Exogenous Ketones as Therapeutic Signaling Molecules in High-Stress Occupations: Implications for Mitigating Oxidative Stress and Mitochondrial Dysfunction in Future Research

Abstract

High-stress occupations (ie, firefighters, military personnel, police officers, etc.) are often plagued by cardiometabolic diseases induced by exposure to chronic stressors. Interrupted sleep cycles, poor dietary patterns, lack of physical activity, and smoke exposure along with simultaneous psychological stressors promote chronic low-grade inflammation and excessive oxidative stress. Collectively, these data suggest that practical interventions which might mitigate the underlying pathologies of these cardiometabolic diseases are warranted. Ketones, specifically R-βHB, modulates intracellular signaling cascades such as the cellular redox ratios of NAD+/NADH, the activity of NAD dependent deacetylases SIRT1 and SIRT3, and promotes a robust mitochondrial environment which favors reductions in oxidative stress and inflammation. To date, the literature examining R-βHB as a signaling metabolite has mostly been performed from endogenous R-βHB production achieved through nutritional ketosis or cell culture and mouse models using exogenous R-βHB. To the authors knowledge, only 1 study has attempted to report on the effects of exogenous ketones and the mitigation of oxidative stress/inflammation. Therefore, the scope of this review is to detail the mechanisms of R-βHB as a signaling metabolite and the role that exogenous ketones might play in mitigating diseases in individuals serving in high-stress occupations.

No Effect of a Ketone Monoester on Markers of Stress and Performance in a Live-Burn Search and Rescue in Firefighters

“…Although ketone salts provide a practical option for fire departments as a result of lower costs, a systematic review showed that ketone salts as currently available off-the-shelf are largely ineffective at elevating bHB concentrations [,1.0 mM (19)] often resulting in a lack of any ergogenic potential. Several investigators have since speculated of a hypothesized bHB minimum threshold (;2.0 mM) to observe metabolic benefits that extend beyond performance (15,19,39,43). Therefore, the present study incorporated a KME (0.5 g/kg body mass) as opposed to a ketone salt.…”

“…Each experimental trial was identical except for the drinks ingested. The present supplement dosing protocol was adopted from Evans and Egan (8) and modified based on previous pilot data aimed at achieving bHB concentrations above a theoretical minimum threshold (;2 mM) where potential metabolic effects might be observed (15,19,39,43). During each experimental trial, subjects ingested a single bolus of a given drink containing 300 ml of water in opaque bottles with either the KME (0.5 g/kg body mass) or PLA, 30 minutes before the live-burn S&R. The KME is a commercially available R-bHB (R)1,3-butanediol (KE4, Fruit Punch, KetoneAid) and was mixed with a bitter blocker (TrueBlock, Danbury, CT).…”

On the nutritional and therapeutic effects of ketone body d-β-hydroxybutyrate

“…Thus, d-3HB have been extensively explored in different fields over the past few years in relation to physical and metabolic health (Møller 2020). Interestingly, it has been proposed that d-3HB may provide protection against cardiometabolic complications in high-stress workers due to its ability to mitigate oxidative stress and inflammation (Waldman and McAllister 2020). Newman and Verdin have extensively reviewed how d-3HB was regulated and its role as an endogenous histone deacetylase (HDAC) inhibitor within the body, which was significant in modulating metabolism and diseases of aging (Newman and Verdin 2014).…”

Toxicity Investigations of (R)-3-Hydroxybutyrate Glycerides In Vitro and in Male and Female Rats

“…Various analogs of ketones continue to present unprecedented opportunities for maintenance of good health [ 17 , 25 , 27 , 28 , 29 , 30 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. Optimum levels of ketones in the body have beneficial effects on brain function [ 25 , 36 , 42 ].…”

“…Increases in plasma ketone levels correlate with brain ketone metabolism and provide a source of energy supply to the brain, helping to mitigate energy crises associated with neurodegenerative diseases which are characterized by a decline in the brain’s glucose metabolism [ 25 , 34 , 36 , 42 ]. Systemic presence of ketone molecules is known to promote resistance to oxidative and inflammatory stress and control transcription of genes associated with aging [ 32 , 33 , 34 , 35 , 36 , 38 , 39 , 41 , 42 ]. Although the effects of a ketogenic diet on exercise performance are controversial, administration of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate ketone ester to trained cyclists has been shown to increase performance [ 43 , 44 ].…”