Early Shifts of Brain Metabolism By Caloric Restriction Preserve White Matter Integrity and Long‐term Memory in Aging Mice

Preservation of brain integrity with age is highly associated with lifespan determination. Caloric restriction (CR) has been shown to increase longevity and healthspan in various species; however, its effects on preserving living brain functions in aging remain largely unexplored. In the study, we used multimodal, non‐invasive neuroimaging (PET/MRI/MRS) to determine in vivo brain glucose metabolism, energy metabolites, and white matter structural integrity in young and old mice fed with either control or 40% CR diet. In addition, we determined the animals’ memory and learning ability with behavioral assessments. Blood glucose, blood ketone bodies, and body weight were also measured. We found distinct patterns between normal aging and CR aging on brain functions ‐ normal aging showed reductions in brain glucose metabolism, white matter integrity, and long‐term memory, resembling human brain aging. CR aging, in contrast, displayed an early shift from glucose to ketone bodies metabolism, which was associated with preservations of brain energy production, white matter integrity, and long‐term memory in aging mice. Among all the mice, we found a positive correlation between blood glucose level and body weight, but an inverse association between blood glucose level and lifespan. Our findings suggest that CR could slow down brain aging, in part due to the early shift of energy metabolism caused by lower caloric intake, and we were able to identify the age‐dependent effects of CR non‐invasively using neuroimaging. These results provide a rationale for CR‐induced sustenance of brain health with extended longevity. Support or Funding Information This research was supported by NIH grant K01AG040164 and American Federation for Aging Research Grant #A12474 to A‐LL. The 7T ClinScan small animal MRI scanner of UK was funded by the S10 NIH Shared Instrumentation Program Grant (1S10RR029541‐01). We thank Max Baker for assisting the experiments. 1 Experimental designC 57/BL6 male mice were obtained from the National Institute on Aging (NIA) Caloric Restriction Colony. At NIA, all mice were fed ad libitum until 14 weeks of age. The CR regimen was initiated by caloric reduction of 10% at week 14, 25% at week 15, and reaching 40% CR by week 16. Young CR (5–6 mo), old CR (18–20 mo), young control (ad libitum; 5–6 mo), old control mice (ad libitum; 18–20 mo) were then purchased from NIA for the study.2 Caloric restriction induced early onset of glucose reduction and ketone bodies increase(A) CMR glc visual map of the four mice groups. The color code indicates the CMR glc (in SUV) in a linear scale. (B) Quantitative global CMR glc . (C) Quantitative hippocampal CMR glc . ( D ) Blood glucose. (E) Blood ketone bodies. Data are presented as Mean ± SEM. * p < 0.05, ** p < 0.01, *** p < 0.001, and **** p < 0.0001.3 Caloric restriction increased production of brain energy metabolite and preserved it with age( A ) The voxel replacement on the hippocampus and ( B ) the representative 1 H‐MRS spectrum, showing total choline (TCho), total creatine (TCr), taurine (Tau), glutamate‐glutamine complex (Glx), myo‐inositol (mI), N ‐acetylaspartate (NAA), in parts per million (ppm). ( C ) TCr levels of the four groups. Data are presented as Mean ± SEM.* p < 0.05; ** p < 0.01; n.s.: non‐significant.4 Caloric restriction preserved white matter structural integrity( A ) The region showing corpus callosum (CC) on MRI diffusion–weighted images. ( B ) The quantitative measurements of fractional anisotropy (FA) in CC. Data are presented as Mean ± SEM. *** p < 0.001 and **** p < 0.0001.5 Caloric restriction prevented age‐dependent long‐term memory deterioration( A ) Average errors corrected over 6 blocks of the control mice, with difference observed on Blocks 3 and 4. ( B ) Average errors corrected over 6 blocks of the CR mice, with difference observed on Block 3. ( C ) Comparison of the errors made by four groups on Block 3. ( D ) Comparison of errors made by four groups on Block 4, an index of long‐term memory. Data are presented as Mean ± SEM. * p < 0.05; ** p < 0.01.6 Association of caloric restriction with blood glucose, body weight and lifespan(A) A positive correlation between blood glucose and body weight among the CR and control mice (r = 0.55, p < 0.001). (B) An inverse association between blood glucose level (measured in the current study) and the lifespan (reported by Froster et al., 2003) of the CR and control mice.