Ketosis regulates K+ ion channels, strengthening brain-wide signaling disrupted by age.

Abstract

Aging is associated with impaired signaling between brain regions when measured using resting-state fMRI. This age-related destabilization and desynchronization of brain networks reverses itself when the brain switches from metabolizing glucose to ketones. Here, we probe the mechanistic basis for these effects. First, we established their neuronal basis using two datasets acquired from resting-state EEG (Lifespan: standard diet, 20-80 years, N = 201; Metabolic: individually weight-dosed and calorically-matched glucose and ketone ester challenge, age = 26.9 {+/-} 11.2 years, N = 36). Then, using the multi-scale Larter-Breakspear neural mass model, we identified the unique set of mechanistic parameters consistent with our clinical data. Together, our results implicate potassium (K+) gradient dysregulation as a mechanism for age-related neural desynchronization and its reversal with ketosis, the latter finding of which is consistent with direct measurement of ion channels.