Diet Doctor Podcast #45 — Brianna Stubbs, PhD

Welcome back to the Diet, Doctor podcast with Dr. Bret Scher. Today, I'm joined by Dr. Brianna Stubbs, who is the chief translational scientist at the Buck Institute., And they are focusing a lot on longevity and prolonging wellness span.

, And she transitioned to this. From an athletic background and an athletic research background studying ketogenicgenic dieting and exogenous ketogenicnes how they affect athletic performance., And now she's transitioning both to athletic performance and wellness span.

. So it's really interesting to sort of get her perspective. On where ketogenicnes fit into the whole picture of performance, for an elite athlete and for an everyday athlete and then how that also may translate to wellness and longevity.

Now, in the beginning part, probably the first half of this interview, we spent a lot of time talking About sports and athletics and athletic performance.. So if that doesn & # 39, t apply to you. If you're, not interested fast-forward halfway through and you'll pick up on some of more of the wellness aspects.

, But it's great to get a perspective.. She thinks from a scientific mind of evaluating the evidence before making big claims, and I think that's, a good take-home message for all of us.. But I think you will get some takeaways here about where ketogenicnes fit into this picture and whether they're right for you.

, So enjoy this interview with Dr. Brianna Stubbs and make sure you go to You can see the full episode and a transcript of it if you are a Diet, Doctor member and also subscribe to our YouTube channel, so get all our regular updates.

. All right, thanks here's, our interview with Dr. Brianna Stubbs., Dr. Brianna Stubbs. Thank you so much for joining me on the Diet, Doctor podcast., What a pleasure to be here, today. And I hope you're, enjoying the fantastic Metabolic Health Summit as much as I am.

. Oh, it's, wonderful ..., and you gave your talk earlier. Very relieved to have that out of the way. Nice to have it done now. You can relax and enjoy the rest of the conference.. After this, I'm off to the bar.

Good, very good.. Now I want to talk a little bit, so viewers get to know sort of where you came from and how you started with this, because you started from a pure athletic background as a world champion rower and actually rowing across the English Channel at age 12.

. Well, that's, not the peak of athletic performance, but I guess it says a little bit about my personality.. That was something that I asked my dad if he would help me do when I was 12., So you certainly started at a young age and then worked your way up to being a world champion rower.

. And how did you find your way into sort of the scientific world and the ketogenicne world Sure I mean I was always really interested in biology and how the human consistency worked so much so that actually, when I went to university or school in America, when I Went off to university, I was studying medicine.

, So my plan, correct choice, was to be an M.D., a medical doctor., And so I was studying all the basic systems of the human biology in my undergraduate course, and also at the University. I was starting to take rowing more and more seriously, and I'd, been on the junior international team and the under 23 international team, so that was getting more and more serious as well.

, And it was almost like this very random, perfect storm of Random events., So I was rowing on the team and all of a sudden. I see this advert for a study looking at ketogenicne esters in rowers and they were offering to pay people come into row, machine test, which I was doing for free otherwise.

, And I was in my freshman year. I was like this sounds like a great way to make a little bit of beer money. You know, go and do that. The irony ... beer money for doing ketogenicne research. I didn't actually and still don't really drink beer.

. I can't really remember what I spent that on --, probably on traveling, to rowing races and things like that, because a lot of it was self-funded at that stage. And it wasn't like tons and tons of money.

. It was nice pocket money., But yes, I went and took part in this study and it was so relevant to my personal interest, but also was really building on what I was studying in the classroom. All of this, biochemistry which kind of seemed bit dry to me, quite frankly, as you study all this big metabolic pathway, the Krebs Cycle and study, all the different pathways of fat burning and carbohydrate burning.

, We didn't, really go into that much detail About ketogenicsis., I do remember, we were taught about it, but it wasn't, something that stuck in my mind.. So doing this study and meeting the research team really started to trigger a lot of questions in me about how metabolism and sport interacted and also how ketogenicnes and supplementing with ketogenicnes could fit into this.

And so on. As part of my medical training, I was able to do a summer research project which I did in a lab group, and I got more and more involved with the research there. And so when it came time, my rowing was actually really taking off and I needed to step back a little bit from my studies to focus on that.

. The research lab offered me a position as an assistant helping to run a number of these studies.. So it was good because it was flexible work and they were really understanding of the fact that my training was really demanding.

And that assistant position kind of somehow converted into a PhD position that you know I was interested in doing good work., And so they brought Me on. And really the good thing is, while I was at the medical school were happy that I was doing a PhD and they could turn a blind eye to the fact that I was rowing all the time.

And they actually held the place open. For me in medical school that I could have come back to at any point which was a really nice safety net.. So I was just really free to go after the research and pursue my own athletic ambitions as well.

The two fitted alongside one another really nicely, because actually, especially as I progressed into the senior team, I moved into the lightweight category. So I had to think I spent a lot of time in caloric restriction and in more of a ketogenicgenic state.

, So actually understanding, starvation, metabolism and ketogenicne metabolism, especially as it pertained to drill. It was not hard work at all for me to really get into the literature and understand the implications of the physiological effects were having on my performance and therefore the implications for other athletes as well.

Yeah. So, first of all, I just have to comment that I think it says a lot about your abilities and your intellect that you can use an M.D. degree as sort of like a safety net. That's, pretty impressive first of all.

. But I really liked what you said about learning the Krebs cycle, but knowing the practical implications of what it can do and then also you personally sort of experiencing it to see how the ketogenicnes work for you in your athletic training.

. I think it's, that personal experience that makes us driven even more and that much more interested in studying it, and subsequently you've, turned into an amazing researcher, doing all the studies and sort of being on the forefront of ketogenicnes And ketogenicgenic dietings for athletic performance.

. Now as we get into this, I think we need to differentiate a couple of different things.. I mean there's, a ketogenicgenic dieting and then there's, exogenous ketogenicnes and then for athletic performance. There's, elite athletic performance, there's, sort of everyday athlete performance and then there are the different sports with different demands.

. So there is really a lot of specifics.. You can't just say it's. Good for sports it's, not good for sports., you sort of have to get into the specifics., So walk us through a little bit. You know how do ketogenicnes in general, help with sports and then kind of help us differentiate the specifics.

Gosh. You want me to start with exogenous endogenous ketogenicsis. We'll, start with endogenous, because the most people -- the low barrier of entry for a lot of people is probably they're already on ketogenicgenic dieting, and they want to know how it's going to affect their Athletic performance and then we can go into exogenous from there.

Okay, so the rationale behind going on a ketogenicgenic dieting for athletic performance is that when you become ketogenic adapted, you get really really good at burning fat for energy. And so Dr. Volek over a high state University, he's, one of the world leaders in this field, and he actually showed that if you get adapted to a ketogenicgenic dieting, the rate of fat oxidation can be two or maybe even three times higher than an regular athlete who is not fat-adapted.

. So some of the values that he published in his study was showing that it was --. I think it was 50 % higher fat oxidation than it had ever been published before, like 1.5 g per minute, plays a normal sort of 0.

6 to 0.8 g per minute.. So when you become ketogenic adapted, you're, really really good at burning fat.. Now, if we take a step back and look at it from a theory based perspective, we have a lot more energy on board our consistency stored as fat compared with glycogen.

. So glycogen is the storage form of carbohydrate and we have it in our liver and we also have it in our muscles and then the energy in glycogen represents about 2000 cal.. So it's. Quite a lot. More than most people would burn on an average 30 minute jog around the park, but for elite athletes with very high-energy rates and especially as the event starts, to get longer that might start to become a limiting factor for their ability to continue that drill.

, And so The theory behind the ketogenicgenic dieting, therefore, is that you ... be able to up-regulate your consistency's. Ability to burn this fat stores, where we have, I think, about 150,000 cal worth of fat store many many more times energy stored as fat.

, And so we can tap into that and, in theory, should pushing out the time in which you would get exhausted.. Now. I think this now brings us on to a point that you mentioned, which is the difference between elite athletes and more recreational athletes.

, So for early athletes. Actually, there is very few events and the marathon is the longest event that is in the Olympics. And then now we're, seeing marathons being consummated in near two hours.. So I mean it's, not what I would class as an extreme endurance --.

Obviously it's, an endurance event, but it's, maybe not something where the glycogen availability, plus the ability to take on exogenous carbohydrate is really the limiting factor and what the limiting factor for performance for these athletes is the ability to Produce energy as fast as possible.

Now fat has a more complex metabolic breakdown pathway. Beta oxidation has many steps and glycolysis by comparison is quick and fast and in terms of oxygen efficiency. Also, glucose is an efficient fuel source for exercising muscle.

. So at the moment, the school of thought is that for elite athletes exercising at a very high intensity in order to consummate their competition, they probably still want to be able to burn carbohydrates.

. But then, if we look at the other part of people here and that's, the people who are trying to run a marathon - maybe they're running three hours if they are quite good, but maybe more people completing marathons in more.

Like five hours long and so actually, people then on -- so interested in that very, very high intensity performance is a consummately different event. And so for those people they actually might benefit from oxidizing, more fat and also for those people.

Things like consistency composition are going to also be more of an issue and being on a ketogenicgenic dieting, might help them with that as well.. So when people ask me & quot, Is the ketogenicgenic dieting good for sport & quot? You have to very clearly defined the type of sport you're interested in, and also the level of the athlete you're talking about, because there have been some studies and it's, not that well studied to date.

. I would say that well, a lot of people who hate the ketogenicgenic dieting saying that it doesn't work ..., but we haven't, seen definitive performance decrements of the ketogenicgenic dieting, -- Right and that's. An important part.

, So can we say the ketogenicgenic dieting is -- As good. -- is better, then, Or as good as carbohydrates. So I think that where we are with the research right now is, that is definitely at least equivalent in many settings for some individuals, because none of the studies report, individuals, who may have been really really good responders, and so you lose a lot of the detail.

The fine resolution of these pictures right So there's, no reason to doubt that some athletes again are going to perform better on the ketogenicgenic dieting. But if we look at all the means it's kind of nang .

.., Which is good, because I think some people are like & quot. You shouldn't, do this. It's, going to kill your performance. & quot. Well, no, I think that some studies, where it helps a little bit some studies where it takes it a little bit off and in some studies there is no effect.

. So when we look at the whole consistency of data, I wouldn't feel I would say to an athlete: do what you feel makes you the best. Right. And if you're going to get all these other wellness benefits from it. Anyway, why not give it a try if it's, not going to hurt your athletic performance, But that is more important for those recreational athletes who drill as part of their lifestyle rather than exercising as their career.

Right. That's, a good point., So you talked about a marathon.. So what about the guy? Who plays pick-up, basketball on a regular basis or the woman who likes to swim in the pool and do interval training in the pool? I mean all of a sudden you're, talking about a different type of drill that is generally referred to as more glycolytic, meaning you need some of that quicker energy for intervals.

Sprints and things. Is then, maybe the ketogenicgenic dieting, not the best choice, or can it still be helpful in those circumstances, I think again it's helpful to segment elite athletes versus non-elite, because if you're an elite athlete - and you Are --? You know you're on the US, women's, soccer team or you're Usain Bolt all that matters.

Is your ability to produce energy by glycolysis so that, if you do anything to blunt that is going to have a big impact on your performance.? But in those two scenarios, even if you are playing pick-up, basketball casually or you are swimming - a 50 m race in a master swim meet a 0.

5 of a percent. Less efficiencies through glycolysis is likely not to be a major limiting factor to your performance., And you know. Interestingly, I've done a lot of work in with the military and this kind of gets a bit emotive because people like -- well, if the soldiers lost their ability to maximally sprint, what if they couldn't run away from an Ambush or something like that.

And I actually had a number of conversations with some veterans who had done years of service and they were like & quot. We never sprint at 100 % & quot, Because we are carrying ammunition. We are carrying our packs & quot.

We are also trying to navigate where is the best way out of the situation.. So there is never an occasion where I am running at 100 % & quot, And so unless you need that 100 %, then actually maybe their potential for the ketogenicgenic dieting to take off that top-end glycolytic.

Maybe it's less important for all, but the very most elite people who sprint performance matters, the most.. So I mean I would agree with something you said, which is that the other benefits in most cases could be said to outweigh the possible biochemical.

Downsides., The only thing as well to say in the spirit of fairness is that not everyone finds the ketogenicgenic dieting easy to adhere to.. So I think you know, as a community, we can't, say & quot, Thou shalt be on ketogenic, And this is the only way.

& quot. I guess if you're enjoying it if it's sustainable with your lifestyle, you are finding good wellness benefits, you are still able to go out and play your pick-up, basketball and all of that - and you feel better and you are Losing weight and all of this, then, of course this is like, obviously what you should be doing, but if you're the type of person and it's, just a struggle every time you walk past the bakery, then you know probably Don't go in the bakery.

-But still ... right. -Right. Works better for some people than others. Yeah. That's, a really good perspective.. Now I want to go back to what you said about the ketogenic adaptation process.. So we talk a lot about sort of the ketogenic flu and becoming fat adapted and usually that takes anywhere from 1 to 2 weeks, depending on your hydration and your electrolytes.

But that's, a very different scenario than athletic ketogenic adaptation or fat adaptation. For athletics., So can you help differentiate between those two? There's, an awful lot to unpack there and an awful lot that we don't really know.

. So, for example, Dr. Volek talks about glycogen levels in athletes who are on the ketogenicgenic dieting., And at the moment we only have three data points.. We have Dr. Phinney study, which was a few weeks long.

I think, and the athletes on a ketogenicgenic dieting had much level lower levels of muscle, glycogen. And then Dr. Volek has a more recent study with military cadets, and that was a more intermediate duration and those athletes had.

I think it was maybe like 10 % decrease in muscle glycogen and then his study, the FASTER study, which is quite well known, with athletes that have been on a ketogenicgenic dieting for a couple of years. Even those athletes had no difference in resting muscle, glycogen.

And muscle glycogen is a really important determinant of athletic performance.. So we actually don't know how long it takes the consistency to adapt to be able to keep muscle glycogen stores optimal. When you're on the ketogenicgenic dieting.

, But Dr. Volek's, long-term data from those athletes who were on the dieting for a long time suggest that you can -- So using muscle glycogen, as the indicator of you have adapted basically.. So this is one marker.

. The flipside of that is the group that's notoriously anti-ketogenic over in Australia. They've shown that some of the chained enzymatic changes inside the muscle cells can occur in as little as four days.

. So that's, why they argue that there is no point in adapting for longer than four days to the ketogenicgenic dieting, because you've, actually got -- and that the change is even reversed that quickly.. So there's.

Big things like muscle, glycogen storage, smaller things like on a cellular level about levels of enzyme expression that may even be reexampleing of adipose tissue. Switching from white fat to brown fat, for example, changes in the amount of lipids in the muscles.

So ketogenic adaptation is a hugely dynamic process and there are so many different things that are changing. Yeah. I think it's very hard to say that we have a good handle on exactly what the timeline of that processes is and maybe to fully ketogenic-adapt is, as Dr.

Volek suggests a couple of years, even -- Wow I mean we can't say for sure: it depends what change you're looking at. And that's, important, because the advice we give as clinicians to our patients when we put them on a ketogenicgenic dieting or carbohydrate restricted dieting for their wellness for Diabetes for weight loss, but if they also are interested in their own athletic performance, you know just how they do in the gym how they do on their 5K runs.

Whatever the case may be, generally, we have to advise them that their performance is going to go down for some period of time before it comes back up, but that some period of time is the hard thing -- It's very individual as well, And it depends how successfully they can implement the dieting and all kinds of things.

So there's, an awful lot to unpack there.. I think it's hard to give a one-size-fits-all recommendation as to how long we should expect that period of time to be.. I would say that I think it's kind of interesting to me how exogenous ketogenicnes might help with bridging that adaptation gap, whether it's in terms of the ketogenic flu or whether it's in terms of athletic Performance, so you know you want to fuel your workout, but not consummately -- with a rapid energy source, but not consummately derail your progress with the ketogenicgenic dieting.

. Yes, so perfect, transition.! So let's, transition to what we know about using exogenous, ketogenicnes ketogenicnes, that we can just drink to boost our ketogenicne levels and how that affects athletic performance for the elite athlete, but also bringing it back to sort of the everyday person.

Yeah. I mean it makes more sense to start with like fairly well trained athletes, because they are the group that we've studied today, and I think there's, an awful lot of work that still needs to be done.

Looking at less trained people and also athletes who were on a ketogenicgenic dieting, because a lot of the athlete studies have been done to date use athletes who were on a mixed dieting.. So the first thing that I always find really interesting is that athletes themselves, regardless of dieting, are quite well poised to metabolize ketogenicnes, because ketogenicnes get taken up into the muscle through the monocarboxylate transporters, as we all know, but that transport is also used for lactate.

And So if you're athletically trained, you've, already up-regulated, that through exposure to lactate., So athletes can get ketogenicnes into the muscles quite efficiently compared with someone who is sedentary.

. So when we are thinking about how ketogenicnes might be useful for athletic performance, it's kind of interesting to think about why ketogenicnes even evolve for starvation.. They evolved as a fuel and they evolved to alter our carbohydrates, burning and turn that down.

Stop us from breaking down our protein into glucose, to complement lipid metabolism and preserve cognitive function., And all those things could be useful for an athlete. Right. Athletes can use BHB as a fuel.

It can mean that you, don't, have to take on as much exogenous carbohydrate and like protect our carbohydrate stores. And then in terms of recovery, setting that protein effect could kind of be interesting as well.

. So at Oxford we were trying to unpack this state of being in like fed state, but also having ketogenicnes present as well, because before the discovery and availability of exogenous ketogenicnes, you either were in ketogenicsis and you had low carbohydrate availability or you were --.

I wanted to say you were either in ketogenicsis and had low carbohydrate availability or you carbohydrates, but no ketogenicnes.. It was one or the other. It was pretty binary.. So now you're talking about a physiological state that has really never existed in the history of humankind, where you could have high insulin, fed state or at least not low insulin.

, So carbohydrate availability insulin, not being low and ketogenicnes being available. ... sort of never existed, before., No and from an athletic perspective. This is really interesting because it's like all of a sudden.

You can get fuel coming in from different pathways that never would've been able to be simultaneously topped at any one time.. So it has certainly made sense to us, as we started studying this, that the reasons why this might end up to be a good thing for athletes.

, But you never know so you have to run the studies.. So first we had to see whether the athletes on a non-ketogenicgenic dieting could even burn ketogenicnes during drill. And so we ran some studies looking at levels of ketogenicnes after identical ketogenicne drinks, taking a rest or during drill, and we could see the drill brought down the levels of ketogenicnes when you were even taking the same drinks.

. So it was like huh ketogenicnes going down. ..., that probably means they're being burned.. I mean there are other possibilities there as well, but we strongly suspected that this decrease in levels of BHB represented ketogenicnes oxidation.

, And then we were looking at other --. So ketogenicnes are burned.. What's happening to the metabolism of other fuels? So we did some muscle biopsy work and looked at muscle, glycogen before and after drill, as normally at an intensity that's very glycolytic, so 75 %, which is normally the most non-fat-adapted athletes that are pretty much consummately relying on carbs for that.

. And we could see that when we gave the athletes ketogenicnes and carbs rather than just carbs, they were hardly touching their muscle, glycogen stores at all, which was kind of bizarre and very useful. When you stop thinking about wanting to pushing out and extend the ability to keep exercising, because we know that when your glycogen stores run out, that's kind of when you have to stop or take on extra fuel.

. Another sign that carb metabolism was being modulated was blood levels of lactic acid., So lactate is produced as a byproduct from glycolysis carb burning again, and we could see the steady-state lactate levels were around about 2 mmol low and you took ketogenicnes prior to drill -- when You took ketogenicnes with --.

Lactate levels were around about 2 mmol low when you took ketogenicnes and carbs before drill, rather than just carbs alone., So that's like -- and lactate is very easy to measure with just a fingerprint test when you're testing athletes, As well so is quite an easy test that people could see that their metabolism was shifting.

, So it can be used then, to prolong the drill by prolonging the glycogen availability and maybe to increase the intensity or duration by not having as high of a lactate level. -- Actually shifts the lactate threshold, so that would be shifting your training zones.

Interesting and then can that also play into recovery as well Mm-hmm.. So it can have multiple different effects from that standpoint.. Exactly it's really interesting. And then the final thing that was kind of neat that we saw was an increase in oxidation, intramuscular lipid.

. So athletes have quite a lot of intramuscular lipid and it's like an adaptation to help athletes with endurance as like put the fat near the mitochondria, where it needs to be.. But typically again, as I said, when you get overset in intensity, you don't burn that intramuscular lipid, because you are reliant on carbohydrates and we saw that at this quite high intensity.

Ketones turn the muscle back on to using fat, even more., Which was ... it was. It was very stuck how different the metabolism was in the presence of ketogenicnes versus conventional carb fuel metabolism in these non-ketogenic-adapted athletes.

, And so what we saw in those athletes - and this is, you know - heavily caveat where there's. A small study - and you know a high-level athletes., But we did see a pretty consistent improvement in performance that was on average at about 400 m over 30 minutes, which is about 2 % And to put in perspective 2 %, would be like separating the first and Fourth place at the Olympic marathon.

So for high-level athletes, an improvement like that is meaningful. Right.. Then, if we try and extrapolate that back to the less trained athletes, this is where I start to get into more. Like speculation.

. There's, reasons to believe that it would work better and reasons to believe that it would work less well.. So, for example, if you are less well-trained, then your performance is probably intrinsically a bit more variable.

. You know the better you get at something the more consistently you're, going to hit certain performances.. So there's, just more room for error in your performance. And then also as I was saying, the training of the muscle actually better equips it to take up and metabolize ketogenicnes.

So maybe there's less benefit when you're less well-trained., But that's, a state we don't know we still need to run the research study. Would, you say, is potentially more beneficial for someone Who is a carb burner as opposed to someconsistency who is already on a ketogenicgenic dieting that has -- Yeah? That's? A great question then - and we can definitely argue this either way.

And I've - worked with athletes at my previous company HVMN. You know we had low-carb athletes using this, who had really great experiences and others who didn't like it as much.. So the way I would argue it both ways is: if you are low-carb and ketogenicgenic, you are even better tool arounded up to oxidize ketogenicnes, and so, when you're presented with this big bolus of ketogenicnes, your consistency is really great at metabolizing it and It fits right in with your preferred metabolism.

, And so that's for the people who I feel like would respond and then, on the other hand, you could argue that actually, when you take a ketogenicnes drink, one of the key things that happens is Ketones dampen lipolysis, which is the process of fat relinquish from our adipose tissue.

, And so, if you take a ketogenicne drink and you dampen lipolysis, and then you decrease your plasma free fatty acids in a fat-adapted athletes ... those people are really quite heavily reliant on those Plasma free fatty, acids.

Right. It's, almost like turning off the tap on their main energy source and actually making it more difficult for them to perform.. So I mean we haven't run the science study and I definitely had both reports come back to me.

. So I can tell you what the real truth is there yet., So it's. Fascinating you put you in a position of. Would you recommend it to sort of the everyday athlete who's already in ketogenicsis.? It sounds like it might be hard to recommend that as a performance enhancer.

Or you just have to try it and see if it works for you.. I would say: definitely don't discount it until you've tried it., Because I couldn't tell you what the predictive factor is as to whether it's working or not.

. You know whether I think some people really like fasted, exercising and other people just feel like really bad, and they have to have something whether it's, MCT coffee or whether it's, slow relinquish carbs.

. So we definitely had a lot of positive feedback from low-carb athletes, building this into like very long, for example, mountain bike, races and especially athletes like Zac Bitter --. I think he holds the world record for 100 miles.

100 miles. He run like a 6:40, a mile. 6:40 miles for 100 miles Unbelievable., But he strategically includes carbohydrates in as well, even though he trains low-carb.. So I think, as you know, your consistency better figuring out what you strategically need to include different fuels.

You become better at it., So for anyone who's on a ketogenicgenic dieting and would like energy for their workout. So maybe they are training for some kind of race or event. I'd, encourage you to try it because at the moment there's very little like risk cost --, You know the cost benefit.

Analysis is try and see how it works for you., And I know, is a way for us to do the science session to be able to give you the definitive, recommendation. Right now. Briefly, let's, get into the difference between salts and esters.

And for those who are not athletes hang with us. We're, going to get to some of the longevity and wellness stuff in a little bit, but just to finish up on the sports part of it, which is interesting to me, especially because I do a lot of mountain biking and I don't compete, but it sure is fun to sort of leave your friends in the dust as you're, going up that last hill.

So every little bit I guess helps., But let's. Talk about the salts versus esters! In terms of tolerability efficacy and sort of what you would recommend to people, if they just wanted to see if they had a little boost in their athletic performance.

, This point is actually relevant to people using ketogenicnes for every single use case. Like all of those things, you know BHB delivery, tolerability, accessibility of the compounds, all of that would play into your --.

You are choosing to use it whether you're, an athlete or whether you are someone looking to like protect your brain wellness over the long time or maybe experimenting with some of the clinical conditions where ketogenicnes are thought to be useful.

. So this is like copying, a question that's relevant to everyone., So I mean let's, maybe start with ketogenicnes salts.. They are the most widely available in consumer products right now, so is the easiest to find ketogenicne salt and they tend to be the most price economical.

. These molecules consist of typically the ketogenicne beta hydroxybutyrate and that's, because acetoacetate and acetone are not very stable and it's, difficult to formulate them into a product., So take beta hydroxybutyrate and you bind it with an ionic bond to A mineral that's, typically something like sodium or calcium or potassium.

. Interestingly enough, but it's also possible to bind ketogenicnes to charge amino acids, but the amino acids have quite a big molecular weight. So you end up having to take like mountains and mountains of powder to get a decent amount of a ketogenicnes if you do that.

. So mostly these minerals, like we'd, think of like table salt kind of thing, but it's. Ketones instead. One consideration that people should look out for and it's not always obvious. Is that typically, the salts mixtures of two optical isoforms of beta hydroxybutyrate --? So when you do chemical synthesis outside the consistency, you end up with --.

Well, I should have explained optical isomerism. Optical isomerism kind of refers to this property of molecules where it's, always like handedness.. So if we think about our left and right hands, we have four fingers and a thumb and they are mirror images of one another, but they don't overlay on one another.

And beta hydroxybutyrate has this property and the enzymes in our consistency that Make ketogenicnes and also that break ketogenicnes down specific to one-handed form --. So if we give, this other handed form that our consistency isn't really used to seeing it.

Certainly won't, be making it, but it also is very slow to be breaking it down or using it for anything.. So people may hear those reference as an L and a D form of the ketogenicne bodies. Yeah it's. Kind of confusing, because people either call them R and S or D and L.

, And I couldn't - tell you exactly in which setting you should be using either one of them, but you use them in pairs. Rs or DL. Got it., But unless on the product it specifies that it's. The D form, then, is likely some mixture of the two and this S or L form, is like the non-natural form.

. So we don & # 39. T really know how that behaves inside the consistency.. We don't think it's useful as an energy form, but a lot of my work now at Buck actually focuses on understanding the signaling implications of S beta hydroxybutyrate, which are fascinating.

, And I am looking forward to finding out more About that., So especially for athletic performance, but also in conditions, for example, Alzheimer's, disease, where energy provision is like one of the really key things that the ketogenicnes are doing in this kind of situation, you'd, always want to be Prioritizing D or R beta hydroxybutyrate over the S or L form of beta hydroxybutyrate.

, So that's, just something to be aware of with the salts. And what about the esters? How do they differ So the esters again? I think it helps to take a step back and we have this bucket of ketogenicne esters and we assume that all of things in it are kind of similar, but actually a ketogenicne ester is quite a broad term, and it refers to a molecule where you have Bhb or acetoacetate joined by a special type of bond called and ester bond to a ketogenicne precursor.

. Those precursors can vary so it can either be 1-3-butanediol or glycerol or a medium chain. Fatty acid., And also you could have monoesters so one ester bond, diesters, two ester bonds, triesters three ester bonds.

. So actually there are tens, maybe even hundreds of different possible ketogenicne esters and the chemical structures of those molecules where they did a level of BHB versus acetoacetate. For example, those are all going to impact on what they are useful for.

There is going to be big difference in like physical properties of those molecules like how they taste, which is a really important one, how easy they are -- Right. And we can get to that later. How easy they are to make and therefore how cheap or expensive They'll be.

, So this is really like a law of differences within that class.. So I think I want to highlight to everyone that if you hear something being like ketogenicne esters do this, you actually have to look and see which ketogenicne ester has been used.

, And I think a really neat example actually is .... There is the acetoacetate diester that Dr. D'Agostino has been working on and they've, actually seen that giving acetoacetate in certain use cases like the CNS oxygen toxicity and in some of the cancer examples.

Actually it's. Better to give acetoacetate than beta hydroxybutyrate. It's, interesting that we talk so much about beta hydroxybutyrate, but there are some circumstances where acetoacetate may be better for neurological function.

Exactly. It is very interesting and we are already just starting to scratch. The surface of understanding the differences because they are so closely related that one wouldn't necessarily just expect that there would be a difference.

. But when you start to look at the biochemistry -- so, for example, beta hydroxybutyrate may just be better for athletic performance, because if you give BHB, then it's going to be converted into acetoacetate and that conversion generates one molecule in part of NADH, Which is used for energy production, so you get this extra energy production step in the conversion of BHB to acetoacetate that you wouldn't get.

If you just gave acetoacetate for example.. I knew all that chemistry I learned would come in handy someday.. Yes, there you go. Yeah, so ketogenicne esters are a very diverse class of molecules, but generally speaking, firstly, they avoid the mineral load that you get with salt and that often means that they are more tolerable.

Because of that mineral load, there seems to be like a bit of a threshold to how many salts you can consume without G.I. upset. And also just sort of around wellness concerns around big boluses of mineral consumption.

You know the effects on your kidneys and your heart and all of that as well., Then you have the esters there's, none of this mineral load, so they are kind of a little bit more potent in terms of BHB delivery, or at least The BHB monoester is very potent in that you could take, maybe like a 30 g or a 40 g dose and be at like 6 or 7 or 8 mmol of ketogenicnes within 30 minutes.

. So a much higher level and a much lower volume of liquid that you have to consume. Yeah I mean it. Doesn't, taste great and consuming 30 g of it is a little bit of a -- -Like, a tequila shot or something.

-Yeah exactly.. So yeah that's, the key difference, ..., you know with the esters depending on the compound again, the BHB monoester is quite well-tolerated and we haven't, seen high incidences of G.I.

effects, whereas the acetoacetate ester in its current form was Quite poorly tolerated by athletes., So you know people like ..., oh esters, make you sick .... Well, it's like no that one ester made people sick .

... It's, going to be different for different compounds, and it is now something that we're, exploring at Buck like. How can we change up how ketogenicne esters work and stick them together to get different clinical end, points.

Yeah? So it's, a great transition., So you are sort of embarking on a new part of your career at the Buck. Institute. And I wanted to read .... So it's, the Buck Institute for Research in Aging and Age-related Diseases, and their mission statement is to extend the wellnessy years of life.

. That sounds like a great mission. Statement. I'll. Tell you what. It's. An awesome place to work., You know we have the ketogenicne biology lab, where we have people researching brain wellness and Alzheimer's, ovarian wellness.

We have people who are specialists in C elegans, which is a little worm and they give the worms all kinds of different things and see how long they live.. What else I mean sleep experts drill experts and it's just so exciting and refreshing to be in a place where there's.

Just so much innovation and creative thinking around science. And the institute is set up in a very collaborative way., So everyone comes together very often, and there's, a lot of sharing of knowledge and expertise between labs.

. So I think it's, a great way to accelerate knowledge and discoveries here.. For example, we are collaborating with the bioinformatics and AI core to do a very broad look at how different biomarkers are changed during ketogenicgenic dietings and compare that to exogenous ketogenicnes.

, And they have this fantastic way of looking at all of the different markers and showing us. Like what are the most important differences. And then we also have a fantastic proteomics and mass spectrometry core, and we are going to be looking at how beta hydroxybutyrate itself is added to proteins as a post-translational modification.

And again, if that's different between The dieting and exogenous ketogenicnes as well., So what I -- bringing into the team a little bit is this knowledge about exogenous ketogenicnes. So we're using it as a tool around and alongside the ketogenicgenic dieting.

Now we will always be comparing dieting to esters or dieting to exogenous ketogenicnes of any kind., And we also are interested in running alongside that arms, where we give just targeted S or L beta hydroxybutyrate by itself, so that we can isolate any energy effects of the Ketones from any potential signaling effects of the ketogenicnes as well.

, So the experimental designs that are being set up will hopefully allow us to start to tease apart things that are down to carbohydrate restriction, things that are down to BHB, potentially as an energy, and then things That are down to BHB as a signal as well.

, And we can really tap into all of our colleagues and PIs over at Buck to be able to do that. So it's, a fantastic environment. Yeah and I can tell your enthusiasm for it.. Just the way you speak about it and you sort of light up.

When you talk about it., That's really interesting. It shows that you love what you do. And you can really see the impact is going to have. When we talk to people about starting a ketogenicgenic dieting for their wellness, whether it's, reversing type 2 diabetes, whether it's for Weight loss, whether it's for treating insulin, resistance or metabolic syndrome, lowering the blood pressure, all these different effects.

Generally, it's, the effect of lowering insulin and glucose. That is the most important., That's, only going to happen with the nutritionary carbohydrate restriction., Adding the ketogenicnes, probably aren't going to help with that.

But can the ketogenicnes have an additive effect or different effect Sounds like that's? What you're starting to research., Do we have any data one way or the other now, Or is it something that we're, going to have to wait and hold on for future studies? Well, we know that giving the C elegans worms beta hydroxybutyrate by itself can extend their lifespan.

. So I suspect that there are isolated effects of the BHB molecule and maybe the acetoacetate molecule as well on gene expression, pathways that are associated with aging and aging well and maybe having better wellness span and lifespan.

. So I wouldn't consummately rule out that ketogenicne, esters or ketogenicne supplements would consummately not have the same effect as being on the ketogenicgenic dieting.. If you put a C elegans on a ketogenicgenic dieting, I don't know if you can.

, You can definitely put mice on a ketogenicgenic dieting, but I don't know about the worms., But I would actually recommend it'S kind of a little bit deep, but it's. A nice place to start. Dr. Richard Veach at the NIH has written a really interesting review, talking about caloric restriction and ketogenicne esters and how all of the different pathways of longevity that they interplay on.

, Because this is actually more complicated than just insulin.. There's, so many different pathways that feed into longevity., And I think that some of these are going to be hit by just consuming ketogenicnes by themselves.

Obviously, not all of it., And we say when we have visitors up at Buck and they are like & quot. What do I need to do to live longer & quot And we are like sleep enough? Do some drill and look at your dieting.

And if you're, not going to go full ketogenicgenic dieting, then do periods of fasting or time restricted eating.. You're, always going to meet people where they're at, and you know. I think that we need to be reinstalling periods off ketogenicsis back into our everyday life, because it's, something that we've, evolved with as a species periods of plenty and periods of less.

, So weather that's. Just getting up to 16 hours of fasting 16/8 kind of eating window, whether it's, doing one 36-hour fast a week or whether it's going on a ketogenicgenic dieting. All of these are going to be small changes that people can make that's, going to promote wellness span and lifespan.

, And I think it's, always important to meet people where they are at. You know --. It would be hard for me to sit down and tell people & quot. You need to do what I'm, doing and train like 18 hours a week like part of my Ironman training.

& quot. Most people will never going to be able to or want to do, that.. So it's, just like anything that you're, doing now, maybe add 5 % more and that's, always going to be a positive step in the right direction.

And another study that I think exemplifies this really. Nice is John Little at the University of British Columbia. Looked at the difference that a low carbohydrate breakfast could make to total glucose exposure during the day.

, And he found that even just taking out the carbohydrate as a breakfast had an impact on overall exposure. During the day that could likely be clinically meaningful., So it's, even if you change out like one of your meals a day and make it very, very low carbohydrate.

This is going to start to help you metabolic wellness and then also help how you age as well. So I think it can be kind of extreme for people some people to contemplate making that big shift to the ketogenicgenic dieting.

, But it's like take the first step start somewhere, whether it's with a little bit of fasting, whether It's with one low carbohydrate meal, a day.. I know that once you start really committing to that lifestyle, you actually have to really commit to end up with that ketogenic adaptation.

, But there are sort of like intermediate steps that you can do just to get your consistency ready for it and understand the process. A little better. And I think that's, a good perspective too, about all the other factors for wellness and longevity.

. So if you're sleeping three hours a night and you are eating your Doritos and your donuts all day long taking a ketogenicne ester is probably not where you want to start.. You want to start looking at your lifestyle.

. No, I mean like none of these things are band-aids for actually making proper lifestyle changes that are going to support wellness into aging., And you know we haven't even touched on being part of community and all of those other things as well, which We are understanding now are increasingly important for being wellnessy as we age.

Yeah. I think that's, really interesting, because there are observational studies, so it doesn't sort of prove that the community is what does it, but you can certainly hypothesize that you know having more meaning being beholden to others.

You know having that love in the relationship makes you want to take better care of yourself.. I mean you can certainly see sort of like the downstream effects, so just being part of the community can have its impact.

Yeah. I mean one could notice that. Actually, when people will start doing the ketogenicgenic dieting, often they'll plug into some kind of an online community, maybe like Diet Doctor or there's. A lot Facebook groups where people are sharing success stories - and you know like encouraging one another and sharing recipe ideas.

And actually for some of these people feeling like that they are making progress and they are not alone. That's, really really powerful. And helps them to reach their goals. Yeah. That makes a lot of sense.

, So I want to also talk a little bit more about when you talk about wellness and longevity. Another topic that comes up frequently is metformin. The drug metformin. Is that something you have any involvement in at Buck.

Are you looking at metformin at all? We are not ... the most related thing to that that we are looking at Dr. Eric Verdin's. Lab is looking a lot at NAD metabolism and NAD supplementation and the roots of NAD synthesis and breakdown.

, So that's. Sort of the least ketogenicne thing that I'm kind of tangentially related to right now, but I mean all of the evidence coming out right now. Around metformin is very interesting and certainly something that I'm following, but not something.

We're actively. Researching in our group. - So people are studying metformin for maybe cancer prevention and for longevity. But now we are learning that there's also, maybe some mitochondrial dysfunction and some drill inhibition from metformin.

So it's, not all rosy.. Well, I would say that with pretty much any intervention there's, a rosy side and a less rosy side. I mean even with ketogenicne esters as an example, you could use it to help you with your performance in recovery, but are you blunting the Other adaptations that you need --, we don't know at this stage, .

.. There's, an argument that you would be blunting the adaptations that you need to like get fitter and stronger and better, and the argument was actually made with Antioxidants., So the way that I like to frame up these whole things is like you're either at a point in your life, where you are prioritizing performance, and in that case you're, often trading off the factors that would help You with longevity.

, I think it's like you kind of have to prioritize one or the other., And when I was an elite athlete it was performance., But for many people, and especially as you age, you need to -- You aren'T going to be pounding like goo shots and all of that.

, You're, going to be taking metformin and it doesn't matter. So much how much you lift in the gym, but maybe the metformin and the wellness span that you'll, get from taking that then that's more worthwhile.

, So yeah.


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