empty plate

At first blush, when I heard about the fad of intermittent fasting as a way to lose weight, improve one’s health, and prolong life—the latter being a major concern for Silicon Valley mega-billionaires—I was skeptical. When it comes to weight loss, isn’t it calories in minus calories out that determines your net gain or loss? Elementary, my dear Watson, the second law of thermodynamics is totally immutable and completely resistant to attempts to apply “alternative facts”. And yet, hope springs eternal.

Attempts to find chinks in the armor of the laws of physics (perpetual motion machines), chemistry (make gold out of lead, or mercury, or…you name it), biochemistry/physiology (dietary fads), have been an integral part of human history since antiquity. This is not to diminish the great benefits these attempts have brought to humanity. They have, in fact, served to confirm, again and again, the validity of the laws of nature discovered by science.


The theory behind intermittent dieting

A common argument used by proponents of intermittent diet is that “it makes evolutionary sense.” It roughly goes along these lines: Since the genus Homo evolved over 2 million years ago, we were largely hunters-gatherers. When the band had a successful hunt, it meant a day or two of feasting on a calorie-rich meat diet. But when the feast was over, it meant surviving on calorie-poor wild cereals, roots, and berries. That, in turn, led over the years to biochemical/metabolic adaptation, through the process of natural selection, that maximized our survival capacity in such uncertain food supply circumstances.

Let’s dissect the argument. What are the adaptations the pro-fasters are talking about? Our carbohydrate, fat, and protein metabolic pathways are the same as those of chimps, gorillas, and bonobos, our closest relatives who did not have to adapt to intermittent disruptions of calorie supply. There is an important adaptation that impacts results of fasting, however. Fasting lowers our metabolic rate precisely because our metabolism is geared to conserve energy related to an uneven supply of calories. The problem is that actually works in opposite direction of the desire of intermittent dieters to burn more calories.

To invoke the hunter-gatherer paradigm is a bit problematic on its face. Since humans invented agriculture about 10,000 years ago, the supply of calories became much more predictable and plentiful. We haven’t lost our metabolic adaptation of conservation of energy, but we got progressively more plump (think of Rubens’ women), and recently even obese (picture any street in the industrialized world). Physiologically, it means that our metabolic set point is probably higher than in the good old days of hunting-gathering, and the hormones geared to maintain homeostasis (physiological stability, or maintenance of the status quo) will resist mightily any change in the metabolic set point, which anyone who ever dieted knows too well.

There is another complication in comparisons with hunter-gatherer metabolism theory. It is amply documented that gut flora plays a crucial role in the metabolic fate of nutrients. Here is the rub: Obesity causes a radical change in the gut flora. And the new flora actually promotes further obesity. Hunters-gatherers probably did not have this problem.


Now let’s look at the scientific evidence

An interesting angle of looking at the problem of intermittent feeding/fasting was employed by Panda and his colleagues, of the Salk Institute. Most of our bodily functions throughout the day are controlled by a master pacemaker situated in a brain structure called the SCN (for supra chiasmatic nucleus). This pacemaker gets neural signals from the eyes and is, thus, controlled primarily by the light/dark periods. But in a similar arrangement to our Federal system, every organ has its own sub-pacemaker, designed to serve the specific requirements of that organ.

In the liver, Panda et al. found that when they withheld food from mice for 24 hours, 90% of the genes that are under the circadian regulation of the clock ceased to function. Not surprisingly, since one would expect the major metabolic organ to be controlled by the supply of food. On the other hand, let mice eat a high-fat diet 24 hours a day and all the genes under the control of the liver circadian pacemaker get activated around the clock. Unsurprisingly, the mice became obese. This explains the mechanism of feeding/fasting on the molecular level. But to definitively settle the question of the benefits obtained by intermittent fasting, there is no substitute for well-designed studies in humans.


The human experience

One of the most consistent advocates of intermittent fasting for weight loss is nutrition researcher Krysta Varady, of the University of Illinois, Chicago. She published widely on the subject and summarized her research in a popular book, The Every-Other-Day Diet, with the tagline: 4 weeks, 12 pounds, 2 sizes. It also includes recipes to accomplish the goal. But to Dr. Varady’s credit, she also ran a critical experiment: A well-controlled study in humans. In a paper published recently in JAMA, her group reported of a study of 100 obese participants (86 women, 14 men) who were randomized to 3 groups for 1 year: alternate-day fasting (25% of energy needs on fast days; 125% of energy needs on alternating “feast days”), calorie restriction (75% of energy needs every day), or a no-intervention control. The trial involved a 6-month weight-loss phase followed by a 6-month weight-maintenance phase.

So, in addition to being randomized and well-controlled, it lasted 1 year, unlike those short-term hit-and-run studies. And the results?

Here are the authors’ conclusions:

“Alternate-day fasting did not produce superior adherence, weight loss, weight maintenance, or cardioprotection vs. daily calorie restriction.”

In an interview for The Scientist magazine, Varady says that intermittent diets work not because of some speculative evolutionary adaptation or complicated genetic/molecular mechanism, but “it’s just tricking your mind and body into eating less, and because you’re losing weight, you’re getting all the metabolic benefits.” In other words, better compliance through mind tricks, although her JAMA study actually said that it “did not produce superior adherence”.

No matter, there is a lot to be admired here. Here is a scientist who devoted her career to proving the benefits of intermittent diets, but had the courage to run the definitive experiment, and the intellectual integrity to state the facts, however inconvenient. So much of it is lacking in our political life nowadays.

You make us proud Professor Varady. Bravo!

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.


  1. Robert, how wonderful to find someone who doesn’t scoff at me saying I get fat off fewer calories than other people eat. It’s not possible for me to do 16/8, though, because I get so hungry I can’t sleep. I’ve tried it more than once. I can manage 14/10 most days and do that. The problem is my feeling of hunger rarely reduces or goes away if I’m restricting what I eat. I wish someone would cut the stomach/brain connection for me! And being ravenously hungry all day long is very hard indeed to live with. I can manage it for one day at a time, not longer. And it’d better not be an important working day, either. In addition, I sleep very badly at the end of a 500 calorie day. Always. Others have said that too. For once, I’m not an outlier.

    As for exercise, with osteo-arthritis and a bad back, vigorous exercise isn’t possible for me ever. I cannot physically run. I do walk on the treadmill for 20 minutes a few times a week, on the principle that any exercise is better than none. Add fibromyalgia and it’s . . . an interesting juggling act to deal with my body.
    When we go back to Australia, our main home, later this year, I’m going to see an unusual holistic physio who has worked wonders for others I know, and who only takes on ‘interesting’ cases, to see if she can get me moving/walking better. I do persevere, you see, and am keeping an eye on stem cell research.

    • Anna I also had the same experience as you. I am 77 and have fought weight all my life despite
      playing hockey, badminton and weight training. I also went on restricted diet with 1200 cals a day and gained weight.
      I was introduced to the Intermitant fasting a few months ago and have lost 27 lbs, feel great and plenty of energy. My blood pressure is low and it seems to be working for me. I eat between 12 noon and 6 pm with no snacking. I eat most anything I want from 12 to 6 but do watch the carbs.

      My buddy is also on it and has lost about 13 lbs.
      Nothing else has ever worked and I am not found anywhere that will allow fecal transplants.

      • Barney, I’m glad this has worked for you. I can’t do such a short time frame for eating – one of the reasons being I wake ravenously hungry, always have, and also need to take meds first thing eg thyroid meds half an hour before I can eat. Boy, that’s hard! My husband isn’t hungry at all in the mornings. Lucky him! I was told by one disapproving sounding doctor that I have a child’s eating pattern. I abandoned 5:2 for a year of medical problems like cataracts and skin cancer, but am back on 6:1 again and will soon be trying 5:2 again. I’ve kept up the 20 minutes walking at least and I haven’t put on most of the weight I took off, at least. I know someone who is gigantic, which helps keep me mindful, I can tell you.

  2. Dov, You side stepped Anna’s response with double talk quoting the second law of thermodynamics. Your response is very atypical of traditional medicine and the failed beliefs of the past half century. No different than saying a btu of diesel fuel is the same as a btu of gasoline with out acknowledging you can not burn diesel in a gasoline car. Upon ingestion, calorie of soda is processed differently than a calorie of kale in the body – PERIOD. We have different systems that treat calories differently with some being more efficient than others. Now if you have research that supports the fact that every calorie is burn the same way than I will retract my statement. If do not have the supporting research (from respected authorities that receive no funding from BIG PHARMA OR the soda industry) then you need to reconsider our statement. Are you aware that most current researchers agree that alternate day fasting is the least effective form of fasting with “Daily Time Restricted Feeding” (research shows a rise in metabolism) and Periodic fasting as being the most effective. I do AGREE when you say to try vigorous exercise while fasting. I do this daily and have amazingly POSITIVE results.

  3. I’d love to talk to you in person! We could have a very animated discussion, I’m sure. I do know about the thyroid problem. I’ve been treated for it since 1980 – I come from the goitre belt of Lancashire, no iodine in the water. Best thing they did was put me on T3/T4 as the thyroxine medication loses its efficacy after decades on it. But I can’t take too much or it affects my heart. Talk about a juggling act! That’s what growing old is. The other excellent thing I did was consult a nutritional medicine doctor who believes in rebalancing the body’s biochemistry. She has sorted out a lot of my health problems like chronic fatigue syndrome, but hasn’t found an easy answer to people like me losing weight. I am gradually increasing the exercise but I ‘sprained’ my knee two months ago and it’s only just getting better enough to enable me to walk on the treadmill. I’m going to consult a specialist holistic physiotherapist once we return to Australia, one who only takes on ‘interesting’ and complex cases. All I want is to be able to walk properly. She’s already helped two people I know who were given up as hopeless.

    But you and I will still have to agree to disagree about calories in/calories out. It sounds a good theory, but it hasn’t convinced me after my lifetime of eating carefully that one size fits all when it comes to applying it. Have a great day!

    • Anna – I highly recommend you look into Daily time restricted feeding (16/8 intermittent fasting) and a whole foods plant based diet. You just might be amazed with the results at any age.

      • I agree, so much research in the area now and hundreds of thousands,if not millions of people use IF and love it. I am about to start after I get my blood work done today.I have been researching IF for months and understand the process. Very exciting really.

  4. Thank you for taking the time and trouble to reply, Dov.

    I smiled wryly at your suggestion of vigorous exercise. I’m 76 with a bad back and arthritis everywhere. I wish I could do vigorous exercise. But I do use a treadmill regularly for steady walking at a pace my back can tolerate (3km per hour) and do stretching swinging exercises for my upper body taught me by a physiotherapist, since as a novelist (80th book out in September, and I write three a year) I inevitably spend a lot of time sitting at my computer.

    You should talk to my husband about calories in/calories out. He sees how little I eat compared to other people and he sees how people don’t believe me when I say I don’t eat a lot. I have an underactive thyroid and multiple food intolerances so live mainly on fruit, veggies and salad, plus low-fat cheese and some beef, the only proteins I can tolerate. I think my body truly ‘believes’ salads and veggies are fattening!

    Some day they’ll do some research about how us older people who can’t do vigorous exercise can still lose weight.

    Have a happy day!

    Anna Jacobs

    PS how does the second law of thermodynamics fit with research results I saw a few years ago, when they showed pictures of fattening food to people struggling to lose weight – and they put on weight?

    • Anna,

      There are several points in your reply that cry out for a comment.

      Arthritis and low back pain can indeed be disabling. I, too, have been suffering from low back pain for over 40 years, a major part of my 82 years. And my joints show their age as well. Yet, despite the chronic and bouts of acute pain, I managed to use pain medication only sparingly and very infrequently. When running became too painful, I switched to low impact aerobic exercise, such as the elliptical. Rather than comfortably staying at a plateau, I increase my exercise routine very gradually by small increments. You’d be surprised how resilient our bodies are, and how adaptable to the increased stress of exercise they are. Judging from your brilliant novels, you are a great believer in women’s capacity to overcome adversity. You can do it!

      As to your question about taking in few calories and still gaining, or not losing weight, the answer rests in your thyroid gland. This hormone determines how much of your caloric intake is used for metabolic activity and how much is dissipated as heat. The lower the thyroid level, the less calories are used for energy metabolism, the less is dissipated as heat, and the more is stored as fat. Therein lies your problem. Fortunately, this can be, most of the time, remedied by adjusting your daily thyroid dose. You need to consult your personal physician, who will most likely order a blood test, and based on the results will adjust the dosage. Good luck.

  5. Rubbish. We are all different, and some diets work for some people, others don’t. Even if a dietary approach works for the majority, it won’t work for all. A calories in/calories out diet was devised for me by a dietician. I adhered to it rigidly for 10 days, even though I was hungry all that time, and put on 5 pounds. She didn’t believe I’d stuck to her diet. I had, absolutely. I abandoned that approach. I did the 5:2 rigidly and lost 12 kg over 6 months. I came off it, put on 2kg and have used 1 day a week fasting to maintain the weight loss ever since – which is the first time in decades my weight has stabilised after weight loss. I’ve struggled all my life against weight gain – I have an underactive thyroid, being treated, but that doesn’t help losing weight.

    So I say again, rubbish to anyone (whatever their qualifications) who insists one size fits all for any diet. We are all different. I have tried every approach under the sun during my 76 years to stop my stupid body (which seems to think even salads are fattening) from gaining weight. The 5:2 diet suits me better than most, and it makes me feel good. Calories in/calories out is awful to live through, with rampant hunger every minute of the day, and for me, weight gain.

    Why haven’t the so-called experts made a dent in the growing obesity problem if they know so much. They don’t. They only think one way suits all, and it doesn’t.

    • Anna, thanks for your comment. Calories in/calories out is not an invention of some ignorant doctors or dietitians. It is based on the second law of thermodynamics and is just as basic and immutable as gravity and the movement of the earth around the sun. Having said that, you highlighted two valid and related issues. The first is that clinical trials, however carefully designed and executed, deal with averages. You can get an idea of how individuals differ from the average by looking at the raw data, which is also captured by the statistical treatment of this dispersion in the form of standard deviation. So how is it that continuous dieting (which you erroneously label calories in/calories out) didn’t work for you or for countless other people? It is because our minds work differently from each other. To borrow a metaphor from the sports world, it is easier to sprint several times with rest in between than to run a marathon. And that’s exactly the point the author, who BTW literally ‘wrote the book’, is making. It doesn’t matter which method works for you – it all boils down to lower calorie intake. And BTW, try vigorous exercise on days of fasting – you might be pleasantly surprised with results.

    • You also need to have your insulin stores depleted for the body to use other fuel for energy. I had an unheard of insulin level of 1500 and was then diagnosed with Type 11 diabetes, I was part of a study with 5 heart surgeons. They tested me because they had a hard time understanding such a high level, it came back the same.Anyways a few years on meds, then I lost 50 lbs and could go off meds.All levels had dropped but I find myself needing to drop about 30lbs which I will do with IF but might take a little time to deplete my insulin levels again.


Please enter your comment!
Please enter your name here

This site uses Akismet to reduce spam. Learn how your comment data is processed.