Of mice and men: Deleterious psychological effects of CR may be limited to rodents

Calorie restriction (CR) extends lifespan and boosts physical health in most organisms studied, but is it any fun? Here I’m referring not to any diminishment of gustatory pleasures (leading to the oft-repeated jest, “You might not live longer, but it would sure seem longer”), but rather to the prospect that CR might have anhedonic psychological effects.

Earlier we’ve discussed evidence that this is indeed the case: Very serious food deprivation (more like starvation or anorexia than well-managed CR) in rats can lead to depression, possibly by exerting an effect on the expression of synaptic vesicle proteins and other molecules involved in neuronal signal transmission.

CR of rodent parents can even have negative effects on offspring: specifically, gestational protein restriction in mother rats leads increased DNA damage and other progeroid symptoms in their young. To these deleterious effects we must now add anxiety: rats whose mothers were gestationally restricted show less interest in exploration and more desire to hide in familar places. This is consistent with the idea that some of CR’s behavioral effects reflect adaptive responses to a hostile world in which the risk-to-reward ratio has grown suddenly higher: if you’re a forager and there’s nothing to forage, then you might as well stay in your burrow.

But to what extent do these rodent experiments reflect the situation in humans? Up until very recently, we’ve had only anecdotes — which, even ignoring inevitable biases in reporting, are inconclusive to say the least. (In my own anecdotal experience, the self-reporting of CR subjects ranges from thoughtful and positive sharing to behavior that is, well, neither of those.) Fortunately, however, a major test of the effects of CR in humans — the CALERIE study — is currently underway, and already yielding interesting data. Williamson et al. report that CR in humans is not associated with either harmful mood changes or any symptom of eating disorders. Indeed, the authors find, CR in humans is associated primarily with neutral or positive psychological and behavioral effects:

Is caloric restriction associated with development of eating-disorder symptoms? Results from the CALERIE trial.

Objective: This study tested a secondary hypothesis of the CALERIE trial (Heilbronn et al., 2006) that a 12-month period of intentional dietary restriction would be associated with an increase in eating disorder symptoms. Design: To test this hypothesis, 48 overweight adults were randomly assigned to four treatment arms in a 12-month study: (1) 25% calorie restriction, (2) 12.5% calorie restriction and 12.5% increased energy expenditure by structured exercise, (3) low-calorie diet, and (4) healthy diet (no-calorie restriction). Main Outcome Measures: Primary outcome measures for the study were changes in: eating disorder symptoms, mood, dietary restraint, body weight, and energy balance. Results: All three dietary restriction arms were associated with increased dietary restraint and negative energy balance, but not with increased ED symptoms or other harmful psychological effects. Participants in the three calorie restriction arms lost significant amounts of body weight. The psychological and behavioral effects were maintained during a 6-month follow-up period. Conclusion: These results did not support the hypothesis that caloric restriction causes increased eating disorder symptoms in overweight adults. In general, caloric restriction had either benign or beneficial psychological and behavioral effects.

Why the difference? Having neither the opportunity nor inclination to construct a panel of rodent-human hybrids, I’m stuck with speculation: It’s entirely possible that rodents and humans are different enough from one another that they have different psychological responses to similar sorts of shortage issues. Perhaps, not having a burrow in which to hide when the going got tough, our own ancestors had to think and act more energetically and enthusiastically in order to survive the lean times. Perhaps consuming 60% of the calories found in our modern diets is closer to the “natural” (evolutionarily optimized) state of affairs for humans — i.e., ad libitum humans might be basically overfed zoo animals, living hazy full-tummied lives far away from the types of stimuli that really light us up, mentally speaking.

Another possibility is less optimistic: the CALERIE subjects may have been screened so stringently that they are no longer a legitimate sample of the general population. Potential subjects were screened both physically and psychologically; fewer than 10% of the initial applicants were ultimately accepted. While only a few percent (8/599) were rejected explicitly on psychological grounds, I’m guessing that several of the larger classes of automatically excluded candidates (“weight instability,” “medications”, “smoker”, “other” and “withdrew during screening” add up to more than 80% of the rejections) included some individuals who might have been eliminated in psychological testing if they’d made it that far. Based on the proportion of “surviving” candidates, one might argue that CALERIE subjects were chosen in part because they were physically and psychically unusual, at least among overweight individuals. On those grounds, one could reasonably wonder whether any of the study’s findings about CR will prove true for those of us in the remaining 90% of the general population.


  1. So I have to admit that I’m not thoroughly versed in the CALERIE study, but I have to be a little more critical of their results. On the CAL homepage it states “Have a body mass index (BMI) of 22-27.9 (lean to slightly overweight” but for the WIlliamson study they only noted “48 overweight adults were randomly assigned.”
    Not to sound too biased, but did they only look at teh fattest people of the test group (my current crummy French e-library access deosn’t let me see the whole article for methods and such)? In such a case mightn’t these “benign or beneficial psychological and behavioral effects” just be the result of losing weight to a healthier level?
    The people on the Biggest Loser seem pretty gleeful just for not being overweight….and let us not forget Subway’s Jared!
    I’d wait until there were psych results focusing on the CR’d population that was lean to start with.

  2. I’m guessing that they took the healthiest, not necessarily the fattest — see the link in the last paragraph of the post.

    The JAMA article announcing the study is currently free and open-access, and you can check it out here.

  3. During the six month extreme CR of the famed Minnesota Semi-starvation Experiment (in the 1940’s) there was well-documented and widespread lethargy and depression in the subjects. These guys were less carefully screened than in the current report. I think until all the arms of the CALERIE trial are completed (including the 12 month CR studies) the jury is still out.

  4. Speaking as someone who “survived” the screening process for CALERIE and is currently 25% calorie restricted (3mo), I do not think I am physically or psychologically different than most food loving adults :). There are quite a few points I would like to make so I will address most of them here (http://weeklyadventuresdietgirl.blogspot.com/). But for those who are curious- I am not any more hungry than I was pre-CR, I eat junk food, I drink alcohol, and on most days I do not miss my old habits. I feel positive about CR, partially because I have lost weight (previous BMI = 26, current BMI = 24), but also because I feel like I am in control of my health and aging.

  5. Interesting and thoughtful post. I agree that it is unlikely that 100% of the human population will be able to do CR or every-other-day fasting (which also extends lifespan), nor benefit from the dietary restriction effect. But I wonder about your comment regarding that dietary restriction might only help 10% of the population. I think the jury is out. My guess is that physiologically dietary restriction would benefit far more people compared to how many humans will be able to stay on such altered diets. Then it becomes a matter of choice
    and will power.


  6. Just to jump in here, as I’ve had a few interesting discussions about this topic recently with a participant in CALERIE – although I agree with your point that such a low participation rate might compromise the external validity of the study, it’s important to keep in mind that this is a pilot study with a very small n, a short follow-up period, and fairly extensive requirements for protocol compliance. Given that the authors ostensibly planned on conducting an intent-to-treat analysis (which they did, and which is the most respectable analysis), if they had not screened with such stringency there may have been a larger group of people who were not able to adhere to the study, thus biasing any treatment effect to the null. The investigators may not have wanted to gamble in the pilot phase of the study, resulting in a smaller sample that is less externally valid but also less susceptible to diluted results.

    Just my 2 cents! Sorry if I’m butting in –


  7. I’d like to add my $.02 anecdote here because I’ve suffered from an eating disorder myself. A 25% reduction in a the RDA 2000 calorie diet is 1500 calories a day, hardly an “extreme” deprivation and nowhere near a typical CR for a person with an ED. Extreme CR is 300 calories a day, an 85% reduction. No anorexic I know would dare eat 1500 calories, and there certainly are psychological and cognitive consequences at the 85% level. Especially for someone already underweight.

  8. Hi Some Girl,

    Just to clarify- the CALERIE study is looking at CR in adults who have never suffered from an eating disorder. The purpose is to determine if a 25% calorie restriction promotes longevity in humans.

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