Influence of calorie restriction on measures of age-related cognitive decline: role of increased physical activity

Abstract

Controversy exists as to whether lifelong 40% calorie restriction (CR) enhances, has no effect on, or disrupts cognitive function during aging. Here, we report the effects of CR versus ad-lib feeding on cognitive function in male Brown Norway x Fisher344 rats across a range of ages (8-38 months), using two tasks that are differentially sensitive to age-related cognitive decline: object recognition and Morris water maze (MWM). All ages performed equally in object recognition, whereas, as a group, CR rats were impaired. In contrast, there was an age-related impairment in the MWM that was attenuated by CR as measured by time in proximity with and latency to reach the platform. Distance to the platform, a more sensitive measure, was not affected by CR. Finally, CR resulted in an overall increase in physical activity, one of several behavioral confounders to consider in the interpretation of cognitive outcomes in both tasks.

Figure 1.

Forelimb grip strength was determined in rats using an automated grip strength meter. Data are reported as means ± SEM. Calorie restriction rats (empty bars) performed consistently better than ad libitum rats (filled bars) and younger rats outperformed older rats.

Figure 2.

Physical activity was assessed by placing rats in an open arena and allowing them to locomote for 5 minutes. Data are reported as means ± SEM. Calorie restriction rats (empty bars) demonstrated increased movement relative to the ad libitum groups (filled bars). In addition, the young group differed from all other age groups with the exception of the middle age groups, which did not differ from the old and very old groups.

Figure 3.

Total time spent by exploring objects was measured during the sample and test phases of the object recognition procedure. Data are reported as means ± SEM. Calorie restriction rats (open bars) spent significantly more time exploring both objects relative to the ad libitum rats (closed bars) during both phases. However, during the sample phase, only the young and middle age groups spent more time exploring objects relative to the old group with no differences observed with the very old.

Figure 4.

The discrimination index for the object recognition test was calculated for all groups. Data are reported as means ± SEM. Overall, ad libitum rats (filled bars) focused more on the novel object relative to the calorie restriction (CR) rats (open bars) indicating that, in this task, CR does not improve memory.

Figure 5.

In the Morris water maze (MWM) procedure, latency (upper left panel) to reach the hidden platform, swimming velocity (upper right panel), distance traveled (lower left panel), and proximity (% of time within 40 cm of the platform; lower right panel) were calculated for each animal. Calorie restriction (CR) rats (open bars) demonstrated a decrease in latency to find the platform, which would be indicative of preserved learning ability. However, there was also an increase in swim speed relative to the ad libitum (AL) group (filled bars). A similar pattern was observed across ages in that middle age rats demonstrated a shorter latency to reach the platform and increased swim speed relative to the old and very old groups. For distance, only the old exhibited greater distances than the middle age and very old groups. Proximity to the platform was analyzed in the MWM procedure as an alternative measure of learning performance that does not rely on swimming speed. In this case, all CR rats performed better on this measure than their AL controls. All data are presented as means ± SEM.

Figure 6.

In the Morris water maze procedure, we assessed immediate (left panels) and long-term memory (right panels) for the platform location using a memory index (upper panels), time spent in goal quadrant (middle panels), and proximity to where the platform was previously located (bottom panels). The pattern of results was similar across all measures. There was a main effect of age that did not interact with diet. Middle age rats performed better than old, and both performed better than very old rats at the immediate and 24-hour time point. However, the middle age group performed better than both at the 24-hour time point. All data are presented as means ± SEM.