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World-First Clinical Trial Will Test Ketone Supplementation on Frailty

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A new clinical trial will test the effects of ketone ester supplementation on frailty. The trial, funded by the National Institutes of Health, is called TAKEOFF (Targeting Aging with Ketone Ester in Older Adults for Function in Frailty) and will recruit 180 participants from the Buck Institute (Buck), Ohio State University and the University of Connecticut (UConn) Center on Aging. 

The rise of the ketogenic diet

As more people seek to manage their health and wellness directly through lifestyle choices, a variety of diets and eating regimens have increased in popularity. This includes the ketogenic diet, first created as a treatment for epilepsy in the early 20th century. Through consuming an increased amount of fat and reduced carbohydrates, this diet forces the body to change its primary source of fuel from carbohydrates to ketones. This metabolic state is known as ketosis

The excitement surrounding the potential health benefits of ketosis is palpable, but research conducted in human subjects is lacking, says Dr. John Newman, assistant professor and principal investigator of the trial at Buck: “Putting aging mice on a ketogenic diet dramatically improves muscle fitness and brain health, but mice are not people; we need to see if the science holds up in people.”

Earlier this year, Buck scientists launched the Buck Institute Ketone Ester pilot study (BIKE), the first clinical trial in the world to assess the effects of ketone ester supplementation in the context of aging. The study recruited 30 healthy individuals aged 65 and over to partake in a 12-week randomized, double-blind, placebo-controlled study. TAKEOFF, in contrast, will recruit adults who are pre-frail, determined by their speed of walking. “We will be looking at people’s muscle strength on a leg press over the course of the study. In BIKE we are primarily interested in safety and tolerance. While we’re still interested in those measures in TAKEOFF, we’re focused on leg press strength because strength is one of the key signs of frailty and we expect that ketosis may improve muscle strength by acting on energy and inflammation,” says Dr. Brianna Stubbs, TAKEOFF co-investigator and lead translational scientist at Buck.

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Beyond walking speed and muscle strength, Dr. Jenna Bartley, assistant professor at the UConn Center for Aging, will be exploring the participants’ immune responses, focusing particularly on immunosenescence – an alteration in the function of the immune system caused by aging – and inflammation. The Buck team will be assessing changes in blood biomarkers of aging throughout the trial, and a team at Ohio State University will be analyzing muscle function and metabolism.

“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 explains.  “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.” 

Creating a trial structure that is compatible with other aging research studies

Participants in the BIKE study are anticipated to finish the study protocol later this year, with results of the study expected in 2024. The TAKEOFF team have designed the trial such that it is compatible with other studies conducted by the Translational Geroscience Network, a cooperative team of researchers testing interventions on the underlying mechanisms of aging. This decision was inspired by a trial known as TAME (Targeting Aging with Metformin) trial, which assessed whether metformin could delay age-related chronic diseases in individuals without diabetes.

“There is such an explosion of interest in testing interventions that could impact aging that it became obvious that we need to be able to compare apples to apples when it comes to trial results,” Newman says.  “The design of TAME has inspired a constellation of smaller studies in both industry and academia testing a whole variety of interventions from metformin and rapamycin to senolytics. We really look forward to Buck becoming a key node in these efforts, helping to accelerate getting the biology of aging out of the laboratory and into the clinic.”   

Evidence-based approaches to supplementation

The research team anticipate that, should TAKEOFF demonstrate ketone supplementation is effective at targeting hallmarks of aging, there will be a growing trend in the number of studies pursuing clinical translation of ketone biology research in this context. “At the Buck we want to use evidence-based reasoning to inform the decisions that people make about what they’re going to do for their own health,” says Stubbs. “The supplement and diet industries can be muddy, with lots of questionable claims based sometimes on no data, and so, hopefully, the results of both BIKE and TAKEOFF will allow people to make wise decisions about what they’re going to do with their own diet and supplement kind of regimes. That’s a role we’re happy to play for the public.”

Both Newman and Stubbs declare stocks in BHB Therapeutics Limited, the company that is providing the ketone supplementation that will be assessed in the trial. 

This article is a rework of a press release issued by The Buck Institute for Research on Aging. Material has been edited for length and content.