by Buck Institute
January 23, 2023 . News
The Buck Institute Launches First Human Clinical Trial
Effort marks the first study of ketone body supplementation in healthy older adults; participants will be recruited in Marin County
The Buck Institute for Research on Aging has launched its first human clinical trial. The BIKE (Buck Institute Ketone Ester) pilot study is the first trial in the world to look at the effects of ketone ester supplementation in the context of aging. Thirty healthy individuals over the age of 65 will take part in a 12-week double-blind, randomized, placebo-controlled study to see whether benefits of ketone bodies in aging that have been observed in mice translate to human beings.
“We are the first research organization in the world to test the impact of a ketone ester on aging mechanisms in older adults,” said Buck assistant professor John Newman, MD, PhD, who is the principal investigator of the study. “We are excited to push cutting-edge aging science discovered in our laboratory and others toward clinical application and are thrilled to be doing it together with people who live in Marin County.”
“This first-ever human clinical trial is a landmark event at the Buck Institute. It’s a hallmark of our growth and the maturation of the field of aging research,” said Buck Institute President and CEO Eric Verdin, MD. “This effort is an important advance in its own right, but it is also a seed to grow the expertise and capabilities to accelerate unlocking the potential of Buck science to improve human health. The trial was funded by members of our local community and we are looking forward to engaging with local organizations such as Vivalon and the Marin Council on Aging to ensure community involvement and diverse, inclusive, and equitable participation as our clinical studies grow.”
The science behind ketone esters
Ketones are naturally occurring compounds made in the liver and are a byproduct of fat metabolism. There is usually only a very small amount of them in the blood at any given time. Ketones increase when 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 first clinical use of ketogenic diets was in children suffering from drug-resistant epilepsy.
Ketogenic diets have been extensively studied in mice. Previous research at the Buck showed that a ketogenic diet improved healthspan and memory in aging mice. But humans don’t live in cages and have a hard time maintaining the diet; additionally, there are health concerns about eating high amounts of fat and limiting the intake of carbohydrates. Taking a ketone ester supplement is a way around these worries because it puts people into ketosis without having to be on the restrictive diet. Several clinical studies are underway testing the use of ketone esters in people with heart disease, type 2 diabetes, obesity and memory deficits, among other conditions.
Newman, who is also an associate professor at UCSF and a practicing geriatrician at the San Francisco VA Health Care System, said studying the effects of ketone supplementation on aging is a totally new endeavor. “We are recruiting independent older individuals with stable health for this first trial. Those interested don’t have to be running marathons, it’s important to include people representative of typical aging. We are particularly interested in testing strength and mobility and looking at markers for aging and inflammation. Our guidepost for taking the research further will be trying to mitigate the effects of frailty, a condition of weakening, slowing, and vulnerability. Frailty is driven by aging and chronic inflammation, impacts the independence of so many older adults, and currently has no treatments other than exercise.”
Newman is quick to point out that the trial is not an investigational drug study that would involve seeking an FDA designation as a treatment for any disease. The study is what the NIH calls basic experimental studies involving humans. “Findings in the lab suggest that ketone bodies impact many of the pathways associated with aging, and this research will verify that in humans and lay the groundwork for the next big steps,” Newman said. “The hardest step in moving discoveries out of the laboratory is that first proof-of-principle: does the biology hold up in people? By growing the capability to do small, cutting-edge clinical studies at Buck we can give Buck scientists and the Marin community the ability to really unlock the Buck’s scientific potential together.”
How will the study be conducted?
Buck Lead Translational Scientist Brianna Stubbs, DPhil, is managing the BIKE study. Those enrolled in it will be paid for their participation. They will take a daily study beverage with half of the participants getting the ketone ester, the others getting a placebo. Study personnel will not know which participants are getting the actual ketone supplement.
All participants will make five visits to the Buck, and at home they will fill out daily activity logs and wear a supplied Fitbit. Blood and other bio-specimens will be collected at various times during the trial and participants will be asked to perform standardized physical function tests involving balance, walking speed, chair sits, leg press performance, walking speed and grip strength. They will also take standardized mental tests which measure short-term memory, visuospatial abilities, executive functions, attention, concentration and working memory as well as orientation to time and place. Study nurses and independent medical officers will help ensure the ketone ester is safe for each participant based on routine clinical labs and any reported side effects.
At the end of the trial participants will receive any clinically relevant results along with final electronic lab blood test values. Other study data will be available after all results are analyzed.
What if someone is interested in participating?
BIKE is recruiting independent older individuals with stable health, 65 years or older, who have access to the internet and can easily be involved in a 12-week program. Those interested should email Bike-Study@buckinstitute.org.
How is the study being funded?
The pilot study is funded via philanthropy. Retired physician Jim Johnson donated $250,000 to kick-start the trial. The Buck’s Impact Circle awarded more than $120,000 to enable researchers to test blood biomarkers in samples taken from participants. All study staff are employees of the Buck Institute except the independent medical officers. Drs. Newman and Stubbs, as well as the Buck Institute, own stock in BHB Therapeutics, LTD which is providing the ketone ester but has no role in funding, designing, or carrying out the trial. BIKE is an academic study intended to advance the science of ketone bodies in aging, not to test or market any specific product for a clinical outcome.
What else is in the pipeline?
Stubbs and Newman have applied for federal funding to expand the pilot study to involve 180 people at risk for frailty at three sites across the US in a study called TAKEOFF ( Targeting Aging with a Ketone Ester for Function in Frailty). In TAKEOFF, collaborators at the University of Connecticut Center on Aging would enroll 60 people and focus on the impact of ketone esters on the aging immune system; collaborators at Ohio State University would enroll a similar number and focus on muscle function and metabolism. The Buck would enroll 60 more participants and analyze state-of-the-art geroscience biomarkers for the entire study. The multisite study would be headquartered at Buck with assistance from the San Francisco Coordinating Center which is experienced at coordinating multisite clinical trials of older adults.
The Buck is also a clinical study site for a research program called STAK(Strategies to Augment Ketones for Enhanced Readiness and Disease Reversal) which is funded by the Department of Defense and run by Ohio State University. Stubbs, who describes the project in this blog post, says the overall goal is to determine if ketone esters would promote resilience in active duty soldiers as well as support the health of veterans who are served by the Veterans Health Administration. The Buck will recruit 100 people (25 per year over a four-year period) of all ages who will make one visit to the Buck to drink one dose of a ketone ester to see how it affects metabolic physiology. Recruitment for STAK is expected to begin in March 2023.
Highlighting the Buck’s impact on the field of aging research
Newman says the BIKE study was inspired by and done in alignment with the NIH-Funded Translational Geroscience Network, a collaboration of researchers enabling translation of clinical interventions that target fundamental mechanisms of aging to delay, prevent or treat age-related diseases and disabilities as a group, instead of singularly. “There is a lot of interest and excitement about ketone bodies in the geroscience field,” said Newman. “We’re very proud to be leading efforts to bring the basic science from the lab to the bedside.”
Newman says the biomarkers measured in BIKE are the same as those that will be measured in the flagship TAME (Targeting Aging with Metformin) Trial, sponsored by the American Federation for Aging Research and meant to be the landmark first large, national, practice-changing clinical trial in geroscience. TAME will test whether older adults given the popular diabetes drug versus placebo experience delayed development or progression of chronic conditions, such as heart disease, cancer and dementia. “It was important to us to be part of the effort to use standardized measurements and biomarkers of aging in clinical trials. Everyone needs to measure apples to apples, so we can share resources and pool results to know which things work and which don’t as quickly as possible.”
Newman helps lead the NIH-Funded Geroscience Education and Training Network, which is developing training programs for scientists to run studies just like BIKE, to make it easier for scientists to test their ideas in humans and speed the translation from basic science into new therapies. “We really are at an exciting inflection point in this field and it is so rewarding to see the Buck’s commitment to basic research pay off in a way that could very well lead to years of extended health for people here in Marin and beyond.”
DISCLOSURE: Dr. John Newman, Principal Investigator for the BIKE study, and Dr. Brianna Stubbs, a study investigator, 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 also has an ownership interest in BHB Therapeutics.
Science is showing that while chronological aging is inevitable, biological aging is malleable. There's a part of it that you can fight, and we are getting closer and closer to winning that fight.
Eric Verdin, MD, Buck Institute President and CEO