#376 - AMA #78: Longevity interventions, exercise, diagnostic screening, and managing high apoB, hypertension, metabolic health, and more

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Welcome to Ask Me Anything AMA episode 78.

In today's AMA, we take on a wide-ranging mix of some of the most common listener questions, from lifespan interventions and cardiovascular risk to fasting, blood pressure management, hormone replacement therapy, diagnostic screening, and more.

This conversation is less about the the deep research dives that we typically do and more about how I think through each of these topics in practice, personally, clinically, and even somewhat philosophically.

So in this episode, we discuss the single most important intervention for extending lifespan and health span, how to motivate midlife patients to prioritize training using the centenary and decathlon framework.

the interplay between lifespan and health span and why separating them is a false dichotomy, how to manage high APOB and cholesterol even with perfect metabolic health and biomarkers such as a zero-calcium score, optimal blood pressure targets, lifestyle levers, and when to use pharmacologic therapy, how to assess and monitor metabolic health beyond the hemoglobin A1C test, including insulin, triglycerides, and zone 2 output, common mistakes people make when trying to improve health and why sustainable habits beat short-term intensity, the effects of time-restricted eating and fasting when calories and protein are controlled, the nuances of ultra-processed food, from practical trade-offs to the difference between nutrient loss and caloric density, approaches to hormone replacement therapy for women in perimenopause and menopause, the evolving understanding of testosterone replacement therapy in men, the risks, the benefits, and certainly the misconceptions, why I recommend earlier and expanded screening and diagnostics, including colonoscopy, PSA, coronary imaging, and low-dose CT for lung cancer, the pros and cons of full-body MRI, how I treat patients with pre-diabetes, tailoring interventions across sleep, nutrition, and exercise, exercise programming for those who are especially time constrained, including strength and zone-based cardio, and how to safely introduce high-intensity training to older adults.

If you're a subscriber and want to watch the full video of this podcast, you can find it on the show notes page.

If you're not a subscriber, you can watch a sneak peek of the video on our YouTube page. So without further delay, I hope you enjoy AMA 78.

Peter, welcome to another AMA. How are you doing? Good.
Thanks for having me back. I'm happy it worked with my schedule and your schedule for you to be here.
Also, like the boxing shirt.

Any boxing that's going to come up in the conversation today, you think? Boxing's not that good for longevity, so I'm not sure, but I wouldn't rule it out. Okay.
All right.

Maybe we can use it as a yin-yang kind of answer. You could manage your Apo B or you could pick up some concussions.
Which one might be better?

On that, today is going to be a very random episode. So what we did is we've been gathering questions from listeners on various topics, all unrelated.

And the focus here will be much less of a deep dive into the science behind it and much more what you do, how you think, and how you approach things personally, clinically.

So it's going to be a little more informal, informal, a little more candid, and we just combined a lot of questions we have recently.

So we're going to cover huge variety of topics, including treating APOB, blood pressure, metabolic dysfunction, thoughts on time-restricted eating and fasting, alter-processed food, HRT, testosterone, screening and diagnostics, what to do if you're pre-diabetic, how you think about exercising if someone's on a huge time crunch, and more.

So I think it should be a fun, kind of a little different pace. But before we get Roland, anything you want to add? I don't think so.
I think you got it. That's why I'm here.
All right.

So first question.

Let's say tomorrow every lifespan intervention vanishes except for one. So if you can only do one intervention for lifespan, what is your non-negotiable for you?

This is for me personally or for society or... It's a good question.
Let's get you personally and then your patience.

Well, you've worded the question for lifespan, but honestly, my answer doesn't change that much if you make it for lifespan and health span.

Although if you say lifespan, health span, the answer becomes even more obvious. It would be exercise.
And the reason is simple.

If you simply look at the data, there's really no intervention we have, including smoking cessation, management of hypertension, management of lipids, reduction of type 2 diabetes.

All of those things have a significant impact on either disease-specific or all-cause mortality.

But when you look at cardiovascular fitness, when you look at muscular strength and even muscle mass, the benefits are greater. And again, this is just talking about it through the lens of mortality.

So I think the answer from a lifespan perspective is exercise.

But again, if you expand that and ask the question through the lens of not just lifespan, but also health span, then I think it becomes even more clear. Because

for most people, the reduction in quality of life in that final decade is actually a movement problem. It is a movement problem.
It is a pain problem. It is a fitness problem.

And that's what I think we should be training for.

There's more detail we could get into here, but I think in the spirit of, I know we want to be a little quicker today, I'd probably just leave it at that.

One follow-up there, which is you kind of mentioned at the end, a lot of what happens towards the end of life is a result of issues around muscle mass, stability, cardiorespiratory fitness.

So how do you talk to patients who are maybe in their 30s, 40s, 50s, and they're like, I can do everything I want to do now without issue. I'm busy.

Exercise, look, I get it's important, but it's hard. Can I kind of do it later? How do you encourage people to focus on this now?

When they think about what they want to do at the end of their life, it's very easy for them to do that currently.

Yeah, I mean, we've developed a tool to actually take the exercise of thinking about that and having that discussion from an abstract discussion into a very tangible discussion. So

what we do with our patients, regardless of their age, is force them to rank the 10 most important

things to them physically that they want to be able to do in their last decade. We call those the centenary and decathlon goals.

And some of these goals are just what we would call activities of daily living, but we want people to be ambitious and be thoughtful. So really think about what it is you'd want to do.

Each of those activities is deconstructed into movement patterns and physiologic requirements. We've gotten pretty good at this now.

This took a couple of years to really, really get down to as close as we could go from an art to a science.

And then for each of those activities, we look at the requirements, the movement requirements, the strength requirements, the physiologic requirements and parameters all across the board.

And we say, okay, well, you want to play 18 holes of golf and walk around. This is what you have to be able to do.

You want to be able to hike for an hour, averaging a pace of two miles per hour on this type of terrain, down to how much ankle movement you'd have to have, hip stability, et cetera, et cetera.

This is what you have to have. Then we project back by decades.

So the only thing you don't know in this exercise is exactly when someone is going to live to, but you want to be ambitious and say, let's assume we're having this discussion and you're 90 years old.

If you're going to be able to do those things at 90, at 80, you have to be this much better. And at 70, you have to be this much better.
And at 60, this much better.

And we back that all the way up until where you are at, say, 30 or 40. And then we measure you against those things right now.

And lo and behold, almost without exception, there is a big gap between where a person is today and where they need to be today in order to take that gravitational slide down to where they're going to be at 90.

For me, that is the most potent way way to have this discussion because it's not as abstract anymore.

Now they sort of can look and see, oh, gosh, even though I can do it now, when I bake in the rate of decline, I'm not going to be sufficient.

In other words, sort of like saying, like, look, just because you have more money in the bank today than you will need at retirement on the day you retire, that doesn't mean you will have enough two years or 10 years after retirement because you have to account for how much money you're going to spend when you're no longer making money.

Getting into all the details of how that is done, it would be beyond the scope of any podcast.

But I think the macro point is it's never too early to start training, but it can be too late to hit all of your goals.

Never too late to start training, but if you show up at 80, unable to do anything, it's going to be hard to be skiing at 90.

But if you want to ski at 90, the time to think about it is when you're 30 and so that you can kind of compound those benefits.

Another thing you said earlier, which is something that we get a lot of questions on, is you were talking about your answer for lifespan and your answer for health span.

In that case, it was very similar for both. But oftentimes you hear people talk about doing interventions for lifespan.

Other people really focus on doing interventions for health span, sometimes at the expense of lifespan. And so how do you kind of reconcile the two concepts to you of lifespan, health span?

I think it's a bit of a false dichotomy to separate them. The truth of the matter is people actually want both.

When I hear people say, I don't care about how long I live, I just want to live a better quality of life. I understand what they're saying.

And I think that's sort of shorthand for, I don't want to get old in a declining state of health. Totally reasonable.

But if we're being honest, I think all of us would love to live longer, provided we can live better.

And the good news is most of the things that you do to pursue health span will also improve lifespan. The reverse is true if you focus on it the right way.
So I'll elaborate.

And I devoted an entire chapter of Outlive. I think chapter four is dedicated to making this point, which is

you could take two strategies to approach lifespan elongation. One strategy might be, Let's figure out ways to live longer with chronic disease.

By the way, that is the strategy that is largely employed today. That's the Medicine 2.0 strategy.
Again, I explain the context of why that's the strategy and why.

I think without assigning judgment, I explain why that's a reasonable conclusion based on the early successes of Medicine 2.0. But what I argue is I don't think that's a great strategy for longevity.

I think for longevity, this right strategy is, how can I live longer without chronic disease? and therefore elongate the period of life that I am free of chronic disease.

And I think if that's your pursuit of lifespan elongation, you're also getting health span.

So I guess in summary there, I would say with every intervention that you can think of, whether it's exercise, nutrition, sleep, pharmacology, whether you're pursuing lifespan or health span with these things, and of course, you're often pursuing both concurrently, if you're pursuing lifespan through the lens of delaying the onset of chronic disease, you're getting health span benefits.

If you're pursuing health span for the sake of health span and you're doing it at least through a reasonable definition, we can maybe talk about that, you're going to be getting health span benefits.

So let's now ask the question through the lens of when are these at odds?

Okay, well, if I define health span, which by the way is subjective, I don't want to suggest that my definition of health span is the right definition.

It's just the one that resonates with me and frankly, with my patients, which is it has a physical, cognitive, and emotional component. But the physical component is not extreme.

The physical component isn't that I want to win the CrossFit games. And I'm not here to dunk on the CrossFit games.
I just use that as an example because everybody understands what it means.

But if an individual said, look, the only thing that matters to me is to be the CrossFit champion of the world or to be the world's best MMA fighter, I mean, that's a remarkable physical task.

But at that level, you might actually be working against your long-term interests in terms of health. at least in physical health and injury.

So every health span optimization must also be viewed through the lens of, does this carry much more risk than I want for later in life, whether it be through head trauma or whether it be through significant orthopedic risk.

That was a great way to tie in boxing to an answer really early on. So props on that.
A follow-up just because I have to. Your age right now, what do you think you'd have a better chance at?

Becoming a CrossFit champion in your age bracket or winning the in-house chess tournament.

Undoubtedly winning the in-house chess tournament. That's good.
That's good to know. So that's some shout out to CrossFitters out there.

You're talking about just the same three or four people in the in-house tournament, though, right? Like it's not like we're bringing sickness in or anything. I'm talking the children you play with.

Yes. So not even adults.
Just

the young kids. All right.
That's good to know. Next question.
Question: We actually get a lot, which is, let's say you have someone 40-year-old coming to you.

They are in shape, no issues with insulin, metabolically very healthy. They get some lab work done and they have a very high ABOB or LDLC,

but they have a zero CAC score. So they got a CAC done, zero.
Again, 40 years old. So when you're thinking about this, let's say from a patient perspective, are you treating their ABOB?

Are you trusting their high-level fitness, good VO2 max, metabolically healthiness? Well, first of all, I love seeing a patient like this.

because the hardest things to fix are the things that this person is already showing up with in great shape.

And it's not that I don't love fixing, we're trying to fix the hard stuff, but for the sake of this person, this is a great place to show up.

Because high cardiorespiratory fitness, insulin sensitivity are absolutely protective against not just ASCVD, but all chronic diseases.

The problem is they don't neutralize completely the role of APOB and atherosclerosis.

And the unfortunate reality of this is that the graveyards across this country and around the world are littered with people who have high APOB, otherwise don't have risk factors, including hypertension, and yet develop ASCVD and can die prematurely.

That's not the majority of people. The majority of people who are dying prematurely of ASCVD have multiple risk factors.

Now, APOB particles are the proximate driver of the atheroma, and therefore every LDL particle is a potential seed regardless of metabolic health.

It's also worth pointing out a zero calcium score carries with it an approximate 15% risk of being a false negative.

I've personally seen, I don't don't know, 10 cases of zero calcium scores that are not zero. No, more than that.

Gosh, if I really stopped to think about it, I would be 10 over the last two years, if I go back and look longer, where a person has a zero calcium score, but shortly thereafter a CTA is done, and we do indeed see soft plaque, which means that there really is some advancing disease.

So I carve that out here, but I'm going to one-up you, Nick, and just assume this person has a perfect CTA.

And let's just assume that you've done all of the advanced testing, you've applied the algorithms that can be layered on the CT scan, and you're really, really confident this person has pristine coronary arteries.

So now the question is, what should you do? Well, it all comes down to a fundamental question of causality. Do we believe APOB is causally related to ASCVD?

I'm not going to address that in detail here because I've done so many, many times. And the answer is unambiguous.
This is one of the few things in biology where there just isn't ambiguity.

As much as anything can be unambiguous in biology, I want to be clear, there has to be some ambiguity in even physics. So if you believe that APO B is causal, then you treat it regardless.

Now, maybe you don't treat it as aggressively. So if this person shows up with an APO B of 150, maybe a reasonable goal for them is 60.

Versus if this person shows up with an APO B of 150, and they have coronary arteries that are littered with plaque, at which point the goal is 30.

So again, there's different ways and different degrees of aggressiveness, but the reason you treat causal risk factors is not because you are sure that this person is going to get ASCBD, but because you understand that by treating something that's causal, you reduce the risk.

And again, the example I've given in the past, and I'll give again is, Nick, I have a 40-year-old person who's insulin sensitive, super healthy, everything about them looks great, and they just started smoking last month, and they're in my office.

Let's just assume I did the most high-fidelity lung scan in the world. They don't have any evidence of lung cancer or COPD for that matter.
Should I encourage them to stop smoking?

Or should I say, look, it's okay to keep smoking, but the moment we start to see evidence of lung cancer, we're going to stop. And of course, the answer was obvious.
Here, nobody would disagree.

We would get that person to stop smoking immediately, not because I know for certain that if they keep smoking, they will get lung cancer. Many smokers do not go on to get lung cancer.

And by the way, 15% of people who get lung cancer have never smoked. But there is still causality between smoking and lung cancer.

And that's, of course, why we would tell this person to stop smoking immediately. Another question we see come through a lot, blood pressure, high blood pressure.

Obviously, we've talked a lot about how high blood pressure can be a silent killer. And in your view, what do you want the average person's target blood pressure to to be?

And let's say someone comes to you and it's higher than that. What are some of the highest impact levers they can have to lower their blood pressure?

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