The federal funding will be used to support a multi-site study known as TAKEOFF (Targeting Aging with Ketone Ester in Older Adults for Function in Frailty), which will recruit 180 participants across the Buck Institute, Ohio State University and the University of Connecticut Health Center.
“TAKEOFF will be the biggest and most rigorous study of any ketone intervention in older adults,” John Newman, MD, PhD, assistant professor at the Buck Institute and principal investigator on the grant, said in a statement. “We are very excited to test this approach in a human population that is at risk for becoming frail, a condition which increases the risks of all sorts of serious problems in older adults from falls and life-threatening infections to becoming disabled and losing independence after surgery.”
Supplementing with ketone esters has emerged as an alternative to following a restrictive diet to induce ketosis, a metabolic state that occurs when the body burns fat for energy instead of carbohydrates. Beyond supplying energy to brain, heart and skeletal muscle tissues, ketosis has been linked to non-energetic (signaling molecule) benefits including reduced inflammation, weight loss, reversal of metabolic syndrome and improved immune function.
Of mice and people
Most previous ketone research in this area has been carried out in aging mice, demonstrating dramatic improvements in muscle fitness and brain health, but as Newman noted “mice are not people” and data is needed in a human population.
The TAKEOFF trial builds on the BIKE (Buck Institute Ketone Ester) pilot study, a 12-week clinical trial initiated in January to explore the effects of ketone ester supplementation in 30 healthy individuals over the age of 65. While the BIKE study is primarily focused on safety and tolerance, TAKEOFF will expand the investigation to a pre-frail population, hypothesizing that ketosis may improve leg press strength by acting on energy and inflammation.
Collaborators at Ohio State University will examine muscle function and metabolism among participants; the UConn Health Center will investigate immune responses, particularly focused on immunosenescence and chronic inflammation; and the Buck Institute will track changes in various blood biomarkers of aging during the course of the trial.
“It’s crucial that we look at the impact of this intervention from several angles because there are so many possible applications of ketone biology for older adults,” Newman added. “If the science works in people, that’s direct evidence that we should be developing ketone-based interventions for other conditions of aging that share similar mechanisms like energy loss and chronic inflammation. This could involve everything from Alzheimer’s to heart disease.”
He also noted that the trial is not an investigational drug study that would involve seeking an FDA designation as a treatment for a disease but rather a basic experimental studies involving humans, as defined by the NIH.
Recruitment for the study will begin in 2024, and the exogenous ketone ester used will be supplied by BHB Therapeutics, a partnership launched in 2019 between The Buck Institute and life sciences and biotech company Juvenescence.
Evolution to geroscience
The Buck Institute is also part of a $10 million Department of Defense grant to Ohio State University called Strategies to Augment Ketones (STAK) for Enhanced Readiness and Disease Reversal—studying both the ketogenic diet and ketone ester drinks as strategies to improve metabolic health among military service members.
The first ketone ester was developed for the Defense Advanced Research Projects Agency (DARPA) in the early 2000s for the Metabolic Dominance program (later renamed to “Peak Soldier Performance”) to prime energetically efficient soldiers in the Iraq War. Ketone research then evolved to sports science (see H.V.M.N and the first commercial ketone drink) and onto geroscience, all linked by the concept of resilience to physical and cognitive stressors.
The connection is detailed in the 2020 review “From bedside to battlefield: intersection of ketone body mechanisms in geroscience with military resilience”.