Calorie restriction and hormesis

One of the first scientifically rigorous demonstrations of the benefits of hormesis was a 1934 study of calorie restriction (often abbreviated “CR”) in laboratory rats, conducted by Mary Crowell and Clive McCay at Cornell. They found that reducing the calories of rats by 30-50%, supplemented with adequate micro-nutrients, could almost double their lifespans. Later studies found continued lifetime extension with calorie restriction up to 65%. In addition, the rats remained energetic and youthful in appearance, with greatly reduced incidence, and delayed onset, of age-related diseases. This same phenomenon has been observed in a variety of other animals.

Studies on calorie restriction in primates or humans are as yet inconclusive. Controlled primate studies only started in the late 1980s and have yet to be completed, although the preliminary indications are very promising. And in humans it is more difficult to conduct controlled studies for both ethical and compliance reasons. An additional factor to consider is that animals raised post-weaning on calorie restricted diets typically have much smaller adult body sizes that animals not restricted in their eating.  Because of the social and physical implications of this consequence, advocates of calorie restricted diets for humans advise that they be started only upon reaching adulthood.

Whether or not a restricted calorie diet extends the human lifespan, the evidence is becoming overwhelming that a nutritionally complete diet with reduced calories has the potential to greatly improve our health, particularly as we age. But is it practical and possible for humans to happily adhere to such a diet?

Monkeys on calorie restriction (left) and normal diet (right)

Benefits. The benefits of calorie restriction in animals are wide-ranging. For example, studies on rhesus monkeys and macaques at the University of Wisconsin have found that the calorie-restricted monkeys have significantly less diabetes, cancer, cardiovascular disease, and neurodegenerative diseases. Their fasting insulin and glucose levels are greatly reduced, and they have higher insulin sensitivity and excellent lipid profiles. While the study is yet to be completed, at the 20 year point, 80% of the calorically restricted monkeys were still alive, compared to only half of the controls.

In a study of humans who restrict their calories by 10-25% relative to baseline, but supplied with adequate vitamins and minerals, similar benefits have been seen, with significantly lower blood pressure, insulin, fasting glucose, triglycerides and LDL cholesterol; and significantly higher HDL cholesterol.

Mechanisms. Nobody knows for sure why calorie restriction works, but there are a number of theories with varying degrees of confirmation. They are not mutually exclusive, so it is possible that more than one, or all of them, are true:

  • Autophagy (“Self digestion”) is a phenomenon whereby the cells degrade and digest damaged or non-essential contents within the cell membrane. During nutrient starvation, autophagy basically “cleans house”: it breaks down non-vital components and releases nutrients, ensuring that the vital processes can continue. How does this come about? Calorie restriction is known to dramatically lower the concentrations of insulin, IGF-1 and growth hormone. Reduced levels of these hormones in turn activates the genes and pathways for autophagy or catabolism. Basically this involves the cell producing enzymes that specifically degrade oxidized or otherwise damaged intracellular molecules. This is an interesting process.During autophagy, the  cell actually builds a special membrane encircling these damaged components, forming a “vesicle”. The cell then fuses the vesicle to the lysosome — a reservoir of digestive enzymes — and digests and removes the contents of the vesicle. This reminds me of how certain insects like spiders or wasps wrap up their prey and then digest them.  The cell is digesting and recycling accumulated “cellular junk” that would otherwise gum up its metabolic machinery, producing extra energy as a consequence.  How clever!
  • Mitohormesis is defense response, which is believed to occur within the mitchondria, the energy factory of the cell.  The mitohormesis theory proposes that calorie restriction is a type of “low-intensity stress” that activates genes involved in defensive responses against aging processes such as oxidation. The mitohormesis concept has been demonstrated in studies of the worm Caenorhabditis elegans, which showed that limiting the amount of glucose being fed to the worm resulted in oxidative stress, to which the organism responded by adapting so as to resist further oxidative stress.  This extended its lifespan. The genetics of mitohormesis have started to be uncovered. Studies at the molecular level have shown that several genes in the sirtuin class, including SIRT1, SIRT3, and SIRT4, create enzymes that increase the activity of the mitochondria and slow the cell’s aging process
  • BDNF. In addition to these general mechanisms, calorie restriction activates some important specific pathways in higher animals. One of the more intriguing and potentially important of these is the connection between calorie restriction and mental health.  An excellent review paper by Gomez-Panilla, linked here, documents how fasting, diet and exercise can stimulate a neuroprotective factor called Brain-Derived Neurotrophic Factor (BDNF). This key neurotransmitter plays a key role in neuroplasticity, the ability of the brain to adapt, learn and respond to stress. Depressed levels of BDNF are associated with deficits in memory and learning, and with a number of psychiatric disorders. BDNF also provides a strong defense within the brain against reactive oxygen species (ROS), and is protective against degenerative neurological conditions such as Alzheimer’s disease. BDNF is induced by calorie restriction, but also by intense exercise and omega-3 fatty acids. Conversely, it is suppressed by a high calorie diet, particularly one high in sugar and fat content. Low BDNF levels can be reversed within a few months: a study by Araya et al showed that BDNF increases significantly in insulin-resistant overweight and obese subjects after three months of a diet in which calories are restricted by 25%.

Scare tactics. First, let us be clear that nobody who is serious in the field of calorie restriction is advocating extreme calorie reduction of the sort that would lead to starvation or eating disorders. All of the responsible advocates of CR base their recommendations on the emerging science, which indicates that a calorie reduction of 10-25% versus the standard American diet, is not only tolerable, but healthful, so long as it is accompanied by adequate micronutrients — vitamins, minerals, and essential fatty acids.  Yet this has not stopped skeptics from attacking calorie restriction. A particularly irresponsible, but not atypical, example is that of Jay Phelan, whose 2006 article in the journal Biogerontology used mathematical models to argue that CR can at best deliver only modest benefits:

Calorie restriction is doomed to fail, and will make people miserable in the process of attempting it,” said Dr. Jay Phelan, an evolutionary biologist at the University of California, Los Angeles, and a co-author of the paper. “We do see benefits, but not an increase in life span.” Mice who must scratch for food for a couple of years would be analogous, in terms of natural selection, to humans who must survive 20-year famines, Dr. Phelan said. But nature seldom demands that humans endure such conditions. Besides, he added, there is virtually no chance Americans will adopt such a severe menu plan in great numbers. “Have you ever tried to go without food for a day?” Dr. Phelan asked. “I did it once, because I was curious about what the mice in my lab experienced, and I couldn’t even function at the end of the day.

Dr. Phelan’s personal “one day experiment” was ill-conceived and his conclusion is not to be taken seriously, in my opinion.  It is no surprise he “couldn’t function” after suddenly downshifting gears so rapidly.  As anyone who has taken the time to research calorie reduction or intermittent fasting realizes, a dietary change of this sort should be approached gradually, allowing time for deconditioning of previous dietary habits and hormonal responses. These changes typically take weeks or longer to become comfortable. But that does not mean that a reduced calorie diet is “extreme”. By historical standards, it would be more accurate to characterize the typical hypercaloric American diet as extreme.

Dietary alternatives. There is no single preferred mode of approaching calorie restriction. People have had success in many different ways in adapting CR to different cultural backgrounds and personal preferences. Here are a few approaches worthy of investigation if you are considering a reduced calorie diet as a means of hormetic stimulus and improved health:

  • Okinawa diet. One of the oldest and best studied traditional diets is that which predominates (or used to predominate) on the island of Okinawa, Japan. This is a diet high in fish, rice, and yellow and green vegetables, many of them fermented.  The Japanese as a whole eat fewer calories than do Americans.  But the Okinawans eat even less. Compared with the average Japanese caloric intake, the Okinawa diet has:
    • 20% fewer calories
    • 25% fewer grains
    • 75% less sugar
    • 300% of level of green/yellow vegetables, especially sweet potatoes
    • small amounts of fish and pork, including pig organs
    • no eggs or dairy
  • The CRON-diet (Calorie Restriction with Optimal Nutrition) was developed by Roy Walford, Lisa Walford and Brian Delaney. They advocate a plan involving three meals per day. Two of these meals are “free choice” recipes. The third is prepared in advanced according to recommended recipes to ensure adequate micronutrients. Meals are carefully weighed and assesed for calorie content. The CRON-diet is popular among members of the Calorie Restriction Society.

Intermittent Fasting. A number of studies have shown that fasting for short periods of time, generally less than 2-3 days, produce many of the same health benefits as general calorie reduction, without having to reduce the average number of calories consumed per week.  However, many adherents of intermittent fasting find that their average calorie intake tends to decrease voluntarily; in other words, they tend not to “make up for lost time” on their non-fasting days.  And many people (myself included) feel that it is psychologically more tolerable to alternate fasting with the ability to eat to fullness, rather than restricting calories at every meal.  In addition, there are some scientific arguments that favor a “cycling” approach for optimizing the secretion of hormones such as leptin, and for avoiding a long term adaptive reduction in basal metabolic rate.  If you are afraid that skipping meals will cause your metabolism to shut down and shift into “starvation mode”, dispel that thought. A study by Zauner et al in the Journal of Clinical Nurtrition showed metabolic rate actually increases during fasting up to 4 days, due to a more than doubling of norepinephrine.  So fasting for 6-24 hours hours has no downside.
There are several variations of intermittent fasting:

  • Alternate day fasting (ADF) as described in a post by Dr. Michael Eades.
  • Occasional fasting (for example, Brad Pilon’s Eat-Stop-Eat program of 1-2 fasting days per week)
  • Partial daily fasting (for example, Fast-5, which restricts eating to a flexible 5 hour daily “window”)

Each of these approaches has their advocates and relative advantages. I suggest clicking on the hyperlinks to check them out in greater detail, if you are interested.

For many years, I followed a low carbohydrate diet that had allowed me to lose some weight, but I soon found that I had plateaued and was unable to shed some excess weight around my belly.  Adding exercise did not seem to help. It is only when I began to seriously reduce calories through intermittent fasting, while adhering to a low carb, moderate protein and high (percent) fat diet that I started to lose weight easily again, including all my excess belly fat.  While my diet is high in percent fat, probably I eat fewer total grams of fat than I did before.

I’ve found that calorie restriction is very easy to practice without any sense of deprivation, but it takes time and patience to get there. Whichever program you choose to try, your chance of success is greatly improved if you gradually transition to calorie reduction. Often this requires adjusting the diet to reduce the hormonal impact that specific foods have on appetite.  These dietary changes–in combination with several psychological deconditioning techniques I’ve investigated–are encapsulated in the Deconditioning Diet described on the Diet page of this blog.

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  1. Aaron Griffin is another good example of the window-style fasting (16hr fast, 8hr eating window).

    Also The Warrior Diet includes fasting every day. I did this for 3 weeks, and actually felt ok doing it – one large meal when I got home from work.

  2. Daan van den Bergh


    Me and my wife are going to do this. We will fast one day a week.

    Do you have any advice on how to go about this?

    I read on your diet page that we should avoid sugars and starches. I guess I should read into that, what kind of meals contain it.

    I proposed as a beginning that 1 day a week we only eat twice a day (no lunch, no snacks). But what drinks are allowed while doing this (besides water)?

    After how much weeks can we switch to not eating at all one day (without passing out :P)?

    Thanks for this great website.


    Daan van den Bergh

    • Todd


      My main advice is to ease into fasting gradually. Don’t attempt to do a full day fast if you have not first (1) successfully cut back on sugars and starches for at least a week; (2) cut out snacks between meals; and (3) cut back to 1 or 2 meals a day. I’ve given my reasons for this in several other articles here. You might start with this one:

      Learning to fast

      Also see my video talk,

      Intermittent fasting for health and longevity

      Good luck,


  3. Ann

    I have always been fascinated by the story of the Uruguayan rugby team that crashed in the Andes in 1972 and survived for 72 days on extremely little food, as well as harsh cold and other stressors too, no doubt. Perhaps those deprivations were too extreme to be considered forms of hormesis, but still, ALL 16 of those original survivors are still alive today, 42 years later. I’m astonished that no one seems to have taken the opportunity to make a study of them, to see whether their experience changed their physiology in any long-term ways. It’s a unique opportunity, and it will soon be lost forever.


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