Why Intermittent Fasting Is More Effective Combined With Ketogenic Diet


  • Fasting upregulates autophagy and mitophagy — natural cleansing processes necessary for optimal cellular renewal and function. It also activates stem cells and stimulates mitochondrial biosynthesis
  • Most of these rejuvenating and regenerating benefits occur during the refeeding phase, not the “starvation” phase. The same holds true for nutritional ketosis, which produces the greatest benefits when pulsed
  • Recent research highlights the importance of nutritional ketosis when intermittently fasting. While the participants lost about 3 percent of their body weight by eating all of their food within eight consecutive hours each day, by not altering their dietary choices, important disease parameters remained unimproved
  • Metabolic health parameters that did not significantly improve included visceral fat mass, diastolic blood pressure, LDL cholesterol, HDL cholesterol, triglycerides, fasting glucose and fasting insulin
  • Cyclical ketosis provides many of the same health benefits associated with intermittent fasting, and when done together, most people will experience significant improvements in their health, including but not limited to mere weight loss

Fasting has been used for thousands of years to keep us well, and it’s the most profoundly effective metabolic intervention I know of. Not only does it upregulate autophagy and mitophagy — natural cleansing processes necessary for optimal cellular renewal and function — but it also triggers the generation of stem cells. The cyclical abstinence from food followed by refeeding also massively stimulates mitochondrial biosynthesis.

There’s even evidence to suggest fasting can help prevent or even reverse dementia, as it helps your body clean out toxic debris. By lowering insulin, you also increase other important hormones, including growth hormone (known as “the fitness hormone”), which is important for muscle development and general vitality.

Most of these rejuvenating and regenerating benefits occur during the refeeding phase, not the “starvation” phase. The same holds true for nutritional ketosis, which produces the greatest benefits when pulsed. I’ve written a number of articles on both of these topics. Here, the focus is on why these two strategies work best when combined.

Fasting Is a Powerful Tool for Rejuvenation and General Health

Research shows fasting is a powerful lifestyle tool for combating obesity, insulin resistance, and related health problems, including cancer. The reason for this is because when autophagy increases, your body starts breaking down and recycling old protein, including beta-amyloid protein in your brain believed to contribute to Alzheimer’s. Then, during the refeeding phase, growth hormone increases, boosting the rebuilding of new proteins and cells. In other words, it reactivates and speeds up your body’s natural renewal cycle.

While water-only fasting can be extremely beneficial for those struggling with excess weight and/or Type 2 diabetes, compliance can be difficult. Fortunately, research has confirmed that similar results (albeit not as profound) can be achieved through intermittent fasting, i.e., following a meal-timing schedule where you’re fasting for at least 16 hours every day and eating all of your meals within eight consecutive hours.

There are also other intermittent fasting plans where you dramatically cut back on your calories for a certain number of days each week while eating normally during the remainder. The 5-to-2 intermittent fasting plan is one such example. The fasting mimicking diet, developed to match the effects of water-only fasting, is another. Most if not all of these plans have similar benefits, which include:1,2,3,4

Upregulating autophagy and mitophagy Increasing growth hormone by as much as 1,300 percent in women and 2,000 percent in men,5 thereby promoting muscle development and vitality
Shifting stem cells from a dormant state to a state of self-renewal Preventing, slowing the progression of, and reversing Type 2 diabetes
Boosting mitochondrial energy efficiency and biosynthesis Reproducing some of the cardiovascular benefits associated with exercise
Lowering inflammation Improving pancreatic function
Improving circulating glucose and lipid levels Protecting against cardiovascular disease
Reducing blood pressure Modulating levels of dangerous visceral fat
Improving metabolic efficiency and body composition Reducing low-density lipoprotein and total cholesterol
Significantly reducing body weight in obese individuals Improving immune function6
Boosting production of a brain-derived neurotrophic factor, which stimulates the creation of new brain cells and triggers brain chemicals that protect against brain changes associated with Alzheimer’s and Parkinson’s disease7

New Research Questions Effectiveness of Intermittent Fasting When Still Eating Poorly

While intermittent fasting may sound like a panacea against ill health and excess weight, it alone may not provide you with all of these benefits. The quality of your diet plays an important role if you’re looking for more than mere weight loss. More specifically, recent research highlights the importance of nutritional ketosis when intermittently fasting.

The study8,9 in question examined the effects of intermittent fasting on weight loss and metabolic disease risk parameters in 23 obese volunteers. The study lasted for three months. Between 10 a.m. and 6 p.m., the participants were allowed to eat whatever they wanted in any quantity. For the remaining 16 hours, they were only permitted water or calorie-free drinks. The outcomes were then compared to a nonintervention control group from a previous fasting trial.

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Overall, participants consumed about 350 fewer calories per day and lost just under 3 percent of their body weight. Systolic blood pressure also dropped about 7 mmHg, compared to the historical control group. Lead author Krista Varady, associate professor at the University of Illinois at Chicago, commented on the results saying,10 “The take-home message from this study is that there are options for weight loss that do not include calorie counting or eliminating certain foods.”

While these findings are similar to other intermittent fasting studies, the participants’ weight loss was slightly less than what’s been observed in other studies. Trials of alternate-day fasting and the 5-to-2 fasting plan have found people lose between 3 and 8 percent in eight to 52 weeks. According to the authors, “We speculate that this difference in weight loss is due to greater overall caloric restriction achieved with other forms of intermittent fasting …”

While this may sound “good enough,” there’s an important detail that needs to be addressed. While participants did lose weight, other metabolic health parameters did not significantly improve compared to no-treatment controls, including visceral fat mass, diastolic blood pressure, LDL cholesterol, HDL cholesterol, triglycerides, fasting glucose and fasting insulin.

Weight Loss Alone Won’t Fix Your Health Problems

As I’ve repeatedly mentioned, one of the key benefits of intermittent fasting is normalizing your glucose and insulin levels — along with many other biological metrics, including all of the ones mentioned above — and that simply didn’t happen here. The question is why? I believe the answer is fairly obvious, based on the evidence. The participants were not instructed to alter WHAT they ate, and if they were anything like a majority of Americans, a large portion of their diet was likely processed food and probably even fast food.

The issue of food choices was a sticking point for me when I interviewed Varady on her alternate-day fasting diet back in 2014. That particular plan consists of eating just 500 calories every other day, but what form those calories take is up to the individual. At the time, I stressed the importance of eating a diet high in healthy fats, moderate in protein with unrestricted amounts of fresh vegetables to optimize overall health on an intermittent fasting program.

The reason for my objection to not including specific guidelines on food choices was exactly what her latest study shows — unless you also balance your macronutrient ratios, you might lose weight, but you’ll forgo many of the most important health benefits. If you lose weight but don’t move the needle on glucose, insulin and other disease risk parameters, then the benefit is little more than cosmetic.

For Optimal Health, Combine Intermittent Fasting With Cyclical Nutritional Ketosis

So, while the featured study presents intermittent fasting as a successful weight loss method, from my perspective it really highlights the importance of combining intermittent fasting with cyclical nutritional ketosis.

The ketogenic diet provides many of the same health benefits associated with fasting and intermittent fasting (listed above), and when done together, most people will experience significant improvements in their health — including not just weight loss, which is more of an inescapable side effect of the metabolic improvements that occur, but other benefits such as:

Improved insulin sensitivity, which is key for preventing insulin resistance, Type 2 diabetes and related diseases. Studies have shown diabetics who stick to a ketogenic diet are able to significantly reduce their dependency on diabetes medication. Many have even successfully reversed their diabetes this way.11 Having a healthy insulin level will also lower your risk of Alzheimer’s, as dementia and insulin resistance are closely linked.12

Increased muscle mass. Ketones are structurally similar to branched-chain amino acids, and since they tend to be preferentially metabolized, they spare whatever branched-chain amino acids you have, thereby promoting muscle mass.

Reduced inflammation. Your body is designed to have the metabolic flexibility to use both sugar and fat as fuel sources. However, fat is preferred as it generates far fewer reactive oxygen species and secondary free radicals when burned. So, by eliminating sugar from your diet, you significantly decrease your risk of chronic inflammation.

Reduced risk of cancer. I believe cyclical ketosis is a revolutionary intervention that can significantly lower your risk of becoming a cancer statistic, for the simple reason that cancer cells lack the metabolic flexibility to use ketones for its energy needs, which your regular cells can. Once your body enters nutritional ketosis, cancer cells no longer have a readily available source of nourishment and essentially “starve” to death before they can become a problem.

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Increased longevity. Ketosis spares protein breakdown, which is one of the reasons you can survive a long time without food. Much like calorie restriction (fasting), ketones also help clear out malfunctioning immune cells13 and reduce IGF-1, which regulates growth pathways and growth genes and plays an important role in aging and autophagy and mitophagy.

Ketone metabolism also increases the negative redox potential of your family of NAD coenzyme redox molecules, which helps control the oxidative damage by increasing NADPH and promoting transcription of enzymes of the antioxidant pathways through activation of FOXO3a.14

In a nutshell, ketone metabolism effectively reduces oxidative damage, which translates into improved health and longevity. The lack of sugar also helps explain why the ketogenic diet is associated with life extension.

Sugar is a very potent accelerator of aging and premature death, in part by activating two genes known as Ras and PKA, both of which are known to accelerate aging.15 A third reason has to do with the fact that both calorie restriction and intermittent fasting inhibit the mTOR pathway, which has been shown to play an important role in life extension.

Weight loss: If you’re trying to lose weight, then a ketogenic diet is one of the best ways to do it because it helps to access your body fat so that it can be shed. In one study,16 obese test subjects were given a low-carb ketogenic diet and a low-fat diet. After 24 weeks, researchers noted that the low-carb group lost more weight (9.4 kilograms; 20.7 pounds) compared to the low-fat group (4.8 kilograms; 10.5 pounds).

Even my own body was able to feel the benefits of following a ketogenic diet. When I first began, my weight dropped from 180 to 164 pounds, despite eating 2,500 to 3,000 calories per day. Since then, I have increased my consumption to 3,500 to 4,000 calories just to maintain my ideal weight.

Why Cyclical Ketosis?

A ketogenic diet and intermittent fasting both allow your body to shift from sugar- to fat-burning — an important metabolic flexibility that in turn promotes optimal function of all the cells and systems in your body. And, while there’s evidence supporting either of these as stand-alone strategies, it seems clear to me that combining them will produce the best results overall.

As there are caveats with intermittent fastings, such as the importance of eating healthy whole or minimally processed foods when you do eat, there are caveats when it comes to nutritional ketosis as well. Most people believe continuous keto is the key to success, but mounting evidence suggests this is not the case. This is why the mitochondrial metabolic therapy (MMT) program detailed in my book, “Fat for Fuel,” stresses cyclical ketosis. There are at least two significant reasons for the pulsed approach:

Insulin suppresses hepatic glucogenesis, i.e., the production of glucose by your liver. When insulin is chronically suppressed long-term, your liver starts to compensate for the deficit by making more glucose. As a result, your blood sugar can begin to rise even though you’re not eating any carbohydrates.

In this situation, eating carbohydrates will actually lower your blood sugar, as the carbs will activate insulin, which will then suppress your liver’s production of glucose. Long-term chronic suppression of insulin is an unhealthy metabolic state that is easily avoidable by cycling in and out of keto.

More importantly, many of the metabolic benefits associated with nutritional ketosis in general actually occur during the refeeding phase. During the fasting phase, clearance of damaged cell and cell content occurs, but the actual rejuvenation process takes place during refeeding.

In other words, cells and tissues are rebuilt and restored to a healthy state once your intake of net carbs increases. (The rejuvenation that occurs during refeeding is also one of the reasons intermittent fasting is so beneficial, as you’re cycling between feast and famine.)

How to Implement Cyclical Keto and Fasting

To reiterate, fasting and nutritional ketosis provide many of the same benefits, and both work best when implemented in a pulsed fashion. Together, I believe cyclical keto and intermittent fasting is a near-unbeatable combination capable of really maximizing the health benefits of both. While the details are provided in “Fat for Fuel,” here is a summary of how to implement these two strategies as a cohesive health program:

1. Implement an intermittent fasting schedule: Eat all of your meals — either breakfast and lunch or lunch and dinner — within an eight-hour window each day. Fast for the remaining 16 hours. If all of this is new to you and the idea of making changes to your diet and eating habits seems too daunting, simply start out by eating your regular diet on this time schedule.

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Once this has become routine, move on to implement the ketogenic diet (step 2), followed by the cyclical component (step 3). You can take comfort in knowing that once you reach step 3, you will be able to cycle in some of your favorite healthy carbs once again on a weekly basis.

If you want to further maximize the health benefits of fasting, consider graduating into doing five-day, water-only fasts on a regular basis. I do it three to four times a year. To make the process easier, slowly work your way up to the point where you’re fasting for 20 hours a day and eating your two meals within a span of just four hours. After a month of doing this, pulling off a five-day water fast will not be nearly as challenging.

2. Switch to a ketogenic diet until you can create measurable ketones: The three-part key is to 1) restrict net carbohydrates (total carbs minus fiber) to 20 to 50 grams per day, 2) replace the lost carbs with healthy fats so that you’re getting anywhere from 50 to 85 percent of your daily calories from fat, and 3) limit protein to one-half gram of protein per pound of lean body mass. (To determine your lean body mass, subtract your body fat percentage from 100, then multiply that percentage by your current weight.)

Vegetables, which are loaded with fiber, can be eaten without restrictions. The primary carb sources that need to be cut out are grains and all forms of sugar, including high-fructose fruits. (Healthy net carbs will be cycled back in once you’ve entered ketosis.)

Examples of healthy fat sources include avocados, coconut oil, animal-based omega-3 from fatty fish, butter, raw nuts (macadamia and pecans are ideal as they’re high in healthy fat while being low in protein), seeds, olives and olive oil, grass-fed animal products, MCT oil, raw cacao butter and organic pastured egg yolks. Avoid all trans fats and highly refined polyunsaturated vegetable oils.

Adding these harmful fats17 can cause more damage than excess carbs, so just because an item is “high in fat” does not mean you should eat it. Maintain these ratios of net carbs, fat, and protein until you’ve achieved ketosis and your body is burning fat for fuel. Keto testing strips can be used to confirm that you’re in ketosis, defined as having blood ketones in the range of 0.5 to 3.0 mmol/L.

Keep in mind that precision is important when it comes to these nutrient ratios. Too many net carbs will effectively prevent ketosis as your body will use any available glucose first since it’s a much faster-burning fuel.

Since it’s virtually impossible to accurately estimate the amount of fat, net carbs, and protein in any given meal, make sure you have some basic measuring and tracking tools on hand. This includes a kitchen scale, measuring cups and a nutrient tracker.

3. Once you’ve confirmed that you’re in ketosis, begin cycling in and out of keto by adding higher amounts of net carbs back in, once or twice a week. As a general recommendation, triple the amount of net carbs on these high-carb days.

Keep in mind it can take anywhere from a couple of weeks to a few months before your body is able to effectively burn fat again. Again, cycling in and out of nutritional ketosis will maximize the biological benefits of cellular regeneration and renewal, while minimizing the potential drawbacks of continuous keto.

While higher net carb amounts are allowed once or twice a week at this stage, I would advise you to still be mindful of what’s healthy and what’s not. Ideally, you’d forgo potato chips and bagels, and focus on adding in healthier alternatives such as digestive-resistant starches.

High net-carb foods such as potatoes, rice, bread, and pasta all become more digestive-resistant when they’re cooked, cooled and then reheated, and this is one way of making such indulgences a bit healthier.

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