the modified alternate-day fasting protocol (mADF). During this protocol, instead of a total fast during each alternating 24-hour period, intake is restricted to 500-600 kcal on these days. Because of the very low intake, the body still needs to dip into energy stores, and because it is hard to make 500 kcal last, it indirectly introduces a fasting window of at least 12 hours (in practice this tends to be much longer) in between eating occasions.
The 5:2 protocol takes the concept of the very low intake (~500-600 kcal) from the mADF and applies it two days per week. The two restricted days can be consecutive or nonconsecutive. There are variations on this protocol, for example 6:1, where the 500-600 kcal intake is consumed just on one day of the week, and the remaining 6 days are nonrestricted.

Q: Doesn’t that seem a little drastic? 

What we know about our ancestral populations indicates that we evolved experiencing time periods with little or no food. Fasting for religious reasons has been documented for thousands of years, so we evolved with an ability to cope with periods of food absence, and this was maintained culturally.1
In many ways we have been mentally programmed to think about having three meals plus snacks every day, but our current eating pattern may be very much at odds with how we how we as a species have eaten in the past, and this can impact our health status.

Q: Are there different patient types associated with each option? Or do practitioners tend to recommend them on a patient-by-patient basis?

We see in the scientific literature that intermittent fasting is effective for a range of outcomes. However, we don’t yet have head-to-head studies comparing their effects. Practitioners can use what we do know and layer in other aspects of personalization in a plan that can work for someone long-term—things like medical history, work schedule, family eating times, trigger points, and so on.
For weight management the four common protocols discussed have been shown to be effective.4-7 Interestingly, these protocols have been shown to be as effective for weight management as traditional diets, but not more effective—at least in the research setting. In the real world we know that weight management can be an ongoing challenge, and one of the benefits of intermittent fasting protocols is that they offer more flexible tools in a person’s toolbox.
Protocols such as 5:2 may be particularly relevant depending on what an individual thinks about “going on a diet,” and what his or her specific pain points are when it comes to weight management. One quote that’s stuck with me from a study of women’s experiences when following a 5:2 protocol was, “For me it’s about not feeling like I’m on a diet.”8 For the women in the study, the intermittent fasting protocol was seen to be sufficiently flexible to fit in with the demands of life and didn’t lead to all-or-nothing thinking when it came to dieting, which can be a barrier to adherence.8
Another theme that’s emerged from work on intermittent fasting is that participants tend to eat less on the unrestricted days than they did before the study started. We see this in studies on 5:2 and mADF studies where although the restriction days over time may not be as low as planned, there is a real carry-over effect, meaning that rather than wanting to overcompensate, participants were naturally eating less on the nonrestricted days. 
Some research has indicated that postmenopausal women lost more weight with mADF than premenopausal women.9 So age and hormonal status are other factors that practitioners may take into account when developing a personalized protocol. 
Finally, when it comes to healthy insulin function, another study that sticks out is a recent study in men following an early time-restricted feeding protocol, where all food was eaten earlier in the day (ate all food in the morning and early afternoon) compared to eating the same amount of food over a standard 12-hour window. Even without any weight change, having a strict eating window of early in the day led to better insulin function.2

Q: Do people tend to stay with one method or switch among them as they get closer to reaching their goals?

This depends on the goals of each individual patient. One of the major benefits of having these additional protocols is that they provide more flexibility for people, as well as more options that a practitioner can work with to get people to where they need and want to be. These can certainly be combined or switched over time. The only word of caution is to work with a practitioner to ensure that the protocol is being applied appropriately before switching to something else. Small tweaks within a protocol may be more effective than bouncing from protocol to protocol.

Q: What else should people know about intermittent fasting before talking to a healthcare practitioner? 

Know that the foundations of healthy food choices still apply. This plan is not just about skipping meals. The quality of food, such as including plenty of raw fruits and vegetables, ensuring you are getting enough fiber, watching your refined sugar intake—these are all still relevant in this eating pattern.
Continue to build physical activity into your week, aiming for at least 150 minutes per week and building from there. Consider activity such as High-Intensity Interval Training (HIIT), which has been shown to be a time-effective tool to reduce abdominal and visceral adiposity, as well as improving insulin sensitivity and building muscle, along with cardio and resistance training. 
Don’t forget to stay hydrated with plenty of plain water and herbal teas or other zero-calorie beverage options throughout the day.
Finally, see a practitioner who can guide you on the intermittent fasting protocol that will help you reach your health goals. Your practitioner can also make sure that intermittent fasting is right for you. There are certain groups, for example women who are pregnant or breastfeeding, whom intermitting fasting is not right for. But there are other important things to keep an eye on when embarking on any new protocol, especially something like intermittent fasting. A practitioner can track hormones and other biomarkers, or for women track menstrual cycle changes, and make any necessary protocol tweaks to keep these parameters where they should be. 
References:
  1. Anton SD et al. Obesity (Silver Spring). 2018;26(2):254-268.
  2. Sutton EF et al. Cell Metab. 2018;27(6):1212-1221 e1213.
  3. Panda S. Nat Rev Endocrinol. 2019;15(2):67-69.
  4. Headland ML et al. Int J Obes (Lond). 2018.
  5. Trepanowski JF et al. JAMA Intern Med. 2017;177(7):930-938.
  6. Gabel K et al. Nutr Healthy Aging. 2018;4(4):345-353.
  7. Catenacci VA et al. Obesity (Silver Spring). 2016;24(9):1874-1883.
  8. Donnelly LS et al. J Hum Nutr Diet. 2018;31(6):773-780.
  9. Barnosky A et al. Nutr Healthy Aging. 2017;4(3):255-263.

Intermittent Fasting on the Ketogenic Diet

By Dr. Robert Silverman
Fat is your friend, not your foe—a claim that followers of the ketogenic diet have been supporting for almost 100 years. Compared with the Standard American Diet (SAD), the ketogenic diet is not only safe for helping overweight and obese people lose weight, it also supports brain health and improves energy levels.1,2,3 Those who have experienced the benefits of the ketogenic diet, or keto diet, might also be curious about trying intermittent fasting and whether it’s feasible to combine the two. Good news: It’s not only possible, it’s a weight loss strategy I highly recommend.
Here, I explore the two dietary approaches and discuss their individual and combined health benefits. Be sure to consult with your own healthcare practitioner before embarking on any new diet plan.
What is the ketogenic diet?
The keto diet is based on the idea that eating mostly healthy fats, consuming high-quality protein in moderation, and restricting carbohydrates to less than 50 grams per day can cause your body to go into a metabolic state called nutritional ketosis.4,5 During ketosis, your body no longer relies on glucose as a primary energy source. Instead, your liver converts fat into ketones–which are an alternative source of fuel for your brain.
On the keto diet, you’ll get most of your calories from healthy fats found in foods like avocados, grass-fed butter, olives, olive oil, medium-chain triglyceride (MCT) oil, coconut oil, nuts, and seeds. However, keep in mind that some nuts and seeds are better than others. Choose those that are high in fats and lower in carbs; brazil nuts, almonds, walnuts, chia seeds, and flaxseed are all good options. You can also eat all of the nonstarchy, leafy vegetables you want, as well as other low-carb vegetables like broccoli rabe, peppers, bok choy, cauliflower, spinach, asparagus, cucumber, and zucchini. In moderation, eat protein in the form of grass-fed meats, pasture-raised poultry, cage-free eggs, and wild-caught fish. When it comes to fish, choose fatty fish by remembering the acronym SMASH: salmon, mackerel, anchovies, sardines, and herring. Finally, if you want to reach for something sweet, a small amount of 90% dark chocolate is your best option.
On the list of what not to eat? For starters, remember that the keto diet restricts the intake of carbohydrates to achieve a shift from glucose to ketones as a primary fuel source. In order to avoid food high in carbs, limit fruit consumption, as it’s higher in sugar content, and forego fruit juice altogether. You should also avoid grains or starches such as rice or pasta, beans or legumes, root vegetables, and any low-fat or diet products, as they are typically high in added sugars and highly processed.
What is intermittent fasting?
While there are different types of intermittent fasting, such as daily, weekly, and alternate day, the most common involves only eating during a specified window of time each day. That window typically spans between four and seven hours of feeding during the day, but it can be reduced or expanded depending on your dietary needs. Of its many benefits, intermittent fasting works on both sides of the calorie equation.6It increases the amount of calories you burn by boosting your metabolic rate and reduces the amount of calories you consume by limiting the food you eat. According to a 2014 review, intermittent fasting can cause weight loss of 3-8% over 3-24 weeks.7 A study also showed that intermittent fasting caused less muscle loss than continuous calorie restriction.8

What are the benefits of fasting on the keto diet?

Individually, the keto diet and intermittent fasting can be effective weight loss tools that help people lead healthier lives. However, there are also a number of health benefits that can be optimally achieved when the two are combined:
    • Intermittent fasting activates autophagy—a phenomenon where the body eats its own cells and tissues—in a good way.9 Autophagy helps the body remove harmful and toxic compounds, recycle damaged proteins, and increase the production of ketones quicker than on the standard keto diet. Different processes of autophagy occur when either the body is starved or protein and carbohydrates are restricted. Both of these occur when intermittent fasting is combined with the keto diet.6 Combining the two allows you to reap the benefits of autophagy in an efficient way.
    • The combination of intermittent fasting and eating a keto diet can help you get into ketosis faster. The keto diet makes intermittent fasting more manageable because your body is already adapted to fasting with ketones. In addition, most people naturally eat less frequently on keto because of the high satiety level, so you’re likely already used to bigger windows without food.
    • One of the foremost reasons people turn to intermittent fasting on the keto diet is to lose weight faster.10 Fasting can help you break through weight loss plateaus in a few different ways: Eating a high-fat keto diet and being in ketosis reduces appetite and increases satiety levels.11 It’s much easier to do intermittent fasting when this is the case, versus a diet of carb-filled foods that often increases cravings.
    • Combining the keto diet with intermittent fasting can help decrease oxidative stress and inflammation in the body.12,13 Inflammation is part of the body’s complex biological immune response to illness, infections, injury, and other forms of stress.14 Up to a point, inflammation is normal and even desirable. But long-term, excessive inflammation can lead to joint pain, digestive issues, and other health problems.
    • The combined efforts of intermittent fasting and the keto diet lead to enhanced cognitive performance and neuroplasticity. Cognitively, the brain operates better on ketones versus glucose from sugar or carbs.15,16,17 Ketones are an efficient, slow-burning fuel source with preserved uptake by the brain–lending itself to heightened levels of concentration and longer periods of focus.18 Ketones also increase the brain-derived neurotrophic factor (BDNF), which works to support the brain’s existing neurons while encouraging new neuron and synapse growth.19,20
  • Finally, using both these strategies together can help stabilize blood sugar levels as compared to intermittent fasting alone.4 Alternating between glucose and ketones for energy can cause spikes in blood sugar, leading to brain fog, mood swings, low energy, and other side effects. Someone eating the SAD might experience this with intermittent fasting; however, during keto-adaptation, liver and muscle glycogen deposits are maintained. With the absence of glucose to burn, you won’t experience the peaks and valleys of varying blood sugar levels. 
While intermittent fasting is not a necessary part of following a keto diet, I definitely recommend the approach if you want to double down on benefits, achieve previously unattainable results, and meet new health goals. Alone, each has its weight loss and healthy lifestyle benefits. Together, they can help you achieve your optimum health from the inside out.
References:
  1. Gibas MK et al. Induced and controlled dietary ketosis as a regulator of obesity and metabolic syndrome pathologies. Diabetes Metab Syndrome. 2017;11(1):S385-S390.
  2. Stafstrom CE et al. The ketogenic diet as a treatment paradigm for diverse neurological disorders. Frontiers in Pharmacology 2012; 3:59.
  3. Hoyer S. Abnormalities of glucose metabolism in Alzheimer’s disease. Annals of the New York Academy of Science. 1991;640:53-58.
  4. Volek JS et al. Comparison of energy-restricted very low-carbohydrate and low-fat diets on weight loss and body composition in overweight men and women. Nutr Met. 2004;1:13.
  5. Abbasi J. Interest in the ketogenic diet grows for weight loss and type 2 diabetes. JAMA. 2018;319(3):215-217.
  6. Klempel MC. Dietary and physical activity adaptations to alternate day modified fasting: implications for optimal weight loss. Nutr J. 2010;9:35.
  7. Barnosky A. Intermittent fasting vs daily calorie restriction for type 2 diabetes prevention: a review of human findings. ScienceDirect. 2014;164(4):302-311.
  8. Varady K. Intermittent versus daily calorie restriction: which diet regimen is more effective for weight loss? Obes Rev. 2011;12(7):e593-601.
  9. McCarty M et al. Ketosis may promote brain macroautophagy by activating Sirt1 and hypoxia-inducible factor-1. Med Hypotheses. 2015;85(5):631-639.
  10. Johnstone A. Fasting for weight loss: an effective strategy or latest dieting trend? Int J Obes. 2015;39(5):727-733.
  11. Van Wymelbeke V et al. Substrate oxidation and control of food intake in men after a fat-substitute meal compared with meals supplemented with an isoenergetic load of carbohydrate, long-chain triacylglycerols, or medium-chain triacylglycerols. Am J Clin Nutr. 2001;74(5):620-630.
  12. Mattson M et al. Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems. Nutr J. 2005;16.
  13. Johnson J. Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma. Free Radic Biol Med. 2007 1;42(5):665-674.
  14. Faris M. Intermittent fasting during Ramadan attenuates proinflammatory cytokines and immune cells in healthy subjects. Nutr Res. 2012;32(12):947-955.
  15. Zhao W et al. Caprylic triglyceride as a novel therapeutic approach to effectively improve the performance and attenuate the symptoms due to the motor neuron loss in ALS disease. PLoS One. 2012:7(11):e49191.
  16. Kim DY et al. Inflammation-mediated memory dysfunction and effects of a ketogenic diet in a murine model of multiple sclerosis. PLoS One. 2012:7(5):e35476.
  17. Henderson ST et al. Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer’s disease: a randomized, double-blind, placebo-controlled, multicenter trial. Nutrition & Metabolism. 2009;6:31.
  18. Volek JS et al. Rethinking fat as a fuel for endurance exercise. Eur J Sport Sci. 2015;15(1):13-20.
  19. Lee J. Dietary restriction increases the number of newly generated neural cells, and induces BDNF expression, in the dentate gyrus of rats. J Mol Neurosci. 2000;15(2):99-108.
  20. Volek JS et al. The art and science of low carbohydrate living. Beyond Obesity;2011.

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