Dr. D'Agostino: so beta-hydroxybutyrate, I was going to go down the path, and acetoacetate too maybe have anti-catabolic effects.

Dr. Patrick: Let's talk about that.

Dr. D'Agostino: Yeah. The research that we've done uses an ester that elevates both of them and shown that it works in a model of cachexia. And we know that acetoacetate has an enhancement, as I said, proliferation or muscle regeneration, and beta-hydroxybutyrate as a fuel undoubtedly has anti-catabolic effects. And we know that when we administer, even in human studies, if we IV administer beta-hydroxybutyrate, there's a sharp decrease in alanine, and also a preservation of branched-chain amino acids like leucine is elevated, and it prevents a drop. So alanine is like your main gluconeogenic amino acid that is liberated under conditions of stress, high cortisol, high gluconeogenesis, glucagon, things like that. We are going to liberate alanine as a gluconeogenic amino acid. It goes to the liver, we make glucose. And elevating ketones seems to reduce that. That could play into the anti-catabolic effects.

Dr. Patrick: What are your thoughts on...? I'm interested in your thoughts on the anti-catabolic effects of ketones in various context of...I mean, I guess in human development or even, you know, with respect to humans that have different lifestyles. So, for example, people that are physically active, more young, athletic versus people that are older and are battling sarcopenia, you know, versus people that are just sedentary. I mean, everyone has...they have different protein requirements, you know, between these groups. How can ketogenic diets or perhaps supplementing with ketone supplements sort of...? Can they have an effect on muscle mass in some way?

Dr. D'Agostino: I think so, and I think skeletal muscle... And maybe I'm a little bit biased because I've always been super interested in strength training and weightlifting and things like that. But muscle mass is probably the most important factor for healthy aging. And focusing on building as much muscle as possible I think is super important in preserving that muscle with time. So, ketogenic diets are probably not optimal for adding as much size and strength as possible, right? But I do think they are important for preserving muscle while improving metabolic parameters like glycemia, hyperinsulinemia, and things like that. I do think the ideal strategy in the context of a calorie deficit to preserve muscle under that sort of condition, right? And it does it by a number of different pathways.

So, I think the elevation of ketones one of the functions is to prevent muscle loss during periods of fasting, right? So with limited glucose availability or limited food availability, we start liberating fatty acids for fuel, and then the body makes ketones, and then the ketones provide energy flow to the brain, which has very high demands for glucose. If we didn't produce ketones, we would liberate a lot of alanine and other gluconeogenic amino acids from skeletal muscle, and we would quickly waste away and die. The fact that we're able to make ketones from fatty acids as a water-soluble fat molecule that could cross the blood-brain barrier, that actually becomes our safeguard to catabolic processes that would allow us...cause us to waste away, right?

And we are sort of wasting away in the context of a weight loss diet or in the context of intermittent fasting. So then the ketones come into play when we're in a calorie deficit like I said, but also when we're doing time-restricted feeding, I think the ketones provide an anti-catabolic effect. But from our perspective, we're super interested in ketones preventing age-related sarcopenia, skeletal muscle wasting associated with cancer cachexia. I think that's important. And they're doing it I think not only providing in the context of a disease phenotype or a chronic aging phenotype, the alternative energy function is there, but the anti-inflammatory effects, I think.

So with cachexia, for example, you have a high elevation of like IL-1 beta, TNF alpha, which used to be called cachexin I think as inflammatory media. So, the ketones then work through anti-inflammatory pathways that can mitigate the inflammation-induced muscle wasting associate. So we did a study with lipopolysaccharide, LPS. So LPS causes massive, you know, muscle wasting and sarcopenia with time. And in that model too, the ketones are protective in some ways by inhibiting some of the anti-inflammatory...inhibiting the inflammatory effects of LPS.

Dr. Patrick: Do you think that...? People that aren't, for example, in a constant state of ketosis because they're on a ketogenic diet, but perhaps they would like to take, you know, a supplement, ketone salt. Do you think that's something that...like the chronic elevation or the constant constituent elevation of these ketones that's important or little bumps throughout the day, you know, or something?

Dr. D'Agostino: That's a good question. So I get that a lot. And I think chronic ketosis is probably not natural or not ideal for most people unless you're managing a chronic disorder that's responsive to chronic ketosis like epilepsy and other metabolic disorders. But I'm a big believer in relative changes. So, even with intermittent fasting like I think I'm fasting today, maybe I just had some ketone supplements but like yesterday I did. So I only do intermittent fasting probably two, maybe three times a week at the most because, if I did it every day, I feel that I lose some of the benefits of it, I also lose too much weight. Like I can't get enough calories. I end up eating too many calories at the end of the day. So, the body works good. You know, relative changes are really good to the body. So you get a lot more...I personally get a lot more benefits doing intermittent fasting if I use it more intermittently, you know, right? I feel the benefits a little bit more.

So I think the same is true with ketosis. And I think Dr. Valter Longo has a great idea, this idea that... I actually gave it a lot of thought. So it was good to see that he came out, you know, with this idea of the fasting-mimicking diet being implemented for just a one week or five day period, right, per month, and that can have long-lasting metabolic benefits even throughout, you know, weeks to even a month or more after you do that as far as resetting insulin sensitivity and improving different metabolic biomarkers. So I think chronic ketosis is probably not ideal for most situations unless you're doing...you're trying to get your insulin managed, you're trying to lose weight and maintain that weight loss over time, and you've had difficulty doing it with other types of diets.

But I think there's so many different factors that need to come into play when you're choosing to do a ketogenic diet, including monitoring. People really need to track nutrients, track calories. Some people put...you know, they eat a ketogenic diet, but they put the same amount of food on the plate. And the caloric density of the ketogenic diet is like 50% higher. So you can't eat...

So, typically, you know, we have auto feedback mechanisms that will tell us when we're satiated full, but for some people, they don't work well. So they do need to count calories and macronutrients and track at least initially so they have some idea of how many calories we're eating. I know, until I started tracking calories, I had no idea how many calories I was eating. So I thought I was eating more like 3,000, but it was more like 4,200 pretty much every day.