The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 11 No.
5 • September 2008
Varying Effects of Calorie Restriction in Two Strains of Mice
A very interesting new paper reports on a comparison of metabolic rate and oxidative stress in two different strains of mice, one of which (C57BL/6) lives longer when calorically restricted and the other of which (DBA/2) does not, in an attempt to identify factors that predispose to benefiting from caloric restriction. The authors did this because, as they note, caloric restriction has not increased lifespan in all genotypes tested, including houseflies, which had lifespans proportionally decreased by reductions in food intake, and various strains of mice.
They particularly focused on the balance between food intake and metabolic expenditure. The factor that struck the researchers as being especially notable was that the strain that lived longer under caloric restriction (C57BL/6) gained more body weight while consuming the same amount of food as the strain that did not live longer under CR (DBA/2). This was true under both ad lib and CR feeding regimens. For example, after 12 months under 40% CR feeding, the DBA/2 mice weighed 13% less than the CB57BL/6 mice, even though both strains ate the same amount of food. Since the food intake was the same, the difference in body weight suggested a greater energy expenditure by the DBA/2 mice. Measurements of metabolic rate showed this to be true. “The rate of resting oxygen consumption, measured at 5–6 months of age, was 30% higher in DBA/2 than the C57BL/6 mice. . . . Compared to C57BL/6 mice, the maximal rate of in vitro oxygen consumption in the DBA/2 was 24% and 27% higher in homogenates of the heart and skeletal muscle, respectively.” Moreover, the rectal temperature of the DBA/2 mice over a 24-hour period was 0.7ºC higher than that of the C57BL/6 mice.
In an earlier study cited by the authors, it was reported that “in an AL[ad lib]-fed population of rats, animals that tended to gain relatively more weight than that expected solely on the basis of their food intake, had a correspondingly shorter life span. Furthermore, retrospective analysis indicated that the positive energy balance, expressed as the time taken to double the body weight, was a significant predictor of life span.” Thus, the researchers reason, “. . . if a positive energy balance under AL-feeding conditions tends to have a life-shortening effect in a particular genotype, then, conversely, a CR-induced decrease in energy balance in such a genotype could have an opposing effect [i.e., induce an increase] on longevity.”
The authors speculate, “. . . though a cause and effect relationship has yet to be established, the present and previous studies tend to point to oxidative stress, generated by a positive energy balance, as a key factor linking the amount of food intake and life span.”
Much of the analysis leading to the authors’ conclusion was not included above to isolate the bottom line. There were other differences between the two strains. The DBA/2 mice had greater oxidative stress at a young age, as shown by a significantly lower GSH/GSSG ratio in heart and skeletal muscle at 3 months of age. However, there was a relatively greater age-related decline in GSH/GSSG in the C57BL/6 mice in both tissues as compared with the DBA/2. The shift to pro-oxidizing conditions (redox potential) took place with age in heart and skeletal muscle of both strains, but the age-related change in redox potential was 40% larger in the C57BL/6 mice. Therefore, as the authors state, “It thus seems that although at the young age, the tissues of the DBA/2 mice displayed a higher level of oxidative stress than the C57BL/6 mice, the extent of the age-related rise in oxidative stress is greater in the latter than in the former.”
So why does CR lengthen the lifespan of C57BL/6 mice, but not that of DBA/2? High energy intakes (not balanced by increased energy expenditure) stimulate regulatory pathways, such as PI3K/mTOR/Akt, that increase cell growth and proliferation while increasing oxidative stress. Hence, a positive energy balance would create pro-oxidative conditions that could be corrected by reducing energy balance to neutral, through CR, for example. But since the DBA/2 already has a neutral energy balance throughout most of its life, the reduction of energy intake through CR wouldn’t “correct” an energy imbalance.
It is still not clear whether healthy people (or even healthy rhesus monkeys!) can live longer through CR, but reduction in food intake certainly does extend the lifespan of people with diseases of positive energy balance, such as diabetes.
- Ferguson et al. Comparison of metabolic rate and oxidative stress between two different strains of mice with varying response to calorie restriction. Exp Gerontol 43:757-63 (2008).
- Ross et al. Dietary practices and growth responses as predictors of longevity. Nature 262:548-53 (1976).