Elsevier

Medical Hypotheses

Volume 85, Issue 5, November 2015, Pages 631-639
Medical Hypotheses

Ketosis may promote brain macroautophagy by activating Sirt1 and hypoxia-inducible factor-1

https://doi.org/10.1016/j.mehy.2015.08.002Get rights and content

Abstract

Ketogenic diets are markedly neuroprotective, but the basis of this effect is still poorly understood. Recent studies demonstrate that ketone bodies increase neuronal levels of hypoxia-inducible factor-1α (HIF-1α), possibly owing to succinate-mediated inhibition of prolyl hydroxylase activity. Moreover, there is reason to suspect that ketones can activate Sirt1 in neurons, in part by increasing cytoplasmic and nuclear levels of Sirt1’s obligate cofactor NAD(+). Another recent study has observed reduced activity of mTORC1 in the hippocampus of rats fed a ketogenic diet – an effect plausibly attributable to Sirt1 activation. Increased activities of HIF-1 and Sirt1, and a decrease in mTORC1 activity, could be expected to collaborate in the induction of neuronal macroautophagy. Considerable evidence points to moderate up-regulation of neuronal autophagy as a rational strategy for prevention of neurodegenerative disorders; elimination of damaged mitochondria that overproduce superoxide, as well as clearance of protein aggregates that mediate neurodegeneration, presumably contribute to this protection. Hence, autophagy may mediate some of the neuroprotective benefits of ketogenic diets. Brain-permeable agents which activate AMP-activated kinase, such as metformin and berberine, as well as the Sirt1 activator nicotinamide riboside, can also boost neuronal autophagy, and may have potential for amplifying the impact of ketogenesis on this process. Since it might not be practical for most people to adhere to ketogenic diets continuously, alternative strategies are needed to harness the brain-protective potential of ketone bodies. These may include ingestion of medium-chain triglycerides or coconut oil, intermittent ketogenic dieting, and possibly the use of supplements that promote hepatic ketogenesis – notably carnitine and hydroxycitrate – in conjunction with dietary regimens characterized by long daily episodes of fasting or carbohydrate avoidance.

Section snippets

Ketosis is neuroprotective

Provision of ketone bodies to the brain has been linked in recent research to marked and versatile neuroprotection, as well as cognitive enhancement – presumably because ketone bodies can serve as an alternative to glucose as a fuel source, but also owing to a range of beneficial metabolic effects which ketone oxidation exerts on the brain [1], [2], [3]. This essay proposes that stimulation of neuronal autophagy may be a key mediator of the neuroprotection afforded by ketosis.

Ketones up-regulate neuronal HIF-1 activity

Puchowicz and colleagues have recently demonstrated that ketogenic diets markedly boost the protein expression of hypoxia-inducible factor-1alpha (HIF-1α) in rat brain cortex [4], [5]. This effect is likely evoked by ketone bodies, as intracerebroventricular infusion of beta-hydroxybutyrate has a similar impact on HIF-1α. The authors speculate that this effect is mediated by a documented increase in neuronal succinate levels, which presumably stems from the fact that the first step in

Ketones modulate protein acetylation

There are also grounds for suspecting that ketosis could increase the activity of the type 3 histone deacetylase Sirt1 (sirtuin 1, an abbreviation of “silent mating type information regulation 2 homolog 1”) in the cytoplasm and nucleus of neurons. A high NAD(+)/NADH ratio promotes Sirt1 activity, as NAD(+) is an obligate substrate for this deacetylase. Neuronal oxidation of glucose, by promoting reduction of NAD+ at the glyceraldehyde-3-phosphate dehydrogenase step of the glycolytic pathway,

Ketogenic diets decrease hippocampal mTORC1 activity

Another recent study demonstrates that mTORC1 (mammalian target of rapamycin complex 1) activity is modestly decreased in the hippocampus of rats fed a ketogenic diet, as indicated by a reduction in the phosphorylation of ribosomal protein S6 [79]. This effect appears to reflect a small decrease in the activation of Akt; a trend toward increased AMPK activity does not achieve statistical significance, but if real could also contribute to reduced mTORC1 activity. An increase in Sirt1 activity

Autophagy may mediate some neuroprotective benefits of ketogenic diets

It is well established that HIF-1α mediates the activation of macroautophagy induced by hypoxia [81], [82]. This effect comes about because HIF-1 induces transcription of BNIP3 (BCL2/Adenovirus E1B 19 kDa Interacting Protein 3) and BNIP3L, BH3-only proteins which disrupt the inhibitory association of beclin 1 with Bcl-2 (B-cell lymphoma 2) by binding to the latter. Once freed from its association with Bcl-2, beclin 1 can then fulfill its obligate role in autophagosome formation, the first step

Adjuvant potential of AMPK activators and nicotinamide riboside

A feasible alternative strategy for boosting cerebral autophagy is to administer brain-permeable activators of AMP-activated kinase (AMPK); this enzyme activates autophagy by inhibiting mTORC1 activation while conferring an activating phosphorylation on ULK1 [87], [111], [112]. The currently available agents metformin and berberine, both employed in the management of diabetes, appear to have potential in this regard [113], [114], [115], [116], [117], [118]; resveratrol, which likewise activates

Overview – versatile protection afforded by brain ketone metabolism

Another mechanism whereby the ketone body beta-hydroxybutyrate may exert neuroprotective effects is via activation of anti-inflammatory GPR109A (a.k.a. HCA2) receptors on microglia and infiltrating monocytes [129], [130]. These receptors are also expressed on adipocytes, and mediate the feedback effect whereby ketosis suppresses adipocyte lipolysis; the anti-lipolytic effect of high-dose niacin therapy reflects the ability of this vitamin to likewise stimulate GPR109A. In microglia,

Practical implementation of ketogenic diets

Medium-chain fatty acids can be stored as triglycerides in adipocytes or other tissues to only a limited degree, and are not employed for phospholipid synthesis [131]. Hence, they tend to be oxidized rapidly after ingestion. This oxidation is particularly rapid because carnitine-mediated transport – subject to regulatory control – is not required for access of these fatty acids to the mitochondrial inner matrix [132]. After ingestion of a bolus of medium-chain fatty acids, their rapid oxidation

Health concerns

Qualms about the long-term consequences of low-carbohydrate diets for overall health have been raised by recent evidence that people who use low-carbohydrate diets composed primarily of animal products on a continuing basis experience increased mortality [142]. However, the same study found a reduction in mortality in those who use low-carb diets based primarily on plant products. Indeed, ketogenic diets composed of nuts, soy products, avocadoes, oils, and low-carb vegetables are feasible [143]

Strategies for accelerating onset of ketosis

Following cessation of carbohydrate ingestion, it may take 2–3 days for important ketosis to develop in humans. Hence, alternate-day fasting or modified alternative-day fasting, while it may benefit brain health, is unlikely to do so via ketosis. However, certain supplementation strategies may have potential for accelerating the liver’s adaptation to ketogenesis that develops gradually after carbohydrate avoidance commences. Conceivably, such supplementation could make short periods of carb

Summing up

In summary, ketosis can be expected to stimulate autophagy in brain neurons by boosting HIF-1α levels, increasing Sirt1 activity, and decreasing mTORC1 activity. Concurrent administration of brain-permeable agents which activate AMPK could be expected to further enhance brain autophagy. Autophagy induction has considerable potential as a strategy for preventing and controlling neurodegeneration, and ketosis exerts a number of additional effects that are neuroprotective. Serum ketone levels can

Conflict of interest

Mark McCarty is owner and science director for a nutraceutical company, some of whose products contain carnitine or hydroxycitrate.

Acknowledgement

We’d like to thank Jeremy J. Stone for suggesting the likely utility of intermittent ketogenic dieting as a practical neuroprotective strategy – and for encouraging us to study these issues.

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