Proposing Ketosis as an Important Component of Calorie Restriction

The practice of calorie restriction, reducing calorie intake by up to 40% while still obtaining optimal levels of micronutrients, is the most studied method by which aging can be slowed. Calorie restriction produces sweeping changes in the operation of metabolism, of which the most notable and relevant are probably the increased levels of cellular recycling and repair processes. Certainly, calorie restriction fails to slow aging in lineages where the cellular maintenance processes of autophagy are disabled, which is fairly compelling evidence for the benefits to primarily result from better maintenance of cells. Still, there are many other equally interesting lines of research and areas of biochemistry to explore in relation to lowered calorie intake. For example, sustained fasting appears to clear out malfunctioning immune cells to some modest degree. Intermittent fasting produces changes that are only similar to those of calorie restriction, not the same. Reducing the intake of proteins, and especially methionine, without reducing calorie intake again produces a similar outcome to calorie restriction, but one that is not exactly the same.

It is clear that the beneficial response to calorie restriction is far from simple: it may involve numerous distinct processes at root, and may have no one single point of control. This is interesting, given that calorie restriction is very well preserved throughout the tree of life. Widely diverse species ranging from yeasts to worms to mammals all have much the same beneficial response to lowered calorie intake, indicating that (a) it evolved very early in the development of cellular life, and (b) that slowing aging in the face of temporary famine confers such an advantage that this trait near always outcompetes the alternatives. The complexity of the calorie restriction response is unfortunate for those research groups seeking to recapture the benefits of calorie restriction through pharmaceutical means. A lot of time and funding has gone towards the development of calorie restriction mimetic drugs, and there is very little to show for those efforts beyond better maps of some of the biochemistry involved. Eating less remains the only reliable methodology.

The complexity of calorie restriction coupled with the current incomplete understanding of cellular metabolism also means that there is a lot of room for new research. It should not be surprising to read arguments for specific processes to be prioritized differently than is the case in the present understanding of what is going on under the hood in response to a low calorie diet. The research here is an example, in which the authors suggest that mechanisms underlying the well known state of ketosis are significant in the calorie restriction response, and thus ketosis is thus a potential avenue for the development of calorie restriction mimetics that might capture some of the beneficial outcomes of calorie restriction. I am agnostic on this point; the situation is complex enough that I’d want to see other researchers weighing in before taking it as read. This is one of those topics where putting it to one side and waiting a few years to see what results is probably the right thing to do. I’d certainly advocate avoiding anything written on the topic of ketosis that is not a part of a peer-reviewed research paper. There is a lot of misinformation and outright nonsense out there, powered by the diet industry in both its professional and amateur incarnations.

Ketone bodies mimic the life span extending properties of caloric restriction

Caloric or dietary restriction has been shown to increase life span in a wide variety of species. A number of proposed mechanisms for the phenomena have been suggested including: retardation of growth, decreased fat content, reduced inflammation, reduced oxidative damage, body temperature, and insulin signaling, and increase in physical activity and autophagy. However, no coherent mechanistic explanation has been generally accepted for this widely observed phenomenon that caloric restriction extends life span across the species. Yet, an obvious metabolic change associated with caloric restriction is ketosis. Increased ketone body concentrations occur during caloric restriction in widely different species ranging from Caenorhabditis elegans to Drosophila to man where ketone bodies are produced in liver from free fatty acids released from adipose tissue.

Ketone bodies were first found in the urine of subjects with diabetes creating in physicians the thought that their presence was pathological. However, it was shown that ketone bodies were the normal result from fasting in man, where they could be used in man in most extrahepatic tissue including brain. The ketone bodies, D-β-hydroxybutyrate (D-βHB) and its redox partner acetoacetate are increased during fasting, exercise, or by a low carbohydrate diet. Originally ketone bodies were thought to be produced by a reversal of the β-oxidation pathway of fatty acids. However, it was definitively and elegantly shown that the β-hydroxybutyrate of the β oxidation pathway was of the L form while that produced during ketogenesis was the D form. This fundamental difference in the metabolism of the D and L form of ketone bodies has profound metabolic effects.

Recently, it was shown that administration of D-βHB to C. elegans caused an extension of life span resulting in that ketone body to be presciently labeled as “an anti-aging ketone body”. In the same experiment, L-β-hydroxybutyrate failed to extend life span. If it is accepted that the ketone body, D-βHB is an “anti-aging” compound, this could account for the widespread observation that caloric restriction, and its resultant ketosis, leads to life span extension. Many aging-induced changes, such as the incidence of malignancies in mice, the increases in blood glucose and insulin caused by insulin resistance, and the muscular weakness have been shown to be decreased by the metabolism of ketone bodies, a normal metabolite produced from fatty acids by liver during periods of prolonged fasting or caloric restriction.

In addition to ameliorating a number of diseases associated with aging, the general deterioration of cellular systems independent of specific disease seems related to reactive oxygen species toxicity and the inability to combat it. In contrast increases in life span occur across a number of species with a reduction in function of the insulin signaling pathway and/or an activation of the FOXO transcription factors, inducing expression of the enzymes required for free radical detoxification. In C. elegans, these results have been accomplished using RNA interference or mutant animals. Similar changes should be able to be achieved in higher animals, including humans, by the administration of d-βHB itself or its esters.

In summary, decreased signaling through the insulin/IGF-1 receptor pathway increases life span. Decreased insulin/IGF-1 receptor activation leads to a decrease in PIP3, a decrease in the phosphorylation and activity of phosphoinositide-dependent protein kinase (PDPK1), a decrease in the phosphorylation and activity of AKT, and a subsequent decrease in the phosphorylation of FOXO transcription factors, allowing them to continue to reside in the nucleus and to increase the transcription of the enzymes of the antioxidant pathway. In mammals, many of these changes can be brought about by the metabolism of ketone bodies. The metabolism of ketones lowers the blood glucose and insulin thus decreasing the activity of insulin signaling and its attendant changes in the pathway described above. However, in addition ketone bodies act as a natural inhibitor of class I HDACs, inducing FOXO gene expression stimulating the synthesis of antioxidant and metabolic enzymes. An added important factor is that the metabolism of ketone bodies in mammals increases the reducing power of the NADP system providing the thermodynamic drive to destroy oxygen free radicals which are a major cause of the aging process.

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