Ketone bodies: Likely good for aging—and maybe for the military too

First the basics: Ketone bodies are metabolites produced in our bodies when the availability of glucose is low. This happens during fasting, or via a ketogenic diet which severely restricts carbohydrates. The Buck is interested in them because ketone bodies are linked to multiple mechanisms of aging and resilience. Previous research at the Buck showed that a ketogenic diet improved memory and healthspan in aging mice. 

In addition to producing them through diet, ketone bodies can also be consumed via supplementation, known as 'exogenous ketones'. Along with supplying energy to tissues such as the brain, heart and skeletal muscle, ketone bodies are also being studied for drug-like activities that regulate inflammation, epigenetics and other cellular processes.

In addition to being studied in a variety of age-related diseases such as Alzheimer’s and type 2 diabetes, ketone bodies are also of interest to the military. The Buck is part of a $10 million grant to Ohio State University called Strategies to Augment Ketones (STAK) for Enhanced Readiness and Disease Reversal.   Buck Assistant professor John Newman and Lead Translational Scientist Brianna Stubbs are Principal Investigators for the Buck effort. Buck’s Senior Director of Communications, Kris Rebillot, talked to Stubbs about the project.

Wow, I’ve been at the Buck for a long time.  I never imagined that we would be involved in a project that involved the military.  What’s the connection??

There are a lot of the hallmarks of aging which are recapitulated in military service. Just think about it – soldiers are under more physical and cognitive stress than the average citizen. We see cellular stress and damage from the extreme environments that they’re in, whether that’s desert heat or low oxygen at high altitudes. Soldiers have to perform at high levels in challenging situations, so resilience is really important. Resilience is a key linkage with aging. The more resilient you are, the better you’re going to age. The more resilient you are, the better you’re going to be at serving in the military.

But this program goes beyond active duty soldiers. The Veterans Administration is a major healthcare provider and is an important safety net for people coming out of active service. Looking at how we can mitigate the cost burden and the disease burden in the veteran population is super important. Also,  more and more young Americans are not fit for service because of the obesity epidemic. So addressing health, even in the general population, is relevant to the military just in terms of their recruiting and keeping people healthy once they’re in the service.

(Newman and Stubbs wrote a terrific review article about ketone bodies and the linkages between aging and the military – you can find it here)

Talk about the overall program and the Buck’s role in it.

The $10 million award aims to understand how to implement ketones, ketone supplements, and ketogenic diets in veterans and the military population for health and performance. Ohio State University is the prime awardee; the Buck is a subcontractor.

There are four major projects under the grant. We’re involved in the first project which is focused on really understanding the fundamental differences between exogenous ketone compounds – the title is “Optimization of Ketone Delivery Strategies.” Our two main questions are 1) How do differences in the exogenous ketone affect the body’s response?  and 2) How do differences between individuals affect the response to an exogenous ketone?  So the idea is, ultimately, to be able to give really good dosing recommendations to people regarding which compounds they should take for their specific-use case and for that individual to understand the kind of considerations that determine how it’s going to work for them.

So for this project, we don’t need to use military people. To answer the question about how different ketone compounds work, we will be using fit, healthy, young men in the study. They will likely be recruited from the student body at Ohio State. For this question, we really want to cut down the possible variants due to sex differences, or training differences, or health differences. We want to know if we had someone who was our typical GI Joe, how is this ketone compound going to be different than that ketone compound etc. We’re not going to determine which is “best” overall because we’re going in with the philosophy that each is going to be best for a different thing. Which one would you take for cognitive performance? Which one would you take for physical performance? Which one would you take for recovery? Which one would you take as a daily supplement versus following an acute injury?

In part two of the project we’ll take out the variability of the compounds and pick one ketone ester compound; then we’ll find a lot of different people, and give them all the same dose of the same compound.  We want to define what’s different between you and me, and me and that 35-year-old athlete versus that 55-year-old with prediabetes. Is age changing the response to ketones? Is training or health status?  Is gender?

Some of the hypotheses that we’ll be testing have come from John’s lab because one of John’s PhD students is studying how ketogenic capacity and the ability to burn ketones change as mice age, and whether there are important sex differences as well.

This is important because no one in the field has ever used a drinkable ketone to exhaustively characterize whether there are differences like that. And that’s really significant when it comes to designing a dosing or supplementation regime. We need to understand how to tailor it differently for men and women and for different ages.

We also want to get at another important question, namely, might be a difference in ketone metabolism in people with healthy blood sugar and people who are unhealthy in terms of their metabolism? So one of the most important questions will address age, sex, and metabolic health.  That second part of the study will be partially at the Buck. Of the 400 people studied, 100 of those will be studied at the Buck. We’re going to be looking at the older, less healthy population. The study will be over four years and each year we will recruit 25 people to drink one dose of the ketone supplement and measure how it changes physiology.

What are some of the other things the overall larger study will be looking at?

One of the projects will look at whether ketones confer resiliency against sleep restriction, based on the fact that the majority of military personnel fail to get the recommended amount of sleep, especially on deployment.  Another project will look at whether ketone therapy improves exercise tolerance in heart failure, since diabetes and heart failure are major risks for disability and death in veterans. The last project involves the use of a ketogenic diet to delay or prevent the progression of diabetic nephropathology. Kidney disease is a major complication of type 2 diabetes, and is a significant problem within the Veterans Health Administration.

These are very different conditions. You’ve got sleep deprivation, heart failure and diabetes-related kidney disease in this grant. There is also a lot of interest in ketones and cognition. Let’s talk about the science of ketone bodies. What is it about ketone bodies that seems so promising for so many different indications?

The ability of the body to make energy is fundamental to life, to performance, and to health. And the ability of the body to make energy is compromised in all of these settings and in many other diseases. One of the main pillars of ketone therapy and ketogenic therapy is providing ketones as an alternative fuel for these parts of our body which are energy stressed. For example, in heart failure, we start to see the heart getting less good at using conventional fuels, which are glucose and fat. Hence, clinical trials are looking at the efficacy of ketone bodies for that condition.

But ketone bodies are more than a fuel supply – right?

Yes, they are also drug-like which means they hit signaling pathways in the body. One of the things that personally gets me super excited about ketones is that with one intervention, you can hit multiple targets.

John and the Buck’s CEO Eric Verdin are important players in this realm. They published a paper in Science in 2013 showing that ketones had a signaling effect and an epigenetic effect, and could modify oxidative stress resistance. That paper was really a landmark; John and Eric are considered to be the people who really foregrounded the non-energetic roles of ketones.

From my perspective as a lay person who works at a scientific institute, it looks like the interest in ketone bodies is really on the rise.

Oh, man. It’s exploded. So I first got involved when I was l9 or 20, that was 10 or 11 years ago when I was a baby researcher. At that point there were not that many researchers, and not that many ketone supplement tools that people could use.  And that continued to expand when people discovered that ketones were having signaling effects, not just energy effects. People started to discover roles of ketones in inflammation and in regulating parts of the immune system. Recently, people have discovered that ketones can regulate vascular senescence. So things started to link into more and more of the hallmarks of aging that we’re interested in here at Buck.

If you want to really complete the circle, the first drinkable ketone was actually developed for the military, for DARPA (Defense Advanced Research Projects Agency). So they’re a super elite, defense research organization. In 2003 DARPA funded a program that they called Metabolic Dominance, and that was to develop ketones for the Iraq War. And so the first drinkable ketone was entirely focused on energy for performance, specifically how to make soldiers going in the field more energetically efficient.

Looking at ketones for physical and athletic performance kicked in between 2007 and 2009.  That’s when I came into the field -- I was a research subject in the studies involving athletes and then, subsequently, I joined the research team. And then John and Eric’s paper published in 2013. And then, since then, you go to PubMed and type in ketogenic, and you just see this huge uptick, an explosion in interest.

So you were a research subject as an athlete? 

Yes, I was an elite rower. I won the World Championships twice with Great Britain. I was on the British rowing team from between when I was 18 to 26. When it came to ketone bodies, first I was a research subject and then I became really interested in the science. (Stubbs got her PhD in metabolic biochemistry from the University of Oxford in 2017).

What’s your sport of choice these days?

I recently qualified for the World Championships in the Ironman Triathlon.

Wow and congratulations! I’m guessing that supplementing with ketone bodies is part of your regimen?

You bet. I train anywhere between 12 and 20 hours a week, depending on where I’m at with the training block. For example, I’ll train swimming three times a week, biking three or four times a week, and running three or four times a week. So most days, I’m doing two workouts. I do three or four triathlons a year, and the rest of the year, I train and do events for each of the individual disciplines. Last year there was an Ironman in Tulsa, and it was the North American Championships. And I won my age group and qualified for the World Championships.

It’s very cool that you get to appreciate ketones from so many angles.

Yes, my interest in the application of ketone biology keeps growing stronger.  It’s naturally evolved from sports science to resilience and now to geroscience and efforts to address the chronic diseases of aging.  It’s an exciting time and I feel lucky that a personal passion has become the basis of a great career.     

Disclosure:

This study mentioned in this article is paid for by a contract between the DoD and the Ohio State University, and a sub-award to the Buck Institute for Research on Aging. All study staff are employees of the Buck Institute. Dr. John Newman, the study investigator, 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.