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.   Intro music [1:33 -3:17] 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) [3:17-5:15] 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. [5:15-7:48] Jody: there you go again. Can we do this with less bioch