Diet modulates brain network stability, a biomarker for brain aging, in young adults. Mujica-Parodi et al. PNAS (2020)

leokitten · Jan 17, 2021

https://www.pnas.org/content/117/11/6170.long

Significance
To better understand how diet influences brain aging, we focus here on the presymptomatic period during which prevention may be most effective. Large-scale life span neuroimaging datasets show functional communication between brain regions destabilizes with age, typically starting in the late 40s, and that destabilization correlates with poorer cognition and accelerates with insulin resistance. Targeted experiments show that this biomarker for brain aging is reliably modulated with consumption of different fuel sources: Glucose decreases, and ketones increase the stability of brain networks. This effect replicated across both changes to total diet as well as fuel-specific calorie-matched bolus, producing changes in overall brain activity that suggest that network “switching” may reflect the brain’s adaptive response to conserve energy under resource constraint.

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.
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The Guardian: Low-carb diet may reverse age-related brain deterioration, study finds

Levant · Jan 18, 2021

Interesting stuff. Brings to mind this older study with using exogenous ketones but with relevance to metabolism (though not a human study), https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fasebj.31.1_supplement.970.7

Abstract
The ketogenic diet (KD) is a high fat, adequate protein, low carbohydrate diet that has been used clinically to treat refractory pediatric epilepsy for nearly a century. Emerging evidence suggests that the KD is broadly neuroprotective and health‐promoting; therefore, it is now being investigated as a preventative strategy and/or treatment for a wide variety of disorders, including many neurological diseases, cancer, obesity, and diabetes, as well as for enhancing athletic performance and human resilience capabilities. Recently, studies have revealed that many of the beneficial effects associated with the KD are mechanistically attributable to the ketone bodies, leading our lab and others to develop and test exogenous ketone supplements (KS) which elevate blood ketones without the need for severe carbohydrate restriction. In order to further our understanding of this new technology, we sought to characterize the metabolic and physiologic effects, safety, and toxicity of KS in healthy rats. The KS tested included the R,S‐1,3‐butanediol acetoacetate diester, 1,3‐butanediol, medium chain triglyceride oil, caprylic acid, and beta‐hydroxybutyrate mineral salts, alone and in various combinations. Healthy rats were administered KS by oral gavage or in their food in an acute (once), sub‐chronic (1 month), or chronic (4 months) fashion, and were analyzed for a variety of metabolic and physiologic biomarkers. Acute and chronic KS rapidly elevated blood ketones to therapeutic levels (2–5mM) and simultaneously decreased blood glucose. Sub‐chronic KS treatment significantly altered the global metabolome. Medium chain fatty acids and dicarboxylic acids were elevated with KS treatment. Carnitine and deoxycarnitine was decreased with KS, while acetyl coA and acetylcarnitine were elevated, suggesting enhanced mitochondrial LCFA oxidation. Kreb's cycle intermediates, including citrate, succinate, and fumarate, were elevated with KS. The neurotransmitter adenosine was elevated with KS, while some purine nucleotide breakdown products were also elevated. Markers of both oxidative stress (oxidized glutathione) and antioxidant capacity (carnosine and anserine) were elevated by KS. Metabolites associated with the gut microbiome or nutrient absorption, such as indoleproprionate, 2‐hydroxyisobutyrate, and coprostanol, were altered. Inflammatory profiling following chronic KS administration revealed decreases in many pro‐inflammatory cytokines, including IL‐1β, IL‐6, IFN‐γ, MCP‐1, and RANTES. KS appears safe as there were no signs of toxicity or adverse changes in total cholesterol, HDL, LDL, triglycerides, or markers of liver/kidney function over the chronic treatment protocol. KS may be a useful alternative or adjuvant to the KD for disorders where nutritional ketosis is therapeutic.
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I also remember reading an article showing that exogenous ketones could also elicit very similar gut microbiome changes to that caused by a ketogenic diet, can't seem to locate it right now though.

Are you still on a ketogenic diet @leokitten?

Trish · Jan 18, 2021

Levant said: ↑

Are you still on a ketogenic diet @leokitten?
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To read a response to this and to discuss individuals' experiences with the keto diet, go to this thread:
https://www.s4me.info/threads/first-time-in-remission-with-ketogenic-diet.5120/page-22#post-318338

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Diet modulates brain network stability, a biomarker for brain aging, in young adults. Mujica-Parodi et al. PNAS (2020)

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Diet modulates brain network stability, a biomarker for brain aging, in young adults. Mujica-Parodi et al. PNAS (2020)

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