Ketone Bodies in Energy, Neuroprotection

The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 6 No. 4 • September 2003

Ketone Bodies in Energy, Neuroprotection, and Possibly in the Effects of Dietary Restriction

Ketone bodies, natural metabolites produced from fatty acids, are sources of energy that can be used when there is insulin deficiency (which may be pathological, as in diabetes, or as a result of consuming low dietary carbohydrate) or mitochondrial senescence. Ketone bodies are found in moderate amounts in prolonged human fasting and in type 2 diabetes.

Interestingly, ketones are very efficient sources of energy. One paper1 reports that the efficiency of cardiac hydraulic work (in rat hearts) was 10.5% in hearts perfused with glucose alone, and increased to 28% in combination with insulin, to 24% with ketones, and to 36% on addition of the combination. Addition of insulin, ketones, and the combination increased acetyl CoA (in the tricarboxylic acid cycle) 9-fold, 15-fold, and 18-fold, respectively, with corresponding decreases in CoA. “Addition of insulin increased the efficiency of hydraulic work per mole of oxygen consumed in [rat] heart 28% by decreasing oxygen consumption by 14% and increasing cardiac work 13%. Addition of ketones, on the other hand, increased the efficiency mainly by increasing hydraulic work, at the same time decreasing oxygen consumption by only a small percentage.”

The authors propose that “The increase in efficiency caused by ketones therefore was compatible with a decrease in proton leakage across mitochondrial membrane due simply to a decrease in potential, as has been previously suggested.” We have written earlier in this newsletter on the hypothesis that increased mitochondrial membrane potential (which increases free radical production in mitochondria) is a mechanism of aging.

The authors propose that “. . . the functional and energetic effects of insulin and ketone bodies may have important clinical consequences.” For instance, they note that elevation of blood ketones to levels that are observed after a 48-hour fast almost completely reverses the mitochondrial abnormalities associated with insulin deficiency. They thus suggest that mild ketosis might be considered a beneficial adaptation to insulin deficiency. They also suggest that ketones might be a beneficial treatment for elderly patients or others suffering from oxidative damage to mitochondria.

The second paper2 found that d-beta-hydroxybutyrate, a ketone naturally found in rat and human metabolism, protected neurons in cell-culture models of Alzheimer’s and Parkinson’s diseases. Addition of a 4-mM solution of the ketone to cells exposed to the cytotoxic amyloid-beta protein1-42 doubled the number of surviving cells and increased cell size and neurite outgrowth compared to cells exposed to the amyloid-beta protein1-42 but not treated with d-beta-hydroxybutyrate. The authors propose that the ketones may ameliorate the amyloid-beta protein1-42 toxicity by overcoming a block at mitochondrial pyruvate dehydrogenase (PDH) that occurs as a result of glycogen synthase 3 beta kinase activation by the amyloid-beta protein. As they put it, “Ketones are the physiological means of overcoming PDH, resulting from a lack of insulin stimulation, and ensure the continuing function of the TCA cycle and hence the provision of NADH, the major substrate required for electron transport and ADP phosphorylation.”

We wonder what the usual dietary restriction (30% below ad libitum levels) does to ketone levels in rodents and in monkeys. We know that insulin and glucose levels are reduced due to dietary restriction. We wouldn’t expect to see the same levels of ketones that occur in prolonged fasting or even in very-high-fat, very-low-carbohydrate diets (medical ketogenic diets, which are sometimes used to treat intractable epilepsy). Yet it may be that ketones contribute to the protective effects of dietary restriction, though we haven’t seen anything on this.*

*After writing this, we received a PubMed search on the subject of ketones and calorie restriction carried out by Will Block (thanks, Will!). One paper reported that a 90% calorie-restricted diet in rats did not increase ketone levels [Cheng et al. A ketogenic diet increases brain insulin-like growth factor receptor and glucose transporter gene expression. Endocrinology 144(6):2676-82 (2003)]. Another found that in male Sprague-Dawley rats fed a normal rodent-chow diet calorie-restricted to 90% or 65%, ketones were elevated in approximate proportion to the degree of calorie restriction [Eagles et al. Calorie restriction of a high-carbohydrate diet elevates the threshold of PTZ-induced seizures to values equal to those seen with a ketogenic diet. Epilepsy Res 54(1):41-52 (2003)]. Yet another paper reported that ketone bodies increased by 65% in old, but not young, CR mice [Hagopian et al. Influence of age and caloric restriction on liver glycolytic enzyme activities and metabolite concentrations in mice. Exp Gerontol 38(3):253-66 (2003)]. Another paper found that mild calorie restriction (15%) in EL mice induced changes in blood glucose levels that were predictive of both blood ketone levels and seizure susceptibility [Greene et al. Caloric restriction inhibits seizure susceptibility in epileptic EL mice by reducing blood glucose. Epilepsia 42(11):1371-8 (2001)].

Moreover, the lower gastrointestinal tract is depleted of carbohydrates, since these are converted to sugar in the small intestine by amylase and then absorbed. The fiber (which includes resistant starch) that reaches the lower GI tract is broken down into short-chain fatty acids, such as butyric acid, which, when oxidized, become ketones, such as d-beta-hydroxybutyrate, that can then be used as energy. Ketones may therefore play a role in the lower-GI-tract anticancer protective properties of butyric acid.

  1. Sato, Kashiwaya, Keon, et al. Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J 9:651-8 (1995).
  2. Kashiwaya, Takeshima, Mori, et al. d-Beta-hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s disease. Proc Natl Acad Sci 97(10):S440-4 (2000).

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