Intermittent Fasting and Time-Restricted Eating (TRE) 2023: The Science Behind

By Dr. Frank Yap, MD - November 16, 2023

If you trying to understand and looking for evidence about time-restricted eating, you've come to the right place.

Time-restricted eating is just what it sounds like. It's a form of intermittent fasting where you eat all of your meals for the day within a restricted window of time, ranging from two to eight hours. That means you're avoiding food (fasting) for 16 to 22 consecutive hours. Eating within a four- to six-hour window is likely close to metabolic ideal for most. As noted in the paper "A Time to Fast," published in the November 2018 issue of Science:

"Adjustment of meal size and frequency have emerged as powerful tools to ameliorate and postpone the onset of disease and delay aging, whereas periods of fasting, with or without energy intake, can have profound health benefits.

The underlying physiological processes involve periodic shifts of metabolic fuel sources, promotion of repair mechanisms, and the optimization of energy utilization for cellular and organismal health …

In general, both prolonged reduction in daily caloric intake and periodic fasting cycles have the power to delay the onset of disease and increase longevity."

Research overwhelmingly supports the notion that ditching the three square meals a day approach in favor of time-restricted feeding — a form of intermittent fasting — can do wonders for your health. Contrary to modern belief, your body isn't designed to be fed throughout the day, and the near-continuous grazing that most engage in can have serious health consequences.

Research by Satchidananda Panda, Ph.D., suggests 90% of people eat for more than 12 hours a day, and over time this habit will wreak havoc on your metabolism and limit your ability to metabolize fat as a primary fuel.

When you eat throughout the day and never skip a meal your body adapts to burning sugar as its primary fuel, resulting in the downregulation of enzymes that utilize and burn stored fat.(1,2)

As a result, you become progressively more insulin resistant and start gaining weight. Efforts to lose weight also become ineffective for this very reason, since to lose body fat, your body must first be able to actually burn fat.

Many biological repair and rejuvenation processes also take place while you're fasting, and this is another reason why all-day grazing triggers diseases while fasting prevents them.

Dr Jason Fung's Story

Dr Jason Fung, in his book entitled “The Complete Guide to Fasting”, articulated the following:

I grew up in Toronto, Canada, and studied biochemistry at the University of Toronto, where I also completed medical school and my residency in internal medicine. After my residency, I chose to study nephrology (kidney disease) at the University of California, Los Angeles, mostly at Cedars-Sinai Medical Center and West Los Angeles VA Medical Centers (then known as the VA Wadsworth). Each field of internal medicine draws its own personalities, and nephrology has the reputation of being a “thinker’s specialty.” Kidney disease involves intricate fluid and electrolyte problems, and I enjoy these puzzles. In 2001 I returned to Toronto to start my career as a nephrologist.

Type 2 diabetes is far and away the leading cause of kidney disease, and I treat many hundreds of patients with this disease. Most type 2 diabetics also suffer from obesity. By the early 2010s my interest in puzzles, combined with my professional focus on obesity and type 2 diabetes, had led me to focus on diet and nutrition.

How did I go from preaching conventional medicine to prescribing intensive dietary strategies, including fasting? Despite what you might think, nutrition is not a topic covered extensively in medical school. Most schools, including the University of Toronto, spend a bare minimum of time teaching nutrition. There were perhaps a handful of lectures on nutrition in my first year of medical school and virtually no teaching on nutrition throughout the rest of medical school, internship, residency and fellowship. Out of the nine years spent in formal medical education, I would estimate I had four hours of lectures on nutrition.

As a result, I had no more than a passing interest in nutrition until the mid-2000s. At the time, the Atkins diet, promoting low-carb eating, was in full swing. It was everywhere. Some family members of mine tried it and were ecstatic with the results. However, like most conventionally trained physicians, I believed their arteries would eventually pay the price. I, along with thousands of other physicians, had been taught and certainly believed that low-carbohydrate diets were simply a fad and the low-fat diet would prove to be the best.

Then studies on the low-carb diet started to appear in the most prestigious medical journal in the world, the New England Journal of Medicine. Randomized controlled trials compared the Atkins diet to the standard low-fat diet that most health-care providers recommended. These studies all came to the same startling conclusion: the low-carb diet was significantly better for weight loss than the low-fat diet. Even more stunning was that all the important risk factors for cardiovascular disease—including cholesterol, blood sugar level, and blood pressure—were also much improved on the low-carb diet. This was a puzzle, a real conundrum. And that was where my journey began.

The new studies proved that the low-carb approach was a viable one. But this didn’t make any sense to me because I was still steeped in the conventional “calories in, calories out” (CICO) approach—the idea that the only way to lose weight is to consume fewer calories than you expend. Diets based on the Atkins methodology, for example, did not necessarily restrict caloric intake, yet people were still losing weight. Something didn’t add up. One possibility was that the new studies were wrong. However, that was unlikely, given that multiple studies all showed the same result. Furthermore, they confirmed the clinical experience of thousands of patients, who were all reporting weight loss on the Atkins diet. Logically, accepting that the studies were correct meant the CICO approach had to be wrong. Much as I tried to deny it, there was no saving the CICO hypothesis. It was dead wrong. And if the CICO hypothesis was wrong, then what was right? What caused weight gain? What was the etiology—the underlying cause—of obesity?

Doctors spend almost no time thinking about this question. Why? Because we think we already know the answer. We think that excessive caloric intake causes obesity. And if eating too many calories is the problem, then the solution is eating fewer calories and burning more through an increase in activity. This is the “eat less, move more” approach. But there’s an obvious problem. “Eat less, move more” has been done to death over the past fifty years, and it doesn’t work. For all practical purposes, it doesn’t really matter why it doesn’t work; the bottom line is that we’ve all done it, and it doesn’t work.

The underlying cause of obesity turns out to be a hormonal, rather than a caloric, imbalance. Insulin is a fat-storage hormone. When we eat, insulin increases, signaling our body to store some of this food energy as fat for later use. It’s a natural and essential process that has helped humans survive famine for thousands of years, but excessively and persistently high insulin levels result inexorably in obesity. Understanding this leads naturally to a solution: if excessive insulin is causing obesity, then clearly the answer lies in reducing insulin. Both the ketogenic diet (a low-carb, moderate-protein, high-fat diet) and intermittent fasting are excellent methods of reducing high insulin levels.

However, in my work with type 2 diabetics, I realized that there was an inconsistency between the treatment of obesity and the treatment of type 2 diabetes, two problems that are closely linked. Reducing insulin may be effective in reducing obesity, but doctors like me were prescribing insulin as a cure-all treatment for diabetes, both types 1 and 2. Insulin certainly lowers blood sugars. But just as surely, it causes weight gain. I finally realized that the answer was really quite simple. We were treating the wrong thing. Type 1 diabetes is an entirely different problem than type 2. In type 1 diabetes, the body’s own immune system destroys the insulin-producing cells in the pancreas. The resulting low insulin level leads to high blood sugar. Therefore, since insulin levels are low to begin with, it makes sense to treat the problem with supplemental insulin. And sure enough, it works. In type 2 diabetes, however, insulin levels are not low but high. Blood sugar is elevated not because the body can’t make insulin but because it’s become resistant to insulin—it doesn’t let insulin do its job. By prescribing more insulin to treat type 2 diabetes, we were not treating the underlying cause of high blood sugar: insulin resistance. That’s why, over time, patients saw their type 2 diabetes get worse and required higher and higher doses of medications.

But what caused the high insulin resistance in the first place? This was the real question. After all, we didn’t stand a chance of treating the underlying disease if we didn’t know what caused it. As it turns out, insulin causes insulin resistance. The body responds to excessively high levels of any substance by developing resistance to it. If you drink excessive alcohol, the body will develop resistance, up to a point—we often call this “tolerance.” If you take narcotics such as heroin, your body will develop resistance. If you use prescription sleep medications such as benzodiazepines, your body will develop resistance. The same holds true for insulin. Excessive insulin causes obesity, and excessive insulin causes insulin resistance, which is the disease known as type 2 diabetes.

With that understanding, the problem with how doctors treat type 2 diabetes became clear: we were prescribing insulin to treat it, when excessive insulin was the problem in the first place. Instinctively, most patients knew what we were doing was wrong. They would say to me, “Doctor, you have always told me that weight loss is critical in the treatment of type 2 diabetes, yet you have prescribed me insulin, which has made me gain so much weight. How is that good for me?” I never had a good answer for this. Now I knew why. They were absolutely right; it wasn’t good for them. As patients took insulin, they gained weight, and when they did, their type 2 diabetes got worse, demanding more insulin. And the cycle repeated: they took more insulin, they gained more weight, and as they gained more weight, they needed more insulin. It was a classic vicious cycle.

We doctors had been treating type 2 diabetes exactly wrong. With the proper treatment, it is a curable disease. Type 2 diabetes, like obesity, is a disease of too much insulin. The treatment is to lower insulin, not raise it. We were making things worse. We were fighting the fire with gasoline. I needed to help my obesity and type 2 diabetes patients lower their insulin levels, but what was the best approach? Certainly, there are no medications that do this. There are surgical options that help, such as bariatric surgery (commonly called “stomach stapling”), but they are highly invasive and have many irreversible side effects. The only feasible treatment left was dietary: reducing insulin levels by changing eating habits.

In 2012, I established the Intensive Dietary Management Program, which has a unique focus on diet as a treatment for the twin problems of obesity and type 2 diabetes. At first, I prescribed low and very low carbohydrate diets. Since refined carbohydrates highly stimulate insulin, reducing these carbohydrates should be an effective method of lowering insulin. I gave my patients lengthy sessions of dietary advice. I reviewed their food diaries. I begged. I pleaded. I cajoled. But the diets just didn’t work. The advice seemed hard to follow; my patients had busy lives and changing their dietary habits was difficult, especially since much of it ran contrary to the standard advice to eat low-fat and low calorie. But I couldn’t just give up on them. Their health, and indeed their very lives, depended upon reducing their insulin levels. If they had trouble avoiding certain foods, then why not make it as simple as possible? They could simply eat nothing at all. The solution was, in a word, fasting.

Fat-Burning Capacity Is Required for Weight Loss

As just mentioned, to shed body fat, your body must have the ability to burn fat for fuel. While it may seem like this ability should be inherent in everyone, all the time (since we know fat can be used as fuel), metabolic dysfunction triggered by an inappropriate diet and feeding schedule can prevent this. In a nutshell, to be an efficient fat-burner, you need to:

Eat a diet with a higher fat-to-sugar ratio (i.e., more healthy fats and less net carbohydrates), and
Restrict the timing of your meals so that you're fasting for a greater number of hours than you're eating

This will (over time) teach your body to burn fat for fuel again, rather than relying on fast-burning carbs, and in addition to burning dietary fats, your body will also start accessing and burning stored body fat.

While either of these strategies alone (fasting or eating a ketogenic diet) will shift your body from carb-burning to fat-burning, doing them together will yield the fastest results. To learn more about this, see "Why Intermittent Fasting Is More Effective Combined With Ketogenic Diet."

How Time-Restricted Feeding Promotes Weight Loss

So, what's the evidence that time-restricted eating actually promotes weight loss? Aside from a number of animal studies,4 consider the following research,5 published in the July 2019 issue of Obesity.

This study was founded on the premise that by eating earlier in the daytime, you properly align with the natural fluctuations in the circadian rhythm that regulates your metabolism. As a result, weight loss is enhanced.

The question it sought to answer was whether this benefit is mediated through increased energy expenditure or simply lower energy intake. To find out, 11 overweight participants first adhered to an early time-restricted eating schedule, eating all meals between 8 a.m. and 2 p.m. for four days.

For the next four days, they ate all meals between 8 a.m. and 8 p.m. They were also required to maintain a regular sleep schedule throughout. On the last day of each trial, energy expenditure and substrate oxidation levels were measured.

Results revealed meal-timing primarily facilitates weight loss by reducing appetite and increasing fat oxidation. Energy expenditure remained unaffected. As explained by lead author Courtney Peterson, Ph.D., associate professor of nutrition sciences at the University of Alabama at Birmingham:6

"We think the longer daily fast gives people's bodies more time each day to dip into their fat reserves and burn fat. The body is typically maximally efficient at burning fat when people fast for at least 12-24 hours at a time."

Overall, eating all meals earlier in the day, between 8 a.m. and 2 p.m., resulted in greater metabolic flexibility, lower ghrelin (known as the hunger hormone) levels, reduced hunger and increased sense of fullness, and this is thought to drive the weight loss.

TRE Improves Weight Loss in Obese Adults

Another study7 published in the Nutrition and Healthy Aging journal in 2018 examined how TRE — without counting calories — affects weight in obese adults. Here, they used an eight-hour restricted eating window.

Twenty-three overweight adults were instructed to eat however much food they wanted between 10 a.m. and 6 p.m. for 12 weeks. For the remainder of the day and night, they were only allowed water. Weight loss and metabolic parameters were compared to the historical records of a group of matched controls.

At the end of 12 weeks, body weight decreased by an average of 2.6% and energy intake decreased by 341 calories per day compared to controls. Systolic blood pressure also decreased by an average of 7 mm Hg.

According to the authors, their findings "suggest that 8-hour time restricted feeding produces mild caloric restriction and weight loss, without calorie counting. It may also offer clinical benefits by reducing blood pressure."

How Restricted Feeding Affects Fat and Muscle in Fit Adults

Overweight individuals are not the only ones who stand to benefit from time-restricted feeding, as evidenced by a 2016 study8 in the Journal of Translational Medicine, which evaluated the effects of TRE on basal metabolism, strength, body composition, inflammation levels and cardiovascular risk factors in fit men. As explained by the authors:9

"Thirty-four resistance-trained males were randomly assigned to time-restricted feeding (TRF) or normal diet group (ND). TRF subjects consumed 100% of their energy needs in an 8-h period of time each day, with their caloric intake divided into three meals consumed at 1 p.m., 4 p.m., and 8 p.m.

The remaining 16 h per 24-h period made up the fasting period. Subjects in the ND group consumed 100% of their energy needs divided into three meals consumed at 8 a.m., 1 p.m., and 8 p.m. Groups were matched for kilocalories consumed and macronutrient distribution."

Strength training consisted of a split routine with three weekly sessions on nonconsecutive days for eight weeks. All participants had engaged in continuous resistance training for at least five years before the study.10

Compared to controls, at the end of the eight-week study, the treatment group experienced a decrease in fat mass while maintaining muscle mass and maximal strength.11

Interestingly, while blood glucose and insulin decreased significantly, as expected, so did testosterone and insulin-like growth factor 1, two anabolic hormones.12 Unfortunately, no hypothesis is presented for these findings.

They also found that, aside from a reduction in triglycerides, the time-restricted feeding protocol did "not confirm previous research suggesting a positive effect of [intermittent fasting] on blood lipid profiles."

The researchers address this in the discussion section of the study, postulating that this may be related to the fact that all of the subjects were "normolipemic athletes," meaning their blood lipid profiles were normal to start with. Despite that, the authors conclude:

"Our results suggest that an intermittent fasting program in which all calories are consumed in an 8-h window each day, in conjunction with resistance training, could improve some health-related biomarkers, decrease fat mass, and maintain muscle mass in resistance-trained males."

A similar study13 published in the European Journal of Sport Science found that men who performed resistance training for eight weeks while eating all meals within four hours on non-workout days (four days a week) lowered their calorie intake while still increasing strength and muscular endurance.

The Many Health Benefits of Intermittent Fasting: More Evidence

Prof. Satchidananda Panda, has published another study on Jan. 3, 2023. The scientists observed two groups of mice given the same diet, with one given free access to food, while the other was restricted to eating within a feeding window of nine hours each day.

After seven weeks, they collected tissue samples from 22 organ groups, including the brain, liver, stomach, lungs, heart, adrenal gland, kidney, and intestine at various times of the day and analysed genetic changes. They discovered that 70 percent of the mouse genes responded to fasting.

“By changing the timing of food, we were able to change the gene expression not just in the gut or in the liver, but also in thousands of genes in the brain,...Our results open the door for looking more closely at how this nutritional intervention activates genes involved in specific diseases, such as cancer.” Panda said.

Nearly 40 percent of genes in the adrenal gland, hypothalamus, and pancreas—key organs for regulating hormones—were affected by fasting. These results suggest that fasting may help manage many diseases from diabetes to stress disorders, with or without pharmaceutical intervention.

Earlier in Dec. 2022, a study published in the Endocrine Society’s Journal of Clinical Endocrinology & Metabolism, found that almost 90 percent of participants with type 2 diabetes reduced their medication intake after intermittent fasting.

Fifty-five percent of these people experienced diabetes remission, stopped their medication, and maintained it for at least one year.

Large and growing body of medical research supports the use of time-restricted feeding (intermittent fasting), showing it has a wide range of biological benefits. Studies show various forms of fasting, including a variety of intermittent fasting protocols and time-restricted feeding, can:

According to research presented at the Endocrine Society's annual meeting, March 23, 2019, intermittent fasting drastically reduces a woman's risk of breast cancer.
Promote insulin sensitivity (15,16), which is crucial for your health as insulin resistance or poor insulin sensitivity contributes to nearly all chronic diseases
Improve leptin sensitivity (17)
Improve blood sugar management by increasing insulin-mediated glucose uptake rates18
Lower triglyceride levels (19)
Increase human growth hormone production (HGH) — Commonly referred to as "the fitness hormone," HGH plays an important role in maintaining health, fitness and longevity, including promotion of muscle growth, and boosting fat loss by revving up your metabolism.
Research (20,21) shows fasting can raise HGH by as much as 1,300% in women and 2,000% in men. The fact that it helps build muscle while simultaneously promoting fat loss explains why HGH helps you lose weight without sacrificing muscle mass, and why even athletes can benefit from intermittent fasting
Suppress inflammation and reduce oxidative damage
Promote multisystem regeneration (22) by upregulating autophagy and mitophagy,23 natural cleansing processes necessary for optimal cellular renewal and function, and promoting regeneration of stem cells (24)
Prevent or reverse Type 2 diabetes, as well as slow its progression
Improve immune function by regenerating damaged stem cells (25,26)
Lower blood pressure (27,28)
Reduce your risk of heart disease (29)
Boost mitochondrial energy efficiency and biogenesis (30)
Reduce your risk of cancer, in part by optimizing autophagy (31)
Increase longevity (32,33,34) — There are a number of mechanisms contributing to this effect. Normalizing insulin sensitivity is a major one, but fasting also inhibits the mTOR pathway,35 which plays an important part in driving the aging process
Regenerate the pancreas36 and improve pancreatic function
Improve cognitive function and protect against neurological diseases (such as dementia, Alzheimer’s disease (37) and Parkinson’s disease (38,39) thanks to the production of ketone bodies (40) (byproducts of fatty acid breakdown, which are a healthy and preferred fuel for your brain) and brain-derived neurotrophic factor (41) (BDNF, which activates brain stem cells to convert into new neurons, and triggers numerous other chemicals that promote neural health).
Animal research (42) also shows intermittent fasting increases neurons resistance to excitotoxic stress.
Eliminate sugar cravings as your body adapts to burning fat instead of sugar.

TRE Is Beneficial for Most

Contrary to longer fasts and calorie restriction, TRE is a strategy that can work for most people. Remember, you're not actually limiting or counting calories — you can (theoretically) eat whatever you want in any amount — you're simply restricting the time in which you eat all this food, although you will get better results by eating healthy non-processed foods and not consuming excessive carbs.

Weakness and lethargy, which are signs of undernourishment, should not occur. It's a practice that should make you feel good and actually reduce your hunger over time.

Your hunger and craving for sugar will slowly dissipate as your body starts burning fat as its primary fuel. Once your body has successfully shifted into fat burning mode, it will be easier for you to fast for as long as 22 hours and still feel satiated. I typically fast for at least 18 hours a day and sometimes as much as 22 hours.

While time-restricted feeding and intermittent fasting will in theory work regardless of your diet, I do not recommend it if you're eating a preponderance of processed foods. The quality of your diet is particularly important if you're looking for more than mere weight loss.

It's critical to avoid refined carbohydrates, sugar/fructose and grains. Focus your diet on vegetable carbohydrates, healthy protein in moderate amounts, and healthy fats such as butter, eggs, avocado, coconut oil, olive oil and raw nuts.

That said, older people are notorious for getting frail very quickly if they skip even one meal. They don’t eat very often, but they need their meal. If you don’t give it to them, they can very quickly decline.

Time-Restricted Eating vs Calorie Restriction in Weight Loss - NEJM (April 2022)

This randomized clinical study concluded that among patients with obesity, a regimen of time-restricted eating was not more beneficial with regard to reduction in body weight, body fat, or metabolic risk factors than daily calorie restriction.

Sources and References

Adapted from the Original Article: https://articles.mercola.com/sites/articles/archive/2022/07/03/time-restricted-eating-science.aspx

This article is part of the intermittent fasting series.

Related: Biological Age vs Chronological Age

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