The Peter Attia Drive - #252 ‒ Latest insights on Alzheimer's disease, cancer, exercise, nutrition, and fasting

00:00:00.000 Hey, everyone. Welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

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00:00:41.760 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay,

00:00:47.800 here's today's episode. I guess this week is Rhonda Patrick. Some of you may recall that Rhonda

00:00:53.900 was one of the original guests on the pilot series of the drive back in July, 2018.

00:00:58.900 when we were trying to figure out if we really wanted to do a podcast. Well, of course we did,

00:01:02.640 and it is awesome to have Rhonda back. Rhonda also hosts her own podcast called Found My Fitness.

00:01:08.940 In this episode, we focus the conversation around a few important concepts, and we talk about Rhonda's

00:01:15.520 current interests along with areas where her perspective has either shifted or evolved over

00:01:19.820 the years. We start the conversation with a deep dive into Alzheimer's disease. We talk about the

00:01:25.080 possibility of a vascular hypothesis for Alzheimer's disease, and we also talk about the different

00:01:29.640 factors that can affect Alzheimer's disease, including type 2 diabetes, omega supplementation,

00:01:34.380 blood pressure, exercise, sauna, and more. We then go on and talk about the relationship between

00:01:38.800 exercise and cancer, and also the relationship between alcohol and cancer. And then finally,

00:01:44.580 we talk about protein and aging, and we talk about fasting, time-restricted feeding. These are two areas

00:01:50.300 where Rhonda and I have had different points of views over times, and both of our views have

00:01:55.720 evolved. I think in some ways, we're actually converging at about the same place now. So this

00:01:59.900 is a really interesting discussion. It was really exciting to sit down with Rhonda. It had been far

00:02:04.520 too long, and so I hope you enjoy this discussion half as much as I did. Rhonda, it is so great to see

00:02:15.740 you, especially on that awesome remote setup that I almost shouldn't have said to people was remote,

00:02:20.720 because it really feels like we are in person, about as close to in person as we've been in a

00:02:25.060 few years. It's really great to see you, Peter. It's been a minute. We'll meet together soon in a

00:02:29.800 couple of months, so I'm looking forward to that. There's a lot to catch up on. Over the past few

00:02:33.880 years, we've obviously exchanged a bunch of emails about things that we each find interesting,

00:02:37.300 and I think in the last couple of years, well, let's just pause it in the last five years was the last time

00:02:42.120 we did a podcast. Just going back to that point, I think both of us have evolved a lot in our

00:02:48.080 thinking, and I think we've done so unapologetically. That's the nature of science. That's the nature of

00:02:52.940 what we do and we're trying to learn. So in thinking about our discussion today, I think we both agreed

00:02:58.600 it would be most enjoyable to at least spend some time talking about areas where your thinking has

00:03:04.600 evolved. But I think first we wanted to start with, I don't want to put words in your mouth, but maybe

00:03:09.460 that which you're thinking about the most right now? Would that be a safe assessment if we were to

00:03:12.980 start to talk about dementia, specifically Alzheimer's disease, and maybe the change in

00:03:18.700 how you think about that? It would. For me personally, I have neurodegenerative disease on my mind quite a

00:03:25.900 lot because Alzheimer's disease and Parkinson's disease both run in my family, and I have a genetic

00:03:32.720 predisposition. So for me, understanding everything I can do with my diet, with my lifestyle, exposure

00:03:41.000 to or limiting exposure to certain things, etc. becomes paramount because I don't want to get

00:03:47.380 Alzheimer's disease and Parkinson's disease. Like as you know, Peter, the Alzheimer's disease field has

00:03:53.340 been, it's been quite a roller coaster in a way. Like we've had this dominating hypothesis,

00:04:00.240 this amyloid hypothesis as it's called. So there's, you know, one of the major pathologies of Alzheimer's

00:04:06.380 disease are amyloid plaques in the brain. And there are other pathologies, tal tangles, also

00:04:11.860 glucose hypometabolism. So glucose uptake into the brain is impaired and also perhaps even the utilization

00:04:19.780 of glucose as well. These are like three major pathologies of Alzheimer's disease. And it seems as

00:04:25.900 though the majority of targeting how science and scientists have decided to target, you know,

00:04:33.200 Alzheimer's disease is through this amyloid, anti-amyloid hypothesis. And as you know, we've

00:04:38.140 had quite a few failed trials, although of recent a little bit more, I would say, you know, possible

00:04:44.860 success maybe. But generally speaking, it's been, are we just trying to treat a symptom here or are we too

00:04:51.500 far downstream? Like what's the deal? And I started reading some studies by Barisov Slovovic at USC

00:04:58.940 and Dr. Axel Montaigne, who was trained with Dr. Slovovic and now has his own lab at the University of

00:05:06.480 Edinburgh in Scotland. I recently did a podcast with him on my podcast. And it was really like, when I

00:05:12.640 started to read some of this literature, and I'm going to talk about like what this sort of new, it's not

00:05:16.860 even necessarily new, but like it's not a new way of understanding it, but it is in a way because in

00:05:21.780 the public opinion, in the public mind, it's a new way. And this is sort of like, okay, well, what are

00:05:26.160 the underlying causes of dementia? And so there's three major types of dementia, Alzheimer's disease

00:05:31.580 being the most common, there's small vessel disease, cerebral small vessel disease, and then

00:05:36.840 vascular dementia. Those are the three most common forms of dementia. But like, is there a common

00:05:41.460 underlying denominator between those? And on top of that, like what sort of lifestyle factors and

00:05:47.680 genetic factors do we know really increase the risk of Alzheimer's disease and dementia?

00:05:51.880 Well, we know having an ApoE4 allele, so this is a version of a gene that is known to increase the

00:05:59.940 risk of Alzheimer's disease. If you have one of them, it increases the risk twofold. If you have two,

00:06:04.980 if you got one from mom and one from dad, it could be up to tenfold. And this isn't like an early

00:06:09.900 onset Alzheimer's disease. It's more of what's called late onset, which is the normal sort of

00:06:15.020 age-related aggression of Alzheimer's disease. But that gene really does play a role in someone's

00:06:20.820 risk. The other thing we know is type 2 diabetes. I mean, that over, I don't know, somewhere between

00:06:27.100 50 to 80% of people with Alzheimer's disease also have type 2 diabetes. That's a lot. There's

00:06:33.620 definitely something going on, right? I mean... And let's sort of pause there for a moment because

00:06:38.000 I want to go back to sort of the premise of your interest, which is you are at increased risk. So

00:06:44.440 even if you just think about this personally, and therefore presumably you're interested in

00:06:48.560 quote-unquote prevention. And as you've probably heard on my podcast, prevention is still a word

00:06:53.340 that doesn't quite resonate within the field. In other words, up until very recently, I think the

00:06:58.480 NIH didn't even acknowledge the idea of prevention as a strategy within this field. And in fact,

00:07:05.140 preventative neurology or preventive neurology, I suppose, is really something that is still kind

00:07:10.640 of on the outskirts. Most people are thinking about what to do when you have Alzheimer's disease.

00:07:15.420 Not as many people are thinking about the question that you're asking and that a few other people are

00:07:19.900 asking, which is, what's in our control? Because yes, you alluded to APOE4, which I'm sure we'll talk

00:07:25.500 more about. But what you just said about type 2 diabetes would suggest that if you believe

00:07:31.620 you can prevent type 2 diabetes, wouldn't that at least suggest you have the probability or

00:07:37.560 possibility of preventing or delaying Alzheimer's disease? Sorry. So I didn't mean to interrupt you,

00:07:41.580 but I want to highlight the important implication of that statement.

00:07:45.600 Exactly. It's so important. I think that looking at Alzheimer's disease and understanding sort of

00:07:51.020 the underlying cause of it opens up, you know, these new avenues for prevention and also treatment.

00:07:58.440 And of course, there are people that do get Alzheimer's disease early in life. I mean,

00:08:03.120 these are people that could come down with it in their 40s or 50s. You know, people are outliers in

00:08:07.860 that case, but it does happen. And there are things that you might do everything right and still like

00:08:14.340 have that terrible genetic combination. With respect to the APOE4 and type 2 diabetes, understanding

00:08:20.280 again, is there something like common going on here that we can sort of understand as a foundation

00:08:27.300 to what are the initial like things going wrong to lead to Alzheimer's disease. And that is where

00:08:34.380 vascular dysfunction, particularly the blood vessels and capillaries that are lining the blood brain

00:08:41.580 barrier, seems to be a really, really early event that is common between all types of dementia and

00:08:50.760 between type 2 diabetes and APOE4. So people with type 2 diabetes, as you know...

00:08:56.080 Can I interrupt for a sec, Rhonda? Tell folks what the blood brain barrier is. I think it's

00:09:00.380 obviously going to be an important part of this discussion and not everybody might understand

00:09:03.660 what it is or why it's so important.

00:09:05.940 I am not a neuroscientist. You know, I am a scientist, but I have interest in this. And so

00:09:10.540 I've done a lot of reading in this field. The blood brain barrier serves a couple of functions. I mean,

00:09:16.440 one is there's a combination of different cell types that make up the blood brain barrier and a lot

00:09:21.800 of vasculature, right? And so blood flow, things are brought to the blood brain barrier and oxygen,

00:09:29.760 glucose, other nutrients, and they are, you know, transported across the blood brain barrier.

00:09:34.580 But it also, as the word implies, barrier provides a barrier to things that you don't want to get into

00:09:40.220 your brain. We don't want red blood cells getting into our brain. We don't want a variety of other

00:09:45.460 molecules, proteins that are floating around in our circulation to get into our brain. And so when

00:09:52.180 the blood brain barrier begins to break down, people I think are a lot more familiar with

00:09:57.500 when the gut barrier starts to break down, it sort of become more of a common theme that people are

00:10:03.940 focused on gut health. And so mostly you hear the word leaky gut. I don't really like that term. I think

00:10:09.700 it's intestinal permeability. But the tight junctions, these proteins that are holding

00:10:14.460 endothelial cells together in the gut, when those open up, you get that term leaky gut or as it really

00:10:21.240 should be called intestinal permeability. Well, in the brain, you also have endothelial cells and you

00:10:25.960 have tight junctions. And when those tight junctions also break apart, and we can talk about like what's

00:10:31.020 at the root of that, that leads to permeability of the blood brain barrier. And therefore, two things

00:10:36.800 happen. One, you are allowing then things from circulation to get in the brain, which, you know,

00:10:43.020 wreaks havoc on the brain and leads to this vicious cycle of neuroinflammation, inflammation in the brain.

00:10:48.440 But also you're disrupting the transport of important nutrients, oxygen, glucose, I mean,

00:10:55.780 blood flow is disrupted to the brain as well. The blood brain barrier and maintaining that integrity

00:11:00.720 is very important. And both ApoE4 and type 2 diabetes lead to permeability of that. And so with

00:11:08.060 type 2 diabetes, people have hypoglycemia, right? They have elevated blood glucose levels. And that

00:11:15.200 over time leads to advanced glycation end products. These are basically like they cross-link proteins and

00:11:22.600 a variety of other things that in the vasculature. And that basically damages the blood brain barrier and

00:11:28.880 leads to permeability. ApoE4, you know, there's a variety of other mechanisms that happen. But

00:11:33.340 essentially, you can measure the permeability of the blood brain barrier looking at a variety of

00:11:38.560 biomarkers and proteins in cerebral spinal fluid, but also in plasma. And these have been shown by

00:11:46.080 Dr. Slovovic, Dr. Montaigne to occur decades before the onset of cognitive impairment. And it's literally,

00:11:54.320 you can find it in more than 50% of all dementias. It's happening independent of amyloid accumulation,

00:11:59.780 tau tangles as well. So it's, you know, either something that's happening before, well before,

00:12:05.480 and in fact, blood brain barrier permeability, the blood brain barrier is essential for removing

00:12:11.780 toxic compounds from the brain. And a variety of different processes, you know, happen to allow this

00:12:18.600 to occur. So for example, you activate the glymphatic system during sleep, right? And a lot

00:12:23.960 of people are aware of this, your brain sort of swells during sleep, and the glymphatic system is

00:12:29.140 pushing the cerebral spinal fluid through the brain, clearing out debris, amyloid plaques, you know,

00:12:34.440 things like that. Well, that you need the blood brain barrier to be intact for that to occur. So I

00:12:39.160 mean, it makes sense that basically, if you have blood brain barrier permeability happening,

00:12:43.840 that you would start to have the accumulation of amyloid. So it's sort of like accumulation of

00:12:48.140 amyloid. I never thought of that, by the way, Rhonda, I'd never thought of what you just said,

00:12:51.540 which is, if your blood brain barrier can't hold the back pressure, which is what would be the case,

00:12:57.480 if it were permeable, you would not have the back pressure to maintain the glymphatic flow. That

00:13:03.500 never actually occurred to me until you said that. So very interesting mechanistic tie to that problem.

00:13:09.420 And I'm not familiar with all the types of ways the brain like there's other like parenchyma and

00:13:13.460 stuff that are like cleaning out the brain, all of those things are not happening as good when

00:13:18.140 your blood brain barrier is dysfunctional. And then another point is the ability of things to

00:13:23.240 interrupt and get into the brain that shouldn't. So one of the things, you know, everybody learns

00:13:26.580 in pharmacology or medical school is that there are certain drugs that penetrate the blood brain

00:13:31.320 barrier. There are certain drugs that do not. The implication being certain molecules can pass

00:13:36.160 through, certain molecules cannot. Well, presumably the leakier that barrier is, the more things that

00:13:43.660 maybe we evolved to not have crossed that barrier do indeed cross. And perhaps that's a part of what

00:13:50.020 you just said, right? Which is this increase in inflammation that is now coupled with an inability or a

00:13:55.300 decreased ability to clear out debris.

00:13:58.620 Exactly. In fact, so work from Dr. Montaigne has shown that fibrinogen, which is you and I are familiar with

00:14:06.360 this protein. It's something, if you're doing an inflammatory biomarker panel, it's a protein that's involved in

00:14:11.600 blood coagulation, but it's also something that is a marker of inflammation. And fibrinogen is not

00:14:18.280 supposed to be in the brain, but it's found in the brain in people with a leaky blood brain barrier.

00:14:24.780 So what's it doing in there? It disrupts a cell type called oligodendrocytes. These are a cell type

00:14:31.420 that make myelin, sort of fatty white structure that's important for electric signals being fired

00:14:38.060 throughout the brain. And it's basically toxic to them. So you basically start to have these,

00:14:44.400 you know, lesions and stuff in the white matter part of the brain, white matter hyperintensities,

00:14:48.860 as you're probably very familiar with, a very common in small vessel disease. Also,

00:14:53.480 you can see that in people with Alzheimer's as well. But getting that fibrinogen in the brain,

00:14:58.040 like that's happening because it's allowed to get in there. So the permeability of the blood

00:15:02.680 brain barrier, basically preventing stuff from getting in your brain that you don't want in there.

00:15:07.340 That's number one. But also the transport, I think you also alluded to this,

00:15:11.740 you're not getting things like glucose into the brain. And in fact, all these transporters,

00:15:16.940 they're in the endothelial cells. They're in these cells that are making up the blood brain barrier.

00:15:22.440 And when you start to disrupt that blood brain barrier, those transporters like are dysfunctional.

00:15:28.440 For example, one of them is the GLUT1 transporter. This transports glucose into the brain.

00:15:33.400 As you start to get a disruption in blood brain barrier function, glucose transporters,

00:15:39.760 they go down. And so you're talking about like not getting enough glucose into the brain, which is,

00:15:45.320 again, that's one of the pathological features of Alzheimer's disease, right? Not getting enough

00:15:49.740 glucose into the brain.

00:15:50.800 That's actually an interesting explanation because a very subtle point you made that might not be picked

00:15:55.060 up on everybody is you mentioned the GLUT1 transporter as opposed to the GLUT4 transporter.

00:15:59.720 And if my memory serves correctly, the brain has GLUT1s as opposed to GLUT4s and GLUT1s are

00:16:06.300 insulin independent. Is that correct?

00:16:08.860 Yeah. For the most part, they're insulin independent. That's my understanding.

00:16:12.860 And why that's interesting is because it seems a bit counterintuitive that a condition that leads

00:16:19.700 to insulin resistance, of course, type 2 diabetes is the essence of insulin resistance. It seems

00:16:25.600 counterintuitive that that would produce a hypometabolic state in an organ whose glucose

00:16:31.260 transporters are insulin independent. Except when you explain it the way you did, which is it's not

00:16:37.660 the insulin resistance of the GLUT1 transporter that's the problem the way it is for the GLUT4

00:16:43.260 transporter in the muscle. Instead, it's the actual mechanical disruption, if I'm understanding you

00:16:48.640 correctly, of that transporter because of the way it's no longer presumably held in place by the

00:16:55.220 barrier itself that allows glucose to get across. Did I understand that correctly?

00:16:59.020 100% correctly. And this isn't like dogma. This is definitely known. It's definitely where I'm

00:17:05.660 heading. It's my opinion. But there is evidence of it. And I think it's time to explore this evidence

00:17:11.260 a little closer and a little deeper because, you know, you hear the term type 3 diabetes. And I think

00:17:17.440 people think about it in the way of the brain being insulin resistant. And, you know, maybe there's

00:17:22.720 something to that, but I don't know if that's exactly what's going on. I think the type 2 diabetes is

00:17:29.340 disrupting the blood-brain barrier through a variety of mechanisms, including the advanced

00:17:35.540 glycation end products and the vascular. I mean, the vasculature disruption in type 2 diabetes is well

00:17:40.700 known. I mean, they have all sorts of problems. Monopathy, neuropathy, like all this. I mean,

00:17:45.160 they are disrupting their vasculature, including these tiny, tiny little blood vessels that are

00:17:49.840 like smaller in size than are the diameter of a hair. Those things are like disrupted at the

00:17:55.620 blood-brain barrier. And when you disrupt them, their blood flows decrease and the transporters are

00:18:00.080 going down. I mean, there's all sorts of problems. And so I think fixing the diabetes obviously would be

00:18:05.820 like the downstream thing to do, but like it's kind of a new mechanism, right? It's a kind of a

00:18:11.420 new way of understanding it. It explains the observation. So there's an observation that is

00:18:15.460 unmistakable, which is type 2 diabetes. I don't know the number, but I think it approximately doubles

00:18:21.920 your risk of Alzheimer's disease. So in other words, even if you're sitting there walking around with

00:18:26.480 two copies of the ApoE3 allele, having type 2 diabetes means you might as well have a copy of an

00:18:32.120 ApoE4 allele from a risk perspective. And what this is saying is, well, it's not entirely clear

00:18:38.500 at the surface why type 2 diabetes would impact the brain through the lens of traditional thinking

00:18:46.440 of GLUT4 transporters, which are insulin dependent. In other words, it isn't just an insulin resistance

00:18:51.320 problem, but I think these two other things matter. What you said about the microvasculature,

00:18:56.500 what I think a lot of people don't realize is how destructive type 2 diabetes is to the kidneys.

00:19:02.120 Because those tiny, tiny blood vessels, people are familiar with amputations and things that occur

00:19:06.860 in digits because of that impotence, all of these things where blood vessel is essential

00:19:11.880 in small blood vessels. And so there's that which feeds into the vascular path that you've discussed,

00:19:16.920 but it's also this disruption of glucose transport directly across that transporter.

00:19:22.180 So I think it's actually a very compelling thesis for how type 2 diabetes could be acting via those

00:19:27.640 two prongs to ultimately result in hypometabolism.

00:19:31.540 I do too. And then, of course, the cascade of inflammation that happens after that. So the other

00:19:36.340 thing that's also very interesting is, so we're talking about type 2 diabetes and very big implications

00:19:42.000 there for the prevention of Alzheimer's disease. There's a lot you can do, as you've talked about,

00:19:46.480 to prevent and even treat with diet and lifestyle, right? Type 2 diabetes. But also, what's really

00:19:53.540 interesting and I was sort of on this trail years ago, I published a sort of integrative review on

00:19:58.960 the role of the omega-3 DHA transporter, MFSD2A, in the brain. What's really interesting that animal

00:20:07.140 studies, when you disrupt that transporter, it causes like 50% breakdown of the blood-brain barrier

00:20:13.420 and like greater than 50% loss of omega-3 in the brain. So in my opinion, you know, that's animal

00:20:21.440 evidence. Of course, there's human evidence where MFSD2A transporters decrease with age,

00:20:26.860 particularly rapidly in Alzheimer's disease and with APOE4. So there are genetic abnormalities

00:20:33.080 and mutations that occur in that transporter where people have less of it and they have

00:20:38.720 microcephaly. So they have like smaller heads and they also have cognitive dysfunction, sort of

00:20:45.200 cognitive impairment, things like that as well.

00:20:47.160 How do we know that, Rhonda? So that's, let's even put the pathology aside,

00:20:51.640 the sort of latter category. But let's just talk about, well, again, what you've said explains

00:20:56.000 something we've empirically felt is true. And the evidence suggests that this provides a mechanism,

00:21:01.800 right? Which is APOE4 carriers need a higher level of EPA and DHA to get the same benefit. That appears

00:21:08.840 to be empirically correct. That would provide an explanation. Something else you said, you know,

00:21:13.800 we talk about amino acid or protein resistance, basically anabolic resistance as a person ages,

00:21:19.620 they need more and more protein to get the same effect. It's almost like you're saying aging itself

00:21:25.400 could create some resistance to dietary EPA and DHA that might require more as time goes on.

00:21:33.020 Do you think there are also just genetic differences within the variant of normal,

00:21:36.680 quote unquote, i.e. non-pathological, where one person would need more EPA and DHA to afford them

00:21:43.720 the same benefit of protection as another person? I do. I know there's at least a couple that are known.

00:21:51.040 And so like some people have certain gene variants that actually they respond better to, for example,

00:21:58.600 omega-3 supplementation and others don't, where they would actually need a higher dose. And I think

00:22:04.540 there's many more to be explored. Like we haven't unlocked all of that yet. When I say we, I mean

00:22:11.100 the scientific community, not me personally. But with the omega-3, and this, again, really hits home

00:22:19.180 the preventative role here that we can have in our Alzheimer's disease risk. So with the MFSD2A,

00:22:27.620 like these transporters are actually lost. So there's a type of cell called pericytes,

00:22:32.100 peri-E with an I, not to be confused with a parasite. They basically have these like big feet

00:22:38.060 that wrap around the endothelial cells at the blood-brain barrier. And they serve really two

00:22:43.920 important, many important, but two main important functions. One is they're basically constricting

00:22:48.540 and dilating and like helping squeeze like the flow of blood. So they're like regulating blood flow

00:22:53.640 to the brain. But they also are very important for that barrier. And they start to fall off with age,

00:23:00.280 these pericytes. And inflammation plays a big role in that. But the MFSD2A transporters are

00:23:07.000 concentrated on those cells too. And so you'll see hotspots of where the pericytes, once those

00:23:13.640 pericytes start to fall off, that is when basically immune cells and everything starts going into the

00:23:19.340 brain. It's like the start of the vicious inflammation cycle in the brain of the leakage,

00:23:25.480 amyloid accumulation, just everything downstream. There's something there with those transporters of

00:23:30.100 omega-3 that are right at the same site of where you lose those pericytes, which is also really

00:23:35.640 interesting. And again, there's a lot of animal evidence that suggests the role of that transporter

00:23:42.440 in blood-brain barrier integrity. Also, again, you can kind of like connect the dots here where you

00:23:47.840 think, okay, well, this is DHA and phospholipid form. So it's like, okay, there's got to be something

00:23:52.360 here with the omega-3. And I know there's a variety of scientists that are investigating this,

00:23:57.940 but I'm sort of excited. I am now going to be part of a team. So I joined the Fatty Acid Research

00:24:04.380 Institute, which is Dr. Bill Harris's research institute. And as a research associate, and we

00:24:10.400 are secured a small grant to look at the role of omega-3 with blood-brain barrier integrity and

00:24:18.140 biomarkers in people, a variety of different people that have small vessel disease that perhaps go on to

00:24:24.640 get Alzheimer's disease. And so I think there needs to be more research in this area because

00:24:30.020 the implications here, I think, are really important. There's two main lifestyle interventions,

00:24:35.000 I think, that are important with respect to the blood-brain barrier. Three, actually, three. So

00:24:40.000 basically not getting or fixing your type 2 diabetes, and then the omega-3 intake. And like

00:24:45.580 defining that will be sort of tricky. But full stop, most people in the United States,

00:24:51.360 they're not eating enough fatty fish, and they're not supplementing with omega-3, which is sort of an

00:24:55.980 alternative. I think it was like a 2012 study out of Harvard that identified omega-3, low omega-3

00:25:02.960 intake from fish, so the marine type of omega-3, not plant AOA, as one of the top six preventable

00:25:11.780 causes of death. So it was up there with- Smoking.

00:25:14.520 It was smoking and blood pressure and obesity and being sedentary. Low omega-3, it blew my mind.

00:25:20.740 And I'm not a biostatistician, but there was some calculation done with estimating the number

00:25:25.600 of deaths caused by not getting in enough omega-3 each year. It was like the same number of deaths,

00:25:31.080 it was like 84,000 deaths a year from low omega-3 intake from fish.

00:25:36.140 I wonder, though, if that's also just a marker for poor health. That's the challenge of all of

00:25:41.240 those studies. Totally.

00:25:42.200 In some cases with smoking, it's pretty obvious that there's causality there. I think there also is

00:25:46.660 blood pressure, but you could argue that never in the history of the world has there been a person

00:25:52.680 who has, I'm being a bit facetious, who has a high omega-3 index, who eats junk food and fast food all

00:26:02.140 day. Those can't coexist. I want to ask one clarifying question, Rhonda. Certainly, I know

00:26:06.700 that when you're talking about omega-3s, you're referring to the marine variant of which we have EPA

00:26:11.820 and DHA. But the transporter, if I understood correctly, is it a transporter only for DHA in

00:26:19.180 its phospholipid form? And if so, what is the importance of EPA in this?

00:26:24.240 Great question. So the MFSD2A transporter that I've been referring to is specific to DHA. And the

00:26:33.800 form of DHA is lysophosphatidylcholine DHA. So we make it. When we take in DHA from fish or from a

00:26:42.940 supplement, the higher amount of DHA that we take in, we add that lysophosphatidylcholine group to

00:26:49.560 the DHA. We also have DHA in free fatty acid form bound to albumin. And albumin is not – that

00:26:56.460 doesn't get into the brain, but it takes it to the brain, blood-brain barrier, and the free fatty

00:27:01.180 acid can sort of diffuse passively across the blood-brain barrier as well. Same with EPA.

00:27:06.240 Oh, I see. But because the phospholipids on the DHA, it needs a dedicated transporter,

00:27:10.900 whereas the unphosphorylated – well, not phosphorylated – the one that doesn't have a

00:27:14.160 phosphatidylipid side chain can diffuse without a transporter.

00:27:18.540 Exactly. So it's free fatty acid bound to albumin, and it can just diffuse across the brain. Yeah. So

00:27:22.760 that's how EPA is generally getting in the brain. And then second question for you on that thread,

00:27:27.300 feel free to go into as much depth as possible because I know this is actually a very

00:27:30.660 important topic that is somewhat controversial. What do you see as the relative importance of DHA

00:27:37.060 and EPA? The conventional thinking, I think, is that EPA probably more important in the heart,

00:27:44.660 DHA probably more important in the brain. I'm sure that's a gross oversimplification,

00:27:49.560 but can you expand on that? I can try. I don't know that it's really known. So the way I personally

00:27:56.940 think about both EPA and DHA, there's a variety of metabolites and of DHA that are involved in

00:28:05.940 resolving inflammation. So these are resolvins, the mericins, the SPMs, protectins. And EPA also has

00:28:13.360 some of those metabolites as well. And it also plays a direct role in inflammation through the – I don't

00:28:22.280 want to say inhibition, but like dampening the prostaglandins and the leukotrienes and a lot

00:28:29.080 of the other inflammatory processes. So it's kind of like an approach where you're affecting

00:28:32.940 inflammation from multiple ways, right? It's like a multi-pronged approach. And I mentioned

00:28:39.240 fibrinogen earlier about like fibrinogen. It's an inflammatory protein. Well, it's involved in

00:28:44.480 coagulation, but it's something that we do measure as a marker of inflammation. So there's studies

00:28:49.800 showing that people that are exposed to particulate air matter, their fibrinogen goes up. But if they

00:28:55.740 have a higher dose of omega-3 or higher intake of omega-3, it blunts that effect. Again, through the

00:29:04.280 inflammation, right? So both DHA and EPA are important in my mind for the brain as well. I mean,

00:29:10.920 there's a variety of studies that have looked at even depression. You can induce depressive symptoms

00:29:17.160 in a person by injecting them with what's called lipopolysaccharide, which is a component of the

00:29:23.620 outer cell membrane of gram-negative bacteria. We have billions of those in our gut. In fact,

00:29:28.580 there's about one gram of lipopolysaccharide or LPS for short. It's also referred to as endotoxin.

00:29:35.660 There's about one gram of that in our gut. Well, you can inject people with a low dose of that,

00:29:39.260 something that actually would be somewhat, you know, I would say equivalent to someone with

00:29:45.060 intestinal permeability. And it can cause depressive symptoms in people compared to those

00:29:49.700 given a placebo. And you can blunt that depressive symptom effect with EPA, probably because of the

00:29:56.360 inflammatory, the blunting of the inflammatory response. And there have been some...this is a

00:30:02.520 field that's, again, understudied, underfunded, but some preliminary evidence, randomized controlled

00:30:09.020 trials, small randomized controlled trials that need to be, of course, repeated with larger sample

00:30:13.860 sizes. They're basically showing that supplementation with EPA can help with depression.

00:30:18.940 Yeah. This is such a frustrating thing for me. And obviously, I know it is for you and for many

00:30:22.740 others, including Bill Harris. If you took the cost of one phase three anti-amyloid failed drug trial,

00:30:31.780 just take one of them. There's been dozens of them. Just take the dollars that were spent on one of those

00:30:39.420 guaranteed to fail phase three trials and put that money into a preventive trial that looks at something

00:30:48.560 that's got real feasibility or something that's really interesting, like the optimal supplementation

00:30:54.800 of DHA in the right patient population group. We could have an answer. And yet, for obvious reasons,

00:31:01.680 there's an incentive to do a phase three drug trial on a candidate with an IND. There's not an incentive

00:31:08.400 from a financial perspective to study these other things. And I think for a disease like Alzheimer's

00:31:13.540 disease, that's particularly problematic. As I suspect we'll discuss, unlike cardiovascular disease,

00:31:20.700 where yes, prevention is still the best strategy, you can come in late to the game and still make

00:31:26.600 a difference. I don't think the evidence is particularly compelling that that is true for

00:31:30.820 Alzheimer's disease. Now, I'd love to be wrong, but I have yet to see compelling evidence that you can be

00:31:36.420 a Johnny come lately to that pathology and have an impact. It's hard to fix those leaks in the brain

00:31:42.320 once they're started. And that also is why I think there have been failed trials also with,

00:31:48.460 there've been a few with omega-3 supplementation people that already have Alzheimer's disease.

00:31:52.640 And you're giving them like, I don't know, at most two grams. I've seen studies like 500 milligrams.

00:31:57.720 I'm like, are you kidding me? You know, patients with high triglycerides or cardiovascular problems

00:32:04.080 are at least four. I know at least four. This is something that has the safety of a nutrient,

00:32:10.260 but literally can act like a pharmacological drug, you know, higher doses. I agree with you. I think

00:32:16.140 it is much more challenging to fix when you have Alzheimer's disease. And certainly like,

00:32:21.120 I'm talking about like the leaks in the brain, but then what happens after that,

00:32:24.820 the amyloid accumulation. And like, when you start to get to this level, when you're,

00:32:28.620 you've got all of that, I mean, good luck. It's going to be, it is going to be challenging

00:32:32.280 and you're going to have to take, it's not going to just be fixing the amyloid. You're going to have

00:32:37.940 to have a cocktail that are going multiple angles, I think, in order to get some improvement.

00:32:42.960 I think the amyloid and perhaps also fixing this, the blood brain barrier leaks as well,

00:32:47.260 maybe at the same time with the cocktail may help a little bit, but prevention is the way to go.

00:32:51.760 I mean, like it's so much better to not get Alzheimer's disease than to try to fix it once

00:32:57.340 you have it, because it is a very complicated disease with lots of things going on. I think

00:33:02.020 that the strategies that can be done and they're not that difficult. We talked about type two

00:33:07.460 diabetes. There's no reason why someone should have it. You should be able to...

00:33:12.340 I would phrase it as, I do not believe for a moment that type two diabetes is inevitable to

00:33:18.180 our species. Whereas I do believe atherosclerosis is inevitable. Of course, I also think most people

00:33:25.260 don't need to die of it. That's a very stark contradiction. The disease is inevitable. And

00:33:30.120 as much as humans will have lipoproteins that carry ApoB, we will get atherosclerosis. But again,

00:33:37.200 we have the technology to delay the onset of that disease to the point where it should not be the

00:33:42.880 cause of death. We should be dying with it, but not from it. I would also argue that cancer is

00:33:47.700 inevitable to our species. It is simply a stochastic problem where if you live long enough and if you

00:33:55.340 accumulate enough genetic mutations, and we can do lots of things to reduce the risk of that and to

00:34:01.200 delay the onset of that and to detect cancer early and be more successful in treating it. But the

00:34:06.860 incidence of cancer strikes me as something that is inevitable with enough age. I actually don't feel

00:34:11.880 that way about type two diabetes. In other words, I think I share your point of view, which is it's

00:34:16.400 not something that is necessary. We don't have to eventually get it. And I think that makes it all

00:34:22.360 that much more tragic that you watch how many people are suffering from this disease and how much damage

00:34:28.160 it's causing, not just in the disease itself, but as you said, it's such an amplifier of the, what I

00:34:35.420 refer to as the horseman, right? It's what it does to your risk of cardiovascular disease, cancer,

00:34:40.480 and Alzheimer's disease is actually why the death toll for type two diabetes is so grossly

00:34:46.400 underappreciated. Yeah. It's accelerating the aging process, the molecular. Yeah. It's gasoline

00:34:52.160 on the fire of aging. I'd have to really reflect on it, but I can't think of a process that accelerates

00:34:57.500 aging more than type two diabetes. Right. Maybe a morbid obesity, but like they're probably also type

00:35:03.300 two diabetes. I would argue only in the context of insulin resistance, which gets us right back on that

00:35:07.640 path. So the good news there is not that it's easy, but we sort of know what it takes to treat

00:35:13.480 it and prevent it. And it doesn't necessarily look like the strategies that are being deployed,

00:35:17.800 unfortunately, at the level of the ADA. I want to ask you one other thing we haven't talked about,

00:35:22.540 but I want to know if it pertains to the blood brain barrier at all, and that's blood pressure.

00:35:26.560 So hypertension and I guess hyperlipidemia also pose enormous risk for not just cardiovascular disease,

00:35:33.420 where they are two of the three biggest drivers of risk, but they also pose a risk in Alzheimer's

00:35:38.840 disease. And I wonder, do either of those act specifically through the blood brain barrier?

00:35:42.720 It is another really important modifiable lifestyle factor that can affect Alzheimer's disease risk.

00:35:51.060 Maintaining good blood pressure. So I mean, basically you want to be systolic below 130. Once you get to

00:35:57.280 130- The sprint trial would even say 120.

00:35:59.920 120, yes. And the blood pressure itself, so getting that blood flow to the brain,

00:36:06.360 blood brain barrier specifically, is so important. When you don't have, when that blood flow doesn't,

00:36:11.920 basically isn't able to get to the blood brain barrier well enough, those tiny little vessels

00:36:17.300 start to like just fall off. And it's one of the reasons why exercise also is so, so important.

00:36:23.260 There's been a variety of studies that have looked, as you mentioned, the observational data is

00:36:27.480 never able to establish causation. But it's still an interesting point to look at in combination with

00:36:33.160 many other types of data.

00:36:34.500 Especially when it's always in the same direction.

00:36:36.540 Exactly.

00:36:36.860 That's what differentiates the epidemiology around, for example, exercise and blood pressure

00:36:41.720 from the epidemiology around nutrition. The epidemiology around nutrition, A, it has very

00:36:46.100 low hazard ratios and it's always changing the direction it's moving in, suggesting that whatever's

00:36:50.860 being studied probably doesn't matter. Yet when you look at the epidemiology of smoking, blood pressure,

00:36:56.540 dyslipidemia, exercise, much bigger hazard ratios, virtually always pointing in the same direction.

00:37:02.480 So it strikes me that the latter is signal, the former is noise.

00:37:07.160 Good point. So, you know, 50% of people, adults in the US have hypertension and about 20% of young

00:37:13.680 adults, like we're talking people age 18 to 39 have hypertension. That's crazy, right? And it's

00:37:19.520 actually the high blood pressure. It's the cumulative exposure to high blood pressure that's

00:37:24.420 really damaging the vasculature. And so it's the younger people. It's the people that have

00:37:29.580 it earlier in life that should be the most concerned and are the least, right? Those are the ones that are

00:37:34.120 like, oh, I'm young. You know, I can worry about it later. But yeah, so high blood pressure is

00:37:38.900 associated with dementia risk, particularly when you have it like before 50s, like when you get it in your

00:37:45.040 before the 50s or midlife. Once you start to get high blood pressure in older age, like 70,

00:37:51.400 80, it's not as much associated with the Alzheimer's disease and dementia risk. It really does seem like

00:37:57.640 cumulative exposure is the key factor there. Again, one of those things that is a lifestyle

00:38:02.920 factor that's easily modifiable, exercise improves blood pressure, sauna improves blood pressure.

00:38:09.360 Those are two basically low-hanging fruit lifestyle interventions. Some people do have

00:38:14.920 gene polymorphisms where they're very sensitive to salt intake and sodium intake. And that combination

00:38:20.960 of those people with a higher sodium intake really seems to skyrocket blood pressure.

00:38:26.320 Nutrition, I think it's also looking at the combination of genes and diet. Most nutrition

00:38:32.300 studies don't do that. There is an interaction going on. And I do think that's why some of the sodium

00:38:38.020 intake blood pressure literature is just a little more, I would say, complicated.

00:38:41.820 Yeah, it's all over the place. I wanted to ask you a question about exercise, but before I do that,

00:38:45.920 I want to actually pick up on something you just said. How optimistic are you, I don't know,

00:38:50.860 let's bracket this with, let's say in the next decade, that we will have more of a sense around

00:38:56.540 what precision nutrition looks like as it pertains to genes and polymorphisms of them. In other words,

00:39:03.800 people talk the talk like, oh, I did this test and it told me I should be eating this, that,

00:39:08.520 and the other thing. But the reality of it is there's nothing that's available today that's

00:39:12.500 come close to offering that type of insight. A, do you believe that that type of insight

00:39:17.960 is available? You used one example, which I would agree with you on, which is that there are probably

00:39:23.140 different levels of genetic susceptibility to sodium that might suggest one person needs to be

00:39:28.620 eating two grams a day of sodium and another person needs four grams a day.

00:39:32.260 Right. But do you think it will get further than that? And how likely do you think we will be to

00:39:38.520 extract that information? I do think in 10 years, we're going to know a lot more about precision

00:39:44.680 nutrition, obviously precision medicine as well, because there's also an interaction between, you

00:39:49.760 know, pharmacological treatments and genes as well, as you know. In 10 years, we're definitely going to

00:39:53.940 be a lot further than we are now. The problem is, and this is always the problem, we've already alluded to

00:39:58.780 it a few times, is the incentive for funding to study those things that aren't necessarily going

00:40:07.640 to be super profitable. The government, the NIH, there's a certain amount of funding that you can get

00:40:12.860 from them. And they often like to study one sort of thing, like the nutrition, when there's like

00:40:17.480 multiple things involved, it's like, they're just like too complicated. And so there's a lot of funding

00:40:22.200 from pharma industry, for example, and then they put in lots of money because they're incentivized

00:40:27.780 to do that when it's a drug. That's my one concern with, I would say, gene diet interaction when it's

00:40:34.160 more on nutrition. But there are people that are, it's a growing field of research for sure. And I do

00:40:40.500 think with technology is advancing too. I mean, so at the point that our technology is advancing with AI

00:40:46.420 and stuff, I think that we're going to start to see an exponential there, honestly. I am optimistic

00:40:51.100 that in 10 years, that's going to be a lot easier to delineate what a person should eat based off of

00:40:58.120 the genetic makeup versus just what generally we think is healthy.

00:41:02.280 And do you think that that will be at the level of macronutrients or micronutrients? Like how much

00:41:09.040 heterogeneity do you think there is among people as it pertains to factors like that?

00:41:14.600 I think both. There are differences in the response to macronutrient intake and the response

00:41:21.480 to micronutrient intake. And there are people, there's vitamin D polymorphisms, right? Where

00:41:26.220 people, for whatever reason, so maybe they evolved in a place where there was so much sun or something.

00:41:32.740 Like, I don't know what the cause is, but like some people, they have to supplement with high doses

00:41:37.800 of omega-3 to be able to convert the precursor to actual, the hormone, right? The steroid hormone.

00:41:43.840 That's just one example. There's selenium, there's magnesium, there's a lot of different

00:41:48.580 micronutrients that are off. And there's omega-3. There's omega-3 as well.

00:41:52.840 And B vitamins.

00:41:53.820 Exactly. There's B vitamins. Yeah. More people are looking into it. And with advancement in technology,

00:41:59.360 things will become cheaper and easier to do. And that's going to create an exponential,

00:42:04.680 in my opinion, where it's like, okay, maybe in a couple of years, we'll start to really see an

00:42:09.640 explosion. And then after that explosion, exponential happens where people are building

00:42:13.320 off of that because that's how it works. That's kind of where I think it's going. And I'm excited

00:42:16.820 about it. I think that's where it needs to head. I think it's going to clear up, as you mentioned,

00:42:20.720 all the conflicting data with nutrition. I mean, nutrition studies are a mess. Designing the right

00:42:26.220 trial. I mean, part of the reason for that is because we have evolved these genes. I mean, it's a drug

00:42:30.860 with the exception of, yes, there's the CYP enzymes and stuff that help us metabolize

00:42:36.140 xenobiotics, things that are not a vitamin or a mineral or essential amino acid or fatty acid,

00:42:40.480 right? Something that's foreign to our body. But by and large, when you give someone a drug,

00:42:45.520 they're starting with zero levels of that drug in their body. And you give them the dose that

00:42:49.240 you're giving them, it's like clear you're giving them a dose. And it's going to be different than

00:42:53.920 people getting a placebo, right? It's going from zero to something. Whereas when you do this

00:42:57.740 nutrition study, a micronutrient, you know, you give them a vitamin or a mineral, nobody's starting

00:43:02.720 with zero. For one, your placebo group could have five levels of that. And unless you measure

00:43:06.920 something, you'll never know. And all the trials are sort of, they're trying to mimic that gold

00:43:11.800 standard of a randomized controlled trial with a pharmacological drug. You have to like put in so

00:43:16.300 much more effort with nutrition, with the drug. You don't have to start doing blood samples of this

00:43:20.640 and that and measure the drug and make sure people aren't deficient in that drug. Of course,

00:43:24.020 they're deficient in the drug before they start the trial. They don't, it's like a drug.

00:43:26.700 It's such a good point, Rhonda. And I'm going to use two examples to highlight why this is so

00:43:31.720 important because it ties to two things we've been talking about. If you look at how a blood

00:43:36.660 pressure trial is done, it is exactly what you say. It's titrated, meaning it's done the way

00:43:44.780 a pharma trial is normally not done. So a blood pressure trial says, let's just bring in a whole

00:43:49.520 bunch of people with high blood pressure. Okay. You guys on the placebo or on the low treatment arm,

00:43:55.240 we're going to manage you to a blood pressure of 140 over 90, but no lower. You guys in the treatment

00:44:00.500 arm, we're going to manage you to 120 over 80 or better. And by the way, we're managing to the

00:44:06.460 outcome, not the drug. So I'm agnostic as to whether this person needs a higher dose or a lesser dose.

00:44:12.280 We're checking the outcome here. And so if we did a vitamin D trial that way, it would be a very

00:44:19.140 different trial. And one of my biggest criticisms of vitamin D trials and why I think we don't have an

00:44:24.420 answer as to whether supplemental vitamin D is valuable is they don't do this. Take the people,

00:44:30.740 you divide them into two groups. You give one group of placebo, you give one group, usually a

00:44:34.420 very low dose, somewhere between two to 4,000 IU daily. But we don't actually know what the level

00:44:41.120 goes to. In other words, a better vitamin D trial would be, we take a bunch of people whose vitamin D is

00:44:45.740 below 30. In one group, we give a placebo. And in another group, we give whatever it takes to get

00:44:51.500 them to, I'm making this up, but 80. Then we would see, is there a difference between this

00:44:56.580 group that's below 30 and this group that gets to 80, regardless of the dose it took to get them

00:45:01.180 there? Because of course, that may include part of the problem. So I think your point is an excellent

00:45:06.220 one. And I think it's something that listeners need to be aware of when they're scrutinizing trials

00:45:11.960 of this nature, which is a negative trial doesn't mean the thing doesn't work if the trial wasn't

00:45:18.000 designed correctly. Right. And it often, it's a matter of money too, right? To measure all those

00:45:23.380 things. It's cheaper to just give someone the vitamin D supplement and then look at the outcome

00:45:27.540 and go, oh, didn't work. And then you have another confusing piece of literature out there that people

00:45:33.680 are like, oh, but says that vitamin D supplements do nothing. Yeah, it's a big problem. And I do, again,

00:45:39.440 I think as our technologies are advancing, that that's going to become less of a problem as well.

00:45:45.720 At least I hope. I mean, I guess you never know. So I want to go back to something you talked about

00:45:49.840 earlier, which is you just touched on exercise. And I want to kind of visit now the suite of things

00:45:57.600 that exercise does. Because people who listen to this podcast know if there's one thing I just

00:46:01.400 can't stop talking about, it's exercise. But I think there's a reason for that, right? It's not

00:46:05.280 just that I love exercise. It's that the evidence is overwhelming that a person who exercises,

00:46:11.660 especially at the right amount, we're talking not just 30 minutes a week type thing,

00:46:15.220 but if you're really doing the work, you're having a greater impact on the reduction of risk

00:46:19.580 of Alzheimer's disease than any other intervention you can take. Now, there are lots of interventions

00:46:24.620 that matter. Sleep matters. Nutrition, as we talked about, type 2 diabetes, all these things matter. But

00:46:28.040 the risk reduction that comes from exercise is enormous. What do you think are the mechanisms by

00:46:33.220 which that is happening? Because I suspect there's many. Oh, definitely many mechanisms happening.

00:46:37.960 And I would, first of all, I 100% agree with you. Like there's nothing better than exercise. Of course,

00:46:45.800 any exercise is better than none. But for me, because as I mentioned at the start of this podcast,

00:46:51.600 I'm very focused on neurodegenerative disease. I specifically sort of designed my workout routine

00:46:59.520 based off of what I think are going to give me the biggest brain benefits. And what I've sort of come

00:47:07.360 to the conclusion of is that intensity does make a difference with respect to the neurobiological

00:47:14.500 effects. Exercise intensity. There are some mechanistic reasons for that. But just talking about

00:47:22.160 what's moderate intensity exercise, what's considered vigorous intensity exercise, right? If you look at some of

00:47:27.660 the recommendations out there by the committees, you know, there's a team of scientists, physicians

00:47:32.080 that sort of analyze all this data and then make these health recommendations based off of that data.

00:47:37.340 It's 150 to 300 minutes of moderate intensity exercise, which I think they define as like 50 to 70%

00:47:46.440 of maximum heart rate. Vigorous intensity, they say 75 minutes, I guess, a week. And that would be

00:47:54.500 more of you're getting above the like 75 to 85% max heart rate. So that's what they I think define

00:48:02.400 as something like that vigorous. And they have a variety of examples. You know, there's the World

00:48:06.060 Health Organization. It's a variety of committees that come to that same conclusion. For me, I like

00:48:12.220 to go higher intensity. This is something I kind of was looking forward to talking to you about because

00:48:17.340 it has to do with how do you measure the estimated heart rate, which is what I do. I've estimated. And

00:48:22.600 again, all sorts of problems with that based on your physical fitness, meaning estimating your maximum

00:48:28.700 heart rate to take a percentage. Okay. So basically, you know, the more fit you are, you could be doing

00:48:33.960 a more vigorous intensity exercise, but your heart rate like doesn't go as high as someone who's not

00:48:38.420 fit. And then people that are older. So there's, of course, I would say problems with that. But

00:48:43.440 generally speaking, that's one way. But I'm also very interested in lactate. And I know you are as

00:48:48.460 well. For me, I actually want to get my lactate levels high. And the reason for that is the

00:48:56.660 neurobiological benefits. So lactate, as you know, was once thought to be this sort of end metabolic

00:49:06.060 byproduct. It was like useless. Well, not only just useless, actually, it's not to be harmful.

00:49:10.360 At least to performance.

00:49:11.760 Right. Harmful to performance with respect to people thought it was like causing their muscle

00:49:15.880 soreness. As you know, now that it's not lactate, it's the proton buildup. Lactate is sort of in

00:49:21.560 homeostasis with lactic acid. And it's the protons that were sort of responsible for that.

00:49:26.180 And neither of them are responsible for the soreness you feel the next day. That's the

00:49:29.520 microtrauma, of course, like the soreness and the burn from the hydrogen ion is gone minutes after you

00:49:36.640 stop exercising. Yeah, exactly. So the lactate that gets into so you're generating lactate,

00:49:42.520 when you basically are pushing your mitochondria inside your muscle cells to a point beyond where

00:49:51.060 they can generate enough energy in the form of ATP, adenosine triphosphate, then they sort of have to

00:49:57.880 figure out another way. Like your cell has to figure out another way to get the energy, right? So this is

00:50:01.980 where glycolysis comes into play. So this is happening outside of the mitochondria. And I'm sure

00:50:08.320 your listeners have heard all this before. But for those that haven't, the lactate generation is

00:50:12.820 then from that, you know, metabolism of glucose outside of the mitochondria. And that's happening

00:50:17.400 when again, you reach that threshold of you're pushing your muscle cells hard enough, and their

00:50:23.380 mitochondria can't keep up with producing enough energy. So the lactate itself, and these studies

00:50:28.460 date back to like the 70s, it's been shown that lactate that gets into circulation, and it's used by

00:50:35.260 other organs as an energy source for one as a fuel, yeah, and the brain being a big one. And this is

00:50:41.620 now decades of research. But Dr. George Brooks has, you know, he was like one of the first to propose

00:50:46.640 this lactate shuttle theory. And he's, of course, provided evidence for that as many others have as

00:50:52.260 well, where, you know, during exercise and after exercise, the lactate that is generated from muscles

00:50:59.740 that gets into circulation is consumed by the brain. This has been shown in humans and animal

00:51:05.960 studies, of course, but it's consumed by the brain. And also, not only is it consumed, it's acting as a

00:51:12.840 signaling molecule, and increasing at the blood brain barrier. Lactate itself has been shown to be

00:51:20.400 responsible for the production of what's called VEGF. It's a vascular endothelial growth factor,

00:51:26.620 VEGF. And what it's doing at the blood brain barrier is it is growing new vessels and repairing

00:51:34.280 damaged ones. So that brings it back to what we were just talking about, right? The damage,

00:51:37.900 the vascular damage at the blood brain barrier. Lactate itself is a signal to increase that VEGF.

00:51:44.080 It also increases brain-derived neurotrophic factor, BDNF, at the brain, at the blood brain barrier and in

00:51:51.100 the brain as well. Where is BDNF produced? Many places. It's produced in capillaries and the

00:51:56.980 vascular system, in the heart, in muscle. It's produced in the brain. So exercise increases

00:52:02.500 brain-derived neurotrophic factor in many different parts of the body, in many different organs and

00:52:07.620 tissues. And it's really interesting because there's some evidence that the sheer force of

00:52:15.580 blood flow. So essentially, like, the more vigorous you are exercising, your heart's pumping, right? And

00:52:21.760 your blood is just going faster. It's moving faster. Well, that sheer force on the actual

00:52:27.120 endothelial cells lining the blood vessels is a signal to increase BDNF as well. Super interesting

00:52:33.060 stuff there. It also increases BDNF in muscle, which it plays a role in repairing damaged muscle.

00:52:39.020 It increases in plasma, brain-derived neurotrophic factor, although there's a little controversy about

00:52:44.400 this. It can cross the blood-brain barrier. And it also is produced in the brain as well.

00:52:49.760 So all of those things. And brain-derived neurotrophic factor is really important for

00:52:52.700 many reasons. It's important for long-term potentiation. It's important for neuroplasticity.

00:52:59.260 So long-term potentiation is basically strengthening the connections of the synapses that are connecting

00:53:03.880 neurons. It's involved in basically long-term memory retention. But also, it's important for

00:53:09.140 neuroplasticity. So brain-derived neurotrophic factor plays a really important role in that.

00:53:13.360 And that is also something that decreases with age. I think a really easy way to think about it is

00:53:18.700 your brain's ability to reshape and restructure with the changing environment. As you're aging,

00:53:24.380 things are changing in the brain. And you have to be able to respond to that. Your brain responds in

00:53:29.020 a plastic way. And that happens very well when we're younger, not so well when we're older,

00:53:33.500 not so well in certain disease states like depression, neurodegenerative disease. And so that

00:53:38.460 brain-derived neurotrophic factor plays an important role in that.

00:53:40.840 I am going for higher lactate. And based off of your recommendation, I got the lactate meter,

00:53:47.000 the NOVA, the one that you have. And I've been using that to kind of try to get my lactate higher

00:53:52.120 than typically what I think you are doing with a completely different type of training.

00:53:57.500 We do kind of both ends, right? So on the one end of the spectrum,

00:54:00.200 what we want to do is increase our mitochondrial capacity to maximize aerobic metabolism. And there

00:54:09.460 are two ways to do that, meaning you have to do two things. So the way I'd describe this to people

00:54:12.760 is the way one of my coaches described it to me when I was a fledgling cyclist. Your aerobic capacity

00:54:19.260 is a pyramid. And the area of that pyramid is your total aerobic capacity. And to have the largest

00:54:28.380 area of a pyramid, you need the widest base and the highest peak. A pyramid with a narrow base and a

00:54:35.200 high peak, eh, not as good. A pyramid with a very wide base and a shallow peak, also not great. You want

00:54:42.560 wide base, high peak? Well, in that analogy, the base is your zone two threshold. It's how much work

00:54:51.000 can you do while keeping lactate at that sort of threshold that George Brooks and Inigo San Milan

00:54:57.800 talk about of about two millimole. So what differentiates the best aerobic athletes from

00:55:04.320 someone, say, with type two diabetes, which would be the opposite end of that spectrum where you have

00:55:08.420 real metabolic dysfunction or rather mitochondrial dysfunction, we're talking a fourfold difference

00:55:13.940 in watts per kilo output. And you just have to train at that level. You have to get to that

00:55:19.420 threshold and train right there. So this morning, that was the workout I did, right? It was a zone two

00:55:23.760 ride where I'm just riding right at a lactate level of 1.9 millimole was where I was today.

00:55:30.660 But you do need to do what you're describing as well. You have to do the pyramid building. You have to

00:55:36.240 build the peak of that pyramid. Those are the VO2 max sets. And generally, the sweet spot for building

00:55:43.060 those is three to eight minutes of all out effort for the respective duration. So obviously, what you

00:55:49.900 can do for three minutes and no more is harder than what you might be able to do for eight minutes and

00:55:54.920 no more. My favorite are four minutes. So for example, on Sunday, that was my workout. I actually did an

00:56:00.360 hour of that zone two, you know, kind of two millimole stuff and then did four minute awful

00:56:07.660 repeats where it was like much, much higher power for four minutes. And then I rested for four minutes

00:56:13.840 and then went again for four minutes and then rested for four minutes. And at the end of those four

00:56:18.140 minute blocks, you know, my lactate will be 15 or 16. Oh, wow. And then at the end of a four minute

00:56:24.800 rest, it might be down to six or seven. And then we do it again and do it again and do it again.

00:56:30.860 Yeah. Long-winded way of saying you want both. You want to build that pyramid to be as wide and as

00:56:36.900 tall as possible. What I don't think I appreciated though, was that the brain is getting a benefit

00:56:43.700 from those lactate peaks. Yes. It's getting a benefit and, you know, it's cleared quite quickly.

00:56:51.140 I mean, it's minute. It's minute. If you do nothing, it's, if you just stopped,

00:56:54.540 and of course, athletes are even better at this, right? An amazing athlete would clear lactate

00:56:59.380 within, they'd go from 10 millimole to two millimole in minutes. For me, you know, 20 minutes

00:57:05.480 later, I'm back to my 0.9 millimole baseline. That lactate also is important for neurotransmitter

00:57:12.520 synthesis. You're making glutamate, the major excitatory neurotransmitter in the brain. It's

00:57:17.000 important for making precursors to that. Norepinephrine. I mean, these are all been shown in human studies,

00:57:22.080 also animal studies. So for me, I do a lot of Tabata training.

00:57:26.200 So that's even more intense because you're only doing 20 seconds on and 10 seconds off. So that's

00:57:30.940 really intense. It is. And I do 16 of those. So I do, you know, like eight and then separated

00:57:37.320 by like a 30 second break. And then I do another eight. So two, four minute blocks.

00:57:42.060 It's a total of about 10 minutes. So the first minute I'm in like zone two. And then by like the

00:57:47.940 end of that minute, I'm like zone three. And then I go into zone four.

00:57:51.980 What are you doing this on? Are you doing this on an air bike or?

00:57:54.980 I'm doing it on a Peloton, right? And my Apple watch is beaming my heart rate and my zones

00:57:59.460 onto my screen, which they're all estimated, of course, again. But I do that five days a week.

00:58:04.900 It's for me, the efficiency also. So I'm trying to maximize the neurobiological effects for me with

00:58:11.980 exercise. And I really find pretty compelling evidence that intensity is really important

00:58:17.600 with respect to that for the brain. Not that there isn't a benefit for lower intensity exercise.

00:58:24.340 Certainly people doing, you know, moderate intensity, like the more time you put in,

00:58:28.520 the volume of training is like, you're going to probably find some equivalent there. But

00:58:33.120 with the lactate, though, that's the one mechanism. I'm like, that is really something

00:58:36.880 I personally am trying to optimize for. It's definitely a consequence of intensity.

00:58:43.400 And the fact that it's cleared so quickly and it's transient, like I'm wanting a lot of it,

00:58:48.580 like each day, I'm wanting to keep doing it. There are other ways to do it that you might

00:58:52.280 want to consider, right? So you might want to say, look, I'll do those Tabatas two days a week.

00:58:57.280 I'll do some longer, slower cardio. And to be clear, like when I'm doing that zone two,

00:59:01.960 it's not trivial. Like, I mean, I'm, my heart rate's still 140 when I'm doing that zone two.

00:59:06.960 But what you could do is use blood flow restriction when you're lifting weights on the other days,

00:59:12.640 and that will get your lactate through the roof. So four days a week, you know, I'll do blood flow

00:59:17.740 restriction at the end of every workout. So two days will be upper body, two days will be lower

00:59:22.220 body. And then especially on the lower body days, so you've got these huge cuffs at the upper part of

00:59:26.460 your thighs and I'll do leg presses, leg extension, leg curl, and finish up on an air bike.

00:59:33.380 And by the time you take those cuffs off, all that lactate that's been pooling in your legs for 10

00:59:38.820 minutes will flush through systemically and your systemic lactate level surges.

00:59:44.760 What do your levels get to? What do your lactate levels get to after?

00:59:47.800 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

00:59:51.560 lactate is about an 18 or 19, but I can still hit the mid-teens doing blood flow restriction.

00:59:57.740 That's incredibly high.

00:59:59.360 You know, it's funny when I used to coach athletes, I worked with an Olympic swimmer who

01:00:04.100 could get to 26 and still be conscious. I mean, I say that sort of half jokingly, not that too much

01:00:11.020 lactate would render you unconscious, but the pain that you must be in when your lactate is 26 is

01:00:17.220 comical to me. He could finish a swim race, something like a 400 individual medley, which is

01:00:22.520 probably the highest lactate generating race there is because it's all out upper body,

01:00:27.000 lower body assault, have a lactate of 26 to 24 to 26 millimole. And four minutes later,

01:00:33.500 jump in the pool again and do a race and enter the pool with a lactate of maybe six. It's pretty

01:00:38.000 amazing. That's amazing. So my point is like you could diversify the training a little bit because

01:00:42.080 again, you'd still get that lactate hit, but you'd also be diversifying the training because I do think

01:00:48.240 performance, it's hard to make the performance gains if you're really doing an all out Tabata five

01:00:56.080 days a week. I think that is hard. What kind of performance gains are you talking about within

01:01:00.240 the Tabata itself? In other words, it's hard to make gains on the power output that you want to

01:01:05.480 be generating because that's when you're doing 20 on 10 off, you're trying to get as much power as you

01:01:10.120 can in those 20 seconds. Those are what we call match burning workouts. Like you're burning all the

01:01:14.900 matches that day. Yeah. I'll tell you something that's interesting. I started, I don't, have you ever

01:01:20.120 tried doing an aerobic or high intensity workout with mouth tape where you're just breathing through

01:01:26.980 your nose? So I mean, you're limited, of course. I mean, at some point you're not going to get to

01:01:32.320 your, you're going to be limited by, for me at least, I can't do my all out best without mouth

01:01:38.280 breathing at the end. Once I reach 215 to 220 Watts, I can't sustain maybe 225 Watts. I need to start

01:01:49.420 breathing through my mouth. I need to at least every other breath use my mouth. I would expect

01:01:55.000 everybody's sort of different there. People are different. I mean, different nasal, I mean, like

01:01:58.920 different sinuses and shapes of your nose and everything. I just recently started doing it and it

01:02:03.280 was kind of odd because I actually, maybe I'm not going, I PR'd the first time I did it. And you know,

01:02:10.600 like I wasn't going as hard on my all outs, but I think on my rests, I was going harder on my 10

01:02:17.560 seconds off. I was like not really bringing my resistance down. Have you tried doing it where you

01:02:22.580 do nothing on the off, a pure off? What do you mean? Just like keep going? Yeah. Don't spin whatsoever.

01:02:29.620 So do the 20 seconds all out and then the 10 seconds you're not spinning at all.

01:02:33.280 Oh, I've never tried that. Give that a try. Well, I think the goal is to make the hard as

01:02:39.140 hard as possible. And so being truly off for 10 seconds will make it more likely that you can

01:02:47.000 deliver the maximum wattage during the 20 seconds. Okay. I've been trying to do the opposite where I'm

01:02:52.520 like, okay, am I off? I like keep, you know, zone three. I like still putting in quite a bit of power,

01:02:58.240 right? That's good too. We used to call that sweet spot workouts where you would go zone three,

01:03:02.320 zone five, zone three, zone five, zone three, zone five. But what you really probably want to be doing

01:03:06.260 in a Tabata is zone six, zone one, six, one, six, one. What's zone six? It depends on the system.

01:03:15.280 Just like maximal? Yeah. Yeah. I mean, so technically the literature on this would suggest that

01:03:20.340 we are only able to hold full maximal effort for 10 seconds. Anything we do that's longer than 10

01:03:27.720 seconds, we are applying some governor to the system. So at 20 seconds, even if you don't

01:03:33.480 realize it, you're somewhat pacing yourself. Even if you're trying to go- I'm not doing maximal. I am

01:03:37.580 not for sure. Like my husband seems like he really gets to that all out, but I'm not for sure. I'm

01:03:43.100 definitely not maximal at my 20 seconds. No way. That makes sense because I don't think one could

01:03:47.300 do that five days a week. I think you would fry yourself. You know, what's also really interesting,

01:03:51.680 Peter, is that though by like the fourth or fifth day, I'll be PRing. So I'm always competing

01:03:56.900 against myself. And my lactate will be lower. By wattage? Oh, the Peloton. No, no. I'm not nearly

01:04:04.620 as scientific as you. Okay. So what metric? So Peloton ranks you based off of- But isn't it based

01:04:10.460 on kilojoules or watts? Isn't it based on average wattage? Yeah, it is. But I don't know all those

01:04:14.400 off the top of my head. Like you're writing everything down. I'm not doing that. But my lactate-

01:04:18.100 But that doesn't surprise me, Rhonda, because the way to get maximum wattage is to hold your highest

01:04:23.120 constant maximal wattage and go. So zone four held indefinitely will produce a much higher average

01:04:28.760 wattage than zone three alternating with five or six alternating with one. So yes, if your metric

01:04:34.760 of success is what is my total average wattage over the course of this workout, it will not be a

01:04:39.920 Tabata. It will be a steady state. All I can, you know, that's actually what's called FTP,

01:04:45.100 functional threshold power, which is what technically the Peloton is using to estimate

01:04:49.020 your zones. Have you ever done the FTP test on the Peloton? No. That's actually probably worth

01:04:54.660 doing. Okay. So if you go into the Peloton, there's something called, I think it's called

01:04:58.060 fitness test. And it's going to have you do either, you get to pick two eight-minute all-outs

01:05:04.400 separated by some rest, I forget how much, or one 20-minute all-out. I prefer the 20-minute

01:05:10.600 all-out. I think it's a better test. It will take your average wattage over 20 minutes. It will

01:05:16.120 multiply it by 0.9, and it will say that is your functional threshold power, which is defined as

01:05:22.360 the maximum power you can hold for one hour. And in cycling, and Peloton uses this system,

01:05:29.000 that is the metric by which the zones are set. So zones one through seven are a function of power,

01:05:35.400 not heart rate. And they are all a function of that FTP number. Now, again, none of that's

01:05:41.800 necessary for Tabata. Tabata didn't rely on knowing those zones. It wasn't about titrating to a given

01:05:47.840 heart rate. It was simply a question of go as hard as you humanly can for 10 seconds and then do

01:05:54.680 nothing for 10 and do that eight times. So- Yeah, I'm definitely using a different-

01:05:59.940 You're using kind of a slightly different protocol where you're doing a workout where you're going

01:06:03.640 much harder during the rest and then not as hard during the workout because you wouldn't be able to.

01:06:08.640 Right. I'm definitely not doing it the way I guess- And how high are your lactates? And you

01:06:12.900 check your lactate at the end of the both sessions, after the two rounds?

01:06:16.300 It's all like a continuous thing. You get like a 30-second rest period between the two eight

01:06:22.480 sessions. But again, I'm not resting. Yeah, you're going hard.

01:06:27.140 I'm going, I'm like probably zone three. Yeah. The end of that, now my lactate doesn't get nearly

01:06:31.640 as high as yours. I'm typically like around seven to eight millimolar. So that could give

01:06:38.620 you an idea of, you know, I'm what I call a committed exerciser. I'm not an athlete as

01:06:43.760 I would consider you are, I'm sure. It's actually quite different. The best

01:06:47.060 athletes in the world, like world-class. So both Michael Phelps and Lance Armstrong, you

01:06:52.400 could argue two of the greatest, both actually put out relatively low lactate levels. So you

01:06:58.100 don't know, you might be one of those people who's so efficient that you don't actually

01:07:02.200 make much lactate. Like I don't think Michael Phelps has probably, even when smashing world

01:07:06.600 records, probably ever seen a lactate above 10. Yeah, but I'm definitely not one of those

01:07:10.380 guys. It would be interesting to differentiate for sure. I mean, for example, so when you are

01:07:16.640 doing at least a high intensity interval type of training, which I would say that this, would

01:07:23.280 you agree this type of training definitely would fall into that. And of course, people generalize

01:07:27.920 this term and stuff, but that's a whole other issue. But you are sort of forcing adaptations

01:07:32.620 on your mitochondria to make more mitochondria. Your body's like, oh, I no longer can use my

01:07:39.640 mitochondria to make energy. I got to rely on this other process, glycolysis. So as an

01:07:44.600 adaptation to that, you increase mitochondrial biogenesis. And that's been shown now in several

01:07:49.020 studies, in human studies, you can increase mitochondrial biogenesis. Now also aerobic training

01:07:54.540 does that as well, but you can kind of get there. It's really a question of time. It sort of comes

01:07:58.280 down to what you were saying earlier. So if somebody says to me, I've only got 10 minutes

01:08:02.380 a day to devote to aerobic training, what does it need to be? Well, the answer is clearly it needs

01:08:08.100 to be the type of training that we're talking about here. Now, if someone says to me, I don't

01:08:12.160 want the minimum effective dose. I want the maximum result. Then I'm going to say, well, would you be

01:08:18.660 willing to give me 90 minutes a day? In which case we could build you the biggest pyramid,

01:08:23.180 basically. I need an hour a day to build you a mega pyramid. But some people don't have the time

01:08:29.080 or desire or interest to do that. In which case, yeah, we would need to just get people to doing,

01:08:34.860 I get asked this question all the time. I think in 10 minutes a day of cardio and probably 30 minutes

01:08:41.980 a day, four times a week with strength, you can get amazing results, but you have to be laser focused

01:08:48.000 and there's no messing around. I'm sure when you're done that 10 minute workout,

01:08:51.320 there's no ambiguity about how hard you've worked. Not at all. And I feel it has to be very vigorous.

01:08:56.800 It does. I do also use Peloton for my strength training as well. And there's a lot of like

01:09:03.080 paired sets and supersets. And so it's like nonstop training where I'm definitely like I'm putting

01:09:08.160 effort in, but it's not a long session either. I do try to do that. Like I'm probably putting in

01:09:14.740 the minimum amount of strength training that I can personally do, which is like 40 to 50 minutes

01:09:20.320 a week. I used to not do any. So like even that's like progress. We have some stuff we're going to

01:09:25.160 talk about at dinner here because I'm not trying to talk you into doing a little bit more. But I

01:09:29.000 want to ask you, where do you put your sauna in relation to this? Do you dissociate in timing

01:09:33.860 sauna from your exercise? Do you go right into the sauna after you work out? How do you incorporate that?

01:09:38.900 It varies. I do both a regular with dry sauna. Actually, I don't use it as a dry sauna. I do a

01:09:46.280 lot of steam as well. But I do that. But I also do hot tub. So I do a jacuzzi as well. And both of

01:09:53.720 those forms of heat stress have been shown to increase heat shock proteins, which is sort of a

01:09:59.640 biomarker of heat stress. And both of them also have been shown to increase brain drive neurotrophic

01:10:05.720 factor as well. So heat, I think, also plays a role in that like stress response. It depends on

01:10:10.980 the day. So I often will in the sauna, I like to read scientific papers or listen to podcasts like

01:10:17.260 The Drive or like I'll listen to like if someone's on Tim Ferriss' show. Like there's only a couple of

01:10:21.900 podcasts that I ever listen to. Yours is one of them. So it's not like that's like my time or I'm

01:10:28.820 like because there's no other time. If I'm in the car with my child, like most of the time I'm

01:10:32.800 listening to frozen music or whatever, you know, like it's not, I'm not listening to The Drive.

01:10:38.720 So it depends on what I'm doing. But also, I like to do hot tubs at night. So typically,

01:10:44.040 the sauna will be in the day. So I do my workout in the morning, I'll have the sauna warmed up and

01:10:47.560 ready to go. And I'll get right into the sauna after my workout. And I either have a paper in hand,

01:10:52.920 or I'm going over a presentation or something. I find it's really interesting. I don't know if you've

01:10:58.940 ever tried this or observed it. But this goes way back to my days as a graduate student when I first

01:11:04.120 started using the sauna. I realized that if I would go over a talk that I was going to give,

01:11:10.200 like a departmental meeting or whatever, you know, I was giving a talk. If I went over it and thought

01:11:14.740 about what I was going to say in the sauna, man, did I remember it better. Like it was like very clear

01:11:21.940 that there was something going on with my memory. And I mean, very, very consistent. Of course,

01:11:28.440 you know, me, I like was diving into the literature. I'm like, there's got to be something

01:11:31.060 to explain this. And, you know, lo and behold, there's certain growth factors that you make

01:11:35.780 that in the sauna with heat stress that do affect like memory. So plausible hypothesis there. But

01:11:41.840 anyways, so if I have something going on, like a podcast or a presentation,

01:11:46.780 What's your protocol? What's your temperature and duration in the sauna?

01:11:49.920 It depends on how hard I went on like my workout too, or if I'm doing it like right after the

01:11:55.700 workout, or if I'm like midday, just like, I'm going to take a break from what I'm doing at my

01:12:00.520 computer and I'm going to go read a science paper in that sauna. So like it really all depends.

01:12:04.940 Generally speaking, if I go in right after I'm do my Tabata session, I probably stay in about 20 to 25

01:12:13.660 minutes. And my temperature is like 175 degree Fahrenheit. If I am not going in right after

01:12:21.140 a training session, then I'll stay in longer, I'll stay in probably a little bit longer than 30 minutes,

01:12:28.040 I'm pretty adapted to and my temperature will be, you know, 175 180. Sometimes I also do the humidity,

01:12:34.680 which makes it hotter feel hotter as well. So I guess anywhere between 20 to 30 minutes,

01:12:40.720 and my temperature is anywhere between 175 to 180. I used to do really, really hot about like 190,

01:12:47.440 like I was doing 190. And I was getting headaches more easier. I just didn't like it. And I didn't

01:12:52.340 feel good. How long did you sauna during your pregnancy? How far were you able to, I'm sure

01:12:58.960 women ask you this all the time. And I don't know that I have an answer to the question.

01:13:01.660 So I first found out that I was pregnant when I was touring Finland. And everyone was like,

01:13:09.540 it was like sauna, right? It was like we were going touring saunas.

01:13:14.660 You're a sauna VIP.

01:13:16.580 I was and I'm like, holy crap, like, what am I going to do? I felt like at that early,

01:13:22.220 early stage, I mean, literally, like I found out I was pregnant in Finland. I did do a lot of sauna

01:13:27.800 touring and stuff and old plunging and all that at that stage. But right after when I got on the

01:13:33.740 plane, come back home, sauna was out. And the reason I sort of erred on the side of caution,

01:13:40.500 I mean, you can I talked to women in Finland, and they were like, Oh, yeah, sauna throughout

01:13:44.220 pregnancy. And you'll find those anecdotes, certainly in that culture. But there is a body

01:13:50.380 of evidence, mostly looking at like hot tub. It's common knowledge, like pregnant women shouldn't

01:13:56.420 get in the hot tub, like you go to any spa, like it's like, known. But there's a body of evidence

01:14:02.180 that it can, something might increase the risk of sort of like a fetal alcohol syndrome,

01:14:08.400 sort of thing in offspring, even neural tube defects. So I was concerned that going in the sauna,

01:14:15.580 perhaps could increase the risk of something like that. And so I decided that it just wasn't worth it.

01:14:22.180 And so I did not sauna at all throughout pregnancy. And I even waited a little bit while

01:14:27.760 breastfeeding and stuff. I waited probably like six months or so before I really got back into

01:14:32.840 saunaing. Now, all the while I was exercising throughout pregnancy and so many benefits to that.

01:14:39.180 But kind of back to your question, the other protocol I do is at night. And it's interesting

01:14:44.380 because doing the hot tub at night, we're in that hot tub. And it's kind of also a time that my husband

01:14:50.360 and I get together away from our child. I mean, it's like our time. We're like out the stars,

01:14:56.380 dark sky, like it's nice. And that is something that my husband likes to do it, like literally,

01:15:01.840 like he wants to do it every night because it helps his sleep so tremendously. I don't have as much of

01:15:06.660 an issue with my latency or my sleep, like in general, but he does. Like I'm asleep by 930. And

01:15:12.880 it's like, no, like I'm asleep in 10 minutes. Like I get in the bed and like I can be asleep in 10

01:15:16.580 minutes. He is not that way. And he likes the hot tub that really helps his sleep. So I ended up

01:15:22.300 doing that a lot as well. And sometimes I'll do like both. I'll do the sauna and hot tub in the

01:15:26.360 same day. It all depends. But exercise is the most important that I have to get. And I go for the

01:15:33.680 vigorous type of exercise. There are studies looking at intensity with respect to dementia risk,

01:15:40.940 cognitive impairment. You'll find all sorts of things. I think the most common thing that is

01:15:47.880 pretty thematic is that the more effort you put in, the more time you put in, the bigger the benefit

01:15:54.680 with respect to cognitive health. So dementia risk. And also it depends on how it's, I'll give you an

01:15:59.960 example. There was a longitudinal study where women who, women, by the way, as you know, are,

01:16:07.200 I think, proximately at a twofold higher risk for Alzheimer's disease. That's right.

01:16:11.900 Super interesting. But so this is in women and they were studied for decades. And I think it was

01:16:16.860 like starting from like the 70s up until like 2010 or something. And they came in for a physical,

01:16:23.020 like put on a bike, exercise bike, and they're like fitness was measured. It was like empirical data.

01:16:28.300 And this was like, I don't know, five to seven times. So like over the course of 40 years or

01:16:33.680 eight years. Yeah, exactly. Something like that. And the women that were the most fit by their

01:16:39.300 measurements on this cycle test, they did probably VO2 max. Yeah. So it's cardiorespiratory fitness.

01:16:44.880 Those women that were the most fit, the reduction in Alzheimer's risk was like so robust. I think

01:16:52.280 there was something like there were nine times less likely to get or something crazy like that.

01:16:56.640 The ones that were moderate, like, so they had like a moderate cardiorespiratory fitness. They had a

01:17:01.320 four or five fold reduction. But then you'll like look at another perspective study. Same deal with

01:17:06.600 they don't come in and get anything measured, but they come in for a questionnaire. They get a

01:17:10.320 questionnaire every whatever it was over the course of like 40 or 50 years or something. So they answer

01:17:15.580 all these questions like, oh, how often do you jog or bike or do you play tennis or whatever?

01:17:20.840 And you look at that study and there's like no association between physical activity and

01:17:27.000 dementia risk. And I'm like, hmm, that's interesting because this other study where they're

01:17:31.580 actually measuring something showed a robust reduction in dementia risk. It hits home this

01:17:37.600 like, okay, what study are we looking at? You'll find questionnaire studies that also show, you know,

01:17:42.640 a benefit like people that are physically fit and the more fit they are, there's like a linear dose

01:17:46.560 response effect where you see, you know, people that put in more effort, they're training for a longer

01:17:51.620 period of time and they're more vigorous or more volume both, right? They have the greatest benefit

01:17:57.200 with respect to dementia risk, which isn't so surprising to me. The studies that are unambiguous,

01:18:02.980 as you said, are the ones that actually measure VO2 max because there's no denying what you're

01:18:08.160 measuring. It's a very objective measurement and it basically takes out the training component

01:18:16.000 because it captures that benefit. It's the readout state of the training. And it basically says,

01:18:22.220 look, maybe it doesn't matter if you do five high intensity workouts a week or two high intensity,

01:18:30.160 five low intensity. Like what matters maybe more is the output. I don't know if that's the case,

01:18:35.860 but there's no denying that people who have a high VO2 max are doing something that people who have a

01:18:41.640 low VO2 max are not. And that's what's being captured in those studies. And the numbers are

01:18:46.860 astronomical. I won't go into them again. People on this podcast have heard it too many times because

01:18:50.740 I can't stop talking about the benefits of having a high VO2 max. But I want to touch on something else

01:18:54.820 you just said a second ago, which is you noted that women are indeed at twice the risk of Alzheimer's

01:19:01.380 disease to men. Of course, Parkinson's flips that. Men are at higher risk. But focusing on

01:19:06.780 Alzheimer's disease for a second, is there any evidence that there are gender differences

01:19:13.120 in response to exercise? In other words, are women more responsive to the benefits or more amenable

01:19:22.140 to the benefits of exercise than men because they are at a higher risk genetically?

01:19:25.420 I haven't seen the studies looking at the response to exercise with respect to the sex differences. But

01:19:33.220 as you mentioned, like there's definitely differences with respect to their Alzheimer's

01:19:37.580 disease risk. There are different mechanisms that could – so women have different – like there's

01:19:45.300 different metabolic responses to exercise maybe. Also hormonally different – this would make sense,

01:19:52.760 right? Like I don't know that this has all been studied. I haven't seen that data. But like

01:19:56.620 hormonally different responses to exercise, that would be plausible. Immune system effects as well.

01:20:02.460 Exercise is affecting the immune system. So we haven't even talked about like myokines. Like

01:20:06.960 these are like molecules being secreted by our muscles. We talked about lactate. That's not a

01:20:11.540 myokine. That's a metabolite. But physical activity, when we force our muscles to work hard,

01:20:16.980 we're making something called a myokine. Sometimes it's referred to as an exerkin. But like this is

01:20:22.120 irisin is one. IL-6 is another. There's other ones as well. But like these are also affecting the brain

01:20:28.360 and they're affecting cancer risk. There may be differences in respect to like myokines that are

01:20:33.280 being secreted with respect to how the stress of exercise, how that response is happening.

01:20:38.840 Let's dive into that. Let's talk about cancer. Because Rhonda, while I think both of us are – I

01:20:44.980 think there are others who share this point of view – completely convinced. In fact, I just don't see how

01:20:50.200 one could not be at this point convinced of the benefit that exercise poses to the brain. It seems

01:20:56.600 much harder to make the case for cancer. In fact, when you think about some of the things that are such

01:21:04.700 obvious problems with respect to dementia, for example, disrupted sleep, poor exercise, etc.,

01:21:12.080 clear relationship. Very hard, at least for me, to make the case that bad sleep is related to cancer.

01:21:19.600 Although I think it is, but the data aren't clear. You can certainly make the case that horrible sleep

01:21:24.840 would lead to a weakened immune system. A weakened immune system, especially the cellular system,

01:21:31.700 more than the humeral system, would easily lead to an increase in not necessarily cancer initiation,

01:21:37.900 but cancer propagation. But again, the data are so much less obvious. Let's talk about this

01:21:43.700 relationship between exercise and cancer, right? On the surface, it should make sense.

01:21:47.200 Exercise is good. Cancer is bad. More exercise should mean less cancer. How compelling are the

01:21:53.420 data? And I'll admit that I haven't gone as deep here as I have on cardiovascular disease and

01:21:58.340 neurodegenerative disease.

01:21:59.700 So it's also another area that I'm very, very interested in. I mean, as you start to get into

01:22:05.060 your fourth decade of life, you've now had a friend or a family member that has come down with cancer,

01:22:11.600 and you see, I mean, you're a physician, so of course you've experienced it on a different level,

01:22:16.660 but like you just see how terrible it is to get cancer. And it really, the best, best hope is

01:22:23.100 obviously to try to not get it, to prevent. And there are, as you mentioned, there are things that

01:22:28.740 can modulate that risk that are a little genetic-wise that are harder to kind of move the needle. But

01:22:35.060 overall, so with respect to cancer incidents, it's interesting if you look at, like, you were talking

01:22:40.920 about some of these elite athletes, people winning the Tour de France, and people that are Olympic

01:22:45.560 medalists, or maybe that have even just entered the Olympics. I mean, you have to be quite an athlete

01:22:50.080 to just get into the Olympics. And there's been a lot of interesting studies, quite a few that I have

01:22:55.560 seen. These are studies where observational data, again, obviously caveated with that, you're looking at

01:23:01.900 people that have just entered the Olympics over the course of, like, from 1912 to 2010, or something

01:23:07.480 like that, like, just decades, and looked at all-cause mortality, cancer-related mortality, and

01:23:12.040 compared it to, like, the general population. So there's a couple of studies that have come out of

01:23:15.800 the US. And if you look at both of those studies, one of them was actually looking at medalists, and

01:23:20.480 the other one was just looking at people that, like, entered the Olympics. They saved about one and a

01:23:25.240 half to two years of life from not getting cancer. They had a five to six-year, what you could call

01:23:31.160 lifespan extension compared to the general population. Same with, like, French Olympians as

01:23:35.900 well. Very similar, where it was, like, they lived, on average, five years longer than the general

01:23:40.580 population. It was attributed that they had basically saved two years of life from not getting and dying

01:23:46.540 from cancer. I guess I should say dying from cancer, because they are two different things. But that would

01:23:51.140 be, like, at the elite level. And it's interesting, because you go, well, two years? Like, that's it?

01:23:55.720 That's how I see it. I'm like, really? Like, two years? And it's funny, because I remember when I was a

01:24:00.600 postdoc, my postdoctoral mentor, Bruce Ames, he had said to me once, or actually more than once,

01:24:07.180 you know, I once read, you know, there's, of all the things that you can do, like, if you prevent

01:24:11.200 cancer, you really only save about two years of your life. And I always thought, I'm like, no way,

01:24:16.800 no way. But anyways, so that would be, like, at the extreme end, when you're looking at the actual

01:24:21.640 athletes, they're definitely less likely to die from cancer than general population people. But when you're

01:24:27.320 talking about prevention, so there's a difference between, if you read a study, and it says people

01:24:33.780 that are physically active are X percent less likely to die from cancer, like, so cancer mortality is

01:24:39.460 decreased. That's not necessarily the same thing as not getting cancer, right? That just means you're

01:24:44.080 not dying from cancer. So the studies looking at cancer prevention really seem to focus on a specific

01:24:51.920 type of exercise, and that is aerobic exercise. For whatever reason, there's not a lot of literature on

01:24:57.860 strength training and cancer prevention. You can find studies on strength training and cancer-related

01:25:04.940 mortality. But with prevention, it's sort of focused on, for whatever reason, on aerobic exercise. And it does

01:25:12.320 seem like there are certain types of cancer that are more responsive to exercise with respect to having a

01:25:21.240 reduced risk. And some of those cancers are ones that we should care about. So breast cancer. What's

01:25:27.960 the lifetime risk of breast cancer? For a woman, it's about 1 in 8. Pretty high. For the average woman,

01:25:33.880 of course, many different lifestyle factors play into that. And exercise is one of those factors.

01:25:40.080 Colon cancer is another one that seems to be quite responsive. Lifetime risk of colon cancer for

01:25:44.640 average woman is like 1 in 23. For a man, it's like 1 in 25 or something like that. The reason I'm

01:25:49.740 mentioning, as you know, Peter, if you're talking about, like, esophageal cancer, some cancer where

01:25:55.240 it's like 1 in 500, I mean, you're more likely to die in a car wreck than get, you know, one of those

01:26:00.380 cancers. I think it was esophageal cancer. But you get my point, where the lifetime risk is already kind

01:26:05.280 of quite low for the general person or the average person. So breast cancer, colon cancer, there's a few

01:26:11.020 other cancer types that are quite responsive. But those two in particular kind of stand up because

01:26:15.880 with prevention with respect to people that are diagnosed with cancer and have those cancers and

01:26:21.080 then they engage in physical activity as well, like, you see a very robust response with respect

01:26:25.360 to reducing cancer mortality and also recurrence. You know, it's like 50%. You know, cancer mortality

01:26:31.640 is reduced by 50%. Cancer recurrence is reduced by 50%. And those individuals diagnosed with breast or

01:26:37.380 colon cancer or colorectal cancer that are engaging in more physical activity. So the question is,

01:26:42.200 well, how much? And you mentioned, like, you have a lot more knowledge with respect to cardiovascular

01:26:46.740 disease. And I would argue the data really, I would say, suggests that you actually probably need

01:26:54.260 to do more exercise to sort of reap the cancer preventative benefits than you do cardiovascular

01:27:02.100 benefits, even, you know, some of the metabolic benefits. I don't know why that is. It seems as

01:27:08.220 though getting more to that upper limit of what these, you know, committees are recommending.

01:27:13.360 So 300 minutes a week of moderate intensity exercise, or maybe 150 minutes more of like what

01:27:20.140 they would define as vigorous, which actually I think they're vigorous is a little bit below what

01:27:24.160 my definition would be. But so it seems like the amount of exercise, you actually have to put in a

01:27:29.360 little bit more time and effort for the cancer, but any amount is beneficial. So it's not like,

01:27:34.920 oh, well, I can't do 300 minutes. Therefore, I shouldn't even care. Well, that's not true,

01:27:38.640 because there are benefits, even with like any type of physical activity. That's all the

01:27:43.860 observational data. And you can find anywhere between a 10 to 20% reduction in people are that

01:27:49.280 they're less likely to get breast or colorectal cancer 10 to 20%. Again, when you're talking about

01:27:54.380 a type of cancer with a higher lifetime risk, it's more compelling. So it's always kind of in

01:28:00.420 I'd be curious to see if the data line up with the cancers that are known to increase in risk

01:28:07.720 due to obesity. So right after smoking, obesity is obviously the second leading modifiable risk

01:28:13.260 factor associated with cancer. I've always thought that was an oversimplification because we use

01:28:18.140 obesity as a proxy, but I think it's probably insulin resistance. That's the true marker that

01:28:23.440 obesity is serving as a poor man's version of. It would be interesting to see because there are

01:28:29.120 certain cancers, including breast and colorectal, by the way, where obesity amplifies risk. There

01:28:35.280 are other cancers where obesity doesn't seem to play as much of a role. It would be very interesting

01:28:40.000 to align the exercise data with the obesity slash insulin resistance data and see if exercise is

01:28:47.660 disproportionately reducing risk in those cancers for which obesity is a risk.

01:28:53.320 Such a good point, Peter. And I think there is at least some data to suggest

01:28:58.240 that you are correct with that. So I mean, what is there like 13 or so cancer types that like

01:29:04.420 obesity is known to increase the risk for?

01:29:05.520 See, they're 13 or 17, something like that. Yeah.

01:29:07.800 Yeah. And breast and colorectal cancer are on that list. Aerobic exercise, I think there's direct

01:29:14.760 mechanisms. So like, you know, aerobic exercise is, you know, directly you're making those myokines.

01:29:20.700 And like, you know, some of these myokines have been shown to decrease the production of like

01:29:25.540 growth factors secreted from cancer cells. And they're like, they also like are killing cancer

01:29:29.660 cells through a variety of other mechanisms. Also the anti-inflammatory effect from exercise as well.

01:29:35.780 You're having a strong anti-inflammatory response. But there is a little bit of that, okay, well,

01:29:41.040 exercise is also improving insulin sensitivity, particularly in combination with dietary strategies.

01:29:46.880 The weight loss itself is basically a important component of the cancer, reduced cancer risk.

01:29:54.480 I think it's a combination of these things where it's like the direct effects from exercise. And it's

01:30:00.840 really interesting because as I mentioned, people that even have cancer, it seems like physical

01:30:06.300 activity, like I am not an oncologist and you know many more oncologists than I do. I don't know how

01:30:12.080 common it is for oncologists to prescribe exercise as an adjunct treatment to, you know, whatever type

01:30:18.320 of treatment, whether it's immunotherapy or radiation or chemotherapy or a combination, whatever.

01:30:24.060 I don't know how common it is, but the data is more and more compelling. And I think it's become more

01:30:28.920 and more compelling over the years that really exercising, it seems to be very important for reducing

01:30:36.820 cancer metastasis and also dramatically decreasing cancer recurrence. And so a really interesting mechanism

01:30:45.460 by which this is likely occurring is literally through that sheer force mechanism I was describing for

01:30:52.900 the brain. As you know, you know, cancer cells, tumor cells sort of escape the site of the tumor and they make

01:30:59.000 their way into circulation. It's called a circulating tumor cell or a circulating cancer cell, depending on the

01:31:03.780 study you read. You know, these circulating tumor cells are like traveling throughout the vascular

01:31:08.260 system to distant sites and they sort of take camp and then like it's like kind of the seed of a new

01:31:13.660 tumor forming in another tissue. Well, it's really interesting because cancer cells are so messed up,

01:31:21.240 as you know, like they're just completely wonky and very, very sensitive to stress, any type of stress.

01:31:26.880 They have these mechanoreceptors on their cell surface that are responsive to force, sheer force.

01:31:34.240 So when you get your blood pumping, it's like a hurricane that like wipes it out. They die because

01:31:40.800 they can't stand just the sheer force of the blood flow through the vascular system. So you compare the

01:31:46.700 mechanistic studies and there've been some studies looking at circulating cancer cells and it's like

01:31:52.080 people with those are like three times more likely to have cancer metastasis and so on. But again,

01:31:58.320 there are studies showing that like physical activity like dramatically decreases. And there's

01:32:02.580 been randomized trials showing it dramatically decreases circulating cancer cells in people

01:32:06.720 compared to whatever their other standard treatment that they're being given. Pairing that data with

01:32:12.260 looking at, you know, other data where exercise is being prescribed to patients and it is beneficial

01:32:18.720 with respect to their cancer metastasis reduction and also mortality reduction, you know, like 50%

01:32:24.860 mortality reduction, you know, versus recurrence as well. So I do think there is substantial evidence

01:32:32.560 to suggest that being physically active is a good measure for cancer prevention. And again,

01:32:41.800 there's also a lot of differences. There are sex differences as well. Like I don't know why,

01:32:46.620 but in some cases women respond better and there's certain cancer types that respond better. Lots of

01:32:51.880 variables here. Like I feel like I'm speaking in a general way, but there are lots of things to

01:32:57.480 consider, right? There are cancer types and there are sex effects and there are, as you mentioned,

01:33:02.640 other covariates. There's obesity and there's, you know, insulin resistance age as well. So there are

01:33:09.600 lots of nuanced as usual, but I do think that you can make the case that like, like what can I do in

01:33:17.760 my life to, you know, reduce my risk of getting cancer, reduce my risk of dying from cancer, reduce my

01:33:23.140 risk of getting Alzheimer's disease, reduce my risk from getting dementia, reduce my risk from getting

01:33:27.280 cardiovascular disease, reduce my risk for type 2 diabetes. The only panacea there is exercise. It's

01:33:33.800 exercise. It is the case. And unfortunately it's the thing that you have to put the most effort in.

01:33:39.880 It's certainly a lot easier to take a supplement, to take a pill. I do think there is an argument that

01:33:45.280 omega-3 is one of the getting yourself to a good omega-3 status and defining what that is, is still

01:33:50.800 like being investigated. But I do think that's a low hanging fruit that should not be ignored. But

01:33:55.680 exercise, as you've talked about many of times, is the king. That's the thing that you should focus

01:34:02.100 on. If you, obviously if you're obese, weight loss, exercise is part of that program. And like,

01:34:07.400 I don't think that anyone that's obese would be worrying about all the other things. Like they

01:34:10.600 need to like lose weight. And any personal trainer and coach like probably is going to help you do

01:34:15.080 that. You eat less. Like calories in, calories out, it like matters to some degree. You're not

01:34:19.380 eating as much. But as you said, exercise matters not just on the energy balance side, but exercise

01:34:26.840 makes you, for example, more sensitive to satiety hormones. So I have kind of a belief here that the

01:34:35.160 person who is overweight, the person who is obese and who is clearly eating more than they should be,

01:34:41.460 isn't doing that by choice. Maybe some are, but for the most part, it's hard for me to imagine

01:34:45.880 there's someone who's listening to this who's obese, who isn't wanting to not be obese and who is

01:34:52.820 otherwise struggling with hunger. And I think that that's one of the challenges is why is it

01:34:58.840 that a person who is not in energy balance is not responding to the normal satiety signals?

01:35:06.220 And I think there's a lot of reasons on the food science side, we could talk about a whole bunch of

01:35:10.260 reasons why our food has been hijacked. Our food is void of nutrients. Our food is hyper palatable.

01:35:15.800 It's far too available. Like there's a whole bunch of reasons, but I think one thing that doesn't get

01:35:19.700 enough attention is this thing, which is an exercising person has a better sense of nutrient

01:35:27.500 requirement. Their body physiologically is more in tune with their appetitive needs. And so even

01:35:35.520 though I don't think exercise matters as much as intake purely on the energy balance side, in other

01:35:42.080 words, I think it's more about reducing input than increasing output. A part of that equation is the

01:35:47.180 feedback loop that exercise brings. So yes, exercise just matters. And I also think that,

01:35:53.800 especially in this discussion of cancer and breast cancer, as the example you brought up,

01:35:57.460 so many women are so petrified of hormone replacement therapy because of this awful study,

01:36:03.740 the Women's Health Initiative, which was completely misinterpreted. But just to use one example of what

01:36:09.240 we spoke about, even the people who ran the study, who to this day, some of them, at least a subset,

01:36:14.720 still maintain that conjugated equine estrogen plus MPA, the synthetic progesterone, increase the risk

01:36:22.240 of breast cancer, even those people will acknowledge it did not increase breast cancer mortality. So even

01:36:28.980 if you take the most favorable to the WHI, the Women's Health Initiative study reading, the reading is

01:36:37.020 that conjugated equine estrogen plus MPA increased the incidence of breast cancer by 0.1% in absolute

01:36:46.220 risk, but did not increase breast cancer mortality. So here you have basically a non-event that has most

01:36:53.320 people panicked senseless, most women panicked senseless when confronted with taking hormones during

01:36:59.120 the perimenopausal period. And yet at the other end of that spectrum, we have a treatment that has

01:37:05.080 more than a log fold benefit in the other direction, i.e. in reducing risk. I wish people

01:37:13.000 would just allow their attention to be allocated proportionate to the size of the impact.

01:37:19.240 I'm 100% with you. And to kind of just highlight or emphasize what you just said, you know, there are

01:37:24.620 studies with women who are doing moderate drinking, which depending on the study you read, for women,

01:37:31.760 moderate drinking is like three drinks a day or something. Like it's a lot. And that literally

01:37:37.480 translates to a lifetime risk of breast cancer. It's like one in six or something like that,

01:37:41.520 where it's pretty significant, but you don't hear about women petrified of like drinking two glasses

01:37:48.920 of wine a night, which some people do. It's actually not uncommon. Looking at like what's going to impact

01:37:55.920 my risk more? What is going to lower my risk more? Like what should I focus on? Like what's like the

01:38:01.860 most important thing? I think obesity does absolutely impacts breast cancer. Same with physical activity

01:38:09.260 in the opposite direction has really enormous benefits. And then alcohol consumption is another

01:38:15.840 one, even mild alcohol consumption. I would say that like, I don't want to go there because it's

01:38:20.820 like so complicated. And I like, I can't even like begin like- I've gone there, Rhonda. I've gone

01:38:26.340 there. I go out on the limb and I'm going to say it. There is no amount of alcohol that is healthy.

01:38:32.200 The J curve is a misnomer. And what I think I would say is somewhere between zero and one,

01:38:39.720 there's not that much of an increase in risk, but there's not a reduction in risk.

01:38:43.900 For what?

01:38:44.580 For mortality in general.

01:38:45.760 Mortality.

01:38:46.100 Yeah, yeah, yeah, yeah. So in other words, you know, they talk about the sort of J curve where

01:38:49.140 complete abstinence is a greater risk than one drink a day. But I think both the Mendelian

01:38:55.320 randomization makes that clear that that's not true. And then secondly, when you look at all the

01:38:59.900 confounders of the people who are drinking zero drinks and what confounds their mortality,

01:39:05.980 I feel very comfortable saying that there is no dose of alcohol that is healthy, but at a very low

01:39:12.500 dose, probably four to seven drinks per week, you probably can't quite quantify the harm. That would be

01:39:18.180 my take. And so I'm comfortable saying that. I really feel confident that that is the case and

01:39:23.320 that things like the French paradox have far better explanations as one example.

01:39:28.040 The data is also a mess. You know, like, can you have your weekend glasses of wine?

01:39:32.900 Absolutely.

01:39:33.880 I think you can. With respect to the cancer risk, that's considered it's mild. I mean,

01:39:37.880 you're having less than one drink a day. And the only evidence I've really seen against the mild is

01:39:43.580 on the National Cancer Institute site, where they're like, it's one of those cancers where

01:39:47.500 it's like one in 500. It increases your risk of a cancer that you already have a lifetime risk of

01:39:52.360 one in 500. And it's still less than 1% of an increase. Like, to me, it's like your lifetime risk

01:39:57.440 goes-

01:39:57.700 That's my point. You can't measure it.

01:39:58.380 Like, you can't measure it.

01:39:59.500 It's a classic example of the dose makes the poison, but don't confuse that the poison is a poison.

01:40:03.700 Another example would be cigarettes. If you smoked a cigarette twice a week, literally one

01:40:08.900 cigarette twice a week, would your risk of cancer go up? Yes, but you wouldn't be able to measure it.

01:40:13.580 That doesn't change the fact that cigarettes are harmful.

01:40:15.360 Not to mention heart disease. Like, that is not a linear-

01:40:18.300 But even just focusing on cancer, right? It really comes down to kind of establishing causality.

01:40:23.440 Is tobacco causally related to disease? Yes. It's a harmful thing to take, but the dose matters.

01:40:31.280 Again, just being glib. One cigarette a week, it's probably increasing risk, but we don't live long

01:40:36.700 enough to see the separation of those Kaplan-Meier curves. Maybe if our natural lifespan was 500,

01:40:42.080 one cigarette a week would be sufficient to see a spreading of those lines. But at an 80-year

01:40:48.020 lifespan, eh, you have to get up to 10 cigarettes a day before we can see where that is. By the way,

01:40:54.140 I'm making that up. I'm not advocating that one can smoke up to nine cigarettes a day, but you know

01:40:58.400 what I'm getting at, right? And I think that's my point. With alcohol, it's simply just a question

01:41:02.980 of that. But I just want to make sure people aren't taking away from this that, look, I probably have

01:41:08.240 anywhere from zero to four drinks a week. But when I'm drinking those four drinks across two or three

01:41:14.180 days, it's not going through my mind that this is healthy. It's like, yeah, this is a hedonic pleasure

01:41:18.980 that's not good for me, but it's enjoyable. That's enjoyable. How do you feel about APOE4 carriers

01:41:24.540 and alcohol consumption?

01:41:26.600 Our view in the practice is that they are indeed more susceptible to the deleterious effects of

01:41:33.620 alcohol. And also I would say they're just more susceptible in general to the deleterious effects

01:41:39.540 of poor sleep, which is one of the ways that I think alcohol is disproportionately hurting the brain.

01:41:45.620 I think poor sleep is causally driving Alzheimer's risk and cardiovascular disease risk. I'm less clear

01:41:53.060 on cancer, but in as much as most people that are drinking alcohol are doing so in the evening

01:41:59.040 and anybody who's used a sleep tracker, you don't need to be Matt Walker to very quickly do the

01:42:04.560 experiment on yourself and compare a night of sleep with no alcohol, a night of sleep with alcohol.

01:42:11.260 They're different. So through that lens, I would just say we have lots of patients with E4 in our

01:42:16.220 practice, including a number of E4, E4s, even though those patients represent only 2% of the population,

01:42:22.400 they're probably about 7% or 8% of our patient population. And again, we say, look, unless this

01:42:28.940 really means the world to you, it's probably not worth the drink. And if you are going to have a

01:42:33.400 drink, here are some principles for how you might minimize the damage, right? In terms of

01:42:36.840 the number you might have, how long you might have it before bed, that kind of thing.

01:42:41.080 Exercise. You know, when I, a couple of things, just because you brought up the sleep and

01:42:45.040 so I started wearing a continuous glucose monitor largely because of you.

01:42:49.320 I've been a very bad influence on some things you've done, the lactate monitor, the CGM.

01:42:53.960 Yeah. Well, I started wearing it when I was a new mom. So this was, you know,

01:42:57.980 like five years ago. And that can't be a good time to wear a CGM, although it must have been

01:43:03.560 interesting, right? It was extreme. So here I am coming into this, like, oh, I'm going to learn

01:43:08.300 about the foods I eat and how my body responds to those foods. And lo and behold, the biggest and

01:43:14.020 most compelling and most important data point, or many points, because I had many of them,

01:43:20.100 that I sort of learned from wearing my continuous glucose monitor, which I'm sure most of your

01:43:25.000 listeners know about where you're measuring your glucose level, like continuously, was the effect

01:43:30.880 that my sleep interruption had on both my fasting blood glucose and my postprande, where I was like,

01:43:39.280 I could get like what we can be considered like pre-diabetic. Like I was like blown away. I was

01:43:44.520 like, what is this is insane. And then what I also sort of gleamed from this was that when I on days,

01:43:52.760 and the effect lasted at about, I would say like about 48 hours or so. When I did work out at the

01:43:58.120 time, I was doing a lot of high intensity interval training. It was like an hour long spin class I used

01:44:02.240 to go to, you know, where they do all this interval training. It almost completely blunted that effect.

01:44:07.280 Even though I was dog tired, last thing I want to do was go to my damn spin class.

01:44:11.880 This is like, it's going to be bad for me if I go. That's how I felt like it's going to be bad for

01:44:16.400 me. But it was completely the opposite where this crazy glucose dysregulation and whatever the causes

01:44:23.920 for that, I'm sure you know much more about that than I do. It was almost completely blunted. And it

01:44:28.240 was so profound. And it was like the one, all the food stuff, you know, I learned a little bit of

01:44:33.080 interesting. But really, that was the thing that for me was like, I have to work out no matter what,

01:44:39.580 no matter what, no matter how I feel. It doesn't matter. It's beneficial. It was a really interesting

01:44:45.400 study, caveat observational data, reverse causation, all the problems with any study. But it was looking

01:44:52.520 at the sleep habits. And so people that had slept, you know, as poor sleep or interrupted sleep,

01:44:59.100 something of that nature, I can't remember the all the exact things that were measured with respect

01:45:03.960 to sleep. But people that didn't sleep as long or had poor sleep, whatever by whatever measurements

01:45:09.620 had a higher all cause mortality, which is not that surprising. But only in people that weren't

01:45:15.480 physically active. And to me, I was like, wow, that's like interesting. It's interesting. And it's

01:45:21.540 like, you know, exercise can forgive a lot of sins in many ways, it really can. So you're talking

01:45:27.560 about your patients with E4, E4. And I'm sitting here going, oh, my gosh, I've got one of those.

01:45:32.300 And I'm already like, it's a lot. It's a burden. You have to calculate things. You have to be very,

01:45:37.140 you know, specific in your actions you take and like things that you don't do things you do,

01:45:41.920 right. And for me, it's like, okay, am I gonna like, I'm having a party, we're gonna have some

01:45:46.400 mimosas, whatever, like, I'm gonna exercise no matter what, like, and that might take off some of

01:45:52.420 the stress. I personally, I hardly drink. And mostly because I am E4, I have one allele.

01:45:59.220 And I have pretty much come to the conclusion that my brain can't repair damage as well as my

01:46:06.540 husband's, who doesn't have an E4 allele. With that said, I occasionally will, I'll have like,

01:46:12.540 maybe a glass or two of wine, usually, if that's my preference, but, you know, a week. Last time I had

01:46:18.100 a drink was like Valentine's Day, you know, so it's been a while. But at least I think with the

01:46:23.260 sleep, sorry, with the exercise, you know, again, it's like, it does, it seems to forgive a lot of

01:46:29.480 sins, honestly. I like that way of describing it. I kind of borrowed that from Stuart Phillips. I think

01:46:34.820 he was the one that said it to me, because I was like, this is like... That's right. I remember him

01:46:39.100 saying that on your podcast. He gets all the credit. And that, of course, brings us into the whole,

01:46:43.600 like, protein intake and muscle mass world, but... So let's set this up for listeners, because,

01:46:49.340 you know, you and I have talked about this a lot. In fact, I remember probably the last time,

01:46:54.240 this is pre-COVID, because we were both in San Diego, you and your husband were over for dinner.

01:46:58.620 I think I cooked up some fresh venison that I had just killed. And we were kind of talking about

01:47:04.880 protein. And I think at the time, both of us were kind of struggling with two competing ideas,

01:47:13.600 in gyroscience. And those two ideas that seemed dialectical, they seemed at odds, was on the one

01:47:21.920 hand, there's this body of mostly kind of animal literature that suggests lower protein intake is

01:47:31.280 associated with a longer life. But on the other hand, there's this literature that says lower protein

01:47:38.960 intake is associated with more frailty in humans. And that's associated with a shorter life.

01:47:45.600 So how do we reconcile these two things? And we didn't have a great resolution on that. I mean,

01:47:49.980 we both kind of felt like we were sort of scratching our heads, thinking, at least, I don't want to speak

01:47:54.600 for you, but my thinking at the time, this is again, three and a half years ago, probably was,

01:47:59.140 we just got to find the minimum effective dose. What's the minimum effective dose of protein

01:48:03.820 protein to not undergo mandatory catabolism? And that's what the dose is. And of course,

01:48:10.400 it's not clear how you find that dose. Theoretically, you would use a metabolic cart and

01:48:15.300 try to identify nitrogen balance and things like that. But of course, no one can do that outside

01:48:19.540 of a lab. So it was a bit of a head scratcher. Now, my thinking has evolved so much on this,

01:48:24.900 but I'd like to hear, first of all, I'd like to hear your formulation of the problem that I

01:48:28.560 formulated the way you would. And I guess more importantly, tell me how you're thinking today.

01:48:31.900 So you actually did a very good job formulating my mentality with respect to protein intake and

01:48:39.280 longevity back in 2019 prior to that. But like, even up until not even that long ago, to be honest,

01:48:46.680 you know, there's, as you mentioned, a large body of animal evidence, but also like there was coupled

01:48:52.020 epidemiological data where you think people are looking at, you know, vegetarians are taking in

01:48:57.260 lower amounts of protein and they're all cause mortality and they're cancer mortality. And they just

01:49:01.360 study after study after study and they have a lower all cause mortality, lower cancer mortality,

01:49:06.300 but, but only in those individuals who are not obese, not sedentary, sorry, are sedentary or smoking

01:49:15.360 or, you know, they had some unhealthy lifestyle factor. So in other words, the people taking in

01:49:21.060 higher protein, animal protein, who were basically healthy, had a similar cancer related mortality,

01:49:28.360 all cause mortality as these vegetarians. Okay. So, and similarly studies where they normalized for

01:49:35.020 fruit and vegetable intake, high protein versus low protein, no difference in early mortality, right? So

01:49:41.360 yes, it seemed that a lot of the data that were espousing low protein were confounded by lifestyle

01:49:50.100 choices and high protein was also negatively confounded by high calorie as the most obvious.

01:49:56.580 Exactly. And with the animal data, and this is probably where my mentality has shifted the most

01:50:04.460 because I wasn't really of the opinion that vegetarian diets were superior to meat eating or

01:50:13.520 I guess omnivore types of diets that were healthy omnivore types of diets because of what you were

01:50:18.200 saying. Like that data was nuanced and it wasn't just like, that wasn't something I was, that has

01:50:23.540 shifted the way I've been thinking. But with respect to a lot of the animal data and mechanisms and you

01:50:31.380 can restrict a mouse of protein and make it live longer and not get cancer and, you know, all these

01:50:36.400 things that you see study after study. I mean, it's just like the longevity science and that whole field

01:50:42.260 is like dominated by that. Like at least was. And there's now, I think, some pushback going on,

01:50:49.660 but there's still a large group of scientists that are still publishing a lot of animal data.

01:50:56.200 And this is where I sort of started to look into some of these exercise physiologists, people

01:51:04.600 like Stuart Phillips. I know you've had Don Lehman on. These like giants in the field that are doing

01:51:10.520 the research. And Brad Schoenfeld is another one where they're looking at protein intake. They're

01:51:16.260 looking at strength training and its effect in humans on muscle protein synthesis. And also just

01:51:22.880 like looking at data with respect to muscle mass and all cause mortality and Alzheimer's disease,

01:51:30.660 dementia. We didn't talk about that, but like strength training also can modify that risk.

01:51:35.800 Also cancer mortality.

01:51:37.260 Yeah. Strong grip versus weak grip, monotonic change in grip strength, 70% reduction in incidence

01:51:45.160 and mortality from dementia. I mean, 70% reduction in risk. Remember, people don't understand you

01:51:51.600 can't reduce risk more than a hundred percent. So it's not like increasing risk, which can be 100,

01:51:56.540 200, 300. When you're talking risk reduction, 70% is staggering.

01:52:01.620 It is.

01:52:02.340 Strength matters.

01:52:03.040 It does. As you know, and many of your listeners, there's two important signals for

01:52:08.100 your muscle. Strength, obviously a big component of that is physically working them, but protein

01:52:14.380 intake plays a role there as well. And I think it was Stuart Phillips like phrased it this way where

01:52:19.760 the animals that are being studied in these labs are in a sterile environment. You know,

01:52:24.940 they're in a sterile environment. They're not being exposed to influenza and all these infectious

01:52:28.760 diseases. And any of us, we've had a parent or a relative or someone that has gone into the hospital

01:52:35.200 and maybe had bed rest and then come out. And like, I had a grandparent who literally couldn't walk

01:52:41.120 after a back surgery forever. Like that was it. That was their downfall. It was like the trajectory

01:52:46.040 just went down, completely down. So losing that muscle mass when you're in older age,

01:52:53.280 obviously building up a bigger reserve in youth, in middle adulthood, whatever, like that's very

01:52:57.980 important. But like these animals that people are manipulating the protein restriction in them,

01:53:02.980 they're not being exposed to that. They're not losing like, I don't know what percentage.

01:53:07.280 It's pretty intense. Like how much, you know, you can lose from like three weeks of bed rest.

01:53:11.580 And also like, as it's been pointed out by people on your podcast, I think Matt Caberlin,

01:53:16.560 you know, mice are dying from like cancer. They're not dying from the same diseases. And it's not even

01:53:20.940 the same type of cancer that humans get. We get a lot of these epithelial like tumors, solid tumors.

01:53:25.860 They're like dying from lymphomas. So there's a lot of differences there as well. Like there's a lot of

01:53:31.240 interesting, and I'm the one to have talked a million times about animal studies. I think they're

01:53:37.120 important mechanistic data. Like there's things you just won't ever get from humans. But at the end

01:53:42.240 of the day, I started to realize that looking at, you know, mice in a sterile environment where they're

01:53:48.040 not really being exposed to the same stimuli as humans, things are very different in terms of

01:53:53.540 aging. It was falling apart in my mind, basically. It was like all falling apart. I'm like, this doesn't

01:53:57.940 make any sense. Like this isn't what to be looking at if I'm wanting to really focus on healthy aging

01:54:04.160 for myself, for everyone else. So I think that's kind of what was the tipping point for me was just

01:54:10.140 kind of that realization of the importance of muscle mass and how, you know, some of these animal

01:54:15.920 studies you look, they have a little bit of an improvement in their cardiovascular health. And

01:54:20.440 I'm like, exercise, okay. Is that better than exercise? No. The things that were improved, I was

01:54:26.060 like, exercise does that. Exercise does that. Like this isn't convincing me that I need to like do that.

01:54:31.280 I think it was just kind of like a shift in the way I viewed the data, like the lens I was seeing

01:54:36.560 it through. I'm still waiting for somebody to demonstrate for me that if there is an increase

01:54:42.820 in the risk of cancer associated with higher protein intake in humans, I'd like to see that

01:54:48.320 quantified. But I would like to see somebody demonstrate that if there is an increase in risk,

01:54:55.100 that quantifiable increase in risk is greater than the offset of sarcopenia. Because that's something

01:55:03.840 for which there is no ambiguity. We have all the data in the world to point to the devastation of

01:55:11.020 sarcopenia on an aging population. And we know full well that two things have to be true to avoid

01:55:19.560 sarcopenia. Adequate protein intake, which as you age, gets bigger and bigger. That number goes up

01:55:26.800 and up and up due to anabolic resistance, coupled with strength training. So here we have something

01:55:33.240 for which there is no uncertainty. You must consume increasing amounts of protein and you must do

01:55:38.600 strength training to ward off sarcopenia as you age. And if you don't, here's your mortality trajectory

01:55:44.620 and it's awful. Let's compare all of that to this questionable risk for which, frankly,

01:55:50.200 I don't see data. And I'll add one more point to what you said, Rhonda, which is I think this story

01:55:54.620 got confounded by our good friend C. Elegance. So let's go back 29 years, roughly, call it 30 years

01:56:03.880 directionally, when some very seminal and interesting work was published looking at the DAF-16 mutation

01:56:12.200 in, or maybe it was DAF-2. I can't remember if it was DAF-2 first or DAF-16, but it was the analog of

01:56:19.000 the IGF receptor. And if you knocked out that gene, you could double the lifespan from roughly two weeks

01:56:25.820 to four weeks or four weeks to eight weeks, I forget what it was, of C. Elegance, this worm.

01:56:30.620 The implication of that was profound. I don't want to downplay the most important takeaway from that,

01:56:38.460 which was lifespan was malleable. That turned out to be very interesting. I could go on my rant about

01:56:44.360 why C. Elegance is not an organism or an animal model that offers any insight into us based on its

01:56:51.380 cell, based on a whole bunch of things about its biology. But nevertheless, it somehow became

01:56:57.520 knocking out DAF-2 or DAF-16 was tantamount to dropping IGF, insulin-like growth factor one,

01:57:04.460 to zero, is the key to longevity. And the way to do that is to have no protein. And I think that

01:57:12.700 story is so incorrect, but somehow it's become part of dogma. I think that's the other piece of this

01:57:19.740 that just kind of won't go away. It's funny because I've done those experiments with my own hands when

01:57:25.940 I was at the Salk Institute and I was in Andrew Dillon's lab who had trained with Cynthia Kenyon,

01:57:30.100 who made the discovery back in, was it early 90s or something? Yeah, I feel like it was 93 or 94.

01:57:35.400 Yeah. And it was very exciting for me at the time because it was like, oh, this is a homologous gene

01:57:40.600 we have. And I'm watching it go from a 15-day lifespan to like a 30-plus day. And not only that,

01:57:48.720 you know, these worms- Healthspan was remarkable.

01:57:51.060 They were youthful. I mean, like you could see them, you look at a microscope and you see how they

01:57:54.980 move around. It is very apparent they were acting like a youthful young larva that had not been born

01:58:01.000 long ago. But then you also realize they go into this dour state where like in order to get that

01:58:07.200 lifespan extension, they're like going into this like metabolic stasis and like this thing that we

01:58:13.100 don't do. Humans don't do a doubt. It's a completely separate pathway that is required for

01:58:20.360 that lifespan extension. And I think to your point about the IGF-1, the insulin growth factor receptor,

01:58:27.380 and also the insulin pathway, they're kind of both tied into that. The fact of the matter is,

01:58:32.680 is that that is a growth factor. You and I have talked about this before, you know, growth factors

01:58:37.280 in the context of a tumor can allow tumor cells to override cell death mechanisms. So they can

01:58:44.720 continue to survive when they otherwise might have been signaled to die. And so there can be a problem

01:58:51.280 with too much IGF-1 in the context of a tumor and what causes that high IGF-1 is up for debate.

01:58:58.440 But at the end of the day, it's not that high IGF-1 that is necessarily causing the tumor. I think

01:59:04.960 there are things that you can do in your lifestyle, like exercise actually causes IGF-1 to go into muscle

01:59:11.320 where you're repairing damaged muscle. It's helping muscle repair. It goes into your brain. It's

01:59:17.560 important for like neurogenesis. A little bit of controversy there, I know. But like, I am in the

01:59:23.180 camp that you adults are. There's studies showing, multiple studies showing that you can take an older

01:59:28.360 adult, train them for a year, and their hippocampus will grow by like 1% to 2%. Like there's multiple

01:59:35.160 studies. Also another study showing this with the subventricular zone. So these are two regions of the

01:59:39.520 brain where I believe data that says that adult neurogenesis or the growth of new neurons as an

01:59:44.540 adult is occurring. And I think exercise is a big... And do you think that part of the vehicle for

01:59:48.980 exercise to do that is through IGF-1? Uh-huh. Yeah, absolutely. It is. Interesting. Animal studies

01:59:54.600 have shown that. Again, you know, we all know about the caveats. Does it translate to humans? We don't

01:59:58.980 know. But oftentimes, you have to take the whole body of evidence, the human evidence, couple it with

02:00:03.900 mechanistic data, with animals, and try to kind of put together a story to the best of your ability.

02:00:10.020 I mean, that's all we're going to get. You always hear about, I want to lower IGF-1, but you know,

02:00:14.360 it's actually like important for the brain and important for muscle. And the way to get it to the

02:00:18.760 brain is through exercise. That's known. And it's been shown, again, in human studies as well.

02:00:23.660 I think also part of the problem here is in some respects, people that are doing, I mean, really

02:00:31.340 impeccable animal research. Like, you look at the data and it's like, oh, they're doing this study.

02:00:36.880 Great. This is a good study. I mean, like, you can't poke holes in it with respect to the animal

02:00:41.900 world. But then sort of translating that to humans and considering, who are we talking to? Are we

02:00:47.860 talking to an overweight, obese person? Maybe they're probably getting enough protein. Like,

02:00:52.440 I don't know that they have to worry so much about protein intake. I think they need to focus on

02:00:56.560 losing that unhealthy weight. But that's also really important. And I think some scientists and

02:01:03.960 also health science communicators also sort of maybe, and I've been sort of guilty of that as

02:01:09.000 well, like disentangling, who are we talking to? Are we talking to the obese person who clearly needs

02:01:15.100 to focus on weight loss? Or are we talking to the healthy, physically active person who's now

02:01:21.060 terrified to take protein in because they read about some animal study where too much protein

02:01:26.000 increases mortality? And also, I think age is such an important part of this again. So if you look at

02:01:31.400 that, I think it was Levine in 2017 had that study where they look at the relationship between protein

02:01:38.600 and IGF-1, but stratified. So they stratified by protein intake, low, medium, high, low, medium,

02:01:44.760 high. And then they looked at middle-aged people, so 50 to 65, and then people over 65. And in people

02:01:53.080 aged 50 to 65, there was a relationship between protein intake and IGF. Higher protein intake

02:02:00.100 was associated with higher IGF. Now, it wasn't a huge difference. This gets overstated constantly,

02:02:06.680 but it was statistically significant. But what often gets ignored is the people over 65,

02:02:13.480 there was no statistical difference whatsoever between protein intake and IGF-1. Again, this is taken

02:02:19.420 as dogma that the more protein you have, the higher your IGF-1. And in people over 65, that's not the

02:02:25.820 case. Now, why do I harp on that? I harp on that because it isn't exactly that population that I am

02:02:32.380 most concerned with sarcopenia. So if the message is somehow getting transmitted to somebody listening

02:02:39.200 to this who's 65 or older, that I shouldn't be eating protein, and they might not even know that

02:02:44.940 it's through IGF, but somehow high protein is going to give me cancer because someone who's telling them

02:02:51.000 that is telling them that through the lens of IGF. The answer is, first of all, no, it's not. And

02:02:54.520 secondly, the greatest risk you face, again, is going to be the results of low muscle mass and low

02:03:01.340 strength. And even if we believed, which I don't, but even if we believed that in that age,

02:03:08.880 in the younger people, eating more protein leads to more IGF, which is bad, I would argue that the

02:03:16.340 absolute risk of death is so much lower in that group that the absolute difference in mortality

02:03:24.200 between the younger and the older in the presence of high protein is no comparison. What I mean is,

02:03:29.740 higher protein across the board is going to save more lives than it would ever hurt in younger people,

02:03:36.420 even if you could convince yourself that higher protein intake was associated with increased

02:03:41.900 mortality. Again, I find these data unassailable, especially in the older population. I think Matt

02:03:47.760 Cable and I did talk about this on a podcast once. And I worry that as you do, that that information

02:03:54.620 is not making its way clearly to people of the susceptible age group.

02:03:59.880 Right. And I think also that a lot of people are focused on the recommended daily allowance of protein,

02:04:04.940 right? Well, then, right. Like, what are these old ass studies that were not done correctly using the

02:04:12.180 wrong tracers? Like, what is that telling me about what how much protein I should take in? And this is

02:04:16.640 also another sort of, like, it was a turning point for me because I knew nothing about how the

02:04:21.680 recommended dietary analysis was determined. Yeah. I know everything about micronutrients and RDAs,

02:04:26.280 but I knew nothing about the protein. Once I talked to Stu, it was clear. He was like,

02:04:31.340 oh, no, we repeated those studies, him and many others, using different tracers. And I can't tell

02:04:36.340 you all this tracers and stuff because it's not my field. But it was like, no, we determined that

02:04:40.940 the minimum was really more like 1.2 grams per kilogram body weight, not 0.8. And to me, I was

02:04:47.900 like, oh, wow, you know, because you know, like, you don't store protein. This is important because I

02:04:53.100 mean, that's a big difference. And then on top of that, when you start to get into the physically

02:04:56.540 active people or elderly population, as you mentioned, anabolic resistance, where they're

02:05:00.480 basically like, their muscle isn't getting that signal as well to increase muscle protein synthesis

02:05:06.700 from the same amount of protein that their younger self would. So they actually need more of a dose

02:05:11.760 up to like, I don't know, 1.6, 1.8.

02:05:14.660 We basically tell people aim for one gram per pound, which would be 2.2 grams per kilo. Because

02:05:21.540 the other thing that complicates it, Rhonda, is not all protein is created equal. So if you're

02:05:27.240 getting a reasonable amount of your protein from plants, you're getting a lower bioavailable amino

02:05:32.600 acid. You're also not getting the same quantity of leucine, lysine, and methionine, which are probably

02:05:38.780 the three most important amino acids anyway. So, you know, one of the things Don Lehman talked about was

02:05:43.960 if you really want to be rigorous about this, you probably want to track those amino acids.

02:05:48.620 And you really want to say, look, make sure you're getting one gram at least of methionine

02:05:53.760 per day, two to four grams per serving of leucine and lysine. Now, again, for a lot of people, that's

02:06:02.400 too nerdy, but you can go through the math a couple of times with certain things that you eat repeatedly,

02:06:07.340 and you'll realize that's probably more protein in aggregate than a person is used to eating.

02:06:12.880 And as you said, when you start to factor in those two other categories of risk, right, more demand.

02:06:19.740 So when you're doing those high-intensity workouts, you are ripping apart muscle fibers when you're lifting

02:06:25.040 weights, when you're rucking, when you're doing all these other things we love to do, you're demanding

02:06:28.900 more amino acids for the turnover. And then, of course, anabolic resistance, I think, is the biggest

02:06:33.160 issue. And something that, truthfully, up until two years ago, I just wasn't paying enough attention

02:06:37.880 to. I wasn't appreciating that my older patients had an additional problem that younger patients

02:06:43.640 didn't have with respect to that signal. 2.2 grams per kilogram by weight, that's,

02:06:48.860 for me to get 1.6, like I'm supplementing, I'm taking whey protein, like, so how many meals?

02:06:54.840 Typically four.

02:06:55.880 It has to be.

02:06:56.660 Yeah, it has to be. So for me, it's really two meals and two snacks. And the snacks are just protein

02:07:03.080 snacks. So it's a shake. So one of them is just a whey protein shake. And then one of them is I eat

02:07:08.440 these venison jerky sticks. So five venison jerky sticks is 50, they're 10 grams a piece. And they're

02:07:16.420 really good. They're super pure venison. It's, you know, wild game, amazing product. I should disclose

02:07:22.300 I'm an investor in the company that makes them, by the way.

02:07:24.340 I was going to ask, do you make them?

02:07:25.600 No, I know the people so well. I know everything about it. And I know that the quality is there.

02:07:29.540 So those are two snacks. Otherwise, they're relatively low in calories. My whey protein

02:07:33.920 shake doesn't really have anything else in it except some frozen berries and almond milk.

02:07:37.120 And then the venison sticks are what they are. And then two meals that are going to have protein.

02:07:41.540 And for me, again, a lot of times like it's going to be an omelet and then protein dinner. So not

02:07:47.880 going to deny it. It's work. It probably consumes more of my dietary planning and dietary attention

02:07:53.720 than anything else. I don't pay any attention to how many carbs and fat I eat anymore. I'm just

02:07:58.840 paying attention to protein intake.

02:08:00.700 It's something I never really paid attention to at much at all until I would say like last

02:08:05.420 June or July is when I really started focusing on strength training, you know, both for my muscle

02:08:10.820 mass and also bone mineral density. Like that's another thing where it's like you want a reserve

02:08:15.400 of that as well, especially as a female. Focusing on the strength training and also the protein intake.

02:08:20.720 And it's been quite challenging. I've always sort of focused on micronutrients. It's still a focus of

02:08:26.580 mine and like making sure I'm getting enough of those. And I do supplement as well, you know,

02:08:31.180 in addition to trying to eat like leafy greens and getting some of the veggies and stuff. It's

02:08:35.460 either going to be roasted veggies for me or like salad. But the protein intake, it's been

02:08:40.340 challenging. And I find I typically do three meals. One of them is a protein meal snack. So it's

02:08:47.180 some salmon or like a homemade turkey burger or something like that. But then the protein shakes also is

02:08:52.340 where I have to do, I guess that I don't really consider it a meal, but it kind of is. It's

02:08:56.580 satiating. The protein like shake is definitely satiating. And I'm already, it's even kind of

02:09:01.160 hard because when you work out, like as you mentioned, your satiety hormones go up. Like

02:09:07.540 I'm not hungry. Like I don't necessarily want to eat. It takes a while before I can actually like even

02:09:12.520 get an appetite. So there's all these like competing things where I'm like trying to get

02:09:16.960 the protein, but I'm like, I'm not really hungry. And I'm like, I know I need it. So all these little

02:09:21.820 important factors. And yet again, important to sort of highlight that I don't know that someone

02:09:26.820 who is overweight or obese necessarily needs to focus so much on that. Right. Do you agree?

02:09:31.380 That's right. Fortunately, most people who are what I call overnourished are also adequately muscled

02:09:38.260 and they can actually in the short run be okay losing lean mass. In fact, it's very difficult

02:09:45.700 to lose heaping amounts of body fat while preserving lean mass. So we tend to focus more

02:09:53.040 on the caloric restriction coupled with the training. We use the training as a way to offset

02:09:59.160 some of that lean mass loss, and then we can come back to it. Now that said, so it depends on the

02:10:04.760 strategy, depends on the dietary strategy. So for people who are using tracking kind of the caloric

02:10:10.160 restriction way, we would still set a protein target that is at two grams per pound because of

02:10:17.200 the satiating benefits that you said. Also, you have the thermogenic effect and the benefits of

02:10:22.120 protein over fat and carbohydrate from a thermogenesis standpoint. But when you have people

02:10:27.380 that are going about it via dietary restriction or time restriction as their strategy for cutting

02:10:32.380 calories, it can become a little overwhelming. And when you force high protein, you sometimes end up

02:10:38.100 getting high calorie with it. So that's where we would say, just don't pay attention to it as much.

02:10:44.900 Just focus on the DRTR approach. The other place, Rhonda, where we do pay a lot of attention to protein

02:10:51.180 is in the few of our patients that are taking GLP-1 agonists. So I've been a pretty public critic

02:10:59.340 might be too strong a word, but I've certainly expressed my reservations about the ubiquitous use

02:11:06.140 and the liberal use of GLP-1 agonists, especially in people just trying to lose 10 pounds. It's one

02:11:12.140 thing if you're 100 pounds overweight and you've tried everything, by all means, the benefits clearly

02:11:16.340 outweigh the risks. But I got to get my beach body on for the wedding this summer. I'm going to lose

02:11:21.540 10 pounds. Let me fire up some semaglutide or trisepatide. I think that's a net negative

02:11:26.720 personally. And in those patients, not that we're giving it to those patients, but in any patient

02:11:31.820 who's on a GLP-1 agonist, we feel it is so essential to hammer home protein because those

02:11:38.580 drugs are so effective at squashing appetite that we've seen people who basically just want to drink

02:11:44.420 alcohol when they're on it. And they'll lose weight like crazy because they're not getting that many

02:11:48.120 calories, but they're like, yeah, I just like wine. Losing muscle.

02:11:51.080 Yeah. I'm just losing muscle drinking wine.

02:11:53.980 Yeah. I've got some acquaintances that are of that category where it's like,

02:11:58.020 stay-at-home mom wants to lose 10 pounds, has the means to get it and does it. And we haven't

02:12:03.860 measured muscle in the, but I look at them and I'm like, you look like you're wasting your,

02:12:06.640 like your muscle is wasting. If you're not eating, you're not taking in protein. So I mean,

02:12:10.440 like that makes a hundred percent sense. And it also, I don't know, maybe we'll talk about this

02:12:14.920 when you come on my podcast, but like, I'd love to like, cause you used to do a lot of fasting

02:12:19.020 and you don't do as much, at least of the long, long fast. And I would love to get into that and

02:12:24.960 decide whether we should do that next time or we could talk a little bit now. But yeah, that was

02:12:29.580 also like the biggest, you know, there was another shift in my understanding of fasting and time

02:12:36.640 restricted eating. A lot of people use time restricted eating. They sort of practice it by

02:12:42.600 skipping meals. And I don't know necessarily that's the way to do it, but people do that. It's just,

02:12:48.140 you know, what people do. And when you're skipping a meal, you're skipping your protein. You're

02:12:52.260 basically becoming losing muscle mass because you're not getting that important signal, especially

02:12:56.420 if you're not doing resistant training, then it's like kind of a disaster. And that was also something

02:13:01.600 I hadn't thought about a lot. And I know you've got a lot of experience in it, both personal and

02:13:06.760 clinically. I'll share with you briefly how we think about that. On the time restricted feeding part,

02:13:11.180 we agree that the greatest drawback is that the patients get protein deficient. So time restricted

02:13:18.420 feeding as a strategy for weight loss vis-a-vis caloric restriction is very effective with a

02:13:24.740 small enough feeding window. So a 16-8, you can eat your way into obesity with a 16-8. But once you

02:13:31.460 start getting down to a 24 or a 22-2, basically just doing one meal a day, really getting restrictive,

02:13:37.620 for the most part, you're going to lose weight. The problem is by definition, you're not going to

02:13:42.580 get enough protein in because even if you managed to scarf down one gram per pound of body weight

02:13:48.780 in a single meal, you wouldn't be able to utilize those amino acids. You kind of tap out at about 40

02:13:54.620 to 50 amino acids per meal. So if you sat there and had 160, you just flushed a bunch of them down

02:14:02.100 the toilet. They're literally not coming down the toilet. They're coming out as a piece of a urine,

02:14:05.340 coming out of the urea cycle. So the thing that we would counsel people on if they're going to

02:14:11.360 use time-restricted eating is they have to have protein snacks outside of their feeding window.

02:14:17.140 So if they're going to say, look, I'm going to only have a lunch at two o'clock and a dinner at

02:14:22.980 seven o'clock, we'll say fine, but you still have to have two protein snacks outside of that.

02:14:28.880 And that becomes challenging because those protein snacks can't really have much else in them.

02:14:32.540 They have to be very low calorie otherwise. Otherwise, you're not really doing time-restricted

02:14:37.260 feeding. And of course, a lot of people get phosphorylated over this. They say, but oh my

02:14:40.480 God, that's like outside of my feeding window. Will that impair autophagy? To which I argue,

02:14:44.660 you're not getting any autophagy doing a single day time-restricted feeding anyway. It doesn't

02:14:48.540 matter. But if people are getting gut benefits from taking that time off, then yeah, they're going to

02:14:55.980 miss out on those because I just don't see how you can get the gut rest if you're trying to get those

02:15:01.580 amino acids. And so you might have to really start to cycle those things. But yeah, long-winded answer

02:15:06.220 to why I think fasting can really be at odds with the adequate maintenance of muscle. And as we get

02:15:14.460 older, I'm just entering my sixth decade. This is a very high priority for me. Oh, really? Wow. You

02:15:19.960 look great, Peter. You're in your late 50s? No, sixth decade. So just turned 50. Yeah. Gotcha.

02:15:25.680 Yeah. I love that you thought I was 60. That's awesome. I'll take that as a...

02:15:31.360 I think Joe Rogan's entering that. And that's kind of what I was thinking. And he looks...

02:15:35.040 You can definitely see the people that put in the work and work out and they do aerobic,

02:15:40.180 they do strength training. You look at them. There was a study published on that too. A bunch of

02:15:45.320 biological markers of aging and biomarkers of aging were measured. And then people looked at pictures

02:15:50.560 and like rank their age and their quote-unquote biomarker biological age, according to all these

02:15:57.580 biomarkers that basically say their chronological age may be older than their biological age. Well,

02:16:02.540 they looked like their biological age, not their chronological age. That's also important.

02:16:07.100 Although I sometimes feel like excess exercise can prematurely age you as well. I've certainly seen

02:16:11.600 a lot of... And I don't know how much of that is the sun damage because, of course, a lot of

02:16:14.980 exercise is done outdoors. And of course, sun can play a horrible role in that.

02:16:19.320 So I've taken up more of your time than I said I would. But I want to ask you kind of just one

02:16:22.480 last thing. Is there any other... Just sticking with this theme of things that you believe today

02:16:31.360 that you didn't believe three or four years ago or things that you believed three or four years ago

02:16:35.720 that you don't believe today? Is there anything we haven't touched on? Because we've talked about

02:16:39.240 some really good ones. I think those are the really important ones off the top of my head.

02:16:44.940 I definitely don't want to get into the whole COVID thing at this point. But my view has changed

02:16:50.460 on things as that has progressed and changed as well. So I don't want to like not mention it. But

02:16:56.200 I think the most important things would be muscle mass, protein intake, also fasting. And I think

02:17:03.220 the effects of time-restricted eating on weight loss specifically when you're looking at that outcome

02:17:10.180 being attributed to caloric restriction. I think that is something that I've, you know,

02:17:15.120 wasn't always, you know, buying into that. But it is still my opinion there are benefits to

02:17:20.720 eating within your circadian rhythm. Eating late at night when you're making melatonin two to three

02:17:26.420 hours before bed, you're basically inhibiting insulin secretion. And there's data showing that

02:17:30.200 glucose levels will be higher with the same exact macronutrient intake as if you eat it earlier.

02:17:34.720 So there are benefits, circadian benefits. And I also think you mentioned the gut rest and like

02:17:40.080 digestion, you know, resting. So DNA repair mechanisms, you mentioned autophagy, like those

02:17:46.120 things happen when you're not digesting and that process like isn't happening. So you have to have

02:17:52.520 like a rest period for repair processes to occur. And I don't know that I necessarily, I think autophagy

02:18:00.780 is as good as the markers that we are sensitive assays that we have to measure it. And I don't

02:18:06.900 know that it's settled. I personally think there's probably even in between meals, there's some amount

02:18:12.400 of autophagy. Autophagy is happening in us. It is. And it's not like we're not. But is it clinically

02:18:17.560 significant more so than say exercise would induce? No, the exercise is like, that's my point. Like how long

02:18:23.720 would you need to fast to get the benefits of an amazing workout? And my thinking is probably a long

02:18:29.900 time. You might have to go a full day without food or a couple of days without food to get the

02:18:34.560 benefits of that. But you're right. I think without biomarkers, a lot of this stuff is very difficult

02:18:41.400 to speculate on because we can't really extrapolate from mice on this stuff. It's so nonlinear that I

02:18:47.540 don't think I could. And I've never heard anybody offer a very compelling argument either for what the

02:18:52.480 quote unquote answer is. I agree. We can extrapolate from mice. And the way I view it though,

02:18:57.840 is more of a cumulative effect where I'm thinking it's better to just eat within a circadian window.

02:19:03.560 And do I think that's going to have a cumulative effect on metabolism? And yes, I think that it's

02:19:09.420 better that I'm not eating within a 15 hour window, which most people in the United States,

02:19:14.580 they actually do. They're eating from start to finish. Like a lot of people are eating within a

02:19:19.360 15 hour period. If you're exercising, maybe it doesn't matter. Maybe you're right. Maybe they can't

02:19:24.040 eat within a 15 hour window. We don't really know, but I tend to think probably the circadian

02:19:29.680 component does play some role. But the question is, is it significant? I am of the opinion that

02:19:36.840 probably is cumulative over years. For no other reason. I think it just is on sleep. On sleep.

02:19:41.900 Yeah, exactly. Like if you just look at the benefits of nighttime food restriction in terms of,

02:19:48.660 as you pointed out, we're least insulin sensitive and the negative impacts probably of thermogenesis

02:19:55.840 and other things on sleep, that's probably the most compelling reason, even if nothing else mattered,

02:20:01.300 if we couldn't measure it. But those are so abundantly clear. That's as clear as how alcohol

02:20:07.560 impairs sleep. You know, a late night meal is a great way to destroy a good sleep.

02:20:12.900 Right. I think most people have, it's anecdotally like people realize that as well. So yeah,

02:20:17.920 I think we covered a lot of the things that of my perspective has shifted as any scientist that's

02:20:24.240 following data should. Some people will argue, oh, you changed, you know, how can I follow you?

02:20:29.640 You're changed your mind. It's like, well, like when new data comes out, you have to reassess things.

02:20:34.220 Like I reassess the supplements I'm taking. I mean, the supplements I take now versus five years ago,

02:20:40.180 totally different. Not all of them. There's some base things like I like vitamin D,

02:20:44.080 omega-3. Like those are like super important, I think. But you have to reassess things because

02:20:49.640 new data comes out and you might have a new understanding of things that we didn't know.

02:20:53.660 We have new tools. It's always getting better. So you have to kind of reassess things.

02:20:58.660 So Rhonda, for folks to follow you, obviously your podcast, Found My Fitness,

02:21:02.900 great way to follow amazing content. Also, you put up a lot of content. I think Instagram is probably

02:21:08.640 where you're putting up most of your content. Is that safe to say that if folks follow you on

02:21:12.720 Instagram, that's where you're doing sort of thorough analyses and stuff like that.

02:21:16.720 Would you recommend people also check out Twitter? Where should people be

02:21:19.560 going to see your thinking on a frequent basis? Well, it depends on what they like to consume.

02:21:24.900 So if they like to consume like in-depth articles, we publish them on my website,

02:21:29.140 foundmyfitness.com. We have like topic articles that we cover. We cover blood-brain barrier is one.

02:21:35.180 So we cover that more in-depth. Some people like to read. They like to nerd out on that.

02:21:39.180 So that would be the place for that. And then some people just like short little to the point,

02:21:43.420 you know, and that is where if they want like quick thing, like the Instagram. So Found My

02:21:48.080 Fitness on Instagram and also Twitter as well. It's kind of like a short. I mean, you only get so

02:21:52.420 much time on Twitter. You can't go in depth and nuance. And then I sort of have a love-hate

02:21:56.520 relationship with Twitter. It is kind of a fun place to also like there's other scientists on

02:22:01.200 there as well. And so I'm on Twitter and Instagram. And it's all the same handle.

02:22:05.560 Yeah. I found My Fitness and then the podcast as well, which is Apple Podcasts, Spotify.

02:22:10.760 Andrew Huberman and I were talking a little while ago and we were sort of singing your praises as

02:22:16.740 truly the OG health podcaster. When did you start? Was it 2014?

02:22:23.240 That was when I started the podcast. It was a weekend. I was doing my postdoc in Oakland and I

02:22:29.580 just started like Ron Krause down the hall, George Brooks. So I have a podcast with George Brooks on

02:22:35.120 lactate. Like he was like my second podcast. I don't think I've heard that. I need to go and

02:22:38.600 listen to that one. Yeah. We went all into the brain. That whole podcast shifted my thinking

02:22:44.580 of like intensity of exercise and the importance of lactate. I don't know if you know this, but like

02:22:49.560 I trained and we probably shouldn't, like we already talked about where people should go find me,

02:22:53.500 but I was a mitochondrial metabolism researcher in grad school. And so I was looking at the role of

02:22:59.500 mitochondria and cancer. And so of course, like lactate, I mean, I was thinking about it in a

02:23:04.180 completely different frame of mind. As opposed to, I mean, we now know it's such an important

02:23:07.760 signaling molecule in addition to all these other things we talked about. You know, we've had at

02:23:11.620 least one guest suggest that George Brooks is deserving of a Nobel prize. His lactate shuttle

02:23:17.240 theory, it's called a theory. And I kind of hate that it's called that because people hear that and

02:23:21.900 they're like, oh, it's not proven. Yeah. But it's been proven. And in fact, there's like studies,

02:23:26.020 like even like there were people looking at this, like even before he proposed, like they were

02:23:29.640 looking at lactate getting in the brain in response to physical activity. And it's like

02:23:34.340 beta-hydroxybutyrate. It's a signaling molecule. It activates BDNF like beta-hydroxybutyrate. They go

02:23:39.600 through the same transporter, monocarboxylate transporter, the MCT transporter to get into the

02:23:44.500 brain. There's also those in mitochondria. But it's so funny because there's a lot of similarities

02:23:49.320 that affects on TBI. So, you know, George Brooks has done some studies, USC looking at some of these

02:23:54.940 victims of TBI and giving them lactate. And it's like improving whatever their Glasgow rating scores

02:24:01.180 and whatever the things that they're looking at. But like, I think beta-hydroxybutyrate,

02:24:06.100 wasn't there some evidence, I think, with TBI? I remember Dom talking about that.

02:24:09.440 Dom has talked about this. Yeah.

02:24:10.720 It's so interesting because also with respect to like Alzheimer's disease and like there's some

02:24:15.460 really preliminary data that of course needs to be repeated, probably won't because you can't get

02:24:19.880 funding. But like giving beta-hydroxybutyrate, BHB to people with Alzheimer's disease,

02:24:24.940 can help improve. Like there's some small clinical studies looking at improvement in like

02:24:29.440 cognition. Lactate's like I think similar. There's a lot of overlap there. Now lactate you can make,

02:24:35.900 beta-hydroxybutyrate you make from exercise as well. You like push yourself into ketosis.

02:24:40.160 So it'd be interesting like, you know, if there's synergy there, trying to get the lactate and the

02:24:45.620 beta-hydroxybutyrate, the neurobiological effects of them to me is, it's so important. It's so

02:24:51.600 interesting. And I just, I kind of want more research in that area. And so I like talking

02:24:56.000 about it because I know scientists listen to your podcast, researchers, physicians. It's good to kind

02:25:01.600 of like spread ideas. I mean, that's part of what the podcast does, spreading ideas. It's not just

02:25:06.660 like I'm communicating the health ideas. And it's like scientists are listening to this and they're

02:25:12.080 outside of their like lens where they're only thinking about the thing that they research and

02:25:15.740 they hear this. And it's like creativity. They start to go, oh, like I've seen that happen.

02:25:20.760 Scientists like doing experiments based off of like listening to podcasts and stuff. I think it's

02:25:25.480 really great. But thank you for the OG. Yeah, it was a weekend thing for me and I loved it. It took

02:25:31.100 off. I just, I love it so much. I know you do as well. I mean, it's like, by the way, phenomenal

02:25:36.200 podcast. It's funny. I don't listen to podcasts much at all, as I mentioned, but there's a few

02:25:42.720 people that I trust to really be vigorous in their research and to be critical, to really like dive

02:25:54.420 down and like get into the root of things. And you are like one of those people. And so people will

02:25:59.560 come to me, you know, and say, oh, Peter, Tia said this. I'm like, oh, okay. You know, this is

02:26:03.320 something I should consider. Or, you know, oftentimes it'll be, oh, yeah, Peter also said that. And so I'm

02:26:08.000 like, oh, good. You know, so I'm always like, okay, what is Peter thinking? Nice to have you as a

02:26:12.060 colleague, as a friend. Likewise. I'm glad we've reconnected. Thank you so much for inviting me on

02:26:16.480 your podcast. Can't wait to speak with you again soon on your amazing book, which I can't wait to

02:26:22.260 read and discuss as well in a couple of months. Well, thank you very much, Ron. I can't wait to

02:26:27.520 see you in person, even though it's been pretty awesome to see you in video. Your setup is, as I

02:26:32.080 said, exceptional. We've treated the people who are watching this to a world-class view of what a

02:26:37.480 home podcast setup can look like. Amazing. Thanks, Peter. Thank you for listening to this week's

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02:29:20.120 Thank you.

02:29:29.900 Thank you.

02:29:32.340 Well,

02:29:32.360 I'm

02:29:33.300 going

02:29:33.800 to

The Peter Attia Drive - May 01, 2023

#252 ‒ Latest insights on Alzheimer's disease, cancer, exercise, nutrition, and fasting ｜ Rhonda Patrick, Ph.D.

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