Diet modulates brain network stability, a biomarker for brain aging, in young adults

Abstract

Epidemiological studies suggest that insulin resistance accelerates progression of age-based cognitive impairment, which neuroimaging has linked to brain glucose hypometabolism. As cellular inputs, ketones increase Gibbs free energy change for ATP by 27% compared to glucose. Here we test whether dietary changes are capable of modulating sustained functional communication between brain regions (network stability) by changing their predominant dietary fuel from glucose to ketones. We first established network stability as a biomarker for brain aging using two large-scale (n= 292, ages 20 to 85 y;n= 636, ages 18 to 88 y) 3 T functional MRI (fMRI) datasets. To determine whether diet can influence brain network stability, we additionally scanned 42 adults, age < 50 y, using ultrahigh-field (7 T) ultrafast (802 ms) fMRI optimized for single-participant-level detection sensitivity. One cohort was scanned under standard diet, overnight fasting, and ketogenic diet conditions. To isolate the impact of fuel type, an independent overnight fasted cohort was scanned before and after administration of a calorie-matched glucose and exogenous ketone ester (d-β-hydroxybutyrate) bolus. Across the life span, brain network destabilization correlated with decreased brain activity and cognitive acuity. Effects emerged at 47 y, with the most rapid degeneration occurring at 60 y. Networks were destabilized by glucose and stabilized by ketones, irrespective of whether ketosis was achieved with a ketogenic diet or exogenous ketone ester. Together, our results suggest that brain network destabilization may reflect early signs of hypometabolism, associated with dementia. Dietary interventions resulting in ketone utilization increase available energy and thus may show potential in protecting the aging brain.

The Effect of Exogenous Ketone Monoester Ingestion on Plasma BDNF During an Oral Glucose Tolerance Test

“…Extending the observation window beyond 120 min in the basal state may reveal the addition of circulating BDNF from genomic sources, as demonstrated in non-human models ( Marosi et al, 2016 ; Sleiman et al, 2016 ; Hu et al, 2018 ). Interestingly, as we were preparing this manuscript, Mujica-Parodi et al (2020) reported a series of brain imaging studies showing that an acute ketone bolus improves brain network stability compared to acute glucose bolus. These findings have implications for aging and brain-health optimization, as reductions in brain network stability relate to decreased brain activity and lower cognitive function ( Mujica-Parodi et al, 2020 ).…”

“…Interestingly, as we were preparing this manuscript, Mujica-Parodi et al (2020) reported a series of brain imaging studies showing that an acute ketone bolus improves brain network stability compared to acute glucose bolus. These findings have implications for aging and brain-health optimization, as reductions in brain network stability relate to decreased brain activity and lower cognitive function ( Mujica-Parodi et al, 2020 ). However, it has yet to be determined if circulating BDNF is involved in these and other improvements in brain health with KME ingestion.…”

Ketotherapeutics for neurodegenerative diseases

“…A collaboration between Stony Brook and Oxford Universities showed that both ketogenic diets and exogenous ketones (ketone monoester) improve network stability in young healthy individuals. By contrast, standard Western diets and glucose decrease network stability ( Mujica-Parodi et al, 2020 ). These data are consistent with the hypothesis that ketogenic interventions could prevent neurodegenerative disease and cognitive decline, as has been demonstrated in mice ( Roberts et al, 2017 ).…”

mTOR Mysteries: Nuances and Questions About the Mechanistic Target of Rapamycin in Neurodegeneration

“…Third, fasting and ketogenic diets share the common feature of stimulating hepatic production of the ketone body, β-hydroxybutyrate, which itself is a signaling molecule that regulates mTORC1 ( Li et al, 2017 ; Newman and Verdin, 2017 ; Norwitz et al, 2019a ). Interestingly, it has recently been demonstrated that both short-term ketogenic diets and acute administration of exogenous β-hydroxybutyrate improve a marker of brain aging called “brain network stability,” in contrast to standard Western diets and sugar which decrease network stability ( Mujica-Parodi et al, 2020 ). Long-term prospective studies will need to be conducted to determine whether fasting and ketogenic diets are truly neuroprotective in humans.…”