Are the benefits of intermittent fasting settled science?

I have been on the IF diet for over ten years now. I do it thinking that the available evidence supports health benefits, but that the jury is still out. I was thus a little surprised to read the following:

Intermittent fasting regimens ... have similar healthspan-extending effects [as caloric restriction] ... [and] the molecular consequences of fasting, rather than weight reduction per se, may account for at least some of the observed positive effects of caloric restriction.
    - Madeo et al. 2014 "Caloric Restriction Mimetics: towards a molecular definition". 

The articles cited (Anson et al. 2003, Li et al. 2013, Heilbronn et al. 2005 and Klempel et al. 2012) were not new to me. Only the authors' certainty was.  In fact, these authors were simply introducing CR and IF as prelude to a discussion of drugs that might have the same benefit ("caloric restriction mimetics"). The article is a thorough review of the underlying science (with an emphasis on autophagy and protein deacetylation), and ought to be read by any scientist interested in this field.

I should have been skeptical. I should be skeptical. I am skeptical. However, I also found seeing the benefits of IFdiet described as settled science to be reassuring. They are telling me to put aside my doubts and carry on. I will.

Making lifestyle choices with imperfect knowledge about what is healthy

Gary Taubes ends his opinion piece in today's New York Times with a rhetorical question:

Before I, for one, make another dietary resolution, I’d like to know that what I believe I know about a healthy diet is really so. Is that too much to ask?

after having spent the article presenting a persuasive case for the conclusion that "Yes, it is too much to ask."  His key point is that

Because the hypotheses [in nutrition] are ultimately about what happens to us over decades, meaningful trials are prohibitively expensive and exceedingly difficult. 

When I was interviewed recently about intermittent fasting, I explained that we don't really know whether it's healthy or not, but I follow it because the idea that it promotes health makes a lot of sense to me, given what I do know about the underlying science. Gary Taubes makes his own decisions. ("My own vote [for what most of us are eating too much of] sugars and refined grains; we all have our biases.") I don't think he's actually biased. His "vote" is based on a career of looking into the matter. It is not so much a bias as an informed guess.

As a scientist, I am aware that much of what we spend our time thinking about is not proven. In fact, I have argued that nothing in science is completely proven (outside of mathematics, and even within mathematics, a lot of time is spent considering the implications of conjectures and lemmas). There are cases, especially in the physical sciences, when residual doubt is absurdly insignificant, and there are cases, including nutritional science, when there is a lot of doubt.

When policy is developed based on science, it has to be based on the best available evidence and the best possible estimate of how likely it is that the prevailing wisdom is wrong.  If appropriate, we want confidence intervals. It's not always true that when there is smoke there is fire, but when there is smoke, you should definitely stop what you're doing and have a look (or get out).

In any case, I very much enjoyed this presentation of what we don't know, and I recommend it (here). One of the better bits:

Since the 1960s, nutrition science has been dominated by two conflicting observations. One is that we know how to eat healthy and maintain a healthy weight. The other is that the rapidly increasing rates of obesity and diabetes suggest that something about the conventional thinking is simply wrong.

I want to soundly endorse his conclusion:

Making meaningful inroads against obesity and diabetes on a population level requires that we know how to treat and prevent it on an individual level. We’re going to have to stop believing we know the answer, and challenge ourselves to come up with trials that do a better job of testing our beliefs.

The ELF diet (Eat Less Food)

Intermittent fasting is a good way to lose weight, and in my case, I think that fasting is good for about 10 or 15 pounds.  However, I've been fasting since 2004, and after a while, I gained some weight back and thought that it would be a good idea to lose some.  For the last few years, I've been watching my weight using the ELF diet, which involves Eating Less Food. The person who introduced me to this acronym did it as a joke (as in "I'm following the ELF diet, where you Eat Less Food, haha"), but I've given it some thought and see two useful aspects.

Eat less than you want. The amount of food that most people eat is dictated by appetite, and their weight, whether it is more than they would like or exactly right, is relatively stable. The body has an exquisite ability to regulate appetite, so if you want to lose weight you have to be a little bit hungry much of the time. I find that paying attention to appetite, and eating just a little less than I want, is an effective way to lose weight.

Eat less than you have been eating. I've read recently that people who record what they eat using smart phone apps are more likely to lose weight. This makes sense to me (although I myself just record what I ate, in words, at the end of each day). If you eat seven cookies, that's a lot, but it might be less than the eight cookies you ate at a similar event the week before. I find keeping track and eating less to be much easier than counting calories. There is a lot less arithmetic, and fewer opportunities for wishful thinking to play a role.

I also find that it's useful to keep track of my weight, so that I know which foods are associated with weight gain and which are not.  Keeping track of what I eat and what I weigh each day makes it possible to predict the effect of different foods, and that is very useful.

Do artificial sweeteners lead to weight gain?

The personal genomics firm 23andMe recently released the results of a user survey indicating that the consumption of diet soda is very highly correlated with high body mass index (BMI).  You can read this surprising result here.

people who drink diet soda five or more times a day have an average BMI nearly 5 units higher than those who never drink diet soda. 

Of course, this could be because people who are obese are more likely to choose diet soda.  However, it fits very well with something I have suspected for some time now, that consumption of artificial sweeteners leads to weight gain.

A 23andMe survey revealed that consumption of diet soda is correlated with BMI.  (The cartoon is also from their site.)

Although I know of no data in support of this hypothesis, I will explain two reasons why I think it likely.

Taste.  Consumption of sweet foods leads to a preference for sweet foods.  This was directly addressed in a study by Sartor et al. (Appetite 2011), who found that "overweight/obese individuals are more implicitly attracted to sweet" and "one month of soft drink supplementation changed sweet taste perception of normal-weight subjects."  My own preferences affect my thinking on this.  While I truly enjoy the sweetness of a ripe peach, fresh sweet corn or dark chocolate, I find many popular foods (including soda and iced cupcakes) to be too sweet and truly unpleasant.  The idea here is that when someone consumes artificial sweeteners they get used to sweet flavors and come to enjoy sweeter tastes, which ultimately leads to the consumption of more calories.  For more on taste, including possible links to obesity, see the Outlook on taste in this week's Nature, especially a summary of research  on taste and obesity. 


Homeostasis. This is a similar idea, but involves unconscious processes.  The gut is filled with sweet taste receptors (Dyer et al. Biochem Soc Trans. 2005). Although I don't know what they are doing there, it seems likely that information from these receptors is used to regulate appetite, or metabolism, or both.  If your gut is constantly full of sweet flavors, then they will be ignored.  The sugars released from real food will not make you feel satisfied, or will be improperly dealt with in some other way.  The body's homeostatic mechanisms are complex and I don't claim to understand them, but I do suspect that artificial sweeteners disrupt the natural response to food and contribute to craving and binge eating.  

Liping Zhao on caloric restriction, gut microbes and aging

I just heard a very interesting talk from Dr. Liping Zhao, who is Director of the Laboratory of Molecular Microbial Ecology and Ecogenomics, and Associate Dean of School of Life Sciences and Biotechnology, at Shanghai Jiao Tong University. He is also associated with the new Shanghai Center for System Biomedicine. He described a consistent effect of diet (high fat vs. normal or normal vs. low fat) and caloric restriction on the composition of mouse gut microflora. I was impressed that even within a treatment, the composition of gut microflora was an indicator of lifespan. This correlation is interpreted by him in terms of a cumulative effect of anergy on health. His working hypothesis is that excess calories feed gut bacteria that cause inflammation, leading to a variety of health problems. A freely available paper from his group was published in PNAS in 2008 ("Symbiotic gut microbes modulate human metabolic phenotypes"). I expect that the results that he presented today will be published somewhere soon, and we're certain to see a lot more about the gut microbiome and health in the years to come.

"The Youth Pill," a new book on aging by David Stipp

I haven't read it, but a review in the Economist (July 24, pg. 80) alerted me to a new book on aging, "The Youth Pill: Scientists at the Brink of an Anti-Ageing Revolution"). If the review is to be believed, this book successfully avoids many of the traps that anti-aging books fall into (such as "embracing decrepitude"). David Stipp is a medical writer for the Wall Street Journal.

One meal each day vs. intermittent fasting

People in the intermittent fasting group on Yahoo are trying out many variations of intermittent fasting. The most popular appears to be daily (or frequent) fasts of greater than 18 hours, without caloric restriction. This normally means following the Fast-5 program of eating all food within a five hour window each day. The Fast-5 approach avoids longer fasts, but provides many more of them. Following this approach, one is fasting most of the time. There has been little scientific data on the relative benefits of different variants of intermittent fasting, so many of us are keen to learn which provide the greatest benefit. Indeed, some remain unconvinced that intermittent fasting provides any benefit at all.

The Mattson group has just published a study of the effects of reduced meal frequency on glucose regulation (Carlson et al. 2007, Metabolism 56:1729. "Impact of reduced meal frequency without caloric restriction on glucose regulation in healthy, normal-weight middle-aged men and women"). They found that people on a diet that involves a single meal each day show elevated fasting glucose levels and impaired glucose tolerance. This is in contrast to an earlier study (Johnson et al. 2007, Free Radical Biology and Medicine 42:665) that tested alternate day calorie restriction and found improved diabetes risk profiles (also see the Johnson upday downday diet, which is promoted by the same James B. Johnson). The authors suggest (in the Carlson et al. paper) that the key difference is an overall reduction in energy intake.

That may be true, but there are two other important differences between the Fast-5 approach and alternate day fasting (including my method of fasting three times each week from dinner one day until dinner the next day, which is less rigorous than a full bedtime-to-waking fast of 30+ hours). First, even a dinner-to-dinner fast is longer (roughly 23 hours, on average, as opposed to 19 or 20). If the benefits of fasting kick in after 12 hours or so, this difference could be more significant than one might otherwise think. Second, the consumption of all daily calories within a five hour window is very intense, and ad lib eating over 24 hours need not be. Between fasts I usually eat dinner, a late-night snack, breakfast, lunch and dinner. Less intense eating means less insulin secretion and less food in the stomach at the beginning of a fast, which would further increase the effective length of the fast.

Perhaps the longer fasts are more effective. Further research will tell, and it's being done.

Gary Taubes on Insulin and Obesity

The new book, "Good Calories, Bad Calories", by Gary Taubes, contains a wealth of information about nutritional research. The book will become famous and controversial, if it hasn't already, because it presents a point of view that is contrary to the medical consensus but growing in popularity (both within and without the medical world). Anyone interested in the science related to intermittent fasting should buy it because it provides a well-documented and thorough review of the science of human nutrition.

Taubes' book argues for the hypothesis that "obesity is caused by the quality of the calories, rather than the quantity, and specifically by the effect of refined and easily digestible carbohydrates on the hormonal regulation of fat storage and metabolism." The theme is that hormones are what matters with respect to obesity and related aspects of health, like heart disease. Insulin is the focus of attention, but glucagon, estrogen, growth hormone and steroids in general are all mentioned in the book. Taubes feels that way too much emphasis has been placed on eating habits. He cites a case where the same person is emaciated above the waist but obese below the waist (yes, there is a picture), and describes mice that will die of starvation without using up fat reserves.

Throughout, he also describes the interpretations given to various observations and experimental results by medical researchers. It's a very interesting case, one that illustrates the importance of going back to the methods and data used in critical experiments.

I bought the book after reading Gina Kolata's review in Sunday's New York Times (Oct. 7). Then, there was then a very interesting article ("Diet and Fat: a Severe Case of Mistaken Consensus" by John Tierney) in Tuesday's science section (Oct. 9). It is interesting to compare that article, which accepts the thesis of the book and focuses on the phenomenon of consensus view that are mistaken, with Kolata's review, which is a bit more skeptical:

"In fact, Taubes convincingly shows that much of what is believed about nutrition and health is based on the flimsiest science....

But the problem with a book like this one, which goes on and on in great detail about experiments new and old in areas ranging from heart disease to cancer to diabetes, is that it can be hard to know what has been left out."

She then cites a study showing that a calorie is a calorie is a calorie; the effect on weight is the same whether from fat or carbohydrate.

I'm inclined to believe that they are both right. It's quite plausible that what really matters is both total calories (because the laws of physics are, after all, inviolable) and how rapidly they lead to an increase in blood glucose (which induces insulin, which leads to the deposition of fat). Ironically, dietary fat, which does not induce insulin, is a preferred source of calories.

What does this have to do with intermittent fasting? I fast three times each week because of evidence that the benefits of caloric restriction (prolonged healthspan) result from the activation of a genetic program rather than from reduced metabolic activity per se, and that this genetic program can also be induced by intermittent fasting. Evidence from animal models for such a genetic program is quite solid. Evidence that this program exists in humans (and it not already fully induced in most people) is less solid. What is really unclear is what that program is and how it can be induced. Much of the science described in Taubes' book will certainly bear on figuring this out.

Intermittent Fasting

What is intermittent fasting?

It has been known for a long time that caloric restriction (a significant reduction in food intake – to 60-70% of normal levels) prolongs life in many species (even including yeast!). Many people are interested in caloric restriction (for example, a caloric restriction support group on Yahoo! has over 2600 members; there is also calorierestriction.org) but relatively few people are willing to actually follow such an extreme diet. However, evidence that the benefits of caloric restriction result from the activation of a genetic program (involving insulin signaling and the gene SIRT1) rather than reduced metabolic activity per se has opened up the possibility that benefits can be achieved by other means. One hope lies in finding a drug or dietary supplement that will do the job (perhaps resveratrol). I have paid more attention to the possibility that the same genetic program may be induced by intermittent fasting.

In May of 2004 I started a diet that involves not eating on Mondays, Wednesdays and Fridays. My diet was inspired in particular by a study (Anson et al., 2003) that reported beneficial effects on glucose metabolism and neuronal resistance to injury without an overall reduction in calorie intake. In this study, mice were assigned to four groups (ad libitum, intermittent fasting, caloric restriction and pair fed; this last group was given as much food as the intermittent fasting group ate, but on a daily basis). The intermittent fasting group did as well as the caloric restriction group on a variety of tests but enjoyed almost as much food as the ad libitum group (by making up the difference on days when food was available). A more recent paper by Hsieh et al. 2005 (Effects of Caloric Restriction on Cell Proliferation in Several Tissues in Mice: Role of Intermittent Feeding: PubMed; Am J Physiol Endocrinol Metab) reaches similar conclusions studying cell proliferation.

I fast between dinner of one day and dinner the next day, but eat dinner every day. The fast consists of no calories at all (I allow myself water, tea and coffee), and the precise duration depends on when we have dinner, according to the details of each day's schedule. While I normally fast three times each week, I am flexible. For example, I might allow myself to schedule lunch on a Friday after having fasted on Monday and Wednesday. In fact, I've done this only a few times since starting the diet. One week I postponed Friday's fast so that I fasted on Monday, Wednesday and Saturday that week.

The health benefits of intermittent fasting in humans are certainly not established, and I'm not recommending this diet for anyone else. I find it likely that caloric restriction works in humans because it works in so many other species. However, it is possible that the genetic program is already constitutive in humans. It is also possible that the particular diet I have selected fails to induce the pathway. Perhaps longer but less frequent fasts would be more effective, or many fewer fasts would be sufficient. I don't know, but I am encouraged by the growing evidence that the induction of extreme longevity can be uncoupled from caloric restriction per se.

I don't find this diet to be terribly difficult. In fact, skipping meals can be convenient (I'm busy, after all). For about three weeks after starting the diet I would experience mild hypoglycemic symptoms on the fast days (I was nervous but tired, just a little irritable and not terribly productive) and became sleepy when I ate again. These symptoms no longer occur. I now feel pretty much the same on fast days and other days. I have used a home kit to verify that my blood sugar does not fall during a 24 hour fast, but I don't know how much it fell before that adaptation occurred.

This diet is not about losing weight. Although I lost about 10 pounds over the first six weeks, my weight then stabilized and slowly returning to the starting point. More recently, I lost those 10 pounds again and that was probably just as difficult as it would have been if I had not been fasting.

This diet is the opposite of the standard "healthy eating" advice that advocates a big breakfast and regular meals, and I must confess that I have passed up opportunities to discuss it with my doctor (although I have mentioned it to friends who are doctors). On the other hand, fasts of various kinds are a part of almost all religious traditions. I suspect that a study with direct tests of the relevant biomarkers (reduced serum glucose and insulin levels, or even elevated expression of SIRT) is possible, and will eventually be carried out, but I've decided not to wait for it.

Most of the forgoing is from a posting I made in 2005. Since then, there has been more research, including a recent review (Varady and Hellerstein 2007, PubMedID 17616757) which concludes that "the findings in animals suggest that ADF may effectively modulate several risk factors, thereby preventing chronic disease, and that ADF may modulate disease risk to an extent similar to that of CR. More research is required to establish definitively the consequences of ADF." There is now a Yahoo! group (fasting), which has 320 members, and most of whom are fasting intermittently. The group exchanges hundreds of messages each month. Most of them are about the personal aspects of fasting.

This blog was started as a way of focusing on the science. Blog team members are all scientists. The relevant literature is cited on Connotea (intermmittent_fasting). Comments are welcome.