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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.

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The ketogenic diet (KD), or the low‐carbohydrate and high‐fat diet, has served as a therapeutic for medically intractable epilepsy for the past ninety years. Recent studies have shown the neurological benefits derived from ketone bodies. However, KD's impact on overall in vivo brain function remains largely unexplored. The aim of this study was to characterize the interaction between specialized nutrition and in vivo brain function. Subjects were age‐matched and gender‐matched young wild type mice models, divided into two groups based on diet: Western (control) diet or KD. We employed multimodal, non‐invasive neuroimaging (MRI/MRS) to determine in vivo brain cerebral blood flow and energy metabolites. We also assessed the animal's memory and learning ability with the Radial Arm Water Maze and the Novel Object Recognition Test. In addition, we performed western blots and BBB function analysis. Blood glucose, blood ketone bodies, and body weight were also measured. We found distinct patterns between Western and Ketogenic diet – the KD group exhibited significantly higher cerebral blood flow in the dorsal thalamus and the hypothalamus compared to the control. We observed significant modulation of the metabolites alanine and lactate, and identified a potential interaction with astrocytes. When examining the behavioral test results, there is indication that KD fortifies various memory and sensory functions, consist with our CBF data. Furthermore, KD mice exhibited significantly higher brain endothelial NOS and brain capillary P‐glycoprotein, as well as a significantly lower expression of the mechanistic target of Rapamycin. Our novel findings demonstrate KD produces noticeable shifts in brain vascular and metabolic function, while maintaining cognition in a young mice model. These results provide rationale for KD as a viable early interventional dietary measure.Support or Funding InformationThis research was supported by NIH grant K01AG040164.