Peter Attia· MD
so the question is I think it's a little hard to tease out how much of that benefit is in the cardio metabolic side versus otherwise the other thing that's really challenging and studying humans is we don't have really good prospective studies in anything that resembles a longevity phenotype so you are now stuck using something I think I recently described as the most servile trash ever shat into civilization which is epidemiologic questionnaires to try to impute based on you know you telling me how you've exercised over the past 10 years how that's going to predict your longevity phenotype and again the problem there is the dose matters the specificity the quantity the quality these things matter and they're very difficult to tease out from these retrospective views so I think the evidence is very compelling that exercise matters and that's maybe less the question I'm interested in I think what I'd love to gain insights into and we may have to rely on non-human models is just as we now can tailor a drug to do something very specific can we tailor our exercise to be as optimal as possible so if you took an individual who said Peter look I'm willing to exercise five hours a week or I'm willing to exercise ten hours a week but I'm not going to be a professional athlete how do I take those five hours a week or ten hours a week or whatever it is and make the best use of it to impact all causes of mortality meaning reduction of the risk of atherosclerosis cancer neoplasm neurodegenerative disease and accidental death from you know strengthening the exoskeleton so that's clinically the question I'm most interested in as it pertains to exercise but I'm convinced that at the center of that question is understanding the role of exercise in mitochondrial health I think this is a very important piece of the puzzle and certainly much more important than I appreciate it even two years ago I think what you described about these age-appropriate or age acknowledged declines in vo2 max mitochondrial density mitochondrial efficiency Venus o to concentration I think there's something really important there and even if exercise is affecting something upstream that is affecting that at least we have a great proxy through which to measure I think there's going to end up being a lot of really interesting nonlinear dynamics of mitochondria as a function of age as a function of exercise there's a few vignettes I'll share as you probably know if you don't use your skeletal muscle you lose lean muscle mass you lose your mitochondria very quickly how quickly you have measurable defects in the vo2 max after 10 days of hospitalized bed rest and to recover the vo2 max that you lose in 10 days it takes about six weeks or so oh my god yeah I knew it was bad he knows that bad so there's quite a bit of hysteresis over here right quite a bit of hysteresis so it's going to be complex and nonlinear the programs that turn on mitochondria during exercise they're really elaborate and the idea that you replacing it in a pill may end up being kind of naive I think that exercised us so many things simultaneously it's like 17 different inputs into the system and it may be the case that it's only if those 17 inputs are provided with the right dynamics and the write-off rates that you get properly functioning more mitochondria in certain disease states some of the muscle disorders that I study the ragged red fiber that you may remember from your board exams the ragged red fiber represents an accumulation of poorly functioning Moya cond Rhea so I think that if you try to bottle up just two of these factors or three these factors we may be able to produce more malfunctioning mitochondria but it could be the case that we've evolved to require 17 inputs provided at the right time and place in order to get proper might of biogenesis it's a really really smart program this ptc one alpha program because it simultaneously turns on mitochondrial biogenesis while also turning on some of the tofu g programs and so you're actually turning over your bad mitochondria while you're turning on your good mitochondria simultaneously and that's what happens with exercise well let's you read my mind and I don't know if you could read my little notes I'm taking over here because as we're talking I'm making little notes of things I want to ask you and that's exactly where I wanted to go which was let's talk about what etaf AG means in the context of mitochondria so people who listen to this podcast know that I'm a big fan of fasting periodic fasting because even though we don't have great ways to measure a toff eg clinically I think we have pretty good evidence that periods of really strict fasting meaning exclusively consuming water for some period of time my hypothesis is three to seven days produces meaningful etaf adji but how does exercise impact that based on what you've seen in the mitochondria so I don't know too much about fasting but when you do have proper exercise regimes what we observe is that there are transcriptional programs with multiple inputs some of which we discussed earlier but those are probably not that will basically turn on all 1000 of those proteins to produce more mitochondria but that same program is also saying hey let's turn over some of the previously produced mitochondria so it's a very very smart system it's not gonna just produce more good mitochondria