Nutritional Ketosis and Mitohormesis: Potential Implications for Mitochondrial Function and Human Health

Abstract

Impaired mitochondrial function often results in excessive production of reactive oxygen species (ROS) and is involved in the etiology of many chronic diseases, including cardiovascular disease, diabetes, neurodegenerative disorders, and cancer. Moderate levels of mitochondrial ROS, however, can protect against chronic disease by inducing upregulation of mitochondrial capacity and endogenous antioxidant defense. This phenomenon, referred to as mitohormesis, is induced through increased reliance on mitochondrial respiration, which can occur through diet or exercise. Nutritional ketosis is a safe and physiological metabolic state induced through a ketogenic diet low in carbohydrate and moderate in protein. Such a diet increases reliance on mitochondrial respiration and may, therefore, induce mitohormesis. Furthermore, the ketone β-hydroxybutyrate (BHB), which is elevated during nutritional ketosis to levels no greater than those resulting from fasting, acts as a signaling molecule in addition to its traditionally known role as an energy substrate. BHB signaling induces adaptations similar to mitohormesis, thereby expanding the potential benefit of nutritional ketosis beyond carbohydrate restriction. This review describes the evidence supporting enhancement of mitochondrial function and endogenous antioxidant defense in response to nutritional ketosis, as well as the potential mechanisms leading to these adaptations.

Ketogenic diets: Opportunities and limitations in practical application (LITERATURE REVIEW)

“…This typically increases circulating ketone bodies (β-hydroxybutyrate (BHB) and acetoacetate (ACA) from concentrations that are typically less than 0.3 mM into the range of nutritional ketosis, which for BHB, we define as 0.5-3 mM (29). This range is below the typical 5-10 mM range for BHB that occurs during prolonged fasting, and well below concentrations characteristic of ketoacidosis (28,29,30). From the perspective of meeting energy demands, the reduced carbohydrate and moderate protein intakes necessarily make ketogenic diets high in fat.…”

“…In terms of trend diets using ketone bodies or the KD, the appetite-reducing effect is one of the most commonly cited advantages (30).…”

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

“…There is also a significant and accumulating body of evidence demonstrating a statistically significant reduction in oxidative and nitrosative stress and upregulation of cellular antioxidant defences in the brains of animals following prolonged dietary ketosis ( [106][107][108][109][110][111]; reviewed by [41]). This decrease would also appear to be clinically significant as several authors have reported a reduction in oxidative damage to neurones and increased neuronal survival as a result of dietary induced ketosis especially in an environment of cerebral glucose deprivation [109,[111][112][113].…”

Mitochondria Inspire a Lifestyle

“…This surge in mitochondrial activity is accompanied by a modest increment in free radical levels, which in turn prompts antioxidant defenses that reduce these levels to values below those seen before the intervention. The net effect is that the worms age more slowly and end up living twice as long as usual (see also Miller et al 2018;Schulz et al 2007).…”