Studies to explore whether achieving beneficial ketone levels can improve metabolic health of military service members

A series of upcoming studies will explore whether the grind of active-duty military life and veterans' disproportionately high incidence of chronic illness could be tamed by lifestyle interventions designed to achieve a metabolic state of nutritional ketosis.

This work, led by Ohio State University exercise science and biomedical researchers, is funded by a $10 million grant from a U.S. Department of Defense program focused on improving the health of military service members, veterans and the American public.

Many Americans, including a significant number of military service members – and especially veterans – are suffering from poor metabolic health. Despite billions of dollars in investments by the private and public sectors, traditional drug and lifestyle treatments have had limited success in curtailing the complications attributed to poor metabolic health, which include disrupted sleep, obesity, type 2 diabetes, heart failure and chronic kidney disease. We expect that whatever we find here will have huge relevance across the board both within and outside the military."

Jeff Volek, principal investigator, professor of human sciences at Ohio State

Two-plus decades of studies have included Volek's findings that the very-low-carbohydrate/high-fat ketogenic diet, which converts fat into ketones used by cells in the body and brain as an alternative to glucose, does not drive up saturated fat in the blood, can help endurance athletes burn fat and holds promise at keeping soldiers fit for service. The popularity of the diet, and scientific evidence of its health benefits and weight-loss results, has spawned the development and marketing of products that can be ingested to rapidly elevate blood ketones without a change in eating habits.

"A big part of the grant is studying both of those strategies to augment ketosis – the ketogenic diet and ketone-based beverages," Volek said. The ketone drinks, formulated as ketone esters, are designed to put the body in nutritional ketosis – the human body's state when it has greater access to ketones as both a fuel and signaling molecule.

"Does the ketogenic diet produce different effects than the ketone esters? Is one better than the other? My work has found the ketogenic diet provides robust health benefits, but there could be some health benefits attributed to taking ketones and not changing the diet. It's a whole new area of investigation."

Studies exploring ketone esters' impact on blood ketone levels and factors influencing individual variation in response to ingesting them are one of four independent project areas that will run concurrently. The other three are intended to expand knowledge about nutritional ketosis in the context of addressing life circumstances and health problems of particular concern for the military: inadequate sleep, chronic kidney disease and heart failure.

"This will be the first work to specifically explore how ketone esters and a ketogenic diet impact clinical outcomes, such as cardiac function and exercise capacity, in patients with heart failure," said Orlando Simonetti, professor of cardiovascular medicine at Ohio State and co-leader of one of the projects. "We're hopeful that the imaging and physiological performance data we collect in this study will pave the way for future research on nutritional ketosis as a preventive and treatment for cardiovascular disease."

All branches of the military are affected by the general population's poor metabolic health, which complicates recruitment, lowers soldier readiness and can harm post-service quality of life. The disrupted sleep and range of stressors associated with training and active duty can have compounding effects on both the body and the brain, increasing risk for obesity and reduced mobility as well as mental health and neurological problems later in life.

The grant, a DOD Peer Reviewed Medical Research Program – Focused Program Award, is called STAK, short for Strategies to Augment Ketosis. Volek's lab is leading coordination of the work. The Buck Institute, an aging research firm, and Virta Health, a company co-founded by Volek that has created a nutritional therapy program to treat and reverse type 2 diabetes at scale, have received sub-awards under the STAK grant to lend additional expertise.

The funding supports four projects:

• Optimization of ketone delivery strategies: Clinical studies will explore ketone ester dosing, formulation and timing of delivery, as well as study participant health markers, to gauge the supplements' physiological and metabolic effects. Researchers aim to create evidence-based guidelines for use of ketone ester compounds based on individual characteristics and soldier performance requirements. Volek's lab will partner with the Buck Institute on this project.
• Ketone-conferred resiliency against sleep restriction: High-quality sleep is key to military mission readiness and success, but isn't always possible to get in the field. This trial will gauge the extent to which ketone esters and a ketogenic diet reduce detrimental effects of sleep loss on cognitive and physical performance in ROTC cadets under demanding physical conditions. Project leader William Kraemer, in human sciences at Ohio State, will collaborate on the work with Ohio State brain imaging and sleep specialists.
• Ketone therapy to improve exercise tolerance in heart failure: Simonetti, a frequent research collaborator with Volek, will co-lead this project with Ohio State Wexner Medical Center cardiologist Yuchi Han. The team will examine effects of ketone esters and a ketogenic diet in patients with type 2 diabetes and heart failure with preserved ejection fraction, a type of the disease marked by typical heart failure symptoms despite the heart's close-to-normal blood pumping capacity. A randomized, double-blind, crossover trial will compare exercise capacity and cardiac function in participants taking ketone esters, eating a ketogenic diet or eating a mixed standard of care diet. Ohio State researchers will partner with Virta Health, using the company's continuous remote care model to manage patient participation for six months after completion of the trial.
• Delay or prevention of progression of diabetic nephropathy: Virta Health scientists will lead this two-year longitudinal study, examining whether the continuous remote care model – which includes biomarker monitoring – and a uniformly delivered ketogenic diet slow or even reverse progression to chronic kidney disease in veterans with type 2 diabetes.

Recruitment and enrollment of study participants is expected to begin in early 2023. Ketone esters used in the studies were developed by Juvenescence.