Episode #386: Longevity Myths- Biological Clocks, GLP-1 Muscle Loss, and What Actually Predicts Lifespan

24:34And for those patients, that means some sort of like diagnostic odyssey of PET scans, CT scans, and perhaps invasive biopsies for cancers they don't actually have. And then on top of that, there's some racial disparities here because the models are generally trained on white people. And while sensitivity appears similar in other populations, the sample sizes in those cohorts were pretty small. So we need to make sure that these tools don't exacerbate the existing access gap in screening due to the large price tag. These things run from like$700 to$1 ,000. So we have a test that appears, you know, statistically like pretty good, but pretty noisy on some other cases.

25:14And when you layer in the fact that the sensitivity for the very early stage one cancers that we actually want to find out, the detection rate is pretty low. The value proposition starts to look a bit shaky. Now, Austin, you've been pretty vocal about the harms of over-screening, kind of alluded to that earlier. When you see these numbers, especially like that relatively high false positive rate, what is your primary concern for the patient sitting across from you who might be wanting a test like this? Yeah, I think it's a matter of managing expectations. and again, this kind of dichotomy that we have of people who are like maximizers who, you know, some people say like, look, I'm an adult, I can handle a false positive and I'm willing to deal with all the complications and I'm like, okay, I mean, I still think we ought to have a conversation about this because there's, you know, some pretty catastrophic potential, they're edge, they're rare for sure but it reminds me of a case study or a paper that was published in JAMA many years ago called the$50 ,000 physical for anyone who's in healthcare who's interested, really interesting story about how kind of a simple in-clinic kind of even guideline-based screening sort of thing led to some pretty catastrophic kind of downstream complications despite everyone having the best of intentions towards their patient and so you know there are certainly those negative outcomes and then there's of course the very also similarly compelling stories of people who say well i got this test and it found this cancer and it saved my life it's like well there's some logical leaps there i won't like push back you know challenge that too hard to your face at least but in my mind i still wonder Well, we caught a cancer.

26:40Was it the bird that flew out of the barn that was, you know, or was it the snail that was never going to kill you no matter what? Or was it the animal that we now have an opportunity to treat and actually meaningfully impact your life? We kind of don't know. We don't have that kind of counterfactual to speak of here. So the idea that we have a test being promoted for screening with relatively poor sensitivity, that is a problem for me because I would prefer a good screening test to have really good sensitivity to tell me that if it's negative, I'm done. I don't need to proceed further. And if it is going to catch something, I would prefer it to actually have pretty good utility for that in the earlier stages when I have the opportunity to intervene.

27:18It is not going to be as useful to diagnose a late stage thing when I already have other methods to diagnose the late stage things like a biopsy for cancer that will tell me what this cancer is when it's at its late stage. And then that can inform my prognostic discussion. So it's almost like the use case for this remains in question for me compared with what we're actually looking for in practice. Yeah, no, that's well said. And I think this is going to become even more important because about two weeks ago, Grail, which is a company, submitted its final module for FDA pre-market approval for their multi-cancer diagnostic called Gallery.

27:53And they teamed up with HIMSS for this. Now, there is an ongoing NHS Gallery trial with over 140 ,000 participants in it. It's the only study that's been designed to show if these tests actually reduce late-stage cancer incidence and mortality at the population level. but the results aren't there yet. So until we see that data, we're basically looking at a surrogate marker, maybe cancer detection, not necessarily a survival benefit, even if it does that well. We've got to be wary of the trap where we find the cancer earlier, but don't actually extend the patient's life. They just get a longer time of being a cancer patient, which, you know, obviously again, managing expectations for somebody who says they can handle it, that can be a challenging discussion.

28:30Totally. Yeah. Sure. It would be nice if we held these things to very legitimate screening test standards and said, hey, show me that this actually improves real outcomes. Yeah. Yeah. So as far as a use case here, I'm thinking about, again, we go back to our first, you know, the first thing we talked about, the biological clock. You got all the traditional risk factors that are known and accounted for, still curious or worried perhaps of either like a personal family history of a particular cancer or something like that. And you have adequate resources financially and, you know, psychologically to potentially manage this.

29:02I guess I could see a use case for this, especially someone's maybe over the age of 50, for example, and again, has that family history. You know, the price point is pretty significant. But I would want to emphasize it's not really a swap. You don't like take existing cancer screens that we have and just, you don't need to do that. You got this blood test, for example, it's more of an add on. There are many other types of cancer screening tests that are have relatively good evidence for that you commonly hear about. So cervical cancer screening, colorectal cancer screening would still want to do those in addition.

29:36So it's not really a swap. And, you know, Austin has some maybe interesting bones to pick with the USPSTF guidelines, especially around breast cancer screening. We'll save that for a separate podcast, but does that seem like a reasonable use case for this? If you were, if you were thinking about it? yeah i would as with many other things i'm like not terribly rigid in these uh in these decisions for patients who are very motivated and have the resources to pursue them as long as i feel like they've been sufficiently informed and are aware of kind of what they're getting themselves into i try not to be like overly paternalistic about these things but rather to like walk with the person through whatever their health journey holds and try to be an a useful advisor to them rather than somebody who's like dictating to them what they can and can't do yep yep well said so So yeah, early detection can be a double-edged sword.

30:23It offers the promise of a cure, but also the risk of maybe unnecessary intervention and workup. As we refine these techniques, the goal remains the same. Adding years to your life and life to your years, not just more time at the doctor's office, even though we're generally happy to see you. Speaking of adding years, we're gonna shift from the lab to the gym. When we come back from the break, we're discussing how to lift for your life in the science of exercise and longevity. This podcast is brought to you by Biggs. At Barbell Medicine, we spent a lot of time talking about what it takes to build a body that can handle high-level performance, but the recovery in the health side is just as critical.

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31:32And of course, the style comes in red, white, and blue. Now, if you want the gear that the medical team behind the world's best athletes are wearing, check out the limited edition Team USA collection. You get 15 % off your first order at wearfigs.com with code FIGSRX. That's wearfigs.com, code FIGSRX. Many people discuss exercise as if it's a single generic pill. Just be more active, they say. But the reality is that exercise is a complex prescription with highly specific ingredients. For example, how much and what type of exercise is best for longevity? And how much does it matter that the person responds to the exercise by getting fitter?

32:10If we can identify specific benchmarks, exactly how much you need to lift or how fast you need to move, we can transition from vague advice to actionable targets that effectively lower your risk of dying early. Now, Austin, we've got so much evidence on medications when it comes to dosing, monitoring, and expected benefits. We know that if we lower blood pressure by five millimeters of mercury, we reduce the risk of major cardiac events like heart attacks by about 10%. Why do you think we don't have anything like this when it comes to exercise? I will gently push back and say, I don't know that it is the case that we don't have anything like this when it comes to exercise.

32:45There is a pretty abundant base of literature around kind of correlational data of dose response and things like that between exercise volume in some data sets, exercise intensity in other data sets, some of which we've actually talked about recently on the podcast, where these things on a sufficiently broad population level, oftentimes using like self-reported data for all the problems that come with that. you know and it's unsurprising that those who do much more and who are able to do more intense generally have better outcomes how much of that is causal from them doing more and doing it more intensely leading to better outcomes how much of it is healthier people can also do those things kind of like the data around depression there's a lot of people who bandy about these papers saying that you know exercise clearly cures depression it's like well how much of it is that extremely depressed people have a hard time doing exercise how much there's probably some blend there's i I would be totally unsurprised to learn that there's some element of causation there, but also some element of kind of correlational, almost accidental association or reverse causation as well.

33:46So I think we have some data on this relating to this dose response phenomenon between volume and intensity and frequency and certain health metrics. I think we would both prefer that it be a little bit more granular in nature and maybe even correlated not just between the dose of exercise and the outcome, but maybe like what are the specific mediating factors between that dosage of exercise and that outcome? What is the thing that mediates it? Does it necessitate a certain degree of adaptation? In which case, like what is the minimum adaptive unit that you need? Like how much of an increase in VO2 max will cause a given health benefit?

34:21because even then we have correlational data between VO2 max and health outcomes, right? But how much of that is causal or how much of it is just like simultaneous? You're adapting in one area and getting health benefits in another. That kind of mediating analysis would be super interesting for like the exercise physiology, like nerds and medical clinicians here. A lot of people don't need that level of granularity, but that would be kind of an additional level that would be interesting to have. Yeah, I just think of like a tiered approach. Like you'd want more physicians, more healthcare providers, to just more people, generally speaking, not only to be recommending exercise, but doing the correct behavior change counseling to manifest that, right?

34:57So that's like on the floor, gotta do that. Thing two would be, okay, ensuring that people are being adherent and doing those things, right? So now, yeah, that's the second part. Third part is, are they actually getting fitter, right? If we think or find that actual improvements in fitness as measured by VO2 max, various strength metrics or whatever, um, are need to happen in order to improve somebody's health, then we should be monitoring them and have like certain benchmarks. Um, that assumes that's true. So let's dive in here. We know that going from zero exercise to some exercise is probably the most useful transition point, uh, the largest bang for the buck, if you will.

35:36So you go from no exercise to doing, you know, half the current guidelines, you're going to get the majority of your health related benefits from that transition compared to going from, all right, I'm doing half the current guidelines amount of exercise to double. Like it's just, yeah, going from zero to something is, is tends to be a bigger bang for your buck. Uh, and if you hit the physical activity guidelines, um, that's light years better. Your resistance training twice a week, you're doing 20 to 30 minutes of, uh, aerobic training, um, on most days. Um, and the current physical activity guidelines do kind of list out like how often you should do it, the general intensity that it should be done at.

36:13And, you know, things of that nature, but it's incomplete. It's incomplete to me because it has no monitoring and recommendations for dosing adjustments to achieve specific benchmarks. Now, maybe this doesn't matter. You know, if you've ever wondered why so many mediocre personal trainers stay in business, it's because exercise is remarkably hard to get wrong enough that it doesn't work. Unlike a surgical procedure or like a narrow therapeutic index drug where a 10 % dosing error is a catastrophe, exercise has a massive safety margin and a physiological buffer that is incredibly forgiving. You can do a lot of stuff wrong and still get benefits.

36:47I think about this often when I'm in the gym. Still, I think we need to move towards a more precise exercise prescription, one that mandates monitoring the specific clinical performance benchmarks that drive health and longevity. Now, Austin, to me, the current general guidelines seem analogous to prescribing a new medication at a fixed dose for every single patient and then never monitoring their physiological response. In what other area of medicine would we ever find that acceptable? Yeah, it doesn't really tend to happen very much. There's lots of areas in medicine where there are broad-based clinical guidelines of like, here is where you start, right?

37:22That might come to, you know, menopausal hormone therapy, or here's how you would initiate, you know, thyroid replacement, you know, hormone replacement, or here's how you would initiate, here's how you would treat somebody's blood lipids or something like that. But most of the time it is based on, hey, here's the reasonable place to start and then monitoring and adjusting from there to achieve the outcome you want. And that's the aspect of this that you're describing that's missing is we have the general guidelines on like where to start. But if somebody is not meaningfully responding to that, whatever starting dose you end up prescribing for them, it does require some kind of iterative adjustment, trial and error, you know, interrogating what are they doing?

37:59Are they actually meeting the recommendations, what are the barriers, and what dosage adjustments need to be made and how to get the outcomes that we're actually looking for rather than assuming that, oh, if I told them to do the guidelines, quote unquote, whatever that means. And even if they are meeting those guidelines, are they getting everything that we're looking for out of their activity? They might be somebody who's a little bit more physiologically resistant to that intervention, or they may be somebody who's even physiologically very sensitive to it in various ways, for better or for worse.

38:26and so that might require some individualization. A lot of this is a bit more theoretical than it is like strongly evidence-based that ultra-individualized exercise programming will lead to better kind of like risk of death, for example, that would need to be proven, but it is an intuitive concept that is broadly applied in many other areas of medicine and so it's reasonable, I think, at this point to, in a sense, extrapolate it here and say like we should actually try to get people not just doing these things, but like objectively benefiting in some way from them. Yeah, yeah. Yeah. So let's get into this longevity and training discussion.

38:58We think generally about the effects of meeting the current physical activity guidelines on things like mortality, so premature death. So for conditioning alone, meeting the aerobic guidelines by themselves, 150 to 300 minutes of moderate intensity conditioning per week, it's associated with about a 30 % reduction in all cause mortality. For resistance training alone, adding those two days of muscle strengthening exercises provides an independent benefit of 10 to 17 % reduction in premature mortality. And when you do both, but you're looking at a more like a 40 % reduction in risk, this is kind of though where the one size fits all prescription fails.

39:39And when we stop looking at just the activity and start looking at the actual physiological response, maybe like a key performance indicator or KPI for exercise, I think that we can get a little more nuanced here. So the two big ones you're going to look at are VO2 max and strength. And now it's long been said, I'm sure that there are clips of many different influencers available for us to clip here and put them in. VO2 max is the strongest predictor of survival. People have been saying that. People have been saying that. And look, there's data here. the mansager study in 2018 122 000 subjects found that elite cardiorespiratory fitness the top 2.3 percent for vo2 max correlated with an 80 percent reduction in mortality risk compared to the lowest vo2 max and there is no ceiling for these benefits that's important it seems like as you continue to go up and up and up in cardiorespiratory fitness the risk uh particularly from cardiovascular disease seems to go down so generally speaking you could say more cardio equals more better and I'd be fine with that.

40:39But historically strength has been like a secondary to that. And I think even on some of our older podcasts, we've said, look, you know, if you're lifting, if you're listening to this podcast, if you're a Barbell Medicine podcast listener, you're probably doing enough for strength, but that's kind of gotten some new, some new legs that maybe strength is even more important than even us. The, maybe the biggest promoters of strength training in the industry, especially for clinical outcomes, maybe it's getting some, some new, some new legs here. So this 2025 Clinimex data, it's about 4 ,000 people that they looked at, they showed a massive discrepancy between muscular power and muscular strength, where muscular power, relative muscular power, so relative to somebody's body weight, provided it nearly 20 times higher risk discrimination than strength when they analyzed the data.

41:25Now why? Well, it's one, the way they tested these things. Maximal muscle power was measured basically like an upright row. They pulled on a weight stack with a handle on it as fast as possible while they measured strength with a hand grip test. And you're like, okay, which one would like tie in multiple systems of the body in a way that is very predictive of like badness happening? It's not going to be just you squeezing on something real hard. It's going to be you doing some sort of dynamic task that coordinates your body to move quickly and powerfully together. Now, that being said, we talked about that on our last podcast about hand grip strength.

41:59It does seem like low muscular power imparts a very high risk of mortality from this study. They found that individuals with the lowest power production had a hazard ratio of up to 6.9, which if you're not familiar with hazard ratios, I'll give it to you in percentages. That's a 590 % increased risk of death compared to those who are in the highest power group. austin do you think that power really is more predictive than strength or it's just the way that's being tested in a in a research study like this probably some element to both it does strike me that power is probably a really good integrator to your point similar to the way that vo2 max might be a good integrator of like the full cardiorespiratory kind of pathway from the oxygen molecule coming into your lungs from the environment to getting delivered to the tissue and metabolize it integrates things at many levels there and then similarly power integrates the entire kind of like neuromusculoskeletal apparatus in a sense a little bit better than strength and it may even be a little bit more of a leading indicator of disease and decline because it does tend to decay more than strength does the magnitude of effect that we're observing here may be a little bit more impacted by that method measurement because of how poor hand grip strength is but I think that the relationship is very plausible to me I buy that and so you know if you tell me for example, somebody is able to, you know, pick your elite VO2 max performance metric of choice.

43:22And you tell me that somebody has it, I'm like, okay, I feel really good in general about their, about their kind of cardiorespiratory fitness level, whether it's by purely VO2 max or performance metric. Similarly, if you said that their power, whether given to me in terms of, you know, power units, or you told me that this person can power snatch, you know, 315 pounds. I'm like, yeah, Yeah, I think they're good. I don't really need to know too much else about them, right? Yeah, no, that's a good point. Yeah, you'd feel, would you feel similarly as confident, you know, 300 pound power snatch is crazy, right?

43:54Or like, hey, they got a four times body weight leg press. Yeah, I think the power snatch tells me more. Now, there are still other metrics that I would need to know about them, for example, because it's like, hey, what's their waist measurement though? What's their resting blood pressure? What's their hypoxia index, right? But insofar as we're in this realm of like muscular performance for example yeah the snatch tells me more than the than the leg press i think yeah leg press more than the hand grip grip strength but maybe the power snatch even more sure yeah now here's where things get interesting you look at these two massive data sets side by side the numbers are are telling review to max a jump from the bottom of the pack to the elite top two percent resulted in an 80 reduction in the risk of premature death but if we put that in reverse if you have elite cardio and you lose it this same data set would suggest that your risk of death doesn't just double, it increases by over 400%.

44:43Now, if we compare that to the Clinimax findings on muscle power, they found that individuals with the lowest power category had a 590 % increased risk of death compared to the high power group. If we just look at these two data sets, this means that while we have historically called VO2max the ultimate predictor, perhaps muscle power may actually provide a higher risk. Thoughts? That's an interesting argument. I have no other thoughts beyond that at this time. Yeah, same, same. Now, okay, so how about some targets here? So let's start off with elite targets for conditioning. And this is gonna vary by age, by sex.

45:15There's also some thought that like ethnicity also matters and things of that nature. But just generally speaking, if you're a man aged 30 to 45, we want your VO2 max greater than 56 mils per kilogram per minute for a VO2 max test. Or as like a field test, if you went for a one and a half mile run, you could do it faster than nine minutes and 30 seconds. For women in this age demo, it's 48 milliliters per kilogram per minute for a VO2 max and a one and a half mile run faster than 11 minutes. And then as we age, these things change. So 45 to 75 for a man, a VO2 max of 48 and a one and a half mile run of less at less than 11 minutes for that.

45:53And for women in that age demographic, it's a VO2 max greater than 38 and a one and a half mile run less than 13 and a half minutes. So those are some ways to maybe to assess your VO2 max and see how you stack up compared to the elite in at least that data set we were referencing. Now, elite targets for strength and power are not quite as clean. There's not a lot of real data here, especially using dynamic strength like a squat, a bench press, or even like a leg press. In fact, there's really only one data set, and it's only in dudes from the Cooper Institute. Basically, they looked at leg press one rep max and chest press one rep max and then kind of saw how their what risk of mortality did they have over the next period of time.

46:34It looked like for dudes, if they had a leg press of one rep max of greater than twice their body weight and about one point six to two times their body weight for women, we're extrapolating that data, obviously, that that seemed to be put them in the elite sort of strength category. For chest press, it was one and a half times body weight for men and one times body weight for women. Again, noting that this is only data in men and this is one study, it's a lot of caveats here. And that's probably best suited for individuals below the age of 50, whereas when we get older, things are going to change again, just like they did with VO2 max.

47:10And so, again, made-up numbers. I think having a leg press one rep max of like 1.5 times body weight for men or higher or 1.2 times body weight or higher for women, it's a reasonable target. and then for the chest press it'd be body weight so one times body weight for men and maybe 0.6 times body weight for women you could also use relative hand grip strength and to the extent there's data on strength and like longevity there's way more data here than there is on like dynamic strength tests so for example we know that for every five kilogram increase in absolute grip strength that's associated with about 10 to 15 reduction in all cause mortality risk for most adults, a 10 % gain in hand grip strength translates to about three to five kilos improvement in hand grip strength, which places folks into a lower risk category.

47:58The biggest improvements, however, we see are people going from low hand grip strength to normal hand grip strength. There's some improvement from normal to even more trained. Now, this is speculative because as we mentioned in our hand grip strength test, that relative hand grip strength is probably a better marker, mainly because it corrects for the obesity paradox. We know that the single biggest predictor of somebody's hand grip strength is how much lean body mass they're carrying. And individuals with obesity tend to carry more lean body mass. So if we compare this to somebody's body weight, so the kilos they're able to produce, you know, force-wise on a hand grip strength test to their kilos of body weight, we can come up with a ratio.

48:35So the average in the population right now is about 0.55 to 0.6 for men and 0.40 to 0.45 for women. And so for thinking about elite targets, right, what's that top sort of cohort? Let's add 10%. Again, admittedly speculative, but I'm showing my work. You have to start somewhere. I get it. So for men, this would be a target range of 0.61 to 0.66 for relative hand grip strength. And for women, a target range of 0.44 to 0.50. Again, they are speculative, but I think if someone, you know, gun to my head, hey, what are some strength metrics I should be monitoring or targeting to make sure that somebody's getting the most out of their exercise program?

49:15Better than nothing, I think. Although I'd like to see that validated because maybe it isn't better than nothing. Maybe exercise just works so damn well that we don't need these targets. It would be nice if that were the case, but I do not think that it is quite that special. So I agree that giving some general, even if speculative guidance here is better than nothing, but yeah, worthy of further study. Yeah. So that's strength, which, you know, most people measure by low velocity force production, one rep max, stuff like that. Or in this case of a hand grip strength test, an isometric test. But what about power?

49:45There are tests of like grip strength power, how quickly you close the thing and with what force. But for maybe a more practical example would be like a vertical jump. Um, and there's some data out there showing that a vertical jump, um, of greater than 10 inches in men, um, and greater than eight inches in women would put them into like an elite power category based on normative data we have of people in their fifties and sixties. I'm thinking about if I had a 60 something year old who's relatively untrained and they came in the gym, am I testing their, their vertical jump? Maybe. It depends on your eyeball test when they walk in, right?

50:18How do they walk in? What is their, you're already paying attention to their gait speed and how they move and things like that to make that kind of a decision. There are some who might surprise you and then others where it's like you can tell just by the way they move that, yeah, this is not wise. Yeah. Yeah. So those are some targets for like strength, cardiovascular fitness, and power. And I think another thing we need to add here is progress, right? So we have some of these KPIs, but we also need to make sure the person's getting stronger, getting fitter. Because getting stronger works better.

50:45We've got two recent systematic reviews that found a dose-response relationship between strength gain and improvements in both resting blood pressure and hemoglobin A1c, so how your blood sugar has been doing for the past few months. In both reviews, the subjects that gained the most strength reduced their blood pressure and their hemoglobin A1c by greater amounts compared to those who didn't improve as much in their strength or who did so to a smaller degree. We think that there are overlapping mechanisms here contributing both to strength and health improvements, mostly mediated by the mTOR pathway and myokines.

51:20These are little hormones that your muscles produce when you use them, which seems to interfere with or otherwise reduce inflammatory pathways. This is an area of active research at the moment. Similarly, we also know that improving the O2 max works better from exercise compared to an exercise plan where you don't actually gain cardiorespiratory fitness. Similar to the data on strength, large-scale studies such as the Heritage Family Study and subsequent analyses demonstrate a clear relationship between the size or magnitude of the cardiorespiratory adaptation and health outcomes. Individuals who exhibited the largest increases in VO2 max experienced the most significant improvements in their metabolic health markers.

52:01So things like insulin sensitivity, lipid profiles, vascular function. Whereas non-responders, those who performed the prescribed exercise but saw little to no change in their cardiorespiratory fitness, well, they showed significantly reduced improvements in these clinical markers. And for this, we think that the health benefits are intrinsically tied to the actual physiological adaptation rather than just the time spent exercising. probably mediated through AMP kinase because that's the major sort of pathway involved in cardiorespiratory fitness. Yeah. So if we had to come up with some barbell medicine, physical activity guidelines for longevity, I think we'd move past the resistance train twice a week and the due conditioning for 150 minutes at minimum for a week.

52:41To me, that's like the floor, not the ceiling. And for longevity, I think that people need to exercise more, probably more than they want to or even can't in the modern environment. So for aerobic training, I think my target would be moving away from 150 to 300 minutes of moderate intensity conditioning per week, but more towards 300 to 600 minutes. Now, that is admittedly a lot. Admittedly, it is. And at this volume, I think training intensity and how you distribute that matters. So the majority of this work should be done in the 60 to 80 percent range for max heart rate, where you can speak comfortably, but not sing a smaller portion, maybe up to a quarter of the total amount of conditioning that you're doing should be done at higher intensities where speaking at all is difficult.

53:24Um, and you should monitor performance to make sure that you're making progress related to your cardiorespiratory fitness, such as objectively testing your VO two max or testing your one and a half mile run. And for resistance training, two to three days a week of lifting weights is the minimum that usually represents about two hours per week. Uh, for, for most folks who are not listeners to the Parvo Medicine podcast, but for longevity, many individuals will need more training, perhaps another hour or two. And this can be split up into as many sessions as the individual prefers. The weights that are being moved should be challenging, but not maximal for most exercise.

53:59So something like two to four repetitions left in reserve, they should be hard, not maximal. And the exercises selected should target all of the major muscle groups of the body with user preference being the primary factor when it comes to specific exercise selection. Importantly, strength progress should be monitored to ensure the maximum return on investment when it comes to time spent exercising. And we detailed some of those. Now, Austin, to me, these seem like a sort of like treat to target strategy when it comes to exercise. What do you think about that? Yeah, I like the idea. It's something that, you know, reminds me of phrases that we used around blood lipids back in the day, which went away for a while and then kind of have come back to some extent in certain circles.

54:42And same with kind of blood pressure of thinking about adjusting treatments to a particular target that is most clearly causally and or associated with lower risk of complications. So I think it's a reasonable way to go about this as with the drug therapies and those sorts of things relating to blood cholesterol, blood pressure, et cetera, where we had stronger outcome data, it would be nice to have the same here. But I like the idea of setting some kind of a target and tinkering and iteratively modifying and adjusting to try to get where you're trying to go. Yeah. So if you're doing the work, but your benchmarks are not moving, we don't want to label you, but it seems like you may be non-responsive to that specific dose and formulation of exercise.

55:22And in that case, we don't want to keep doing the same thing. We should adjust the prescription just like you would with medications. But that adaptation doesn't happen in a vacuum. If we're moving the goalposts from generic activity to these sort of elite performance targets that we associate with health, we have to address the most contested topic in the longevity and recovery communities, dietary protein. We're essentially caught between two competing biological realities. On one side, you have the argument that high protein, especially that from animal sources, is like stepping on a gas pedal for aging by over-activating growth pathways like mTOR and IGF-1.

55:59And then on the other side, we have this frailty trap where losing muscle mass and power is a much more immediate threat to your independence than theoretical cellular signaling. Between these arguments and the recent changes to the dietary guidelines that have raised the target protein intake, the question is, how much protein should people be eating for longevity? So Austin, before we get into some of the science, how would you even go about answering this question? A lot of it would depend on the person I'm talking to and trying to kind of meet them where they're at in both their level of understanding, knowledge, what their goals are, and what they're trying to accomplish.

56:33There are going to be those who come from a background of either relatively little knowledge or purely from the all I've read everything in the world around the longevity space. And so I'm coming in with a bias towards protein restriction, in which case we might need to discuss like, oh, there's actually some potential benefits to consuming some dietary protein, particularly in a supportive role for the resistance exercise that we just went into great detail on to support the adaptations that we're looking for there. And then we may also, and more likely, in our context, have somebody coming in who is coming from the strength and power athlete world, bodybuilding, et cetera, who is trying to consume very, very large amounts of dietary protein, in many cases, more than they might actually need.

57:16I think that both of us would retain some skepticism that that level of intake would be necessarily actively harming them in many situations, but the level that they actually require is probably less than they think. And through smart substitutions with other types of food sources. And so, you know, it really, as with many of these kinds of patient level conversations, it's just individualized based on who I'm talking to. As far as answering this question on the scientific level, that's like another whole kind of question here that is not really our niche of like, how would I go about designing a research study to answer this question?

57:51Because then you have to start out by defining like, well, how are we defining longevity? And then going through the whole process of setting up a nutritional epidemiological study, which is, yeah, I would defer to our friend, Dr. Flanagan, to help us with that kind of thing. Yeah. It still doesn't absolve us from answering the question, you know, do we need to lower our protein targets or raise them? And so I think we should look at some data and just see the arguments on both sides and maybe we can come to some sort of agreement or consensus here. All right. So the argument for lower protein, the case for protein restriction is built on the nutrient sensing pathway known as mTOR.

58:26Okay, so you eat a bunch of dietary protein, this pathway sort of kicks off and it is an anabolic pathway. And if you're a lifter, you're familiar with this because you're like, yeah, when I lift weights, it does the same pathway to you're very concerned with your mTOR related signaling. But advocates of a lower protein diet argue that chronic activation of this growth pathway via high amino acid high protein intake, especially from leucine-rich animal sources, accelerates cellular deterioration or senescence. Now, this view is backed by significant rodent data where low-protein diets consistently lead to longer lifespans in controlled environments, and proponents of this view suggest that the higher IGF-1, so insulin-like growth factor 1, that those levels, particularly during middle age, are the primary driver of cancer and metabolic dysfunction.

59:16From this perspective, the modern high protein diet is a biological mismatch for long-term cellular health. And for reference, most adults in the United States are eating a decent amount of protein. It's about 88 grams of protein per day or about 1.07 grams of protein per kilogram body weight per day. Now, again, there's a lot of variation here. That's the average. Austin, what do you think about the idea that adults should be eating less protein to live longer? Based on what has been laid out here so far, I take kind of multiple issues with this. The first is that living longer itself is, in my mind, an incomplete goal, like living longer at all costs.

59:53And so there is a threshold beyond which there would actually start to be costs from further and further protein restriction. The other is that this argument so far is based predominantly on mechanistic type arguments, which I think, as we've laid out before, you and I are both a little bit reticent to adopt in our clinical recommendations with great confidence. it might be something that comes up in our conversations but is heavily caveated and tempered when it is based purely on on mechanistic evidence and the last reason is that protein is not one thing and i suspect that the effects of the actual foods themselves is probably of greater significance like everything that comes in the whole food source that you are consuming rather than the fact that you were consuming an amino acid or a chain of amino acids in particular Yeah.

1:00:39Yeah, I think that's well said. And I think when we dive into some of this research on higher protein intakes and how does that correlate, this will start to kind of reveal itself. So there is a 2020 BMJ meta-analysis of 31 prospective studies that found that total protein intake is associated with a lower cause mortality. But this is primarily driven by plant sources. So what they found is that people with higher total protein intake, they had a lower risk of premature death. provided that that protein was coming mostly from plants. So for every 3 % increase in calories from plant protein, that correlated with a 5 % reduction in the risk of premature mortality.

1:01:18It's thought that plant protein signals or may signal longevity more effectively because it typically results in a lower IGF-1 level than animal protein, particularly in sedentary individuals. There's also this weird kind of signal in the data that's related to age, something this transition between like middle age and older age so for adults aged 50 to 65 higher protein intake 20 or more of calories that was associated with a fourfold increase in cancer mortality these are mostly sedentary individuals we're not talking about lifters who are protein maxing for example and there is a risk of dietary pattern confounding basically means like what else are you eating and where's this protein coming from it's not plant-based it's more animal processed processed food, for example, it does seem to disappear with more plant protein intake.

1:02:07But then it shifts. For adults over the age of 65, high protein intake is associated with reduced cancer and all-cause mortality, maybe acting as like a protective factor against frailty, if you were thinking about sarcopenia risk, for example. So Austin, do you think that this age - related change in protein's effects are due to maybe developing anabolic resistance and subsequent sarcopenia risk or it's just like you know an artifact of the data set and it's just you know noisy yeah i think it's super noisy i do not have confident conclusions here um and so i think it's honestly a waste of time for me to speculate a ton on this because this whole body of literature is really complex and nuanced to interpret even though at the same time the conclusions that we tend to draw and how that informs our recommendations is not nearly as as complex.

1:02:56I think that for me, if anything, over the years, my protein recommendations for folks have been revised downward. And I think that that's emerged from a transition from a focus on optimizing kind of musculoskeletal adaptations without really much consideration for much else. And also the fact that a decade ago, our understanding and the body of evidence was more limited compared with where we are now to now having more data to inform these things having a better kind of fund of knowledge around it and then other considerations as well so now i tend to much more often recommend falling somewhere north of 1.2 grams per kilo and i tend to bias it much more predominantly towards plant-based sources and that also reflects my own dietary pattern especially in in recent years i think that we have seen compelling evidence that when people are consuming protein at this dose range of say one somewhere in the range of 1.2 to 1.6 grams per kilo per day.

1:03:52Even if the vast majority of it is coming from plant-derived protein sources, they can get very similar, if not equivalent, musculoskeletal adaptations. They get tons of other health benefits. Those protein sources also tend to come with decent amounts of dietary fiber and other kind of like beneficial plant-based bioactives and things like that. And so that is kind of where things have landed. I do not personally eat a diet that is entirely exclusionary of certain animal-derived food products, particularly dairy, as a very common source in my own diet. But others may obviously weigh and make these decisions differently.

1:04:27But that's been, I think, the predominant kind of shift over the years in terms of my recommendations and conclusions from the available evidence, even though some of these little nuances and interesting quirks and age-related variations, I don't really know what to make of it at this time. Yeah, I'm more just looking at straight up just outcome data, to the extent that we have them. And then just realizing this whole field is much more complex when people say, Oh, this singular factor does X. I'm like, are you sure? Like that's pretty challenging. Um, so I think right now my recommendations on protein, I don't know that they're any different than they were a year ago, two years ago.

1:05:02Uh, if anything, I'm more tolerant of an even lower intake. Like if I was a hard line, 1.6 grams of protein per kilogram body weight per day. Yeah. okay if it's 1.2 like it's fine you know absolutely and i think mainly when people are thinking about protein maxing particularly those who are not training i think i could maybe maybe guess that there are some benefits like okay if you're increasing protein intake and you're displacing previously like ultra processed foods with now more minimally processed or unprocessed protein sources that's probably a net win from an energy intake perspective um otherwise i think if you were otherwise eating like mostly chicken press and fish and eggs and dairy and whatever and they're like should i lower my protein intake i'm like eh or should i raise my protein intake i'm like probably not yeah if anything you could take some of that protein and allocate it towards plant-based sources you get like a double whammy one more plant-based food in general likely to be better more fiber generally better um for people that are not eating that much protein and they're like should i increase my protein i'm like yeah but probably do it through plant-based sources if you can.

1:06:06Otherwise, I just don't find this particularly interesting. I'm like, it's part of this larger dietary pattern that's much more concerning to me compared to, you know, is it 1.2? Is it 1.4? Is it 1.6? Is it 1.8? And look, if you are a highly competitive, you know, strength athlete, physique athlete or whatever, I understand that this whole thing, you don't care. Like you just probably turned the podcast off. But if you still happen going to be listening. I also don't know that there's a risk of eating that much protein. I really, I truly don't, particularly with that sort of dietary pattern. Yeah.

1:06:38Um, you're probably eating a lot of vegetables. We hope you're probably not eating a lot of ultra processed foods and the energy intake is likely correct for, for your goals. And so this isn't meant to mean like you shouldn't eat as much protein. I'm not trying to fear monger. I just think like we probably went a little too far. Yeah. I mean, but the thing is you still hear this from a lot of folks and influencers out there and certain social media personalities who are like, look, you must consume an extremely high dose of protein. Otherwise you're going to have no chance of building sufficient muscle, or you're going to be at very high risk of sarcopenia.

1:07:09And it's like, none of those things are true when you get above this like modest level, because the context of comorbid disease and your physical activity are way more important variables when it comes to your muscle outcomes compared with whether you're consuming 1.2 or 1.6, or if you go up to 2.2 or 3.1 or any of those sorts of things. I think that like we're kind of shifting this to put it in its appropriate level of weighting. If you're going to care about like musculoskeletal health, like the risk of sarcopenia for most people is not like off the charts high compared with the risk of like cardiovascular disease, much higher risk, right?

1:07:44And so, you know, even just by doing a modest amount of physical training, you can avert the risk of sarcopenia, even if you were consuming a relatively lower protein diet, you would be fine from that standpoint. Whereas the converse is not true. If you cranked up your dietary protein, but you were like completely physically, you know, inactive or insufficiently active, I'd be more worried about that person. And so we're kind of weighting these things a little bit more appropriately, I think, at this point in time for what are the actual risks that we're being faced with? And what are the outcome data that we have available to us to inform those things?

1:08:15Rather than like this chain of either mechanistic reasoning or reasoning that ignores the outcome data to say you need protein for muscles more protein is better animal protein is the most bioavailable therefore like eat all the you know ribeye in the world and it's like yeah that breaks apart at multiple levels along the way yeah yeah well said all right well when we come back from this break we're going to talk about the most potent peptide that's trending on tiktok oh god if you want quick break from our podcast because i want to mention today's sponsor caraway now i've been going through the process of moving into a new house and I've been finding a lot of things that I'm ready to replace.

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1:10:23All right, so we are back and we're talking again about the most popular peptide on TikTok. But this is different than what the rest of the influencers are talking about. This one actually has a bunch of good evidence that it does interesting things. and perhaps it is a longevity drug cloaked in obesity treatments, clothing. You've heard about the weight loss and you may have even heard about the sleep apnea benefits, but do you know how these medications affect the heart, the kidneys, the brain, and potentially more? Now, Austin, you work with a lot of people who are taking these medications.

1:10:52Has anyone ever come to you requesting a prescription purely for a longevity benefit? Yeah, so I would, yeah, many, many, many hundreds, probably even getting into the well over a thousand plus folks on these medicines that I've accrued at this point. And the number of people who are looking at this purely through a longevity lens is pretty small. I will say non-zero, a couple. And those really are relating to one of a small handful of conditions that they're most worried about. But a lot of times it is relating to hypothetical neuroprotective benefits. Because I think that, you know, the management and risk reduction for cardiovascular disease at this point is pretty well established, how we go about that, ensuring good metabolic health and blood pressure, lipid control, insulin sensitivity, physical activity, all those kinds of things.

1:11:44And fortunately, many of those same things have benefits across numerous other organ systems to include the brain. But that neurodegenerative disease, you know, is a tough nut to crack in terms of our ability to prevent and mitigate morbidity and certainly premature death as a result of its complications. So that's actually been an area where I've had a handful of patients that I can think of off the top of my head inquire about. It's not one where I have a large body of evidence that I can stand on and say, yes, these drugs or even like microdosing, which is another common question around them, that that will confer that degree of benefit.

1:12:19But it's an interesting conversation to have. Many of these folks, as you can imagine, tend towards that like health maximizer, optimizer, get tons of data, things like that end of the spectrum. Yeah, that makes sense. Now, I think, you know, if we're steel manning the other side of that argument, we're going to set maybe the risks of muscle loss aside. I feel like we have pounded that into the ground. We beat that horse. We're going to talk about it again, to be clear. Yeah, I think we should with some new listeners here as an overblown thing, but go on. We'll set that aside for now. But I think, you know, maybe many people in the general public Like think of drugs like Wegovi and ZepBound and, you know, whatever they're going to call retatratide.

1:12:59They're thinking about these drugs. They're just obesity medications. And so the extent that we're seeing these knock-on benefits on whether it's cardiovascular disease, kidney health, perhaps even cognitive benefit, whatever, longevity, just more generally speaking, well, it's just due to managing the weight. That's the, you know, and then there's this high collateral cost of sarcopenia. It's the muscle loss. It all comes down to muscle loss. And the first thing I should say is none of these studies so far are directly looking at muscle tissue. They're looking at lean mass and fat mass. So effectively, anything that is not fat is considered lean mass.

1:13:34So that's water, bone, any sort of proteinaceous protein-based thing in your body, which certainly includes but is not limited to just skeletal muscle. And so when we look at what would be maybe like a predicted loss or predicted composition of weight loss, you look at dietary interventions alone. So just calorie restriction. And on average, for every pound or unit of weight that people lose, about 75 % of it will be fat mass and 25 % will be not fat mass. Some of that is muscle, but certainly not all of it is actual skeletal muscle tissue. That would be our sort of like line in the sand. Like do GLP ones do way worse than that, for example, and it doesn't really appear so on average.

1:14:20Yes, the step one trial initially, that was the sort of like, wow, they're losing 40 percent lean mass for unit weight loss. But no study since that has shown that that proportion. So it does seem to be a little outlier. Again, you look at the lifestyle only group there and their lean mass losses in that step one trial. And you're like, okay, it seemed maybe like a measurement issue or a population issue or something else. But again, if this signal was reliable and robust, you'd see it every single time. And we just don't. That's thing one. Thing two, what you would expect is, okay, if these people lose weight, right, and they tend to lose more weight with these anti-abesity medications.

1:14:57And so then, therefore, they're losing way more muscle. That would be your prediction. then you would predict at the end of the study if they were to check strength functional status anything like that those would also be decreased they would have a worse hand grip strength they'd have a worse sit to stand they would have worse walking speed and this was actually tested in the semoline study and in fact despite no exercise or at least programmed exercise during the year-long study it got better the people who would have been diagnosed with sarcopenia there was reduced their muscle quality improved and so while their muscle cross-sectional area may have gone down we think maybe they lost some intramuscular fat for example other sort of things that don't really contribute to the muscle actually functioning or maybe in fact corrected by administration of these uh these medicines um and then the third part of this is like your this concern around too much muscle loss comes down to the fact that people will bypass some sort of threshold where they were previously functional.

1:15:59Now they've lost enough muscle mass. Their function has been decreased. They're starting from a higher point anyway. They have more muscle as is. You compare an individual with obesity to a lean counterpart, you know, similar activity levels, notwithstanding, uh they have way more muscle it's just it's not it's not really compared you can't really compare them um does the muscle work as well generally not but they just have more of it and so they're at such they're so far removed for being at risk for sarcopenia due to carrying too little muscle mass and sarcopenia again it's not just the loss of muscle mass it's the loss of muscle function this doesn't really register to me it's like a real risk like an individual with obesity who's appropriately prescribed this medication and monitored.

1:16:46It just doesn't seem like a real risk. I think it's overblown. 100 % agree. Yes, I'm inclined to agree. I also think that part of the conversation has been muddied by the fact that nobody actually, a lot of people making these arguments don't really understand the differences in terms of the terminology used around body composition analysis. So they'll hear lean body mass or fat-free mass or muscle mass. These are all different things. They are not the same thing. There is the water element. There is non-muscle tissue that is also present in muscle, what is being measured and assumed to be muscle mass.

1:17:18That is the fat that's in there that can interfere with muscle quality. And so conflating all these terms into one thing and then saying, oh, people are hemorrhaging 40 % of their muscle mass and then turning, you know, conflating that with the idea that these people are developing sarcopenia left and right and that they're dying prematurely as a result. It's like, these are, these are like logical triple jumps that you're making from one to the other, compared with what we actually observe in reality. Yeah. The last part, and this is more of just another annoyance that happens when you spend too much time on the internet, particularly on social media, where you see talking head clips like this, you may be watching.

1:17:55People claim, well, look, obesity is really just a risk of under muscle. You're just under muscled. And so the risk of losing that muscle, it far outweighs the benefits of losing fat mass. and that is completely opposite to what all of the evidence shows us. Again, not only do individuals with obesity tend to carry more muscle than their lean counterparts, but the muscle is not as protective as the fat is risky. Yes. We do prefer, if you were an individual with obesity, we would prefer that you also are carrying a lot of muscle mass, but it's most important for you to not necessarily gain more muscle, but actually to lose the fat if you were open to weight management at that time.

1:18:33Yes, agree. I think that that is accurate and should be foot stomped a bit more, especially when we, again, find ourselves in these arguments with people. Yeah. Yeah. Maybe just to tie it all together, like why do people care? They're like, well, look, I would never take these drugs personally, and I would never recommend them to other folks either because you should just do it through diet and exercise. One, it's better. We don't have this risk of muscle loss. Two, there's no shortcuts in life. and you get these better habits, all these sorts of things. How does that strike you? I'm looking at your face right now and it's not big.

1:19:09Because I think that now the Threads algorithm just feeds me all of the GLP-1 rage bait that is out there. And that is what all of the things that you just said are most of the things that I see. And I have to disregard rather than engage with because it's just deeply frustrating to hear and to listen to. So the first part of somebody said, I would never take one of those things. It's like, fine, nobody's, you know, you don't have to do it. Like nobody's forcing you to take these things. It's like perfectly okay to not if you don't want to. As far as whether or not you would recommend it to somebody else, I may take some quibbles with that depending on like what is your level of authority?

1:19:45What sort of patients are you advising? What are they coming to you for? Are you a doctor? Whether you are advising or should be advising on anything is in question here. Because if you are not going to advise their use, I have questions about your ability to interpret data here, right? So if, and this is a post that I have been like kind of drafting and editing in my mind for a long time that has yet to really bear fruit just yet. But let's say that these medicines were much more harmful than beneficial. Let's say that they dissolved all of your muscle mass and did not confer any benefits compared with, you know, quote unquote, natural weight loss by regular diet and exercise, things like that.

1:20:27if it had this like net harm effect, we have ample research in randomized trials at this point that should show us those effects. We should see from the multiple different lines of evidence across the numerous different agents, right, that these things are causing harm, that more people are getting hospitalized, more people are falling, fractures, premature death, all sorts of things, and the drugs get pulled from the market. There is not even a signal for that. Now, that is not to say that these medicines are completely have no potential harm, that they can be used carelessly, that they don't require monitoring.

1:21:04All of those things are in fact the case that there are potential downsides that should be weighed against potential benefits for the individual patient. There are dosage adjustments that need to be accounted for. There are monitoring that should be in place. And that is why these things require, you know, care by a physician who knows what they're doing with these medications. But those folks are not honest brokers of information or accurate interpreters of the evidence around it. They hear something about muscle and because maybe their whole world is fitness and muscle, then any effect on muscle that might not be the most favorable thing on earth is catastrophic.

1:21:41Well, fortunately, that's not the case. This is quantifiable. We see improvements in muscle quality. We see improvements in functional status, again, with typical use of these medicines for appropriately selected patients. It is possible to push people's weight loss way too far, but I almost never see that happening. Of course, I work in a practice where we are monitoring and paying attention to people and reassessing them when it comes time for refills and dose adjustments and things like that. But if you take somebody whose BMI is, I don't know, 20, and you put them on a GLP-1 agonist and don't monitor them and their BMI ends up 16, yeah, you probably didn't select your patient very well or there was not enough monitoring or something like that.

1:22:19but the idea that we're taking patients with clinical obesity and pushing them into sarcopenia like left and right is not happening i just need to be very clear about that in practice and so if the argument is that the net harms are exceeding the net benefits or you know that that's how this math shakes out the evidence should show it otherwise you are alleging that there is a widespread multi-center multi-randomized trial multi-researcher conspiracy happening to where they are all colluding to generate ample amounts of favorable outcome data across numerous organ systems, numerous disease states, numerous patient populations, numerous countries around the world.

1:22:59It's kind of, you know, not super plausible. Well, Rockefeller controls all of this. So that's, that's what happened. Now, the truth about GLP-1 receptor agonists and their ilk is that the weight of the evidence suggests they provide protection for a lot of different things that seem to be weight independent or at least have some weight independent effects, especially when it comes to the heart and the kidneys, although there's some more interesting data emerging related to inflammation, potentially some cognitive benefits, and even just longevity more broadly speaking. So with respect to the heart, the SELECT trial showed that in 17 ,000 adults with pre-existing heart disease but without diabetes, semaglutide reduced major cardiac events by 20%.

1:23:43And here's what's interesting because if you were like a you know this is just because of obesity management yeah the benefit appeared almost immediately before significant weight loss had occurred like these sort of risk factors had decreased and there was like a direct cardio protective effect which to me is like interesting like what's what else is this just an inflammation thing right because people say that about statins too they're like well statins work by decreasing inflammation not lowering cholesterol it's like well two things can be true like we can be seeing a benefit from obesity reduction and also a benefit from like inflammation control or even something else we don't even know what we're looking at i don't know how do you view the select trial yeah i similarly to other areas we've talked about on this podcast i'm focused on the outcome and the outcomes being in a net favorable direction is where i hang my hat it's a good thing that we see improvement in cardiovascular risk by whatever mechanism here it would be unsurprising to me if there is a fraction, potentially a large fraction of that mediated by weight-related benefits, but also some that are weight independent.

1:24:46That is not surprising to me. That would not be a novel sort of thing, as you are alluding to here. One of the other areas where it's really interesting that I'm observing this more and more in my patient population are patients with inflammatory conditions and things like osteoarthritis and psoriatic arthritis and endometriosis and PCOS and things like that who have this kind of like generalized inflammatory state and potentially some musculoskeletal aches and pains is improvements in those pains nearly immediately upon initiation of the medicine before substantial weight loss has occurred. And to preempt a little bit of a caveat there that I would make to myself is like, I'm not priming them to expect improvement in pain or, you know, purporting this or putting it forth as a potential treatment for that.

1:25:32It's almost more of like an incidental observation that they are not necessarily expecting unless they have been primed elsewhere. But it's another interesting thing that suggests that there are likely to be some non-weight-related mechanisms of benefit from these agents. Yeah, we saw that in the TRIUMPH-IV study. That's the phase three clinical trial on ritatratide. It was originally on osteoarthritis and pain scores. We saw a massive reduction there, but also weight loss too. So you're like, is this mostly related to the weight loss? Is it mostly related to some other sort of mechanism? Can it be both?

1:26:05Yeah, to your point. Mechanisms, interesting, fodder for around the campfire at the pub, but ultimately are the outcomes good and what are the risks? There was actually another paper by one of our favorites, friend of the show, Dr. Speakman. I don't know if you saw this. It was basically a mechanistic study looking at how semaglutide affected chondrocytes. Those were like the cells in the various tissues around the joint and favorable changes. there with so perhaps that is mediating an effect not just inflammation not just weight loss perhaps some actual like cell level um activity going on there yeah the idea of cartilage regrowth has been like the aspirational goal of like orthopedics uh for decades now and uh there was a signal that that might actually be happening i don't actually know how that would happen but um you know i'm glad there are smart people trying to figure that out yeah well look if you were a bpc person or a TB500 peptide person, you'd say, well, that's, that's what these peptides do.

1:27:02And it's like, interesting, if true, where's the data in humans? And they're like, oh, it doesn't exist. Like, okay. So anyway, we do have this data in humans. Right. Yeah. So maybe, maybe just replace the BPC with the terzepatum. Anyway. So we talked about osteoarthritis. We talked about heart disease. We've mentioned before that there's some good evidence on reducing kidney disease. The flow trial here with semaglutide reduced the risk of major kidney disease by events by 24 % in patients with type 2 diabetes and chronic kidney disease. So you would expect that vulnerable population to see the biggest benefit.

1:27:37Any, you want to take a stab or a prediction on how this would work on individuals who maybe are at risk for chronic kidney disease? Perhaps they have a high blood pressure, for example, like the medication might help. Yeah, I think that the lower the patient's absolute risk is at baseline, the less likely they are to have benefit, or at least the harder it would be to show it. And so like if somebody is at elevated, but still low overall absolute risk of developing this, you would have to have a massive study for a really long time to show a substantial improvement in that risk. But it also depends on like, what does that at risk mean?

1:28:14So if it is, you know, do you know, if they have a history of high blood pressure, then maybe that's indicative of do they have, you know, some metabolic disease that itself would increase their risk of developing chronic kidney disease. Yeah, I would expect some benefit. It would probably be modest at that stage. It's just easier to show bigger effects in people with bigger levels of risk compared with those with smaller levels of risk. So I would expect that if you had a sufficiently powered trial, you might find a signal. It might not be earth shattering for people who are that early, but I would expect to see one nonetheless.

1:28:43Yeah. And for our longevity maxers or health maxers, if you will, it's actually a new study that recently was published showing that a year of GLP-1 therapy can actually reduce the grim age clock. If you remember back to the biological clock, this is one of the second generation clocks that we were talking about. So actually changes the DNA methylation that is picked up on that test. To the extent, again, that affects outcomes, you know, we need some better mortality data, for example, to really correlate that, but look, it's not nothing. That seems pretty interesting to me. And the other thing I would add is, again, not a signal for harm, right?

1:29:26Which who knows what the meaning of that potential beneficial signal is, even if it's a false positive and things are neutral, like, cool, but we're not seeing signals of harm. And because that's the thing is, you know, in these frustrating conversations that I find myself trying to avoid more and more on the internet, it is often people kind of inappropriately weighting the relative benefits and potential risks of these medicines, blowing theoretical or potential risks way out of proportion while underweighting the potential benefits, mainly by saying that, oh, you could instead just as easily lose this weight through diet and exercise.

1:30:03Like if it were truly that easy, then sure just do it right but it is in fact not that easy for the vast majority of people who are benefiting from these medicines otherwise intensive lifestyle intervention we have randomized trials on it they would have shown oh like equivalent success rates right um in terms of clinically significant weight loss that's able to be sustained as long as people are sustaining the intervention in the same way that is not in fact what we observe so you know uh hard to know how to argue with folks in these situations. It's tough. Yeah. Well, we should say it's not all rainbows and roses here.

1:30:35A few different studies have been published recently showing maybe not the effect we were thinking about when it came to these GLP-1 receptor agonist. One had to do with that cancer risk reduction. This was a really hot topic maybe like six months ago. It was like, look, we're seeing a reduction in risk of all these various different types of cancer. And it's like, well, is this mediated by weight loss? Is it mediated by something else? doesn't really pan out outside of the obesity related risk that seems to be the case right now that may change in the future but that was kind of a bummer yeah um i don't have a ton of additional thoughts on this outside of i think that proving cancer risk reduction um in this type of way for example if we do think it's going to be mediated by weight reduction similarly going to need a really big study and it's probably going to need to run for a really long time to detect the signal.

1:31:23And so that initial trial was negative. Doesn't, you know, rule out this possibility for me entirely. It makes me less enthusiastic about it, but I still find that potential outcome plausible enough that I think a more strongly powered study or a longer duration study may show it. Now, what would that turn into on the back end? Let's say it did show something. Does that mean that we just put everyone on these medicines under the idea of, hey, if you're just on it for long enough, then it might reduce your risk of cancer. I actually don't see it gaining like an FDA indication for like cancer prevention anytime in, you know, for in the foreseeable future, but rather again, it may be like another kind of quote unquote off target benefit in people who are otherwise appropriately selected for the use of these medicines.

1:32:01Yeah. And the last sort of a bummer here has to do with Alzheimer's, some other neurodegenerative disorders. The evoke trials were recently kind of published, basically showing that the GLP ones did not really slow the progression of established Alzheimer's disease. Now, reducing the risk of developing Alzheimer's disease in the first place or other neurodegenerative conditions, that's a separate thing from actually like reducing the risk of progression. So we'll be interested to see how data pans out there. But yeah, look, we're not we're not chilling for big pharma here. We're just here's the data and like do with it what you will.

1:32:37I kind of like your approach to this. It's like, look, you asked me to be your consultant. I'm happy to do that. But ultimately, we decide to do is your decision. Yeah. And the, and the evoke trials, my recollection of them was that it was actually looking at oral semaglutide, not any of the injectables. And it was using the ribelsis form. So like the older form of oral semaglutide up to 14 milligrams for patients with early Alzheimer's disease. So I have like kind of multiple issues with that. Like in general, Alzheimer's, like nothing really works for it. We have some medicines that are approved, but yeah i don't really for established alzheimer's disease um yeah we the the older medicines that have been around for a long time trivial benefit the newer medicines i think we talked about some of those the monoclonal infusions i definitely don't love those i'm not surprised that a like low potency low efficacy agent like ribelsus didn't have a significant benefit in an exceedingly difficult to treat condition um i reserve some degree of i wouldn't say optimism but like there's still something there to be studied as far as, again, longer term, more potent agents, longer lead time, maybe for patients who have not yet developed it already, or even potentially more potent agents in people who have, than something kind of crummy like oral, the ribalsis form compared with now more, or newer oral Wagovi or any of the injectables or the increasingly potent options.

1:33:56But yeah, I would never be terribly optimistic about treatment of Alzheimer's disease, at least based on history to date. I don't know that we're likely to crack that nut anytime soon, but we'll see. Yeah. So it seems like we've got some good signals in the evidence, but we don't really have any 30-year trials showing that GLP-1 receptor agonists extend maximum human lifespan. But it does seem like there's something there with respect to healthspan, delaying the onset of disease, particularly in individuals with obesity. Are there any results or any sort of leads there that are more interesting to you than anything we've discussed so far, something that's coming out?

1:34:34I mean I think that by far the most prevalent issue that we observe in the population is just this kind of constellation of actually now what's been termed ckm syndrome right like cardiovascular kidney metabolic syndrome obesity and its effects on all of these different organs like instead of hey I'm going to put you on medicines for your heart disease and then medicines for your kidney disease and then medicines for your fatty liver disease and then medicines for your diabetes. it's like we have something that is truly attacking like the root of this issue and so that's where most of my optimism stands as like the the biggest and most prevalent health problem leading to preventable morbidity and mortality kind of worldwide at the moment you know we've talked about other kind of promising avenues in this space to include some of the ones that to whatever extent you worry about lean mass they're all looking at these agents that are maybe combined agonists of things that will not only promote fat mass loss but maybe accretion or gain of lean body mass or muscle mass.

1:35:26So like a jacked medicine, I think that the fitness industry would really lose its mind when that kind of thing comes around. But essentially, it would turn this into a solved problem if that kind of thing pans out. TBD, we'll see. That's an interesting idea for me. Yeah. Yeah. I think I feel pretty confident saying that these are definitely good for longevity in those with obesity, type 2 diabetes, sleep apnea, particularly if that's a comorbidity and some forms of heart disease, again, especially if they have an obesity as a comorbidity, possibly good for longevity and those without any of those conditions, uh, unclear on, on evidence because mainly it hasn't been investigated in just generally healthy population.

1:36:04They're taking these at a whatever dose. Let's see what happens. I feel confident that the sarcopenia risk is overstated when appropriately prescribed and monitored. I can think of a use case where things would get dicey thinking about a woman in her early thirties, who's trying to lose like five pounds or something. Um, doesn't resistance train and Pilates princess, uh, getting some research chemicals and a DIY sort of situation. Right. And it's like, sure. I don't think she's at risk of quote sarcopenia, like full, you know, the actual diagnosis, but losing some precious muscle mass, she didn't need to lose or couldn't really afford to lose.

1:36:41But yeah, if you use powerful agents inappropriately, like, I don't, I don't know that that was really like a surprise, I guess. Yeah, tools have uses. I mean, that's the bottom line. All right, so that's the story on using GLP-1s for longevity. We'll see how the data continues to evolve and change over time, particularly any notable effects that occur independent of weight loss. But there's another pharmacological lever that people often pull to protect that same muscle mass and cardiovascular health as they age, and it's arguably even more controversial. We've spent this segment talking about the potential metabolic downside of aging, and now we need to look at the hormonal decline.

1:37:20Let's shift gears to the latest data on hormone replacement therapy and whether it actually moves the needle on cardiac risk. Now, Austin, there's a massive wave of fear that still surrounds hormone replacement therapy, or HRT, especially women, largely driven by a misunderstanding of 20-year-old data. You see patients every day who are interested in HRT. Now, are they curious because they heard about this on the news? Like, well, they removed the black box warning. It's good. Or, and if they are, do they express concerns about heart disease or breast cancer risks? Well, I think you're probably talking about the black box warning that was on, I believe, vaginal estrogen products.

1:37:58And most patients that I'm coming across are actually not terribly aware of that as a thing, nor is that really informing them seeking it. more often the conversations around systemic kind of menopausal hormone therapy, that would be things like transdermal, estradiol, or oral forms of estrogen replacement, etc., that can provide benefit for a variety of other symptoms compared with local vaginal estrogen therapy, which is beneficial and essentially has no significant risks and can be used safely in pretty much everyone, which is a big reason why that black box warning was appropriately removed.

1:38:32But the concerns around things like heart disease risk, yeah, they go back decades at this point. And I think that if we are to do our own treatment of the data around the Women's Health Initiative and the implications that had both at the time and for how we should use these therapies these days, certainly would benefit from its own podcast. But that was definitely a different era using different agents and also in a different context compared with the way that they're more often being used now. So what I mean is literally different formulations of the hormones and also in a population that in general was quite a bit older than a lot of the folks who are interested in pursuing menopausal hormone therapy these days among the women that I tend to see day to day in practice now who are interested in it for a variety of reasons.

1:39:16Now, to be clear, the current kind of approved uses or indications of menopausal hormone therapy are only for a handful of things. It includes the vasomotor symptoms, so that's things like hot flashes and night sweats, etc. Those include the genitourinary syndrome of menopause, so vaginal kind of atrophy, dryness, pain, recurrent UTIs, things like that, and osteoporosis prevention or protecting bone health through the menopausal transition and beyond, although that benefit necessitates kind of staying on therapy longer term, which is becoming an increasingly accepted practice. The evidence for benefits beyond those is increasingly slim, even though it is an area of lots of discussion and interest, whether it comes to claims around prevention of cardiovascular disease or prevention of dementia or addressing other symptoms that can be associated with menopause like musculoskeletal aches and pains and improving sleep and mood disturbances.

1:40:09is a lot of people claim benefits of these things. I do not push back or challenge them when they report experiencing these things. I more often frame it as people's experience is pretty individual here. And as long as it is being done safely, I'm very open to trying menopausal hormone therapy for women who may be going through the menopausal transition, whether in quote unquote perimenopause or beyond it, as long as it is being done safely. And there's a whole set of criteria that we use to assess patients and kind of risk stratify them, determine whether they are candidates for therapy and if they are, which type is the safest because there are a bunch of different types.

1:40:43Again, very different from the type that was originally studied a couple decades ago in that original trial. So whether we're using transdermal or gels or creams or patches or orals or vaginal rings or all sorts of other kind of methods of administration, I'm happy to talk about the pros and cons with people individually about those as well as the other kind of complementary hormones that may or may not need to be included as part of their regimen. So in general, it's a hot topic. Lots of people are discussing it. I think that leaning too heavily on data from 20 plus years ago is not wise. And fortunately, things seem to be evolving at multiple levels with patients, among clinicians, and even at the level of the FDA, clearly, because they're paying attention to this and kind of modifying things as we go.

1:41:24Yeah, it is kind of interesting, as you mentioned, that 20-something-year-old women's health initiative. Yeah, it seemed like at the time that it would increase the risk of blood clots, major cardiac events. That's what the data said. You know, you just, I got the studies are in the show notes. You just pull them up and it'll say right there in the conclusions. And yeah, it seemed like, and you can correct me if I'm wrong, when researchers went back and kind of did this like subgroup analysis based on various, certain age ranges in there, they didn't find that signal. In fact, they found like a cardiovascular disease, like risk reduction in a certain cohort, like women aged 50 to 59 within 10 years of menopause.

1:42:08So like a 30 % lower risk of heart attacks and death if they were in that trial. But that's not what the original data kind of like was how it was reported. Kind of an interesting shift. Do you think more people are going to end up on HRT now that this sort of like reversal? Oh, I think they should. I think that only a tiny fraction of women who are eligible to use menopausal hormone therapy are in fact using it. And there are tons of persistent fears about this. I encounter them regularly. In fact, had a woman recently who was still quite young in her 40s, but she had, for other reasons, had to undergo surgery that removed her ovaries.

1:42:42So she was essentially put into what's called surgical menopause. And that is a situation that absolutely requires hormone replacement afterwards. Otherwise, an extremely high risk of osteoporosis developing. And she, presumably because of maybe poor counseling, inadequate conversation from the clinician, was afraid of getting cancer. So she didn't take the hormones. And then I'm kind of trying to, you know, nudge in the direction of, hey, we ought to take a close look at your bone density. And this is something that really ought to be addressed because in a completely other context, I've seen women who are a couple decades older in the hospital setting get admitted for multiple, you know, osteoporotic fractures.

1:43:17And when I take their history, they're like, yeah, I had my ovaries removed in my 30s and nobody ever put me on hormones. And here I am. And I'm like, this was 100 % preventable. It's just decades too late. And so we know that there remains a lot of fear, a lot of stigma around the use of these things. It can be tricky to learn because this is not something that I would say that I received exceptionally thorough training in internal medicine residency. It's something that I had to kind of go out of my way to acquire additional training, education, and experience in being able to use these things safely and to be able to counsel and discuss these risks on an individual basis.

1:43:50So it takes time and effort, but it is ultimately worthwhile to be able to guide people through this kind of like a major transition in life, mitigate their risk of unpleasant symptoms, and also improve their longer-term health outcomes. Yeah. Yeah. I also want to know, are you seeing some tie-ins with like the musculoskeletal system? You talked about, you know, bone density and risk of fracture and falls and stuff like that. But what about actual just like muscle function? You know, because the loss of muscle and menopause, it's not a testosterone problem. Estrogen withdrawal. You know, estrogen is like this shield, you know, has to having to do with muscle cell, not just atrophy, but also just apoptosis and such.

1:44:29And so are you seeing like a signal there where people who are being placed on HRT, they're having better, you know, muscular function and stuff like that? Or perhaps they're more apt to go to the gym, anything like that? Yeah, it's hard for me to draw confident conclusions about like a direct causation there. I think that in general, for example, let's say that there's a woman going through the, you know, perimenopausal and menopausal transition and, and their sleep is just wrecked from like, you know, drenching night sweats and hot flashes throughout the day. And they're exhausted during the day and that impacts motivation to, you know, exercise.

1:45:01And certainly if they're able to maybe limits their, you know, load tolerance, volume tolerance, intensity. And so maybe, you know, if you address those symptoms and they're able to sleep better, rest better, recover better, then they're like more energized and motivated. And so there's like multiple different ways that you could impact the kind of final, what we'll call the final common pathway to like muscle hypertrophy and physical performance. And it's really difficult just like either anecdotally or on a patient by patient basis to draw confident conclusions from this. So this is something that would just require a larger scale research.

1:45:29And I do not feel like it would be appropriate for me to comment confidently on this. Perhaps that is to our own detriment in the medical podcasting influencer space. space. Whereas a lot of people would just spit out hot takes about this and say, well, here's what I observe. And then that becomes a source of, yeah, a lot of discussion, debate, interest, whatever. I would not claim confident conclusions there. I think there's a lot of potential plausible mechanisms of benefit, but not sure. Yeah. Well, and it's not just about the ladies, but also there's some stuff on men here, particularly with respect to testosterone deficiency.

1:46:04Now we've talked at length about testosterone deficiency, low testosterone on this podcast i expect we're going to talk about it more we got a book that talking about it like i can't get away from it it's not possible um but there's some tie-in here between low testosterone testosterone deficiency and heart disease risk of major adverse cardiac events now we think that for most low testosterone and again more appropriately named testosterone deficiency is frequently a symptom um of it the larger picture of what's going on health-wise not necessarily the cause, most notably due to obesity. That's been the biggest change.

1:46:40People talk about like this secular decline in testosterone. It's like, yeah, mostly related to obesity. Now with respect to replacing somebody's testosterone and its effect on a cardiovascular health, there's a lot of interesting fodder around that. But when you look at the actual data, it seems like it's mostly neutral with respect to heart attacks and major adverse cardiac events. there's some signal that there's like this uh maybe metabolic paradox that occurs at the level like with respect to lipids so like ldl goes down triglycerides go down visceral fat goes down all these risk factors for heart disease but hdl cholesterol slightly goes down too on with folks who are taking testosterone replacement therapy and oh by the way there's no real outcome data like long term on this how do you how do you view um you know testosterone replacement therapy in an individual testosterone deficiency with respect to like cardiovascular disease trajectory?

1:47:37Yeah, I think we should look at this from a few different angles. One is, well, the historical or more traditional perspective would be, oh, this significantly increases risk. And I think that we have increasing data that would challenge that position at this point. That again, when it is appropriately used and monitored, that we do not have evidence that it is, you know, causing people to drop from heart attacks left and right. That is fortunately not the case. So that side of the equation or of the curve is reassuring to me. The other side being, well, if it is not causing harm, that's great, but how confident can we be that it is directly leading to benefit?

1:48:16And that is where I am a bit less confident. I think that we have a fair amount of evidence indicating some essentially like neutral effects. We have association type data that is suggestive of benefit, meaning that when they look at kind of in an observational way, looking at those who are on testosterone therapy versus who are not. Those who are on might have lower cardiovascular risk, but that is not nearly enough or strong enough data to conclude that the testosterone therapy itself is what is lowering their risk. There is still all sorts of both measured and unmeasured kind of biases in those types of data sets to where the people who are put on are fundamentally different from those who are not.

1:48:53And that could lead to a big part of those differences. So we do not yet have what I would call a strong prospective like randomized trial showing that like putting men with testosterone deficiency on testosterone therapy like directly leads to a reduction in their risk of having incident cardiovascular events or cardiovascular death if we had that that would be you know earth-shattering that would be a pretty big deal but we do not have that at this point so that caveats or is kind of how i couch the conversation i think that to your point that in the developed world, if we want to call it that, the vast majority of, you know, situations where we see testosterone deficiency tend to be in association with metabolic disease.

1:49:33And so we also see that addressing that metabolic disease by way of lifestyle measures, through GLP-1 receptor agonists, through metabolic bariatric surgery, we tend to see improvements in blood testosterone levels when people lose weight through whatever means. Whether that is enough to fully resolve their testosterone deficiency is variable. Some people will normalize their testosterone levels, others will not and for those who do not who may have clinical symptoms that still are suggestive of testosterone deficiency totally reasonable and in general quite safe unless they have some other contraindication that hasn't been brought up yet to try them on a course of testosterone therapy and it does not necessarily need to be oh if i give you your first dose you are on this for the rest of your life like it is actually okay to trial it see if they get benefit and if not there is a reasonable early time frame in which you can stop it and not lead to a significant risk of like permanent HPG or testicular suppression.

1:50:26And so that's a, I think a pretty reasonable, safe approach to take if somebody has like maximized the lifestyle levers. And if they've, you know, been able to lose as much weight as they're able to through those means or through pharmacologic means, or if maybe they do, or don't want to go through metabolic surgery, and you want to try it, I would not promote the use of it to say, oh, this is going to be used to lower your heart disease risk because I don't have a ton that I can hang my hat on there. But it can be something that, hey, this can improve your overall quality of life potentially in a similar way to how I have that conversation on menopausal hormone therapy.

1:50:57Any benefits on other stuff like cardiovascular risk are as yet unproven. And so that's kind of how I have that conversation. Yeah, no, well said. So for women, if you're a candidate for hormone therapy, the benefits for like vasomotor symptoms like flushing, bone density, and genitourinary syndrome of menopause likely outweigh the risks. Big benefits there for those things. Other cardiovascular health and muscle preservation benefits remain hypothetical, mostly unproven, but interesting. You should consult with a clinician who's familiar with this and who can discuss your specific case. Both the Dr.

1:51:32Barakis are available for this. Link that in the show notes. For men, testosterone deficiency is often a symptom of underlying disease, most commonly obesity, as you mentioned. Addressing overall health may be sufficient to restore testosterone levels to normal. Um, if testosterone replacement therapy, TRT is indicated, it seems to improve risk factors related to heart disease, thereby theoretically lowering the risk of having a major, uh, cardiac event, though long-term data isn't currently available. So TBD. Yeah, we'll see. All right. Before we end this podcast, I want to introduce you to something I thought about this.

1:52:04And it's like, look, we're talking about longevity. Doctors Feigenbaum and Baraki, if you were coming up with, you know, a series of markers that you would use for longevity, Are you using biological clock? Are you using telomere length? Are you using high sensitivity CRP? No, we are not. So I came up with the Vital 5, the Barbell Medicine Vital 5. Tell me what you think about this. So at the top, your favorite, blood pressure. Got to measure blood pressure. It's got to be within range. And I can't say lower is better because obviously that's not true. Yeah, not entirely true for blood pressure.

1:52:39But I would be very hesitant to be permissive of blood pressure that's elevated above 120 over 80 for most individuals unless there was a specific reason to kind of permit it to go above that. I'd be pretty aggressive at treating it or managing it mainly because we think there's like this dose-dependent risk. Not only how high is it, but for how long is it elevated. So the sooner we can get it under control and the better controlled it is, the better off the individual. What do you think about that? I think it's a reasonable take when viewed through the lens of this kind of like longevity promotion, because there are certainly, you know, situations I'm thinking about lots of the older folks that I see who are already multimorbid and in the hospital or who are like, you know, on the very later stages of their life for whom this is like not at all a major consideration.

1:53:22And I'm much more permissive and I don't particularly care if their blood pressure is 130 or 140, sometimes even 150, because it's like, you know, if you're on hospice, then that is not something we, why are we even checking your blood pressure? So that context matters, but through the lens of longevity, if that's the lens we're taking here, then yeah, we know that risk starts to go up as that blood pressure starts to creep up over, I think, like 115, over 75 or so. That is not to say that necessarily pharmacologically lowering it back down to that level is always going to lead to benefit, but that is just kind of what we observe in a population-wide kind of data set.

1:53:56So if you are one of these kind of like maximizers, then yeah, being stringent lower for longer to that threshold would be wiser. Yeah. So that's our first of the Barwell Medicine Vital 5. Second thing we're talking about here is apolipoprotein B or APOB. I could have just put standard lipid panel and we say non-HDL component. But, you know, look, if I get to make the list. Yeah, sure. I'm going to do a better job. So apolipoprotein B, mainly because this represents your atherogenic load as far as a single test goes, you can do that. And similar to blood pressure is another dose-dependent relationship between this risk factor and cardiovascular disease.

1:54:35The higher it is and the longer it is elevated for, we think that incurs more risk. Now, this is a probability-based thing. We think that if we lower it, generally speaking, lower is better unless you've developed a medical condition that lowers it for you, in which case that is more problematic. but generally speaking, lower is better. And this would be another part of the Barbell Medicine Vital 5. What do you think about that? Also fair. And similarly, the context of lowering matters and how aggressive you choose to be is a very individual decision in terms of maximizing lifestyle stuff versus the use of single agent pharmacology, multiple agent pharmacology, and should also be couched in the context of your overall risk.

1:55:13You could have also made an argument, of course, as many people may, to include a lipoprotein little a here. I'm also in agreement with you of not including it here if we're just being limited to five. For several reasons, the ApoB particle burden in our bloodstream drastically outnumbers the number of lipoprotein little a particles that we have. The numbers are just so much higher of ApoB. And that is currently the focus of therapy. As we mentioned, I think on a recent podcast, we actually don't even have the randomized trials yet on lipoprotein little a lowering therapies. And so that remains an unproven thing.

1:55:45Once that is proven one way or the other, then we'll have more to say on that topic. But I agree with excluding that for now. All right. So we've got blood pressure, got apolipoprotein B for first two. They're not in any particular order, but number three is VO2 max. I think, look, if you're going to go through the trouble of getting things measured and you want sort of actionable insights on what's next, I think having a VO2 max is a reasonable test to be done. Now, whether you do it in a lab, you know, hooked up to a metabolic cart or you just do a one and a half mile run or the 12 minute Cooper test or whatever, all of those things would be fine.

1:56:17to get you in the right ballpark to see, hey, do I have an average VO2 max? Is it below average or is it nearing elite? And we would try to push people who are able to, to get closer to elite, because we think there are continued benefits above just doing the exercise, just meeting the guidelines, going beyond that and making sure that you're achieving the actual elite level fitness relative to health. Um, as far as that's possible for a person, what do you, what do you think about that? Yeah. Uh, I would just pick a performance test if it were me, but I'm more of a pragmatist in this than somebody who wants very specific data points like a proper VO2 max measurement.

1:56:52And so I would say if you want to pick your performance test of choice among those you listed and try to PR that, then go for it. Sounds great. Yeah. It moves us on to our fourth factor here on the Barbell Medicine Vital 5, relative strength. I think we've hemmed and hawed about absolute strength levels. Like, do we care about your absolute grip strength? Maybe it's relative grip strength. Do we care about your absolute leg press one rep max? Or should it be relative like a body weight multiplier and i think we just need a good sort of test for your musculoskeletal and neuromuscular systems being integrated together in a functional way some sort of functional test i don't think a sit-to-stand test is going to be useful enough for a young healthy you know otherwise healthy population who's interested in longevity right and i further i think that test generally speaking is not as predictive as we'd want it to be as far with like for an intervention point it's not a great screening tool it's like you can identify folks who already have sarcopenia, for example, or poor function, but it's like the change in very maybe small changes over time, less noticeable until it becomes, you know, frank and overt.

1:57:56And at that point, you might not have even needed the test. So what do you think about this? Yeah, I think it's a late indicator. I mean, there are other examples of this in medicine, like a hemoglobin A1C, for example, is a late indicator of insulin resistance. By the time that that gets up over the threshold to diagnose diabetes, the insulin resistance has been present for over a decade in most people. And there are other potentially more sensitive metrics to catch this earlier on that, you know, we'll probably discuss at another time, but that this would be an example of that by the time the sit to stand is abnormal.

1:58:25Yeah. That's a, that's a late stage indicator compared with other potential tools. Yep. All right. So that's the first four of the Barbell Medicine Vital 5. And the last one, this may be surprising to you, but I needed something for body composition. um didn't feel like bmi fit the bill i didn't think that waist circumference fit the bill and it's like can we just put these things together and have like a joint metric oh that does exist and we call it the body roundness index now look the the name needs work to be clear needs to be workshopped change it right i don't think anybody wants to have their body roundness index assessed might be more inflammatory than just than bmi generally speaking but like some decent data available on this so far, not as much as I'd want, but I think reasonably it tells people, are you at risk, uh, based on your, not only the amount of body fat that you're carrying, but where it's located.

1:59:16And that's really, really what I want here. Um, does that strike you as totally like, look, you should have picked something else. This is stupid or what do you think? I think it's a reasonable argument. And you also preempted somebody who might have said, well, why don't I just go get my body fat percent tested? Because the distribution is something that you actually care about and want to have captured in your metric. So I think that's a reasonable choice if you can get an mri or a ct that can otherwise tell you how much visceral adipose tissue you have and you are okay in the case of a ct with villain being exposed to those receivers of radiation more power to you but i'm like we could just do this based on measurements and get close enough yeah no i think that that's fair the only thing that i see you know that um you you might want to think about some sort of assessment for which i'm not the expert to provide that would be some metric of like psychosocial health and functioning totally how many friends do you have exactly when was the last time you went outside yeah look we're starting the clock 60 seconds name as many friends you could call right now they pick up their phone yeah there's some sort of mark yeah and interestingly this is probably bad for business but like the total cost on these tests on apolipoprotein b is what like you know maybe 75 bucks 50 bucks not even yeah so yeah we're gonna be selling our barbell medicine vital 5 screening test it's 50 bucks yeah right get a blood pressure check get the get the lipid check do a performance test for strength and conditioning and then body fat assessment pretty straightforward that'll take you quite far in this game and then have some friends that's the hard part for wow nailed it nailed it love that all right well that is a wrap on the barbell medicine longevity podcast at least part one we'll see as stuff comes down the pike i'm sure we'll get some feedback on this before you guys go anywhere please leave us a five-star rating and a review it really helps drive traffic to our podcast so we can keep bringing you all the latest nuance and health and fitness.

2:01:03Special shout out to Dr. Austin Brockie for joining me today. Catch you next week and every week right here on the Barbell Medicine Podcast.