The Peter Attia Drive - #252 ‒ Latest insights on Alzheimer’s disease, cancer, exercise, nutrition, and fasting | Rhonda Patrick, Ph.D.

Episode Date: May 1, 2023

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Rhonda Patrick, Ph.D., is a scientist with expertise in the areas of aging, cancer, and nutrition who translates complex scientific topics into actionable insights on her podcast, Found My Fitness. In this episode, Rhonda provides her latest thinking as it relates to Alzheimer's disease including the possibility of a vascular hypothesis as well as the factors that can impact disease risk such as type 2 diabetes, blood pressure, omega supplementation, exercise, sauna, and more. She also touches on cancer risk including the relationship between cancer and exercise as well as the link between alcohol consumption and cancer. Additionally, Rhonda explains her new focus on exercise and protein consumption as well as how her perspective has shifted as it pertains to fasting and time-restricted feeding. We discuss: Alzheimer’s disease: Rhonda’s evolved thinking on neurodegenerative diseases [2:30]; The breakdown of the blood-brain barrier in neurodegenerative disease [8:45]; An explanation for the observation that type 2 diabetes increases risk of Alzheimer’s disease [15:45]; The role of omega-3 fatty acids (EPA and DHA) in brain health and prevention of neurodegeneration [19:45]; Comparing the preventable nature of type 2 diabetes, atherosclerosis, cancer, and dementia [32:15]; Blood pressure: an important modifiable lifestyle factor that can affect Alzheimer's disease risk [35:15]; Rhonda’s outlook on “precision medicine” as it pertains to one’s genetic predispositions [38:45]; Possible mechanisms by which exercise reduces the risk of Alzheimer’s disease [45:45]; Building your aerobic pyramid: neurobiological effects of exercise, benefits of lactate peaks, and more [53:45]; Maximizing mitochondrial biogenesis: alternative training approaches and strategies [58:45]; Possible brain benefits of sauna, and Rhonda’s personal protocol [1:09:30]; The relationship between cardiorespiratory fitness and dementia risk [1:15:30]; How exercise may reduce the risk of cancer [1:20:30]; The overarching impact of exercise on health, and the importance of focusing the factors that matter most [1:33:15]; Impact of alcohol consumption on breast cancer risk and overall health [1:37:15]; Exercise as an intervention for poor sleep habits [1:42:30]; The longevity benefits of consuming adequate protein and strength training to preserve muscle mass and strength [1:46:30]; How to get enough of the right kind of protein in your diet [2:05:15]; Fasting: weighing the risk vs. reward [2:12:15]; How Rhonda’s views have shifted on diet and exercise [2:15:30]; How to follow Rhonda’s work and more about the benefits of lactate for the brain [2:21:00]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Atia. This podcast, my website, and my weekly newsletter, I'll focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of this space to the next level. At the end of this episode, I'll explain

what those benefits are, or if you want to learn more now, head over to peteratia MD dot com forward slash subscribe. Now without further delay, here's today's episode. I guess this week is Rhonda Patrick. Some of you may recall that Rhonda was one of the original guests on the pilot series of the drive back in July 2018 when we were trying to figure out if we really wanted to do a podcast. Well, of course, we did and it is awesome to have Rhonda back. Rhonda also hosts her own podcast called Found My Fitness. In this episode, we focus the conversation

around a few important concepts. And we talk about Rhonda's current interests along with areas where her perspective has either shifted or evolved over the years. We start the conversation with a deep dive into Alzheimer's disease. We talk about the possibility of a vascular hypothesis for Alzheimer's disease. I want to also talk about the different factors that can affect Alzheimer's disease, including type 2 diabetes, omega supplementation, blood pressure, exercise, sauna, and more. We then go on to talk about the relationship between exercise and cancer, and also the relationship between alcohol and cancer. And then finally, we talk about protein and aging,

and we talk about fasting, time-restricted feeding. These are two areas where Rhonda and I have had different points of view, over times, and both of our views have evolved, I think in some ways, we're actually converging at about the same place now. So, this is a really interesting discussion. It was really exciting to sit down with Rhonda. It had been far too long. And so, I you enjoy this discussion half as much as I did. Rhonda, it is so great to see you, especially on that awesome remote setup that I almost

shouldn't have said to people was remote because it really feels like we are in person, about as close to in person as we've been in a few years. It's really great to see you here. It's been a minute. We'll be together soon in a couple of months, so I'm looking forward to that. There is a lot to catch up on. Over the past few years, we've obviously exchanged a bunch of emails about things that we each find interesting. And I think in the last couple of years, well, let's just pause it in the last five years. It was the last time we did a podcast. Just going back to that point, I think both of us have evolved a lot in our thinking. And I think we've done so unapologetically.

That's the nature of science, that's the nature of what we do and we're trying to learn. So in thinking about our discussion today, I think we both agreed it would be most enjoyable to at least spend some time talking about areas where your thinking has evolved. But I think first we wanted to start with, I don't want to put words in your mouth, but maybe that what you're thinking about the most right now, would that be a safe assessment if we were to start to talk about dementia, specifically Alzheimer's disease, and maybe the change in how you think about that? It would. For me personally, I have neurodegenerative disease on my mind quite a lot because Alzheimer's disease and Parkinson's disease both run in my family. And I have a genetic predisposition. So for me, understanding everything I can do with my diet, with my lifestyle, exposure to

or limiting exposure to certain things, etc, comes paramount because I don't want to get Alzheimer's disease in Parkinson's disease. Like as you know, Peter, the Alzheimer's disease field has been, it's been quite a rollercoaster in a way. Like we've had this dominating hypothesis, this amyloid hypothesis as it's called. So there's, you know, one of the major pathologies of Alzheimer's disease are amyloid hypothesis as it's called. So there's one of the major pathologies of Alzheimer's disease are amyloid plaques in the brain. And there are other pathologies, taltangles, also glucose hypometabolism.

So glucose uptake into the brain is impaired and also perhaps even the utilization of glucose as well. These are like three major pathologies of Alzheimer's disease. And it seems as though the majority of targeting how science and scientists have decided to target, you know, Alzheimer's disease is through this amyloid, anti-amyloid hypothesis. And as you know, we've had quite a few failed trials, although of recent a little bit more, I would say, you know, possible success maybe, but generally speaking, it's been,

are we just trying to treat a symptom here or are we too far down stream? Like what's the deal? And I started reading some studies by Barisob Slovak at USC and Dr. Axel Montaine, who was trained with Dr. Slovakavik, and now has his own lab at the University of Edinburgh in Scotland. I recently did a podcast with him on my podcast, and it was really like, when I started to read some of this literature, and I'm gonna talk about

the sort of new, it's not even necessarily new, but it's not a new way of understanding it, but it is in a way, because in the public opinion, the public mind, it's a new way. And this is sort of like, okay, well, what are the underlying causes of dementia? And so there's three major types of dementia, Alzheimer's disease being the most common,

there's small vessel disease, cerebral, small vessel disease, and then vascular dementia. Those are the three most common forms of dementia. But like, is there a common underlying denominator between those? And on top of that, like what sort of lifestyle factors and genetic factors do we know really increase the risk of Alzheimer's disease in dementia? Well we know having an ApoE4 allele, so this is a version of a gene that is known to increase

the risk of Alzheimer's disease. If you have one of them, it increases the risk to fold. If you have two, if you got one from mom and one from dad, it could be up to 10 fold. And this isn't like an early onset Alzheimer's disease. It's more of what's called late onset, which is the normal sort of age-related aggression of Alzheimer's disease, but that gene really does play a role in someone's risk. The other thing we know is type 2 diabetes. I mean, that over, I don't know, somewhere between 50 to 80% of people with Alzheimer's disease also have type 2 diabetes.

That's a lot. There's definitely something going on, right? I mean, And let's sort of pause there for a moment because I want to go back to sort of the premise of your interest, which is you are at increased risk. So just even if you just think about this personally, and therefore presumably you're interested in quote unquote prevention. And as you've probably heard

on my podcast, prevention is still a word that doesn't quite resonate within the field. In other words, up until very recently, I think the NIH didn't even acknowledge the idea of prevention as a strategy within this field. And in fact, preventative neurology or preventive neurology, I suppose, is really something that is still kind of on the outskirts. Most people are thinking about what to do when you have Alzheimer's disease, not as many people are thinking about the question that you're asking and that a few other people are asking, which is, what's in our control? Because yes, you alluded to ApoE4, which I'm sure we'll talk more about.

But what you just said about type 2 diabetes would suggest that if you believe you can prevent type 2 diabetes, wouldn't that at least suggest you have the probability or possibility of preventing or delaying Alzheimer's disease? Sorry, so it didn't mean it interrupt you, but I want to highlight the important implication

of that statement. Exactly. It's so important. I think that looking at Alzheimer's disease and understanding sort of the underlying cause of it opens up, you know, these new avenues for prevention and also treatment. And of course, there are people that do get Alzheimer's disease early in life. I mean, these are people that could come down with it in their 40s or 50s You know people are outliers in that case But it does happen and there are things that you might do everything right and still like have that terrible genetic combination with respect to the apoe for and type to diabetes Understanding again. Is there something like common going on here that we can sort of understand as a foundation to what are the initial like things going wrong to lead to Alzheimer's disease?

And that is where vascular dysfunction, particularly the blood vessels and capillaries that are lining the blood brain barrier, seems to be a really, really early event that is common between all types of dementia and between type 2 diabetes and APA-WIFOR. So people will type 2 diabetes, as you know. Can I interrupt for a second, Rhonda? Tell folks what the blood brain barrier is. I think it's obviously going to be an important part of this discussion, and not everybody might understand

what it is or why it's so important. I am not a neuroscientist. I am a scientist, but I have interest in this, and so I've done a lot of reading in this field. The blood brain barrier serves a couple of functions. I mean, one is there's a combination of different cell types that make up the blood brain barrier and a lot of vasculature, right? And so blood flow, things are brought to the blood-brain barrier and oxygen, glucose, other nutrients,

and they are transported across the blood-brain barrier. But it also, as the word implies, barrier provides a barrier to things that you don't want to get into your brain. We don't want red blood cells getting into our brain. We don't want a variety of other molecules, proteins that are floating around in our circulation to get into our brain. And so when the blood brain barrier begins to break down,

people I think are a lot more familiar with when the gut barrier starts to break down, I've sort of become more of a common theme that people are focused on gut health. And so mostly you hear the word leaky-gut. I don't really like that term. I think it's intestinal permeability, but the tight junctions, these proteins

that are holding endothelial cells together in the gut, when those open up, you get that term leaky-gut, or as it really should be called intestinal permeability. Well, in the brain, you also have endothelial cells and you have tight junctions. And when those tight junctions also break apart and we can talk about like what's at the root of that, that leads to permeability of the blood brain barrier

and therefore two things happen. One, you are allowing then things from circulation to get in the brain, which you know, wreaks havoc on the brain and leads this vicious cycle of neuro-inflammation inflammation in the brain. But also, you're disrupting the transport of important nutrients, oxygen glucose. I mean, blood flow is disrupted to the brain as well. The blood brain barrier and maintaining that integrity is very important.

And both APOE4 and type 2 diabetes lead to permeability of that. And so with type 2 diabetes, people have hypoglycemia, right? They have elevated blood glucose levels. And that over time leads to advanced glycation and products. These are basically like they cross link proteins and a variety of other things that in the vasculature.

And that basically damages the blood brain barrier and leads to permeability. Apathy for, you know, there's a variety of other mechanisms that happen, but essentially you can measure the permeability of the blood brain barrier looking at a variety of biomarkers and proteins in cerebral spinal fluid, but also in plasma. And these have been shown by Dr. Slobavik, Dr. Montaine,

to occur decades before the onset of cognitive impairment. And it's literally you can find it in more than 50% of all dimensions. It's happening independent of amyloid accumulation, taltangles as well. So it's either something that's happening before, well before before and in fact blood brain barrier permeability, the blood brain barrier is essential for removing toxic compounds

from the brain. And a variety of different processes happen to allow this to occur. So for example, you activate the eglumphatic system during sleep, right? And a lot of people are aware of this. Your brain sort of swells during sleep and theglumphatic system during sleep, right? And a lot of people are aware of this. Your brain sort of swells during sleep, and the eglumphatic system is pushing this cerebral spinal fluid through the brain, clearing out debris, amyloid plaques, you know, things like that. Well, that, you need the blood brain barrier to be intact for that to occur. So I mean, that makes sense.

That basically, if you have blood brain barrier permeability happening, that you would start to have the accumulation of amyloid. So it's sort of like accumulation of amyloid. I never thought of that by the way, Rhonda. I'd never thought of what you just said, which is if your blood brain barrier can't hold the back pressure, which is what would be the case, if it were permeable, you would not have the back pressure to maintain the glimphatic flow. That never actually occurred to me till you said that. So, very interesting mechanistic tie to that problem.

And I'm not familiar with all the types of ways of brain. Like there's other like parent kai ma and stuff that are like cleaning out the brain. All of those things are not happening as good when your blood brain barrier is dysfunctional. And then another point is the ability of things to interrupt and get into the brain that shouldn't. So, one of the things, you know, everybody learns in pharmacology or medical school is that dysfunctional. And then another point is the ability of things to interrupt and get into the brain that shouldn't.

So one of the things, you know, everybody learns in pharmacology or medical school is that there are certain drugs that penetrate the blood brain barrier. There are certain drugs that do not. The implication being certain molecules can pass through certain molecules cannot. Well, presumably the leakier that barrier is the more things that maybe we evolved to not have across that barrier do indeed cross. Perhaps that's a part of what you just said, right, which is this increase in inflammation that is now coupled with an inability or a decreased ability to clear out debris.

Exactly. In fact, so work from Dr. Montaine has shown that Frinogen, which is, you and I are familiar with this protein. It's something, if you're doing an inflammatory biomarker panel, it's a protein that's involved in blood coagulation, but it's also something that is a marker of inflammation. And fibrinogen is not supposed to be in the brain, but it's found in the brain in people with a leaky blood brain barrier. So what's it doing in there? It disrupts a cell type called oligodendrocytes. These are a cell type that make myelin, sort of fatty white structure that's important for electric signals being fired throughout the brain.

And it's basically toxic to them. So you basically start to have these lesions and stuff in the white matter part of the brain, white matter hyperintensities, as you're probably very familiar with. A very common in all vessel disease. Also, you can see that in people with Alzheimer's as well. But getting that fibroindogen in the brain,

like that's happening because it's allowed to get in there. So the permeability of the blood-bring barrier, basically preventing stuff from getting in your brain that you don't want in there. That's number one. But also the transport, I think you also alluded to this, you're not getting things like glucose into the brain. And in fact, all these transporters, they're in the endothelial cells. They're in these cells that are making up the blood-brain barrier. and when you start to disrupt that blood brain barrier, those transporters are dysfunctional. For example, one of them is the glute-1 transporter. This transports glucose into the brain. As you start to get a disruption in

blood brain barrier function, glucose transporters, they go down. And so you're talking about not getting enough glucose into the brain, which is again, that's one of the pathological features of Alzheimer's disease, right? Not getting enough glucose into the brain. That's actually an interesting explanation because a very subtle point you made that might not be picked up on everybody is you mentioned the Glute 1 transporter as opposed to the Glute 4 transporter. And if my memory serves correctly, the brain has Glute 1s as opposed to Glute 4s and Glute 1 ones are insulin independent. Is that correct? Yeah, for the most part, they're insulin independent. That's my understanding.

And why that's interesting is because it seems a bit counterintuitive that a condition that leads to insulin resistance, of course, type two diabetes, is the essence of insulin resistance. It seems counterintuitive that that would produce a hypometabolic state in an organ whose glucose transporters are insulin independent, except when you explain it the way you did, which is it's not the insulin resistance of the glute-1 transporter. That's the problem, the way it is for the glute-four transporter in the muscle, instead it's the actual mechanical disruption,

if I'm understanding you correctly, of that transporter because of the way it's no longer, presumably held in place by the barrier itself that allows glucose to get across. Did I understand that correctly? 100% correctly. And then this isn't like dogma, like this is definitely known,

it's definitely where I'm heading. It's my opinion, but there is evidence of it. And I think it's time to explore this evidence a little closer and a little deeper because, you know, you hear the term type three diabetes. And I think people think about it in the way of the brain being insulin resistant. And, you know, maybe there's something to that,

but I don't know if that's exactly what's going on. I think the type 2 diabetes is disrupting the blood brain barrier through a variety of mechanisms, including the advanced glycation end products and the vascular. I mean, the vascular disruption in type 2 diabetes is well known. I mean, they've all sorts of problems,

not the neuropathy, like all this. I mean, they are disrupting their vasculature, including these tiny, tiny little blood vessels that are like smaller in size than are the diameter of a hair. Those things are like disrupted at the blood brain barrier. And when you disrupt them, their blood flows decrease, and the transporters are going down. I mean, there's all sorts of problems. And so I think fixing the diabetes obviously would be like the downstream thing to do. But like, there's ulcerative problems. And so I think fixing the diabetes obviously would be like the downstream thing to do, but like it's kind of a new mechanism, right? It's a kind of a new way of understanding it. It explains the observation. So there's an observation that is unmistakable, which is type

two diabetes. I don't know the number, but I think it approximately doubles your risk of Alzheimer's disease. So in other words, even if you're sitting there walking around with two copies of the APOE3 allele, having type 2 diabetes means you might as well have a copy of an E4 allele from a risk perspective. And what this is saying is, well, it's not entirely clear at the surface why type 2 diabetes would impact the brain through the lens of traditional thinking of glute for transporters, which are insulin dependent. In other words, it isn't just an insulin resistance problem, but I think these two other

things matter. What you said about the microvascular, what I think a lot of people don't realize is how destructive type 2 diabetes is to the kidneys because those tiny, tiny blood vessels, people are familiar with amputations and things that occur in digits because of that impotence. All of these things where blood vessel is essential in small blood vessels. And so there's that, which feeds into the vascular path that you've discussed. But it's also this disruption of glucose transport directly across that transporter.

So I think it's actually a very compelling thesis for how type two diabetes could be acting via those two prongs to ultimately result in hypometabolism. I do too. And then of course, the cascade of inflammation that happens after that. So the other thing that's also very interesting is, so we're talking about type two diabetes

and very big implications there for the prevention of Alzheimer's disease. There's a lot you can do as you've talked about to prevent an even treat with diet and lifestyle, right? Type to diabetes. But also what's really interesting and I was sort of on this trail years ago, I published a sort of integrative review on the role of the omega-3 DHA transporter MF-SD2A in the brain. What's really interesting that animal studies when3 DHA transporter MF-S-D2A in the brain. What's really interesting that animal studies when you disrupt that transporter,

it causes like 50% breakdown of the blood brain barrier and like greater than 50% loss of omega-3 in the brain. So in my opinion, that's animal evidence. Of course, there's human evidence where MF-S-D2A transporters decrease with age, particularly rapidly in Alzheimer's disease and with apoi for. So there are genetic abnormalities and mutations that occur in that transporter where people have less of it and they have microcephalese, they have like smaller heads and they also have cognitive dysfunction, sort of cognitive impairment, things

like that as well. How do we know that, Rhonda? So let's even put the pathology aside, this sort of ladder category, but let's just talk about, well, again, what you've said explains something we've empirically felt is true, and the evidence suggests that this provides a mechanism, right, which is apoe for carriers need a higher level of EPA and DHA to get the same benefit. That appears to be empirically correct. That would provide an explanation. Something else you said, you know, we talk about amino acid or protein resistance,

basically, anabolic resistance as a person ages. They need more and more protein to get the same effect. It's almost like you're saying aging itself could create some resistance to dietary EPA and DHA that might require more as time goes on. Do you think there are also just genetic differences within the variant of normal, quote unquote, IE non-pathological, where one person would need more EPA and DHA to afford them the same benefit of protection as another person? I do. I know there's at least a couple that are known. And so like some people have certain gene variants that actually they respond better to, for example, omega-3 supplementation and others don't, where they would actually need a higher dose. And I think there's many more to be explored.

Like, we haven't unlocked all of that yet. When I say we, I mean the scientific committee, not me personally. But with omega-3, and this again, really hits home the preventative role here that we can have in our Alzheimer's disease risk. So with the MFSD2A, these transporters are actually lost.

So there's a type of cell called pericytes, pair E with an eye, not to be confused with a parasite. They basically have these big feet that wrap around the endothelial cells at the blood brain barrier. And they serve really too important, many important, but too main important functions. One is they're basically constricting and dilating and like helping squeeze like the flow of blood, so they're like regulating blood flow to the brain,

but they also are very important for that barrier. And they start to fall off with age, these peri-sites, and inflammation plays a big role in that, but the MFSDD2A transporters are concentrated on those cells too. And so you'll see hotspots of where the peri-cytes, once those peri-cytes start to fall off, that is when basically immune cells and everything starts going into the brain. It's like the start of the vicious inflammation cycle in the brain, of the leakage, amyloid accumulation, just everything downstream.

There's something there with those transporters of omega three that are right at the same site of where you lose those parisites, which is also really interesting. And again, there's a lot of animal evidence that suggests the role of that transporter in blood brain barrier integrity. Also, again, you can kind of like connect the dots here

where you think, okay, well, this is DHA in phospholipid form. So it's like, okay, there's got to be something here with the omega-3. And I know there's a variety of scientists that are investigating this, but I'm sort of excited. I am now going to be part of a team. So I joined the fattyadi Acid Research Institute,

which is Dr. Bill Harris' Research Institute, and as a research associate, and we are secured a small grant to look at the role of Omega-3 with blood-brain barrier integrity and biomarkers and people, a variety of different people that have small vessel disease that perhaps go on to get Alzheimer's disease. And so I think there needs to be more research in this area because the implications here I think are really important. There's two main lifestyle interventions, I think, that are important with respect to the blood brain barrier, three, actually three.

So basically not getting or fixing your type 2 diabetes. And then the omega-3 intake and like defining that will be sort of tricky. But full stop, most people in the United States, they're not eating enough fatty fish. And they're not supplementing with omega-3, which is sort of an alternative. I think it was like a 2012 study out of Harvard that identified omega-3 low omega-3 intake from fish, so the marine type of omega-3, low omega-3 intake from fish, so the marine type of omega-3, not plant AOLA, as one of the top six preventable causes of death.

So it was up there with... Smoking. It was smoking and blood pressure and obesity and being sedentary. Low omega-3, it blew my mind, and I'm not a biosdatician, but there was some calculation done with estimating the number of deaths caused by not getting in enough omega-3 each year.

It was like the same number of deaths. It was like 84,000 deaths a year from low omega-3 intake from fish. I wonder though, if that's also just a marker for poor health, that's the challenge of all of those studies. Totally. In some cases with smoking, it's pretty obvious that there's causality there. I think there also is with blood pressure. But you could argue that never in the history of the world

has there been a person who has, I'm making a bit facetious, who has a high omega-3 index, who eats junk food and fast food all day. Those can't coexist. I want to ask one clarifying question, Rhonda. Certainly, I know that when you're talking about omega-3s, you're referring to the marine variant of which we have EPA and DHA. But the transporter, if I understood correctly, is it a transporter

only for DHA in its phospholipid form? And if so, what is the importance of EPA in this? And if so, what is the importance of EPA in this? Great question. So the MFS-D2A transporter that I've been referring to is specific to DHA. And the form of DHA is lysophosphatatylcholine DHA. So we make it when we take in DHA from fish or from resupplement. The higher amount of DHA that we take in DHA from fish or from resupplement, the higher amount of DHA that we take in, we add that

lysophosphatol colon group to the DHA. We also have DHA in free fatty acid form bound to albumin, and albumin is not, that doesn't get into the brain, but it takes it to the brain, blood brain barrier in the free fatty acid, can sort of diffuse passively across the blood brain barrier as well. Same with EPA. Oh, I see, but because the phospholipids on the DHA, it needs a dedicated transporter, whereas the unfosphorylated, we're not phosphorylated. The one that doesn't have a phosphatidolipid side chain

can diffuse without a transporter. Exactly. So it's free fatty acid, bountail, buman, and it can just diffuse across the brain. Yeah, so that's how EPA is generally getting in the brain. Then second question for you on that thread, feel free to go into as much depth as possible because I know this is actually a very important topic

that is somewhat controversial. What do you see as the relative importance of DHA and EPA? The conventional thinking, I think, is that EPA probably more important in the heart, DHA, probably more important in the brain. I'm sure that's a gross oversimplification, but can you expand on that? I can try. I don't know that it's really known. So the way I personally think about both EPA and DHA, there's a variety of metabolites and of DHA that are involved in resolving inflammation.

So these are resolving the mericens, the SPMs, protectants, and EPA also has some of those metabolites as well. And it also plays a direct role in inflammation through the, I don't want to say inhibition, but like dampening the prostate glandins and the leukotrenines and a lot of the other inflammatory processes. So it's kind of like an approach where you're affecting inflammation from multiple ways, right? It's like a multi-pronged approach. And I mentioned Fribrenogen earlier about like Fribrenogen, it's an inflammatory protein, well

it's involved in coagulation, but it's something that we do measure as a marker of inflammation. So there's studies showing that people that are exposed to a particular air matter, their fibrinogen goes up. But if they have a higher dose of omega-3 or higher intake of omega-3, it blunts that effect again through the inflammation, right? So, both DHA and EPA are important in my mind for the brain as well. I mean, there's a variety of studies that have looked at even depression. You can induce depressive symptoms in a person by injecting them with what's called lipopolysaccharide, which is a component of the outer cell

membrane of gram-negative bacteria. We have billions of those in our gut. In fact, there's about one gram of lipopolysaccharide or LPS for short. It's also referred to as endotoxin. There's about one gram of that in our gut. Well, you can inject people with a low dose of that. Something that actually would be somewhat,

I would say equivalent to someone with intestinal permeability, and it can cause depressive symptoms in people compared to those given a placebo. And you can blunt that depressive symptom effect with EPA, probably because of the inflammatory, the blunting of the inflammatory response. And there have been some, this is a feel that's, again, understudied, underfunded, but some preliminary evidence randomized controlled trial, small randomized controlled trials that need to be, of course, repeated with larger sample sizes.

They're basically showing that supplementation with EPA can help with depression. Yeah, this is such a frustrating thing for me. And obviously, I know it is for you and for many others, including Bill Harris. If you took the cost of one phase three anti-amiloid failed drug trial, just take one of them. There's been dozens of them. Just take the dollars that were spent on one of those guaranteed to fail phase three trials and put that money into a preventive trial that looks at something that's got real feasibility or something that's really interesting, like the optimal supplementation of DHA in the right patient population group, we could have an answer. And yet, for obvious reasons, there's an incentive to do a phase three drug tile on a candidate

with an IND. There's not an incentive from a financial perspective to study these other things. And I think for a disease like Alzheimer's disease, that's particularly problematic. As I suspect, we'll discuss, unlike cardiovascular disease, where, yes, prevention is still the best strategy. You can come in late to the game and still make a difference. I don't think the evidence is particularly compelling that that is true for Alzheimer's disease.

Now, I'd love to be wrong, but I have yet to see compelling evidence that you can be a Johnny come lately to that pathology and have an impact. It's hard to fix those leaks in the brain once they're started. And that also is why I think there have been failed trials also with, we've been a few with omega-3 supplementation people that already have Alzheimer's disease. And you're giving them like, I don't know, at most, two grams.

I've seen studies like 500 milligrams. I'm like, are you kidding me? You know, patients with high triglycerides or cardiovascular problems are... We're giving them four, right? For. I know, at least four. This is something that has the safety of a nutrient, but literally an act like a pharmacological drug,

you know, at higher doses. I agree with you. I think it is much more challenging to fix when you have Alzheimer's disease. And certainly, like, I'm talking about, like, the leaks in the brain, but then what happens after that? The amyloid accumulation. and like, when you start to get to this level when you're, you've got all of that, I mean, good luck. It's going to be, it is going to be challenging. And

you're going to have to take, it's not going to just be fixing the amyloid. You're going to have to have a cocktail that are going multiple angles, I think, in order to get some improvement. I think the amyloid and perhaps also fixing the blood-brain barrier leaks as well, maybe at the same time with the cocktail may help a little bit. But prevention is the way to go. I mean, like, it's so much better to not get Alzheimer's disease than to try to fix it once you have it

because it is a very complicated disease with lots of things going on. I think the strategies that can be done, and they're not that difficult. We talked about type 2 diabetes. There's no reason why someone should have it. You should be able to... I would phrase it as, I do not believe for a moment that type 2 diabetes is inevitable to our species. Whereas, I do believe atherosclerosis is inevitable. Of course, I also think most people don't need to die of it. That's a very stark contradiction. The disease is inevitable, and as much as humans will have

lipoproteins that carry APOB, we will get atherosclerosis. But again, we have the technology to delay the onset of that disease to the point where it should not be the cause of death. We should be dying with it, but not from it. I would also argue that cancer is inevitable to our species. It is simply a stochastic problem where if you live long enough and if you accumulate enough genetic mutations, and we can do lots of things to reduce the risk of that and to delay the onset of that and to detect cancer early and be more successful

in treating it. But the incidence of cancer strikes me as something that is inevitable with enough age. I actually don't feel that way about type 2 diabetes. In other words, I think I share your point of view, which is it's not something that is necessary. We don't have to eventually get it. And I think that makes it all that much more tragic that you watch how many people are suffering from this disease and how much damage it's causing, not just in the disease itself, but as you said, it's such an amplifier of the, what I refer to as the horseman, right? It's what it does to your risk of cardiovascular disease, cancer, and Alzheimer's disease is actually why the death toll for type 2 diabetes is so grossly

underappreciated. Yeah, it's accelerating the aging process, the molecular, gasoline on the fire of aging. I'd have to really reflect on it, but I can't think of a process that accelerates aging more than type 2 diabetes. Right, maybe a morbid obesity, but like they're probably also type 2 diabetes. I would argue only in the context of insulin resistance, which gets us right back on that path. So the good news there is, not that it's easy, but we sort of know what it takes to treat it and prevent it, and it doesn't necessarily look like the strategies that are being deployed, unfortunately, at the level of the ADA. I want to ask you one other thing. We haven't talked about, but I want to know if it pertains to the blood brain barrier at all, and that's blood pressure. So hypertension and I guess hyperlipidemia also pose enormous risk for not just cardiovascular

disease where they are two of the three biggest drivers of risk, but they also pose a risk in Alzheimer's disease. And I wonder, do either of those act specifically to the blood brain barrier? It is another really important, modifiable lifestyle factor that can affect Alzheimer's disease risk, maintaining good blood pressure. So I mean, basically you want to be systolic below 130. Once you get to 130, a sprint trial would even say 120.

120, yes. And the blood pressure itself, so getting that blood flow to the brain, blood brain barrier specifically is so important. When you don't have, when that blood flow doesn't basically isn't able to get to the blood brain barrier well enough, those tiny little vessels start to like just fall off. And it's one of the reasons why exercise also is so,

so important. There's been a variety of studies that have looked, as you mentioned, the observational data is never able to establish causation. But it's still an interesting point to look at in combination with many other types of data. Especially when it's always in the same direction. Exactly. So it differentiates the epidemiology around, for example, exercise in blood pressure from the epidemiology around nutrition. The epidemiology around nutrition, A, it has very low hazard ratios and it's always changing the direction it's moving in, suggesting that whatever's being studied probably doesn't matter. Yet when you look at the epidemiology of smoking, blood pressure, dyslipidemia, exercise, much bigger hazard ratios, virtually always pointing in the same direction. So it strikes me that the latter is signal,

the former is noise. Good point. So, you know, 50% of people, adults in the US, have hypertension. And about 20% of young adults, like we're talking people, age 18 to 39, have hypertension. That's crazy, right?

And actually, the high blood pressure, it's the cumulative exposure to high blood pressure that's really damaging the vasculature. And so it's the cumulative exposure to high blood pressure that's really damaging the vasculature. And so it's the younger people. It's the people that have it earlier in life that should be the most concern and are the least, right? There's the ones that are like, I'm young, you know, I can worry about it later.

But yeah, so high blood pressure is associated with dementia risk, particularly when you have it like before 50s, like when you get it in your before the 50s or mid life. Once you start to get high blood pressure in older age, like 70, 80, it's not as much associated with the Alzheimer's disease and dementia risk. It really does seem like cumulative exposure is the key factor there. Again, one of those things that is a lifestyle factor that's easily modifiable, exercise improves blood pressure, sauna improves blood pressure. Those are two basically low hanging fruit lifestyle interventions. Some people do have gene polymorphisms where they're very sensitive to salt intake and

sodium intake and that combination of those people with a higher sodium intake really seems to skyrocket blood pressure. Nutrition, I think it's also looking at the combination of genes and diet. Most nutrition studies don't do that. There is an interaction going on, and I do think that's why some of the sodium intake blood pressure literature is just a little more, I would say. Yeah, it's all over the place. I was on to ask you a question about exercise, but before I do that, I want to actually pick up

on something you just said, how optimistic are you, I don't know, let's bracket this with, let's say in the next decade, that we will have more of a sense around what precision nutrition looks like as it pertains to genes and polymorphisms of them. In other words, people talk the talk, like, oh, I did this test and it told me

I should be eating this, that and the other thing. But the reality of it is, there's nothing that's available today that's come close to offering that type of insight. A, do you believe that that type of insight is available? You used one example, which I would agree with you on, which is that there are probably different levels of genetics susceptibility to sodium that might suggest one person needs to be eating two grams a day

of sodium and another person needs four grams a day. But do you think it will get further than that? And how likely do you think we will be to extract that information? I do think in 10 years we're going to know a lot more about precision nutrition, obviously precision medicine as well, because there's also an interaction between pharmacological treatments and genes as well, as you know. In 10 years we're definitely going to be a lot further than we are now. The problem is, and this is always the problem, we've already alluded to it a few times, is the incentive for funding to study those things

that aren't necessarily going to be super profitable. The government, the NIH, there's a certain amount of funding that you can get from them. And they often like to study one sort of thing, like the nutrition when there's like multiple things involved, it's like, they're just like too complicated. And so there's a lot of funding from

pharma industry, for example, and then they put in lots of money because they are incentivized to do that when it's a drug. That's my one concern with I would say gene diet interaction when it's more on nutrition But there are people that are it's a growing field of research for sure and I do think with Technology is advancing too. I mean, so at the point that our technology is advancing with AI and stuff, I think that we're going to start to see an exponential there, honestly. I am optimistic that in 10 years,

that it's going to be a lot easier to delineate what a person should eat based off of the genetic makeup versus just what generally we think is. And do you think that that will be at the level of macronutrients or micronutrients? Like how much heterogeneity do you think there is among people as it pertains to factors like that? I think both.

There are differences in the response to macronutrient intake and the response to micronutrient intake. And there are people, there's vitamin D polymorphisms, where people, for whatever reason, so maybe they evolved in a place where there was so much sun or something. I don't know what the cause is,

but like some people, they have to supplement with high doses of omega-3 to be able to convert the precursor to actual the hormone, right? The steroid hormone. That's just one example. There's selenium, there's magnesium, there's a lot of different micronutrients that are off, and there's omega-3.

There's omega-3 as well. And B vitamins. Exactly, there's B vitamins. Yeah, more people are looking into it, and with advancement in technology, things will become cheaper and easier to do, and that's going to create an exponential, in my opinion, where it's like, okay, maybe in a couple of years, we'll start to really see an explosion.

And then after that explosion, exponential happens where people are building off of that, because that's how it works. That's kind of where I think it's going. And I'm excited about it. I think that's where it needs to head. I think it's going to clear up, as you mentioned, all the conflicting data with nutrition. I mean, nutrition studies are a mess, designing the right trial.

I mean, part of the reason for that is because we have, if all these genes, I mean, it's a drug with the exception of, yes, there's the CYP enzymes and stuff that help us metabolize xenobiotics, things that are not a vitamin or a mineral or essential amino acid or fatty acid, right? So it's foreign to our body. But by and large, when you give someone a drug, they're starting with zero levels of that drug in their body, and you give them

the dose that you're giving them, it's like clear. You're giving them a dose, and it's going to be different than people getting a placebo, right? It's going from zero to something. Whereas when you do this nutrition study, a micronutrient, you know, you give them a vitamin or a mineral, nobody's starting with zero for one. Your placebo group could have high levels of that, and unless you measure something, you'll never know. And all the trials are sort of, they're trying to mimic that gold standard of a randomized controlled trial

with a pharmacological drug. You have to like put in so much more effort with the nutrition, with the drug. You don't have to start doing blood samples of this than that and let measure the drug and make sure people aren't deficient in that drug. But of course they're deficient in the drug before they start the trial.

They don't, it's like a drug. It's such a good point, Rhonda. And I'm going to use two examples to highlight why this is so important because it ties to two things we've been talking about. If you look at how a blood pressure trial is done, it is exactly what you say. It's titrated, meaning it's done the way a pharma trial is normally not done. So a blood pressure trial says, let's just bring in a whole bunch of people with high blood pressure.

Okay. You guys on the placebo or on the low treatment arm, we're going to manage you to a blood pressure of 140 over 90, but no lower. You guys in the treatment arm, we're going to manage you to 120 over 80 or better. And by the way, we're managing to manage you to 120 over 80 or better. And by the way, we're managing to the outcome, not the drug. So I'm agnostic as to whether this person needs a higher dose or a lesser dose. We're checking the outcome here. And so if we did a vitamin D trial that way, it would be a very different trial. And one of my biggest

criticisms of vitamin D trials and why I think we don't have an answer as to whether supplemental vitamin D is valuable, is they don't do this. Take the people, you divide them into two groups, you give one group of placebo, you give one group, usually a very low dose, somewhere between two to four thousand IU daily. But we don't actually know what the level goes to. In other words, a better vitamin D trial would be, we take a bunch of people whose vitamin D is below 30. In one group, we give a placebo, and in another group, we give whatever it takes to get them to, I'm making this up, but 80. Then we would see, is there a difference between this group that's below 30 and this group that gets to 80, regardless of the dose it took to get them there?

Because of course, that may include part of the problem. So I think your point is an excellent one and I think it's something that listeners need to be aware of when they're scrutinizing trials of this nature, which is a negative trial doesn't mean the thing doesn't work if the trial wasn't designed correctly. Right. And it often, it's a matter of money too, right? To measure all those things, it's cheaper to just give someone the vitamin D supplement and then look at the outcome and go, oh, it didn't work.

And then you have another confusing piece of literature out there that people are like, oh, but says that vitamin D supplements do nothing. Yeah, it's a big problem. And I do, again, I think as our technologies are advancing that that's gonna become less of a problem as well, at least I hope, I mean, I guess you never know. So I wanna go back to something you talked about earlier,

which is you just touched on exercise. And I wanna kind of visit now the suite of things that exercise does, because people who listen to this podcast know if there's one thing I just can't stop talking about its exercise, but I think there's a reason for that, right? It's not just that I love exercise. It's that the evidence is overwhelming that a person who exercises, especially at the

right amount, we're talking not just 30 minutes a week type thing. But if you're really doing the work, you're having a greater impact on the reduction of risk of Alzheimer's disease than any other intervention you can take. Now there are lots of interventions that matter. Sleep matters, nutrition as we talk to, I type 2 diabetes, all these things matter. But the risk reduction that comes from exercise is enormous. What do you think are the mechanisms

by which that is happening? Because I suspect there's many. Oh, definitely many mechanisms happening. And I would, first of all, 100% agree with you. Like, there's nothing better than exercise. Of course, any exercise is better than none, but for me, because as I mentioned at the start of this podcast, I'm very focused on neurodegenerative disease. I specifically sort of designed my workout routine based off of what I think are going

to give me the biggest brain benefits. And what I've sort of come to the conclusion of is that intensity does make a difference with respect to the neurobiological effects, exercise intensity. There are some mechanistic reasons for that, but just talking about what's modern intensity exercise, what's considered vigorous intensity exercise. If you look at some of the recommendations out there by the committees, there's a team of scientists, physicians, that sort of analyze all this data,

and then make these health recommendations based off of that data. It's 150 to 300 minutes of moderate intensity exercise, which I think they define as like 50 to 70% of maximum heart rate. Vigorous intensity, they say 75 minutes, I guess, a week. And that would be more of you're getting above the like 75 to 85% max heart rate.

So that's what they, I think, to find is something like that. Vigorous. And they have a variety of examples. You know, there's the World Health Organization. It's a variety of committees that come to that same conclusion. For me, I like to go higher intensity. This is something I kind of was looking forward to talking to you about because it has to do with how do you measure the estimated heart rate, which is what I do. I've estimated. And again, all sorts of problems with that based on your physical Fitness meaning estimating your maximum heart rate to take a person event. Okay. So basically, you know the more fit

You are you could be doing a more vigorous intensity exercise, but your heart rate like doesn't go as high as someone who's not fit And then people that are older so there's of course, I would say problems with that, but generally speaking, that's one way, but I'm also very interested in lactate. And I know you are as well. For me, I actually want to get my lactate levels high. And the reason for that is the neurobiological benefits. So lactate, as you know, was once thought to be this sort of end metabolic byproduct, it was like useless. Well, not only just useless, actually, it's thought to be harmful. At least to performance. Right.

Harmful to performance with respect to people thought it was like causing their muscle soreness. As you know now that it's not lactate, it's the proton buildup. Lactate is sort of in homestase at the phl acid, and it's the protons that were sort of responsible for that. And neither of them are responsible for the soreness you feel the next day. That's the mythotroma, of course, like the soreness and the burn from the hydrogen ion is gone

minutes after you stop exercising. Yeah, exactly. So the lactate that gets into, so you're generating lactate when you basically are pushing your mitochondria inside your muscle cells to a point beyond where they can generate enough energy in the form of ATP, adenosine triphosphate, then they sort of have to figure out another way, like your cell has to figure out another way to get the energy, right? So this is where glycolysis comes into play. So this is happening outside of the mitochondria.

And I'm sure your listeners have heard all this before, but for those that haven't, the lactate generation is then from that metabolism of glucose outside of the mitochondria. And that's happening when, again, you reach that threshold of you're pushing your muscle cells hard enough and their mitochondria can't keep up with producing enough energy. So the lactate itself, and these studies date back to like the 70s,

it's been shown that lactate that gets into circulation and it's used by other organs as energy source for one as a fuel. Yeah, and the brain being a big one. And this is now decades of research, but Dr. George Brooks has, you know, he was like one of the first to propose this lactate shuttle theory, and he's, of course, provided evidence for that as many others have as well, where, you know, during exercise and after exercise, the lactate that is generated from muscles that gets into circulation is consumed by the brain. This has been shown in humans and animal studies, of course, but it's consumed by the brain. And also, not only is it consumed, it's acting as a signaling molecule

and increasing at the blood brain barrier, lactate itself has been shown to be responsible for the production of what's called veg F. It's a vascular endothelial growth factor, veg F. And what it's doing at the blood brain barrier is it is growing new vessels and repairing damage one. So it brings it back to what we're just talking about, right? The damage, the vascular damage at the blood brain barrier. Lactated self is a signal to increase that veg F.

It also increases brain-driventrophic factor BDNF at the brain At the blood brain barrier and in the brain as well. Where is BDNF produced? Many places it's produced in capillaries and the vascular system in the heart and muscle It's produced in the brain. So exercise Increases brain drive neurotrophic factor in many different parts of the body, in many different organs and tissues. And it's really interesting because there's some evidence that the sheer force of blood flow, so essentially like the more vigorous you're exercising, your heart's pumping, right, and your blood is just going faster. It's moving faster.

Well, that sheer force on the actual endothelial cells lining the blood vessels is a signal to increase BDNF as well. Super interesting stuff there. It also increases BDNF in muscle, which it plays a role in repairing damage muscle. It increases in plasma, brain drive neurotrophic factor, although there's a little controversy about this,

it can cross the blood brain barrier, and it also is produced in the brain as well. So all of those things. And brain drive neurotrophic factor is really important for many reasons. It's important for long-term tension, it's important for neuroplasticity. So long-term tension is basically strengthening the connections of the synapses that are connecting neurons. It's involved in basically long-term memory retention, but also it's important for neuroplasticity.

So brain drive neurotrophic factor plays a really important role in that, and that is also something that decreases with age. I think a really easy way to think about it is your brain's ability to reshape and restructure with the changing environment. Like as you're aging, things are changing in the brain. And like you have to be able to respond to that. Brain responds in a plastic way, and that happens very well when we're younger,

not so well when we're older, not so well in certain disease states like depression, neurodegenerative disease. And so that brain-driven neurotropic factor plays an important role in that. But I am going for a higher lactate. And based off of your recommendation, I got the lactate meter, the Nova, the one that you have.

And I've been using that to kind of try to get my lactate higher than typically what I think you are doing with a completely different type of training. We do kind of both ends, right? So on the one end of the spectrum, what we want to do is increase our mitochondrial capacity to maximize aerobic metabolism. And there are two ways to do that. Meaning you have to do two things. So the way I described this to people is the way one of my coaches described it to me when I was a fledgling cyclist. Your aerobic capacity is a pyramid. And the area of that pyramid is your total aerobic capacity. And to have the largest area of a pyramid, you need the widest base and the highest peak. A pyramid with

a narrow base and a high peak, yeah, not as good. A pyramid with a very wide base and a shallow peak, also not great. You want wide base high peak. Well, in that analogy, the base is your zone two threshold. It's how much work can you do while keeping lactate at that sort of threshold that George Brooks and Enigo San Melon talk about of about two millimole. So what differentiates the best aerobic athletes from someone, say with type two diabetes, which would be the opposite into that spectrum where you have real metabolic dysfunction or rather mitochondrial dysfunction,

we're talking a four-fold difference in watts per kilo output. And you just have to train at that level. You have to get to that threshold and train right there. So this morning, that was the workout I did, right? Was a zone two ride where I'm just riding right at a lactate level of 1.9 mm was where I was today. But you do need to do what you're describing as well. You have to do the pyramid building. You have to build the peak of that pyramid. Those are the VO2 max sets. And generally,

the sweet spot for building those is three to eight minutes of all-out effort for the respective duration. So obviously what you can do for three minutes and no more is harder than what you might be able to do for eight minutes and no more. My favorite are four minutes. So for example, on Sunday, that was my workout. It was, I actually did an hour of that zone two,

kind of two-millimal stuff, and then did four-minute awful repeats, where it was like much, much higher power for four minutes, and then I rested for four minutes. And then went again for four minutes, and then rested for four minutes. And at the end of those four minute blocks, you know, my lactate will be 15 or 16. Oh, wow. And then at the end of a four minute rest, it might be down to six or seven. And then we do it again and do it again and do it again.

Yeah, a long-winded way of saying, you want both. You want to build that pyramid to be as wide and as tall as possible. What I don't think I appreciated, though, was that the brain is getting a benefit from those lactate peaks. Yes, brain is getting a benefit from those lactate peaks. Yes, it's getting a benefit. And, you know, it's cleared quite quickly. I mean, it's minute.

It's minute. If you do nothing, it's, if you just stopped. And of course, athletes are even better at this, right? An amazing athlete would clear lactate within, they'd go from 10 mM to 2 mM in minutes. For me, you know, 20 minutes later, I'm back to my 0.9 mB. That lactate also is important for neurotransmitters synthesis. You're making glutamate, the major excitatory neurotransmitter in the brain. It's important for making precursors to that, nor up and naffron.

I mean, these are all been shown in human studies, also animal studies. So for me, I do a lot of tibata training. So that's even more intense because you're only doing 20 seconds on and 10 seconds off. So that's really intense. It is, and I do 16 of those. So I do, you know, like eight

and then separated by like a 30 second break and then I do another eight. So two four minute blocks. It's a total of about 10 minutes. So the first minute, I mean, like zone, and then by like the end of that minute, I'm like zone three, and then I go into zone four. What are you doing this on? Are you doing this on an air bike or? I'm doing it on a peloton, right? And my Apple Watch is beaming my heart rate and my zones

onto my screen, they're all estimated, of course, again. But I do that five days a week. It's for me the efficiency also. So I'm trying to maximize the neurobiological effects for me with exercise, and I really find pretty compelling evidence that intensity is really important with respect to that for the brain. Not that there isn't a benefit for lower intensity exercise. Certainly, people doing, you know, moderate intensity, like the more time you put in, the volume of training is like, you're going to probably find some equivalent there. But with the lactate, though, that's the one mechanism. I'm like, that is really something I personally am trying to optimize for. It's definitely a consequence of intensity.

And the fact that it's cleared so quickly and it's transient, I'm wanting a lot of it each day. I'm wanting to keep doing it. There are other ways to do it that you might want to consider, right? So you might want to say, look, I'll do those tabatas two days a week. I'll do some longer slower cardio. And to be clear, when I'm doing that zone two, it's not trivial.

I mean, my heart rate's still 140 when I'm doing that zone two, it's not trivial. Like, I mean, my heart rate still 140 when I'm doing that zone two. But what you could do is use blood flow restriction when you're lifting weights on the other days and that will get your lactate through the roof. So four days a week, you know, I'll do blood flow restriction at the end of every workout.

So two days will be upper body, two days will be lower body. And especially on the lower body days, so you've got these huge cuffs at the upper part of your thighs, and I'll do leg presses, leg extension, leg curl, and finish up on an air bike. And by the time you take those cuffs off, all that lactate that's been pooling in your legs for 10 minutes will flush through systemically and your systemic lactate level surges. What do your levels get to? What's your levels get to? What's your level?

Oh, I mean, not as high as I would get on an all-out sprint. I mean, like the highest I've ever had my lactate is about an 18 or 19, but I can still hit the mid teens doing blood flow restriction. That's incredibly high. You know, it's funny when I used to coach athletes, I worked with an Olympic swimmer who could get to 26 and still be conscious. I mean, I say that sort of half jokingly, not that too much lactate would render you

unconscious, but the pain that you must be in when your lactate is 26 is comical to me. He could finish a swim race, something like a 400 individual medley, which is probably the highest lactate generating race there is because it's all out upper body lower body assault have a lactate of 26 to 24 to 26 millimole and Four minutes later jump in the pool again and do a race and enter the pool with a lactate of maybe six. It's pretty amazing That's amazing. So my point is like you could diversify the training a little bit because again You'd still get that lactate hit But you'd also be diversifying the training because I do think performance, it's hard to make

the performance gains if you're really doing an all out tabata five days a week. I think that is hard. What kind of performance gains are you talking about within the tabata itself? In other words, it's hard to make gains on the power output that you want to be generating. Because when you're doing 20 on 10 off, you're trying to get as much power as you can in those 20 seconds. Those are what we call match burning workouts. Like you're burning all the matches that day.

Yeah. I'll tell you something that's interesting. I started, I don't, have you ever tried doing an aerobic or high intensity workout with a mouth tape where you're just breathing through your nose. I mean, you're limited, of course. I mean, at some point, you're not going to get to your, you're going to be limited by, for me at least, I can't do my all out best without mouth breathing at the end.

Once I reach 215 to 220 watts, I can't sustain maybe 225 watts. I need to start breathing through my mouth. I need to at least every other breath use my mouth. I would expect everybody's sort of different there. People are different. I mean, different nasal, I mean, like different sinuses and shapes of your nose and everything. I just recently started doing it. It was kind of odd because I actually, maybe I'm not going, I PR'd the first time I did it. And, you know, like, I wasn't going as hard on my all-out, but I think on my rests, I was going harder on my 10 seconds off. I was like, not really bringing my resistance down. Have you tried doing it where you do nothing on the off, a pure off?

What do you mean? Just like keep going. Yeah, don't spin whatsoever. So do the 20 seconds all out and then the 10 seconds you're not spinning at all. Oh, I've never tried that. I've never tried that. Well, I think the goal is to make the hard as hard as possible. And so being truly off for 10 seconds will make it more likely that you can deliver the maximum

wattage during the 20 seconds. Okay. I've been trying to do the opposite where I'm like, okay, on my off, I like keep, you know, zone three, I like still putting in quite a bit of power, right? That's good too. We used to call that sweet spot workouts where you would go zone three zone five, zone three, zone five, zone zone three zone five. But what you really probably want to be doing in a tabata is zone six, zone one, six, one, six, one, what's zone six. It depends on the system. So yeah, yeah. I mean, so technically,

the literature on this would suggest that we are only able to hold full maximal effort for 10 seconds. Anything we do that's longer than 10 seconds, we are applying some governor to the system. So at 20 seconds, even if you don't realize it, you're somewhat pacing yourself, even if you're trying to go, I'm not doing maximal. I am not, for sure. Like my husband, like, seems like he really gets to that all that, but I'm not, for sure, I'm definitely not maximal at my 20 seconds. No way. That makes sense because I don't think one could do that five days a week. I think you would fry yourself. You know, it's also really interesting. Peter is that though by like the fourth

or fifth day, I'll be PRing. So I'm always competing against myself. And my life will be lower by wattage. Oh, the peloton. No, no, I'm not nearly as scientific as you. Okay, so what? The peloton ranks you based off of. But isn't it based on kilojoules or watts? Isn't it based on average wattage? But I don't know all those off-top of hell. I said, okay. You're writing everything down. I'm not doing that. But my lactate. But that doesn't surprise me, Rhonda, because the way to get maximum wattage is to hold your highest constant maximum wattage and go. So zone four held indefinitely will produce a much higher average wattage than zone three

alternating with five or six alternating with one. So yes, if your metric of success is what is my total average wattage over the course of this workout, it will not be a tabata. It will be a steady state. All I can, you know, that's actually what's called FTP functional threshold power, which is what technically the Peloton is using to estimate your zones. Have you ever done the FTP test on the Peloton? No. No.

That's actually probably worth doing. Okay. So if you go into the Peloton, there's something called, I think it's called fitness test. And it's going to have you do either, you get to pick two eight minute all-outs, separated by some rest, I forget how much, or one 20 minute all-out. I prefer the 20 minute all-out. I think it's a better test. It will take your average wattage over 20 minutes. It will multiply it by 0.9, and it will say that is your functional threshold power, which is defined as the maximum power you can hold for one hour. And in cycling, and Peloton uses this system, that is the metric by which the zones

are set. So zones 1 through 7 are a function of power, not heart rate. And they are all a function of that FTP number. Now again, none of that's necessary for Tabata. Tabata didn't rely on knowing those zones It wasn't about titrating to a given heart rate It was simply a question of go as hard as you humanly can for 10 seconds and then do nothing for 10 and do that eight times So yeah, I'm definitely using it different you're using kind of a slightly different protocol where you're doing a workout Where you're going much harder during the rest and then not as hard during the workout because you wouldn't be able to.

Right. I'm definitely not doing it the way I guess. And how higher your lactates and you check your lactate at the end of the both sessions after the two rounds. It's all like what continuous thing. Like it's you get like a 30 second rest period between the two eight sessions. But like I'm again, I'm not resting.

Yeah, you're going hard. I'm going, I'm like probably zone three. Yeah, the end of that, now my lactate doesn't get nearly as high as yours. I'm typically like around seven to eight, millimolar. So that could give you an idea of, you know, I'm what I call a committed exerciseer.

I'm not an athlete as I would consider you are. It's actually quite different. The best athletes in the world, like world class. So both Michael Phelps and Lance Armstrong, you could argue to the greatest, both actually put out relatively low lactate levels. So you don't know. You might be one of those people who's so efficient

that you don't actually make much lactate. Like I don't think Michael Phelps is probably even when smashing world records probably ever make much lactate. Like, I don't think Michael Phelps has probably even when smashing world records probably ever seen a lactate above 10. Yeah, but I'm definitely not one of those guys. I'm not. Well, it would be interesting to differentiate for sure.

I mean, for example, so when you are doing at least a high intensity interval type of training, which I would say that this, would you agree this type of training definitely would fall into that? And of course, people generalize this term and stuff, but that's a whole other issue. But you are sort of forcing adaptations on your mitochondria to make more mitochondria. Your body's like, oh, I no longer can use my mitochondria to make energy. I got to rely on this other process, glycolysis. So as an adaptation to that, you increase mitochondrial biogenesis.

And that's been shown now in several studies and human studies. You can increase mitochondrial biogenesis now, also aerobic training does that as well. But you can take it out there with... It's really a question of time. It sort of comes down to what you were saying earlier. So if somebody says to me, I've only got 10 minutes a day to devote to aerobic training. What does it need to be? Well, the answer is clearly it needs to be the type of training that we're talking about here. Now, if someone says to me, I don't want the minimum effective dose, I want the maximum

result. Then I'm going to say, well, would you be willing to give me 90 minutes a day? In which case, we could build you the biggest pyramid, basically. I need an hour a day to build you a mega pyramid, but some people don't have the time or desire or interest to do that. In which case, yeah, we would need to just get people to doing, I get asked this question all the time. I think in 10 minutes a day of cardio and probably 30 minutes a day, four times a week with strength, you can get amazing results, but you have to be laser focused and there's no messing around.

I'm sure when you're done that 10-minute workout, there's no ambiguity about how hard you've worked. Not at all. And I feel amazing. It has to be very vigorous. It does. I do also use Peloton for my strength training as well, and there's a lot of like paired sets and supersets, and so So it's non-stop training where I'm putting effort in, but it's not a long session either. I do try to do that. I'm probably putting in the minimum amount of strength training that I can personally do, which is 40 to 50 minutes a week.

I used to not do any. So even that's pro. We have some stuff we're going to talk about at dinner here because I'm not trying to talk you into doing a little bit more. But I want to ask you, where do you put your sauna in relation to this? Do you dissociate in timing, sauna from your exercise? Do you go right into the sauna after you work out? How do you incorporate that? It varies. I do both a regular with dry sauna. Actually, I don't use it as a dry sauna. I do a lot of steam as well, but I do that,

but I also do hot tub. So I do a jacuzzi as well. And both of those forms of heat stress have been shown to increase heat shock proteins, which is sort of a biomarker of heat stress. And both of them also have been shown to increase brain-driven or atrophic factor as well. So heat, I think also plays a role in that like stress

response. It depends on the day. So I often will in the sauna, I like to read scientific papers or listen to podcasts like the drive or like I'll listen to like if someone's on Tim Ferriss issue. Like there's only a couple of podcasts that I ever listened to. Yours is one of them. So, it's not like, that's like my time, or I'm like, there's no other time. If I'm in the car with my child, like, most of the time I'm listening to frozen music, or whatever, you know, like, it's not, I'm not listening to the drive. So, it depends on what I'm doing, but also, I like to do hot tubs at night. So typically the sauna will be in the day. So I do my workout in the morning.

I'll have the sauna warmed up and ready to go and I'll get right into the sauna after my workout and I either have a paper in hand or I'm going over a presentation or something. I find it's really interesting. I don't know if you've ever tried this or observed it, but this goes way back to my days as a graduate student when I first started using the sauna. I realized that if I would go over a talk that I was

going to give like a departmental meeting or whatever, you know, I was giving a talk. If I went over it and thought about what I was going to say in the sauna, man, did I remember it better? Like it was like very clear that there was something going on with my memory. And I mean, it very, very consistent. Of course, I was diving into the literature. I'm like, there's got to be something to explain this. Lo and behold, there's certain growth factors that you make, that in the sauna with heat

stress, that do affect memory, so plausible hypothesis there. But anyways, so if I have something going on like a podcast or a presentation. What's your protocol? What's your temperature and duration in the sauna? It depends on how hard I went on like my workout too, or if I'm doing it like right after the workout, or if I'm like midday, just like, I'm going to take a break from what I'm doing at my computer, and I'm going to go read a science paper in that sauna. So like it really all depends. Generally speaking, if I go in right after I'm doing my Tabbata session, I probably stay in about 20 to 25 minutes and my temperature is like 175 degree Fahrenheit. If I am not going in right after a training session, then I'll stay in longer.

I'll stay in longer. I'll stay in probably a little bit longer than 30 minutes. I'm pretty adapted to. And my temperature will be 175, 180 sometimes. I also do the humidity, which makes it hotter, feel hotter as well. So I guess anywhere between 20 to 30 minutes and my temperature is anywhere between 175 to 180.

I used to do really, really hot about like 190, like I was doing 190 and I was getting headaches more easier. I just didn't like it and I didn't feel good. How long did you sauna during your pregnancy? How far were you able to, I'm sure women asked you this all the time and I don't know that I have an answer for the question. So I first found out that I was pregnant when I was touring Finland and everyone was like, it was like sauna, right? It was like we were going tour, you can sauna.

Yeah. And so for, I was and I'm like, holy crap. Like what am I gonna do? I felt like at that early, early stage, I mean, literally like I found out it was pregnant in Finland. And I did do a lot of son or touring and stuff and old plunging and all that at that stage. But right after when I got on the plane, come back home, son was out.

And the reason I sort of aired on the side of caution, I mean, you can, I talked to women in Finland and they were like, oh, yeah, I saw it throughout pregnancy and you'll find those anecdotes, certainly in that culture. But there is a body of evidence, a mostly looking at like hot tub. It's common knowledge, like pregnant women shouldn't get in the hot tub. Like you go to any spa, like it's like known. But there's a body of evidence that it can,

something might increase the risk of sort of like a fetal alcohol syndrome sort of thing in offspring, even neural tube defects. So I was concerned that going in the sauna perhaps could increase the risk of something like that and so I decided that it just wasn't worth it and so I did not sauna that I just wasn't worth it. And so I did not sauna at all throughout pregnancy. And I even waited a little bit while breastfeeding and stuff. I waited probably like six months or so before I really got back into saunaing. Now all the while I was exercising

throughout pregnancy and so many benefits to that. But kind of back to your question, the other protocol I do is at night. And it's interesting because doing the hot tub at night, we're in that hot tub, and it's kind of also a time that my husband and I get together away from our child. I mean, it's like our time. We're like out the stars, dark sky, like it's nice.

And that is something that my husband likes to do it, like literally like he wants to do it every night because it helps his sleep so tremendously. I don't have as much of an issue with my latency or my sleep like in general, but he does. I like, I'm asleep by 930 and it's like no, like I'm asleep in 10 minutes. Like I get in the bed and like I can be a sleep in 10 minutes. He is not that way. And he likes the hot tub.

That really helps his sleep. So I end up doing that a lot as well. And sometimes I'll do like, I'll do the sauna and hot tub in the same day. It all depends. But exercise is the most important that I have to get. And I go for the vigorous type of exercise. There are studies looking at intensity

with respect to dementia risk, cognitive impairment. You'll find all sorts of things. I think the most common thing that is pretty thematic is that the more effort you put in, the more time you put in, the bigger the benefit with respect to cognitive health. So dementia risk. And also it depends on how it's, I'll give you an example. There was a longitudinal study where women, who women, by the way, as you know, are, I think, proximally at a two-fold higher risk for Alzheimer's disease. That's right. Super interesting. But so this was in women, and they were studied for decades, and I think it was like starting from like the 70s up until like 2010 or something. And they came in for a physical,

like, put on a bike, exercise bike, and they're like fitness was measured was like empirical data. And this was like, I don't know, five to seven times. So like over the course of 40 years or something. Exactly. Something like that. And the women that were the most fit by their measurements on this cycle test, they do. Yeah, it's probably VO2 max. Yeah. So it's cardiovascular tree fitness. Those women that were the most fit, the reduction in Alzheimer's risk was like so robust.

I think there was something like, there were nine times that's likely to get or something crazy like that. The ones that were moderate, so they had a moderate cardiovascular trifitness, they had a four or five full reduction. But then you'll like look at another perspective study. Same deal with they don't come in to getting things measured, but they come in for a questionnaire.

They get a questionnaire every whatever it was over the course of like 40 or 50 years or something. So they answer all these questions like, oh, how often do you jog or bike or do you play tennis or whatever. And you look at that study and there's like no association between physical activity and dementia risk. And I'm like, hmm, that's interesting because this other study where they're actually measuring something showed a robust reduction in dementia risk. It hits home this like, okay, what study are we looking at? You'll find questionnaire studies that also show a benefit, like people that are physically fit.

And the more fit they are, there's like a linear dose response effect where you see, you know, people that put in more effort, they're training for a longer period of time and they're more vigorous or more volume both, right? They have the greatest benefit with respect to dementia risk, which isn't so surprising to me. The studies that are unambiguous, as you said,

are the ones that actually measure VO2 max because there's no denying what you're measuring. It's a very objective measurement and it basically takes out the training component because it captures that benefit. It's the readout state of the training and it basically says look maybe it doesn't matter if you do of the training. And it basically says, look, maybe it doesn't matter if you do five high intensity workouts a week or two high intensity, five low intensity, like what matters maybe more is the output. I don't know if that's the case, but there's no denying that people who have a high VO2 max are doing something that people who have a low VO2 max are not. And that's what's being captured in those studies. And the numbers are astronomical.

I won't go into them again. People on this podcast have heard it too many times because I can't stop talking about the benefits of having a high VO2 max. But I want to touch on something else you just said a second ago, which is you noted that women are indeed at twice the risk of Alzheimer's disease to men. Of course, Parkinson's flips that manner at higher risk, but focusing on Alzheimer's disease to men. Of course, Parkinson's flips that manner at higher risk, but focusing on Alzheimer's disease for a second, is there any evidence that there are gender differences

in response to exercise? In other words, are women more responsive to the benefits or more amenable to the benefits of exercise than men because they are at a higher risk genetically? I haven't seen the studies looking at the response to exercise with respect to, you know, the sex differences, but as you mentioned, like, there's definitely differences with respect to their Alzheimer's disease risk. There are different mechanisms that could, so women have different,

like there's different metabolic responses to exercise, maybe also hormonally different, this would make sense, right? Like I don't know that this has all been studied, I haven't seen that data, but like hormonally different responses to exercise, that would be plausible immune system effects as well. Exercise is affecting the immune system,

so we haven't even talked about like myocons. Like these are like molecules being secreted by our muscles. We talked about lactate. That's not a myocon. That's a metabolite. But physical activity, when we force our muscles to work hard, we're making something called a myocon. Sometimes it's referred to as an extra-kind,

but like this is irisin, is one. Isle 6 is another. There's other ones as well, but like these are also affecting the brain and they're affecting cancer risk. There may be differences in respect to like myokines that are being secreted with respect to how the stress of exercise, how that response is happening. There's also something. Let's talk about cancer because Rhonda, while I think both of us, or I think there are others who share this point of view, completely convinced. In fact, I just don't see how one could not be at this point convinced of the benefit

that exercise poses to the brain. It seems much harder to make the case for cancer. In fact, when you think about some of the things that are such obvious problems with respect to dementia, for example, disrupted sleep, poor exercise, etc., clear relationship, very hard, at least for me, to make the case that bad sleep is related to cancer, although I think it is, but the data aren't clear. You can certainly make the case that horrible sleep would lead to a weakened immune system, a weakened immune system, especially the cellular system, more than the humoral system, would easily lead to an increase in not necessarily

cancer initiation, but cancer propagation. But again, the data are so much less obvious. Let's talk about this relationship between exercise and cancer, right? On the surface, it should make sense. Exercise is good, cancer is bad, more exercise should mean less cancer. How compelling are the data? And I'll admit that I haven't gone as deep here as I have on cardiovascular disease

and neurodegenerative disease. So it's also another area that I'm very, very interested in. I mean, as you start to get into your fourth decorative life, you've now had a friend or a family member that has come down with cancer and you see, I mean, you're a physician. So of course, you've experienced it on a different level, but like, you just see how terrible it is to get cancer. And really, the best, best hope is obviously to try to not get it, to prevent. And there are, as you mentioned, there are things that can modulate that risk,

that are a little genetic wise, that are harder to kind of move the needle. But overall, so with respect to cancer incidents, it's interesting. If you look at, like, you were talking about some of these elite athletes, people winning the Tour de France, and people that are Olympic Olympic medalists or maybe that have even just entered the Olympics. I mean, you have to be quite an athlete to just get into the Olympics. And there's been a lot of interesting studies, quite a few, that I have seen. These are studies where observational data, again, obviously caveated with that. You're looking at people that have just entered the Olympics over the course

of like from 1912 to 2010 or something like that, like just decades and looked at all-cause mortality, cancer-related mortality, and compared it to like the general population. So there's a couple of the studies that have come out of the US. And if you look at both of those studies, one of them is actually looking at medalists and the other one is just looking at people that like entered the Olympics. They saved about one and a half to two years of life from not getting cancer. They had a five to six year, what you could call a lifespan extension compared to the general population, same with like French Olympians as well. Very similar where it was like they lived on average five years longer than the general population.

It was attributed that they had basically saved two years of life from not getting and dying from cancer. I guess I should say dying from cancer because they are two different things. But that would be like at the elite level. And it's interesting because you go, well, two years, that's it. That's how I see it. I'm like, really? Like, two years.

And it's funny because I remember when I was a postdoc, my postdoctoral mentor, Bruce Ames, he had said to me once me, actually more than once, you know, I once read, you know, all the things that you can do, like if you prevent cancer, you're really only saved about two years of your life. And I always thought I'm like, no way, no way. But anyways, so that would be like at the extreme end

when you're looking at the actual athletes, they're definitely less likely to die from cancer than general population people. But when you're looking at the actual athletes, they're definitely less likely to die from cancer than general population people. But when you're talking about prevention, so there's a difference between, if you read a study and it says, people that are physically active are X percent less likely to die from cancer.

So cancer mortality is decreased. That's not necessarily the same thing as not getting cancer, right? That just means you're not dying from cancer. So the study is looking at cancer prevention really seem to focus on a specific type of exercise and that is aerobic exercise. For whatever reason, there's not a lot of literature on strength training and cancer prevention. You can find studies on strength training and cancer-related mortality.

But with prevention, it's sort of focused on for whatever reason on aerobic exercise. And it does seem like there are certain types of cancer that are more responsive to exercise with respect to having a reduced risk. And some of those cancers are ones that we should care about. So breast cancer, what's the lifetime risk of breast cancer? For a woman, it's about one in eight. Pretty high for the average woman. Of course, many different lifestyle factors play into that.

And exercise is one of those factors. Colon cancers, another one that seems to be quite responsive. Lifetime risk of colon cancer for average woman is like one in 23, for a man it's like one in 25 or something like that. The reason I'm mentioning, as you know, Peter, if you're talking about like esophageal cancer, some cancer where it's like one in 500, I mean, you're more likely to die in a car rack

than get, you know, one of those cancer, I think it was esophageal cancer, but you get my point where the lifetime risk is already kind of quite low for the general person or the average person. So breast cancer, colon cancer, there's a few other cancer types that are quite responsive but those two in particular kind of stand up because with prevention, with respect to people that are diagnosed with cancer and have those cancers and then they engage in physical activity as well.

Like you see a very robust response with respect to reducing cancer mortality and also recurrence. It's like 50%. Cancer mortality is reduced by 50% cancer recurrence is reduced by 50% in those individuals diagnosed with breast or colon cancer or colorectal cancer that are engaging in more physical activity. So the question is, well, how much?

And you mentioned like you have a lot more knowledge with respect to cardiovascular disease. And I would argue the data really, I would say, suggests that you actually probably need to do more exercise to sort of reap the cancer preventative benefits than you do cardiovascular benefits, even some of the metabolic benefits.

I don't know why that is. It seems as though getting more to that upper limit of what these committees are recommending. So 300 minutes a week of moderate intensity exercise, or maybe 150 minutes more of what they would define as vigorous, which actually I think their vigorous is a little bit below what my definition would be, but so it seems like the amount of exercise you actually have to put in a little bit more time and effort for the cancer.

But any amount is beneficial. So it's not like, oh, well, I can't do 300 minutes therefore I shouldn't even care. Well, that's not true because there are benefits even with like any type of physical activity. That's all the observational data and you can find anywhere between a 10 to 20% reduction in people are that they're less likely to get breast or colon rectal cancer,

10 to 20%. Again, when you're talking about a type of cancer with a higher life-term risk, it's more compelling. So it's always kind of... I'd be curious to see if the data line up with the cancers that are known to increase in risk due to obesity. So right after smoking obesity is obviously the second leading modifiable risk factor associated with cancer. I've always thought that was an oversimplification because we use obesity as a proxy, but I think it's probably insulin resistance. That's the true marker that obesity is serving as a poor man's version of.

It would be interesting to see, because there are certain cancers, including breast and colorectal, by the way, where obesity amplifies risk. There are other cancers where obesity doesn't seem to play as much of a role. It would be very interesting to align the exercise data with the obesity slash insulin resistance data and see if exercise is disproportionately reducing risk in those cancers for which obesity is a risk. Such a good point, Peter. And I think there is at least some data to suggest that you are correct with that. So I mean, what is your like 13 or so cancer types that like obesity is known to

either 13 or 17 something like that? Yeah. And breast and whole erectile cancer are on that list. Aerobic exercise, I think there's direct mechanism. So like, you know, aerobic exercise is, you know, directly you're making those myocons and like, you know, some of these myocons have been shown to decrease the production of like growth factors to create different cancer cells. And they're also like, are killing cancer cells through a variety of other mechanisms. Also the anti-inflammatory effect

from exercise as well. You're having a strong anti-inflammatory response. But there is a little bit of that. Okay, well, exercise is also improving insulin sensitivity, particularly in combination with dietary strategies, the weight loss itself is basically a important component of the cancer, reduced cancer risk. I think it's a combination of these things where it's like the direct effects from exercise and it's really interesting because, as I mentioned, people that even have cancer, it seems like physical activity,

like I am not a non-collegist and you know many more oncologists than I do. I don't know how common it is for oncologists to prescribe exercise as an adjunct treatment to whatever type of treatment, whether it's immunotherapy or radiation or chemotherapy or a combination, whatever. I don't know how common it is,

but the data is more and more compelling, and I think it's become more and more compelling over the years that really exercising, it seems to be very important for reducing cancer metastasis and also dramatically decreasing cancer recurrence. And so a really interesting mechanism by which this is likely occurring is literally through that sheer force mechanism.

I was describing for the brain. As you know, cancer cells, tumor cells escape the site of the tumor, and they make their way into circulation. It's called a circulating tumor cell or circulating cancer cell, depending on the study you read. These circulating tumor cells are traveling throughout the vascular system to disincytes, and they take camp, and then it's the seed of a new tumor forming in another tissue.

Well, it's really interesting because cancer cells are so messed up, as they're just completely wonky and very, very sensitive to stress, any type of stress. They have these mechanoreceptors on their cell surface that are responsive to force, sheer force. So when you get your blood pumping, it's like a hurricane that wipes it out. They die because they can't stand just the sheer force of the blood flow through the vascular system.

So you compare the mechanistic studies. And there have been some studies looking at circulating cancer cells, and it's like people with those are like three times more likely to have cancer metastasis, and so on. But again, there are studies showing that like physical activity like dramatically decreases. And there's been randomized trials showing it dramatically decreases circulating cancer cells and people compared to whatever there are other in a standard treatment that they're being given.

Pairing that data with looking at, you know, other data where exercises being prescribed to patients and it is beneficial with respect to their cancer metastasis reduction and also mortality reduction, you know, like 50% mortality reduction, you know, like 50% mortality reduction universes recurrence as well. So I do think there is substantial evidence to suggest that being physically active is a good measure for

cancer prevention and again, there's also a lot of differences. There are sex differences as well. Like, I don't know why, but in some cases, women respond better. And there's certain cancer types that respond better. Lots of variables here, like I feel like I'm speaking in a general way, but there are lots of things to consider, right? There are cancer types and there are sex effects. And there are, as you mentioned, other covariates. There are obesity and there's, you know, insulin resistance age as well. So there are lots of nuanced as usual. But I do think that you can make the case that like, like, what can I do in my life to, you know, reduce my risk of getting cancer, reduce my risk of dying from cancer, reduce my

risk of getting Alzheimer's disease, reduce my risk of getting dementia, reduce my risk of dying from cancer, reduce my risk of getting Alzheimer's disease, reduce my risk of getting dementia, reduce my risk of getting cardiovascular disease, reduce my risk for type 2 diabetes. The only panacea there is exercise. It's exercise. It is the case and unfortunately it's the thing that you have to put the most effort in. It's certainly a lot easier to take a supplement, to take a pill. I do think there is an argument

that omega-3 is one of the getting yourself to a good omega-3 status and defining what that is is still like being investigated, but I do think that's a low-hanging fruit that should not be ignored, but exercise, as you've talked about many of times, is the king. That's the thing that you should focus on. If you obviously, if you're obese, weight loss, exercise is part of that program. And like, I don't think that anyone that's obese should be worrying about all the other things. Like they need to like lose weight and any personal trainer and coach, like probably is going to help you do that. You eat less. Like calories and calories out. It like matters to some degree. You're not eating as much. But as you said, exercise matters not just on the energy balance side, but exercise makes you, for example, more sensitive to satiety hormones.

So I have kind of a belief here that the person who is overweight, the person who is obese and who is clearly eating more than they should be, isn't doing that by choice. Maybe some are, but for the most part, it's hard for me to imagine there's someone who's listening to this, who's obese, who isn't wanting to not be obese and who is otherwise struggling with hunger. And I think that that's one of the challenges is why is it that a person who is not in energy balance is not responding to the normal satiety signals. And I think there's a lot of reasons. On the food science side, we could talk about a whole bunch of reasons why our food has

been hijacked, our food is void of nutrients, our food is hyper-palatable. It's far too available. There's a whole bunch of reasons. But I think one thing that doesn't get enough attention is this thing, which is an exercising person has a better sense of nutrient requirement. Their body physiologically is more in tune with their repetitive needs. And so even though I don't think exercise matters as much as intake purely on the energy balance side, in other words, I think it's more about reducing input than increasing output.

A part of that equation is the feedback loop that exercise brings. So yes, exercise just matters. And I also think that, especially in this discussion of cancer and breast cancer as the example you brought up, so many women are so petrified of hormone replacement therapy because of this awful study the Women's Health Initiative, which was completely misinterpreted.

But just to use one example of what we spoke about, even the people who ran the study, who to this day, some of them, at least a subset, still maintain that conjugated equine estrogen plus MPA, the synthetic progesterone, increased the risk of breast cancer, even those people will acknowledge it did not increase breast cancer mortality. So even if you take the most favorable to the WHOI, the Women's Health Initiative study, reading, the reading is that conjugated equine estrogen plus MPA increased the incidence of breast cancer by 0.1% in absolute risk, but did not increase breast cancer mortality. So here you have basically a non-event that has most people panicked senseless, most women

panicked senseless when confronted with taking hormones during the period. And yet at the other end of that spectrum, we have a treatment that has more than a log-fold benefit in the other direction, i.e. in reducing risk. I wish people would just allow their attention to be allocated, proportionate to the size of the impact. I'm 100% with you. And to kind of just highlight or emphasize what you just said, you know, there are studies with women who are doing moderate drinking, which depending on the study you read. For women, moderate drinking is like three drinks a day or something like it's a lot. And that literally translates to a lifetime risk of breast cancer. It's like one in six or something like that, where it Whereas pretty significant, but you don't hear about women petrified of like drinking two

glasses of wine and I, which some people do. It's actually not uncommon. Looking at like what's going to impact my risk more, what is going to lower my risk more? Like what should I focus on? Like what's like the most important thing? I think obesity does absolutely impact stress cancer, same with physical activity in the opposite direction, has really enormous benefits.

And then alcohol consumption is another one, even mild alcohol consumption. I would say that like, I don't wanna go there because it's like so complicated. And I like can't even like begin like. I've gone there Rhonda, I've gone there. I go out on the limb and I can't even begin. I've gone there, I've gone there. I go out on the limb and I'm going to say it, there is no amount of alcohol that is healthy. The J curve is a misnomer and what I think I would say is somewhere between zero and one,

there's not that much of an increase in risk, but there's not a reduction in risk. Or what? For mortality in general. Mortality. Yeah, yeah, yeah. So in other words, you know, they talk about the sort of J curve where complete abstinence is a greater risk than one drink a day. But I think both the Mendelian randomization makes that clear that that's not true. And then secondly, when you look at all the confounders of the people who are drinking zero drinks and what confounds their mortality.

I feel very comfortable saying that there is no dose of alcohol that is healthy, but at a very low dose, probably four to seven drinks per week, you probably can't quite quantify the harm. That would be my take. And so I'm comfortable saying that. I really feel confident that that is the case and that things like the French paradox have far better explanations as one example. The data is also a mess. Can you have your weekend glasses of wine?

Absolutely. I think you can. With respect to the cancer risk, that's considered it's mild. I mean, you're having less than one drink a day. And the only evidence I've really seen against the mild is on the National Cancer Institute site where they like it's one of those cancers where it's like one and 500. It increases your risk of a cancer that you already have a lifetime risk of one and 500. And it's still less than 1% of an increase. Like to me, it's like your lifetime risk goes, you can't measure it. Like you can't measure it.

It's a classic example of the dose makes the poison, but don't confuse that the poison is a poison. Another example would be cigarettes. If you smoked a cigarette twice a week, literally one cigarette twice a week, would your risk of cancer go up? Yes, but you wouldn't be able to measure it. That doesn't change the fact that cigarettes are harmful. Not to mention heart disease. Yeah, yeah, yeah. That is not a linear.

But even just focusing on cancer, right? It really comes down to kind of establishing causality. Is tobacco causally related to disease? Yes. It's a harmful thing to take, but the dose matters. Again, just being glib. One cigarette a week. It's probably increasing risk, but we don't live long enough to see the separation of those

capplin-myer curves. Maybe if our natural lifespan was 500, one cigarette a week would be sufficient to see a spreading of those lines. But at an 80 year lifespan, you have to get up to 10 cigarettes a day before we can see where that is. By the way, I'm making that up. I'm not advocating that one can smoke up to nine cigarettes a day, but you know what I'm getting at, right?

And I think that's my point. With alcohol, it's simply just a question of that. But I just want to make sure people aren't taking away from this that look, I probably have anywhere from zero to four drinks a week. But when I'm drinking those four drinks across two or three days, it's not going through my mind that this is healthy. It's like, yeah, this is a hedonic pleasure. That's not good for me, but it's enjoyable. That's enjoyable. What, how do you feel about apoi-4 carriers and alcohol consumption? Our view in the practice is that they are indeed more susceptible to the dilatarius

effects of alcohol. And also, I would say they're just more susceptible in general to the dilatarius effects of poor sleep, which is one of the ways that I think alcohol is disproportionately hurting the brain. I think poor sleep is causally driving Alzheimer's risk and cardiovascular disease risk. I'm less clear on cancer, but in as much as most people that are drinking alcohol are doing so in the evening, and anybody who's used a sleep tracker, you don't need to be mat walker to very quickly do the experiment on yourself and compare a night of sleep with no alcohol, a night of sleep with alcohol. They're different. So through that lens, I would just say we have lots of patients with E4 in our practice, including a number of E4, E4s. Even though those patients represent only 2% of the population,

they're probably about 7 or 8% of our patient population. And again, we say, look, unless this really means the world to you, it's probably not worth the drink. And if you are going to have a drink, here are some principles for how you might minimize the damage, right? In terms of the number you might have, how long you might have it before bed, that kind of thing. Exercise, you know, when I, a couple of things, just because you brought up the sleep in. So I started wearing a continuous glucose monitor largely because of thing. Exercise. You know, when I, a couple of things, just because you brought up the sleep in. So I started wearing a continuous glucose monitor largely because of you. I've been a very bad influence on some things you've done, the lactate monitor, the CGM.

Yeah, well, I started wearing it when I was a new mom. So this was, you know, like five years ago. And I can't be a good time to wear a CGM, although it must have been interesting, right? It was extreme. So here I am coming into this, like, oh, I'm gonna learn about the foods I eat and how my body responds to those foods. And lo and behold, the biggest and most compelling and most important data point, or many points,

because I had many of them, that I sort of learned from wearing my continuous glucose monitor, which I'm sure most of your listeners know about, where you're measuring your glucose level continuously, was the effect that my sleep interruption had on both my fasting blood glucose and my post-print, where I was like, I could get what we can be considered pre-diabetic. I was blown away. I was like, what is this is insane? And then what I also sort of gleamed from this was that on days, and the effect lasted at about,

I would say about 48 hours or so. When I did work out, at the time I was doing a lot of high-intensity interval training. It was like an hour-long spin class I used to go to, where they do all this interval training. It almost completely blunted that effect. Even though I was dog tired, the last thing I wanted to do was go to my damn spin class. This is like, it's gonna be bad for me if I go,

that's how I felt, it's gonna be bad for me. But it was completely the opposite, where this crazy glucose dysregulation and whatever the causes for them, sure you know much more about that than I do. It was almost completely blunted and it was so profound and it was like the one, all the food stuff, you know, I learned a little bit of interesting, but really that was the thing that for me was like, I have to work out no matter what, no matter what, no matter how I feel, it doesn't matter,

it's beneficial. It was a really interesting study, caveat, observational data, reverse causation, all the problems with any study. But it was looking at the sleep habits. And so people that had slept, you know, was poor sleep or interrupted sleep. Something of that nature, I can't remember all the exact things that were measured with respect to sleep. But people that didn't sleep as long or had poor sleep, whatever measurements, had a higher all cause mortality, which is not that surprising. But only in people that weren't physically active. And to me, I was like, wow, that's interesting. That's interesting. It's interesting. And it's like, you know, exercise can forgive a

lot of sins in many ways. It really can. So you're talking about your patients with E4, E4, and I'm sitting here going, oh my gosh, I've got one of those, and I'm already like, it's a lot. It's a burden. You have to calculate things. You have to be very, you know, specific in your actions you take and like things that you don't do, things you do, right?

And for me, it's like, okay, am I going to, I'm having a party, we're gonna have some memos as whatever, like, I'm gonna exercise no matter what. And that might take off some of the stress. I personally, I hardly drink. And mostly because I am E4, I have one allele, and I have pretty much come to the conclusion that my brain can't repair damage as well as my husband's who doesn't have any for allele.

With that said, I occasionally will, I'll have like maybe a glass or two of wine, usually that's my preference, but you know, a week. Last time I had a drink was like Valentine's Day, you know, so it's been a while. But at least I think with the sleep, sorry, with the exercise, you know, again, it's like, it does. It seems to forgive a lot of sins, honestly. I like that way of describing it. I kind of borrowed that from Stuart Phillips.

I think he was the one that said it to me because I was like, this is like... That's right. I remember him saying that on your podcast. He gets all the credit. And that, of course, brings us into the whole, like, protein intake and muscle mass world But so let's set this up for listeners because you know you and I have talked about this a lot In fact, I remember probably the last time this is pre-COVID because we were both in San Diego

You and your husband were for dinner. I think I cooked up some fresh venison that I had just killed and We were kind of talking about protein. And I think at the time, both of us were kind of struggling with two competing ideas in neuroscience. And those two ideas that seemed dialectical, they seemed at odds, was on the one hand, there's this body of was on the one hand, there's this body of mostly kind of animal literature that suggests lower protein intake is associated with a longer life. But on the other hand, there's this literature that says lower protein intake is associated with more frailty in humans, and that's associated with a shorter life. So how do we reconcile these two things?

And we didn't have a great resolution on that. I mean, we both kind of felt like we were sort of scratching our heads thinking, at least, I don't want to speak for you, but my thinking at the time, this is again three and a half years ago, probably was we just got to find the minimum effective dose. What's the minimum effective dose of protein to not undergo

mandatory catabolism, and that's what the dose is. And of course, it's not clear how you find that dose. Theoretically, you would use a metabolic cart and try to identify nitrogen balance and things like that, but of course, no one can do that outside of a lab. So it was a bit of a head scratcher. Now, my thinking has evolved so much on this, but I'd like to hear, first of all, I'd like to hear your formulation of the problem that I formulated the way you would. And I guess more importantly, tell me how you're thinking today. So you actually did a very good job on formulating my mentality with respect to protein intake and longevity back in 2019 prior to that.

But like, even up until now, even that long ago to be honest, there's, as you mentioned, a large body of animal evidence, but also there was coupled epidemiological data where you think people are looking at vegetarians are taking in lower amounts of protein and they're all cosm mortality and they're cancer mortality and they're just study after study after study and they have a lower all-cause mortality, lower cancer mortality. But only in those individuals who are not obese, not sedentary, sorry, are sedentary or smoking or, you know, they had some unhealthy lifestyle factor. So in other words, the people taking in higher protein, animal protein, who were basically healthy, had a similar

cancer related mortality, all caused mortality as these vegetarians. Okay. Similarly, studies where they normalized for fruit and vegetable intake, high protein versus low protein, no difference in early mortality. Yes, it seemed that a lot of the data that were espousing low protein were confounded by lifestyle choices and high protein was also negatively confounded by high calorie as the most obvious. Exactly. And with the animal data, and this is probably where my mentality has shifted the most because I wasn't really of the opinion that vegetarian diets were superior to meat eating or, I guess, omnivore types

of diets that were healthy omnivore types of diets because of what you were saying. Like that data was nuanced and it wasn't just like, that wasn't something I was that has shifted the way I've been thinking. But with respect to a lot of the animal data and the mechanisms and you can restrict a mouse of protein and make it live longer and not get cancer and you know, all these things that you see study after study, I mean, it's just like the longevity science

and that whole field is like dominated by that. Like, at least was. And there's now, I think some pushback going on, but there's still a large group of scientists that are still publishing lots of animal data. And this is where I sort of started to look into some of these exercise physiologists, people like Stuart Phillips. I know you've had a ton of layman on these like giants in the field that are doing

the research. And Brad Shownfeld is another one where they're looking at protein intake. They're looking at strength training and its effect in humans on muscle protein synthesis. And also just like looking at data with respect to muscle mass and all cause mortality. And Alzheimer's disease dementia, we didn't talk about that, but strength training also can modify that risk, also cancer mortality. Yeah, strong grip versus weak grip, monotonic change in grip strength, 70% reduction in incidence and mortality from dementia. I mean, 70% reduction in risk.

Remember, people don't understand you can't reduce risk more than 100%. So it's not like increasing risk, which can be 100, 200, 300. When you're talking risk reduction, 70% is staggering. It is. Strength matters. It does. As you know, in many of your listeners, there's two important signals for your muscle. Of strength, obviously, a big component of that is physically working them, but protein

intake plays a role there as well. And I think it was Stuart Phillips, like, phrased it this way where the animals that are being studied in these labs are in a sterile environment. You know, they're in a sterile environment. They're not being exposed to influenza and all these infectious diseases. And any of us, we've had a parent or a relative or someone that has gone into the hospital and maybe had bed rest. And then come out and like, I had a grandparent who literally couldn't walk after a back surgery forever.

Like, that was it. That was their downfall. It was like the trajectory was their downfall. It was like the trajectory just went down, completely down. So losing that muscle mass when you're in older age, obviously building up a bigger reserve in youth in middle adulthood, whatever. Like that's very important. But like these animals that people are manipulating

the protein restriction in them, they're not being exposed to that. They're not losing like, I don't know what percentage it's pretty intense, like how much you can lose from like three weeks of bed rest. And also, like, as it's been pointed out by people in your, I think, Matt Kiberlein, you know, mice are dying from, like, cancer. They're not dying from the same diseases. And it's not even the same type of cancer that humans get.

We get a lot of these epithelial tumor, solid tumors. They're like dying from lymphomas. So there's a lot of differences there as well. There's a lot of interesting, and I'm the one to have talked a million times about animal studies. I think they're important, mechanistic data. There's things you just one never get from humans. But at the end of the day, I started to realize that looking at mice in a sterile environment,

whether or not really being exposed to the same stimuli as humans, things are very different in terms of aging. It was falling apart in my mind, basically. It was like all falling apart. I'm like, this doesn't make any sense. This isn't what to be looking at if I'm wanting to really focus on healthy aging

for myself, for everyone else. So I think that's kind of what was the tipping point for me was just kind of that realization of the importance of muscle mass and how, you know, some of these animal studies you look, they have a little bit of an improvement in their cardiovascular health. And I'm like, exercise, okay, is that better than exercise? No. The things that were improved, I was like, exercise, does that? Exercise, does that? Like, this isn't convincing me that

I need to like do that. I think it was just kind of like a shift in the way I viewed the data, like the lens I was seeing it through. I'm still waiting for somebody to demonstrate for me that if there is an increase in the risk of cancer associated with higher protein intake, in humans, I'd like to see that quantified. But I would like to see somebody demonstrate that if there is an increase in risk, that quantifiable increase in risk is greater than the offset of sarcopenia. Because that's something for which there is no ambiguity. We have all the data in the world to point to the devastation of sarcopenia on an aging

population. And we know full well that two things have to be true to avoid sarcopenia. Adequate protein intake, which as you age gets bigger and bigger, that number goes up and up and up due to anabolic resistance coupled with strength training. So here we have something for which there is no uncertainty. You must consume increasing amounts of protein and you must do strength training to ward off sarcopenia as you age. And if you don't, here's your mortality trajectory in its awful. Let's compare all of that to this questionable risk for which frankly, I don't

see data. And I'll add one more point to what you said, Ronda, which is, I think this story got confounded by our good friend C. elegance. So let's go back 29 years, roughly, call it 30 years directionally, when some very seminal and interesting work was published, looking at the DAF 16 mutation in, or maybe it was DAF 2. I can't remember if it was DAF 2 first or DAF 16, but it was the analog of the IGF receptor.

And if you knocked out that gene, you could double the lifespan from roughly two weeks to four weeks or four weeks to eight weeks I forget what it was of sea elegans this worm. The implication of that was profound. I don't want to down play the most important Take away from that which was lifespan was malleable. That turned out to be very interesting. I could go on my rant about why sea elegans is not an organism or an animal model that offers any insight into us based on its cell based on a whole bunch of things about its biology but nevertheless it somehow became knocking out, Daph 2 or Daph 16 was tantamount to dropping IGF insulin-like growth factor 1 to 0 is the key to longevity and the way to do that is to have no protein. And I think that story is so incorrect,

but somehow it's become part of dogma. I think that's the other piece of this that just kind of won't go away. It's funny because I've done those experiments with my own hands when I was at the Salk Institute and I was in Andy Dillon's lab who had trained with Cynthia Kenyan who made the discovery back and was it early 90s or something. Yeah, I feel it was 93 or 94. Yeah, and it was very exciting for me at the time because it was like, oh, this is a homologous, we have, and I'm watching it go from a 15-day lifespan to like a 30-plus day. And not only that, you know, these were- No, the lifespan was remarkable. They were youthful. I mean, like, you could see them, you look at a microchip and you see how they move around.

And as very apparent, they were acting like a youthful young larva that had not been born long ago. But then you also realize they go into this dour state where like in order to get that lifespan extension, they're like going into this like metabolic stasis and like this thing that we don't do, humans don't do a doubt. It's a completely separate pathway that is required for that lifespan extension. And I think to your point about the IGF-1, the insulin growth factor receptor, and also the insulin pathway,

they're kind of both tied into that. The fact of the matter is, is that that is a growth factor. You know, and I've talked about this before, you know, growth factors in the context of a tumor can allow tumor cells to override cell death mechanism, so they can continue to survive when they otherwise might have been signal to die. And so there can be a problem with too much IGF1 in the context

of a tumor and what causes that high IGF1 is up for debate. But at the end of the day, it's not that high IGF1 that is necessarily causing the tumor. I think there are things that you can do in your lifestyle, like exercise actually causes IGF1 to go into muscle where you're repairing damaged muscle, it's helping muscle repair. It goes into your brain, it's important for like neurogenesis, a little bit of controversy there I know, but like I am in the camp that you adults are. Their studies showing, multiple studies showing that you can take an older adult, train them

for a year, and their hippocampus will grow by like one to two percent. Like, there's multiple studies. Also another study showing this with the sub-friend-trickular zone. So these are two regions of the brain, where I believe data that says that adult neurogenesis or the growth of new neurons as an adult is occurring. And I think exercise is a big thing. And do you think that part of the vehicle for exercise to do that is through IGF1? Uh-huh, yeah, absolutely. It is.

Interesting. Animal studies have shown that. Again, you know, we all know about the caveats as a transit to humans, and we don't know. But often time you have to take the whole body of evidence. The human evidence, couple it with mechanistic data, with animals, and try to kind of put together a story to the best of your ability. I mean, that's all we're going to get. You always hear about, I want to lower IGF1, but you know, it's actually like important

for the brain and important for muscle. And the way to get it to the brain is through exercise that's known, and it's been shown again in human studies as well. I think also part of the problem here is in some respects, people that are doing, I mean, really impeccable animal research. You look at the data and it's like, oh, they're doing this study gray. This is a good study.

I mean, like, you can't poke holes in it with respect to the animal world, but then sort of translating that to humans and considering who are we talking to? Are we talking to an overweight obese person? Maybe they're probably getting enough protein. Like I don't know that they have to worry so much about protein intake.

I think they need to focus on losing that unhealthy weight. But that's also really important. And I think some scientists and also health science communicators also sort of maybe, and I've been sort of guilty that as well, like disentangling who are we talking to? Are we talking to the obese person who clearly needs to focus on weight loss? Or are we talking to the healthy, physically active person who's now terrified to take protein in because of they read about some animal study, where too much protein increases mortality. And also, I think age is such an important part of this again.

So if you look at that, I think it was Levine in 2017 had that study where they look at the relationship between protein and IGF1, but stratified. So they stratified by protein intake, low medium high, low medium high, and then they looked at middle-aged people, so 50 to 65 and then people over 65. And in people aged 50 to 65, there was a relationship between protein intake and IGF. Higher protein intake was associated with higher IGF. That wasn't a huge difference. This gets over stated constantly, but it was statistically significant. But what often gets

ignored is the people over 65, there was no statistical difference whatsoever between protein intake and IGF 1. Again, this has taken as dogma that the more protein you have, the higher your IGF 1. And in people over 65, that's not the case. Now, why do I harp on that? I harp on that because it isn't exactly that population that I am most concerned with sarcopenia. So if the message is somehow getting transmitted to somebody listening to this who's 65 or older,

that I shouldn't be eating protein, and they might not even know that it's through IGF, but somehow, I protein is going to give me cancer because someone who's telling them that is telling them that through the lens of IGF, the answer is, first of all, no, it's not. And secondly, the greatest risk you face, again, is going to be the results of low muscle mass and low strength. And even if we believed, which I don't, but even if we believed that in that age, in the younger people eating more protein leads to more IGF, which is bad, I would argue that the absolute risk of death is so much lower in that group

that the absolute difference in mortality between the younger and the older in the presence of high protein is no comparison. What I mean is higher protein across the board is going to save more lives than it would ever hurt in younger people, even if you could convince yourself that higher protein intake was associated with increased mortality. Again, I find these data unassailable, especially in the older population. I think Matt Kibbleman, I did talk about this

on a podcast once, and I worry that as you do, that that information is not making its way clearly to people of the susceptible age group. Right, and I think also that a lot of people are focused on the recommended daily allowance of protein, right? Well, then, right. Like, what are these old ass studies that were not done correctly using the wrong tracers? Like, what is that telling me about how much protein I should take in? And this is also

another sort of, like, it was a turning point for me because I knew nothing about... How the recommended dietary analysis would determine, yeah. And I know everything about micronutrients and RDAs, but I knew nothing about how the recommended dietary analysis was determined, yeah. And everything about micronutrients and RDAs, but I knew nothing about the protein. Once I talked to Stu, it was clear. He was like, oh no, we repeated those studies, him and many others, using different tracers. And I can't tell you all this tracers and stuff

because it's not my field. But it was like, no, we determined that the minimum was really more like 1.2 grams per kilogram body weight, not 0.8. And to me, I was like, oh, wow, because you know, you don't store protein. This is important because, I mean, that's a big difference. And then on top of that, when you start to get into the physically active people or elderly population, as you mentioned, anabolic resistance, where they're basically like, their muscle

isn't getting that signal as well to increase muscle protein synthesis from the same amount of protein that they're younger self-wood. So they actually need more of a dose up to like, I don't know, 1.6, 1.8. We basically tell people aim for one gram per pound, which should be 2.2 grams per kilo, because the other thing that complicates it, Rhonda, is not all protein is created equal. So if you're getting a reasonable amount of your protein from a plants, you're getting a lower bioavailable amino acid. You're also not getting the same quantity of lucine lysine and methionine, which are probably the three most important amino acids anyway. So, you know, one of the things Don Laman talked about was, if you really want

to be rigorous about this, you probably want to track those amino acids. And you really want to say, look, make sure you're getting one gram at least of methionine per day, two to four grams per serving of lousine and lysine. Now, again, for a lot of people, that's too nerdy, but you can go through the math a couple of times with certain things that you eat repeatedly, and you'll realize that's probably more protein and aggregate than a person is used to eating. And as you said, when you start to factor in those two other categories of risk, right, more demand. So when you're doing those high intensity workouts, you are ripping apart muscle fibers when you're lifting weights, when you're rucking, when you're doing all these other things you have to do,

you're demanding more amino acids for the turnover, and then of course, antibiotic resistance, I think, is the biggest issue. And something that truthfully, up until two years ago, I just wasn't paying enough attention to. I wasn't appreciating that my older patients had an additional problem that younger patients didn't have with respect to that signal. 2.2 grams per kilogram by way, that's for me to get 1.6, like I am supplementing. I'm taking way protein, like, so how many meals?

Typically four. It have to be. Yeah, it has to be. So for me, it's really two meals and two snacks. And the snacks are just protein snacks. So it's a shake. So one of them is just a way protein shake. And then one of them is I eat these venison jerky sticks.

So five venison jerky sticks is 50, they're 10 grams a piece. And they're really good. They're super pure venison. It's, you know, wild game. Amazing product. I should disclose them and invest in the company that makes them by the way.

I was gonna ask do you make them? Is it like a career? No, I know that people say, well, I know everything about it and I know that the quality is there. So those are two snacks. Otherwise, they're relatively low in calories. My way protein shake doesn't really have anything else. And it except some frozen berries and almond milk. And then the medicine sticks are what they are. And then two meals that are going to have protein. And for me, again, a lot of times like it's going to be an omelet and then protein dinner. So not going to deny it, it's work. It probably consumes more of my dietary planning

and dietary attention than anything else. I don't pay any attention to how many carbs and fat I eat anymore. I'm just paying attention to protein intake. It's something I never really paid attention to at much at all until I would say like last June or July is when I really started focusing on strength training, you know, both for my muscle, mass, and also bone mineral density. Like that's another thing where it's like you want to reserve of that as well, especially as a female. Focusing on the strength training and also the protein intake.

And it's been quite challenging. I've always sort of focused on micronutrients. It's still a focus of mine and like making sure I'm getting enough of those. And I do supplement as well, you know, in addition to trying to eat like leafy greens and getting some of the veggies and stuff. It's either going to be roasted veggies for me or like salad. But the protein intake, it's been challenging. And I find I typically do three meals. One of them is a protein meal snack. So it's some salmon or like a homemade turkey burger or something like that. But then the protein shakes also is where I have to do.

I guess that I don't really consider it a meal but it kind of is. It's satiating. The protein shake is definitely satiating. And I'm already, it's even kind of hard because when you work out, like as you mentioned, your satiety hormones go up. Like I'm not hungry, like I don't necessarily want to eat.

It takes a while before I can actually like even get an appetite. So there's all these like competing things where I'm like, trying to get the protein, but I'm like, I'm not really hungry and I'm like, I know I need it. So all these little important factors and yet again, important to sort of highlight that I don't know that someone who is overweight or obese

necessarily needs to focus so much on that, right? Do you agree? That's right. Fortunately, most people who are what I call overnourished are also adequately muscled. And they can actually in the short run be okay, losing lean mass. In fact, it's very difficult to lose heaping amounts of body fat while preserving lean mass. So we tend to focus more on the coloric restriction coupled with the training. We use the training as a way to offset some of that lean mass loss, and then we can come back to it. Now, that said, so it depends on the strategy, depends on the dietary strategy. So for people who are using tracking, kind of the caloric restriction way, we would still set a protein target that is at two grams per pound because of

the satiating benefits that you said. Also, you have the thermogenic effect and the benefits of protein overfat and carbohydrate from a thermogenesis standpoint. But when you have people that are going about it via dietary restriction or time restriction as their strategy for cutting calories, it can become a little overwhelming and when you force high protein, you sometimes end up getting high calorie with it. So that's where we would say, just don't pay attention to it as much, just focus on the DRTR approach. The other place, Rhonda, where we do pay a lot of attention to protein, is in the few of our patients that are taking GLP1 agonists. So, I've been a pretty public critic might be too strong a word, but I've certainly expressed my reservations about the ubiquitous use

and the liberal use of GLP1 agonist, especially in people just trying to lose 10 pounds, right? Like it's one thing if you're 100 pounds overweight and you've tried everything by all means, the benefits clearly outweigh the risks. But I got to get my beach body on for the wedding this summer. I'm going to lose 10 pounds. Let me fire up some semi-gluteide or Terzepatide. I think that's a net negative personally. In those patients, not that we're giving it to those patients, but in any patient who's

on a GLP1 agonist, we feel it is so essential to hammer home protein because those drugs are so effective at squashing appetite that we've seen people who basically just want to drink alcohol when they're on it. And they'll lose weight like crazy, because they're not getting that many calories, but they're like, yeah, I just like wine. I'm losing muscle. Yeah, I'm just losing muscle, drinking wine. Yeah, I've got some acquaintances that are of that category where it's like stay at home

home, once they lose 10 pounds, has the means to get it and does it. And we haven't measured muscle in the, but I look at them and I'm like you look like you're wasting your like your muscle is wasting. If you're not eating you're not taking in protein so I mean like that makes hundred percent sense and it also I don't maybe we'll talk about this when you come on my podcast but like I'd love to like because you used to do a lot of fasting and you don't do as much at least of the long long fast and I would love to get into that and decide whether we should do that next time or we could talk a little bit now.

But yeah, that was also like the biggest, you know, there was another shift in my understanding of fasting and time restricted eating. A lot of people use time restricted eating. They sort of practice it by skipping meals. And I don't know necessarily that's the way to do it, but people do that. It's just, you know, what people do. And when you're skipping a meal, you're skipping your protein.

You're basically becoming losing muscle mass because you're not getting that important signal, especially if you're not doing resistance training. Then it's like kind of a disaster. And that was also something I hadn't thought about a lot. And I know you've got a lot of experience in it both personal and clinically. I'll share with you briefly how we think about that. When the time restricted feeding part, we agree that the greatest drawback is that the patients get protein deficient. So time restricted feeding as a strategy for weight loss vis-a-vis caloric restriction

is very effective with a small enough feeding window. So a 16-8, you can eat your way into obesity with a 16-8. But once you start getting down to a 24 or a 22-2, basically just doing one meal a day, really getting restrictive, for the most part you're gonna lose weight. The problem is, by definition,

you're not gonna get enough protein in because even if you managed to scarf down one gram per pound of body weight in a single meal, you wouldn't be able to utilize those amino acids. You kind of tap out at about 40 to 50 amino acids per meal. So if you sat there and had 160, you just flushed a bunch of them down the toilet. They're literally not coming down the toilet. they're coming out as piece of a urine, coming out the urea cycle. So the thing that we would counsel people on

if they're going to use time restricted eating is they have to have protein snacks outside of their feeding window. So if they're gonna say, look, I'm gonna only have a lunch at two o'clock and a dinner at seven o'clock, we'll say fine, but you still have to have two protein snacks outside of that. And that becomes challenging because those protein snacks can't really have much else in them. They have to be very low calorie otherwise. Otherwise, you're not really

doing time restricted feeding. And of course, a lot of people get phosphorylated over this. They say, oh my god, that's like outside of my feeding window. Well, that imparatophagy to which I argue, you're not getting any autophagy doing a single day time restricted feeding. Anyway, it doesn't matter. But if people are getting gut benefits from taking that time off, then yeah, they're going to miss out on those. Because you're, I just don't see how you can get the gut rest

if you're trying to get those amino acids. So you might have to really start to cycle those things. But yeah, long-winded answer to why I think fasting can really be at odds with the adequate maintenance of muscle, and as we get older, I'm just entering my sixth decade. This is a very high priority for me. Oh, really?

Wow, you look great, Peter. You're in your life at least. No, six decades. So just turn 50. Oh, so you're 50. Yeah, gotcha. I love that you thought I was 60, that's awesome. You know who's.

I'll take that as a. I think Joe Rogan's entering that, and that's kind of what I was thinking. And he looks, you can definitely see the people that put in the work and work out, and they do aerobic, they do strength training, you look at them. There was a study published on that too.

A bunch of biological markers of aging and biomarkers of aging were measured. And then people looked at pictures and like ranked their age. And they're quote unquote, biomarker biological age, according to all these biomarkers that's basically say their chronological age

may be older than their biological age, but they looked like their biological age and not their chronological age. That's also important. Although I sometimes feel like excess exercise can prematurely age you as well. I've certainly seen a lot of, and I don't know how much of that is the sun damage,

because of course a lot of exercises done outdoors, and of course sun can play a horrible role in that. So I've taken up more of your time than I said I would, but I want to ask you kind of just one last thing. Is there any other just sticking with this theme of things that you believe today that you didn't believe three or four years ago, or things that you believe three or four years ago that you don't believe today? Is there anything we haven't touched on because we've talked about some really good ones. I think those are the really important ones off the top of my head. I definitely don't want to get into the whole COVID thing at this point.

My view has changed on things as that has progressed and changed as well. So I don't want to like not mention it, but I think the most important things would be muscle mass, protein intake. Also fasting, and I think the effects of time-restricted eating on weight loss specifically when you're looking at that outcome being attributed to caloric restriction. I think that is something that I've, you know, wasn't always, you know, buying into that. But it is still my opinion there are benefits to eating within your circadian rhythm. Eating late at night when you're making melatonin

two to three hours before bed, you're basically inhibiting insulin secretion. And there's data showing that glucose levels will be higher with the same exact macronutrient intake as if you eat it earlier. So there are benefits, circadian benefits. And I also think you mentioned the gut rest and like digestion, you know, resting.

So DNA repair mechanisms, you mentioned atophagy, like those things happen when you're not digesting and that process, like, isn't happening. So you have to have like a rest period for repair processes to occur. And I don't know that I necessarily, I think atophagy is as good as the markers that we are sensitive assays that we have to measure it.

And I don't know that it's settled. I personally think there's probably even in-between meals. There's some amount of a topogy. A topogy is happening in us. It is. And it's not like we're not clinically significant. More so than say exercise would induce. No. The exercise is is not like how long would you need to fast to get the benefits of an amazing workout? And my thinking is probably a long time. You might have to go a full day without food or a couple days without food to get the benefits of that. But you're right. I think without biomarkers, a lot of this stuff is very difficult to speculate on because we can't really extrapolate from mice on this stuff.

It's so non-linear that I don't think I could, and I've never heard anybody offer a very compelling argument either for what the quote-unquote answer is. I agree. We can extrapolate from mice, and the way I view it though is more of a cumulative effect, where I'm thinking it's better to just eat within a circadian window. And do I think that's going to have a cumulative effect on metabolism? And yes, I think that it's better that I'm not eating within a 15 hour window, which most people in the United States actually do. They're eating from start to finish like a lot of people are eating within a 15 hour period. If you're exercising, maybe it doesn't matter.

Maybe you're right. Maybe they can't eat within than a 15 hour window. We don't really know, but I tend to think probably the circadian component does play some role, but the question is, is it significant? I am of the opinion that probably is cumulative, or... For no other reason, I think it just is on sleep.

On sleep. Yeah, exactly. Like if you just looked at the benefits of nighttime food restriction in terms of, as you pointed out, we're at least insulin sensitive. And the negative impacts, probably of thermogenesis and other things on sleep, that's probably the most compelling reason, even if nothing else mattered, if we couldn't measure it. But those are so abundantly clear. That says clear as how alcohol impairs sleep. even if nothing else mattered, if we couldn't measure it. But those are so abundantly clear.

That's as clear as how alcohol impairs sleep. A late night meal is a great way to destroy a good sleep. Right, I think most people have, is anecdotally like people realize that as well. So yeah, I think we covered a lot of the things that my perspective has shifted. As any scientist that's following data should. Some people will argue, oh, you changed, you know,

how can I follow you, you changed your mind? And it's like, well, like when new data comes out, you have to reassess things. Like I reassess the supplements I'm taking. I mean, the supplements I take now versus five years ago, totally different. Not all of them, there's some base things. Like I like vitamin D omega-3 like those

are like super important, I think. But you have to reassess things because new data comes out and you might have a new understanding of things that we didn't know. We have new tools. It's always getting better. So you have to kind of reassess things. So Rhonda, for folks to follow you, obviously your podcast found my fitness. Great way to follow amazing content. Also, you put up a lot of content. I think Instagram is probably where you're putting up most of your content. Is that safe to say that if folks follow you on Instagram, that's where you're doing sort of thorough analyses and stuff like that. Would you recommend people also check out Twitter? Where should people be going to see your thinking on a frequent basis? Well, it depends on what they like to consume.

So if they like to consume like in-depth articles, we publish them on my website, foundmyfitness.com. We have like topic articles that we cover, we cover blood brain barrier is one. So we cover that in more in-depth. Some people like to read, they like to nerd out on that. So that would be the place for that. And then some people just like short little to the point,

you know, and that is where if they want like quick thing like the Instagram, so I found my fitness on Instagram and also Twitter as well. It's kind of like a short, I mean, you only get so much time on Twitter, you can't go in depth and nuance. And then I sort of have a love hate relationship with Twitter. It is kind of a fun place to also like, there's other scientists on there as well. And so I'm on Twitter and Instagram. And it's all the same handle. Yeah, I found my fitness and then the podcast as well, which is Apple Podcasts Spotify.

Andrew, Kuber and I were talking a little while ago. And we were sort of singing your praises as truly the OG health podcaster. When did you start? Was it 2014? That was when I started the podcast. It was a weekend. I was doing my postdoc in Oakland.

And I just started like Ron Kraus down the hall. George Brooks. So I have a podcast with George Brooks on Lacta. Like he was like my second podcast. I don't think I've heard that I need to go and listen to that one. Yeah, we went all into the brain. That whole podcast shifted my thinking of like intensity of exercise and the importance of lactate. I don't know if you know this, So fast-wraiting. So fast-wraiting. So fast-wraiting. So fast-wraiting. So fast-wraiting. So fast-wraiting.

So fast-wraiting. So fast-wraiting. So fast-wraiting. So fast-wraiting. So fast-wraiting. So fast-wraiting. So fast-wraiting. So fast-wraiting.

So fast-wraiting. So fast-wraiting. So fast-wraiting. So fast-wraiting. So fast-wraiting. So fast-wraiting. So fast-wraiting. So fast-wraiting.

So fast-wraiting. So fast-wraiting. So fast-wraiting. So fast-wraiting. So fast-wraiting. So fast-wraiting. So fast-wraiting. and cancer. And so of course, like lactate, I mean, I was thinking about it in a completely different frame of mind. As opposed to, I mean, we now know it's such an important signaling molecule. In addition to all those other things we talked about, you know, we've had at least one guess suggest that George Brooks is deserving of a Nobel Prize.

His lactate shuttle theory, it's called a theory. And I kind of hate that. It's called tap because people hear that and they're like, oh, it's a theory. Yeah, it's not proven, yeah. But it's been proven. And in fact, there's like studies like even, like there were people that and they're like, oh, it's not proven. Yeah. But it's been proven. And in fact, there's like studies like even like there were people looking at this

like even before he proposed like they were looking at lactate getting in the brain in responsive physical activity. And it's like beta hydroxybutyrate. It's a signaling molecule. It activates BDNF like beta hydroxybutyrate. They go through the same transporter monocarboxylate transport of the MCT transporter to get into the brain. There's also those in mitochondria, but it's so funny because there's a lot of similarities

that affects on TBI. So, you know, George Brooks has done some studies, USC looking at some of these victims of TBI and giving them lactate and it's like improving whatever their glass-cow or rating scores and whatever the things that they're looking at. But like, I think beta hydroxy butyrate wasn't there some evidence, I think, with TBI. I remember Dom talking about that. Dom talked about this. It's so interesting because also with respect to Alzheimer's disease and there's some really

preliminary data that of course needs to be repeated, probably won't because you can't get funding. But giving beta hydroxy butyrate BHB to people with Alzheimer's disease can help improve. There's some small clinical studies looking at improvement in cognition. Lactate's like, I think similar. There's a lot of overlap there. Now lactate you can make. Beta hydroxybutyrate you make from exercise as well.

You like push yourself into ketosis. So to be interesting, if there's synergy there, trying to get the lactate and the beta hydroxybutyrate, the neurobiological effects of them, to me, it's so important. It's so interesting. I kind of want more research in that area, and so I like talking about it because I know scientists listen to your podcast, researchers, physicians. It's good to kind of like spread ideas. I mean, that's part of what the podcast does. Spreading ideas is not just like, I'm a communicating the health ideas. And it's like scientists are listening to this

and they're outside of their like lens where they're only thinking about the thing that they research and they hear this at, and it's a creativity. They start to go, oh, like, I've seen that happen. Scientists like doing experiments based off of like listening to podcasts and stuff. I think it's really great. But thank you for the OG. Yeah, it was a weekend thing for me What happened? Scientists like doing experiments based off of like listening to podcasts and stuff.

I think it's really great. But thank you for the OG. Yeah, it was a weekend thing for me and I loved it. It took off. I just, I love it so much. I know you do as well. I mean, it's like, by the way, phenomenal podcasts. It's funny.

I don't listen to podcasts much at all, as I mentioned. But there's a few people that I trust to really be vigorous in their research and to be critical to really like dive down and like get into the root of things. And you are like one of those people. And so people will come to me, you know, and say, oh Peter, Tia said this, I'm like, oh, okay, you know, this is something I should consider. Or, you know, oftentimes it'll be, oh yeah, Peter also said that. And so I'm like, oh, good, you know, so I'm always like, okay, what is Peter thinking? Nice to have you as a colleague as a friend. Likewise. I'm glad we've reconnected. Thank you so much for inviting me on your podcast. Can't wait to speak with you again soon on your amazing book, which I can't wait to read and discuss as well in a couple of months. Well, thank you very much, Rhonda. I can't wait to see you in person. Even though it's been

pretty awesome to see you in video, your setup is, as I said, exceptional. We've treated the people who are watching this to a world-class view of what a home podcast setup can look like. Amazing. Thanks, Peter. Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring you more in-depth exclusive content without relying on paid ads. It's our goal to ensure members get back much more than the

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