Caloric restriction increases ketone bodies metabolism and preserves blood flow in aging brain

Abstract

Caloric restriction (CR) has been shown to increase the life span and health span of a broad range of species. However, CR effects on in vivo brain functions are far from explored. In this study, we used multimetric neuroimaging methods to characterize the CR-induced changes of brain metabolic and vascular functions in aging rats. We found that old rats (24 months of age) with CR diet had reduced glucose uptake and lactate concentration, but increased ketone bodies level, compared with the age-matched and young (5 months of age) controls. The shifted metabolism was associated with preserved vascular function: old CR rats also had maintained cerebral blood flow relative to the age-matched controls. When investigating the metabolites in mitochondrial tricarboxylic acid cycle, we found that citrate and α-ketoglutarate were preserved in the old CR rats. We suggest that CR is neuroprotective; ketone bodies, cerebral blood flow, and α-ketoglutarate may play important roles in preserving brain physiology in aging.

Keywords: Aging; Brain metabolism; Cerebral blood flow; Ketone bodies; Mammalian target of rapamycin; Neuroimaging; α-ketoglutarate.

Fig. 1

Caloric restriction reduced cerebral metabolic rate of glucose (CMR_Glc) (A) CMR_Glc of representative control and CR rats; (B) Quantitative global CMR_Glc (gCMR_Glc); (C) Quantitative cortical CMR_Glc (cCMR_Glc); (D) Quantitative hippocampal CMR_Glc (hCMRGlc); (E) Quantitative hypothalamic CMR_Glc (htCMR_Glc). N = 6 per experimental group. Data are presented as mean ± standard error of mean. *p < 0.05; **p < 0.01; ***p < 0.001. Abbreviations: CR, caloric restriction; SUV, standardized uptake value.

Fig. 2

Caloric restriction preserved cerebral blood flow (CBF). (A) CBF maps of representative control and CR rats obtained by ASL; (B) quantitative global CBF (gCBF); (C) quantitative cortical CBF (cCBF); (D) quantitative hippocampal CBF (hCBF); and (E) quantitative hypothalamic CBF (htCBF). N = 6 per experimental group. Data are presented as mean ± standard error of the mean.**p < 0.01. Abbreviation: CR, caloric restriction.

Fig. 3

Caloric restriction reduced glycolysis, elevated ketone body metabolism, and preserved brain mitochondrial tricarboxylic acid (TCA) cycle metabolites. (A) Glucose 1-phosphate/d-fructose 6-phosphate, intermediates in the glycolytic metabolic pathway; (B) lactate, the end product of glycolysis; (C) brain ketone bodies, β-hydroxybutyrate (BHB); (D) blood ketone bodies; (E) citrate; and (F) α-ketoglutarate, 2 intermediates in the mitochondrial TCA cycle. N = 6 per experimental group. Data are presented as mean ± standard error of the mean. *p < 0.05; **p < 0.01; ***p < 0.001. Abbreviations: AUD, area under the curve; CR, caloric restriction.

Fig. 4

Proposed metabolic and hemodynamic changes induced by caloric restriction (CR). This figure shows the comparison between old control and CR rats. CR downregulated glucose metabolic pathway (with reduced glucose uptake, glycolysis, lactate, and glucose-glycogen recycling) but upregulated ketogenic pathway. The ketone bodies may come from astrocytic fatty acid oxidation or blood stream. Ketone bodies are converted to acetoacetate and then further metabolized to acetyl-CoA. The altered metabolic pathway resulted in enhanced TCA cycle flux and glutamate-glutamine recycling (V_cyc(tot)) between neurons and astrocytes. Elevated CBF may be due to enhanced neuronal activity and increased ketone bodies levels. *This was shown in our previous study (Lin et al., 2014). Abbreviations: BHB, β-hydroxybutyrate; CBF, cerebral blood flow; TCA, tricarboxylic acid.