A calorie-restricted diet decreases brain iron accumulation and preserves motor performance in old rhesus monkeys

Abstract

Caloric restriction (CR) reduces the pathological effects of aging and extends the lifespan in many species, including nonhuman primates, although the effect on the brain is less well characterized. We used two common indicators of aging, motor performance speed and brain iron deposition measured in vivo using MRI, to determine the potential effect of CR on elderly rhesus macaques eating restricted (n = 24; 13 males, 11 females) and standard diets (n = 17; 8 males, 9 females). Both the CR and control monkeys showed age-related increases in iron concentrations in globus pallidus (GP) and substantia nigra (SN), although the CR group had significantly less iron deposition in the GP, SN, red nucleus, and temporal cortex. A diet x age interaction revealed that CR modified age-related brain changes, evidenced as attenuation in the rate of iron accumulation in basal ganglia and parietal, temporal, and perirhinal cortex. Additionally, control monkeys had significantly slower fine motor performance on the Movement Assessment Panel, which was negatively correlated with iron accumulation in left SN and parietal lobe, although CR animals did not show this relationship. Our observations suggest that the CR-induced benefit of reduced iron deposition and preserved motor function may indicate neural protection similar to effects described previously in aging rodent and primate species.

Figure 1.

The correlation of age at scan and R2 signal. Statistical parametric map of significant decreases in R2 signal were found within bilateral globus pallidus. The maximum voxel in the left hemisphere is plotted and depicts the main effect. As age increases, the R2 signal decreases and represents increased iron concentration. The voxel and cluster thresholds were, respectively, p < 0.005 (uncorrected) and p < 0.05 (corrected).

Figure 2.

R2 relaxation signal differing by diet group. Statistical parametric map indicating decreased R2 signal (i.e., increased iron deposition) in control versus CR monkeys in basal ganglia, red nucleus, substantia nigra, and temporal cortex. A peak voxel in left globus pallidus represents the main effect of group as bar graphs. Lower R2 values among controls correspond to increased brain iron. The voxel and cluster thresholds were, respectively, p < 0.005 (uncorrected) and p < 0.05 (corrected).

Figure 3.

The differing association of R2 relaxation signal and age as a function of dietary group. A–F, As age increased per year, controls showed significantly lower R2 signal (i.e., increased iron deposition) versus diet group monkeys within the temporal lobe, including perirhinal cortex (A), superior temporal sulcus (B), and bilateral hippocampus (C). Other subcortical structures included substantia nigra and thalamus (C and D). Clusters were also seen in the parietal (E) and parieto-occipital regions (F). G, A representative voxel in dorsal superior temporal sulcus depicts the interaction. The voxel and cluster thresholds were, respectively, p < 0.005 (uncorrected) and p < 0.05 (corrected).

Figure 4.

Fine motor performance during mMAP and the effect of dietary group. Bars represent mean time required to complete the fine motor component of the platform, rod, or q-mark task during the acquisition (Acq.) and proficiency (Prof.) phases for control and CR monkeys. Unlike the more simple motor tasks, CR monkeys exhibited faster fine motor performance during both test phases. *p < 0.05 for ANCOVA at a given phase.

Figure 5.

Association of result map-derived ROI with the acquisition phase of fine motor performance during the q-mark task. Among representative voxel maxima in left SN and the right dorsal bank of the STS, control animals with greater iron deposition (i.e., lower R2 signal) performed the task more slowly. By contrast, CR monkeys did not show this relationship.