The Critical Factors of Healthspan and Lifespan [transcript]

Written by Christopher Kelly

Nov. 20, 2018

[0:00:00]

Tommy:    Hello, and welcome to the Nourish Balance Thrive podcast. My name is Tommy Wood, and today I am in Austin in person with Dr. Peter Attia who has been held at gunpoint or more accurately, at F1 Paddock Pass point to come on the podcast. Peter, thank you so much for joining me.

Peter:    Oh, man, thanks for having me.

Tommy:    We're going to dig into the whole healthspan, lipidology, cardiovascular disease area that you are well-known for. Before we start recording, we very quickly mentioned the fact that Peter is wearing a Mellow Johnny's hat. That's obviously Lance Armstrong's bike shop here in Texas. I was planning to go there with Pete who is a member of the [0:00:37] [Indiscernible] team after we record this podcast. You said you had a few thoughts about Lance Armstrong and all of his history, so I'd love to hear that just to get started.

Peter:    Well, I'm just a huge fan of Lance. I have been since I first learned about him which was in '93 when he won the World Championship Road Race which was incredible. It was basically the second coming of an American cyclist and then followed his story all along, including everything through the Tours and "the downfall" and all those things. I'm constantly and consistently miffed by people's -- I think it's a relatively minor vocal minority, but people who just have this obsession with demonizing him as somehow he is persona non grata in the sport.

    I think, honestly, the single most ridiculous thing in the history of all sports is that somehow he was stripped of his seven titles when it is so abundantly clear that from at least 1991 through probably 2008, certainly 2007-8, there was basically just the high octane era of cycling, and a number of those cyclists have very readily acknowledged their use of those compounds and yet somehow Lance is the one that's supposed to be erased from the record book while all of these others are not. It's comical to me and speaks to just ridiculous hypocrisy within the sport.

Tommy:    Yeah, how, when all of your peers are essentially doing the same thing, at least the top of the sport, the playing field is fairly leveled. You should be able to --

Peter:    Yeah, and certainly the opponents of Lance will argue, but it wasn't level and US Postal had an advantage and Lance had a higher appetite for risk and all those things. But when you actually look at the details of how much EPO they used and how much they used in terms of blood products, while those things absolutely provided an advantage and without those things, any given team or any given GC contender could not have been competitive; the public, I think, is led to understand or believe that the amount of those compounds that they used were so overwhelming in their ability to enhance performance that they tend to overlook all of the other stuff which is those things don't matter if you're not training.

    It's the same thing with Barry Bonds hitting all of those home runs and Mark McGwire hitting those home runs. Could they have hit 70 or high 60s of home runs without those things? No, they would have been less, but the point is that 10% boost required an enormous increase in effort. It's such a slippery slope to say, well, should we allow drugs in sports? That's not what I'm here to acknowledge, one way or another, because I think that's a much more complicated discussion, but these cyclists in Lance's era which is basically late-'90s to mid-2000s, had far lower hematocrits than just three or four years earlier. When you look at '95, '96, '97, '98, they were running much higher hematocrits therefore getting a much more greater advantage. Yeah, I've always found it to be more about people not liking Lance personally.

Tommy:    Yeah, and there is obviously a personality factor that comes into it.

Peter:    Yeah, and, look, people can say what they want but just be honest about it and say, "Look, we've decided to remove Lance from the record books because we don't like him as a person." At least when you say it that way, you are forced to acknowledge that that sounds a little silly and that's a silly reason to remove someone's accomplishments from the record book who, unquestionably, was, I would say, along with Eddy Merckx, the greatest Tour de France rider of all time.

Tommy:    I think we're probably in quite significant agreement on a lot of that, so that's a nice way to start. Where I wanted to dig into this conversation was your approach to healthspan. I'm sure many people listening to this may have seen you in front of a blackboard with a piece of chalk drawing out graphs of lifespan and healthspan and your framework for the four different areas that encompass that. I think to give a broad approach to how maybe we'd work with somebody to improve their healthspan, if that's their goal, I think that's a great place to start, so maybe you could elucidate those areas and then we can start to dig into how you then actually track and mark those things in people that you're working with.

Peter:    I would say that three years ago, maybe 80% of my energy, intellectual energy, went into thinking about lifespan, how do you live longer, how do you delay the onset of the big three or four chronic diseases and maybe then, ten to 20% of my energy went into thinking about how do you extend healthspan. I think today that has shifted. Today I find myself thinking more and more about the extension of healthspan to the tune of probably half my energy is really devoted to that.

[0:05:09]

    That talk you're referring to -- I know which one you're talking about because there's only one talk I've ever done in front of a blackboard, it's usually a whiteboard -- that was, I've lost track of time, it was a little over a year ago. It was the summer of '17. I've simplified my thinking a little bit because, as you alluded to, I talked about it in four phases. I really think of healthspan now as having three components; a cognitive component, a physical component and, for lack of a better word, an emotional component. Some would argue that that's a spiritual component, and the word spiritual seems a bit loaded so maybe I'll refrain from it.

    The cognitive component has such a strong overlap with the prevention of neurodegenerative disease. On the lifespan side, we think about how do you delay the onset of cardiovascular disease, cerebrovascular disease, cancer and neurodegenerative disease and virtually without exception, the things that you're doing to delay the onset of dementia are also going to enhance cognition. There are going to be some differences, so there are certainly things we can talk about as far as short-term cognitive boosts that we would have no reason to believe would necessarily delay the onset of Alzheimer's disease but can certainly be performance-enhancing, cognitively.

    I think the emotional stuff is one of my favorite topics of all time but generally not one that people want to talk about because it's too touchy-feely.

Peter:    Let's talk about it because I really wanted to talk about the aspects so, hopefully, you'll be willing to dig into that.

Tommy:    Yeah, yeah, sure, if people want to talk about it, but the physical one is the one where I think we have to be the most diligent. That's the one that's easiest to take for granted. Yes, just exercise and you'll be fine, and exercise plays such an important role in the prevention of chronic disease.

    I think where I've adjusted my thinking is now, based on just a little bit more clinical experience and a little bit more discussion with people who are the end of the line, what I've realized is that most of us, myself certainly included, aren't really training with much thought. We don't really have a purpose in mind or we have a vague purpose in mind but it's not maybe what our purpose should be, so probably less than 1% of the population train for a very specific reason.

    We're here in Austin today because we're going to be seeing some amazing F1 racing in the next couple of days. Okay, so Lewis Hamilton has a very specific reason to train. Everything that Lewis does has to be geared towards enhancing his performance in a car.

    My favorite example of this was when you look back at the footage of Ayrton Senna, how seriously he took the conditioning. He would go and run ten miles in the summer, their summer, our winter, in Brazil in his fire suit. That sounds crazy, but why did he do that? Well, if anybody has driven a race car, they know how hot it can be and how uncomfortable it can be.

    So his training took on a specificity that outside of the context of why he was doing it, seems ridiculous. I would never put on a fire suit and go and run in 100-degree weather. There's risk that comes with it, and it's absolutely not serving my purpose, but it served that purpose.

    If you take out professional athletes, you take out college athletes, you take out people who are neither professional nor serious athletes but who have specific goals, they want to run their first 10K or they want to break three hours on a marathon, when you strip all those people out who are training for a specific goal, you have the 99% of us who are training for this nebulous goal of just being healthy.

    That's the problem I now think more about than almost any other problem because I don't think we have a clear sense of what we should be doing to achieve that goal. The way I've been thinking about this problem is through a reverse engineered lens which is the way I tend to default into thinking which is asking the question, what does somebody look like when they're 90? If they managed to avoid getting all of these chronic diseases and they make it to 90, what does their body look like and how can that be improved upon?

    We're too young guys, relatively speaking, sitting here, there are so many things we take for granted. I notice you've got a suitcase here the size of a bed. You take for granted how easy it is to lug that thing around and if you needed to, you could lift that up and load it omto the back of a car or even carry it over your head, I'm sure. Those are some of the things that start to go away and to me, those are the things that I want to understand clearly.

    What does it mean to be able to squat down quickly and easily to pick up a grandkid? What does it mean to be able to stand for a long period of time or walk for a long period of time? What does it mean to have joints that don't ache constantly with both symmetric and asymmetric movement? All of these things that, again, we think are so trivial.

    You can probably carry your body weight, half your body weight in each hand and walk around, like farmer's carry, you can do that with very little effort. That tells us something about the strength in your grip and your forearms that could certainly save your life if you slipped down a flight of stairs and you could easily grab a stairwell. Those things start to vanish.

[0:10:06]

    So what I'd like to spend the rest of my professional career thinking about is how do we train people to be better athletes of life, for the 99% of us who aren't Lewis Hamilton or professional at something. So it starts with, first of all, what are the required things that one must be able to do by the end of life? By end of like, I mean, let's assume that we can really get better at delaying the onset of chronic disease and we can make it to 100, on average. That would be a step function change from where we are today. That's a two-decade extension of life span.

    What has to happen? What do you need to be able to do? I've been thinking through those things. I think everybody should be able to dead-hang for at least 30 seconds, if not a minute. You should have the grip strength to be able to hang yourself. You should have the shoulder stability, the scapular stability to be able to do that. You should be able to do a farmer's carry with a certain amount of your body weight. You should be able to hip-hinge effortlessly. You should be able to do boom-boom-boom-boom.

    Now, think, okay, to be able to do those things at 100, what do you need to be able to do at 40? Because you're going to get less able as time goes on, there's no question about that. An analogy would be, if you're a long jumper and you know you want to jump X number of feet, you can back-calculate how high you need to jump to reach that distance, and that is certainly one of the problems I think most about in terms of healthspan.

Tommy:    Do you have any thoughts on what a minimum effective dose would look like in terms of some kind of training? Because obviously most of the things that you've mentioned are strength-based, so you need some kind of strength-based training. When people knew we were going to sit down and talk, I got a lot of questions about, what does Peter think I should be doing in terms of exercise or that would recommend people do in terms of exercise? Do you have any general guidelines that you would have people follow?

Peter:    Well, I think it goes even broader than just that. There have to be certain metrics you can achieve with respect to strength. There have to be certain metrics you need to achieve with respect to power. Obviously strength and power are different. You'd have to have a certain degree of aerobic fitness, and you have to have a certain degree of anaerobic fitness. You have to have a certain degree of flexibility.

    Again, I'm sure that as I think about this more and more, I will refine my thinking, but broadly, I think about those five categories plus freedom from pain. In many ways there's even a sixth category that goes into sexual function and things like that but also enhance quality of life. But just thinking about it through the exercise standpoint, I don't yet know the answer but there's clearly a level of aerobic and anaerobic capacity below which, quality of life diminishes.

    Now part of it also depends on what a person's objective is. I may want more of myself when I'm 100 than someone who is not that active today anyway. Someone's goal at 100 may be, I'd be really happy to just be able to take care of myself. I'd be really happy to be able to cook my own food, brush my own teeth, wipe my own ass and hang out a little bit with my grandkids. If that's your objective then I think you have a different set of requirements that are necessary to do that.

    I suspect, if I'm going to be lucky enough to live to 100, I'm going to want more. I'm going to want to be able to lay on the floor and play with great grandkids and stand up on my own. That's a very different demand and that's going to require much greater strength and flexibility than if I just want to be able to sit on a chair. I'm going to want to do more stuff, I suspect. I will actually want to get on a bicycle. Now I probably won't be able to put out more than 100 watts or something like that, but I'm probably still going to want to do that.

    I'm going to want to lift weights. I don't know what it is about weight training. I just find it so enjoyable even if it's very brief. Yesterday I was at a friend's house. He had a bunch of stuff in his garage. It wasn't like a big fancy gym, but it's just like heaven on earth to be able to play with the cattle bells and do a bunch of pull-ups and screw around. So that means I'm going to, because I'm going to demand more of myself than maybe someone else would, I will need to do more today.

    I think that any training program that is geared towards this being the best athlete of your life is going to have to focus on specifically training those energy systems. Aerobic and anaerobic are quite different. We're definitely seeing a much bigger push towards anaerobic training because it's certainly more efficient and generally speaking, you can do it in a shorter period of time.

    I think a mistake a lot of people make is they don't appreciate the importance of having an aerobic base under that anaerobic peak. I also think not enough people, myself included, are paying enough attention to patterns of movement that at our age are minor irritants when you're not doing them correctly but become debilitating injuries later in life.

    There are really two type of debilitating injuries later in life. There are the debilitating ones that kill you in a short period of time. While the person is walking, they fall, they break their hip, within 48 hours they're dead because they've fractured their femoral neck, they've got a fat embolism, they die, but the more sinister injuries are the ones that kill people slowly. It's the last ten years of the person's life, they are unable to do the things that they once took for granted.

[0:15:22]

    They can't mow their lawn. They can't tend to their garden. They can't play golf. They can't pick up their grandkids. They can't carry their luggage. You'll spend ten years in decline there and the question is why? What is it that got you to the point where you couldn't do those things anymore? It's so often things like overloading joints at a young age which we tend to do all the time. In fact so many orthopedic injuries are the result of overloaded joints.

    In some cases the answer is "obvious." Someone weighs 100 pounds more than they should, they're clearly going to overload their knees and hips. But a lot of times it's not that obvious. It's patterns of movement that disproportionately put a load to one joint over another. I think that's the interesting stuff to me is how do we figure that out when we're still relatively able to do anything and force the discipline of relearning movement patterns.

Tommy:    There are two points there that I wanted to ask your thoughts on, the first one being the aerobic base. If you look at epidemiological studies, they'd suggest that 30 to 45 minutes of moderate to vigorous activity, and they define that as a 100 steps per minute or more, brisk walking, that kind of level, plus above that, that's where you've reached the diminishing returns area in terms of aerobic performance. Is that enough in your mind or do you see a bigger, more physiological headroom now is going to give you greater healthspan later on down the line?

Peter:    It's such a good question, and I really don't know the answer, Tommy, because the epidemiology is so difficult to truly infer cause and effect from. I can come up with 100 reasons why the epidemiology would show that above a certain level you're going to see not just a flattening of returns but potentially even worsening of returns.

    So there are certainly mechanistic reasons to explain why someone who runs a lot of marathons is going to be worse off than someone who has never run a marathon but who has gone out and run 5K three times a week or four times a week. The two most obvious are the increase we see in atrial fibrillation in extreme athletes. I think that's a real issue. Something much more interesting to me and probably keeps me up at night more is some of the recent data looking at mitochondrial injury in excessive exercise.

    The mitochondria contains proteins, proteins are denatured as temperature goes up and during prolonged rigorous exercise, the mitochondrial temperature goes up. So what happens as the mitochondria get damaged? Well, a number of things do but among them, mitochondrial DNA can leak out of the mitochondria. Now this is problematic for reasons that I didn't appreciate until recently which is that mitochondrial DNA is foreign DNA. It's bacterial DNA. It's far less methylated than our DNA.

    Our body is pretty hardwired. Our immune system, specifically our innate immune system is particularly hardwired to recognize those types of threats. One of the differences between the muscles of you and the muscles of you in 30 years and frankly the muscles of you 20 years ago is the amount of inflammation. As we age, we see more and more inflammatory cells, innate inflammatory cells within the muscle.

    There's a paper that came out a few weeks ago that used a compound that blocks the DNA sensing, and they were able to completely ameliorate that immune response. In other words, suggesting that the immune response was indeed brought on by this defective or leaked or damaged mitochondrial DNA.

    So therein lies your bookends, right? Too much, you run this risk of AFib, which again is, we're probably talking about a 7% risk versus 0.7% risk. There's a log fold difference between the ultra endurance athlete versus the normal person, but there's also this other subtle thing around mitochondrial damage.

    Again, I don't know the answer. All I can tell you is I have generally toned down what I've done. Four years ago, I used to know the numbers, I don't remember, but I had calculated how many hours per week I spent at or above my threshold. In cycling we talk about this thing called FTP, functional threshold power, which is the greatest power and wattage you can hold for an hour. Instead of thinking of it as a number, think of it as plus or minus 10%, so you've got this FTP zone, this threshold zone.

    Because I was competing in cycling, you obviously wanted to spend a lot of time at or above that. It was like hours a week that you were in that zone. Well, now I would say it's much less. Now I would say, if I spend 90 minutes a week above my threshold, that would be, now we're doing Math, but that's probably about all I spend. I probably spend more time below it and fortunately, just having more and more responsibility in life has forced me to become a little bit more efficient with what I do.

[0:20:10]

    There are certain exercises I've just said, I'm not going to do these because, one, the risk of injury outstrips what I think the benefit is and two, I just don't have the time. I have to pick and choose what I'm going to do. So, as important as these questions are, I don't have the answers yet. It frustrates me just on a personal level and at the level of my patients, let alone, anyone who is listening to this who is going, "Shut up, you just tell me the answer." I don't know the answer yet.

Tommy:    I've been thinking about the adaptations to high-level endurance exercise and how that then changes muscle fiber types and the structure of the muscle. If you look at the cross-section or you do a muscle biopsy of, say, a high-level endurance runner, you're going to see a depletion of type 2 muscle fibers, you're going to see an increase in intramuscular triglycerides. All of those things look very similar to a sarcopenic old person in terms of the quality of the muscle. I've asked people though if they have thoughts whether then one is potentially increasing the risk of the other, and nobody seems to have the answer. I was wondering if you have any thoughts on that.

Peter:    I have two thoughts that neither of which offer an answer. The first is it's very difficult to look at static tests and infer a dynamic process. For example, I was fasting last week. I do these fasts once a quarter, and I always do a ton of blood testing, before, during and after. I just got my results back yesterday from the sixth day of the fast, so I'd been basically without anything but water for six days.

    One of the things that I always love to look at is how high do my free fatty acids get? So my insulin was unmeasurable. It was less than one. Glucose is 60 or something like that. Free fatty acids were through the roof, ten times normal. Now people with type 2 diabetes have very elevated free fatty acids as well. In fact on the lab, it gets flagged as a big red box, like, wow, be careful. Of course the context is missing. Of course my free fatty acids are elevated. There's an enormous flux of free fatty acid as I'm undergoing massive amounts of glycolysis to basically stay alive.

    Similarly, when you look at the triglyceride level in muscles, and I'm not familiar with the literature, maybe this has already been done, but the first question I'd want to do is throw some tracers on those things and actually look at the flux of those triglycerides because my intuition is that they are in enormous patterns of movement. Those muscles are utilizing triglycerides at a geometric rate compared to the sarcopenic individual for whom it's probably a much more static pool of triglyceride.

    Similarly, with respect to muscle fiber composition, I think people sometimes confuse the relative percentage of a muscle fiber versus the absolute percentage of a muscle fiber. I'll just throw this in for the person listening who is not familiar with it, or maybe your audience is so familiar with it, at this point, it's irrelevant, but type 1 and type 2 muscle fibers are not differentiated in the speed with which they contract which makes the nomenclature very confusing.

    They're referred to as, type 1 and type 2 muscle fibers, as fast and slow twitch. The speed refers to the speed at which they fatigue, so the type 2 fibers fatigue much more quickly. They are fast to fatigue, hence, fast twitch, but they simply have a greater force when they contract. They have a greater number of motor end units.

    My guess is that while the portion of type 1 fibers is higher in the endurance athlete when you compare that muscle to that of the sarcopenic individual, the absolute number of type 2 fibers is going to be higher in the athletes because great athletes still have a number in absolute terms of type 2, they just don't have the same proportion as, say, a sprinter would.

Tommy:    That makes sense. I think the absolute number is going to be important but you do see with that chronic training. One of the studies that comes to mind is one that Andy Galpin did where he took twins and one was just, I think he was a truck driver, sat and did very much little, and his brother was a marathon runner. There had been a loss or a conversion of type 2 to type 1 fibers in the runner, versus the other guy who still had a larger proportion of type 2 fibers. The question is whether one becomes protective in the long-term.

Peter:    Again these things are so multifactorial that I'd be willing to place all of my dollars that, knowing nothing else, the truck driver is probably going to be at increased risk of cardiometabolic disease because of other things.

 

Tommy:    Of course, yeah, absolutely. So in terms of the aspect of healthspan, I did say I wanted to talk to it, so let's go back to it. In the talk, you mentioned it was purpose and social support, and this stress tolerance now, maybe you're spiritual or however you want to phrase it, for want of a better word, area. Some aspects of this, an interview I did on your podcast, were even more important than cholesterol.

    So maybe we can talk about why that's important and how you then work with patients to improve this area of their life. Because it's often, you might know what the answer is, what this person needs, but getting them to want what they need, getting them to enact those behavior changes, lifestyle changes, relationship changes, how do we start to work with people to be able to do that because that's the biggest part of the work that we do with the athletes and the other people that we work, is all of that stuff has come so much more to the fore recently.

[0:25:20]

Peter:    It's funny you said that. I totally forgot about that. This is an example of why Twitter can be so stupid, why I try to minimize the -- I take a lot of Twitter diets.

Tommy:    To be honest what happens is Twitter occasionally sends me an email about something that happened and then I go on and look at it. This was one of those things because I never log on.

Peter:    Oh, no, I'm not at all being critical.

Tommy:    No, it just happened to pop up in my email.

Peter:    Yeah, and what it was, was somebody made a comment about something I had written or talked about, and it was someone who I know and who is very passionate about cholesterol. He made some comment about, wow, thanks for sharing this other thing, which was much more about happiness.

Tommy:    I think it was Dave Feldman.

Peter:    Yeah, it was. So I just responded by saying, "Yeah, this is probably more important than cholesterol," which is a very sincere comment. Of course all of the LDL-deniers out there were like, how dare you be so disrespectful and mock what he's doing? I'm like, what the fuck are you idiots talking about? I'm acknowledging that there's no benefit to living longer if you're not happier. Anyway, that's why I think one needs to take a very long view of Twitter --

Tommy:    Yeah, absolutely.

Peter:    -- and step very far back from it. Too many people don't have enough to do in life. That said, what I just said is really how I do think about this, and I've been influenced by a number of people, probably chief among them has been Sam Harris who I feel fortunate to be able to call Sam a very dear friend.

    Sam's work on consciousness and meditation has really brought me to think so much more critically about this idea that our state of mind, our state of happiness, the way we perceive and manage our emotions is really the ultimate thing that matters. Without it, nothing matters.

    To live in, cognitive is the wrong word, but mental and emotional purgatory, there is no benefit to living longer. It literally would be torture to extend your life if you were unhappy. Therefore the pursuit of happiness has to be a high priority for anybody who is thinking meaningfully and deeply about longevity.

    Now I think that for some people, myself included, this is a more challenging objective than reducing your risk of cardiovascular disease or increasing muscle mass or things like that because those are skills that some of us have just honed. We have the discipline to "exercise" or eat a certain way or do a certain thing, but it's an entirely new skill to be able to look inside your mind, to be able to reflect on how your thoughts are shaping your emotions and your response to the world.

    Now, I wish I could say I had a great way that I could achieve a meaningful dialogue with every one of my patients. I don't. Patients have to be willing to accept this, so what do I do? I certainly share books that I recommend and talk about these things and because my practice is so small, I have the luxury of, if I'm seeing a patient in the office for an hour, that would be a relatively short visit, so you have that luxury of being able to say, "Okay, what else is going on in your life?"

    There are some of my patients who are very open about that. In many ways those are the patients I can probably help more because they can share with me what's going on, and in many cases I've become quite close to some of my patients. They know what I think about and how I struggle with these things.

    I guess that's the first step is if someone really wants to pursue happiness, which I don't, even for a second, propose to be an expert in, I think this is the hardest of the dimensions, they have to be willing to be vulnerable. They have to be willing to take a step back and say, what am I doing and why?

    You can be the most successful person in the world, and I've seen these people and I've seen people who are staggeringly successful by every metric you could ever imagine and yet they are so unhappy if they're not at least willing to acknowledge that and then also take a step back and say, well why am I so unhappy?

    For example, one of the litmus tests I use is I always have a patient listen to the commencement speech by David Foster Wallace from 2005 at Kenyon College, This is Water, which I listen to about once a week, so I pretty much know that by heart. Maybe not once a week, probably twice a month I listen to it. When someone hears that for the first time, if that has absolutely no resonance, they're probably not ready to go down the next step in the rabbit hole.

    I have one patient in particular who I'm so fond of her. It probably took me six months to even get her to listen to it. She was just too busy. She's like, "There's no way I'm going to spend 22 minutes or whatever it is, listening to that thing. I'm too busy, I'm too busy, I'm too busy." Then I get a call from her one night. It's like 10:00 at night and she's like, "I just listened to it twice, oh, my God." It was like the floodgates opened and she got it. Does that mean she's happy overnight? Of course not, but it meant she finally saw -- she took the, I can never remember the pill colors in The Matrix, but she took the one that basically revealed the matrix, and now she was willing to start to think about all of these things.

[0:30:30]

    Again, here's another example of something for which I don't really know the answer but I feel like I'm sniffing in the right direction which is we have to be willing to be much more vulnerable about our emotions and about our fears.

Tommy:    Does that involve being more vulnerable as a practitioner yourself with the person in front of you? How do you get that connection such that these conversations become more meaningful?

Peter:    I think it does and, again, I think I have the luxury of having such a small practice. I have so few patients that I know things about them that I probably wouldn't be able to know if I had a thousand patients in my practice or something like that. It's not the case with all of them. I think there are still many patients who I have a very formal relationship with them. I am the doctor. They are the patient. Luckily none of my patients call me Dr. Attia. That would be just a bridge too far.

    But the patients with whom I have the closest personal relationship, I also tend to know things about them that I don't think they're even thinking they would want to talk about with their "regular docs," the struggles that they're having in their lives and their marriages, with their kids, things that they're concerned about, just as far as their legacy in life or their work and things like that.

    Yeah, I think that's the most remarkable privilege of medicine. In fact I generally am much more interested in talking about those things than talking about their lipoproteins. Because in some ways, the lipoprotein stuff is so much more straightforward, but this other stuff is the unique stuff. That's the signature of the person. That's where everybody really is different.

    When it comes to the lipids, the lipoproteins, the hormones, I honestly feel like I've seen almost every pattern there is. Once every two months I see something where I'm like, wow, I've never seen that before, and that's the fun stuff from a purely biochemical standpoint, but the interpersonal stuff is remarkable with everybody because truly everyone is going through a slightly different variation of their own hell.

Tommy:    How does this look when somebody comes in as a new patient? You've got your framework you're thinking. It's obviously continuously evolving. Healthspan is the goal, that's an "easy target." How do you apply that framework to an assessment conversations, the testing, the potentials about dietary or lifestyle or other pharmaceutical interventions, as necessary? How does that start to build up as you assess somebody?

Peter:    It's hard because I think so much of that stuff is a function of what they're willing to do, and I have to remind myself that the stuff that I do now and take for granted would have been crazy if suggested to me ten years ago, if ten years ago, somebody said, "Look, all you've got to do is not eat."

    If you look at the way I exercise today versus the way I exercised ten years ago, it's as though you would have told me, "You're never exercising again," it would have been so dramatic given how much I was exercising back then or how much I ate or when I ate or what I ate or all these other things or even the discipline around sleep.

    Nothing I'm doing today resembles what I did a decade ago, and I try to remind myself of that when I'm working with patients to figure out, okay, this is a person who we're going to try to change one little thing. Almost without exception, something "as simple as time-restricted feeding" for a patient who starts out thinking, that's impossible, you mean not eat breakfast, you mean not eat until 1:00 in the afternoon, that would not be possible especially if I have to exercise or something.

    It's just always fun to see how they come back to you in a month and they're like, "Oh, my God, I feel so much better. I can't believe it. I don't feel so tethered to food all the time." There are other patients, by the way, who have done so much of this tinkering before they come to me that they're now coming for the more advanced class and, okay, how do we dial in these things and how do we put in place much more elaborate protocols around eating, sleeping, monitoring of these things?    

    I have patients now that are frankly coming to me on Day 1, they want a continuous glucose monitor, something that would have been unheard of two years ago. I couldn't get a patient to put on a CGM, two or three years ago if their life depended on it, let alone, mine. Whereas today, I feel like 20% of my patients are wearing CGM. Virtually every one of my patients is wearing an Oura ring, certainly at least 80% of my patients are wearing an Oura ring, tracking sleep and starting to see, oh, wow, two drinks really yorks your sleep, eating a late meal at night really jacks your sleep.

    I like thinking about this stuff because it gives me the appreciation that in five years, we'll a totally different discussion about this. There will be so much more to talk about.

[0:35:01]

Tommy:    Yeah. I had a question. It was based on one of the things you mentioned when you did your own Nothingburger test. Why don't we start there. You can talk about what you've done, potentially why you're doing it, and I know you've potentially taken some samples, potentially going to get some interesting data through some collaborations, so maybe you can talk about some of that.

Peter:    I don't have a great reason for why I think this is the right fasting protocol, so I couldn't say that. There are certain principles I think are reasonable. When you span all of the literature on longevity, two things really stand out, which is some deprivation of calories and the use of rapamycin. Those two things just stand out over and over again. No matter how far and wide, how narrow and deep you look into the science of longevity, those two things stand out as really being the only two interventions that have consistently extended life.

    Now, the details of that go beyond the scope of any discussion we're going to have. Luckily I'm writing a book about it so hopefully in a year-and-a-half or whenever the book comes out, the person who really wants to dig into the details can see it, and I've already done a bunch of podcasts on some of these topics. The question then becomes, how can you, focusing on the caloric restriction part of it, apply that to yourself? We don't know.

    It's very important that I use the word we there because I think there's a lot of hype in the space where people are claiming to know the optimal fasting routine and regimen. That's simply impossible. That's like saying, I absolutely, positively know what the organic and inorganic matter look like on Neptune. You can't know it because you don't have a probe that has been able to assess it.

    Similarly, we absolutely, positively do not know what the optimal regimen is for fasting, caloric restriction, dietary restrictions, intermittent fasting, all of these things. We simply don't know it because we do not have a probe that is remotely sensitive enough to measure the things that matter.

    We can measure a whole bunch of crude things, and I've measured all of them, inflammation changes, changes in insulin-like growth factor, all of the hormones' chemistry, metabolic stuff. That's like having a satellite image from several million miles away. It provides some insight, but it doesn't provide the level of granularity that then allows you to even suggest that you know that doing this fasting routine versus that fasting routine, excluding these foods from your diet versus those food is going to prove the best measure of longevity.

    So I have basically two choices. I can say, well I'm going to wait until those probes are developed, but in the meantime do nothing, just status quo. Or I'm going to do my best guess at what I think that looks like and measure what I can measure and keep probing. In the context of the latter, I'm doing something now which is I've just observed, after doing a number of fasts, that something really special happens when you completely remove calories. It seems much more profound when you just reduce calories.

    There is a real drop in glucose and a complete amelioration of variability in glucose in response to almost anything. The reduction in IGF is quite profound, and it seems to require at least three days. For example, would fasting one day a week every year which would still offer 50 days of fasting which is still a lot, would that pose the same benefit as doing, call it five ten-day fasts a year? No, I don't think those are equivalent at all because something really different is happening.

    Just playing that thought experiment, you can very quickly realize that, one, there are literally an infinite number of combinations that always pose as a problem, from a combinatorial standpoint, and, two, you have to put a stake in the ground based on your beliefs. So, for me, I just think that sweet spot has to be north of three days, and I think it has to be a complete fast, water only.

    The frequency with which that needs to happen, I have no clue, but I've certainly noticed, measuring time course of IGF response, that seven days every three months seem to produce a pretty impressive response because I don't think we want low IGF all the time despite what some people believe. I think you want cyclic IGF, and exposure to amino acids plays a big role on that but, similarly, so does exposure to insulin.

    What I would like though is to be sitting here in five years and having this discussion and being able to say, well, actually, now we've also been able to monitor the metabolic profile of autophagy and mitophogy. Because going back to something we talked about earlier, what's going to protect you from that DNA damage, to that mitochondrial DNA damage that is potentially causing this immune response? Lysosomes.

    The more that cells can be protected from those things by putting those damaged organelles that are triggering an inflammatory response, the more those can be put into lysosomes as part of autophagy, the self-eating cell or mytophogy, self-eating dimitochondria, the better off we are.

[0:40:17]

    So until we have a really good dynamic, not static, but dynamic signature for that, which we don't have, we don't even have something close to that right now, then I think the better we can fine tune that. Because, again, it really could be that it's three days once a month is the optimal amount of fasting as opposed to seven days every three months. So this problem and the how to reverse engineer healthspan, are probably the two problems I think most about.

Tommy:    In terms of the satellite a million miles away, there's obviously a number of things that you track in yourself, you'll track in your patients. One of the things that came up that I think was mentioned was the free T3 to reverse T3 ratio and how that changed during your fast.

    The first question was, where does that optimal ratio in your mind come from? The broader question is, do you something similar with all the markers that you use? Because I don't imagine you using standard, mean plus or minus two standard deviation, normal ranges for your patients, so how do you create in your mind better target ranges that are going to get you closer to the goal that you have?

Peter:    You're obviously very familiar with laboratory data because that's typically how they're reported, is plus or minus two standard deviations which, in a normal distribution, is about 95% of the population will be contained within a "normal range." You don't need to spend a lot of time thinking about it to realize that if 95% of the population is "normal" then we have to redefine our statistics of what normal means.

    Unfortunately, to come up with what I think are the right values on all of these things, including lipoproteins and hormone levels, you have to bootstrap it. Part of it is looking back at historical levels. I'll give you one example is estradiol. Estradiol levels are continually inching up and up and up in men. Estradiol, of course, being the second of the three estrogens, so it's E2.

    We understand that extreme levels in either direction, so very, very low estrogen levels or very, very high estrogen levels in men are troubling, well-understood and well-documented, but we don't have a great sense of what the right level is. In many ways, here's an example of looking back in time and saying, well, look, what was a man's estrogen level in the '50s, when, on average, a man was much healthier than he is today. That's a dangerous game to play because there could be a million other factors that contributed to his health, obviously there were, and it may be that estrogen is irrelevant.

    In as much as you have to draw a stake in the ground, you have both mechanistic and epidemiologic data and frankly, at least one really good trial to point to which was in the New England Journal of Medicine, I believe in 2011 or 2012, that chemically castrated a bunch of men and then replaced testosterone with them with Arimidex so you could basically look at ten subgroups of high-low testosterone with high-low estrogen.

    The data from that were quite clear. There was a level of estrogen and a level of testosterone that optimized mood, sexual function, muscle mass and things like that. Again, it's still within the bounds of what's normal, but it allows us to shrink what is normal around a tighter standpoint. That would be an example of how then I would zero in on what I think is an optimal estradiol level rather than just relying on a lab test.

    Similarly, looking at the transaminases, I've talked about this in the past with Rob Lustig, they just keep inching up and up and up. Both estradiol and transaminases, I've seen upward revisions of those in the same lab, three or four times in ten years. So if you believe that the population is getting healthier and healthier then we should accept these upward trends, so be it, but I don't think that's the case.

    Again, I look back to where we were before 1980, what was considered a normal ALT and AST and then that becomes a standard. Some of it is just empirical and some of it is also based on individual patient variations. There are some people who function, perform better with dihydrotestosterone levels that are high versus low. There are some people who, if it's too low, they succumb to side effects that would be unacceptable. So, I wish, I mean, I wouldn't say I wish we just had a standard answer for everybody. That just wouldn't make any sense. It would be easier to talk about though.

Tommy:    In line with that, optimal ranges for, say, lipoprotein, if you're doing a very in-depth analysis, doing some like adrenals diagnostics panel, what about those ranges, obviously because we don't have the historical data just because of the development of the testing, those ranges, I imagine, are generated in the average American population whereby the majority, i.e. 50%, have chronic disease and taken medication for that and are probably pre-diabetic or worse. How do we then translate some of that stuff to the people that you and I tend to work with who probably don't fit that normal distribution?

[0:45:02]

Peter:    Yeah, when it comes to NMR, we basically are drawing most of our inferences at a population level from the MESA population which is the multi-ethnic study of atherosclerosis. Certainly people who would suggest that lipoproteins might not matter in the context of metabolic health, would argue that, hey, all of our data is based on metabolically ill patients. I think that's possible and a little exhausted from the discussion, but I think that's possible.

    The question is, there's an asymmetric risk and reward here in my mind which is, if you're wrong, if having an LDL-P at the 90th percentile or an ApoB at the 90th percentile, in the context of metabolic health, is problematic, you've made a gross miscalculation that was very easy to prevent. Now, the question then becomes, what are the options?

    Again, I think that there's a lot -- it's not quite as ridiculous as the anti-vaccine rhetoric, but there is a really, really odd anti-statin rhetoric out there that, like any drug, these things have side effects but like vaccines, you have tens of millions, in fact you have hundreds of millions of patient years, so patient taking times year duration, of data. It's like cellphones and brain cancer which was a big scare for people.

    I had this discussion with somebody recently, and they were still convinced that cellphones cause brain cancer. I was like, I will grant you that we will never know the answer to this question, but you have to look at signal-to-noise ratio. Given how many people have had cellphones and how many people are on them and all these other things, if there is a true increase in the risk of brain cancer, you're going to see a bigger signal than you see. The question becomes, what is the alternative, is it to never use a cellphone or to only use a headset? Okay, great, knock yourself out.

    When it comes to managing dyslipidemia, of which, by the way, statins are simply one of five or six classes of drugs -- that's the other thing that amuses me in this discussion is everybody wants to fixate on this one class of drugs and frankly look at side effects from generations ago where the drugs were simply not used as much, meaning, where we were using drugs that we, today, don't use as much. I think the question is, be empirical about it.

    There are two, basically, short-term side effects of statins that afflict between five and 10% of the population. If you're a half-competent doctor, you can certainly assess those things and determine which patients can't tolerate -- and I actually probably have even a more conservative standard of that. If I think about all the patients that I've ever put on statins in my life, I would say at least 20% of them, I've discontinued that therapy due to some side effect, which is probably higher than what would be reported in the literature.

    It really, to me, does come down to a little bit of a Pascal's wager. The real tough cases, tough cases meaning the ones where I do think a watchful waiting approach is fine or the patients who are perfect in every way except the lipoprotein is elevated, so you've got an elevation of the lipoprotein, of ApoB in particular -- by the way, the older they get, the more willing I am to avoid treatment.

    I have a patient that I just saw last week, 60 years old, he looks like he's 40. He literally might be one of the most ridiculously healthy, fit 60-year-old you'll ever meet, has a very elevated Lp(a) so with that comes high risk. His LDL-P is also elevated, not through the roof but it's about the 60th percentile. The standard of care for a patient with an elevated Lp(a) is to manage their ApoB to the 10th percentile.

    We've spent three years or two-and-a-half years trying every cockamamie scheme under the sun because he doesn't want to take any medication for cholesterol to try to reduce that. We've never been able to do it. For a day, you might be able to get him down to the 20th percentile, but he just can't get down there. Everything else looks amazing. His oxidized LDL is incredibly low, his CRP is unmeasurable, his homocysteine has normalized, his fibrinogen is normal.

    We finally did a calcium score and a CTA in him, and the calcium score was zero which, again, tells us that over the next decade, the probability that he's going to suffer a major cardiac event is less than 5%. Keep in mind the flip side of that, about 40% of people who experience a major adverse cardiac event have so at an uncalcified lesion. You always have to be able to see both sides of that equation.

    His CT angiogram confirmed that not only were there no calcifications but there were no soft plaques and he had wildly beautifully painted coronary arteries. I also understand that his appetite for treatment is low. So this is a patient in which I said, "Great, man, we're going to just keep doing nothing on this front. I'm more comfortable doing it, but had your CTA shown a bunch of soft plaque or had your"-- we also did an echo on him because I always wanted to do an echo on someone with an elevated Lp(a), or cardiac MRI to look at aortic function to make sure they don't have stenosis. His aorta was perfect, his aortic valve, rather.

[0:50:15]

    That also tells me, maybe he doesn't have a particularly virulent version of Lp(a). Unfortunately Twitter doesn't allow for that level of discussion, so that's why this has turned into a black-white, us versus them whatever nonsense. The reality of it is unless we treat patients, I'm not much convinced you really get a voice on this. Again that sounds very arrogant, but I do get a little put off by all the non-physician rhetoric on this. It's one thing that a non-physician talk about what you want or what you want to do which of course you're entitled to but to start suggesting that your worldview is the right worldview for somebody else when you've never taken medical, ethical or legal liability of caring for a person, to me, is deplorable actually.

    So, yeah, in every case, every patient is an individual, in the risk of sounding cliche, and you have to make these decisions with patients and in the end, the patient's right, meaning, the patient is right for them. In this patient's case, he really didn't want to take medication and we negotiated. If these studies found evidence of disease, it was probably the time to do something about it.

    Now the other end of the spectrum, I have patients, one patient in particular who, he has been so brainwashed by this stuff that it is a tragedy, and this is the flip side to this discussion. He is 57, 58 years old. He has a calcium score that places him in the 90th percentile, so it's virtually all in his left anterior descending artery, plus he has some soft plaques that looked quite unstable in the proximal LAD.

    He absolutely refuses to even consider a pharmacologic intervention. He thinks statins cause every disease that has ever been caused. He might even think they're responsible for global warming. He won't even take a PCSK9 inhibitor in monotherapy because it's another drug. To me, that's a very dangerous -- this is a guy who is, I think, playing with fire but in the end I have to respect his wishes.

    My job is to do the best job I can, hopefully in a nonjudgmental way which I admit, sometimes is hard. Sometimes my frustration leaks out after a year of agonizing over this with him and looking at these results and a number of other results I won't even get into where, with other conditions in him that are quite morbid.

    I can't help but wonder, how much is this guy being brainwashed by the endless barrage of emails he sends me of complete and utter bullshit about this drug. You're guaranteed to get Alzheimer's disease if you take this and anything. It's like, all right. For anyone out there who is spewing that stuff, there is collateral damage, and this patient is going to likely be some of that collateral damage.

Tommy:    In terms of putting that into bigger picture, there's certainly no point debating, LDL particles and the outside of the carotid intima, accumulating, becoming oxidized, being consumed by macrophages. That's atherosclerosis, so they have to go there. They have to then become resident. I don't think there's any debate on that.

    I guess where people are often coming from the other side, that side of the debate is the process there. We know that diffuse wall thickening starts from birth, involves [0:53:25] [Indiscernible] of the smooth muscle cell into the outer layers of the intima. More collagen in the area means you're more likely to retain the particles that go in there.

    What other things might be affecting smooth muscle cell growth, RGF1 or insulin, or what might affect the health of [0:53:41] [Indiscernible] glucose. So if you're somebody who is avoiding all of those things, I guess the question is whether you then trigger that, to a large extent, the atherosclerosis becomes a problem. I know you don't have the answer but can you maybe talk about that.

Peter:    Absolutely. I can't remember if this came across in any of these podcasts that I've done on this topic with either Dave Feldman or with Tom Dayspring or with Ron Krauss. I feel like between those three podcasts, I think I've done my civic duty on all lipoproteins for the rest of my life.

Tommy:    For anybody who has listened to them all, myself included, has done --

Peter:    You've done a fellowship in lipidology.

Tommy:    You've done a fellowship in lipidology. They're fascinating. They're brilliant. I can't deny that.

Peter:    One of the things that people don't understand well enough, I suspect it's just in part, failure on my part to explain it, is what is meant by necessary but not sufficient, sufficient but not necessary, necessary insufficient, neither necessary nor sufficient. These are four different states that different genes and different physiologic parameters drive this process.

    It's very important to understand that I can't think of an example of something that is necessary and sufficient to cause atherosclerosis. Most people are used to thinking of problems through that lens. If you have the gene for Huntington's disease, you will get Huntington's disease. It is both necessary and sufficient. By the way, before I say that, I'm not even positive if there's a way to get Huntington's with that disease but let's assume, for argument's sake, that's pretty straightforward example.

[0:55:14]

    Okay, atherosclerosis doesn't work that way, and that's what causes so much confusion in here. What is the single greatest epidemiologic risk, and I will argue, causal risk for atherosclerosis besides age?

Tommy:    [0:55:29] [Indiscernible].

Peter:    Smoking.

Tommy:    Oh, smoking, sorry.

Peter:    Smoking is actually number one. Okay, so would you agree smoking is a causal risk?

Tommy:    Yeah.

Peter:    Yeah, I think anyone serious about this study would agree that smoking plays a causal role in increasing risk for atherosclerosis and after age, it is the second greatest risk factor. Is it necessary? No. Is it sufficient? No. It's neither necessary nor sufficient. You can have a very strong causal driver of atherosclerosis that is neither necessary nor sufficient. What's the second biggest risk factor? It's a tie between ApoB and hypertension.

Tommy:    If I could just interject, the other question I have in line with all of this is a paper that came out in Lancet Public Health this year, looking at lead levels and median follow-up is 19 years. They attributed, the population attributed risk to lead exposure. Of course lead in your blood may be a biomarker of some other thing in the environment that you're being exposed to.

    If you live in Flint, Michigan, it's not just lead in the water that may be is affecting your health, but the death from ischemic heart disease, they said, is 37 point something percent attributed to lead exposure. Then once you add smoking and lead, that's actually more than two-thirds.

    I'm not saying that those are the main causal things to worry about, but there's a lot of things that seem to stuck up in the environment that then fuels the argument on the other side that maybe if we fix the environment then some of this will not --

Peter:    Yeah, the lead is a little bit complicated because honestly, people who are exposed to lead have so many biases already existing. Lead is an environmental exposure is generally going to track with the lower socioeconomic status just based on the paint exposure or water exposure, things like that. So it will be very difficult for me to know how causal that relationship is.

Tommy:    It, at least, suggests environmental as a --

Peter:    It could be, but it could just be a proxy for something else. It could be a proxy for people who can't afford the same quality of food or same quality of medical care or something like that. So I would just be very hesitant without knowing more, meaning, I know nothing about this but just my chief intuition is that I wouldn't draw too much on that.

    Back to this point of necessary and sufficient, hypertension, is hypertension necessary? No. Is it sufficient? No. Again, you have another enormously strong driver of atherosclerosis that is neither necessary nor sufficient. Okay, let's talk about insulin resistance. Let's just go extreme and type 2 diabetes. Is there any dispute that type 2 diabetes increases the risk of atherosclerosis disease? No, this is very well-understood.

    Now what's not well-understood and what is still debated is, is the risk, and I've had this debate with the world's best lipidologist and we've got long email chains where there are seven people going back and forth, debating this hotly, but there is debate about whether the risk, the clear causal relationship between diabetes is an independent risk beyond ApoB. Because clearly if you have type 2 diabetes, you generally run with higher triglycerides, you generally run with a higher ApoB, is that where the risk is coming from or is the risk itself potentially coming from the hyperglycemia and the hyperinsulinemia?

    I think the evidence is quite clear that the hyperinsulinemia and hyperglucosemia or the high levels of glucose are playing an independent role beyond the role of ApoB and therefore I would argue that high levels of insulin and high levels of glucose also play a causal role in atherosclerosis that is independent of those other things. But again, it's neither necessary nor sufficient.

    LDL is quite unique in that it is necessary though not sufficient. Elevated levels of LDL alone do not cause atherosclerosis. We know this just empirically so there is something to this argument that says everybody with LDL is not equal. What I find so dishonest about this argument is the effort put forth by people who want to diminish the causal relationship with LDL in this space.

    That, to me, it reflects one of two things, either you don't understand the science well enough, in which case you probably shouldn't be talking about it, or you're dishonest. Neither of those, to me, are acts of reasonable faith and so I would just say, let's be open and acknowledge that if you don't have an ApoB-bearing lipoprotein enter into subepithelial space, you can't get atherosclerosis. It is therefore necessary. It is not sufficient. Again, that's like second order thinking which is probably a bit too much for the average person who gets most of their information from Twitter.

[1:00:09]

Tommy:    One of the things that really interests many people, interests myself, I know interests Dave Feldman who is a friend of mine who obviously you know fairly well, is that the effect of ApoB levels in somebody who is metabolically healthy which he has been trying to find some population where he can maybe look at that. The best that I could think of is potentially the Quebec heart study where at least they stratify people by insulin levels and ApoB but where the lowest level of [1:00:39] [Indiscernible] was something less than 12 and ApoB was less than 119, so we would probably --

Peter:    That's still a pretty big --

Tommy:    That's pretty high.

Peter:    Yeah, you'd still want to stratify those further.

Tommy:    Do you have any other thoughts about -- and the problem is that I think most people try and use stuff like LDLC and HDLC and triglycerides because those are the metrics that we've had for a long period of time such that there has been a long follow-up -- do you have any thoughts about where data like that might exist such that question could be looked at?

Peter:    Yeah, Dave and I did spend quite a bit of time talking about this, and I can't remember how much of this we talked about in the podcast versus -- a lot of times what happens is you talk after, the mike is off and you continue the discussion and stuff like that.

    I guess I still struggle with the constraint of not including all of the FH variants. There are at least 2,000 variants of familial hypercholesterolemia, so these people will have a level of metabolic health or unhealth that mirrors the population, meaning, they will not all be metabolically healthy but they will not all be metabolically -- they're going to reflect the population as a whole.

    They have a genetic defect and, again, there are at least 2,000 of these snips that have been identified, and I suspect many more that haven't been that lead to a hyperapoB phenotype. Now, some of these we know pretty well where the defect is. It's a defect on a receptor that takes the LDL particle out of circulation via the liver.

    When you look at those patients on balance, are there exceptions? Yes, some of those patients walk around with FH until they're 90 and they have no heart disease, amazing, and I'm not sure why. But most of those patients don't, and they don't despite being metabolically healthy.

    So, to my knowledge, and this is where I would be digging up, and again I don't know how well this has been quantified, but I'd want to double click on that population. Let's look at all of the FH patients and see if there's a way to stratify them based on metabolic health because to me that's the perfect natural experiment.

    This is where Dave and I just didn't see eye to eye. I was like, I don't know why you'd want to discount the world's biggest gift to you which is a natural experiment of 2,000 genetic mutations where ApoB is through the roof. Look at those populations, go into those databases, there's an FH Foundation that would know everywhere you'd want to look, and see if you can stratify those patients based on metabolic health. Because some of those patients will have high triglycerides and high insulin, some will have low triglycerides and low insulin. Does that afford the ability to predict?

    Again, in my mind, that is the first, second and third place to be looking at this because as you said, looking at MESA or framing him, your data are going to be more confounded because I think more of those patients are going to be medicated. I understand his desire to avoid the medicated population, but I guess I'm still struggling to understand why you wouldn't want to look at the FH population and stratify them metabolically.

    

Tommy:    From what I've seen, certainly those that seem to have cardiovascular events, I think they've looked at Hb1c, certainly seems to be higher in those that do, and I think also they tend to --

Peter:    Well, it will be higher. There's no question. It has to be higher. Why is that the case? Because we've already established that high levels of insulin, high levels of glucose are also going to be causally related though neither necessary nor sufficient.

    I want to be clear that showing that the metabolically ill versions of FH are going to have higher rates than the non-metabolically ill, doesn't all discount the benefit of ApoB. A much more elaborate discussion is required and a much more elaborate analysis is required, but you could start to contrast, what is the rate of the metabolically healthy FH patient and what is that hazard ratio compared to the metabolically ill non-FH patient? You could start to look at an equivalency in that way.

Tommy:    Yeah, that makes a lot of sense, and I will endeavor to see if I can get him to work on that. The one last talk in this area, which I apologize for because I know you've done so much talking about lipids and diets and all that kind of stuff, is the discussion on hypo-responders and why they might be hypo-responders.

    I think you talked extensively about how increased fat, saturated fat likely increases cholesterol production. I can't find any evidence for that in the literature. It all seems to be affecting down-regulation or number of function of LDL receptors. So I was just wondering, in terms of your thoughts of why particularly saturated fat might be increasing cholesterol synthesis.

[1:05:06]

Peter:    It's basically just an empirical observation based on the patients that are getting advanced testing when they have this done. You're generally seeing an up-regulation in cholesterol intermediaries that are in the synthetic pathway. Now we don't have an assay to measure LDL clearance, so the four things we talked about that drive up ApoB, the triglycerides, cholesterol synthesis, cholesterol reabsorption and LDL clearance. Hepatic LDL clearance would be the dominant form of clearance. That last one we can measure. Again, I don't know the answer, and the bigger question is why is that a more important question than what should we do about it?

Tommy:    I don't think it's a more important question, it's just, if you think about the bigger picture, when you talk about the advances of science in new research, that's interesting. So when that happens, I'm very interested as to why it happens and that taking an approach, say from what Dr. Dayspring has talked about on your series. He often talked about, well, evolution clearly wanted it that way. He was talking about phytosterols, I think, at the time.

    So if there's some kind of regulated response, I'm really interested to know why that is. I've seen one tracer study where they increased saturated fat and humans didn't seem to increase cholesterol synthesis, so I'm just wondering. If you think about starting with cholesterol synthesis, it's just the condensation of 3 acetyl-CoAs, 2 HMG-CoA and then obviously reduction to mevalonate which is where statins act.

    If you take the oleic acid versus stearic acid, they both have 18 carbons, you get 9 acetyl-CoAs from each. Other than some differences in FADH2 to NADH production, they're pretty much the same in terms of the synthetic precursors to creating cholesterol. I'm just trying to figure out where that drive is other than, obviously the other end has been looked at in terms of the receptors, but in terms of starting the synthetic production. I'm just interested.

Peter:    Look, my guess is there are so many replicated and overlapping mechanisms in something so important. It's probably why we even see excess ketones being shunted into cholesterol biosynthesis. I think we talked about this, I can't remember which podcast, maybe with Dave. We talked about the patients with ketoacidosis and how high their cholesterol levels are when they show up.

    

    I suspect that the body will figure out how to make cholesterol under almost any circumstance. In fact, even during my fast, though total levels of cholesterol go down, there's still more than sufficient for cellular requirements. It's clear when you look at the precursor hormones that the reduction in hormone levels are more about a signal that says, stop making this hormone, rather than an absence of substrate, for example, as evidenced by DHEA levels remaining basically normal even as testosterone plummets.

    So the short answer is I don't know the answer, and I think it's absolutely interesting and worth pursuing, but I think it's also a third order question. The first order question is what do we do about it. Again, that's, to me, the less scientific question, but that's the one that has to be answered because every day, there's someone that has to be confronted with that question as an individual or as a doctor. They have to figure out, well, what do we do with the best available knowledge we have today?

    Again, right now, I still think that it is an unnecessary risk to avoid elevated levels of LDL-P or ApoB without at least going through the very, very elaborate type of testing that we talked about where, okay, get the CTA, get the CAC, get the CIMT, make sure every other single biomarker that has some predictive value in atherosclerosis is normal.

    In that situation, then it's probably not irresponsible to avoid treating those patients and then having the luxury of waiting to think about these questions that you pose which are interesting and relevant, but my fear with this type of inquiry is that it is coming at the expense of asking the jugular question which is what to do, and it's also providing a little bit of a decoy to people who are looking for an excuse to not be treated, and I see a lot of that. I really do.

    Again, I hate sounding like the guy with 100 stories, but they just happen so often. I have another patient, really young guy, he's 40 years old, elevated Lp(a) diagnosed four years ago, didn't want to take any medication, ApoB was elevated, 80th percentile, should have been at the 10th percentile, I share care with him with another physician and he felt that there was something maybe to this Feldman Protocol. Maybe he could try this and try that and try this and try that. It didn't really matter what his LDL was.

    The other physician requested a calcium score and it came back at 170 which for a 40-year-old is pretty high, or thereabouts. That was his wake-up call which was, man, all this fucking around, trying to come up with 100 different ways to rationalize my LDL and in reality, I probably spent the last four years not properly medicating myself, and I still want to have kids one day. So I think there needs to be a little bit more of a focus on the asymmetry of the risk here.

[1:10:16]

Tommy:    I guess the important point, many of which you have made, is the what to do is the crucial thing. That's where we should focus, and we should separate that from the interesting scientific questions which --

Peter:    I think the two go hand in hand. My fear is that the latter is being used as a proxy to ignore the former. That's effectively what I see from my peanut gallery is there's a lot of machinating about the latter question at the expense of thinking about the former question.

 

Tommy:    Especially from people who don't have to make those decisions.

Peter:    Yeah, it does seem to be disproportionately from people who don't have to make those decisions. Everybody is technically making that decision for themselves, but it does get a little harder when you have to make that decision or at least help people inform that decision about themselves.

Tommy:    Okay, I think that's a very important place to stop, and I know that you're running off to another interview, so it would be nice to kind of zoom back out. We will put the videos of your talks and all the things, so we're looking at the whole picture rather than just focusing on this one particular thing, which we love to do, but I think it really detracts from the bigger issue of what we need to do to be healthy for as long as possible.

Peter:    Yeah, I still maintain my point on Twitter which is, despite all this discussion about LDL, I don't think any of this stuff matters nearly as much as the emotional happiness and health.

Tommy:    I completely agree with you.

Peter:    For all the Twitter haters who are pissed at me for saying that and think that I'm somehow disrespecting all of the LDL skeptics out there, I'm sorry you can't appreciate and understand what's actually being said here.

Tommy:    Thank you so much for your time, Peter. We will link to everything that you produce, unless there's anything else that you'd like to say or ask people to go to, to learn more or hear more about your work.

Peter:    peterattiamd.com is the blog where most of this stuff resides and you can subscribe to the podcast which is called The Drive, through any of the usual technologies that provide podcasts.

Tommy:    Fantastic, thank you so much.

Peter:    Yeah, my pleasure.

[1:12:13]    End of Audio

 
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