Peter Attia MD252 ‒ Latest insights on Alzheimer’s disease, cancer, exercise, nutrition, and fasting
EVERY SPOKEN WORD
150 min read · 30,108 words- 0:00 – 0:38
Intro
- PAPeter Attia
[upbeat music] Hey everyone, welcome to the Drive podcast. I'm your host, Peter Attia. 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, 'cause it really feels like we are in person. About as close to in person as we've been in a few years.
- RPRhonda Patrick
It's g- it's really great. It's really great to see you, Peter. It's, it's, it's been a minute. [laughs]
- PAPeter Attia
Yeah. Well, we'll, we'll be together soon in a couple of months, so I'm looking forward to that. Um, there's 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.
- 0:38 – 8:00
Alzheimer’s disease: Rhonda’s evolved thinking on neurodegenerative diseases
- PAPeter Attia
Um, and I think in the last couple of years, uh, well, let's just posit in the last five years was the last time we did a podcast. Uh, just going back to that point, I think both of us have evolved a lot in our thinking. Uh, 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, um, in thinking about our discussion today, I, 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 wanna put words in your mouth, but maybe that which 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?
- RPRhonda Patrick
It wou- it would. Um, so, you know, I... 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. So, and I have a genetic predisposition. So for me, you know, understanding everything I can do, you know, with my, with my diet, with my lifestyle, just, you know, exposure to or limiting exposure to certain things, et cetera, um, becomes paramount, right? Because I don't wanna get Alzheimer's disease and Parkinson's disease. So, um, like as you know, Peter, the, the Alzheimer's disease field has been, it's been quite a rollercoaster in a way. Like, I mean, we've had this dominating sort of, I think, um, hypothesis, this amyloid hypothesis as it's called. So there's, you know, one of the major pathologies of Alzheimer's disease are amyloid plaques in the brain, and there are other pathologies, tau tangles, also glucose hypometabolism. So, you know, glucose uptake into the brain is impaired and also, uh, perhaps even the utilization of glucose as well. So, uh, these are like three major pathologies of Alzheimer's disease, and it seems as though the majority of targeting, you know, how, how science and scientists have decided to target, you know, Alzheimer's disease is through this amyloid, anti-amyloid, you know, hypothesis. And, um, 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, um, generally speaking, it's been... It's like we need to go, okay, like are we just, are we just trying to treat a symptom here or are we too far downstream? Like what, what's the deal? Um, and I started reading some studies by Borislav Slavovik at USC, and Axel, Dr. Axel Montaine, who was trained with, um, Dr. Slavovik and now has his own lab at the University of Edinburgh, um, in, in Scotland. And, um, I recently did a podcast with him on my, on my podcast and, uh, Axel. And it was really like when I started to read some of this literature, and I'm gonna talk about like what, you know, the sort of new... I don't e- it's not even necessarily new, but like, you know, it's, it's not a new way of understanding it, but it is in a way because in, in the public opinion, in the public mind, it's a new way. Um, and this is sort of like, okay, well what are the underlying causes of, you know, of dementia? And so there's, you know, three major types of dementia. Alzheimer's disease being like the most common. There's, uh, s- um, 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, what sort of lifestyle factors and genetic factors do we know really increase the risk of Alzheimer's disease and 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 twofold. If you have two, if you got one from mom and one from dad, it could be up to tenfold. And this isn't like an early onset Alzheimer's disease. It's, it's more of what's called late onset, which is the normal sort of age-related, you know, progression of Alzheimer's disease. But that gene really does play a role in, in, in, in, you know, in someone's, uh, risk. The other thing we know is type 2 diabetes, right? I mean, so, I mean, that over, I don't know, somewhere between 50 to 80% of people with Alzheimer's disease also have type 2 diabetes. Like that's a lot. There's definitely something going on, right? I mean-
- PAPeter Attia
Y- yeah, and-
- RPRhonda Patrick
And this is where you hear-
- PAPeter Attia
A- and let's sort of pause there for a moment because I wanna 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, you know, prevention is still a word that doesn't quite resonate within the field. Which is, [clears throat] 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. Uh, and in fact, preventative neurology or preventive neurology, I suppose, um, is, 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? 'Cause, 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 I didn't mean to interrupt you, but I wanna highlight the important implication of that statement.
- RPRhonda Patrick
Exactly. Exactly. The... It- it's so important. I think that, um, 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, you know. Um, and of course, there are people that do get Alzheimer's disease early in life. I mean, these are, these are people that could come down with it in their 40s or 50s. That's sort of an out- you know, people are outliers in that, in that case, but it does happen. And, um, so obvi- obviously there's not... There are, there are, there are things that, um, you know, you might do everything right and still, like, have that terrible genetic combination, right? So, um, but with, with respect to the APOE4, um, and, and type 2 diabetes, understanding, again, c- is there something, like, common going on here that we can sort of understand as a foundation to what is the... what are the initial, like, things going wrong to lead to Alzheimer's disease? And, um, 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 APOE4. So people with type 2 diabetes, as you know-
- PAPeter Attia
S- can I, can I interrupt
- 8:00 – 16:03
The breakdown of the blood-brain barrier in neurodegenerative disease
- PAPeter Attia
for a sec, Rhonda?
- RPRhonda Patrick
Yeah.
- PAPeter Attia
Tell folks what the blood-brain barrier is. I think it's, it's, uh, obviously gonna be an important part of this discussion, and I... and not everybody might understand what it is or why it's so important.
- RPRhonda Patrick
So the blood-brain barrier, and, um, you know, this is, again, you know, I am not a neuroscientist. I'm just, you know, I am a scientist, but I have a- I have an interest in this, and so I've done a lot of, of reading in this, in this field. Um, the blood-brain barrier serves a couple of functions. I mean, one is it is providing... It's, it's... There's a, a combination of different cell types that make up the blood-brain barrier and a lot of vasculature, right? And so, um, blood flow, you know, things, things are brought to the blood-brain barrier, and oxygen, glucose, other nutrients, and they are, you know, 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. So, you know, we don't want red blood cells getting into our brain. You know, we don't, 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, and it's kind of an e- people, I think, are a lot more familiar with, um, when the barrier, the gut barrier starts to break down. I think it's a, it's a, sort of become more of a common, uh, theme that people are focused on gut health. And so you'll heal- hear the word, um, mostly you hear the word leaky gut. I don't really like that term. I think it's intestinal permeability. But, you know, the tight junctions, these proteins that are holding endothelial cells together in the gut, when those open up, you, you get that term, you know, 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, you know, at the root of that, um, that leads to permeability of the blood-brain barrier. And therefore, two things happen. You know, one, you are allowing then things from circulation to get in the brain, cause- which, you know, wreaks havoc on the brain and sort of leads to this vicious cycle of neuroinflammation, inflammation in the brain. But also, um, you're disrupting the transport of important nutrients, oxygen, you know, glucose. I mean, blood flow is disrupted to the brain as well. So, um, the blood-brain barrier and, and maintaining that integrity is very important. And both APOE4 and type 2 diabetes lead to permeability of that. And so with, um, type 2 diabetes, you know, people, people have hypoglycemia, right? They have elevated blood glucose levels, and that, over time, leads to advanced glycation end products. These are basically like the cross- they cross-link proteins and, you know, a variety of other things that, you know, in, in the vasculature, and that basically damages the blood-brain barrier and leads to permeability. Um, APOE4, it's a, 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, um, but also in plasma. And these have been shown by, uh, Dr. Slivovic, Dr., Dr. Montagne to occur, I mean, it's like decades before the onset of, you know, cognitive impairment, and it's literally you can find it in more than 50% of all dementias. So it's re- and it, it's happening independent of, of, of amyloid accumulation, tau tangles as well. So, uh, it's, you know, either something that's happening before, well before, and in fact, blood-brain barrier permeability is also, um... The blood-brain barrier is essential for removing toxic compounds from the brain and, um, a variety of different processes, you know, happen to allow this to occur. So, um, for example, you, you activate the glymphatic system during sleep, right? And a lot of people are aware of this. Your brain sort of swells during sleep, and the glymphatic system is pushing the cerebral spinal fluid through the brain, clearing out debris, um, amyloid plaques, you know, things like that. Uh, well, that doesn't... You need the blood-brain barrier to be intact for that-
- PAPeter Attia
Right
- RPRhonda Patrick
... to, to, to occur. Yeah. 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, um... And accumulation of amyloid then-
- PAPeter Attia
I never, I never thought of that, by the way, Rhonda. That's the... 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 glymphatic, g- glymphatic flow. That never actually occurred to me till you said that, so very interesting mechanistic tie to that problem.
- RPRhonda Patrick
Right. And there's also, like, the other types of... And I'm not familiar with all the types of ways the brain, like there's other like parenchyma and stuff that are like, you know, cleaning out the brain. All of those things are not happening as good when your blood-brain barrier, you know, is dysfunctional, right?
- PAPeter Attia
A- 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 cross that barrier do indeed cross. And 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, to clear out debris.
- RPRhonda Patrick
Exactly. In fact, um, you know, so work from, uh, Dr. Montagne has shown that fibrinogen, which is... You and I are familiar with this protein. It's something if you are measuring your... If you're doing an inflammatory biomarker panel, right? I mean, so, so that's... It's, it's an, it's, it's a protein that's involved in blood coagulation, but it's also something that is a marker of inflammation, you know. And fibrinogen is not supposed to be in the brain, but it's found in the brain in people-
- PAPeter Attia
Hmm
- RPRhonda Patrick
... with a leaky blood-brain barrier. And not only, um... So what's it doing in there? It disrupts a, a cell type called oligodendrocytes. These are a cell type that make myelin, um, that sort of fatty white structure that's, uh, important for, you know, electric signals being, uh, fired throughout the, you know, brain. And it, it's basically toxic to them. So you basically start to have these in, you know, lesions and stuff in the white matter part of the brain, white matter hyperintensities-
- PAPeter Attia
Hmm
- RPRhonda Patrick
... as you're probably very familiar with. Are very common in, um, small vessel disease. Also you can see that in, in people with Alzheimer's as well. Uh, but, you know, um, getting that fibrinogen in the brain like that, that's happening because it's allowed to get in there and that h- you know. So, so the, the, the permeability of the blood-brain barrier, again, like, as, as you mentioned, you know, basically preventing stuff from getting in your brain that you don't want in there, that's number one. But also the transport, and 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, they're in the endothelial cells.
- PAPeter Attia
Hmm.
- RPRhonda Patrick
They're in these, these, these cells that are, that are making up the blood-brain barrier. And when you start to disrupt that blood-brain barrier, those transporters, like, are dysfunctional. Um, you know, so you're... For example, one of them is the GLUT1 transporter. This transports glucose into the brain. As you start to get a disruption in blood-brain barrier function, glucose transporters, they, they go down. And, and so you're talking about, like, not getting enough glucose into the brain, which is, again, that's one of the, you know, pathological features of Alzheimer's disease, right? Not getting enough glucose into the brain.
- PAPeter Attia
That's
- 16:03 – 20:53
An explanation for the observation that type 2 diabetes increases risk of Alzheimer’s disease
- PAPeter Attia
actually an interesting explanation because, um, a very subtle point you made that might not be picked up on everybody is you mentioned the GLUT1 transporter as opposed to the GLUT4 transporter. And if my memory serves correctly, the brain has GLUT1s as opposed to GLUT4s, and GLUT1s are insulin independent. Is that correct?
- RPRhonda Patrick
Yeah. For the most part, I mean, it, they're, they're insulin independent. I mean, that's, that's to my understanding. Um-
- PAPeter Attia
And why that's interesting is because it seems a bit counterintuitive that a condition that leads to insulin resistance, of course type 2 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 dependent. Except when you explain it the way you did, which is it's not the insulin resistance of the GLUT1 transporter that's the problem the way it is for the GLUT4 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. Is that... Did I, did I understand that correctly?
- RPRhonda Patrick
Exactly.
- PAPeter Attia
Okay.
- RPRhonda Patrick
100% correctly. And I mean, this is, you know, this isn't like dogma. Like, this is 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 I'm, I think it's time to explore this evidence a little closer and a little deeper because, um, y- type 2 diabetes... And it, you know, you hear the, the term type 3 diabetes.
- PAPeter Attia
Right.
- RPRhonda Patrick
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, you know, 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, um, a variety of mechanisms, including, you know, the, the advanced glycation end products and the vascular. I mean, the vasculature disruption in type 2 diabetes is well known. I mean, they've all sorts of, you know, problems, right? Retinopathy, di- you know, the-
- PAPeter Attia
Sure
- RPRhonda Patrick
... the neuropathy, like all this. I mean, they are, they, they are disrupting their vasculature, including these tiny, tiny little blood vessels that are, like, smaller in size than our, like the diameter of a hair. Those things are, like, disrupted at the blood-brain barrier. And when you disrupt them, your, their blood flows decrease and the transporters are going down. You, I mean, there's all sorts of problems. And so I think, um- The, you know, fixing the diabetes obviously would be like [laughs] the, you know, downstream thing to do. But like, it's kind of a new mechanism, right?
- PAPeter Attia
Yeah.
- RPRhonda Patrick
It's a kind of a new way of understanding it. And, um, you know, so it's not just-
- PAPeter Attia
Right. In other words, it, it, it explains the observation. So there's an observation that is unmistakable, which is type 2 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 GLUT4 transporters, which are insulin dependent. In other words, it isn't just an insulin resistance problem, but I think these two other things matter, right? This, what you said about the microvasculature. Um, again, what, what I think a lot of people don't realize is how destructive type 2 diabetes is to the kidneys. Um, right? Because those tiny, tiny blood vessels, right? People are familiar with amputations and things that occur in digits because of that. Impotence, right? 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 this also this disruption of glucor- glucose transport directly across that transporter. So, um, I think it's actually a very compelling, uh, thesis for how type 2 diabetes could be acting via those two prongs, um, to, to ultimately result in hypometabolism.
- RPRhonda Patrick
I do too. Yeah. And, um, and then of course, the cascade of inflammation that happens after that. So, um, you know, the other thing that's also very interesting is... And again, this... So we are talking about type 2 diabetes and very big implications there for the prevention of Alzheimer's disease, right? I mean, y- y- there's a lot you can do, as you've talked about, you know, to prevent and even, you know, treat-
- PAPeter Attia
Yeah
- RPRhonda Patrick
... in a, with diet and lifestyle, right?
- PAPeter Attia
Yep.
- RPRhonda Patrick
Type 2 diabetes. But also, um, what's really interesting and, you know, I was sort of on this trail years ago. I published a sort of integrative review on the role of
- 20:53 – 35:30
The role of omega-3 fatty acids (EPA and DHA) in brain health and prevention of neurodegeneration
- RPRhonda Patrick
the omega-3-
- PAPeter Attia
Mm-hmm
- RPRhonda Patrick
... DHA transporter MFSD2A in the brain. And, um, what's really interesting that, is that animal studies, when you disrupt that transporter, it causes like 50%, you know, breakdown of the blood-brain barrier.
- PAPeter Attia
Hmm.
- RPRhonda Patrick
And like f- like greater than 50% loss of omega-3 in the brain. So in my opinion, it sort of... It's, it's, you know, that's animal evidence. Of course, there's human evidence where MFSD2A transporters decrease with age, s- particularly rapidly in Alzheimer's disease and with APOE4. Um, it leads to... So there are genetic, you know, abnormalities and mutations that occur in that transporter where people have less of it and they have microcephaly, so they have like smaller heads, and they also have cognitive dysfunction, um, sort of cognitive impairment and things like that as well.
- PAPeter Attia
Hmm. H- how do we know that, Rhonda? So that's, um... Let's even put the pathology aside, the, the, the, the sort of latter category, but let's just talk about, um... Well, again, what you've said explains something we've empirically felt is true, and the evidence suggests it, but this provides a mechanism, right? Which is APOE4 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-
- RPRhonda Patrick
Yeah
- PAPeter Attia
... you said is, is almost like a... You know, we talk about amino acid or protein, uh, uh, r- resistance, basically. Um, anabolic resistance as a person ages. They need more and more protein to get the same effect. It's almost like you're saying if, uh, you know, aging itself could create some resistance to dietary EPA and DHA that might require more as time goes on. D- uh, do you think there are also just genetic differences within the variant of normal, quote, unquote, i.e. non-pathological, where one person would need more EPA and DHA to afford them the same benefit of protection as another person?
- RPRhonda Patrick
I do. I know there's at least a couple that are known. Um, and, and so like some people have certain gene variants that actually they respond better to, for example-
- PAPeter Attia
Hmm
- RPRhonda Patrick
... omega-3 supplementation and others don't, um, 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 community, not me, not me personally. Um, [laughs] but I, I do... You know, with the omega-3, and this again really hits home the preventative sort of role here that we can, you know, have in our Alzheimer's disease risk. I... So with the MFSD2A, like this, the, the, these transporters are actually lost. Um, so there's a type of cell called pericytes. Peri with an I, not to be confused with a parasite. They, um, they bac- they basically have these like big feet that wrap around the endothelial cells at the blood-brain barrier, and they serve really two important... Many important, but two main important functions. One is they are, they're basically constricting and dilating and like helping squeeze like the flow of blood. So they're like, they're regulating blood flow to the brain. But they also are, uh, very important for that barrier. And they start to fall off with age, these pericytes, and inflammation plays a big role in that. Um, but the MFSD2A transporters are concentrated on those cells too, right?
- PAPeter Attia
Hmm.
- RPRhonda Patrick
And so you'll see like hotspots of where the pericytes basically went... Once those pericytes start to fall off, that is, uh, when basically immune cells and everything starts going into the brain. It's like the start. It's like the start of the vicious- ... inflammation cycle in the brain of the leakage, amyloid accumulation, just everything downstream, right? And so, um, those... it, it... there's something there with those transporters of omega-3 that are right at the same site, you know, of where you lose those pericytes, 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 a DHA, specifically a DH- uh, it's DHA in phospholipid form transporter." So it's like, okay, there's gotta be something here with the omega-3 and, you know, there's... I know there's a v- a variety of, um, scientists that are investigating this, but I'm sort of excited that I, I am now going to be part of, of, of a team. So I, I've joined the Fatty Acid Research Institute, um, which is Bill, Bill Harr-
- PAPeter Attia
Mm-hmm
- RPRhonda Patrick
... Dr. Bill Harris's research institute, and as a research associ- associate. And we are, um, we've sort of secured a, a, a small grant to look at the role of omega-3 with blood-brain barrier integrity and biomarkers in people, um, a variety of different, uh, people that have small vessel disease, um, that perhaps go on to get Alzheimer's disease. And so I think there needs to be more research in this area because it really, it, it, it... the implications here I think are really important. Um, with omega-3 intake, I mean, it's one of like, you know... So there's two main lifestyle interventions I think that, that are important with, with respect to the blood-brain barrier. Three, actually. Three. So not... basically not getting or fixing your type 2 diabetes.
- PAPeter Attia
Mm-hmm.
- RPRhonda Patrick
And then the omega-3 intake. And like defining that will be sort of tricky, but, you know, full stop, most people in the United States don't... they're not eating enough fatty fish, and they're not supplementing with omega-3, which is sort of an alternative. And it was like, 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, not, not the plant ALA, as one of the top six preventable causes of death. So it was up there with basically like-
- PAPeter Attia
Smoking. Yeah
- RPRhonda Patrick
... it was smoking-
- PAPeter Attia
Yeah
- RPRhonda Patrick
... and blood pressure and, you know, obesity and being sedentary. Low omega-3 was like... I... it blew my mind. And the, the, the calculate... there's some... You know, I'm not a biostatistician, 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 as... the same number of deaths, it was like 84,000 deaths a year from low omega-3 intake from fish.
- PAPeter Attia
I wonder, though, if that's also just a marker for poor health. Uh, I kn- that's the challenge of all of those studies, right? Is-
- RPRhonda Patrick
Totally
- PAPeter Attia
... in some cases with smoking, it's pretty obvious that there's causality there. I think there also is with blood pressure. Um, I, I... but, you know, you could argue that never in the history of the world has there been a person who has, you know... I'm making... I'm being a bit facetious, who has, you know, a high omega-3 index who eats junk food and fast food all day, right? Like those, those can't coexist. I, I wanna 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, where... what is the importance of EPA in this?
- RPRhonda Patrick
Great question. Um, so the MFSD2A transporter that I've been referring to is specific to DHA. And DHA, the form of DHA is lysophosphatidylcholine DHA, and that, you know... So that, that specific... we, we make it. And so b- we basically get D- when we take in DHA from fish or from a supplement, uh, our bodies, the higher amount of DHA that we take in, we add that lysophosphatidylcholine group to the DHA. We also have DHA in free fatty acid form bound to albumin. And albumin is not supposed to... that doesn't get into the brain, but it takes it to the brain, blood-brain barrier, and the free fatty acid can sort of diffuse passively, uh, across the blood-brain barrier as well. Um, same with EPA. Um, with respect to your question-
- PAPeter Attia
Oh, I see
- RPRhonda Patrick
... um, where-
- PAPeter Attia
But because the phospholipids on the DHA, it needs a dedicated transporter, whereas-
- RPRhonda Patrick
Yes
- PAPeter Attia
... the unphosphorylated... not phosphorylated, the one that doesn't have a phosphatidyl, uh, a, um-
- 35:30 – 38:53
Comparing the preventable nature of type 2 diabetes, atherosclerosis, cancer, and dementia
- RPRhonda Patrick
but like 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 gonna be, it is gonna be challenging and you're gonna have to take... It, it's not gonna just be fixing the amyloid. You're gonna have to have a cocktail that are going multiple angles, I think, in, in order to get some improvement. Uh, I think the amyloid and perhaps also fixing this, 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's, it is a very complicated disease with lots of things going on. So, um, you know, I think that the strategies that, that can be done, um, and they're not that chal- they're not that difficult, right? So w- we talked about type 2 diabetes. I mean, there's, there, th- there's no, there's no reason why someone should have it. Like, right? I mean, like you, you should be able to-
- PAPeter Attia
Yeah, it's... I would, 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. So there's a, there's a, that's a very stark contradiction. The disease is inevitable. As, in, 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. I, it, you know, 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, what I refer to as the horsemen, right? It's what it does to your risk of cardiovascular disease, cancer, and Alzheimer's disease, um, is actually why the death toll for type 2 diabetes is so grossly underappreciated.
- RPRhonda Patrick
Yeah. It's accelerating the aging process, right? I mean, like the, the molecular and cellular processes.
- PAPeter Attia
Yeah. It's gasoline on the fire of aging. I don't s- I do, I am, I would... I'd have to really reflect on it, but I can't think of a process that accelerates aging more than type 2 diabetes.
- RPRhonda Patrick
Right. I mean, and maybe morbid obesity, but like they're probably also type 2 diabe- people that are morbidly obese diabetics
- PAPeter Attia
I would argue only, only in the context of insulin resistance, which gets us right back on that path. Yeah, yeah. So-
- RPRhonda Patrick
Right
- PAPeter Attia
... um, so I mean, I think the good news there is, uh, not that it's easy, but it's sim- like we, we sort of know what it takes to, to treat it and prevent it. Um, and it doesn't necessarily look like the strategies that are being deployed, unfortunately, at the level of the ADA.
- 38:53 – 43:08
Blood pressure: an important modifiable lifestyle factor that can affect Alzheimer's disease risk
- PAPeter Attia
I want to ask you one other thing that we haven't talked about, but I, 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, um, in, in Alzheimer's disease, and I, I wonder do either of those act specifically through the blood-brain barrier?
- RPRhonda Patrick
It, it is another really, uh, important modifiable lifestyle factor that can affect Alzheimer's disease risk. And, you know, so blood pressure, maintaining good blood pressure. So I mean, basically you want to be systolic below 130, right? I mean, like once you get to 130, that's-
- PAPeter Attia
The, the SPRINT trial would even say 120.
- RPRhonda Patrick
120.
- PAPeter Attia
Yeah.
- RPRhonda Patrick
Yes.
- PAPeter Attia
Yeah.
- RPRhonda Patrick
Yeah. Um, and the, the, the blood pressure itself, so getting that blood flow to the brain, blood-brain barrier specifically, is so important. Um, when you don't have, you know, that, that, when that blood flow doesn't, you know, basically isn't able to get to the blood-brain barrier well enough, um, those tiny little vessels start to like just fall off, and it's one of the reasons why exercise also is so, so important. Um, so yeah, blood pre- so there's, there's been a variety of studies that have looked, you know, of course, as you mentioned, you know, the, the observational data is, is never a- able to establish causation. But it's still a, an interesting point to look at in combination with many other types of data, right? But, um, people that-
- PAPeter Attia
Es- especially when it's always in the same direction. I mean, I think that's what always-
- RPRhonda Patrick
Exactly
- PAPeter Attia
... that's what differentiates the epidemiology around, for example, exercise and 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, you know, 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.
- RPRhonda Patrick
Right. Good point. Um, yeah, so blood pressure is associated particularly, um... So, you know, 50% of, 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. Like that's crazy, right? And, and it's actually the, the high blood pressure, it's the cumulative exposure to high blood pressure that's really damaging the vasculature. And so it's the younger people, um, it's the people that have it earlier in life that should be the most concerned and are the least, right? Those are the ones that are like, "Oh, I'm young, you know, I can worry about it later." Uh, but yeah, so high, high blood pressure is associated with dementia risk, particularly when you have it like before, you know, the 50s. Like, so when you start, when you get it in your, you know, before the 50s or, you know, midlife. Um, once you start to get high blood pressure in older age, like 70, 80, um, it's not as much associated with, you know, the, the Alzheimer's disease and dementia risk. So, um, it really does seem like cumulative exposure is the, uh, the key factor there. But, um, you know, again, one of those things that, you know, is a, is a lifestyle factor that's easily modifiable. Exercise improves blood pressure, sauna improves blood pressure, right? Those are two, you know, basically low-hanging fruit lifestyle interve- interventions. Some people do have gene, um, polymorphisms where they're very sensitive to salt intake-
- PAPeter Attia
Mm-hmm
- RPRhonda Patrick
... and sodium intake. And, and that combination of those people with like a higher sodium intake really seems to skyrocket blood pressure. It also, I think, is one, uh, like you were mentioning nutrition, I think it's also looking at the combination of genes and diet. Most nutrition studies don't do that. Like they don't. And there, 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, um- I don't, I would say-
- PAPeter Attia
Yeah, it's all over the place
- RPRhonda Patrick
... uh, complicated.
- PAPeter Attia
Yeah.
- RPRhonda Patrick
Right.
- PAPeter Attia
It, uh, uh, I want- I was wanting to ask you a question about exercise, but before I do that, I want to actually pick up on something you just said. How
- 43:08 – 51:28
Rhonda’s outlook on “precision medicine” as it pertains to one’s genetic predispositions
- PAPeter Attia
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 genetic 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?
- RPRhonda Patrick
I, I do think in 10 years we're gonna lo- know a lot more about, you know, prec- precision nutrition, um, o- obviously prec- precision medicine as well, uh, because there's also an interaction between, you know, pharmacological treatments and, and genes as well, as you know. So, um, you know, in 10 years we're definitely gonna be a lot further than we are now. The, the problem is, and this is, this is always the problem, we've already alluded to it a few times, is the incentive for funding-
- PAPeter Attia
Mm
- RPRhonda Patrick
... to study those things that aren't necessarily going to be super profitable. Um, it's, you know, you... The, the, the, the government, the NIH, we get... There's a certain amount of funding that you can get from them, and, and they often like to study one sort of thing. You know, it's hard for... Like, the nutrition when there's, like, multiple things involved, it's like, they're just, like, too complicated, you know? Um, and so, you know, there's a lot of funding from pharma industry, for example, and then they put in lots of money because they're incentivized to do that when it's a, when it's a drug, right? So, um, the, that's my one concern with the, I would say, gene diet interaction when it's more on nutrition. But there, there are people that are... There's a, there's... It's, it's a growing field of research for sure, and I do think with, uh, there's... Technology is advancing too. I mean, so at, uh, at the point that our technology is advancing with AI and stuff, I think that's, we're gonna start to see an exponential there honestly. So I, I am optimistic that in 10 years that it's gonna be a lot easier to sort of delineate what a person should eat based off of, you know, their, the genetic makeup, you know, versus just what, you know, generally we think is healthy.
- PAPeter Attia
And, and, and do you think that that will be at the level of macronutrients or micronutrients? Like, what, what do you think... How much heterogeneity do you think there is among people as it pertains to factors like that?
- RPRhonda Patrick
I think both for sure.
- PAPeter Attia
Mm.
- RPRhonda Patrick
I mean, there, there's, there are, there are differences in the response to macronutrient intake and the response to micronutrient intake, and there are people... You know, like, there's, there's vitamin D polymorphisms, right?
- PAPeter Attia
Yep.
- RPRhonda Patrick
Where people, um, you know, for whatever reason, they actually even... So, so maybe they, they evolved in a, in a place where they were so... like, there was so much, um, sun or something. Like, I don't... Like, I don't know what the cause is, but, like, some people, they have to supplement with high doses of omega-3 to get, uh, you know, to be able to convert the-
- PAPeter Attia
Of vitamin D
- RPRhonda Patrick
... precursor-
- PAPeter Attia
Yeah
- RPRhonda Patrick
... to actual the hormone.
- PAPeter Attia
Yeah.
- RPRhonda Patrick
Right. The steroid hormone. Um, and, and so and that's... And like, you know, that's just one example. There's selenium. I mean, there's, there's magnesium. There's a lot of different micronutrients that are als- And there's omega-3.
- PAPeter Attia
Yeah.
- RPRhonda Patrick
There's omega-3 as well. So, um-
- PAPeter Attia
And B vitamins.
- RPRhonda Patrick
Exactly. There's B vitamins. Yeah. So I, I do think that it plays... It, it does. It, it will kind of... More people are looking into it and, um, again, with advancement in technology, uh, things will become cheaper and easier to do, and that's going to create an exponential in my opinion, where it's like, okay, uh, 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 'cause, you know, that's how it works, right? So, um, yeah, that's, 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 gonna clear up, as you mentioned, all the conflicting data with nutrition. I mean, nutrition studies are a mess. Designing the right trial. I mean, the, part of the reason for that is because we have evolved these genes, and when it's a drug and you don't have... I mean, with the, with the exception of yes, there's, there's the, the, 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? Something that's foreign to our body. But by and large, when you give someone a drug, like, 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, uh, it's, it's gonna be different than people getting a placebo, right? It's going from zero to something. Whereas when you do this nutrition study, a sel- a micronutrient, you know, you give them a vitamin or a mineral, they're not, they're not... Nobody's starting with zero for one.
- PAPeter Attia
Mm.
- RPRhonda Patrick
Your, your placebo group could have high levels of that, and unless you measure something, you'll never know, right? So it's, it's very different when you're... And all the trials are sort of, um, they're trying to mimic that gold standard of a randomized controlled trial with a pharmacological drug, and it's just you, you can't... You have to, like, put in so much more effort with nutrition. With a drug, you don't have to start doing blood samples of this and that and measure the drug and make sure people aren't deficient in that drug. Of course they're deficient in the drug before they start the trial. They don't... It's like a drug, you know? So, um, yeah.
- PAPeter Attia
It, it's such a good point, Rhonda, and I, I'm gonna use two examples to highlight why this is so important, um, and because it ties to two things we've been talking about, right? So if you look at, um, how a blood pressure trial is done- It is exactly what you say. It's titrated, me- 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 gonna manage you to a blood pressure of 140 over 90, but no lower. You guys in the treatment arm, we're gonna 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. You take the people, you divide them into two groups. You give one group a placebo. You give one group usually a very low dose, somewhere between 2 to 4,000 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.
- RPRhonda Patrick
Right, and it often, it's... I mean, it's a matter of money too, right? Like, to measure all those things to... You know, it's just, it's cheaper to just give someone the vitamin D supplement and then look at the outcome.
- PAPeter Attia
Right.
- RPRhonda Patrick
And go, "Oh, didn't work." And then you have another confusing piece of literature out there that people are like, "Oh, but it's, you know, it says that vitamin D supplementa- supplements do nothing." Yeah, it's, it's, it's a b- it's a big problem, and I do, again, I think as, you know, our technologies are advancing that that's gonna become less of a problem as well. Um, so I mean, at least I hope. I mean, I guess [laughs] you never know, but, um,
- 51:28 – 1:01:09
Possible mechanisms by which exercise reduces the risk of Alzheimer’s disease
- RPRhonda Patrick
yeah.
- PAPeter Attia
So I wanna go back to something you, you talked about earlier, which is you just touched on exercise, and, um, I, I wanna kind of visit now the suite of things that exercise does 'cause people who listen to this podcast know if there's one thing I just can't stop talking about, it's exercise. But I think there's a reason for that, right? It's not just that I love exercise. It's that the, the evidence is overwhelming that a person who exercises, especially at the right amount, right? Like, 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 talked about, type 2 diabetes, all these things matter, but, but the risk reduction that comes from exercise is enormous. What do you think are the mechanisms by which that is happening? 'Cause I suspect there's many.
- RPRhonda Patrick
Oh, definitely. Um, there's d- d- definitely many mechanisms happening, and, um, I would, I would, first of all, 100% agree with you. Like, there's nothing better than exercise, and I mean, of course, any exercise is better than none. But for me, because as I mentioned at the start of this, this podcast, I'm very focused on neurodegenerative disease. I specifically sort of design my workout routine based off of what I think are gonna 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, and there are some mechanistic reasons for that. Uh, but just talking about, like, what's moderate intensity exercise? What's considered vi- vigorous intensity exercise, right? If you look at some of the recommendations out there by the committees that have, you know, 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-
- PAPeter Attia
Moderate
- RPRhonda Patrick
... exercise.
- PAPeter Attia
Right.
- RPRhonda Patrick
Which I think they define as, like, 50 to 70% of maximum heart rate. In vigorous intensity, i- they, they say, you know, 75 minutes, I guess, a week. Um, and that would be more of, you know, you're getting s- above the, like, 75 to 85% max heart rate. So, um, that's, that's what they, I think, define as something like that, vigorous. And they have a, a variety of examples. You know, there's, there's the w- the World Health Organization, and, um, you know, there's a, a variety of committees that are sort of... they come to that same conclusion. Uh, for me, I like to go higher intensity, and I... This is something I kind of was looking forward to talking to you about because it has to do with, um, how do you measure... Like, so there's the, there's the ma- the estimated heart rate, which is what I do. I've estimated. And again, all sorts of problems with that based on your physical-
- PAPeter Attia
Meaning e-
- RPRhonda Patrick
... uh, fitness
- PAPeter Attia
... es- estimating your maximum heart rate to take a percentage then?
- RPRhonda Patrick
Yes.
- PAPeter Attia
Okay.
- RPRhonda Patrick
Right. Yeah, right. I mean, so, so basically, you know, like, if y- the, the more fit you are, like, you could be doing a, a more vigorous intensity exercise, but your heart rate, like, doesn't go as high as someone who's not fit, right? Um, and then people that are older. So there's, of course, I would say, problems with that, but, um, generally speaking, that's one way. But I'm also very interested in lactate, and I know you are as well. Um, for me, I, I actually want to get [laughs] my lactate levels high, like high.
- PAPeter Attia
Yeah.
- RPRhonda Patrick
Um, and, 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 with no, like, it, it was like, you know, useless. Well, not only just useless, actually har- it was thought to be harmful, right? So, um, so, and this is-
- PAPeter Attia
At least to performance. Yeah.
- RPRhonda Patrick
Right. Harmful to performance with respect to people thought it was, like, causing their muscle soreness, right? And that's sort of, you know, as you know now, that it's not, it's not lactate, it's the, the proton buildup, right? So lactate is sort of in homeostasis with lactic acid, and it's the protons that were sort of-
- PAPeter Attia
Yeah
- RPRhonda Patrick
... responsible for that.
- PAPeter Attia
And, and neither of them are responsible for the soreness you feel the next day. That's the microtrauma-
- RPRhonda Patrick
Right. [laughs]
- PAPeter Attia
... of course. Like, the, the soreness and the burn from the hydrogen ion is gone, you know, minutes after you stop exercising.
- RPRhonda Patrick
Min- right.
- PAPeter Attia
Yeah.
- RPRhonda Patrick
Yeah, exactly. Uh, 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 w- they can, 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, um, for those that haven't, you know, the, the lactate generation is then from, from that, you know, metabolism of glucose outside of the mitochondria. And that's happening when, again, you reach that threshold of, you know, basically you're pushing your, your, your muscle cells hard enough and their mitochondria can't keep up with, you know, producing enough energy. So the lactate itself, and this is... This, I mean, these studies date back to, like, the '70s. Uh, it's been shown that lactate, that it gets into circulation, and it's used by other organs as, uh, a, a, energy source-
- PAPeter Attia
As a fuel
- RPRhonda Patrick
... for one.
- PAPeter Attia
Yeah.
- RPRhonda Patrick
As a fuel, yeah, and the brain being a big one. And, and this is now, like, you know, this has been, you know, decades of, of, of research, but, um, Dr George Brooks has... You know, he was, like, some- one of the first to propose this lactate shuttle theory, and he's, you know, of course, provided evidence for hi- for that, as many others have as well, where, you know, during exercise and after exercise, the lactate that is generated, you know, 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, uh, it's acting as a signaling molecule and increasing... At the blood-brain barrier, it... Lactate itself has been shown to be responsible for the production of what's called VEGF. This is a... It's a, it's a vascular endothelial growth factor, VEGF. And what it's doing at the blood-brain barrier is it is growing new vessels-
- PAPeter Attia
Hmm
- 1:01:09 – 1:06:55
Building your aerobic pyramid: neurobiological effects of exercise, benefits of lactate peaks, and more
- PAPeter Attia
of the spectrum, w- w- what, what we wanna do is increase our mitochondrial capacity To maximize aerobic metabolism. And, uh, there are two ways to do that. Uh, meaning you have to do two things. So the way I describe this to people is the way one of my coaches described it to me when I was a, you know, 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, right? A pyramid with a narrow base and a high peak, eh, 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, right? It's how much work can you do while keeping lactate at that sort of threshold that George Brooks and, and you go... San Milan talk about, of about 2 millimole. So what differentiates the best aerobic athletes from someone, you know, say, with type 2 diabetes, which would be the opposite end of that spectrum, where you have real metabolic dysfunction or mi- 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 you know, 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 millimole 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, you know, generally, the sweet spot for building those is three to eight minutes of all-out effort for the respective, um, 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, was I actually did an hour of that zone two, you know, kind of 2 millimole 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. And-
- RPRhonda Patrick
Wow.
- PAPeter Attia
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. So yeah, long-winded way of saying you want both, right? 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.
- RPRhonda Patrick
Yes, it's getting a benefit, and they don't... Like, you know, it's cleared quite quickly.
- PAPeter Attia
Yeah.
- RPRhonda Patrick
So I mean, like, you know...
- PAPeter Attia
I mean, it's minutes. I, I, I-
- RPRhonda Patrick
It's minutes, yeah
- PAPeter Attia
... if, if you do nothing, it's... Yeah, if you just stopped, y- you know, you'll... I mean, and of course, athletes are even better at this, right? Like, a, an amazing athlete would clear lactate within... You know, they'd, they'd go from 10 millimole to 2 millimole in minutes.
- RPRhonda Patrick
Yeah. Uh, for me, um, yeah, like, you know, 20 minutes later, I'm back to my 0.9, you know, millimole baseline. But, um, you know, that, that lactate also is, is... it's, it's important for neurotransmitter synthesis. You're, you're, um, making glutamate, the major excitatory neurotransmitter in the brain. It's, it important for making precursors to that, norepinephrine. I mean, these have all been shown in human studies, also-
- PAPeter Attia
Mm
- RPRhonda Patrick
... animal studies. Um, so for me, I do a lot of Tabata training, and, um-
- PAPeter Attia
Yeah
- RPRhonda Patrick
... I think-
- PAPeter Attia
So that's even more intense because you're only doing 20 seconds on and 10 seconds off. So that's-
- RPRhonda Patrick
I do-
- PAPeter Attia
... that's really intense. Yeah.
- RPRhonda Patrick
It is. I do, um... and I do 16 of those. Um, so I do, you know, like eight and then separated by like a 30-second, you know, break, and then I do another eight. Um, and I, and I do-
- PAPeter Attia
So two four-minute blocks.
- RPRhonda Patrick
Yeah. And then... Well, it's a, it's a total of about 10 minutes, but, um, so the first minute I'm in like zone two, and then by like the end of that minute, I'm like zone three, and then I go into zone four. Like, you know, so it's like, um-
- PAPeter Attia
And what are, what are you doing this on? Are you doing this on an Airbike or-
- RPRhonda Patrick
Peloton
- PAPeter Attia
... Peloton.
- RPRhonda Patrick
I'm doing it on a Peloton.
- PAPeter Attia
Spin, okay.
- RPRhonda Patrick
Right. And my Apple Watch is, is, you know, beaming my heart rate and my zones, um, onto my screen, which is kind of... Uh, they're all estimated, of course, again.
- PAPeter Attia
Yeah.
- RPRhonda Patrick
Uh, you know, so... But, but I do that five, five days a week. It's... Again, I think, um, you know, the... For me, the efficiency also... So I'm, I'm trying to maximize the, the neurobiological effects for me with exercise, and I really find, um, pretty compelling evidence that intensity is really important with respect to that for, for the brain. Um, not that there isn't a benefit for, you know, lower intensity exercise, uh, but... And it's certainly people doing, you know, moderate intensity, like the more time you put in, like the volume of training, right? Is like-
- PAPeter Attia
Mm-hmm
- RPRhonda Patrick
... you know, you're gonna probably find some equivalent there, right? But, um, with the lactate, though, that's the one mechanism I'm like, that is really something I personally am trying to optimize for, and I... it, it's definitely a, a consequence of intensity, right? Um, but I... And, and the fact that, uh, it's, it's cleared so quickly, uh, and it's transient, like I'm wanting it on a... I'm wanting a lot of it, like each day. I'm wanting to keep doing it, right? Like, so I kind of, uh, I do those, those types of training.
- 1:06:55 – 1:19:44
Maximizing mitochondrial biogenesis: alternative training approaches and strategies
- PAPeter Attia
But, you know, there are, there are other ways to do it that you might wanna consider, right? So you might wanna say, "Look, I'll do those Tabatas two days a week. I'll do some longer, slower cardio." And to be clear, like, when I'm doing that zone two, it's still... It's not trivial. Like, I mean, I'm still... My heart rate's still 140 when I'm doing that zone two. Um, but what you could do is use blood flow restriction Um, when you're lifting weights on the other days, and that will get your lactate through the roof. So, um, four days a week, you know, I'll do blood flow restriction at the end of every workout. So, uh, two days will be upper body, two days will be lower body, and then especially on the lower body days, so you've got these huge cuffs at the upper part of your thighs, and I'll do, you know, 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. So even though I-
- RPRhonda Patrick
What, what do your levels get to? What do your lactate levels get to afterward?
- PAPeter Attia
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, um, doing blood flow restriction. So-
- RPRhonda Patrick
That's incredibly high.
- PAPeter Attia
Yeah, point... You know, it's funny, when I used to coach, uh, athletes, I, 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, is comical to me. But he could, he could finish a swim race, like a, something like a 400 individual medley, which is, you know, probably the highest lactate generating race there is, 'cause it's a 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, and enter the pool with a lactate of maybe six. It's pretty amazing.
- RPRhonda Patrick
That's amazing. What, um, [lips smack] so with the-
- PAPeter Attia
So my point is, like, you could diversify the training a little bit, and if you're still... 'Cause again, you'd still get that lactate hit, but you'd also be diversifying the training. Um, because I do think performance, it's hard to make the performance gains if you're really doing an all-out Tabata, uh, five days a week. I think that is hard-
- RPRhonda Patrick
What kind of performance gains are you talking about?
- PAPeter Attia
Uh, within the Tabata itself. In other words, it's hard to make gains on the power output that you want to be generating, 'cause that's... When you're doing 20 on, 10 off, right? You're, you're trying to get as much power as you can in those 20 seconds. Um, and that, th- those are, those are what we call match burning workouts. Like, you're, you're, you're burning all the matches that day, right? Those are-
- RPRhonda Patrick
Yeah. I'll tell you something that's interesting. I started, I don't... Have you ever tried doing an aerobic or a high, you know, a high intensity workout with, like, a mouth tape where you're just breathing through your nose?
- PAPeter Attia
Mm-hmm.
- RPRhonda Patrick
Um, so I started-
- PAPeter Attia
I mean, you're limited of course. I mean, at, at some point you're, you're not going to get to your... You're gonna be limited by, uh, depending on, you know, for me at least, I'm, I can't do my all-out best without mouth breathing at the end. One- 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.
- RPRhonda Patrick
Mm.
- PAPeter Attia
And I, and I would expect everybody's sort of different there.
- RPRhonda Patrick
Right. Exactly. People are different. I mean, different nasal, I mean, like, different sinuses and shapes-
- PAPeter Attia
Yeah
- RPRhonda Patrick
... of your nose and everything. Um, I just recently started doing it, and it was kind of odd because I actually... Maybe I'm not going... Like, I'm, I PR'd the first time I did it, and I, I didn't f- you know, like, I wasn't going as hard on my all-outs, but I think on my rests, I was going harder. On my 10 seconds off, I was, like, not really bringing my resistance down.
- PAPeter Attia
Have you tried doing it where you do nothing on the off? A pure off?
- RPRhonda Patrick
What do you mean? Just, like, keep going?
- PAPeter Attia
Don't, don't, don't, don't, yeah, don't, don't spin whatsoever. So do the 20 seconds all out, and then the 10 seconds you're not spinning at all.
- RPRhonda Patrick
Oh, I've never tried that. Why, why would I do that?
- PAPeter Attia
Give, give that a try. 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.
- RPRhonda Patrick
Okay. I've been do- I've been trying to do the opposite where I'm like, "Okay, on my off, I, like, keep... I'm like, you know, zone three. I like... I'm, I'm really, like, uh, I'm still, I'm still, I'm still putting in quite a bit of, um, power," right? Like-
- PAPeter Attia
That, that's good too. I, I don't wanna say just that there's... You know, those are, those are... We used to call that sweet spot workouts where you would go zone three, zone five, zone three, zone five, zone three, zone five. Um, but what you really probably wanna be doing in a Tabata is zone six, zone one, six, one, six, one.
- RPRhonda Patrick
What's zone six?
- PAPeter Attia
It depends on the system.
- RPRhonda Patrick
Just, like, maximal?
- PAPeter Attia
So, uh, yeah, yeah. Ba- basically, t- 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. Now, so even, so at 20 seconds, you're tr- you're, even if you don't realize it, you're somewhat pacing yourself, even if you're trying to go all out.
- RPRhonda Patrick
Yeah, I'm not doing maximal.
- 1:19:44 – 1:27:30
Possible brain benefits of sauna, and Rhonda’s personal protocol
- PAPeter Attia
more. But I wanna ask you, where do you put your sauna in relation to this? Do you, um, 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?
- RPRhonda Patrick
Um, it varies. So I, um, I, I do both a, you know, a regular what's c- you know, dry sauna. Actually, I don't use it as a dry sauna. I, I do a lot of steam, um, as well, but, but I do that, but I also do hot tub. So I do a jacuzzi as well. And, um, both of those, you know, forms of heat stress have been shown to increase, um, you know, heat shock proteins, which is sort of a biomarker of heat stress and, um, both of them also have been shown to increase brain-derived neurotrophic factor as well. So heat, I think, also plays a role in that, like, stress response. But, um, I... It depends on the day. So, um, I often will in the sauna, I like to read scientific papers or listen to podcasts like, like The Drive or like I'll listen to, like, if someone's on Tim Ferriss's show. Like, there's only a couple of podcasts that I ever listen to. Uh, yours is one of them. Um, so and it's not like... That's, like, my time where I'm like... 'Cause there's no other time. Like, if I'm in the car with, like, my child, like, most of the time I'm listening to, you know, Frozen music or whatever. You know, like, it's not [laughs]
- PAPeter Attia
[laughs]
- RPRhonda Patrick
I'm not listening to, to, to The Drive. So, um, uh, so I... So it's like what... it depends on what I'm doing, but also we- I like to do, 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. Um, I find it's really interesting. I don't know if you've ever tried this or observed it, but, uh, I've... This goes way back to my, you know, s- days as a graduate student when I first started using the sauna. I realized that, like, if I would go over a talk that I was gonna give, like a departmental meeting or whatever, you know, I was giving a talk-
- PAPeter Attia
Hmm
- RPRhonda Patrick
... if I went over it and thought about, like, what I was gonna say in the sauna, man, did I remember it better.
- PAPeter Attia
Hmm.
- RPRhonda Patrick
Like, it was, like, very clear that there was something going on with my memory.
- PAPeter Attia
Hmm.
- RPRhonda Patrick
And I mean, very, very consistent. Of course, you know me, I, like, was diving into the literature. I'm like, "There's gotta be something to explain this." And, uh, you know, lo and behold, there's, like, a vari- like, there's, like, certain growth factors, uh, that you, that you make, um, that in the s- i- in the sauna with heat stress that do affect, like, memory. So, um, you know, plausical, plausible, um, you know, hypothesis there. But anyways, so if I have something going on like a podcast or a presentation.
- PAPeter Attia
What's your protocol? Um, what's your temperature and duration in the sauna?
- RPRhonda Patrick
So typically, um, I like to... It depends on how hard I went on my, like, my workout too, or if I'm doing it, like, right after the workout-
- PAPeter Attia
Mm-hmm
- RPRhonda Patrick
... or if I'm, like, midday, just like I'm gonna take a break from what I'm doing at my computer and I'm gonna go read a science paper in the, in the sauna. So, like, it really all depends. Um, generally speaking, if I go in right after I'm... I do my Tabata session, uh, I probably stay in about 20 to 25 minutes, and it'll... my temperature is, like, 175 degree Fahrenheit.
- PAPeter Attia
Okay.
- RPRhonda Patrick
Um, if I am not going in right after a, uh, you know, training session, then I'll stay in longer. I'll, I'll stay in probably a little bit longer than 30 minutes, um, sometimes. I'm pretty, I'm pretty adapted, too. And my temperature will be, you know, 175, 180 sometimes. I also do the, the humidity, which makes it hotter, feel hotter-
- PAPeter Attia
Yeah
- RPRhonda Patrick
... as well. Um, so, so I guess anywhere between 20 to 30 minutes, and my temperature's anywhere between 175 to 180. Um, I find that I, like, I like... I used to do really, really hot, and I just sort of like about, like, 190. Like, I was doing 190, and I, I... It was giving me, like, my head... I was getting headaches more, like easier.
- PAPeter Attia
Mm-hmm.
- RPRhonda Patrick
And, um, and so I didn't, you know, I just didn't like it, and I didn't feel good. I was getting dehydrated.
- PAPeter Attia
How, how long did you sauna during your pregnancy How, how far, uh, did you... were you able to, to... And what, what do you, what do you adv- I'm sure women ask you this all the time, and I, I've never... I don't, I don't know that I have an answer to the question.
- RPRhonda Patrick
Um, I did n- So I first found out that I was, uh, pregnant when I was, um, touring Finland, and the, like, everyone was like... It was like sauna, right? It was like we were going touring saunas [laughs] in Finland.
- PAPeter Attia
Yeah. You're a sauna VIP.
- RPRhonda Patrick
And so of course-
- PAPeter Attia
Yeah
- RPRhonda Patrick
... I was, and I'm like, "Holy crap. Like, what am I gonna do?" Um, so I, I felt like at that early, early stage, I mean, literally, like, I found out I was pregnant in Finland. [laughs] So, um, I, I did do a lot of sauna touring and stuff and, and cold and, you know, cold plunging and all that, um, at that stage. But right after, when I got on the plane, come back home, sauna was out. And the reason I sort of erred on the side of caution... I mean, you can... I talked to women in Finland and I was... and they were like, "Oh yeah, I sauna throughout pregnancy." And like, you know, you'll, you'll find those anecdotes-
- PAPeter Attia
Right
- RPRhonda Patrick
... and, uh, you know, certainly, certainly in that culture. Um, but I, you know, there, there is a body of evidence, uh, mostly looking at, like, hot tub, um, you know.
- PAPeter Attia
Mm-hmm.
- RPRhonda Patrick
And, and, and it's... This is common. Like, k- it's common knowledge. Like, pregnant women shouldn't get in the hot tub, right? I mean, like the, like, you go to any spa, like, it's, like, um-
- 1:27:30 – 1:33:45
The relationship between cardiorespiratory fitness and dementia risk
- RPRhonda Patrick
are studies looking at intensity with respect to dementia risk-
- PAPeter Attia
Mm-hmm
- RPRhonda Patrick
... cognitive, you know, impairment. You know, you'll find all sorts of things, but liter- like, I think the most common thing that is, is pretty thematic is that the more, um, effort you put in, the more time you put in, the, the bigger the, uh, the benefit with respect to cog- cognitive health. So dementia risk. And also it depends on how it's... I'll give you an example. [lips smack] There was a, a longitudinal study where women who... Women, by the way, as you know, are, I think, approximately at a twofold higher risk for Alzheimer's disease than men.
- PAPeter Attia
That's right. Yeah.
- RPRhonda Patrick
Super, super interesting. But, um, so this is in women, and they were studied for, you know, decades, and I think it was, like, starting from, like, the '70s up until, like, 2010 or something. And they came in, um, for a physical... Like, they were, like, they were put on a bike, exercise bike, and their, like, fitness was measured. Like, it was, like, empirical data, okay? And this was, like, I don't know, five to seven times, so, like, over the, you know, course of, you know, it was, like-
- PAPeter Attia
40 years or something
- RPRhonda Patrick
... 40 odd years. Or s- yeah, exactly. Something like that. Um, and, and the, and the women that, you know, were the most fit by their measurements on the, you know, this, like, cycle test they did-
- PAPeter Attia
Yeah, it was probably VO2 max
- RPRhonda Patrick
... VO2 max, um, and [sighs] I think... Yeah, so it was cardiorespiratory fitness. That's right. And then, um, those, those women that were the most fit had, like, a... Like, they were, like... The reduction in, um, like, Alzheimer's, like, risk was, like, so robust. I think there was something like, um, like they were nine times less likely to get or something crazy like that. Uh, the, the ones that were moderate, like, so they had, like, a moderate cardiorespiratory fitness, they were, like, f- four or five times, you know, uh... Like, they had a four or fivefold reduction. [lips smack] But then you'll, like, look at another perspective study. Same deal where they c- like, they're, they, um, they don't come in and get anything measured, but they come in for a questionnaire, or they get, they get a questionnaire every, you know, what- whatever it was over the c- course of, like, 40 s- 40 or 50 years or something. And, and it's like there's... It's, 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 [laughs] between physical activity and dementia risk. And I'm like, "Hmm." Like, that's interesting because this other study where they're actually measuring something showed a robust reduction, uh, in dementia risk. Uh, and so I th- again, it go- it hits home this, like, okay, what study are we looking at?
- PAPeter Attia
Yeah.
- RPRhonda Patrick
Like, question... You'll find questionnaire studies that also show, you know, a benefit. Like, you know, people that are physically fit, and the more fit they are, there's, like, a linear dose response effect, right? Where you see, you know, people that put in more effort, they're training for a longer period of time, and they're, um, [lips smack] you know, doing it at more vigoru- more vigorous or more volume, both, right? Like, they have the, the greatest benefit with respect to dementia risk. It... Which isn't so surprising to me.
- PAPeter Attia
Yeah. But, but the, 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 five high intensity workouts a week or two high intensity, five low intensity. Like, what matters maybe more is the output. I, I don't know if that's the case, but, 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-
- RPRhonda Patrick
Exactly
- PAPeter Attia
... being captured in those studies. And, you know, the, the numbers are astronomical. Uh, you know, I, I won't go into them again because I... people on this podcast have heard it too many times because I, I can't- [laughs]
- RPRhonda Patrick
[laughs]
- PAPeter Attia
... I can't stop talking about the, the benefits of having a high VO2 max. Um, but I want to touch on something else you just said a second ago, [lips smack] which is y- you, you noted that, that women are indeed at twice the risk of Alzheimer's disease to men. Um- Of course, Parkinson's flips that. Men are 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, uh, more amenable to the benefits of exercise than men because they are at a higher risk genetically?
- RPRhonda Patrick
Um, it's, it's... I do- I haven't seen the studies looking at the response to exercise with respect to, um, you know, the sex differences, but, like, as you mentioned, like, there's definitely differences with respect to their, you know, Alzheimer's disease risk. Um, so... And I, I do know, like, there are, there are, um, different mechanisms that could, you know... Like, so women have different... Like, there's different metabolic responses to exercise maybe. Also, uh, you know, hormonally different... I, I'm just like, this, this would make sense, right?
- PAPeter Attia
Mm-hmm.
- RPRhonda Patrick
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.
- PAPeter Attia
Mm.
- RPRhonda Patrick
Immune system effects as well. You know, there's, there's so many... Exercise is affecting the immune system, so we haven't even talked about, like, myokines. Like, these are like, you know, these are molecules being secreted by our muscles. We talked about lactate. That's not a myokine. That's a, you know, it's a metabolite. But, I mean, we're m- physical activity, when we force our muscles to work hard, we're making something called a myokine. Sometimes it's referred to as an exokine. But, like, this is m- you know, this is irisin, is one. IL-6 is another. Um, there's, there's other ones as well. But, like, these, these are also affecting the brain, and they're affecting cancer risk, right? Um, there may be differences in, in respect to, like, myokines that are being secreted, uh, with, with respect to how, um, you know, the stress of exercise, how, how that's, uh, response is happening. Um, there's
- 1:33:45 – 1:49:09
How exercise may reduce the risk of cancer
- RPRhonda Patrick
also something-
- PAPeter Attia
Let, let's dive into that. Uh, let's talk about cancer because, Rhonda, while I think both of us are, and, and I think there are others who share this point of view, completely convinced, uh... And I- in fact, I d- I just don't see how, 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, et cetera, clear relationship. Very hard, at least for me, to make the case that bad sleep is related to cancer, although I think it is, right? But I, I don't... The data aren't clear, right? Like, 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, are so much less obvious. Let, 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.
- RPRhonda Patrick
So I... It's also another area that I'm very, very interested in, uh, because, I mean, as you start to get into your fourth decade of life, you, like, you've, you've now had a friend or a family member that has come down with cancer, and you see just... I mean, I mean, you're a physician, so of course you've, you've experienced it on, you know, at, at a different level. But, like, you just see how terrible it is, you know, to get cancer and, um, and, like, and that it really, the best, best hope is obviously to try to not get it, to prevent. And there are, uh, as you mentioned, there are things that, I mean, there, there are definitely things that, uh, can modulate that risk, that are a little, you know, genetic, you know, wise, that are harder to kind of, uh, move the needle. But, um, overall, so with respect to cancer incidents, uh, it's interesting. If you look at, like, you, you were talking about some of these elite at- elite athletes, right? I mean, like, people winning the Tour de France and, uh, people that are Olympic medalists or maybe that have even just entered the Olympics. I mean, you have to be quite an athlete-
- PAPeter Attia
Yeah
- RPRhonda Patrick
... to just get into the Olympics, right? And there's been a lot of interesting studies, quite a f- quite a few, um, that I have seen and, you know, uh, this is... These are studies where, um, you know, observational data again, um, so obvious- obviously caveated with that. You're looking at people, um, that have just entered the Olympics and, you know, over the course of, like, from 1912 to 2010 or something like that, like, you know, just decades. Um, and looked at all-cause mortality, cancer related mortality, and compared it to, like, the general population. So there's a couple of studies that have come out of the US, um, and if you look at, you know, both of those studies, one of them was actually looking at medalists, and the other one was just looking at people that, like, were in- entered the Olympics. Um, they, they saved about one and a half to two years. Like, in, in other words, they were, uh, of life, um, from not getting cancer, and, um, about five to six of just basically they, they, they had a five to six year, um, uh, what you could call lifespan expe- extension-
- PAPeter Attia
Hmm
- RPRhonda Patrick
... compared to the general population. Same with, like, French, uh, French Olympians as well. Some very similar, where it was like You know, five years, they lived on average five years longer than people, you know, than the general population, and they were, they... It was attributed that they had basically saved, you know, two years of life from not getting and dying from cancer. Um, I guess I should say dying from cancer, because they're, they are two different things.
- PAPeter Attia
Right.
- RPRhonda Patrick
But that would be, like, at the elite level, and it's interesting because you go, well, two years. Like, that's it? I mean, that's kind of what I... That's how I see it. I'm like, really? Like, two years? Um, and it's funny because I remember when I was a post-doc, my, my post-doctoral mentor, Bruce Ames, um, he had said to me once, or m- actually more than once, um, "You know, I once read, you know, this, you know, of all the things that you can do, like if you prevent cancer, you really only save about two years of [laughs] your life." And I always thought, I'm like, no way. No way. Uh, but anyways, um, so, so that would be like at the extreme, extreme end when you're looking at the, the, you know, the actual athletes. Um, they are, they're definitely less likely to die from cancer than, than general population people. But when you look, when you're talking about prevention, so there's a difference between, you know, if you read a study and it says, you know, people that are physically active are X percent less likely to, to, you know, die from cancer. Like can- 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. Uh, so the studies 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 g- you can find, uh, studies on, you know, strength training and cancer-related mortality. But with prevention, I really, um, it's, it's, 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, um, you know, basically having a reduced risk, and some of those cancers are ones that, that are... We should care about. So breast cancer, you know. What's the lifetime risk of breast cancer? For a woman, it's about one in eight. It's pretty, pretty high, uh, for the average woman, right? Um, of course, many different lifestyle factors play into that, and exercise, you know, is, is one of those factors. Colon cancer is another one that seems to be quite responsive. Um, 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, as you know, Peter, lifetime [laughs] risk of can- Like, 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 wreck than get esophag- Like, you know, one of those cancers, I think it was esophageal cancer, but you get my point, where the lifetime risk is, is already kind of, you know, quite low, uh, for, for the general person or the average person. Um, so, so breast cancer, colon cancer, and then, uh, there's a few other cancer types that are, are quite responsive, but those two in particular kind of stand out because with prevention, um, and also with, like, with respect to people that are diagnosed with cancer and have those cancers, and then they engage in physical activity as well, um, it's very... Like, you see a very robust response with respect to, like, reducing cancer mortality and also recurrence. Being, you know, being, you know, it's, like, 50%. Like, so you see, like, ca- you know, 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, um, to sort of reap the cancer preventative benefits than you do cardiovascular benefits or, you know, even-
- PAPeter Attia
Mm
- RPRhonda Patrick
... you know, some of the metabolic benefits. Um, and I don't know why that is, but, um, it seems as though, you know, like, like getting more to that upper limit of what these, you know, committees are recommending, so 300 minutes a week of moderate intensity exercise, um, or maybe 150 minutes more of, like, what they would define as vigorous, which actually I think is a little bit... Their vigorous is a little bit, um, below what my definition would be. But, um, anyways, so, so it seems like the, the, the amount of exercise, you actually have to put in a little bit more time and effort for, for the cancer. But any a- any amount is beneficial, so it's not like, you know, oh, well, I can't do 300 minutes, therefore I, I shouldn't even care. Well, that's not true, because there i- there are benefits, you know, even with, like, any type of physical activity. Uh, so, you know, that's all the observational data, and you can find anywhere between a 10 to 20% reduction in, uh, basically people are that, you know, they're less likely to get ca- but, you know, breast or colorectal cancer, 10 to 20%. Again, when you're talking about a type of cancer with a, with a higher lifetime risk, um, it, it makes more... It's, it's more compelling, right? Um, so it's always gonna be-
- PAPeter Attia
I'd be, 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, uh, 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. Um, it would be interesting to see, 'cause 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. Um, it would be very interesting to align the exercise data with the obesity/insulin resistance data and see if exercise is disproportionately reducing risk in those cancers for which obesity is a risk.
- RPRhonda Patrick
Such a good point, Peter, and, um, I think there is at least some data to suggest that you are, uh, correct with that. So, um, I mean, what is there, like 13 or so cancer types that, like, obesity is now-
- PAPeter Attia
Yeah
- RPRhonda Patrick
... considered a risk for?
- PAPeter Attia
It's either 13 or 17, something like that, yeah.
- RPRhonda Patrick
Yeah. And, um, and, and, and breast and, uh, colorectal cancer [laughs] are on that list, and so, um, yes. So, uh, it, the aerobic exercise, um, it... You know, there's, I think there's direct mechanisms. So, like, you know, aerobic exercise is, you know, directly you're making those myokines, and, like, you know, some of these myokines have been shown to, to basically, um, decrease the production of, like, growth factors secreted from cancer cells, and they're like, they also, like, kill, you know, are killing cancer cells, um, uh, you know, through a variety of other mechanisms. Also, the anti-inflammatory effect, you know, from, from exercise as well, so you're, you're having a, a strong anti-inflammatory response. But ac- also, like, there is the b- little bit of that, okay, well, exercise is also, like, improving insulin sensitivity.
- PAPeter Attia
Mm-hmm.
- RPRhonda Patrick
And it's, you know, you're in combination s- particularly in combination with dietary strategies, weight loss, you know, y- your, your... The weight loss itself is, is basically a important component of the cancer, uh, reduced cancer risk. So, I think you're totally... I think it's a combination of these things-
- PAPeter Attia
Mm
- RPRhonda Patrick
... where it's, like, the, the direct effects from, from exercise, and there's also... You know, it's really interesting because, as I mentioned, um, people that even have cancer, um, the, the, the respon- like, it, it seems like, you know, with physical activity... Like, I am not an oncologist, and you know many more oncologists than I do. I don't know that I've... You know, I don't know how common it is for e- for, for oncologists to prescribe exercise as an adjunct, um, sort of treatment to, you know, whatever the person, you know, whatever type of treatment, whether it's immunotherapy or radiation or chemotherapy or a combination, whatever. Um, I, I don't know how common it is, but, um, the, the data is more and more compelling, and I think it's become more and more compelling over the years that really, uh, exercising is, it seems to be very important for reducing cancer metastasis and also dramatically in, you know, 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-
- PAPeter Attia
Mm
- RPRhonda Patrick
... for the brain. Well, as you know, you know, cancer cells, tumor cells sort of escape the site of the tumor and they make their way into circulation. It's called a circulating tumor cell or a circulating cancer cell, depending on the study you read. And, you know, these circulating tumor cells are, like, traveling throughout the vascular system to dis- distant sites, and they sort of take camp and then, like, it's like kind of the seed of, you know, a new tumor forming in another tissue. Um, well, it's really interesting because, um, these cancer cells, cancer cells are so messed up, as you know. Like, they're just... They're, like, they're, they're completely wonky and very, very, uh, sensitive to stress, any type of stress. They have these mechanico- mechanoreceptors on their cell surface that are responsive to force, sheer force. So when you get your blood pumping, it's like, it's like a hurricane that, like, just wipes it out. Um, they die because they can't, they can't, they can't stand just the sheer force-
- PAPeter Attia
Mm
- RPRhonda Patrick
... of the blood flow through, you know, the vascular system. And so, um, and this is where you'll see, you know, studies. You can sort of pair it, so you compare the mechanistic studies, and there've been, 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, um, and so on. But, um, there, there, there... Again, there are studies showing that, like, physical activity, like, dramatically decreases, and this, there's been randomized trials showing it dramatically decreases circulating cancer cells in people, um, compared to whatever their, the other, you know, standard treatment that they're, you know, p- being given. Um, and so, like, kind of pairing that data with looking at, you know, other data where, uh, exercises is being prescribed to, 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, versus recurrence as well. So, I do think there is substantial evidence to suggest that being physically active is a good measure, um, for cancer prevention. And, uh, you know, I don't... A- 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. Um, you know, and there's certain cancer types that respond better. Lots of variables here. Like, I'm, I feel like I'm speaking in a general way, but, like, but, like, there are lots of things to consider, right? There are cancer types and, and there are sex effects and there are, as you mentioned, other covariates. There's obesity and there's, you know, insulin resistance and, um, age as well. So, I mean, there are lots of... It's nuanced,
- 1:49:09 – 1:55:07
The overarching impact of exercise of health, and the importance of focusing the factors that matter most
- RPRhonda Patrick
as, as, as usual. But I do think that you can make the case that, like, if you... Like, what can I do i- you know, in my life to redu- you know, reduce my, my risk of getting cancer, reduce my risk of dying from cancer, reduce my risk of getting Alzheimer's disease, reduce my risk from getting dementia, um, reduce my risk from getting cardiovascular disease, reduce my risk for [laughs] type 2 diabetes? Like, the only panacea there is, is exercise. It's exercise, right?
- PAPeter Attia
Yep.
- RPRhonda Patrick
I mean, that, that, that is... It is, it is the case, and, um, 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... It's up there, I think. I think, like, getting yourself to a good omega-3 status and defining what that is is still, like, being investigated. But, um, 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. It's the king. Um, and, and that's, that's the thing that you should focus on if you... I mean, anyth- I mean, obviously if you're obese, weight loss, exercise is part of that program.
- PAPeter Attia
Yeah.
- RPRhonda Patrick
And, like, 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 gonna help you do that. Like, just you eat less. Like, that's... Calories in, calories out, it, like, matters to some degree. [laughs] Like, if you're not eating as much.
- PAPeter Attia
Yeah, but, 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, um, y- you know, look, I, I, I have kind of a belief here that the, the person who is overweight, uh, the person who is obese and who is clearly eating more than they should be, uh, isn't doing that by choice. May- maybe some are, but, but for the most part, I, 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, right? Um, and I think that, you know, 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. Like, 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. They have a better... Their body physiologically is more in tune with their appetitive 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, um, a part of that equation is the feedback loop that exercise brings. So yes, exercise just matters. And, and, and I also think that, you know, I, I... Especially in this discussion of cancer, and breast cancer is the example you brought up, you know, so many women are so petrified of hormone replacement therapy because of this awful, you know, 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, increase 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 WHI, 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 perimenopausal 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.
- RPRhonda Patrick
Right.
- PAPeter Attia
And I wish, I wish people would just allow their attention to be allocated proportionate to the size of the impact.
- RPRhonda Patrick
I'm, I'm, I'm 100% with you. And, and with... K- kind of, to kind of even just highlight, um, or emphasize what you just said, you know, there are studies with women who are doing moderate drinking, which, I mean, depending on the study you read, it's like... I mean, for women, moderate drinking is like, it's like, you know, two, three drinks a, a day or some- like, it's a lot.
- PAPeter Attia
Wow.
- RPRhonda Patrick
Um, and, like, that incr- like, that literally, like, translates to a lifetime risk of breast cancer. It's like one in six or something like that.
- PAPeter Attia
Mm.
- RPRhonda Patrick
Where it's pretty significant, but you don't hear about women petrified of, like, drinking, you know, like, two glasses of wine a night, um, which, I mean, some people do. Like, it's, you know-
- PAPeter Attia
Yeah
- RPRhonda Patrick
... not, it's actually not uncommon. Um, and, and so I... It's like, again, it's one of those things that you were saying where it's like, like, looking at, like, what's gonna 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... You know, it, it absolutely impacts breast cancer. Um, same with, you know, uh, physical activity in the opposite direction has, I mean, just really enormous benefits.
- 1:55:07 – 2:00:45
Impact of alcohol consumption on breast cancer risk and overall health
- RPRhonda Patrick
And then alcohol consumption, um, is another one, even, even a mild alcohol consumption. I would say that, like, I don't wanna go there because it's, like, so, it's complicated and I, like, [laughs] I can't even, like, begin. Like, there's, there's so much-
- PAPeter Attia
I've, I've gone there. I've gone there, Rhonda. I've gone there.
- RPRhonda Patrick
[laughs]
- PAPeter Attia
I'm, I, I go out, I go out on the limb and I'm gonna say it. There is no amount of alcohol that is healthy. Um, the J-curve is a misnomer, and what I think I would say is somewhere between zero and one, there's probably that much of... There's not that much of an increase in risk, but there's not a reduction in risk, right? So the-
- RPRhonda Patrick
For what?
- PAPeter Attia
For, for, for-
- RPRhonda Patrick
Cancer or just in-
- PAPeter Attia
... for mortality in general.
- RPRhonda Patrick
Mortality.
- PAPeter Attia
Yeah, yeah, yeah, yeah, yeah.
- RPRhonda Patrick
Okay.
- PAPeter Attia
So in other words, you know, they talk about the sort of J-curve where- n- complete abstinence is a greater risk than, you know, one drink a day. Uh, but, but I think both the Mendelian randomization makes that not... Makes it 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, um, I, I feel very comfortable saying that there is no dose of alcohol that is healthy, but, you know, at a very low dose, again, probably four to seven drinks per week, it probably has immeasurable h- um, or pardon me, not immeasurable. You probably can't quite quantify the harm.
- RPRhonda Patrick
Mm-hmm.
- PAPeter Attia
Um, that, that, that would be my take. And, and so I, I, I'm, I'm, I'm comfortable saying that. I, I really feel confident that that is the case, um, and that, you know, things like the French paradox have far better explanations, as one example.
- RPRhonda Patrick
Yeah. I, I, I tend to think, I mean, there's, uh, the data is also a mess like you s- like I agree with you, and, um, it does seem like, you know, like can you have your weekend, you know, glasses of wine, like Friday, Saturday?
- PAPeter Attia
Absolutely.
- RPRhonda Patrick
I think you can. And, you know, with respect to the cancer risk and like that's, that's considered, you know, it's mild. I mean, it's less than-
- PAPeter Attia
Yeah
- RPRhonda Patrick
... you're having less than one drink a day. And the only evidence I've really seen against the, the mild is on the National Cancer Institute site, where they like, it's one of those cancers where it's like one in 500. Like it, it, it increases your risk of a cancer that you already have a lifetime risk of one in 500, and it's still less than 1% of an increased... Like-
- PAPeter Attia
Yeah
- RPRhonda Patrick
... to, to me it's like your lifetime risk is-
- PAPeter Attia
Yeah, you, that's my point. You can't, you can't measure it.
- RPRhonda Patrick
Right. You can't-
- PAPeter Attia
Uh, I mean-
- RPRhonda Patrick
Like you can't measure it. Yeah.
- PAPeter Attia
It's a classic example of the dose makes the poison, but don't confuse that the poison is a poison, right?
- RPRhonda Patrick
Right.
- PAPeter Attia
So another example would be cigarettes. If you smoked a cigarette twice a week, literally one cigarette twice, 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.
- RPRhonda Patrick
[laughs]
- PAPeter Attia
Right?
- 2:00:45 – 2:05:25
Exercise as an intervention for poor sleep habits
- RPRhonda Patrick
brought up the sleep and, uh, for one, so I started wearing a t- continuous glucose monitor largely because of you, um, and
- PAPeter Attia
I've been a very bad influence on some things you've done.
- RPRhonda Patrick
[laughs]
- PAPeter Attia
The lactate monitor, the CGM. I don't know.
- RPRhonda Patrick
Yeah. Well, I started wearing it l- when I was a new mom, so this was, you know, like five years ago, and, um-
- PAPeter Attia
That can't be a good time to wear a CGM. But that, but although it must have been interesting, right?
- RPRhonda Patrick
It, it, it was extreme. So here, here I am coming into this like, oh, I'm gonna learn about the foods I eat and how my body, you know-
- PAPeter Attia
Yeah, yeah
- RPRhonda Patrick
... responds to those foods. And lo and behold, the biggest and most compelling and most important data point, or many points, 'cause 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, um, glucose level, like continuously, was the effect that my sleep interruption-
- PAPeter Attia
Yeah
- RPRhonda Patrick
... had on both my fasting blood glucose and my postprand- where I was like, like it, I could get like pre, like what would, can be considered like pre-diabetic. Like I was like blown away. I was like, what is... This is insane. Um, and then what I also sort of- gleaned from this was that when I, like, s- was... On days, and the effect lasted at about, I would say, like, about 48 hours or so. When I did work out, and I w- at the time I was doing a lot of high intensity interval training. I was d- it was like an hour-long sp- spin class I used to go to, you know, where they do all this interval training, um, that it almost completely blunted that effect.
- PAPeter Attia
Mm-hmm.
- RPRhonda Patrick
Where I... And even though I was dog tired, last thing-
- PAPeter Attia
[laughs]
- RPRhonda Patrick
... I wanna do was go to my damn spin class. I was just like, "This is, like... I can't. It's gonna be bad for me if I go." That's how I felt.
- PAPeter Attia
[laughs]
- RPRhonda Patrick
Like, it's gonna be bad for me, but it was completely the opposite, where, I mean, like, this crazy glucose, you know, dysregulation and whatever the cause is for that. I'm sure you know much more about that than I do. Um, 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. Like, I have to w- no matter how I feel, it doesn't matter. It's beneficial. And, um, there's also a... It was a really interesting study, uh, caveat observational data. You never know. Like, there's d- reverse causation, all the problems with any study. But it was, it was looking at the, um, you know, sleep habits, and so people that had slept, you know, it was poor sleep or interrupted sleep, something of that nature. I can't remember the, all the exact things that were measured with respect to sleep. But, um, people that, you know, didn't sleep as long or had poor sleep, whatever by whatever measurements, had a higher all-cause mortality, which is not that surprising, but only in people that weren't physically active.
- PAPeter Attia
Hmm.
- RPRhonda Patrick
And to me, I was like, "Oh, wow, that's like-
- PAPeter Attia
That's interesting.
- RPRhonda Patrick
It's interesting, and it's like, you know, exercise can forgive a lot of sins-
- PAPeter Attia
Mm-hmm
- RPRhonda Patrick
... in a, in many ways. It really can. And, you know, so you're talking about your, you know, 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 like it's a lot. It's a burden. You have to, like, you have to calculate things. You have to be very, um, you know, specific in your, the actions you take and, like, things that you don't do, things you do, right? And, and for me, it's like, okay, am I gonna, like... I'm having a party. We're gonna have some mimosas, whatever. Like, I'm gonna exercise no matter what. Like, and that might take off some of the stress, right? I'm not saying I go out. Like, I, I, I personally, um, I hardly drink, and mostly because I am E4. I have one allele, and I have, uh, pretty much come to the conclusion that it, my brain can't repair damage as well as my husband's [laughs] who doesn't have an E4 allele. Um, with that said, um, you know, I w- occasionally will... I'll have, like, maybe, you know, a glass or two of wine. Usually that's my, my preference. But, um, on, you know, a week. But even, I mean, last time I had a drink was, like, Valentine's Day, you know? So it's, it's been, it's been a while. Um, but at least I think with the sleep... Sorry, with the exercise, you know, again, it's like it, it does. It seems to forgive a lot of sins, honestly.
- PAPeter Attia
I, I like that way of describing it.
- RPRhonda Patrick
You know?
- PAPeter Attia
Yeah, yeah. I think, um-
- RPRhonda Patrick
Well, I, I kinda borrowed that from Stuart Phillips. I think, I think he was the one that said it to me, 'cause I was like, "This is, like-
- PAPeter Attia
Yeah, that's right. I, I heard that. That's right.
- RPRhonda Patrick
Yeah.
- PAPeter Attia
I remember him saying that on your podcast.
- 2:05:25 – 2:27:15
The longevity benefits of consuming adequate protein and strength training to preserve muscle mass and strength
- PAPeter Attia
yeah
- RPRhonda Patrick
... muscle mass world, but-
- PAPeter Attia
So, so, 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, 'cause we were both in San Diego. You and your husband were over for dinner. I think I cooked up some fresh venison that I had just killed, and we were kind of talking about protein. And y- I think at the time, both of us were kind of struggling with two competing ideas in geroscience. Um, and those two ideas that seemed dialectical, they seemed at odds, 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, and we didn't, 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 thought, 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 w- that's what the dose is. So, 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, I... 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, that I formulate it the way you would, and, and I guess more importantly, tell me how you're thinking today.
- RPRhonda Patrick
Yeah. So you actually did a very good job [laughs] formulating sort of, uh, my, my mentality with respect to protein intake and longevity, um, back in, you know, 2019, prior to that. But, like, you know, even, even up until not even that long ago, to be honest, you know, there's of go- of, like, as you mentioned, a large body of animal evidence, but also, like, there was coupled, you know, this coupled, you know, epidemiological data where you think... where y- you know, people are looking at, you know, vegetarians are taking in lower amounts of protein, and their all-cause mortality and their cancer mortality, and then just study after study after study, and they have a lower all-cause mortality, lower cancer mortality. But- But [laughs] only in those individuals who are not obese, not sedentary, uh, sorry, are sedentary, are s- are smoking, or, you know, they had some unhealthy lifestyle factor. So in other words, the people taking in higher protein, animal protein, uh, who were basically healthy had a similar cancer-related mortality, all-cause mortality as these vegetarians. Okay, so-
- PAPeter Attia
And, and similarly, studies where they normalized for fruit and vegetable intake, high protein versus low protein, no difference in-
- RPRhonda Patrick
Right
- PAPeter Attia
... in, in, in, in early mortality, right? So 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.
- RPRhonda Patrick
Exactly. And, and with the animal data, and this is probably where my mentality has shifted the most because I had never... Like, I wasn't really of the opinion that vegetarian diets were superior to, you know, meat-eating or, I guess, omnivore-types of diets that were healthy omnivore types of diets. Like, I, I, I, I... Like, because of what you were saying. Like, that data was, you know, it was nuanced, and it wasn't just like, you know? So I wasn't... That wasn't something I was... that has shifted in my, you know-
- PAPeter Attia
Mm
- RPRhonda Patrick
... the way I've been thinking. But with respect to, you know, a lot of the animal data and the, you know, and the mechanisms, and you can, you can, you know, 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, and there's now I think some pushback going on, but there's still a large, you know, group of scientists that are, you know, still, you know, publishing lots of animal data. And, and this is where I sort of started to look into some of these exercise physiologist people, um, that... like Stuart Phillips. I know you've had, like, um, Don-
- PAPeter Attia
Don Layman
- RPRhonda Patrick
... Don Layman on.
- PAPeter Attia
Yeah.
- RPRhonda Patrick
Like, exact- Like, these, these, like, giants in the field that are doing the research, and, uh, Brad Schoenfeld is another one, where they're, they're looking at protein intake. They're looking at, uh, you know, strength training and its effect in humans, right? In humans. Um, on muscle protein synthesis, and also just, like, looking at data with respect to muscle mass and, you know, all-cause mortality and, you know, Alzheimer's disease, dementia. We didn't, you know, talk about that, but, like, strength training also, you know, can modify that risk. Um, also cancer mortality. And so, um-
- PAPeter Attia
Yeah, stro- strong grip versus weak grip, monotonic change in grip strength, 70% reduction in incidents 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.
- RPRhonda Patrick
It is.
- PAPeter Attia
Str- strength matters. Yeah.
- RPRhonda Patrick
It, it does. It does. And you're not like there, uh, you know, as you know and many of your listeners, like, there's two important signals for, you know, your, your muscle of strength. Obviously, a big component of that is, like, physically working them. But, you know, protein intake plays a, plays a role there as well. And I think it was Stuart Phillips, like, phrased it this way, where, you know, the, the animals that were s- that, that are being studied in these labs are in a sterile environment, right? You know, they're in a sterile environment. They're not being exposed to influenza and all these infectious diseases. And, you know, like, like any of us have ha- that we've had a parent or a relative or someone that has gone into the hospital and maybe had bed rest, um, and then come out and, like, like, I had a grandparent who, like, I mean, literally couldn't walk after a back surgery. I, it was like, I mean, for forever. Like, that was it. That was like-
- PAPeter Attia
Mm
- RPRhonda Patrick
... that was their downfall. It was like the trajectory just went down, completely down. And, you know, so losing that muscle mass, you know, when you're in older age, um, obviously building up a bigger reserve in, in youth, like in, in, in middle adulthood, whatever, like, that's, that's very important. But, like, you know these animals that, like, people are manipulating the protein restriction in them, like, they're not being exposed to that, right? They're not g- they're not losing, like, [laughs] I don't know how, what percentage, a qu- like it's, it's pretty intense, like how much they, you know, you can lose from, like, three weeks of bed rest. Um, and, and also, like, you know, as it's been pointed out by, um, people in your po- I think Matt Kibberlene, like these... You know, mice are dying from, like, cancer, right? Like, cardiovascular dise- They're, they're not, they're not dying from the same diseases, and it's not even the same type of cancer that humans get. Like humans-
- PAPeter Attia
Right
- RPRhonda Patrick
... we get a lot of these epithelial, like, tumors, solid tumors. They're, like, dying from lymphomas.
- PAPeter Attia
Right.
- RPRhonda Patrick
And, you know, like, that's... So there's a lot of differences there as well, um, where I j- you know, I don't... Like, there's a lot of interesting... And I'm al- the one to... I've talked a million times about animal studies [laughs] . Um, and it's, I think they're important mechanistic data. Like, there's things you just won't ever get from humans, uh, you know? But I d- at the end of the day, I started to realize that, you know, looking at this, you know, mice in a sterile environment where they're not really being exposed to the same stimuli as humans, things are very different in terms of aging. Um, I don't... I just, I wasn't... I was like, this... It was falling apart in my mind, basically. It was, like, all falling apart. I'm like, "Oh, my goodness. This isn't, doesn't make any sense. Like, this isn't what to be looking at if I'm, if I'm wanting to really focus on healthy aging." For myself, you know, and for ev- for everyone else, right? So I think that's kind of what was the tipping point for me, was just kind of that realization of the importance of, um, muscle mass and how... You know, some of these animal studies you look and you're like, oh, they're... They have, you know, they're a little bit of an improvement in their cardiovascular health. And I'm like, uh, exercise. Okay. Is that better than exercise? No. Um, you know, like, the, 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, you know? So, um, I think it was just kind of like the shift in the way I viewed the data, like the lens I was seeing it through.
- PAPeter Attia
Yeah. The, I- 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, and it's awful. Let's compare all of that to this questionable risk for which, frankly, I don't see data. And I'll, I'll add one more point to what you said, Rhonda, which is I think this story got confounded by our good friend C. elegans. Right? 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-
- RPRhonda Patrick
Daf
- PAPeter Attia
... or DAF-16, but w- 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, uh, C. elegans, this worm. And the implication of that was profound. I mean, that, that... I d- I don't wanna downplay the most important takeaway from that, which was lifespan was malleable. That, that, that turned out to be very interesting. Um, I could go on my rant about why C. elegans is not a, an organism or a, or a, an animal model that offers any insight into us, um, you know, based on its cell, based on a whole bunch of things about its biology. But nevertheless, it somehow became knocking out DAF-2 or DAF-16 was tantamount to dropping IVF... Uh, uh, IGF, insulin-like growth factor one to zero is the key to longevity, and the way to do that is to have no protein. And I think that story s- [laughs] is so incorrect, but somehow it's become part of dogma. So I think, I think that's the other piece of this that just kind of won't go away.
- RPRhonda Patrick
Um, yeah. It's, it's funny because I, I've done those experiments in, with my own hands when I was at the Salk Institute and I was in Andy Dillin's lab, who had trained with Cynthia Kenyon, who made the discovery-
- PAPeter Attia
Right
- RPRhonda Patrick
... back in, what was it? Early 90s or something. Um-
- 2:27:15 – 2:35:35
How to get enough of the right kind of protein in your diet
- PAPeter Attia
kilo. Um, because the other thing that complicates it, Rhonda, is not all protein is created equal. So, you know, if you're eating un- if you're getting a reasonable amount of your protein in, uh, in, from, from, uh, plants, you're getting a lower bioavailable amino acid. You're also not getting the same quantity of leucine, lysine, and methionine, which are probably the three most important amino acids anyway. So, um, you know, one of the things Don Layman talked about was if you really wanna be rigorous about this, you probably wanna track those amino acids, and you really wanna say, look, make sure you're getting one gram at least of methionine per day, two to four grams per serving of leucine and lysine. Now, again, for a lot of people, that's too nerdy, but, but, you know, 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 in 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 we love to do, you're demanding more amino acids for the turnover. And then of course, anabolic resistance, I think, is the biggest issue, and, and something that truthfully up until two years ago, I just wasn't paying enough attention to. I, I wasn't appreciating that my older patients had a, had an additional problem that younger patients didn't have with respect to that signal.
- RPRhonda Patrick
So that's a lot. 2.2 grams, um, per kilogram body weight, that's... I mean, I struggle, like I... To get, for me to get 1.6, like, I'm supplementing. I'm, I'm taking whey protein. Like-
- PAPeter Attia
Mm-hmm
- RPRhonda Patrick
... I, I just ca- it's like, how many, like... So how many meals, like, do you think-
- PAPeter Attia
Typically four. Yeah, 'cause it's hard to-
- RPRhonda Patrick
Yeah. You have, you have to-
- PAPeter Attia
It's hard. Yeah. It has to be... And, and, and one of, like... So, so for me, it's really two meals and two snacks, and the snacks-
- RPRhonda Patrick
Mm-hmm
- PAPeter Attia
... are just protein snacks.
- RPRhonda Patrick
Protein.
- PAPeter Attia
So-
- RPRhonda Patrick
Right
- PAPeter Attia
... so it's a, it's a shake. So one of them is just a whey 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 apiece, um, and they're really good. They're, you know, super pure venison. Um, it's, you know, wild game. A- amazing product, and th- I, I should disclose I'm an investor in the company that makes them, by the way. Um-
- RPRhonda Patrick
I was gonna ask, do you make them? Is it like in your-
- PAPeter Attia
No. Yeah, but I, I, I know the people so well. I know everything about it, and I know the, the quality is there. Um, so those are two snacks, right? They're, otherwise, they're relatively low in calories, right? Like, my whey protein shake doesn't really have anything else in it except some frozen berries and almond milk. Um, and then the, the venison sticks are what they are. And then, uh, and then two meals that are, you know, gonna have protein in. For me, again, a lot of times, like, it's gonna be an omelet, and then, you know, protein dinner. So yeah, it's, um, not gonna deny it. It's work. It's, it's not, um... It probably consumes more of my, um, dietary planning and dietary attention than anything else. I, I, I don't pay any attention to how many carbs and fat I eat anymore. Uh, I'm, [laughs] I'm just paying attention to protein intake.
- RPRhonda Patrick
It's something I never really paid attention to, uh, much at all, um, you know, until in, 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, I mean-
- PAPeter Attia
Yep
- RPRhonda Patrick
... like, like, that's another thing where it's like you want, you wanna, like, that's, you want a reserve of that as well, especially as-
- PAPeter Attia
Absolutely
- RPRhonda Patrick
... as a female, right? Like-
- PAPeter Attia
Yeah
- RPRhonda Patrick
... so that, that, those are, like, focu- focusing on the s- the strength training and also the protein intake, and it's been quite challenging. I've always sort of focused on micronutrients, and I, and it is, you know, it's still a focus of mine, and, like, making sure I'm getting enough of those, and I do supplement as well, um, uh, you know, in addition to trying to eat, like, leafy greens and getting some, you know, some of the veggies and stuff. It's either gonna be roasted veggies for me or, like, salad. But, um, the protein intake is, like, it's been, it's been challenging, and I find I typically do three meals. Um, one of them is, is, like, a, a, a protein meal snack, so it's, like, some salmon or, like, a, um, a homemade turkey burger or something like that. Um, but then the protein shakes also is where I ha- I just have to do. I guess that I don't really consider it a meal, but it kind of is.
- PAPeter Attia
Yeah.
- RPRhonda Patrick
And, um, you know, it's, it is, like, it's s- it's satiating. The protein, like, shake is definitely satiating, and I'm already... It's al- even kind of hard because when you work out, like, as you mentioned, your, your satiety- ... you know, hormones go up. Like, you're... Like, I'm not hungry. Like, I don't, like, necessarily want to eat. Like, it, it takes a while before I can actually, like, even get an appetite, you know?
- PAPeter Attia
Yep.
- RPRhonda Patrick
So there's all these, like, [laughs] competing things where I'm like trying to get the protein, but I'm like, "I'm not really hungry." And I'm like, "But I know I need it." And you know, so all these little, um, important factors. And yet again, um, important to sort of, you know, highlight that, you know, I don't know that someone who is overweight or obese necessarily needs to focus so much on that, right? I mean, would you agree?
- PAPeter Attia
Right. That's right. Y- yeah.
- RPRhonda Patrick
But-
- PAPeter Attia
I mean, fortunately, most people who are what I call over-nourished 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 caloric restriction coupled with the training. We use the training as a way to offset some of that lean mass loss. Um, and, and then we can come back to it. But, but yeah. Now, that said, for people... So it depends on the strategy, right? 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, right? Also, you have the thermogenic effect and the benefits of protein over fat 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, 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 GLP-1 agonist. So, uh, I've been a pretty public... Uh, critic might be too strong a word, but I've certainly expressed my reservations about the ubiquitous use and the liberal use of GLP-1 agonist, especially in people, you know, 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 you know, the, um, I gotta get my beach body on for the wedding this summer. I'm gonna lose 10 pounds. Let me fire up some semaglutide or tirzepatide. I, I think that's a net negative personally. And in those patients, not that we're giving it to those patients, but in any patient who's on a GLP-1 agonist, we feel it is so essential to hammer home protein because those drugs are so effective at squashing appetite that... I mean, we've seen people who basically just wanna drink alcohol when they're on it, and they'll lose weight like crazy 'cause they're, you know, not getting that many calories, but they're like, "Yeah, I just like wine."
- RPRhonda Patrick
Losing muscle. [laughs]
- 2:35:35 – 2:39:38
Fasting: weighing the risk vs. reward
- RPRhonda Patrick
I, I don't know, maybe we'll talk about this when you come on my podcast, but like, I'd love to like... 'Cause you used to do a lot of fasting, and-
- PAPeter Attia
Yeah
- RPRhonda Patrick
... um, I know you've kind of n- you don't do as much, at least of the long, you know-
- PAPeter Attia
Right
- RPRhonda Patrick
... long fasts. And boy, we could... I would love to get into that. Um, you can decide whether we should do that [laughs] do that next time, or we could talk a little bit now. But, um, but yeah, that was also like, like the biggest... You know, there was another shift in my, um, understanding of, you know, fasting and time-restricted eating. A lot of people use time-restricted eating. They, they sort of practice it by skipping meals. Um, and I don't-
- PAPeter Attia
Yeah
- RPRhonda Patrick
... know necessarily that's the way to do it, but people do that. Um, it's just, you know, what people do. And when you're skipping a meal, you're skipping your protein, right? And so you're not getting as much pro- As... You're, you're basically becoming, uh, you... losing muscle mass because you're not, you're not getting that, that important signal, especially if you're not doing resistance training, right? Then it's like kind of a disaster, and that was also something, uh, that I hadn't thought about a lot, and I know you've h- you've got a lot of experience in it, um, both personal and clinically. Uh, but, um-
- PAPeter Attia
I mean, I'll, I'll, I'll share with you briefly how we think about that. So, so on the, on the time-restricted feeding part, we, we agree that, that the greatest drawback is that the patients get protein deficient. So, 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 you know, a 16/8, you can eat your way into obesity with a 16/8. But once you start getting down to a 20/4 or a 22 to 2, basically just doing one meal a day, really getting restrictive, um, y- for the most part, you're gonna lose weight. Um, 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 kinda 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, right? They're, they're literal- not coming down the toilet. They're coming out as via, via v- vis-a-vis urine, right? Coming out via urea cycle. So, um, the, um, 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 I'm gonna only have kind of a, a lunch at 2:00 and a dinner at 7:00. We'll say fine, but you still have to have two protein snacks outside of that. And that becomes challenging, 'cause 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, "But oh my God, that's like outside of my feeding window. Will that impair autophagy?" To which I argue, you're not getting any autophagy doing a [laughs] single day time-restricted feeding anyway. It doesn't matter. Um, but if people are getting gut benefits from taking that time off, then yeah, they're gonna miss out on those, 'cause you're... I just don't see how you can get the gut rest if you're trying to get those amino acids. And so you might have to really start to cycle those things. Um, 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, you know, I think that... I'm, I'm, I'm just entering my sixth decade. This is a very high priority for me.
- RPRhonda Patrick
Oh, really? Wow. You look great, Peter. I didn't... So you're, you're in your late 50s?
- PAPeter Attia
I'm 50. No, sixth decade, so I-
- RPRhonda Patrick
Oh.
- PAPeter Attia
Yeah, yeah, yeah.
- RPRhonda Patrick
So you just... So you're 50.
- PAPeter Attia
Just turned 50. Yeah.
- RPRhonda Patrick
Okay.
- PAPeter Attia
Yeah.
- RPRhonda Patrick
Yeah. Gotcha. [laughs] Yeah. Um, well, y- the, the time-
- PAPeter Attia
But I love that, I love that you thought I was 60. That's awesome. [laughs]
- RPRhonda Patrick
Well, you know, you know who's Joe Rog-
- PAPeter Attia
I'll take that as a-
- RPRhonda Patrick
I think Joe Rogan's entering that, and that's kinda what I was thinking.
- PAPeter Attia
Yeah.
- RPRhonda Patrick
And he looks, I mean,
- 2:39:38 – 2:46:17
How Rhonda’s views have shifted on diet and exercise
- RPRhonda Patrick
like, you know, the... You can, you can definitely see the people that like, put in the work and work out and, and you know, they do aerobic, they do strength training. Like, you look at them. There was like a study published on that, too. Like, a bunch of bio- biological markers of aging and biomarkers of aging were measured, and then like, there was like, people looked at pictures and like, ranked their, their age. And their, their, you know, quote-unquote, "biomarker biological age," so like according to all these biomarkers that basically say their chronological age-
- PAPeter Attia
Yeah
- RPRhonda Patrick
... may be older than their biological age, but they looked like their biological age, not their chronological age. You know? So that, that's, that's also important.
- PAPeter Attia
Although I sometimes feel like excess exercise can prematurely age you as well. I, I've certainly seen a lot of... Uh, and I don't know how much of that is the sun damage, 'cause of course a lot of-
- RPRhonda Patrick
Yeah
- PAPeter Attia
... exercise is done outdoors, and of course, uh, sun can play a, a horrible role in that. Um, well, so I- we've been, you know, we s- we've, 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 believed three or four years ago that you don't believe today? Is there anything we haven't touched on? 'Cause we've, we've talked about some really good ones.
- RPRhonda Patrick
Um, I think those are the, the really important ones off the top of my head. Um, I definitely don't want to get into the whole COVID thing at this point, but [laughs] I've... My, my view has changed on, on things as that has progressed and changed as well. Um, so I don't wanna like, not mention it, but, uh, yeah. So but, um, the, the most im- I think the most important things would be, um, muscle mass, protein intake. Also, I d- like 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.
- PAPeter Attia
Mm-hmm.
- RPRhonda Patrick
I think that is something that I've ... It's, it's, you know, I wasn't always, you know-
- PAPeter Attia
Yep
- RPRhonda Patrick
... buying into that. But I do, it is still my opinion there are benefits to eating within your circadian rhythm. I mean, so like, you know, eating, eating late at night when you're m- making melatonin two to three hours before bed, you're basically inhibiting insulin secretion, and I don't... Like, there's data showing that you will, you know-
- PAPeter Attia
Yeah
- RPRhonda Patrick
... your glucose levels will be higher with the same exact mac- macronutrient intake as if you eat it earlier. So I do, there are benefits, circadian benefits, and I also think you mentioned the, the, the, the gut rest and like, digestion. Um, you know, resting, like having that rest per- like, your body can't... So DNA repair mechanisms, you mentioned autophagy, like those things happen when you're not digesting. So like, and that process, like isn't happening. So you have to have like a rest period, um, for repair processes to occur. And I don't know that I necessarily... I think autophagy is as good as the, the markers that we, or sensitive assays that we have to measure it. And I don't know that it's settled with respect to how long... I, I personally think there's probably even in between meals, there's some, um, amount of autophagy. Autophagy is happening in us. It is.
Episode duration: 2:53:27
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