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Conflict of interest: JSV receives royalties for low-carbohydrate nutrition books. He is founder, consultant, and stockholder of Virta Health Corp.; a member of the advisory boards for Atkins Nutritionals Inc., UCAN Co., Ketone Sciences, and Axcess Global; and has received honoraria from Metagenics and Pruvit. SDP receives royalties for low-carbohydrate nutrition books. He is founder and stockholder of Virta Health Corp. and a member of the advisory board for Atkins Nutritionals Inc. RMK has had investigator-initiated research funding from the National Dairy Council and the Almond Board of California. He receives royalties from a patent for ion mobility analysis of lipoproteins and from a textbook on nutrition and cardiometabolic health. He is on the scientific advisory boards of, and has stock options from, Virta Health, and DayTwo, and is a part-time employee of JumpstartMD.

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.

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Introduction Ketogenic diets (KDs) that elevate ketones into a range referred to as nutritional ketosis represent a possible nutrition approach to address the emerging physical readiness and obesity challenge in the military. An emerging body of evidence demonstrates broad-spectrum health benefits attributed to being in nutritional ketosis, but no studies have specifically explored the use of a KD in a military population using daily ketone monitoring to personalize the diet prescription. Materials and Methods To evaluate the feasibility, metabolic, and performance responses of an extended duration KD, healthy adults (n = 29) from various military branches participated in a supervised 12-wk exercise training program. Fifteen participants self-selected to an ad libitum KD guided by daily measures of capillary blood ketones and 14 continued their normal mixed diet (MD). A battery of tests were performed before and after the intervention to assess changes in body mass, body composition, visceral fat, liver fat, insulin sensitivity, resting energy metabolism, and physical performance. Results All KD subjects were in nutritional ketosis during the intervention as assessed by daily capillary beta-hydroxybutyrate (βHB) (mean βHB 1.2 mM reported 97% of all days) and showed higher rates of fat oxidation indicative of keto-adaptation. Despite no instruction regarding caloric intake, the KD group lost 7.7 kg body mass (range −3.5 to −13.6 kg), 5.1% whole-body percent fat (range −0.5 to −9.6%), 43.7% visceral fat (range 3.0 to −66.3%) (all p < 0.001), and had a 48% improvement in insulin sensitivity; there were no changes in the MD group. Adaptations in aerobic capacity, maximal strength, power, and military-specific obstacle course were similar between groups (p > 0.05). Conclusions US military personnel demonstrated high adherence to a KD and showed remarkable weight loss and improvements in body composition, including loss of visceral fat, without compromising physical performance adaptations to exercise training. Implementation of a KD represents a credible strategy to enhance overall health and readiness of military service members who could benefit from weight loss and improved body composition.

Animal data indicate that ketogenic diets are associated with improved mitochondrial function, but human data are lacking. We aimed to characterize skeletal muscle mitochondrial changes in response to a ketogenic diet combined with exercise training in healthy individuals. Twenty-nine physically active adults completed a 12-week supervised exercise program after self-selection into a ketogenic diet (KD, n=15) group or maintenance of their habitual mixed diet (MD, n=14). Measures of metabolic health and muscle biopsies (Vastus lateralis) were obtained before and after the intervention. Mitochondria were isolated from muscle and studied after exposure to carbohydrate (pyruvate), fat (palmitoyl-L-carnitine), and ketone (β-hydroxybutyrate+acetoacetate) substrates. Compared to MD, the KD resulted in increased whole-body resting fat oxidation (p<0.001) and decreased fasting insulin (p=0.019), insulin resistance (HOMA-IR, p=0.022), and visceral fat (p<0.001). The KD altered mitochondrial function as evidenced by increases in mitochondrial respiratory control ratio (19%, p=0.009), ATP production (36%, p=0.028), and ATP/H2O2 (36%, p=0.033) with the fat-based substrate. ATP production with the ketone-based substrate was 4 to 8 times lower than with other substrates, indicating minimal oxidation. The KD resulted in a small decrease in muscle glycogen (14%, p=0.035) and an increase in muscle triglyceride (81%, p=0.006). These results expand our understanding of human adaptation to a ketogenic diet combined with exercise. In conjunction with weight loss, we observed altered skeletal muscle mitochondrial function and efficiency, an effect that may contribute to the therapeutic use of ketogenic diets in various clinical conditions, especially those associated with insulin resistance.

The beneficial cardiometabolic and body composition effects of combined protein-pacing (P; 5–6 meals/day at 2.0 g/kg BW/day) and multi-mode exercise (resistance, interval, stretching, endurance; RISE) training (PRISE) in obese adults has previously been established. The current study examines PRISE on physical performance (endurance, strength and power) outcomes in healthy, physically active women. Thirty exercise-trained women (>4 days exercise/week) were randomized to either PRISE (n = 15) or a control (CON, 5–6 meals/day at 1.0 g/kg BW/day; n = 15) for 12 weeks. Muscular strength (1-RM bench press, 1-RM BP) endurance (sit-ups, SUs; push-ups, PUs), power (bench throws, BTs), blood pressure (BP), augmentation index, (AIx), and abdominal fat mass were assessed at Weeks 0 (pre) and 13 (post). At baseline, no differences existed between groups. Following the 12-week intervention, PRISE had greater gains (p < 0.05) in SUs, PUs (6 ± 7 vs. 10 ± 7, 40%; 8 ± 13 vs. 14 ± 12, 43% ∆reps, respectively), BTs (11 ± 35 vs. 44 ± 34, 75% ∆watts), AIx (1 ± 9 vs. −5 ± 11, 120%), and DBP (−5 ± 9 vs. −11 ± 11, 55% ∆mmHg). These findings suggest that combined protein-pacing (P; 5–6 meals/day at 2.0 g/kg BW/day) diet and multi-component exercise (RISE) training (PRISE) enhances muscular endurance, strength, power, and cardiovascular health in exercise-trained, active women.

Background: Acute ingestion of ketone supplements alters metabolism and potentially exercise performance. No studies to date have evaluated the impact of co-ingestion of ketone salts with caffeine and amino acids on high intensity exercise performance, and no data exists in Keto-Adapted individuals. Methods: We tested the performance and metabolic effects of a pre-workout supplement containing beta-hydroxybutyrate (BHB) salts, caffeine, and amino acids (KCA) in recreationally-active adults habitually consuming a mixed diet (Keto-Naïve; n ¼ 12) or a ketogenic diet (Keto-Adapted; n ¼ 12). In a randomized and balanced manner, subjects consumed either the KCA consisting of $7 g BHB (72% R-BHB and 28% S-BHB) with $100 mg of caffeine, and amino acids (leucine and taurine) or Water (control condition) 15 minutes prior to performing a staged cycle ergometer time to exhaustion test followed immediately by a 30 second Wingate test. Results: Circulating total BHB concentrations increased rapidly after KCA ingestion in KN (154 to 732 lM) and KA (848 to 1,973 lM) subjects and stayed elevated throughout recovery in both groups. Plasma S-BHB increased >20-fold 15 minutes after KCA ingestion in both groups and remained elevated throughout recovery. Compared to Water, KCA ingestion increased time to exhaustion 8.3% in Keto-Naïve and 9.8% in Keto-Adapted subjects (P < 0.001). There was no difference in power output during the Wingate test between trials. Peak lactate immediately after exercise was higher after KCA ($14.9 vs 12.7 mM). Conclusion: These results indicate that pre-exercise ingestion of a moderate dose of R-and S-BHB salts combined with caffeine, leucine and taurine improves high-intensity exercise performance to a similar extent in both Keto-Adapted and Keto-Naïve individuals.