Influence Of Caloric Restriction On El Mice 61 Study Design

We used EL mice to evaluate the effects of mild (15%) and moderate (30%) CR on body weight, epileptogenesis, and serum levels of glucose and ketone bodies at both juvenile (30 d) and adult (70 d) ages (41). In addition, we compared the antiepileptic effects of CR with those of the KD in juvenile mice.

All mice were matched for age and body weight before initiation of CR, and all received a regular chow diet that contained a balance of mouse nutritional ingredients and delivered 4.4 kcal per gram of gross energy. We implemented CR in individually housed mice using a total dietary restriction. This involved restricting the amount of food a mouse normally consumed per day under ad libitum (AL) conditions. The average daily food intake (grams) was measured under AL conditions in individual male and female mice at both juvenile and adult ages throughout the study (41). Each AL-fed mouse received a known amount of food (approx 50 g), and the difference in chow weight was recorded every 2 d at approximately the same time (11 am-1 pm). The amount of food given to the CR-fed juvenile mice was 85% (15% CR) of that given to the AL mice daily. At adult ages, the CR-fed mice received 85 and 70% (30% CR) of

Fig. 3. Influence of CR on body weight in (A) juvenile and (B) adult EL mice. The mean body weight was significantly lower in the juvenile 15% CR mice than in the AL mice over wk 1-10 (p < 0.01). The reduction in body weight was greater in the 30% CR mice than in the 15% CR mice at the adult ages. Despite the initial weight loss, body weights in both adult CR groups remained stable over wk 3-10. Values are expressed as the mean ± SEM. From ref. 41, with permission.

Fig. 3. Influence of CR on body weight in (A) juvenile and (B) adult EL mice. The mean body weight was significantly lower in the juvenile 15% CR mice than in the AL mice over wk 1-10 (p < 0.01). The reduction in body weight was greater in the 30% CR mice than in the 15% CR mice at the adult ages. Despite the initial weight loss, body weights in both adult CR groups remained stable over wk 3-10. Values are expressed as the mean ± SEM. From ref. 41, with permission.

the AL amount. The average daily food intake (grams) for the AL-fed mice was determined every other day, and the CR-fed mice were given either 85 or 70% of the daily ration of the AL-fed group.

No adverse side effects were seen in the mice receiving either the 15% CR diet (at juvenile ages) or the 30% CR diet (at adult ages). The CR-fed mice were healthy and more active than the AL-fed mice as assessed by ambulatory and grooming behavior. No signs of vitamin or mineral deficiency were observed in the CR-fed mice. The juvenile EL mice receiving mild CR lost approx 8% of their body weight during the first week of treatment, and their weights remained significantly lower than those of the AL group throughout the study (Figure 3A). Despite this initial body weight loss, the rates of body weight gain beyond wk 2 were similar in the AL-fed and CR-fed mice. These findings, together with the overall healthy appearance of the mice, indicate that mild CR has no adverse effect on global body growth or development. It is important to mention, however, that the young mice were unable to tolerate a moderate CR of 30%. This emphasizes the need for careful health monitoring of young mice following dietary modifications.

The adult AL-fed and CR-fed EL mice were also matched for age and body weight prior to treatment (Figure 3B). The total energy intake of the AL-fed mice was about 30 kcal/d and remained relatively constant over the 10-wk treatment period. The total energy intake of the CR-fed mice was adjusted to 85 (15% CR) or 70% (30% CR) of the AL energy intake. As at juvenile ages, body weights were pooled for males and females because the effects of CR were similar in both sexes. In contrast to the juvenile AL-fed mice, the body weights of the adult AL-fed mice remained relatively constant over the 10-wk testing period. The body weights in the 15 CR and 30% CR groups were about 12 and 15% lower, respectively, than the weights of the AL-fed group and remained stable over the testing period (Figure 3B). The CR-induced reductions in body weights were correlated with the degree of CR.

Week of Treatment Week of Treatment

Fig. 4. Influence of CR on seizure susceptibility in (A) juvenile and (B) adult EL mice. The number of mice seizing was significantly lower in the CR groups than in the control groups. From ref. 41, with permission.

Week of Treatment Week of Treatment

Fig. 4. Influence of CR on seizure susceptibility in (A) juvenile and (B) adult EL mice. The number of mice seizing was significantly lower in the CR groups than in the control groups. From ref. 41, with permission.

It is important to emphasize the distinction between CR, malnutrition, and starvation. In contrast to the juvenile mice, which could not tolerate a 30% CR diet, the adult mice showed no adverse effects from the 30% CR diet. Indeed, we find that adult EL mice can easily tolerate a 50% CR diet. In general, adult mice have more body fat and a more stable metabolic rate than juvenile mice. These findings emphasize the importance of age and initial body weight in studies involving CR. CR is designed only to restrict calories, not to restrict essential vitamins or minerals that could produce malnutrition. The therapeutic health benefits of CR are lost if the degree of restriction is too extreme. Excessive calorie restriction produces starvation involving malnutrition, failure to thrive, or kwashiorkor at young ages. The levels of CR that we used, and our findings in EL mice, are consistent with the well-recognized health benefits of mild to moderate diet restriction in rodents (70).

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