The Buck Institute for Research on Aging has received a $3.5 million federal grant to lead the first-ever double-blind, randomized, placebo-controlled clinical trial to understand the effects of ketone ester supplementation on frailty, a condition that develops following age-related decline in multiple physiological systems. TAKEOFF (Targeting Aging with Ketone Ester in Older Adults for Function in Frailty) will recruit a total of 180 people at the Buck, Ohio State University, and the University of Connecticut (UConn).
Developed 20 years ago, ketone esters are precursor molecules that the body quickly breaks down into ketone bodies when carbohydrates aren’t available.
A well-formulated nutritional ketogenic diet was found effective for controlling seizures, the treatment of diabetes and metabolic syndrome. An extensive body of literature has documented their use in athletes, but less is known regarding conditions such as heart disease and dementia.
“We’ve learned so much recently about how ketone bodies interact with aging biology,” says John Newman, MD, PhD, 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.”
As a practicing geriatrician, Newman measures frailty by evaluating patients’ strength, endurance, and how they react to stresses. He and his colleagues believe certain molecular and cellular changes may make patients more likely to fall, to recover more slowly from surgery, or to lose mobility.
The main hypothesis of the TAKEOFF study is “that if you target these fundamental mechanisms of aging, you would be able to impact many different diseases of aging across different organ systems.”
Researchers from the Ohio State University and the University of Connecticut will also participate in the TAKEOFF trial, which seeks to recruit a total of 180 people across the three sites.
Here at the UConn Center on Aging, Jenna Bartley, PhD, assistant professor in the Department of Immunology, will focus on how immune responses and physical function decline with age.
As a graduate student in the Department of Kinesiology at UConn, Bartley worked with Jeff Volek, PhD. While there she studied the effects of the ketogenic diet on elite athletes, now her focus is on the senior population. Serendipitously, Dr. Volek who is now a professor in the Department of Human Sciences at the Ohio State University, in Columbus, is also a Principal Investigator on this study and they will work together again to uncover the power of ketones for targeting aging physiology along with Dr. Newman.
“Ketogenic diets and ketone bodies — mainly beta-hydroxybutyrate — have been shown to have really powerful influences on a lot of things that go wrong with aging,” Bartley 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.”
In her lab, she’ll assess serum markers of inflammation in patients, as well as cytokine secretion following stimulation of T cells. T cells in culture from older people produce more inflammatory cytokines than those from younger people, leading to a dysfunctional immune response. Bartley is curious to see whether ketones can fix that. Additional work will include single-cell RNA sequencing of different classes of immune cells to investigate how ketones might change metabolic pathways.
The anti-inflammatory property of ketones may provide another benefit to older people. They can reduce oxidative stress, which is considered one of the chief pathologic mechanisms responsible for conditions such as heart disease, Alzheimer’s disease, asthma, and arthritis.
During the study that will start active recruitment in early 2024, participants will not be following a ketogenic diet, but will consume a ketone ester or placebo supplement daily alongside their regular diet to investigate if it can improve physical function in older adults.
Why use ketone ester supplements instead of having people consume ketogenic diets? “There are generally no cheat days in the keto diet and adherence is difficult for many people,” Bartley said. “Use of supplements generally has higher adherence compared to a full dietary change. From a clinical perspective, this also makes any findings translatable to more of the population,” she said.
Ketones are naturally occurring compounds that increase when the availability of dietary carbohydrates (sugars in various forms) are limited forcing the body to use fat instead of sugar for energy. Various forms of fasting and the popular high-fat, moderate-protein, and low-carbohydrate ketogenic diet can put people into ketosis. Both have been linked to several health benefits, including weight loss, a reversal of metabolic syndrome and reduced inflammation. The supplement used in the trial is aimed to provide the same benefits without requiring an extensive change in diet.
In addition to the main study outcomes, Volek’s lab will study muscle physiology in the study participants by performing biopsies at baseline and after consumption of ketogenic supplements to assess metabolic changes in muscle cells as they consume energy. Study participants will also undergo MRIs to detect subtle changes in muscle size before and after treatment.
The primary outcome measure at all three study sites will be leg press strength. Researchers will also assess a variety of secondary outcomes that cover geriatric and cognitive function — measures such as gait speed and walking endurance, cognitive tests, and quality of life. And at the Buck, Newman and co-investigator, Brianna Stubbs, PhD will be evaluating the use of biomarkers that are often available in clinical labs ― insulin, C-reactive protein, cystatin, and natriuretic peptide tests ― for use as outcome measures that are responsive to treatment interventions and that can be used to track outcomes in future research on aging.
“It’s exciting to be on the cutting edge of geroscience research in the first ketone-focused clinical trial aimed at targeting aging physiology,” says Bartley. “These trials are necessary to move translational research forward. Better understanding how ketones modulate age-related immune declines and frailty can lead to meaningful new therapeutics for older adults.”
Disclosure: Newman and Stubbs own stock in BHB Therapeutics, Ltd, the company providing the product being studied, and are inventors on patents that relate to the product being studied. The Buck Institute has an ownership interest in BHB Therapeutics. Bartley and Volek report no relevant financial relationships.