Intermittent fasting: A potential modifier of DNA methylation landscape in a chronic cerebral hypoperfusion mouse model of vascular dementia.

Abstract

DNA methylation landscape of a Vascular dementia (VaD) mouse model was studied to better understand the molecular happenings in the disease and hence its contribution to mixed dementia. A prophylactic intervention of intermittent fasting (IF) was introduced and its role in modulating the DNA methylation landscape was also studied. A representative VaD mouse model (Chronic cerebral hypoperfusion (CCH) model) was established using the bilateral common carotid artery stenosis (BCAS) method that involves surgically inserting micro-coils in mice. The coils were left in the mice for different timepoints of 7, 15 and 30 days respectively to study the temporal differences in the DNA methylation landscape. Additionally, as a nexus between the gene-environment interaction, IF, which involves time restricted feeding, was introduced as a prophylactic intervention. Hence, a parallel group of mice with the same timepoints were fasted for 16 hours every day for a period of 4 months before BCAS surgery was performed. At the end of the respective timepoints, the mice were sacrificed, and the DNA extracted from the cerebral cortex was subjected to DNA methylation sequencing. CCH altered the DNA methylation landscape compared to the controls and overall DNA methylation was significantly reduced (hypomethylated state). With IF, the DNA methylation landscape was re-modelled and the overall DNA methylation was significantly increased. IF seems to restore the expression of neuroinflammation-related genes which are altered in CCH mice that are fed ad libitum. White matter lesions are also reportedly reduced in CCH mice under IF regimen. IF, at an epigenetic level, shows promise in offering potential beneficial effects under CCH.