“Does caloric restriction extend life in wild mice?”

…ask Harper et al. in their study of the effects of calorie restriction (CR) on mice caught in the field (as opposed to standard strains commonly used in laboratory research).

The study (from the lab of veteran mouse wrangler Steven Austad) comes to a startling (and, to CR aficionados and practitioners, disturbing) conclusion: No.

To investigate whether mice genetically unaltered by many generations of laboratory selection exhibit similar hormonal and demographic responses to caloric restriction (CR) as laboratory rodents, we performed CR on cohorts of genetically heterogeneous male mice which were grandoffspring of wild-caught ancestors. Although hormonal changes, specifically an increase in corticosterone and decrease in testosterone, mimicked those seen in laboratory-adapted rodents, we found no difference in mean longevity between ad libitum (AL) and CR dietary groups, although a maximum likelihood fitted Gompertz mortality model indicated a significantly shallower slope and higher intercept for the CR group. This result was due to higher mortality in CR animals early in life, but lower mortality late in life. A subset of animals may have exhibited the standard demographic response to CR in that the longest-lived 8.1% of our animals were all from the CR group. Despite the lack of a robust mean longevity difference between groups, we did note a strong anticancer effect of CR as seen in laboratory rodents. Three plausible interpretations of our results are the following: (1) animals not selected under laboratory conditions do not show the typical CR effect; (2) because wild-derived animals eat less when fed AL, our restriction regime was too severe to see the CR effect; or (3) there is genetic variation for the CR effect in wild populations; variants that respond to CR with extended life are inadvertently selected for under conditions of laboratory domestication.

Why might laboratory selection select for animals that show a CR effect?

First of all: The best lab mouse is a fertile and fecund mouse, one that reproduces early and often. These animals might have an ad libitum (AL) intake far in excess of their wild cousins, consistent with the observation that lab mice eat more than wild ones when confronted with an all-you-can-eat kibble buffet.

The beneficial effects of CR are generally a biphasic function of total caloric intake: there’s a sweet spot of maximum benefit at, say, 60% AL, but below that the mice are generally less healthy than the AL cohort, because they’re frankly starving.

One upshot of the selection of lab mice for efficient conversion of kibble into more mice (and their concomitant bigger appetites) is that wild mice on AL diets might be closer to the CR “peak” than lab mice — so that reducing their intake to 60% actually puts them below the peak, into the starvation part of the dose-response curve. If this is the case, then wild mice might well benefit from CR, just at a higher percentage of AL calories.

But it might also be, as the authors point out, that lab mice have been inadvertently selected for some trait that enhances the benefits of CR. Wild populations may be a mix of some mice that benefit from CR and some that don’t (e.g., the early-mortality subjects in this study).

This is the possibility that’s of particular concern for humans. Via the emerging field of pharmacogenomics, we’re becoming increasingly aware of the impact that genetic variation can play on the efficacy of therapeutics: Sometimes a drug will benefit only 20% of the trial population, but it later turns out that 100% of those 20% had the same haplotype at a particular locus, making the drug great for them and lousy for everyone else. This phenomenon isn’t limited to drugs; it extends (e.g.) to the benefits people reap from exercise and the risk of getting cancer after a lifetime of smoking.

What if calorie restriction is the same? I would argue that we’re more like wild mice than lab mice, and that there are going to be existing variants in the human population that benefit differently from CR (just like any other course of treatment). What do we do if it turns out that CR confers both early mortality (on one subset of the population) and delayed aging (in another, or in everyone who survives the increased early-mortality risk)?

We’ve based a lot of our optimism about CR in humans on data from rodents, and while the human and primate data is promising so far, it’s also limited in statistical power and temporal depth. Simple intellectual honesty mandates that these results give us pause, and encourage rational reflection about all the possibilities that might result from being our own guinea pigs.

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9 comments

  1. Hi there,

    While it’s not crystal-clear, the data from this study support the conclusion that CR *does* work in wild mice. As the abstract alludes and the full text details, while there was no effect on MEAN lifespan, that was the result of an increase in early mortality combined with an apparent effect on maximal, leading to a reduction in the mortality rate doubling time:

    However, visual inspection of the distribution of deaths in the two dietary groups (Fig. 3B) suggested that while more CR animals died early in the experiment (age 1350 days). In fact, the six longest-lived individuals in the experiment were all on restricted diets. The longest-lived AL mouse died at 1403 days compared with 1601 days for the longest-lived CR mouse.

    Analysis of age-specific mortality patterns can reveal subtle differences that might be overlooked by survival or longevity analyses … The initial mortality rate (intercept of the Gompertz curve) is higher (−4.22 vs. −5.29) in the CR relative to AL group, whereas mortality rate doubling time (inversely related to the Gompertz slope), which is often considered to be a measure of *aging rate*, was longer for CR compared with AL animals (10.9 months for CR vs. 6.4 months for AL).

    Twenty-four AL and 25 CR animals underwent necropsy. … As has been reported numerous times, CR appeared to have a protective effect against tumors (Table 1). Almost 60% of the AL animals had at least one tumor at necropsy compared with only 12% of the CR group (P = 0.001, Fisher’s exact test). The only three CR animals with tumors were among the oldest individuals in the study (mean age at death = 1449 days).

    What this suggests is that something about teh conditions in the lab — including possibly something about the CR regimen itself — was not well suited to these animals, thus causing early mortality unrelated to aging, but that aging was indeed slowed (which is what it means to say that “CR works” in these animals), so that those animals that survived whatever killed their cohorts off early on enjoyed slowed aging and a resulting extension of maximum lifespan.

    Cf the many early studies in which CR didn’t extend lifespan when imposed in middle age. This was mostly the result of early deaths. When, famously, Weindruch and Walford revised the regimen by imposing CR gradually instead of all at once, and made sure that the diet was isonutrient outside of Calories and carbs, a robust and proportional effect on lifespan was observed. Cf also the minimal effect of genetics on one’s odds of reaching one’s 70s, but the profound influence on one’s odds of becoming a centenarian.

    It’d be good to see a re-analysis of the Gompertz data including only animals that survived to mean longevity, to eliminate the confounding of the high intercept on the slope.

    -Michael

  2. […] Reflecting on Calorie Restriction As noted at Ouroboros, not all calorie restriction (CR) studies produce what appear to be positive results. As the first comment demonstrates, however, we non-scientists can’t assume that something as conceptually simple as demonstrating extended healthy life span in mice is actually simple to carry out in practice. “[The results suggest] that something about the conditions in the lab – including possibly something about the CR regimen itself – was not well suited to these animals, thus causing early mortality unrelated to aging, but that aging was indeed slowed (which is what it means to say that ‘CR works’ in these animals), so that those animals that survived whatever killed their cohorts off early on enjoyed slowed aging and a resulting extension of maximum lifespan. … When, famously, Weindruch and Walford revised the regimen by imposing CR gradually instead of all at once, and made sure that the diet was isonutrient outside of calories and carbs, a robust and proportional effect on lifespan was observed.” View the Article Under Discussion: https://ouroboros.wordpress.com/2006/10/30/does-caloric-restriction-extend-life-in-wild-mice/ Read More Longevity Meme Commentary: http://www.longevitymeme.org/news/ Published Wednesday, November 01, 2006 3:13 PM by Longevity Meme News and Commentary Tags: Caloric restriction […]

  3. hmm….i think there is more to CR than these two studies. And, in a cartain way many of us are more like lab mice than wild mice……we usually have much more food than we need (almost an all you can eat buffet)…(even poor grad students eat more Ramen noodles than can ever be necessary :-))

    But there is no question about different effects of CR on different genetic types, and that CR is going to work on some human populations better than others.

  4. […] But before you all hit the bottle now, you should head over to Science Made Cool, where Jim Cambias reminds us of the negative effects of wine. What’s more, Chris Patil of Ouroboros points out that caloric restriction does not extend the lifespan of wild mice, and discusses the risk of extending lab controlled animal experiments to non-lab conditions. Okay, so what other options do we have to extend our lives if red wine doesn’t necessarily do the trick? Head on over to Balacing Life, where Sunil notes that a lower body temperature also leads to a longer lifespan. There are also still all kinds of food supplements that you can take, but Cathy Davies of Lab Cat explains that the regulation of dietary supplements is a very fuzzy area. Finally, Fight Aging is a blog entirely devoted fighting aging. Its author, Reason, discussed the difference between slowing aging and reversing aging in two posts. […]

  5. there was an experiment in which one group of mice was fed too much and the other under calories restriction. the thinner mice lived longer than the very fat mice, but no longer than normal mice.
    so cr isn’t really the foundation of youth. it just prevents heart attacks and cancer caused by too much fat. the same results could be achieved by not overfeeding the mice, instead of a sever cr.
    besides, humans can’t stand it for a long time.

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