“We’ve learned so much recently about how ketone bodies interact with aging biology,” John Newman, MD, Ph.D., of the Buck Institute for Research on Aging in Novato, California, and the study’s principal investigator. “And we’re only just starting to translate that out of the laboratory and into human studies to see how we can take advantage of ketone bodies to improve people’s health.”
The TAKEOFF Trial (Targeting Aging With Ketone Ester in Older Adults for Function in Frailty) will be seeking to recruit 180 people across three sites: Ohio State University, the University of Connecticut, and the Buck Institute for Research on Aging.
During aging, tissues such as the heart, brain, and muscles lose the ability to metabolize glucose effectively, which can lead to insulin resistance. Areas of the brain can be mapped out where glucose uptake drops in those affected by Alzheimer’s disease, and in heart failure, the heart has difficulty obtaining enough energy from glucose, so it burns fats and ketone bodies instead. But how might this affect frailty in the elderly?
It is believed that certain molecular and cellular changes may make patients more likely to fall, recover more slowly from injury/surgery, and lose mobility. Measuring frailty by evaluating patient endurance, strength, and how they react to stress, could help map these changes, and “that if you target these fundamental mechanisms of aging, you would be able to impact many different diseases of aging across different organ systems.”
The BIKE (Buck Institute Ketone Ester) Pilot Study is in the process of finishing up. This was the first double-blind, randomized, placebo-controlled study to evaluate the use of ketone ester supplements in adults older than 65 years.
“The BIKE study is 12 weeks long. That’s actually the longest that anyone has studied ketone ester supplements in humans,” Stubbs said. The results will help them firm up the protocol for the TAKEOFF trial, which will likely treat patients for up to 24 weeks, to achieve the goal of broadly looking at different organ systems likely to be affected by the ketogenic supplements.
“They could help offset some of the muscle loss with aging, which would in turn improve their physical functioning and ability to do daily activities,” said Jeff Volek, Ph.D., a professor in the Department of Human Sciences at the Ohio State University, in Columbus.
Ketones may provide another benefit to the elderly due to their anti-inflammatory properties: reducing oxidative stress. Oxidative stress is considered to be one of the main pathologic mechanisms responsible for conditions like arthritis, asthma, Alzheimer’s disease, and heart disease.
“Ketogenic diets and the main ketone bodies — mainly beta-hydroxybutyrate — have been shown to have really powerful influences on a lot of things that go wrong with aging,” a graduate student in Volek’s lab, Jenna Bartley, Ph.D., now an assistant professor in the Department of Immunology and the Center on Aging at the University of Connecticut in Farmington said. The decline in immune function in the elderly is not isolated to one cell type or even one arm of the immune system. There is reason to believe ketone supplementation could improve immune function.
“T cells really love ketones for energy,” Bartley said. Some data show that the production of ketone bodies is impaired in individuals with severe SARS-CoV-2 infection. Mouse models of SARS-CoV-2 infection have found that ketogenic diets led to improvement in the response to antiviral therapy.
Supplements are being used because the keto diet itself is very strict and hard to follow/maintain, using it in a trial would require intense supervision to enforce complete adherence. The use of supplements will significantly improve compliance and will likely make the findings translatable to more of the population. Studies such as this are the building blocks of geroscience, aimed at translating the fundamental mechanisms of aging into therapies to treat disease.
“We’re hoping that this will be an example of a proof-of-concept geroscience study that will really help to translate ketone body biology out of the laboratory and hopefully into a diversity of clinical applications,” said Newman. “There’s a lot we don’t understand still about the molecular mechanisms of frailty.”
