Skip to content

Instantly share code, notes, and snippets.

Embed
What would you like to do?

Overview

Diet modulates brain network stability, a biomarker for brain aging, in young adults https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084077/

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.

[...] irrespective of whether ketosis was achieved with a ketogenic diet or exogenous ketone ester.

[...] suggesting that even the earliest stages of T2D induce hypometabolism of neurons, as with other cells in the body and as per brain glucose hypometabolism commonly seen in dementia. Finally, infusing insulin, without increasing glucose, has been shown to increase memory for Alzheimer’s disease patients (12). These clinical studies suggest that deleterious cognitive effects of insulin resistance may result from metabolic stress, as neurons gradually lose access to glucose. If so, it may be possible to bypass insulin resistance to refeed neurons by exploiting ketone bodies as an alternative fuel.

Likewise, in humans there is evidence that even as older brains become hypometabolic to glucose, neural uptake of ketone bodies remains unaffected, even for the most severe glucose hypometabolism endemic to Alzheimer’s disease (15, 16). Finally, lifelong hypocalorically induced ketosis preserves synaptic plasticity (17) and cognition (18) in elderly animals [chronological age equivalent to ∼87 to 93 human years (19)].

[...]

Mechanistically, this increase in synaptic efficiency was linked to increased expression of the N-methyl-d-aspartate (NMDA) receptor for glutamate.

[...]

While glucose is normally considered to be the brain’s default fuel, β-hydroxybutyrate metabolism increases by 27% the Gibbs free energy change for ATP compared to glucose (23, 24). Consistent with that advantage, our results showed that even in younger (<50 y) adults, dietary ketosis increased overall brain activity and stabilized functional networks.

[...]

Ketone bodies, whenever present, are immediately utilized by the brain regardless of need, whereas glucose is only taken up by cells via GLUT transporters as required (15, 44). Thus, in the (inherently physiologically unnatural) state in which exogenous ketones are administered concomitantly with glucose, ketone bodies saturate cells, and the cerebral metabolic rate of glucose is down-regulated (44).

[...]

Thus, following the typical overnight fast of ∼10 to 12 h, it is likely that the brains of non-insulin-resistant participants had already transitioned to endogenous ketosis, even if it was not yet detectable with assays of peripheral ketosis measured by blood or urine. Overall, our neuroimaging **results support the hypothesis that at least some of the beneficial neural effects reported with hypocaloric states, such as intermittent fasting, severe caloric restriction, and exercise, may result from the brain’s transition to ketone bodies as fuel **

tl;dr: Ketones increase brain energy availability independent of metabolic status, and increase stability of brain networks (as opposed to glucose which has the opposite effect), reversing some of the impairment found in brain aging(starting around 47yo, accelerating around 60), insulin resistance, and neurodegenerative disease implicating brain hypometabolism. Brains likely enter ketosis within 10-12h of fasting, and ketone body availability increases synaptic plasticity(via NMDAr density) and general cognition, likely mediating a significant portion of benefits reported with intermittent fasting, caloric restriction, and exercise. It also reduces blood glucose spikes. I'd like to add the note that ADHD implicates brain network destabilization

Therapeutic Potential of Exogenous Ketone Supplement Induced Ketosis in the Treatment of Psychiatric Disorders: Review of Current Literature (2019) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543248/

Globally, psychiatric disorders, such as anxiety disorder, bipolar disorder, schizophrenia, depression, autism spectrum disorder, and attention-deficit/hyperactivity disorder (ADHD) are becoming more prevalent.

[...]

Emerging evidence from numerous studies suggests that administration of exogenous ketone supplements, such as ketone salts or ketone esters, generates rapid and sustained nutritional ketosis and metabolic changes, which may evoke potential therapeutic effects in cases of central nervous system (CNS) disorders, including psychiatric diseases. Therefore, the aim of this review is to summarize the current information on ketone supplementation as a potential therapeutic tool for psychiatric disorders. Ketone supplementation elevates blood levels of the ketone bodies: D-β-hydroxybutyrate (βHB), acetoacetate (AcAc), and acetone. These compounds, either directly or indirectly, beneficially affect the mitochondria, glycolysis, neurotransmitter levels, activity of free fatty acid receptor 3 (FFAR3), hydroxycarboxylic acid receptor 2 (HCAR2), and histone deacetylase, as well as functioning of NOD-like receptor pyrin domain 3 (NLRP3) inflammasome and mitochondrial uncoupling protein (UCP) expression. The result of downstream cellular and molecular changes is a reduction in the pathophysiology associated with various psychiatric disorders. We conclude that supplement-induced nutritional ketosis leads to metabolic changes and improvements, for example, in mitochondrial function and inflammatory processes, and suggest that development of specific adjunctive ketogenic protocols for psychiatric diseases should be actively pursued.

tl;dr: Exogenous ketone administration appears to confer the benefits of ketosis, without many of the downsides of a ketogenous diet(e.g. difficult adherence, many serious adverse effects and risks, no control over dose-response)

NOTE: Therapeutic concentration is 1-7mM(mmol/L), normal is 0.1-0.4, diabetic ketoacidosis over 25

Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC4617348/

When Owen et al. (2) reported that during a prolonged fast KBs can provide 60% or more of the brain’s daily energy requirement (thereby sparing ∼80 g/day of glucose that otherwise would have been derived largely from breakdown of the body’s limited protein stores)

[...]

During glucose scarcity, the astrocytes also may contribute to KB formation. Astrocytes in culture have been shown to produce KBs from FAs (6) and from leucine (7).

[...]

Nevertheless, the major determinants of cerebral KB metabolism are the prevailing plasma KB concentrations and availability of suitable monocarboxylic acid transporter (MCT) isoforms

[...]

For example, degradation of histone acetylation is associated with age-dependent memory impairment in mice. In contrast, restoration of histone acetylation leads to recovery of cognitive performance (45). More recent studies suggest that there is an urgent need to develop additional selective histone deacetylase (HDAC) inhibitors (46).

[...]

Recently, βHB was found to inhibit HDACs 1, 3, and 4 at concentrations of 5.3, 2.4, and 4.5 mM, respectively. Thus, millimolar concentrations of βHB appeared to increase histone acetylation via inhibition of HDACs. Moreover, the same study provided evidence that βHB exerts a suppressive effect on oxidative stress (47).

[...]

The human and rodent genome encodes for 11 HDAC proteins that are divided into four classes (HDAC I–IV). There is evidence that inhibition of HDACs 1–3 (class I) reverses memory dysfunction in a mouse model of AD (49). Agents reported to inhibit HDAC include sodium butyrate, trichostatin A, suberoylanilide hydroxamic acid, and sodium phenylbutyrate. βHB also qualifies as an HDAC inhibitor (47, 48).

[...]

Conversion of KBs to KEs eliminates KB acidity, making the KEs suitable vehicles for the delivery of KBs to the blood circulation via the gastrointestinal route. Ingestion of KE can directly increase plasma KBs to levels within the range achieved during fasting. The degree of KB elevation attained is readily controlled by the dose size (Fig. 1).

Supplementation strategies

Ketosis After Intake of Coconut Oil and Caprylic Acid—With and Without Glucose: A Cross-Over Study in Healthy Older Adults https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175812/

to;dr: Metabolism to BHB very variable. Glucose dampens the response, possibly on altering prior overnight fast ketosis status. Other oils don't alter the response. AUC/h within first 4h is .4mmol/L for 20g C8, but the peak did not seem to be reached. Some people get (mostly mild) GI symptoms. Only BHB was assayed but AcAc was also elevated, and different MCTs have different BHB/AcAc ratios.

An Open-Label, Single-Dose, Crossover Study of the Pharmacokinetics and Metabolism of Two Oral Formulations of 1-Octanol in Patients with Essential Tremor https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811161/

[...] Here we report on the findings of a phase I/II study of 1-octanol designed to explore pharmacokinetics, efficacy, and safety. The most significant finding was the identification of octanoic acid as the product of rapid 1-octanol metabolism. Furthermore, the temporal profile of efficacy closely matches the plasma concentration of octanoic acid.

[...] Plasma concentrations of 1-octanol were detectable at low levels whereas octanoic acid (OA) concentrations were approximately 100-fold higher. The half-life of OA was 87.6minutes. This was matched by a clinical reduction in tremor severity of 32% at 90 minutes, assessed using spirography. The safety profile was favorable, with the most commonly reported adverse effect being dysgeusia (38%). Early detection and higher plasma concentrations of OA are a product of rapid metabolism of 1-octanol.OA pharmacokinetics mirrored the timing of clinical improvement.

[...]

Similar to ethanol, 1-octanol has been found to block low-threshold calcium channels in the inferior olive using a rat model of ET [...] Both studies attempted to characterize pharmacokinetics, but were unable to detect 1-octanol. [...] alcohol dehydrogenase (ADH) playing a major role. This pathway involves the conversion of octanol to its corresponding aldehyde (octanal) before forming octanoic acid; however, under in vitro incubation of octanol with ADH, octanal disappears rapidly (<5 min) leaving only octanoic acid [7]. This led us to hypothesize that octanoic acid was the most likely stable metabolite.

[...] and [excluded] patients from far East Asian or Native American descent (due to their likelihood for possessing variant alleles of the genes for alcohol metabolism that could result in slower metabolism and potentially increase their sensitivity to alcohols and their metabolites).

[...] In both study parts, subjects fasted overnight for 6 hours before receiving 1-octanol at 6 AM.

[...] detectable octanoic acid concentrations seen within 5 minutes of oral ingestion in most individuals

[...] dose [of 1-octanol] required to reduce harmaline-induced tremor by 50% (ED50) of 0.26 mg/kg compared with 100 mg/kg of ethanol in animal models [3, 16]. Although animal data of 1-octanol and ethanol show similar acute toxicology profiles, 1-octanol is approximately 5 to6 times less potent in inducing intoxication [17–19]. These data would suggest an approximate 1-octanol ED50 for intoxication of 5.8 g for a single dose, close to our 64 mg/kg dosing, although we found no signs of intoxication at this level or in the 2 subjects we studied at 128 mg/kg.

[...]

First, octanoic acid has a bioavailability of nearly 100% [21]. Second, reaching the plasma concentrations of octanoic acid achieved in this study would require a lower oral dose of octanoic acid than that of 1-octanol. Finally, octanoic acid also has Food and Drug Administration generally recognized as safe status and human dietary consumption of up to 710 mg/kg is considered safe [22].

Tricaprylin Alone Increases Plasma Ketone Response More Than Coconut Oil or Other Medium-Chain Triglycerides: An Acute Crossover Study in Healthy Adults https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998344/

The acetoacetate-to-β-HB ratio increased 56% more after CO than after C8 after both doses.

On each metabolic study day, the participants arrived at 0730 after a 12-h overnight fast and a minimum of 24 h without alcohol intake. A forearm venous catheter was installed, and a baseline blood sample (time 0) collected. Participants then received a standard breakfast during which they consumed the test beverage. The breakfast consisted of 2 pieces of toast with raspberry jam, a piece of cheese, and 2 scrambled eggs. A second dose of the test beverage was given alone for lunch (i.e., with no other food)

C8 alone induced the highest plasma ketone AUCs from 0–4 h (780 ± 348 μmol ⋅ h/L) and from 4–8 h (1876 ± 564 μmol ⋅ h/L), values that were 26% and 21% more than C8-C10 alone and 813% and 870% more than the CTL, respectively (P < 0.01). The 2 half-day AUCs (0–4 and 4–8 h) were significantly different from each other during all tests (P < 0.05).

[...]

Although C10 is not very ketogenic, it may have an indirect effect on brain fuel availability because it promotes glycolysis and stimulates lactate release in isolated cultured astrocytes (14).

Nutritional state has an important effect on ketogenesis, with fasting stimulating ketone production more than the postprandial state for any given load of C8 [...] This could explain the higher plasma ketone response during our 4- to 8-h study period compared with the 0- to 4-h period.

[...]

For ketones to be a useful energy source in glucose-deprived parts of the AD brain, the estimated mean daily plasma ketone concentration needs to be >200 μmol/L (21). With a total 1-d dose of 40 mL C8, plasma ketones peaked at 900 μmol/L and the day-long mean was 363 ± 93 μmol/L, whereas with the same amount of CO, they peaked at 300 and 107 ± 57 μmol/L, respectively

Sign up for free to join this conversation on GitHub. Already have an account? Sign in to comment