Nov 26, 2018
What’s it take to make a ketone?
Jody: OK, so what’s up. Last night at dinner I saw you guys order the exact same food, painstakingly divide up the olives and cheese and pickles on the charcuterie board, and then 50:50 split a dessert. And you’ve been pricking your fingers and testing your blood. I know you’re both super weirdos, but I feel like there’s something more going on.
Matt: You caught us. So, we have a hypothesis about how we each metabolize ketones differently based on our genetics, and we’re doing a controlled 40 hour experiment where we eat the exact same calories, do the exact same workouts, sleep the same, and basically compare our BHB levels before and after exogenous ketones and also after a workout to look at utilization.
Jody: Oh. that’s like one of the least weird things I’ve seen you guys do, but I do think I’d like to hear more.
Mike: Matt and I have been obsessed about ketones for some time now. First, we were both playing around with ketogenic diets. Actually, I did my first ketogenic diet back in 1998. Lost like 50 pounds, then immediately put 70 back on when I went back to carbs. But then after I got healthy, we both started playing around with ketosis, for its health benefits, not diet.
Matt: Yeah, a lot of people believe that ketones are the glue that hold together the fabric of longevity. Weather that’s true or not remains to be seen, but we at least know that ketones, specifically BHB has a host of beneficial effects for overall health. Alot which mimic calorie restriction.
Mike: Calorie restriction has been shown to extend lifespan in a host of animals. It does this through a reduction in the insulin and the growth hormone/IGF-1 axis which eventually leads to more FOXO proteins in the nucleus and an upregulation of antioxidant production by the cell. Ketones do the same thing generally, we think by inhibition of histone deacetylases that repress transcription of the FOXO3a gene - allowing for more antioxidant production, but because ketones also directly reduce blood glucose and igf, they also affect the GH/IGF axis.
In fact, it may have been the presence of ketone bodies during calorie restriction all along that lead to an increase in lifespan. (1)
Matt: Ketones, administered exogenously in non-human studies have been shown to extend lifespan as well, suggesting they ketones independently have an effect on lifespan, without the need for starvation or a ketogenic diet.
Jody: what are you guys even talking about? I thought we were going to talk about your stupid dieting crap you’re always texting me about.
Mike: Sorry man, maybe we jumped the gun. Matt and I just get so excited about ketones. I can’t help but get to talking about it in depth.
Jody: Yeah, ketones and everything else on this podcast. Alright so the other day I get the text from you with a picture of a blood ketone device and the number 1.9 on it, along with a text saying 24 hour fast + hard bike ride. I could tell you were super proud of yourself, but honestly, I have no clue what youre talking about. I mean, I’m super proud about your fast bike, but that’s not groundbreaking. I remember talking a little bit about ketones in the fasting podcast, what are you doing with monitoring your ketones and why?
Matt: Well, as we got into in the beginning, Ketones appear to function as cellular signals which in essence may prolong lifespan.
Mike: Yeah basically independent of their effect on metabolism and the reduced oxidative stress associated with using fats instead of sugar for cellular energy, they also function on a molecular level to activate portions of your genome to promote longevity through transcription of FOXO3 gene which leads to production of things like superoxide dismutase and glutathione. Two huge players in the antioxidant world. Basically histone deacetaylaces block FOXO3 and BHB blocks these deacetylates.
Jody: there you go again. Can we do this with less biochem and more bro?
Matt: Sure, circulating ketones may be the reason calorie restriction works. I’d like to live forever, therefore, I want ketones in my blood.
Jody: So just go into ketosis, cool podcast over…..
Mike: Hold up, let’s be honest. Ketosis is pretty tough for most people. I’d say the minority, like 2%, can stay in ketosis all the time. In fact I don’t personally know anyone who has stayed in ketosis for more than a few years without at least cycling some. So the question Matt and I keep playing with is:
Jody: Finally 15 min into the podcast to tell me what we’re talking about.
Matt: Yeah, this is super cool. So Mike and I have been playing around with blood ketone monitors. Basically a glucose monitor like where you prick your finger and get a value for your blood ketones. The number will usually be in the 0-3 mmol/L although some people in deep ketosis can crank it up to 5.
Jody: Right, I’m familiar with this to some degree. But I thought you had to be on a ketogenic diet for like 3 days to really drop into ketosis.
Mike: Ketosis is the body’s response to starvation. You can dip into mild ketosis pretty quickly through combining a relatively low carb diet at baseline, fasting, and throwing in some exercise to help deplete your glycogen stores early.
Matt: Yeah Valter Longo’s work on the FMD is basically doing the same thing, just over a longer period of time. Granted, what we’re talking about is bigger shock to the system, but it’s also a lot faster
Mike: yeah and we think, could put you into a spot of ketone production, histone acetylation, FOXO3 activation, and mTOR inhibition much quicker.
Jody: Right, what data do you have to support that.
Mike: Yeah, let's be clear here, there is no data to support this, kinda. Well actually, now that I think about it there is some mouse data. This study in SCIENCE, yes I said SCIENCE from 2011 showed that fasting, CR and the administration of exogenous ketones to human and mouse tissue decreased histone deacetylase activity. IN human kidney cells treated with bHB levels as low as 1 mmol, with an almost linear relationship. Meaning the higher the ketones, the higher to blockage and the more advantage.
Next they tested the theory on live mice through fasting 24 hours (about the equivalent of 3 days for humans) a CR diet, and also with exogenous ketone administration. They found ketone levels of 1.5 with 24 hour fast, 0.6 with CR and 1.2 with exogenous ketones. All levels and methods of increasing bhb at the cellular level lead to histone deacetylation, as well as FOXO3 activation and in this study even helped protect kidney cells from oxidative stress.
Jody: So, what are those empty bottles over on the counter? I feel like they’re relevant to this discussion.
Matt: Yep. That’s 2 25g bottles of ketone esters.
Jody: Seriously, sign me up so basically anyway I can get ketones in my body is the way to go?
Mike: According to this study, I don’t really see a downside. Although there is some evidence that people like me, with PPARalpha mutations may have increased cholesterol production in the face of circulating ketone bodies. I’ve been enacting my plan for some time now, with pretty regular ketone production and exogenous ingestion, and haven’t seen a big spike in cholesterol.
--Personal test N of 1.
Matt: This is super interesting, because I can’t get my ketones as high as you. If I fast all day, workout, and ingest exogenous ketones, I’m maybe at like 1.2. Not the 1.9 you’re getting.
Mike: Yeah could be my cells just aren’t as good at utilizing ketones. In which case, that could make for some pretty nice advantages assuming they still have the histone deacetylase activity. Wow we are way off topic now, and in the realm of fake science. Let’s get back to the pseudo science instead.
Discussion of previous day foods and results
Jody: Yep, Matt, tell me how you do this, whats the protocol.
Matt: So i’ve told you how I eat previously, but briefly, I wake up, have breakfast which is black coffee, cinnamon and chaga. Then skip lunch. Drink a bunch of water. Exercise late morning or midday, then have some MCT oil around lunchtime. Sometimes I’ll take exogenous instead, but that’s expensive, so usually not. If I do, I prefer the ketone esters because I’m not a huge fan of some of the other stuff in ketone salts, and also cause a higher bump in bHB. That’s sort of my lunch. Then I don’t eat again until dinner. The goal, is to deplete glycogen stores as soon as possible to push the liver into fatty oxidation and increase bhb in the blood. That way I spend more time with ketones circulating during the day and get all the benefits we are talking about.
Mike: Similar for me, although I try to workout in the morning. Get that glycogen depleted as soon as possible. The advantage here, as you might notice is that we’re only doing time restricted eating. So still consuming the same number of calories, but getting several hours of ketosis and pumping it up with exogenous ketones to improve the histone deacetylation. The other thing that matter is to have a relative low glycogen store in the first place. You’ll see higher ketone levels sooner if you’re not filled to the brim with glycogen. So a higher fat diet at baseline say 60% or so, along with regular exercise should put you closer to nutritional ketosis and allow you to jump off the cliff a little sooner.
Jody: Ok, so in general, low carb diet at baseline. Start fasting after dinner the night before. Work out the next morning, don’t eat until dinner and take some exogenous ketones in the afternoon.
Matt: That’s one way to do it. Of course you could just water fast for 3 days or do the FMD for 5 days and probably get a similar response, although you may be in ketosis a bit longer.
Mike: Yeah, but the nice thing about this protocol is it allows me to spend more days in doing this. If I do a 3 day water fast or a 5 day FMD, realistically, I’m gonna refeed for a few weeks before doing it again. With this protocol, I can get away with this every other day. Thats a lot of time with ketones, granted not as much as long term keto diet, but a nice alternative, especially for someone like me to cannot tolerate ketosis with my genetics.
Jody: So what sort of exercise are you guys doing.
Mike: My preference is HIIT stuff. I want glycogen depletion, so I I’m going for intensity. Studies have shown that work near your VO2 max or lactate threshold deplete glycogen the fastest, to the tune of 5 x faster than easier slower efforts. (3) If you think about it physiologically you get 32 mols of ATP for every glucose molecule during aerobic exercise versus 2 mmol of atp for every glucose molecule from anaerobic exercise. Thus for the same cellular energy usage, you burn way more glucose with anaerobic exercise. So interval anaerobic efforts should burn way more glycogen than a slow easy talkative aerobic effort.
Matt: Furthermore, HIIT has also been shown to improve basal metabolic rate for hours after exercise leading to even more glycogen depletion.
Jody: How about the exogenous ketones. You guys mentioned esters and salts. How do I know which one to buy.
Matt: That’s pretty easy, how rich are you.
Jody: like in pesos?
Matt: Exactly, you’re probably buying the salts then. They are way cheaper, like maybe a 2-3$ per serving, but have a ton of salt in the form of sodium, potassium, and magnesium. They use the salts to stabilize the ketones. They are pretty salty, but not too bad tasting. Many of them come with some MCT power as well, which you may or may not want. Technically the MCT is breaking the fast, , but you should still have a relative uptick of ketone levels - which is out goal.
Mike: Yeah, I’m not a fan of the MCT, too much sat fat for me and messes up my cholesterol. You can find ketone salts without the MCT as well.
Matt: And then there are esters. They taste like rocket fuel and cost as much as I paid for my first car.
Jody: that's not much.
Matt: well, per serving, they are close to $30 per serving. But they have about double the effect on blood ketones. Which is hard to argue with. I think basically if money isn’t an issue, esters are the way to go, although there have been some concerns about contaminants.
Jody: Ok, so to summarize:
Wake up fasted and continue with some black coffee and water, exercise sometime in the morning with a long HIIT workout to deplete glycogen. Drink plenty of water, and down some ketones after your workout to bump your ketones back up. Esters are best, but salts are cheaper, with or without MCT in them. Then stay fasting for the rest of the afternoon, and eat dinner. This should get your blood bHB to at least the mmol range and should be causing some histone deacetylation, activation of antioxidant, life prolonging genes like FOXO3 as well as improving your insulin sensitivity, and spending more time with inactivation of the GH/IGF-1 axis which can prolong life as well.
Mike: You got it. So Tomorrow, let's all do this together. Jody, you can use my old used finger lancets to check your bHB. Sorry, those things are expensive, can’t have you using fresh ones. Then we’ll report back and record a follow up talking about how we felt and how high we got our ketones and thus our FOXO3 activation.
Dudes prick their fingers(!!) and discuss results