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Genotype and age influence the effect of caloric intake on mortality in mice¹

MICHAEL J. FORSTER^*,2, PAUL MORRIS^* and RAJINDAR S. SOHAL

^* Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer’s Disease Research, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas, USA; and
Department of Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles, California, USA

²Correspondence: Department of Pharmacology and Neuroscience University of North Texas Health Science Center at Fort Worth Fort Worth, TX 76107, USA. E-mail: forsterm{at}hsc.unt.edu

SPECIFIC AIMS

Caloric restriction (CR) is presently the only known regimen that significantly increases the maximum life span of rodents. It is being widely used to study mechanisms of aging in animals and is speculated to be of possible relevance to the retardation of deleterious effects of aging in humans. The current study addressed two specific issues regarding the relationship between caloric restriction and life span: 1) does CR increase the life span in all genetic strains of mice or are the effects selective? and 2) do the beneficial effects of CR accrue gradually or are they rapidly inducible and reversible upon shift from ad libitum (AL) to CR regimens, and vice versa?

PRINCIPAL FINDINGS

1. Long-term caloric restriction did not increase the life span of all genotypes
The effect of CR on life span was compared between two mouse strains, C57BL/6 and DBA/2, and their F₁ hybrids (B6D2F₁). One-half of the mice of each genotype had ad libitum (AL) access to food beginning at weaning; the other half, beginning at 4 months of age, were fed a caloric restriction (CR) regimen that permitted daily access to only 60% of the intake of the ad libitum-fed mice. The restricted mice were fed a NIH-31 formulation providing a supplementation of essential nutrients so that their intake of such nutrients was equal to that of the AL group. Mice were maintained on AL or CR conditions until death or a moribund state. The age-related survival of C57BL/6, B6D2F₁, and DBA/2 mice maintained under AL or CR are shown in Fig. 1 . Under ad libitum conditions, the strains of mice differed only slightly in their median life span, with B6D2F₁ and C57BL/6 mice living 1 to 2 months longer than DBA/2. In contrast, under conditions of reduced caloric intake, the C57BL/6 and B6D2F₁ mice showed increases of 6 to 7 months in median and 8 to 11 months in maximum (oldest death) life span under the CR regimen, whereas in the DBA/2 mice, the CR regimen resulted in a slight decrease in life span. The absence of beneficial effects of CR in the DBA/2 mice suggests that genetic factors either modulate resistance to the effect of CR or, alternatively, affect tolerance to the adverse consequences of CR. In either case, the findings argue that lifelong CR does not prolong life span in all strains of mice.

View larger version (23K): [in this window] [in a new window]   Figure 1. Survivorship of C57BL/6, B6D2F1, and DBA/2 mice (top to bottom panels) as a function of age. Separate groups of each genotype were maintained, from 4 months of age until dead or moribund, under ad libitum (AL) or 40% calorie-restricted (CR) feeding regimens. A two-way analysis of variance on age at death indicated a significant interaction of Genotype with Diet [F(2,124) = 10.5, P < 0.001]. The data are based on a total of 130 mice, 40–50 of each genotype.

2. Caloric restriction had a deleterious effect on mortality when it was implemented in mice of advanced age
The question of whether the effects of CR are reversible was addressed by transferring mice fed on AL to CR and vice versa at different ages. C57BL/6, B6D2F₁, and DBA/2 mice were maintained under the AL or CR condition until they reached 7-, 17-, or 22–25 months of age. After that, these mice were further divided into subgroups in order to discern the short- and long-term consequences of the different levels of caloric intake. One-half of the original ad libitum-fed mice of each genotype and age were switched and maintained under the calorie restriction regimen (ALCR); conversely, one-half of the original restricted mice were switched and maintained on the ad libitum feeding regimen (CRAL). These groups were maintained for at least 11 wk along with control groups that remained under their original long-term dietary regimen (ALAL and CRCR groups).

The characteristics of survival during the subsequent 11 wk after the shifts in caloric intake are plotted as a function of age in Fig. 2 . Transfer of CR mice to AL feeding (CRAL) at advanced age had little or no effect on mortality over the 11 wk period relative to CRCR, suggesting that beneficial effects of CR in C57BL/6 and B6D2F₁ are not rapidly reversible, but instead depend on cumulative exposure to the CR regimen. Similarly, switching the old AL-fed mice to the CR regimen (ALCR) not only failed to increase the probability of survival, it tended to increase mortality relative to the ALAL groups. This effect was pronounced for the DBA/2 mice, but the same trend was evident in the C57BL/6 and B6D2F₁ mice. The decrease in probability of survival was evident by 17 months in the DBA/2 and C57BL/6 mice, but not until 24 months in B6D2F₁. These findings suggest that CR is not beneficial and may in fact have deleterious effects when initiated at a relatively advanced age in any of the genotypes.

View larger version (30K): [in this window] [in a new window]   Figure 2. Probability of survival for 11 wk after shifts in caloric intake for separate age groups (left to right panels) of C57BL/6, B6D2F1, and DBA/2 mice (top to bottom panels). Separate groups of each genotype were maintained continuously on the AL or CR regimen prior to the shifts. A log-rank test considering all genotypes and ages indicated an overall difference in survival distributions of ALAL and ALCR groups (X2=12.1, P=0.001), but failed to indicate a survival difference between CRCR and CRAL (P=0.153). Separate log-rank analyses for ALAL vs. ALCR groups at the oldest age of each genotype indicated significant effects for DBA/2 (P=0.002) and B6D2F1 (P=0.033). Data are based on a total of 988 mice (331 DBA/2, 338 C57BL/6, and 319 B6D2F1).

CONCLUSIONS

The current experiments support two important generalizations relevant to the possibility that caloric restriction can be used as a tool for retardation of the aging process in animals(summarized in Fig. 3 ). The first is that lifelong restriction of calories does not increase longevity in all mouse genotypes. The simplest interpretation of this finding is that there are genetic factors that confer resistance or intolerance to the anti-aging effects of calorie restriction. The nature of such genetic variations cannot be provided on the basis of this study. Previous studies of the relationship between CR and aging have focused on genotypes exhibiting robust effects of CR, with a view toward understanding its biological consequences and mechanisms. Notwithstanding, the current finding suggests that CR-resistant/intolerant models should be considered as potential controls for experimental studies of the effects of CR.

View larger version (14K): [in this window] [in a new window]   Figure 3. A schematic depiction of the interaction between biological age, CR, and genotype. The ordinate represents a continuum of beneficial (extended longevity) to deleterious (decreased longevity) effects. The abscissa represents biological age at the time of CR initiation. Beneficial effects of CR are lost in advanced age with an increase in likelihood of deleterious effects. Genetic factors modulate the physiological consequences of CR and the likelihood of deleterious or beneficial effects at a given biological age.

The second generalization is that CR instituted at a relatively advanced age may be without benefit and, depending on genotype, could have significant deleterious effects. This finding is relevant in light of the popular conception that CR might be a practical anti-aging intervention in all animal species, including humans. The current studies suggest that implementation of CR in animals of advanced age may be harmful.

The results of this study do not support the hypothesis that the increased life span conferred by long-term caloric restriction involves a direct and reversible modulation of vulnerability to mortality. Instead, our study suggests that the reduction of mortality risk, at least for C57BL/6 and B6D2F₁, occurs via the interaction of CR and physiological systems over a relatively prolonged period of the life span. Thus, the effects of caloric restriction on mortality are not rapidly inducible or reversible and may indeed be harmful if initiated in old age.

FOOTNOTES

¹ To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.02-0533fje; to cite this article, use FASEB J. (February 5, 2003) 10.1096/fj.02-0533fje

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