The ‘article’ “avoid this ketogenic ripoff” published by Mike Sheridan contains a great deal of misinformation, which mistakenly suggest that you should avoid exogenous ketone supplementation. I would like to respond by summarizing the most important results based on research studies on both animals and humans and clinical information. It is important to note that no studies to date have been done to assess body composition alterations after ketone supplementation administration, an important consideration of the bodybuilding and fitness community that the article targets. The research on exogenous ketone is mainly focused on applications which may not be of interest to the target audience, including CNSO2 toxicity, seizures, genetic disorders and cancer.
- To be clear, ketones are not ‘a byproduct of ketosis’. This would suggest that ketones are an unintended consequence. Ketone bodies, such as β-hydroxybutyrate (βHB or β-OHB), acetone and acetoacetate (AcAc) are synthetized by liver cells from fatty acids, which process leads to ketosis when blood levels rise above 0.5 mmol/L (to about 5-7 mmmol/L) (Veech, 2013).
- The body makes ketone bodies and uses them when it’s both in a calorie or carb-restricted state, and‘without the presence of glucose in the blood. Under normal physiological conditions, ketone bodies are synthetized in liver mitochondria mainly from fatty acids derived from human milk and adipose tissues, which provide energy for certain tissues/organs such as skeletal and heart muscle, renal cortex and brain (Künnecke et al., 1993; Dedkova and Blatter, 2014). βHB is also synthesized in astrocytes, which serve as fuel for brain cells (Edmond et al., 1987; Achanta and Rae, 2017). Moreover, under normal conditions, ketone bodies are major metabolic fuels for the brain of the suckling rats and human newborn (Hawkins et al., 1971b; Cahill, 2006) and later, when glucose is the main source of energy in the brain, ketone bodies are synthetized and used as fuel for certain tissues/organs such as the brain (Künnecke et al., 1993; Dedkova and Blatter, 2014).
- Consumption of ketone ester and βHB salt may have beneficial effects in the treatment of obesity: ketone ester and βHB salt enhanced the level of anorexinogenic malonyl CoA in the brain (Kashiwaya et al., 2010), and reduced visceral adipocyte volume (Caminhotto et al., 2017), respectively.
- Absorption of ketone bodies is rapid, thus, desired level of ketone bodies can be achieved by ketone ester consumption without potential side effects, which may be evoked by consuming the ketogenic diet (such as elevation of blood cholesterol and triglyceride levels) (Kwiterovich et al., 2003; Veech, 2013).
- Under fasting conditions, ketone bodies provide about 75% of energy for brain tissue. In different circumstances, when the level of ketone bodies increase in the body, the use of other substrates (e.g., glucose and lactate) as fuel, even if at a lower level, but is continued (Cahill, 2006). Thus, after consuming ketone supplements, the use of other energy substrates as fuel will not stop.
- The effect of ketone body administration on insulin levels may depend on the way of administration and the type of ketone bodies. However, increase in insulin level after ketone body administration has not been observed under any conditions in human, rats and dogs after βHB/βHB salt infusion, in contrast the insulin levels were rather decreased (Balasse et al., 1967; Balasse an Ooms, 1968; Devecerski et al., 1968; Hawkins et al., 1971a). Moreover, results from animal and human studies suggest that ketone ester and ketone salt (βHB salt) supplemented diet may decrease both blood glucose and insulin levels and increase insulin sensitivity in the brain and heart (Amiel et al., 1991; Sato et al., 1995; Kashiwaya et al., 2010; Kesl et al., 2016).
- Beneficial effects, which may be attributable to ketone bodies/exogenous ketone supplementation (partly theoretically), for example: 1) consuming ketone esters decreased brain amyloid-β and phosphorylated tau and improved cognitive functions in a genetic mouse model of Alzheimer’s disease (Kashiwaya et al., 2013); (2) ketones prevented free radical damage and βHB increased the destruction of free radicals; βHB suppressed oxidative stress by inhibition of histone deacetylase (Shimazu et al., 2013; Veech, 2013); 3) ketone salt Na-βHB dissolved in resuscitation fluids can prevent apoptosis in lung that occurs after severe hemorrhage in a rodent model (Alam et al., 2001); 4) βHB may extend the lifespan for example via inhibition of histone deacetylase by AMP kinase (AMPK) and sirtuin Sir2-dependent mechanisms, and reduction of apoptosis (Xiao et al., 2007; Edwards et al., 2014; Newman and Verdin, 2014); 5) ketone bodies increased mitochondrial efficiency and biogenesis (Bough et al., 2006; Kashiwaya et al., 2010); 6) βHB has a homeostatic function, which allow us to survive prolonged starvation (Taggart et al., 2005); 7) βHB may improve reaction time and exercise performance (Cox et al., 2016; Egan and D’Agostino, 2016);8) ketone bodies serve as alternative energy source for the brain, heart, and skeletal muscle (Yudkoff et al., 2007; Branco et al., 2016); 9) ketosis/βHB may improve the symptoms of certain diseases such as Alzheimer’s disease, Parkinson’s disease, schizophrenia, amyotrophic lateral sclerosis (ALS), glucose transporter 1 (GLUT1)-deficiency syndrome, anxiety, depression, autism, cancer, and epilepsy (Veech, 2004; Stafstrom and Rho, 2012; D’Agostino et al., 2013; Hashim and VanItallie, 2014; Poff et al., 2015; Ari et al., 2016; Branco et al., 2016; Achanta and Rae, 2017; Bostock et al., 2017; Kovács et al., 2017; Tefera et al., 2017); and 10) βHB may have other different physiological role in different species (Hawkins and Biebuyck, 1979; Achanta and Rae, 2017). Most recently there has been an intense interest in the potential for ketones to increase longevity, since exogenous ketones target many of the signaling pathways associated with calorie-restriction induced extension of life span in several model systems.
In summary, exogenous ketones provide an alternative form of energy that has many applications and metabolic advantages over glucose. Ketones also have a profound effect on gene expression and suppression of inflammatory pathways tightly linked to several pathologies and age-related chronic illnesses. Like creatine, it may take several years for the studies to validate the optimal dose, formulation and performance application of exogenous ketones. The emerging data on this new energy source suggests a broad range of therapeutic and performance applications. The main advantage associated with exogenous ketones may be linked to preserving CNS function under environmental extremes, which was the original application of funded DARPA and DoD-funded studies on these compounds. Exogenous ketones may also be effective for mitigating pathologies associated with limited glucose availability or impaired glucose transport, which could describe a broad range of pathologies.
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