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

26:06Certainly I know that when you're talking about omega -3s, you're referring to the marine variant of which we have EPA and DHA. But the transporter, if I understood correctly, is it a transporter only for DHA and its phospholipid form? And if so, what is the importance of EPA in this? Great question. So the MFS -D2A transporter that I've been referring to is specific to DHA. And the form of DHA is lysophosphatital colon DHA. So we make it when we take in DHA from fish or from resupplement. The higher amount of DHA that we take in, we add that Lysophosphatol colon group to the DHA. We also have DHA in free fatty acid form bound to albumin.

26:55Albumin is not, that doesn't get into the brain, but it takes it to the brain, blood brain barrier in the free fatty acid can sort of diffuse passively across the blood brain barrier as well. Same with EPA. Oh, I see. But because the phospholipids on the DHA, it needs a dedicated transporter, whereas the unfossful related, we're not phosphorylated. The one that doesn't have a phosphatidolipid sidechain can diffuse without a transporter. Exactly. So it's free fatty acid, bountail, bumanine, it can just diffuse across the brain. Yeah. So that's how EPA is generally getting in the brain. Then second question for you on that thread.

27:27Feel free to go into as much depth as possible because I know this is actually a very important topic that is somewhat controversial. What do you see as the relative importance of DHA and EPA? The conventional thinking, I think, is that EPA probably more important in the heart, DHA probably more important in the brain. I'm sure that's a gross oversimplification, but can you expand on that? I can try. I don't know that it's really known. So the way I personally think about both EPA and DHA, there's a variety of metabolites and of DHA that are involved in resolving inflammation. So these are resolvins, the mericens, the SPMs, protectants, and EPA also has some of those metabolites as well.

28:16And it also plays a direct role in inflammation through the, I don't want to say inhibition, but like dampening the the prostate glandons and the leukotreines, and a lot of the other inflammatory processes. So it's kind of like an approach where you're affecting inflammation from multiple ways, right? It's like a multi -pronged approach. And I mentioned Fribrenogen earlier about like Fribrenogen, it's an inflammatory protein, well, it's involved in coagulation, but it's something that we do measure as a marker of inflammation. So there's studies showing that people that are exposed to a particular air matter, their Fribrenogen goes up.

28:54But if they have a higher dose of omega -3 or higher intake of omega -3, it blunts that effect again through the inflammation, right? So both DHA and EPA are important in my mind for the brain as well. I mean, there's a variety of studies that have looked at even depression. You can induce depressive symptoms in a person by injecting them with what's called lipopolysaccharide, which is a component of the outer cell membrane of gram -negative bacteria. We have billions of those in our gut. In fact, there's about one gram of lipopolysaccharide or LPS for short. It's also referred to as endotoxin.

29:35There's about one gram of that in our gut. Well, you can inject people with a low dose of that. Something that actually would be somewhat, you know, I would say equivalent to someone with intestinal permeability. And it can cause depressive symptoms in people compared to those given a placebo. And you can blunt that depressive symptom effect with EPA, probably because of the inflammatory, the blunting of the inflammatory response. And there have been some, this is a field that's, again, understudied, underfunded, but some preliminary evidence randomized controlled trial, small randomized controlled trials that need to be, of course, repeated with larger sample sizes.

30:14They're basically showing that supplementation with EPA can help with depression. Yeah, this is such a frustrating thing for me and obviously I know it is for you and for many others including Bill Harris. If you took the cost of one phase three anti -amiloid failed drug trial, just take one of them. There's been dozens of them. Just take the dollars that were spent on one of those guaranteed to fail phase three trials and put that money into a preventive trial that looks at something that's got real feasibility or something that's really interesting, like the optimal supplementation of DHA in the right patient population group, we could have an answer.

31:00And yet for obvious reasons, there's an incentive to do a phase three drug tile on a candidate with an IND. There's not an incentive from a financial perspective to study these other things. And I think for a disease like Alzheimer's disease, that's particularly problematic. As I suspect we'll discuss, unlike cardiovascular disease, where, yes, prevention is still the best strategy, you can come in late to the game and still make a difference. I don't think the evidence is particularly compelling that that is true for Alzheimer's disease. Now, I'd love to be wrong, but I have yet to see compelling evidence that you can be a Johnny come lately to that pathology and have an impact.

31:39It's hard to fix those leaks in the brain once they're started. And that also is why I think there have been failed trials also with, we've been a few with omega -3 supplementation people that already have Alzheimer's disease. And you're giving them like, I don't know, at most, two grams. I've seen studies like 500 milligrams. I'm like, are you kidding me? You know, patients with high triglycerides or cardiovascular problems are... We're giving them four grams. Four. I know. at least for this is something that has the safety of a nutrient but literally an act like a pharmacological drug, you know, higher doses.

32:14I agree with you. I think it is much more challenging to fix when you have Alzheimer's disease and certainly like I'm talking about like the leaks in the brain. But then what happens after that the amyloid accumulation and like when you start to get to this level when you're you've got all of that I mean good luck. It's gonna be it is gonna be challenging and you're gonna have to take, it's not going to just be fixing the amyloid. You're going to have to have a cocktail that are going multiple angles, I think, in order to get some improvement. I think the amyloid, and perhaps also fixing the blood -brain barrier leaks as well, maybe at the same time with the cocktail may help a little bit.

32:50But prevention is the way to go. I mean, like, it's so much better to not get Alzheimer's disease than to try to fix it once you have it, because it is a very complicated disease with lots of things going on. I think that the strategies that can be done, and they're not that difficult. We talked about type 2 diabetes. There's no reason why someone should have it. You should be able to... I would phrase it as, I do not believe for a moment that type 2 diabetes is inevitable to our species. Whereas, I do believe atherosclerosis is inevitable. Of course, I also think most people don't need to die of it.

33:26That's a very stark contradiction. The disease is inevitable and as much as humans will have lipoproteins that carry APOB, we will get atherosclerosis. But again, we have the technology to delay the onset of that disease to the point where it should not be the cause of death. We should be dying with it, but not from it. I would also argue that cancer is inevitable to our species. It is simply a stochastic problem where if you live long enough and if you accumulate enough genetic mutations. And we can do lots of things to reduce the risk of that and to delay the onset of that and to detect cancer early and be more successful in treating it.

34:06But the incidence of cancer strikes me as something that is inevitable with enough age. I actually don't feel that way about type 2 diabetes. In other words, I think I share your point of view, which is it's not something that is necessary. We don't have to eventually get it. And I think that makes it all that much more tragic that you watch how many people are suffering from this disease and how much damage it's causing, not just in the disease itself, but as you said, it's such an amplifier of the, what I refer to as the horseman, right? It's what it does to your risk of cardiovascular disease, cancer, and Alzheimer's disease, is actually why the death toll for type 2 diabetes is so grossly underappreciated.

34:47Yeah. It's accelerating the aging process, the molecular... Yeah, it's gasoline on the fire of aging. I'd have to really reflect on it, but I can't think of a process that accelerates aging more than type two diabetes. Right. Maybe a morbid obesity, but like they're probably also type two. I would argue only in the context of insulin resistance, which gets us right back on that path. So the good news there is not that it's easy, but we sort of know what it takes to treat it and prevent it. And it doesn't necessarily look like the strategies that are being deployed. Unfortunately, at the level of the ADA, I want to ask you one other thing.

35:21we haven't talked about, but I want to know if it pertains to the blood brain barrier at all, and that's blood pressure. So hypertension and I guess hyperlipidemia also pose enormous risk for not just cardiovascular disease where they are two of the three biggest drivers of risk. But they also pose a risk in Alzheimer's disease, and I wonder, do either of those act specifically through the blood brain barrier? It is another really important, modifiable lifestyle factor that can affect Alzheimer's disease risk. maintaining good blood pressure. So I mean, basically you want to be systolic below 130.

35:56Once you get to 130. The sprint trial would even say 120. 120, yes. And the blood pressure itself, so getting that blood flow to the brain, blood brain barrier specifically is so important. When you don't have, when that blood flow doesn't basically isn't able to get to the blood brain barrier well enough, those tiny little vessels start to like just fall off. And it's one of the reasons why exercise also is so, so important. There's been a variety of studies that have looked, as you mentioned, the observational data is never a to establish causation. But it's still an interesting point to look at in combination with many other types of data.

36:34Especially when it's always in the same direction. Exactly. So it differentiates the epidemiology around, for example, exercise and blood pressure from the epidemiology around nutrition. The epidemiology around nutrition, A, it has very low hazard ratios and it's always changing the direction it's moving in suggesting that whatever's being studied probably doesn't matter. Yet when you look at the epidemiology of smoking, blood pressure, dyslipidemia, exercise, much bigger hazard ratios, virtually always pointing in the same direction. So it strikes me that the latter is signal, the former is noise.

37:06Good point. So you know, 50 % of people adults in the US have hypertension and about 20 % of adults, like we're talking people age 18 to 39 have hypertension. That's crazy, right? And actually the high blood pressure, it's the cumulative exposure to high blood pressure that's really damaging the vasculature. And so it's the younger people. It's the people that have it earlier in life that should be the most concern and are the least, right? There's the ones that are like, I'm young, you know, I can worry about it later. But yeah, so high blood pressure is associated with dementia risk particularly when you have it like before 50s, like when you get it in your before the 50s or mid -life, once you start to get high blood pressure in older age, like 70, 80, it's not as much associated with the Alzheimer's disease and dementia risk.

37:56It really does seem like cumulative exposure is the key factor there. Again, one of those things that is a lifestyle factor that's easily modifiable, exercise improves blood pressure, sauna improves blood pressure. those are two basically low hanging fruit lifestyle interventions. Some people do have gene polymorphisms where they're very sensitive to salt intake and sodium intake, and that combination of those people with a higher sodium intake really seems to skyrocket blood pressure. Nutrition, I think it's also looking at the combination of genes and diet. Most nutrition studies don't do that.

38:33There is an interaction going on, and I do think that's why some of the sodium intake blood pressure literature is just a little more, I would say. Yeah, it's all over the place. Complicated. I was on to ask you a question about exercise, but before I do that, I want to actually pick up on something you just said, how optimistic are you? I don't know, let's bracket this with, let's say in the next decade, that we will have more of a sense around what precision nutrition looks like as it pertains to genes and polymorphisms of them. In other words, people talk the talk, like, oh, I did this test and it told me I should be eating this that and the other thing.

39:09But the reality of it is there's nothing that's available today that's come close to offering that type of insight. A, do you believe that that type of insight is available? You used one example, which I would agree with you on, which is that there are probably different levels of genetics susceptibility to sodium that might suggest one person needs to be eating two grams a day of sodium and another person needs four grams a day. But do you think it will get further than that? And how likely do you think we will be to extract that information? I do think in 10 years we're going to know a lot more about precision nutrition, obviously precision medicine as well, because there's also an interaction between pharmacological treatments and genes as well as you know.

39:52In 10 years we're definitely going to be a lot further than we are now. The problem is, and this is always the problem, we've already alluded to it a few times, is the incentive for funding to study those things that aren't necessarily going to be super profitable. The government, the NIH, there's a certain amount of funding that you can get from them. And they often like to study one sort of thing, like the nutrition when there's like multiple things involved. It's like, they're just like too complicated. And so there's a lot of funding from Pharma industry, for example, and then they put in lots of money because they are incentivized to do that when it's a drop.

40:29That's my one concern with, I would say, gene diet interaction when it's more on nutrition. But there are people that are, it's a growing field of research for sure. And I do think with technology is advancing too. I mean, so at the point that our technology is advancing with AI and stuff, I think that we're going to start to see an exponential there, honestly. I am optimistic that in 10 years, that it's going to be a lot easier to elineate what a person should be based off of the genetic makeup versus just what generally we think. And do you think that that will be at the level of macronutrients or micronutrients?

41:08Like how much heterogeneity do you think there is among people as it pertains to factors like that? I think both. There are differences in the response to macronutrient intake and the response to micronutrient intake. and there are people, there's vitamin D polymorphisms, right? Where people, for whatever reason. So maybe they evolved in a place where there was so much sun or something. Like, I don't know what the cause is, but like some people, they have to supplement with high doses of omega -3 to be able to convert the... A vitamin D. Curse, or to actual the hormone, right? The steroid hormone.

41:44That's just one example. There's selenium, there's magnesium, there's a lot of different micronutrients that are off. And there's omega -3. There's a mega three as well. And B vitamins. Exactly, there's B vitamins. Yeah, more people are looking into it and with advancement in technology, things will become cheaper and easier to do. And that's going to create an exponential in my opinion where it's like, okay, maybe in a couple of years, we'll start to really see an explosion and then after that explosion, exponential happens where people are building off of that because that's how it works. That's kind of where I think it's going.

42:16And I'm excited about it. I think that's where it needs to head. I think it's going to clear up, as you mentioned, all the conflicting data with nutrition. I mean, nutrition studies are a mess, designing the right trial. I mean, part of the reason for that is because we have, if all these genes, and we want to drug with the exception of, yes, there's the CYP enzymes and stuff that help us metabolize xenobiotics, things that are not a vitamin or a mineral or essential amino acid or fatty acid, right? So, it's foreign to our body. But by and large, when you give someone a drug, they're starting with zero levels of that drug in their body and you give them the dose that you're giving them, it's like clear you're giving them a dose and it's going to be different than people getting a placebo, right?

42:55It's going from zero to something. Whereas when you do this nutrition study, a micronutrient, you know, you give them a vitamin or a mineral, nobody's starting with zero for one. Your placebo group could have high levels of that. And unless you measure something, you'll never know. And all the trials are sort of, they're trying to mimic that gold standard of a randomized controlled trial with a pharmacological drug. You have to put in so much more effort with nutrition with the drug. You don't have to start doing blood samples of this and that and let me measure the drug and make sure people aren't deficient in that drug.

43:23Of course, they're deficient in drug before they start the trial. They don't know it's like a drug. It's such a good point, Rhonda, and I'm going to use two examples to highlight why this is so important because it ties to two things we've been talking about. If you look at how a blood pressure trial is done, it is exactly what you say. It's titrated, meaning it's done the way a pharma trial is normally not done. So a blood pressure trial says, let's just bring in a whole bunch of people with high blood pressure. Okay. You guys on the placebo or on the low treatment arm, we're going to manage you to a blood pressure of 140 over 90, but no lower.

43:59You guys in the treatment arm, we're going to manage you to 120 over 80 or better. And by the way, we're managing to the outcome, not the drug. So I'm agnostic as to whether this person needs a higher dose or a lesser dose. We're checking the outcome here. And so if we did a vitamin D trial that way, it would be a very different trial. And one of my biggest criticisms of vitamin D trials and why I think we don't have an answer as to whether supplemental vitamin D is valuable is they don't do this. Take the people, you divide them into two groups, you give one group of placebo, you give one group, usually a very low dose somewhere between two to four thousand IU daily, but we don't actually know what the level goes to.

44:41In other words, a better vitamin D trial would be we take a bunch of people whose vitamin D is below 30. In one group, we give a placebo and in another group, we give whatever it takes to get them to I'm making this up, but 80. Then we would see is there a difference between this group that's below 30 and this group that gets to 80, regardless of the dose it took to get them there, because of course, that may include part of the problem. So I think your point is an excellent one, and I think it's something that listeners need to be aware of when they're scrutinizing trials of this nature, which is a negative trial doesn't mean the thing doesn't work if the trial wasn't designed correctly.

45:19Right. And it often, it's a matter of money, too, right? To measure all those things, it's cheaper to just give someone the vitamin D supplement and then look at the outcome and go, oh, it didn't work. And then you have another confusing piece of literature out there that people are like, oh, but says that vitamin D supplements do nothing. Yeah, it's a big problem. And I do, again, I think as our technologies are advancing that that's gonna become less of a problem as well. At least I hope, I mean, I guess you never know. So I want to go back to something you talked about earlier, which is you just touched on exercise.

45:53And I want to kind of visit now the suite of things that exercise does because people who listen to this podcast know if there's one thing I just can't stop talking about its exercise. But I think there's a reason for that, right? It's not just that I love exercise. It's that the evidence is overwhelming that a person who exercises, especially at the right amount, we're talking not just 30 minutes a week type thing. But if you're really doing the work, you're having a greater impact on the reduction of risk of Alzheimer's disease, then any other intervention you can take. Now, there are lots of interventions that matter, sleep matters, nutrition as we talk to about type 2 diabetes, all these things matter.

46:28But the risk reduction that comes from exercise is enormous. What do you think are the mechanisms by which that is happening? Because I suspect there's many. Oh, definitely many mechanisms happening. And I would, first of all, 100 % agree with you. Like, there's nothing better than exercise. Of course, any exercise is better than none. But for me, because as I mentioned at the start of this podcast, I'm very focused on neurodegenerative disease. I specifically sort of designed my workout routine based off of what I think are going to give me the biggest brain benefits. And what I've sort of come to the conclusion of is that intensity does make a difference with respect to the neurobiological effects.

47:15exercise intensity. There are some mechanistic reasons for that, but just talking about what's moderate intensity exercise, what's considered vigorous intensity exercise. If you look at some of the recommendations out there by the committees, there's a team of scientists, physicians that sort of analyze all this data and then make these health recommendations based off of that data. It's 150 to 300 minutes of moderate intensity exercise, which I think they define as like 50 to 70 % of maximum heart rate. Vigorous intensity, they say 75 minutes, I guess, a week, and that would be more of you're getting above the like 75 to 85 % max heart rate.

48:00So that's what they, I think, define as something like that, And they have a variety of examples. You know, there's the World Health Organization. There's a variety of committees that come to that same conclusion. For me, I like to go higher intensity. This is something I kind of was looking forward to talking to you about because it has to do with how do you measure the estimated heart rate, which is what I do. I've estimated. And again, all sorts of problems with that based on your physical fitness. Meaning estimating your maximum heart rate to take a person's event. So basically, the more fit you are, you could be doing a more vigorous intensity exercise, but your heart rate doesn't go as high as someone who's not fit.

48:39And then people that are older, so there's, of course, I would say problems with that, but generally speaking, that's one way, but I'm also very interested in lactate, and I know you are as well. For me, I actually want to get my lactate levels high. And the reason for that is the neurobiological benefits. So lactate, as you know, was once thought to be this sort of endometabolic byproduct. It was like useless. Well, not only just useless, actually, it's not to be harmful. At least to performance. Right. Harmful to performance with respect to people thought it was like causing their muscle soreness.

49:16As you know now that it's not lactate, it's the proton buildup. Lactate is sort of in homie states, it's the phlactic acid and it's the protons that were sort of responsible for that. And neither of them are responsible for the soreness you feel the next day. That's the matter of trauma, of course. Like the soreness and the burn from the hydrogen ion is gone, minutes after you stop exercising. Yeah, exactly. So the lactate that gets into, so you're generating lactate when you basically are pushing your mitochondria inside your muscle cells to a point beyond where they can generate enough energy in the form of ATP, adenosine triphosphate, then they sort of have to figure out another way, like your cell has to figure out another way to get the energy, right?

50:01So this is where glycolysis comes into play. So this is happening outside of the mitochondria. And I'm sure your listeners have heard all this before, but for those that haven't, the lactate generation is then from that, you know, metabolism of glucose outside of the mitochondria. And that's happening when, again, you reach that threshold of you're pushing your muscle cells hard enough and there might a congeurate can't keep up with producing enough energy. So the lactated itself, and these studies date back to like the 70s, it's been shown that lactate that gets into circulation and it's used by other organs as energy source for one, as a fuel.

50:39Yeah, and the brain being a big one. And this is now decades of research, but Dr. George Brooks has, you know, he was like one of the first to propose this lactate shuttle theory, and he's, of course, provided evidence for that as many others have as well, where, you know, during exercise and after exercise, the lactate that is generated from muscles that gets into circulation is consumed by the brain. This has been shown in humans and animal studies, of course, but it's consumed by the brain. And also, not only is it consumed, it's acting as a signaling molecule, and increasing At the blood brain barrier, lactated self has been shown to be responsible for the production what's called veg F.

51:23It's a vascular endothelial growth factor, veg F. And what it's doing at the blood brain barrier is it is growing new vessels and repairing damaged ones. So it brings it back to what we were just talking about, right? The damage, the vascular damage at the blood brain barrier. Lactated self is a signal to increase that veg F. It also increases brain -driven or atrophic factor, BDNF, at the brain, at the blood -brain barrier, and in the brain as well. Where is BDNF produced? Many places. It's produced in capillaries and the vascular system in the heart and muscle is produced in the brain. So exercise increases brain -driven or atrophic factor in many different parts of the body in many different organs and tissues.

52:07And it's really interesting because there's some evidence that the sheer force of blood flow, so essentially like the more vigorous you're exercising, your heart's pumping, right? And your blood is just going faster. It's moving faster. Well, that sheer force on the actual endothelial cells lining the blood vessels is a signal to increase BDNF as well. Super interesting stuff there. It also increases BDNF in muscle, which plays a role in repairing damage muscle. It increases in plasma. Brain drive neurotrophic factor, although there's a little controversy about this. It can cross the blood brain barrier, and it also is produced in the brain as well.

52:49So all of those things. Brain drive neurotrophic factor is really important for many reasons. It's important for long -term tension, it's important for neuroplasticity. So long -term potentiation is basically strengthening the connections of the synapses that are connecting neurons. It's involved in basically long -term memory retention, but also it's important for neuroplasticity. So brain drive neurotrophic factor plays a really important role in that, and that is also something that decreases with age. I think a really easy way to think about it is your brain's like ability to reshape and restructure with the changing environment.

53:23Like as you're aging, things are changing in the brain, and like you have to be able to respond to that. brain responds in a plastic way and that happens very well when we're younger, not so well when we're older, not so well in certain disease states like depression, neurodegenerative disease. And so that brain -drobinerotropic factor plays an important role in that. But I am going for a higher lactate. And based off of your recommendation, I got the lactate meter, the Nova, the one that you have. And I've been using that to kind of try to get my lactate higher than typically what I think you are doing with a completely different type of training.

53:57We do kind of both ends, right? So on the one end of the spectrum, what we want to do is increase our mitochondrial capacity to maximize aerobic metabolism. And there are two ways to do that. Meaning you have to do two things. So the way I described this to people is the way one of my coaches described it to me when I was a fledgling cyclist. Your aerobic capacity is a pyramid. And the area of that pyramid is your total aerobic capacity. And to have the largest area of a pyramid, you need the widest base and the highest peak. A pyramid with a narrow base and a high peak? Yeah, not as good. A pyramid with a very wide base and a shallow peak, also not great.

54:42You want wide base high peak. Well, in that analogy, the base is your zone two threshold. It's how much work can you do while keeping lactate at that sort of threshold that George Brooks and Enigo San Melon talk about of about two millimole. So what differentiates the best aerobic athletes from someone, you know, say with type two diabetes, which would be the opposite into that spectrum where you have real metabolic dysfunction or rather mitochondrial dysfunction, we're talking a four -fold difference in watts per kilo output. And you just have to train at that level. You have to get to that threshold and train right there.

55:20So this morning, that was the workout I did, right? Was it zone two ride, where I'm just riding right at a lactate level of 1 .9 mm was where I was today. But you do need to do what you're describing as well. You have to do the pyramid building. You have to build the peak of that pyramid. Those are the VO2 max sets. And, you know, generally the sweet spot for building those is three to eight minutes of all -out effort for the respective duration. So obviously what you can do for three minutes and no more is harder than what you might be able to do for eight minutes and no more. My favorite are four minutes.

55:57So for example on Sunday, that was my workout. It was I actually did an hour of that zone two, you know, kind of two -millimole stuff and then did four -minute awful repeats where it was like much, much higher power for four minutes and then I rested for four minutes and then went again for four minutes and then rested for four minutes. And at the end of those four minute blocks, you know, my lactate will be 15 or 16. Oh, wow. And then at the end of a four minute rest, it might be down to six or seven. And then we do it again and do it again and do it again. Yeah, long winded way of saying you want both.

56:33You want to build that pyramid to be as wide and as tall as possible. What I don't think I appreciated though was that the brain is getting a benefit from those lactate peaks. Yes, it's getting a benefit and, you know, it's cleared quite quickly. I mean, it's minute. It's minute. If you do nothing, it's, if you just stopped. And of course, athletes are even better at this, right? An amazing athlete would clear lactate within, they'd go from 10 millimole to 2 millimole in minutes. It's for me, you know, 20 minutes later, I'm back to my 0 .9 mm baseline. That lactate also is important for neurotransmitters synthesis.

57:12You're making glutamate, the major excitatory neurotransmitter in the brain. It's important for making precursors to that, nor up and naffron. I mean, these are all been shown in human studies, also animal studies. So for me, I do a lot of tibata training. So that's even more intense because you're only doing 20 seconds on and 10 seconds off. So that's really intense. It is and I do 16 of those. So I do, you know, like eight and then separate it by like a 30 second break and then I do another eight. So two four minute blocks? It's a total of about 10 minutes. So the first minute I mean like zone two and then by like the end of that minute I'm like zone three and then I go into zone four.

57:51What are you doing this on? Are you doing this on an air bike or? I'm doing it on a peloton, right? And my Apple Watch is beaming my heart rate and my zones on to my screen. with they're all estimated of course again. But I do that five days a week. It's for me the efficiency also. So I'm trying to maximize the neurobiological effects for me with exercise and I really find pretty compelling evidence that intensity is really important with respect to that for the brain. Not that there isn't a benefit for lower intensity exercise. Certainly people doing you know, moderate intensity, like the more time you put in, the volume of training is like, you're going to probably find some equivalent there.

58:32But with the lactate, though, that's the one mechanism. I'm like, that is really something I personally am trying to optimize for. It's definitely a consequence of intensity. And the fact that it's cleared so quickly and it's transient, like I'm wanting a lot of it like each day. I'm wanting to keep doing it. There are other ways to do it that you might want to consider, right? So you might want to say, look, I'll do those tobadas two days a week. I'll do some longer slower cardio. And to be clear, like when I'm doing that zone two, it's not trivial. Like I mean, my heart rate still 140 when I'm doing that zone two.

59:06But what you could do is use blood flow restriction when you're lifting weights on the other days. And that will get your lactate through the roof. So four days a week, you know, I'll do blood flow restriction at the end of every workout. So two days will be upper body, two days will be lower body. And especially on a lower body day. So you've got these huge cuffs at the upper part of your thighs. And I'll do leg presses, leg extension, leg curl, and finish up on an air bike. And by the time you take those cuffs off, all that lactate that's been pooling in your legs for 10 minutes will flush through systemically and your systemic lactate level surges.

59:44What do your levels get to? What do your lactate levels have after? Oh, I mean, not as high as I would get on an all -out sprint. I mean, or 19, but I can still hit the mid teens doing blood flow restriction. That's incredibly high. You know, it's funny. When I used to coach athletes, I worked with an Olympic swimmer who could get to 26 and still be conscious. I mean, I say that sort of half jokingly, not that too much lactate would render you unconscious, but the pain that you must be in when your lactate is 26 is comical to me. He could finish a swim race, something like a 400 individual medley, which is probably the highest lactate generating race There is because it's all out upper body lower body assault have a lactate of 26 to 24 to 26mm Amol and Four minutes later jump in the pool again and do a race and enter the pool with a lactate of maybe six.

1:00:37It's pretty amazing That's amazing. So my point is like you could diversify the training a little bit because again You'd still get that lactate hit but you'd also be diversifying the training because I do think performance, it's hard to make the performance gains if you're really doing an all -out tabata five days a week. I think that is hard. What kind of performance gains are you talking about? Within the tabata itself. In other words, it's hard to make gains on the power output that you want to be generating because that's when you're doing 20 on 10 off, you're trying to get as much power as you can in those 20 seconds.

1:01:11Those are what we call match burning workouts. Like you're burning all the matches that day. Yeah. I'll tell you something that's interesting. I started, I don't, have you ever tried doing an aerobic or high intensity workout with a mouth tape where you're just breathing through your nose? Mm -hmm. So I started. I mean, you're limited, of course. I mean, at some point you're not going to get to your, you're going to be limited by, for me at least, I can't do my all out best without mouth breathing at the end. Once I reach 215 to 220 watts, I can't sustain maybe 225 watts. I need to start breathing through my mouth.

1:01:50I need to at least every other breath use my mouth. I would expect everybody sort of different there. People are different. I mean, different nasal, I mean, like different sinuses and shapes of your nose and everything. I just recently started doing it. It was kind of odd because I actually, maybe I'm not going... I PR'd the first time I did it. And, you know, like I wasn't going as hard on my all -out, but I think on my rests, I was going harder on my 10 seconds off. I was like not really bringing my resistance down. Have you tried doing it where you do nothing on the off, a pure off? What do you mean, just like keep going?

1:02:27Yeah, don't spin whatsoever. So do the 20 seconds all out, and then the 10 seconds you're not spinning at all. Oh, I've never tried that. Well, I've never tried that. Well, I think the goal is to make the hard as hard as possible. And so being truly off for 10 seconds will make it more likely that you can deliver the maximum wattage during the 20 seconds. Okay. I've been trying to do the opposite where I'm like, okay, on my off, I like keep, you know, zone three, I like still putting in quite a bit of power, right? That's good too. We used to call that sweet spot workouts where you would go zone three zone five, zone three zone five, zone three zone five.

1:03:04But what you really probably want to be doing in a tabata is zone six, zone one, six, one, six, one. What's zone six? It depends on the system. It depends on the system. Yeah, yeah. I mean, so technically, the literature on this would suggest that we are only able to hold full maximal effort for 10 seconds. Anything we do that's longer than 10 seconds, we are applying some governor to the system. So at 20 seconds, even if you don't realize it, you're somewhat pacing yourself, even if you're trying to go... I'm not doing maximal. I am not, for sure. Like, my husband seems like he really gets to that all -out, but I'm not.

1:03:42For sure. I'm definitely not maximal at my 20 seconds. No way. That makes sense, because I don't think one could do that five days a week. I think you would fry yourself. You know, it's also really interesting, Peter, is that though, by like the fourth or fifth day, I'll be PR -ing, so I'm always competing against myself. And my last take will be lower. By wattage? Oh, the Peloton. No, no. I'm not nearly as scientific as you. Okay, so what, the Peloton ranks you based off of, but isn't it based on kilojoules or watts? Isn't it based on average wattage? But I don't know all those off -top of hell like you're writing everything down.

1:04:16I'm not doing that. But my last take, but that doesn't surprise me, Rhonda, because the way to get maximum wattage is to hold your highest constant maximum wattage and go. So zone four held indefinitely will produce a much higher average wattage than zone three alternating with five or six alternating with one. So yes, if your metric of success is what is my total average wattage over the course of this workout, it will not be a tabata. It will be a steady state all I can, you know, that's actually what's called FTP functional threshold power, which is what technically the peloton is using to estimate your zones.

1:04:49Have you ever done the FTP test on the peloton? No. That's actually probably worth doing. Okay. So if you go into the Peloton, there's something called, I think it's called Fitness Test. And it's going to have you do either, you get to pick two, eight minute all -outs separated by some rest. I forget how much. Or one 20 minute all -out. I prefer the 20 minute all -out. I think it's a better test. It will take your average wattage over 20 minutes. It will multiply it by 0 .9. And it will say that is your functional threshold power, which is defined as the maximum power you can hold for one hour.

1:05:25And in cycling, and Peloton uses this system, that is the metric by which the zones are set. So zones 1 through 7 are a function of power, not heart rate. And they are all a function of that FTP number. Now again, none of that's necessary for Tabata. Tabata didn't rely on knowing those zones. It wasn't about titrating to a given heart rate. It was simply a question of, go as hard as you humanly can for 10 seconds, and then do nothing for 10 and do that eight times. So yeah, I'm definitely using a different, slightly different protocol where you're doing a workout where you're going much harder during the rest and then not as hard during the workout because you wouldn't be able to.

1:06:08Right. I'm definitely not doing it the way I guess. And how higher your lactates and you check your lactate at the end of the both sessions after the two rounds. It's all like what continuous thing. Like it's, you get like a 30 -second rest period between the two eight sessions, but like, I'm, again, I'm not resting. Yeah, you're going hard. I'm going, I'm like probably zone three. Yeah, the end of that. Now, my lactate doesn't get nearly as high as yours. I'm typically like around seven to eight, millimolar. So that could give you an idea of, you know, I'm what I call a committed exerciseer. I'm not an athlete as I would consider you are.

1:06:45It's actually quite different. The best athletes in the world, like world class. So both Michael Phelps and Lance Armstrong, you could argue to the greatest, both actually put out relatively low lactate levels. So you don't know. You might be one of those people who's so efficient that you don't actually make much lactate. Like I don't think Michael Phelps is probably even when smashing world records probably ever seen a lactate above 10. Yeah, but I'm definitely not one of those guys. Well, it would be interesting to differentiate for sure. I mean, for example, so when you are doing at least a high intensity interval type of training, which I would say that this, would you agree this type of training definitely would fall into that?

1:07:26And of course, people generalize this term and stuff, but that's a whole other issue. But you are sort of forcing adaptations on your mitochondria to make more mitochondria. your body's like, oh, I no longer can use my mitochondria to make energy. I got to rely on this other process, glycolysis. So as an adaptation to that, you increase mitochondrial biogenesis. And that's been shown now in several studies and human studies. You can increase mitochondrial biogenesis now. Also, aerobic training does that as well. But you can get there with it. It's really a question of time. It sort of comes down to what you were saying earlier.

1:07:59So if somebody says to me, I've only got 10 minutes a day to devote to aerobic training. what does it need to be? Well, the answer is clearly it needs to be the type of training that we're talking about here. Now, if someone says to me, I don't want the minimum effective dose, I want the maximum result. Then I'm going to say, well, would you be willing to give me 90 minutes a day? In which case, we could build you the biggest pyramid, basically. I need an hour a day to build you a mega pyramid. But some people don't have the time or desire or interest to do that, in which case, yeah, we would need to just get people to doing, well, I get asked this question all the time.

1:08:36I think in 10 minutes a day of cardio and probably 30 minutes a day, four times a week with strength, you can get amazing results, but you have to be laser focused and there's no messing around. I'm sure when you're done that 10 minute workout, there's no ambiguity about how hard you've worked. Not at all. And I feel amazing. It has to be very my strength training as well. And there's a lot of like paired sets and supersets. And so it's like non -stop training where I'm, it's definitely like I'm putting effort in, but it's not a long session either. I do try to do that. Like I'm probably putting in the minimum amount of strength training that I can personally do, which is like 40 to 50 minutes a week.

1:09:21I used to not do any. So like even that's like prock. We have some stuff we're gonna talk about at dinner here because I'm not trying to talk you into doing a little bit more. But I want to ask you, where do you put your sauna in relation to this? Do you dissociate in timing sauna from your exercise? Do you go right into the sauna after you work out? How do you incorporate that? It varies. I do both a regular with dry sauna. Actually, I don't use it as a dry sauna. I do a lot of steam as well. But I do that, but I also do hot tub. So I do a jacuzzi as well. and both of those forms of heat stress have been shown to increase heat shock proteins, which is sort of a biomarker of heat stress, and both of them also have been shown to increase brain -driven or atrophic factor as well.

1:10:06So heat, I think, also plays a role in that stress response. It depends on the day. So I often will, in the sauna, I like to read scientific papers or listen to podcasts like The Drive, or I'll listen to, like, if someone's on Tim Ferrississio, like, there's only a couple of podcasts that I ever listened to. Yours is one of them. So it's not like, that's like my time, or I'm like, there's no other time. If I'm in the car with my child, most of the time I'm listening to frozen music or whatever, you know, it's not. I'm not listening to the drive. So it depends on what I'm doing, but also I like to do hot tubs at night.

1:10:43So typically the sauna will be in the day. So I do my workout in the morning. I'll have the sauna warmed up and ready to go and I'll get right into the sauna after my workout and I either have a paper in hand or I'm going over a presentation or something. I find it's really interesting. I don't know if you've ever tried this or observed it, but this goes way back to my days as a graduate student when I first started using the sauna. I realized that if I would go over a talk that I was gonna give like a departmental meeting or whatever, you know, I was giving a talk, if I went over it and thought about what I was gonna say in the sauna, man, did I remember it better?

1:11:19Like, it was like very clear that there was something going on with my memory. And I mean, it very, very consistent. Of course, you know me, I like was diving into the literature. I'm like, there's got to be something to explain this. And, you know, low and behold, there's certain growth factors that you make that in the sauna with heat stress that do affect, like, memory, so plausible hypothesis there. But anyways, so if I have something going on, like a podcast or a presentation. What's your protocol? What's your temperature and duration in the sauna? It depends on how hard I went on my workout too, or if I'm doing it right after the workout, or if I'm midday, just like, I'm going to take a break from what I'm doing at my computer, and I'm going to go read a science paper in the sauna.

1:12:03It really all depends. Generally speaking, if I go in right after I'm doing my Tabata session, I probably stay in about 20 to 25 minutes, and my temperature is like 175 degree Fahrenheit. If I am not going in right after a training session, then I'll stay in longer. I'll stay in probably a little bit longer than 30 minutes. I'm pretty adapted to. And my temperature will be 175, 180 sometimes. I also do the humidity, which makes it hotter, feel hotter as well. So I guess anywhere between 20 to 30 minutes and my temperature is anywhere between 175 to 180. I used to do really, really hot about like 190, like I was doing 190 and I was getting headaches more, easier.

1:12:51I just didn't like it and I didn't feel good. How long did you sauna during your pregnancy? How far were you able to... I'm sure women ask you this all the time, I don't know that I have an answer for the question. So I first found out that I was pregnant when I was touring Finland and everyone was like, it was like sauna, right? It was like we were going tour, you can sauna. You're a sauna VIP. I was and I'm like holy crap. What am I going to do? I felt like at that early, early stage, I mean literally like I found out it was pregnant in Finland. I did do a lot of son or touring and stuff and all plunging and all that at that stage.

1:13:31But right after when I got on the plane, come back home, son was out. And the reason I sort of aired on the side of caution, I mean, you can, I talked to women in Finland and they were like, oh yeah, I saw it throughout pregnancy and you'll find those anecdotes, certainly in that culture. But there is a body of evidence, a mostly looking at like hot tub. It's common knowledge like pregnant women shouldn't get in the hot tub like you go to any spa like it's like known But there's a body of evidence that it can Something might increase the risk of sort of like a fetal alcohol syndrome Oh, well sort of thing in offspring even neural tube defects So I was concerned that going in the sauna Perhaps could increase the risk of something like that and so I decided that it just wasn't worth it And so I did not sauna at all throughout pregnancy.

1:14:26And I even waited a little bit while breastfeeding and stuff. I waited probably like six months or so before I really got back into soaring. Now all the while I was exercising throughout pregnancy and so many benefits to that. But kind of back to your question, the other protocol I do is at night. And it's interesting because doing the hot tub at night, we're in that hot tub, and it's kind of also the time that my husband and I get together away from our child. I mean, it's like our time. We're like out the stars, dark sky, like it's nice. And that is something that my husband likes to do it, like literally like he wants to do it every night because it helps his sleep so tremendously.

1:15:05I don't have as much of an issue with my latency or my sleep like in general, but he does. I'm asleep by 9 .30 and 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 minutes. He is not that way. And he likes the hot tub that really helps his sleep. So I end up doing that a lot as well. And sometimes I'll do both, I'll do the sauna and hot tub in the same day. It all depends. But exercise is the most important that I have to get. And I go for the vigorous type of exercise. There are studies looking at intensity with respect to dementia risk, cognitive impairment.

1:15:42You'll find all sorts of things. I think the most common thing that is pretty thematic is that the more effort you put in, the more time you put in, the bigger the benefit with respect to cognitive health. So dementia risk. And also it depends on how it's, I'll give you an example. There was a longitudinal study where women, who women by the way, as you know, are, I think, proxamely out of two -fold higher risk for Alzheimer's disease. That's right. Super interesting. But so this was in women and they were studied for decades and I think it was like starting from like the 70s up until like 2010 or something.

1:16:20And they came in for a physical like put on a bike, exercise bike and their like fitness was measured was like empirical data. And this was like I don't know five to seven times. So like over the course of 40 years or something. Yeah, exactly. Something like that. And the women that were the most fit by their measurements on this cycle test they did. Yeah, it's probably VO2 max. Yeah, so it's cardiovascular treatment. Those women that were the most fit, the reduction in Alzheimer's risk was like so robust. I think there was something like there were nine times less likely to get or something crazy like that.

1:16:56The ones that were moderate, like so they had like a moderate cardiovascular treatment, they had a four or five full reduction. but then you'll like look at another perspective study. Same deal with, they don't come in to getting anything measured, but they come in for a questionnaire. They get a questionnaire every, whatever it was over the course of like 40 or 50 years or something. So they answer all these questions like, oh, how often do you jog or bike or do you play tennis or whatever? And you look at that study and there's like no association between physical activity and dementia risk.

1:17:28And I'm like, hmm, that's interesting because this other study where they're actually measuring something showed a robust reduction in dementia risk. It hits home this like, okay, what study are we looking at? You'll find questionnaire studies that also show, you know, a benefit like people that are physically fit and the more fit they are, there's like a linear dose response effect where you see, you know, people that put in more effort, they're training for a longer period of time and they're more vigorous or more volume both, right? They have the greatest benefit with respect to dementia risk, which isn't so surprising to The studies that are unambiguous, as you said, are the ones that actually measure VO2 max.

1:18:05Because there's no denying what you're measuring. It's a very objective measurement, and it basically takes out the training component, because it captures that benefit. It's the readout state of the training. And it basically says, look, maybe it doesn't matter if you do five high intensity workouts out so weak or too high intensity, five low intensity. Like, what matters maybe more is the output. I don't know if that's the case, but there's no denying that people who have a high VO2 max are doing something that people who have a low VO2 max are not. And that's what's being captured in those studies.

1:18:45And the numbers are astronomical. I won't go into them again. People in this podcast have heard it too many times because I can't stop talking about the benefits of having a high VO2 max. But I won't touch on something else. you just set a second ago, which is you noted that women are indeed at twice the risk of Alzheimer's disease to men. Of course, Parkinson's flips that men are at higher risk, but focusing on Alzheimer's disease for a second, is there any evidence that there are gender differences in response to exercise? In other words, are women more responsive to the benefits or more higher risk genetically?

1:19:25I haven't seen the studies looking at the response to exercise with respect to, you know, the sex differences, but as you mentioned, like there's definitely differences with respect to their Alzheimer's disease risk. There are different mechanisms that could... So women have different, like there's different metabolic responses to exercise maybe, also hormonally different. This would make sense, right? I don't know that this has all been studied. I haven't seen that data, but hormonally different responses to exercise that would be plausible immune system effects as well. Exercise is affecting the immune system.

1:20:04So we haven't even talked about myocines. These are molecules being secreted by our muscles. We talked about lactate. That's not a myocine. That's a metabolite. But physical activity, when we force our muscles to work hard, we're making something called a myocine. Sometimes it's referred to as an extra -kind, but like this is irisin is one isle six is another. There's other ones as well, but like these are also affecting the brain and they're affecting cancer risk. There may be differences in respect to like myokines that are being secreted with respect to how the stress of exercise, how that response is happening.

1:20:38There's also something. Let's talk about cancer because Rhonda, while I think both of us are, I think there are others who share this point of view, completely convinced. In fact, I just don't see how one could not be at this point convinced of the benefit that exercise poses to the brain. It seems much harder to make the case for cancer. In fact, when you think about some of the things that are such obvious problems with respect to dementia, for example, disrupted sleep, poor exercise, etc., clear relationship, very hard at least for me to make the case that bad sleep is related to cancer. Although I think it is, but the data aren't clear.

1:21:22You can certainly make the case that horrible sleep would lead to a weakened immune system, a weakened immune system, especially the cellular system, more than the humoral system, would easily lead to an increase in not necessarily cancer initiation, but cancer propagation. But again, the data are so much less obvious. Let's talk about this relationship between exercise and cancer, right? On the surface, it should make sense. Exercise is good. Cancer is bad. More exercise should mean less cancer. How compelling are the data? And I'll admit that I haven't gone as deep here as I have on cardiovascular disease and neurodegenerative disease.

1:21:59So it's also another area that I'm very, very interested in. I mean, as you start to get into your fourth decade of life, you've now had a friend or a family member that has come down with cancer and you see, I mean, you're a physician, so of course you've experienced it on a different level, but like you just see how terrible it is to get cancer. And really, the best best hope is obviously to try to not get it, to prevent. And there are, as you mentioned, there are things that can modulate that risk that are a little genetic wise that are harder to kind of move the needle, but overall, so with respect to cancer incidents, it's interesting if you look at like you were talking about some of these elite athletes, people winning the Tour de France and people that are Olympic medalists or maybe that would even just enter the Olympics.

1:22:48I mean, you have to be quite an athlete to just get into the Olympics. And there's been a lot of interesting studies, quite a few, that I have seen. These are studies where observational data, again, obviously caveated with that. You're looking at people that have just entered the Olympics over the course of like from 1912 to 2010 or something like that, like just decades. And looked at all cosmotality, cancer -related mortality and compared it to like the general population. So there's a couple of studies that have come out of the US. And if you look at both of those studies, one of them was actually looking at medalists and the other one was just looking at people that like entered the Olympics.

1:23:23They saved about one and a half to two years of life from not getting cancer. They had a five to six year, what you could call life span extension compared to the general population Same with like French Olympians as well very similar where it was like they lived on average five years longer than the general population It was attributed that they had basically saved two years of life from not getting and dying from cancer I guess I should say dying from cancer because they are two different things But that would be like at the elite level and it's interesting because you go well two years like that's it And that's how I see it.

1:23:56I'm like, really? Like, two years. And it's funny because I remember when I was a postdoc, my postdoctoral mentor, Bruce Ames, he had said to me once, or actually more than once, you know, I once read, you know, there's all the things that you can do, like if you prevent cancer, you're really only saved about two years of your life. And I always thought I'm like, no way, no way. But anyways, so that would be like at the extreme moment when you're looking at the actual athletes that are definitely less likely to die from cancer than general population people. But when you're talking about prevention, so there's a difference between, if you read a study and it says, people that are physically active are X percent less likely to die from cancer like, so cancer mortality is decreased.

1:24:40That's not necessarily the same thing as not getting cancer, right? That just means you're not dying from cancer. So the study is looking at cancer prevention really seem to focus on a specific type of exercise, and that is aerobic exercise. For whatever reason, there's not a lot of literature on strength training and cancer prevention. You can find studies on strength training and cancer -related mortality, but with prevention, it's sort of focused on for whatever reason on aerobic exercise. And it does seem like there are certain types of cancer that are more responsive to exercise with respect to having a reduced risk.

1:25:22And some of those cancers are ones that we should care about. So breast cancer, what's the lifetime risk of breast cancer? For a woman, it's about one in eight. Pretty high for the average woman. Of course, many different lifestyle factors play into that and exercise is one of those factors. colon cancers, another one that seems to be quite responsive. Lifetime risk of colon cancer for average woman is like one in 23 for a man, it's like one in 25 or something like that. The reason I'm mentioning, as you know, Peter, if you're talking about like esophageal cancer, some cancer where it's like one in 500, I mean, you're more likely to die in a car rack than get, you know, one of those cancer, I think it was a soft, but you get my point where the lifetime risk is already kind of quite low for the general person or the average person.

1:26:08So breast cancer colon cancer, there's a few other cancer types that are quite responsive, but those two in particular kind of stand up because with prevention, with respect to people that are diagnosed with cancer and have those cancers and then they engage in physical activity as well. Like you see a very robust response with respect to reducing cancer mortality and also recurrence. You know, it's like 50 percent. You know, cancer mortality is reduced by 50 percent. Cancer recurrence is reduced by 50 percent in those individuals diagnosed with breast or colon cancer, or colorectal cancer, that are engaging in more physical activity.

1:26:41So the question is, well, how much? And you mentioned like you have a lot more knowledge with respect to cardiovascular disease and I would argue the data really, I would say, suggests that you actually probably need to do more exercise to sort of reap the cancer preventative benefits than you do cardiovascular benefits, even some of the metabolic benefits. But I don't know why that is. It seems as though getting more to that upper limit of what these committees are recommending. So 300 minutes a week of moderate intensity exercise, or maybe 150 minutes more of what they would define as vigorous, which actually I think their vigorous is a little bit below what my definition would be.

1:27:25So it seems like the amount of exercise you actually have to put in a little bit more time and effort for the cancer. But any amount is beneficial. So it's not like, oh, well, I can't do 300 minutes, therefore I shouldn't even care. Well, that's not true because there are benefits even with like any type of physical activity. That's all the observational data. And you can find anywhere between a 10 to 20 % reduction in people are that they're less likely to get breast or colorectal cancer, 10 to 20%. Again, when you're talking about a type of cancer with a higher lifetime risk, it's more compelling.

1:27:59So it's always kind of... I'd be curious to see if the data line up with the cancers that are known to increase in risk due to obesity. So right after smoking, obesity is obviously the second leading modifiable risk factor associated with cancer. I've always thought that was an oversimplification because we use obesity as a proxy, but I think it's probably insulin resistance. That's the true marker that obesity is serving as a poor man's version of. It would be interesting to see, because there are certain cancers, including breast and colorectal, by the way, where obesity amplifies risk. There are other cancers where obesity doesn't seem to play as much of a role.

1:28:39It would be very interesting to align the exercise data with the obesity, slash insulin resistance data and see if exercise is disproportionately reducing risk in those cancers for which obesity is a risk. That's such a good point, Peter. I think there is at least some data to suggest that you are correct with that. What is your 13 or so cancer types that obesity is known to... See, their 13 or 17, something like that. And breast and whole erectile cancer are on that list. Aerobic exercise, I think there's direct mechanism. Aerobic exercise is directly you're making those myokines. in like, you know, some of these myocons have been shown to decrease the production of like growth factors to create different cancer cells.

1:29:27And they're like, they also like are killing cancer cells through a variety of other mechanisms. Also, the anti -inflammatory effect from exercise as well. You're having a strong anti -inflammatory response. But there is a little bit of that. Okay, well, exercise is also improving insulin sensitivity, particularly in combination with dietary strategies, the weight loss itself is basically an important component of the cancer, reduced cancer risk. I think it's a combination of these things where it's like the direct effects from exercise and it's really interesting because as I mentioned, people that even have cancer, it seems like physical activity, like I am not a non -collegist and you know many more oncologists than I do.

1:30:11I don't know how common it is for oncologists to prescribe exercise as an adjunct treatment to whatever type of treatment, whether it's immunotherapy or radiation or chemotherapy or a combination, whatever. I don't know how common it is, but the data is more and more compelling and I think it's become more and more compelling over the years that really exercising, it seems to be very important for reducing cancer metastasis and also dramatically decreasing cancer recurrence. And so a really interesting mechanism by which this is likely occurring is literally through that sheer force mechanism I was describing for the brain.

1:30:54As you know, cancer cells, tumor cells sort of escape the site of the tumor and they make their way into circulation. It's called a circulating tumor cell or circulating cancer cell depending on the study you read. The circulating tumor cells are like traveling throughout the vasco system to disinsights and they sort of take camp and then like it's like kind of the seed of a new tumor forming in another tissue. Well it's really interesting because cancer cells are so messed up as you know like they're just completely wonky and very very sensitive to stress, any type of stress. They have these mechanoreceptors on their cell surface that are responsive to force, sheer force.

1:31:34So when you get your blood pumping, it's like a hurricane that like wipes it out. They die because they can't stand just the sheer force of the blood flow through the vascular system. So you compare the mechanistic studies. And there have been some studies looking at circulating cancer cells and it's like people with those are like three times more likely to have cancer metastasis and so on. But again, there are studies showing that physical activity dramatically decreases. And there's been randomized trials showing it dramatically decreases circulating cancer themselves and people compared to whatever their other standard treatment that they're being given.

1:32:11Pairing that data with looking at other data where exercise is being prescribed to patients, and it is beneficial with respect to their cancer metastasis reduction and also mortality reduction, you know, 50 % mortality reduction versus recurrence as well. So I do think there is substantial evidence to suggest that being physically active is a good measure for cancer prevention. And again, there's also a lot of differences. There are sex differences as well. Like, I don't know why, but in some cases women respond better. And there's certain cancer types that respond better. Lots of variables here, like I feel like I'm speaking in a general way, but there are lots of things to consider, right?

1:32:58There are cancer types and there are sex effects and And there are, as you mentioned, other covariates. There are obesity and there's insulin resistance, age as well. So there are lots of nuanced as usual. But I do think that you can make the case that like, what can I do in my life to reduce my risk of getting cancer, reduce my risk of dying from cancer, reduce my risk of getting Alzheimer's disease, reduce my risk of getting dementia, reduce my risk of getting cardiovascular disease, reduce my risk of type 2 diabetes. the only panacea there is exercise. It's exercise. It is the case. And unfortunately, it's the thing that you have to put the most effort in.

1:33:39It's certainly a lot easier to take a supplement, to take a pill. I do think there is an argument that omega -3 is one of the getting yourself to a good omega -3 status and defining what that is is still like being investigated. But I do think that's a low -hanging fruit that should not be ignored. But exercise, as you've talked about many of times is the king. That's the thing that you should focus on. If you, obviously, if you're obese, weight loss, exercise is part of that program. And I don't think that anyone that's obese should be worrying about all the other things. I think you need to lose weight.

1:34:11And any personal trainer and coach, probably is going to help you do that. You eat less. Calories and calories out, it matters to some degree. You're not eating as much. But as you said, exercise matters not just on the energy balance side, but exercise makes you, for example, more sensitive to satiety hormones. So I have kind of a belief here that the person who is overweight, the person who is obese, and who is clearly eating more than they should be, isn't doing that by choice. Maybe some are, but for the most part, it's hard for me to imagine there's someone who's listening to this, who's obese, who isn't wanting to not be obese, and who is otherwise struggling with hunger.

1:34:54And I think that that's one of the challenges is why is it that a person who is not in energy balance is not responding to the normal satiety signals? And I think there's a lot of reasons. On the food science side, we could talk about a whole bunch of reasons why our food has been hijacked, our food is void of nutrients, our food is hyper palatable. It's far too available. Like there's a whole bunch of reasons. But I think one thing that doesn't get enough attention is this thing, which is an exercising person has a better sense of nutrient requirement. Their body physiologically is more in tune with their repetitive needs.

1:35:34And so even though I don't think exercise matters as much as intake purely on the energy balance side, in other words, I think it's more about reducing input than increasing output, a part of that equation is the feedback loop that exercise brings. So yes, exercise just matters. And I also think that, especially in this discussion of cancer and breast cancer as the example you brought up, so many women are so petrified of hormone replacement therapy, because of this awful study that Women's Health Initiative, which was completely misinterpreted. But just to use one example of what we spoke about, even the people who ran the study, who to this day, some of them, at least a subset, still maintain that conjugated equine estrogen plus MPA, the synthetic progesterone, increase the risk of breast cancer.

1:36:23Even those people will acknowledge it did not increase breast cancer mortality. So even if you take the most favorable to the WHOI, the Women's Health Initiative study, reading, the reading is that conjugated equine estrogen plus MPA increased the incidence of breast cancer by 0 .1 % in absolute risk, but did not increase breast cancer mortality. So here you have basically a non -event that has most people panicked senseless, most women panicked senseless when confronted with taking hormones during the paramedic pausal period. And yet at the other end of that spectrum, we have a treatment that has more than a log -fold benefit in the other direction, i .e.

1:37:10in reducing risk. I wish people would just allow their attention to be allocated, proportionate to the size of the impact. I'm 100 % with you. And to kind of just highlight or emphasize what you just said, you know, there are studies with women who are doing moderate drinking, which depending on the study you read. For women and moderate drinking is like three drinks a day or something. Like, it's a lot. And that literally translates to a lifetime risk of risk and so it's like one in six or something like that. Whereas pretty significant, but you don't hear about women petrified of like drinking two glasses of wine and I, which some people do.

1:37:51It's actually not uncommon. Looking at like what's going to impact my risk more, what is going to lower my risk more? Like what should I focus on? Like what's like the most important thing? I think obesity does absolutely impact stress cancer, same with physical activity in the opposite direction has really enormous benefits. And then alcohol consumption is another one. Even mild alcohol consumption. I would say that like, I don't want to go there because it's like so complicated. And I like can't even like begin like gone there. I've gone there. I go out on the limb and I'm going to say it. there is no amount of alcohol that is healthy.

1:38:32The J -curve is a misnomer, and what I think I would say is, somewhere between zero and one, there's not that much of an increase in risk, but there's not a reduction in risk. Or what? For mortality in general. Mortality. Yeah, yeah, yeah. So in other words, you know, they talk about this sort of J -curve where complete abstinence is a greater risk than one drink a day, but I think both the Mendelian randomization makes that clear that that's not true. And then secondly, when you look at all the confounders of the people who are drinking zero drinks and what confounds their mortality, I feel very comfortable saying that there is no dose of alcohol that is healthy, but at a very low dose, probably four to seven drinks per week, you probably can't quite quantify the harm.

1:39:17That would be my take. And so I'm comfortable saying that. I really feel confident that that is the case and that things like the French paradox have far better explanations as one example. The data is also a mess. You know, like, can you have your weekend glasses of wine? Like, absolutely. I think you can. With respect to the cancer risk, that's considered it's mild. I mean, you're having less than one drink a day. And the only evidence I've really seen against the mild is on the National Cancer Institute site, where they're like, it's one of those cancers where it's like one in 500. It increases your risk of a cancer that you already have a lifetime risk of one in 500.

1:39:53and it's still less than 1 % of an increase. Like to me, it's like your lifetime risk goes up. You can't measure it. Like you can't measure it. It's a class example of the dose makes the poison, but don't confuse that the poison is a poison. Another example would be cigarettes. If you smoked a cigarette twice a week, literally one cigarette twice a week, would your risk of cancer grow up? Yes, but you wouldn't be able to measure it. That doesn't change the fact that cigarettes are harmful. Not to mention heart disease. Like that is not a linear. But even just focusing on cancer, right? And it really comes down to kind of establishing causality.

1:40:23Is tobacco causally related to disease? Yes. It's a harmful thing to take, but the dose matters. Again, just being glib. One cigarette a week. It's probably increasing risk, but we don't live long enough to see the separation of those cappelinmyer curves. Maybe if our natural lifespan was 500, one cigarette a week would be sufficient to see a spreading of those lines. but at an 80 year lifespan, you have to get up to 10 cigarettes a day before we can see where that is. By the way, I'm making that up. I'm not advocating that one can smoke up to nine cigarettes a day, but you know what I'm getting at, right?

1:40:59And I think that's my point. With alcohol, it's simply just a question of that. But I just want to make sure people aren't taking away from this that, look, I probably have anywhere from zero to four drinks a week. But when I'm drinking those four drinks across two or three days, it's not going through my mind that this is healthy. It's like, yeah, this is a hedonic pleasure. That's not good for me, but it's enjoyable. That's enjoyable. What, how do you feel about apoi -four carriers and alcohol consumption? Our view in the practice is that they are indeed more susceptible to the deleterious effects of alcohol.

1:41:34And also, I would say they're just more susceptible in general to the deleterious effects of poor sleep, which is one of the ways that I think alcohol is disproportionately hurting the brain. I think poor sleep is causally driving Alzheimer's risk and cardiovascular disease risk. I'm less clear on cancer, but in as much as most people that are drinking alcohol are doing so in the evening, and anybody who's used a sleep tracker, you don't need to be mat walker to very quickly do the experiment on yourself and compare a night of sleep with no alcohol, a night of sleep with alcohol, they're different.

1:42:12So through that lens, I would just say we have lots of patients with E4 in our practice, including a number of E4, E4s. Even though those patients represent only 2 % of the population, they're probably about 7 or 8 % of our patient population. And again, we say, look, unless this really means the world to you, it's probably not worth the drink. And if you are going to have a drink, here are some principles for how you might minimize the damage, right? In terms of the number you might have, how long you might have it before bed, that kind of thing. Exercise. You know, when I, a couple of things, just because you brought up the sleep in.

1:42:45So I started wearing a continuous glucose monitor largely because of you. I've been a very bad influence on some things you've done, the lactate monitor, the CGM. Yeah. Well, I started wearing it when I was a new mom. So this was, you know, like five years ago. And I can't be a good time to wear a CGM, although it must have been interesting, right? It was extreme. So here I am coming into this like, oh, I'm going to learn about the foods I eat and how my body responds to those foods and lo and behold, the biggest and most compelling and most important data point or many points because I had many of them that I sort of learned from wearing my continuous glucose monitor, which I'm sure most of your listeners know about where you're or glucose level like continuously, was the effect that my sleep interruption had on both my fasting blood glucose and my post print, where I was like, I could get like, what would be considered like prediabetic.

1:43:42I was like blown away. I was like, what is this is insane? And then what I also sort of gleamed from this was that when I on days, and the effect lasted at about, I would say like about 48 hours or so. know, when I did work out at the time I was doing a lot of high intensity interval training, I was like an hour long spin class I used to go to, you know, where they do all this interval training. It almost completely blunted that effect. Even though I was dog tired, last thing I want to do was go to my damn spin class. This is like, it's going to be bad for me if I go, that's how I felt. It's going to be bad for me.

1:44:17But it was completely the opposite where this crazy glucose dysregulation and whatever the causes for them, sure, you know much more about that than I do. It was almost completely blunted and it was so profound and it was like the one, all the food stuff, you know, I learned a little bit of interesting, but really that was the thing that for me was like, I have to work out no matter what, no matter what, no matter how I feel, it doesn't matter, it's beneficial. It was a really interesting study, caveat, observational data, reverse causation, all the problems with any study, but it was looking at the sleep habits and so people that had slept, you know, was poor sleep or interrupted sleep, something of that nature.

1:45:00I can't remember all the exact things that were measured with respect to sleep, but people that didn't sleep as long or had poor sleep, whatever measurements, had a higher all -cause mortality, which is not that surprising. But only in people that weren't physically active. And to me, I was like, wow, that's like - interesting and it's like, you know, exercise can forgive a lot of sins in many ways. It really can. So you're talking about your patients with E4, E4 and I'm sitting here going, oh my gosh, I've got one of those and I'm already like, it's a lot. It's a burden. You have to calculate things.

1:45:36You have to be very, you know, specific in your actions you take and like things that you don't do, things you do, right? And for me, it's like, okay, am I going to like, I'm having a party. We're going to have some memos as whatever. like I'm gonna exercise no matter what. Like, and that might take off some of the stress. I personally, I hardly drink. And mostly because I am E4, I have one allele, and I have pretty much come to the conclusion that my brain can't repair damage as well as my husbands who doesn't have an E4 allele. With that said, I occasionally will, I'll have like maybe a glass or two of wine, usually that's my preference, but, you know, a week.

1:46:17Last time I had a drink was like Valentine's Day, you know, so it's been a while. But at least I think with the sleep, sorry, with the exercise, you know, again, it's like, it does. It seems to forgive a lot of sins, honestly. I like that way of describing it. I kind of borrowed that from Stuart Phillips. I think he was the one that said it to me because I was like, this is like... That's right. I remember him saying that on your podcast. He gets all the credit, and that, of course, brings us into the whole, like, protein intake and muscle mass world. So let's set this up for listeners because, you know, you and I have talked about this a lot.

1:46:51In fact, I remember probably the last time this is pre -COVID because we were both in San Diego, you and your husband were over for dinner. I think I cooked up some fresh venison that I had just killed. And we were kind of talking about protein. And I think at the time, both of us were kind of struggling with two competing ideas. in neuroscience. And those two ideas that seemed dialectical, they seemed to odds, was on the one hand there's this body of mostly kind of animal literature that suggests lower protein intake is associated with a longer life. But on the other hand there's this literature that says lower protein intake is associated with more frailty in humans, and that's associated with a shorter life.

1:47:45So, how do we reconcile these two things? And we didn't have a great resolution on that. I mean, we both kind of felt like we were sort of scratching our heads, thinking, at least, I don't want to speak for you, but my thinking at the time, this is again three and a half years ago, probably was, we just got to find the minimum effective dose. What's the minimum effective dose of protein to not undergo mandatory catabolism? and that's what the dose is. And of course, it's not clear how you find that dose. Theoretically, you would use a metabolic cart and try to identify nitrogen balance and things like that, but of course, no one can do that outside of a lab.

1:48:20So it was a bit of a head scratcher. Now, my thinking has evolved so much on this, but I'd like to hear, first of all, I'd like to hear your formulation of the problem that I formulated the way you would, and I guess more importantly, tell me how you're thinking today. So you actually did a very good job on the formulae, my mentality with respect to protein intake and longevity back in 2019, prior to that. But even up until not even that long ago, to be honest, there's, as you mentioned, a large body of animal evidence, but also like there was coupled epidemiological data where you think people are looking at vegetarians are taking in lower amounts of protein and they're all cosmortality and they're cancer mortality and they're just study after study after study and they have lower all cosm mortality, lower cancer mortality, but only in those individuals who are not obese, not sedentary, sorry, are sedentary or smoking or, you know, they had some unhealthy lifestyle factor.

1:49:18So in other words, the people taking in higher protein, animal protein, who were basically healthy, had a similar cancer related mortality, all And similarly, studies where they normalized for fruit and vegetable intake, high protein versus low protein, no difference in early mortality. So yes, it seemed that a lot of the data that were espousing low protein were confounded by lifestyle choices and high protein was also negatively confounded by high calorie as the most obvious. Exactly. And with the animal data, and this is probably where my mentality has shifted the most because I wasn't really of the opinion that vegetarian diets were superior to meat eating, or I guess omnivore types of diets that were healthy omnivore types of diets because of what you were saying.

1:50:18Like that data was nuanced and it wasn't just like, that wasn't something I was that has shifted the way I've been thinking. But with respect to a lot of the animal data and the mechanisms and you can restrict a mouse of protein and make it live longer and not get cancer and all these things that you see study after study, I mean it's just like the longevity science and that whole field is like dominated by that. Like at least was and there's now, I think some pushback going on, but there's still a large group of scientists that are still publishing lots of animal data. And this is where I sort of started to look into some of these exercise physiologists, people like Stuart Phillips.

1:51:06I know you've had a ton of laymen on these giants in the field that are doing the research. And Brad Shownfeld is another one where they're looking at protein intake. They're looking at strength training and its effect in humans on muscle protein synthesis. And also just like looking at data with respect to muscle mass and all cause mortality and Alzheimer's disease dementia. We didn't talk about that, but like strength training also can modify that risk also cancer mortality. Yeah, strong grip versus weak grip, monotonic change in grip strength, 70 % reduction in incidence and mortality from dementia.

1:51:47I mean, 70 % reduction in risk. Remember, people don't understand you can't reduce risk more than 100%. So it's not like increasing risk, which can be 100, 200, 300. When you're talking risk reduction, 70 % is staggering. It is. Strength matters. It does. Now, as you know, in many of your listeners, there's two important signals for your muscle. Strengths, obviously, a big component of that is physically working them, but protein and take plays a role there as well. And I think it was Stuart Phillips like phrased it this way where the animals that are being studied in these labs are in a sterile environment.

1:52:24You know, they're in a sterile environment. They're not being exposed to influenza and all these infectious diseases. And any of us, we've had a parent or a relative or someone that has gone into the hospital and maybe had bedrest. And then come out and like, I had a grandparent who literally couldn't walk after a back surgery forever. Like, that was it. That was their downfall. It was like the trajectory just went down, completely down. So losing that muscle mass when you're in older age, obviously building up a bigger reserve in youth, in middle adulthood, whatever. Like, that's very important.

1:52:58But like, these animals that people are manipulating the protein restriction in them, they're not being exposed to that. They're not losing, like, I don't know what percentage it's pretty intense. Like, how much, you know, you can lose from like three weeks of bed rest. And also like, as it's been pointed out by people in your, I think, Matt Kiberlin, you know, mice are dying from like cancer. They're not dying from the same diseases. And it's not even the same type of cancer that humans get. We get a lot of these epithelial tumor, solid tumors. They're like dying from lymphomas. So there's a lot of differences there as well.

1:53:30There's a lot of interesting, and I'm the one to have talked a million times about animal studies. I think they're important, mechanistic data. Like there's things you just one never get from humans. But at the end of the day, I started to realize that looking at, you know, mice in a sterile environment where they're not really being exposed to the same stimuli as humans, things are very different in terms of aging. It was falling apart in my mind, basically. It was like all falling apart. I'm like, this doesn't make any sense. Like this isn't what to be looking at if I'm wanting to really focus on healthy aging for myself, for everyone else.

1:54:06So I think that's kind of what was the tipping point for me was just kind of that realization of the importance of muscle mass and how, you know, some of these animal studies you look, they have a little bit of an improvement in their cardiovascular health and I'm like exercise, okay, is that better than exercise? No. The things that were improved, I was like, exercise, does that? Exercise, does that? Like, this isn't convincing me that I need to like do that. I think it was just kind of like the shift in the way I viewed the data like the lens I was seeing it through. I'm still waiting for somebody to demonstrate for me that if there is an increase in the risk of cancer associated with higher protein intake in humans, I'd like to see that quantified.

1:54:49But I would like to see somebody demonstrate that if there is an increase in risk, that quantifiable increase in risk is greater than the offset of sarcopenia. Because that's something for which there is no ambiguity. We have all the data in the world to point to the devastation of sarcopenia on an aging population. And we know full well that two things have to be true to avoid sarcopenia. adequate protein intake, which as you age gets bigger and bigger, that number goes up and up and up due to anabolic resistance coupled with strength training. So here we have something for which there is no uncertainty.

1:55:35You must consume increasing amounts of protein and you must do strength training to ward off sarcopenia as you age. And if you don't, here's your mortality trajectory in its awful. Let's compare all of that to this questionable risk for which frankly I don't see data. I not had one more point to what you said, Ronda, which is I think this story got confounded by our good friend C. elegance. So let's go back 29 years roughly, call it 30 years directionally, when some very seminal and interesting work was published looking at the DAF 16 mutation in or maybe it was DAF 2. I can't remember if it was DAF 2, first or DAF 16, but it was the analog of the IGF receptor.

1:56:20And if you knocked out that gene, you could double the lifespan from roughly two weeks to four weeks or four weeks to eight weeks. I forget what it was of C -allegans this worm. The implication of that was profound. I don't want to downplay the most important takeaway from that, which was lifespan was malleable. That turned out to be very interesting. I could go on my rant about why sea elegans is not an organism or an animal model that offers any insight into us based on its cell based on a whole bunch of things about its biology. But nevertheless, it somehow became knocking out, Daph -2 or Daph -16 was tantamount to dropping IGF insulin -like growth factor 1 to 0 is the key to longevity, and the way to do that is to have no protein.

1:57:11And I think that story is so incorrect, but somehow it's become part of dogma. I think that's the other piece of this that just kind of won't go away. It's funny because I've done those experiments with my own hands when I was at the Salk Institute and I was in Andy Dillon's lab who had trained with Cynthia Kenyan who made the discovery back in was it early 90s or something? Yeah, I feel he was 93 or 94. Yeah, and it was very exciting for me at the time because it was like, oh, this is a homologous gene we have. And I'm watching it go from a 15 day lifespan to like a 30 plus day and not only that that you know these were.

1:57:49Span was remarkable they were youthful I mean like you could see them you look at my micromania see how they move around it is very apparent they were acting like a youthful young larvae that had not been born long ago. But then you also realize they go into this dour state where like in order to get that lifespan extension, they're like going into this like metabolic stasis and like this thing that we don't do, humans don't do a doubt. It's a completely separate pathway that is required for that lifespan extension. And I think to your point about the IGF -1, the insulin growth factor receptor and also the insulin pathway.

1:58:29They're kind of both tied into that. The fact of the matter is that that is a growth factor. You know, when I've talked about this before, you know, growth factors in the context of a tumor can allow tumor cells to override cell death mechanism. So they can continue to survive when they otherwise might have been signal to die. And so there can be a problem with too much IGF1 in the context of a tumor and what causes that high IGF1 is up for debate. But at the end of the day, it's not that high IGF1 that is necessarily causing the tumor. I think there are things that you can do in your lifestyle like exercise actually causes IGF1 to go into muscle where you're repairing damaged muscle.

1:59:14It's helping muscle repair. It goes into your brain. It's important for neurogenesis, a little bit of controversy there I know, but I'm in the camp that you adults are. Their studies showing, multiple studies showing that you can take an older adult, train them for a year, and their hippocampus will grow by 1 to 2%. There's multiple studies. Also another study showing this with the sub -friendricular zone. These are two regions of the brain where I believe data that says that adult neurogenesis or the growth of new neurons as an adult is occurring. And I think exercise is a big. And do you think that part of the vehicle for exercise to do that is through IGF1?

1:59:51Uh -huh, yeah, absolutely. It is. Interesting. Animal studies have shown that. Again, we all know how the caveats does a transit to humans, and we don't know. But often time you have to take the whole body of evidence. The human evidence, coupled with mechanistic data, with animals, and try to kind of put together a story to the best of your ability. I mean, that's all we're going to get. And you always hear about, I want to lower IGF1, but you know, it's actually like important for the brain and important for muscle. And the way to get it to the brain is through exercise that's known. And it's been shown again in human studies as well.

2:00:24I think also part of the problem here is in some respects, people that are doing, I mean, really impeccable animal research. Like, you look at the data and it's like, oh, they're doing this study gray. This is a good study. I mean, like, you can't poke holes in it with respect to the animal world. But then sort of translating that to humans and considering who are we talking to? Are we talking to an overweight obese person? Maybe they're probably getting enough protein. Like I don't know that they have to worry so much about protein intake. I think they need to focus on losing that unhealthy weight.

2:00:59But that's also really important. And I think some scientists and also health science communicators also sort of maybe, and And I've been sort of guilty that as well, like disentangling who are we talking to? Are we talking to the obese person who clearly needs to focus on weight loss? Or are we talking to the healthy, physically active person who's now terrified to take protein in because of they read about some animal study where too much protein increases mortality? And also, I think age is such an important part of this again. So if you look at that, I think it was Levine in 2017 had that study where they look at the relationship between protein and IGF1, but stratified by protein intake, low medium high, low medium high, and then they looked at middle -aged people, so 50 to 65, and then people over 65.

2:01:51And in people aged 50 to 65, there was a relationship between protein intake and IGF. Higher protein intake was associated with higher IGF. That wasn't a huge difference. This gets overstated constantly, but it was statistically significant. But what often gets ignored is the people over 65, there was no statistical difference, whatsoever between protein intake and IGF1. Again, this has taken as dogma that the more protein you have, the higher your IGF1. And in people over 65, that's not the case. Now, why do I harp on that? I harp on that because it isn't exactly that population that I am most concerned with sarcopenia.

2:02:34So if the message is somehow getting transmitted to somebody listening to this who 65 or older, that I shouldn't be eating protein, and they might not even know that it's through IGF, but somehow I protein is going to give me cancer because someone who telling them that is telling them that through the lens of IGF, the answer is, first of all, no, it's not. And secondly, the greatest risk you face again is going to be the results of low muscle mass and low strength. And even if we believed, which I don't, but even if we believed that in that age, in the younger people eating more protein leads to more IGF, which is bad, I would argue that the absolute risk of death is so much lower in that group that the absolute difference in mortality between the younger and the older in the presence of high protein is no comparison.

2:03:28What I mean is higher protein across the board is going to save more lives than it would ever hurt in younger people even if you could convince yourself that higher protein intake was associated with increased mortality. Again, I find these data unassailable, especially in the older population. I think Matt Kableman and I did talk about this on a podcast once, and I worry that as you do, that that information is not making its way clearly to people of this susceptible age group. Right. And I think also that a lot of people are focused on the recommended daily allowance of protein, right? Well, then, right.

2:04:07Like, what are these old ass studies that were not done correctly using the wrong tracers? Like, what is that telling me about how much protein I should take in? And this is also another sort of, like it was a turning point for me because I knew nothing about... How the recommended dietary analysis was determined, yeah. And everything about micronutrients and RDAs, but I knew nothing about the protein. Once I talked to Stu, it was clear. He was like, oh no, we repeated those studies, him and many others using different tracers. And I can't tell you all this tracers and stuff because it's not my field.

2:04:38But it was like, no, we determined that the minimum was really more like 1 .2 grams per kilogram the ground body weight, not 0 .8. And to me, I was like, oh wow, because you know, like you don't store protein. This is important because, I mean, that's a big difference. And then on top of that, when you start to get into the physically active people or elderly population, as you mentioned, antibiotic resistance, where they're basically like, their muscle isn't getting that signal as well to increase muscle protein synthesis from the same amount of protein that they're younger self -foot. So they actually need more of a dose up to like, I don't know, 1 .6, 1 .8.

2:05:14We basically tell people aim for one gram per pound, which should be 2 .2 grams per kilo, because the other thing that complicates it, Rhonda, is not all protein is created equal. So if you're getting a reasonable amount of your protein from a plants, you're getting a lower bioavailable amino acid. You're also not getting the same quantity of lucine lysine and methionine, which are probably the three most important amino acids anyway. So, you know, one of the things Don Laman talked about was, if you really want to be rigorous about this, you probably want to track those amino acids. And you really want to say, look, make sure you're getting one gram at least of methionine per day, two to four grams per serving of lousine and lysine.

2:06:01Now again, for a lot of people, that's too nerdy, but you can go through the math a couple of times with certain things that you eat repeatedly. And you'll realize that's probably more protein in aggregate than a person is used to eating. And as you said, when you start to factor in those two other categories of risk, right? More demand. So when you're doing those high intensity workouts, you are ripping apart muscle fibers when you're lifting weights, when you're rucking, when you're doing all these other things you have to do, you're demanding more amino acids for the turnover. And then of course, antibiotic resistance, I think is the biggest issue.

2:06:33And something that truthfully, up until two years ago, I just wasn't paying any money enough attention to. I wasn't appreciating that my older patients had an additional problem that younger patients didn't have with respect to that signal. 2 .2 grams per kilogram by way. That's for me to get 1 .6. I'm supplementing. I'm taking way protein. How many meals? Typically four. It has to be. Yeah, it has to be. For me, it's really two meals and two snacks. The snacks are just protein snack. So it's a shake. So one of them is just a way protein shake. And then one of them is I eat these venison jerky sticks.

2:07:10So five venison jerky sticks is 50, they're 10 grams of piece. And they're really good. They're super pure venison. It's, you know, wild game. Amazing product. I should disclose them and invest in the company that makes them by the way. I was going to ask do you make them? Is it like you're? No, I know that people say, well, I know everything about it. And I know that the quality is there. So those are two snacks. Otherwise, they're relatively low in calories. My way protein shake doesn't really have anything else, and it accepts some frozen berries and almond milk. And then the medicine sticks are what they are.

2:07:39And then two meals that are going to have protein. And for me, again, a lot of times like it's going to be an omelet and then protein dinner. So not going to deny it. It's work. It probably consumes more of my dietary planning and dietary attention than anything else. I don't pay any attention to how many carbs and fat I eat anymore. I'm just paying attention to protein intake. It's something I never really paid attention to at much at all until I would say like last June or July is when I really started focusing on strength training, you know, both for my muscle, mass, and also bone mineral density.

2:08:13Like that's another thing where it's like you want to reserve of that as well, especially as a female. Focusing on the strength training and also the protein intake. And it's been quite challenging. I've always sort of focused on micronutrients. It's still a focus of mine and like making sure I'm getting enough of those and I do supplement as well, you know, in addition to trying to eat like leafy greens and getting some of the veggies and stuff, it's either going to be roasted veggies for me or like salad. But the protein intake, it's been challenging and I find I typically do three meals. One of them is at protein meal snack, so it's some salmon or like a homemade turkey burger or something like that.

2:08:50But then the protein shakes also is where I have to do, I guess that I don't really consider it a meal, but kind of is. It's satiating. The protein shake is definitely satiating and I'm already, it's even kind of hard because when you work out, like as you mentioned, your satiety hormones go up. Like I'm not hungry. Like I don't necessarily want to eat. It takes a while before I can actually even get an appetite. So there's all these competing things where I'm like trying to get the protein, but I'm like I'm not really hungry and I'm like, I know I need it. So all these little important factors and yet again, important to sort of highlight that I don't know that someone who is overweight or obese necessarily needs to focus so much on that, right?

2:09:30Do you agree? That's right. Fortunately, most people who are what I call overnourished are also adequately muscled, and they can actually in the short run be okay, losing lean mass. In fact, it's very difficult to lose heaping amounts of body fat while preserving lean mass. So we tend to focus more on the caloric restriction. coupled with the training. We use the training as a way to offset some of that lean mass loss and then we can come back to it. Now that said, so it depends on the strategy. Depends on the dietary strategy. So for people who are using tracking kind of the caloric restriction way, we would still set a protein target that is at two grams per pound because of the satiating benefits that you said.

2:10:19Also you have the thermogenic effect and the benefits of protein overfat and carbohydrate from a thermogenesis standpoint. But when you have people that are going about it via dietary restriction or time restriction as their strategy for cutting calories, it can become a little overwhelming and when you force high protein, you sometimes end up getting high calorie with it. So that's where we would say just don't pay attention to it as much, just focus on the DRTR approach. The other place Ronda where we do pay a lot of attention to protein is in the few of our patients that are taking GLP1 agonists.

2:10:56So I've been a pretty public critic might be too strong a word, but I've certainly expressed my reservations about the ubiquitous use and the liberal use of GLP1 agonists, especially in people just trying to lose 10 pounds, right? Like it's one thing if you're 100 pounds overweight and you've tried everything by all means, the benefits clearly outweigh the risks, but I gotta get my beach body on for the wedding this summer, I'm going to lose 10 pounds. Let me fire up some semi -gluteide or Terzepatide. I think that's a net negative personally. In those patients, not that we're giving it to those patients, but in any patient who's on a GLP1 agonist, we feel it is so essential to hammer home protein because those drugs are so effective at squashing appetite that we've seen people who basically just want to drink alcohol when they're on it.

2:11:45They'll lose weight like crazy because they're not getting that many calories, but they're like, yeah, I just like wine. I'm losing muscle. Yeah, I'm just losing muscle, drinking wine. Yeah, I've got some acquaintances that are of that category where it's like stay at home mom, wants to lose 10 pounds, has the means to get it and does it and we haven't measured muscle in the, I look at them and I'm like, you look like you're wasting your, like your muscle is wasting. If you're not eating, you're not taking in protein. So I mean, like that makes 100 % sense. And it also, I don't, maybe we'll talk about this when you come on my podcast, but like I'd love to, like, because you used to do a lot of fasting.

2:12:19And you don't do as much, at least of the long, long fast. And I would love to get into that and decide whether we should do that next time or we could talk a little bit now. But yeah, that was also like the biggest, you know, there was another shift in my understanding of fasting and time restricted eating. A lot of people use time restricted eating. They sort of practice it by skipping meals. And I don't know necessarily that's the way to do it. but people do that. It's just, you know, what people do. And when you're skipping a meal, you're skipping your protein. You're basically becoming losing muscle mass because you're not getting that important signal, especially if you're not doing resistance training.

2:12:58Then it's like kind of a disaster. And that was also something I hadn't thought about a lot. And I know you've got a lot of experience in it on both personal and clinically. I'll share with you briefly how we think about that. On the time -restricted feeding part, we agree that the greatest drawback is is that the patients get protein deficient. So time restricted feeding as a strategy for weight loss vis -a -vis caloric restriction is very effective with a small enough feeding window. So a 16 -8, you can eat your way into obesity with a 16 -8. But once you start getting down to a 24 or a 22 -2, basically just doing one meal a day, really getting restrictive, for the most part you're gonna lose weight.

2:13:40The problem is by definition, you're not gonna get enough protein in because even if you managed to scarf down one gram per pound of body weight in a single meal, you wouldn't be able to utilize those amino acids. You kind of tap out at about 40 to 50 amino acids per meal. So if you sat there and had 160, you just flushed a bunch of them down the toilet. They're literally not coming down the toilet. They're coming out as vis -a -vis urine, coming out the urea cycle. So the thing that we would counsel people on if they're going to use time restricted eating is they have to have protein snacks outside of their feeding window.

2:14:17So if they're going to say, look, I'm going to only have a lunch at two o 'clock and a dinner at seven o 'clock. We'll say fine, but you still have to have two protein snacks outside of that. And that becomes challenging because those protein snacks can't really have much else in them. They have to be very low calorie otherwise. Otherwise, you're not really doing time restricted feeding. And of course, a lot of people get phosphorylated over this. they say, oh my god, that's like outside of my feeding window. Well, that imparatophagy to which I argue you're not getting any autophagy doing a single day time restricted feeding.

2:14:47Anyway, it doesn't matter. But if people are getting gut benefits from taking that time off, then yeah, they're going to miss out on those because you're, I just don't see how you can get the gut rest if you're trying to get those amino acids. And so you might have to really start to cycle those things. But yeah, long -winded answer to why I think fasting can really be at odds with the adequate maintenance of muscle. And as we get older, I'm just entering my sixth decade. This is a very high priority for me. Oh, really? Wow. You look great, Peter. You're in your life at least. 50. No, six decades.

2:15:23Oh, so you're 50? Yeah. Gotcha. I love that you thought I was 60. That's awesome. I'll take that as a… I think Joe Rogan's entering that. and that's kind of what I was thinking. And he looks, you can definitely see the people that put in the work and work out and they do aerobic, they do strength training, you look at them. There was a study published on that too. A bunch of biological markers of aging and biomarkers of aging were measured. And then people looked at pictures and ranked their age and their quote unquote biomarker biological age according to all these biomarkers that basically say their chronological age may be older than their biological age.

2:16:02but they looked like they're biological age and not their chronological age. That's also important. Although I sometimes feel like excess exercise can prematurely age you as well. I've certainly seen a lot of, and I don't know how much of that is the sun damage, because of course a lot of exercises done outdoors and of course sun can play a horrible role in that. So I've taken up more of your time than I said I would, but I want to ask you kind of just one last thing. Is there any other just sticking with this theme of things that you believe today that you didn't believe three or four years ago, or things that you believed three or four years ago that you don't believe today.

2:16:37Is there anything we haven't touched on because we've talked about some really good ones? I think those are the really important ones off the top of my head. I definitely don't wanna get into the whole COVID thing at this point, but my view has changed on things as that has progressed and changed as well. So I don't wanna like not mention it, but I think the most important things would be muscle mass, protein intake. Also, fasting, and I think the effects of time -restricted eating on weight loss, specifically when you're looking at that outcome, being attributed to caloric restriction, I think that is something that I've, you know, wasn't always, you know, buying into that.

2:17:17But it is still my opinion there are benefits to eating within your circadian rhythm, eating late at night when you're making melatonin two to three hours before bed, you're basically inhibiting insulin secretion. There's data showing that glucose levels will be higher with the same exact macronutrient intake as if you eat it earlier. So there are benefits, circadian benefits. And I also think you mentioned the gut rest and digestion, resting. So DNA repair mechanisms, you mentioned atop a G. Those things happen when you're not digesting and that process isn't happening. So you have to have a rest period for repair processes to occur.

2:17:55And I don't know that I necessarily, I think autophagy is as good as the markers that we are sensitive assays that we have to measure it. And I don't know that it's settled. I personally think there's probably even in between meals. There's some amount of autophagy. Autophagy is happening in us. It is. And it's not like we're not... But is it clinically significant? More so than say exercise would induce. No. The exercise is not... Like that's my point. like how long would you need to fast to get the benefits of an amazing workout? And my thinking is probably a long time. You might have to go a full day without food or a couple days without food to get the benefits of that.

2:18:35But you're right. I think without biomarkers, a lot of this stuff is very difficult to speculate on because we can't really extrapolate from mice on this stuff. It's so nonlinear that I don't think I could, and I've never heard anybody offer a very compelling argument, either, for what the quote -unquote answer is. I agree. We can't extrapolate for mice. And the way I view it, though, is more of a cumulative effect, where I'm thinking, it gets better to just eat within a circadian window. And do I think that's going to have a cumulative effect on metabolism? And yes, I think that it's better that I'm not eating within a 15 -hour window, which most people in the United States actually do.

2:19:15They're eating from start to finish, like a lot of people are eating within a 15 -hour period. If you're exercising, maybe it doesn't matter. Maybe you're right. Maybe they can't even have 15 hour window. We don't really know, but I tend to think probably the circadian component does play some role, but the question is, is it significant? I am of the opinion that probably is cumulative over the years. For no other reason, I think it just is on sleep. On sleep. Yeah, exactly. Like if you just look at the benefits of nighttime food restriction in terms of, as you point it out, We're at least insulin sensitive and the negative impacts probably of thermogenesis and other things on sleep.

2:19:57That's probably the most compelling reason even if nothing else mattered if we couldn't measure it. But those are so abundantly clear. That says clear as how alcohol impairs sleep. A late night meal is a great way to destroy a good sleep. Right. I think most people have, is anecdotally like people realize that as well. So yeah, I think we covered a lot of the things that my perspective has shifted. As any scientist that's following data should, some people will argue, oh, you changed, you know, how can I follow you? You changed your mind. And it's like, well, like when you data comes out, you have to reassess things.

2:20:34Like I reassess the supplements I'm taking. I mean, the supplements I take now versus five years ago, totally different. Not all of them. And there's some base things like I like vitamin D omega three, like those are like super important, I think. But you have to reassess things because new data comes out and you might have a new understanding of things that we didn't know we have new tools. It's always getting better. So you have to kind of reassess things. So Rhonda, for folks to follow you, obviously your podcast found my fitness. Great way to follow amazing content. Also you put up a lot of content.

2:21:07I think Instagram is probably where you're putting up most of your content. Is that safe to say that if folks follow you on Instagram, that's where you're doing sort of thorough analyses and stuff like that Would you recommend people also check out Twitter? Where should people be going to see you're thinking on a frequent basis? Well, it depends on what they like to consume so if they like to consume like in -depth articles We publish them on my website found my fitness calm. We have like topic articles that we cover we cover Blood brain barrier is one so we cover that in more in depth some people like to read they like nerd out on that.

2:21:39So that would be the place for that. And then some people just like short little to the point, you know, and that is where I if they want like quick thing like the Instagram. So I found my fitness on Instagram and also Twitter as well. It's kind of like a short I mean you only get so much time on Twitter. You can't go in depth and nuance and then I sort of have a love hate relationship with Twitter. It is kind of a fun place to also like there's other scientists on there as well. And so I'm on Twitter and Instagram. And it's all the same handle. Yeah, I found my fitness and then the podcast as well, which is Apple Podcasts Spotify.

2:22:10Andrew, you remember now we're talking a little while ago and we were sort of singing your praises as truly the OG health podcaster. When did you start? Was it 2014? That was when I started the podcast. It was a weekend. I was doing my postdoc in Oakland and I just started like Ron Kraus down the hall. George Brooks. So I have a podcast with George Brooks on lack to like, he was like my second -hand I think I've heard that I need to go and listen to that one. Yeah, we went all into the brain. That whole podcast shifted my thinking of like intensity of exercise and the importance of lactate. I don't know if you know this, but like I trained, I probably shouldn't, like we already talked about, where people should go find me, but I was a mitochondrial metabolism researcher grad school.

2:22:57And so I was looking at the role of mitochondria and cancer. And so of course, like lactate, I mean, I was thinking about it in a completely different frame of mind. As opposed to, I mean, we now know it's such an important signaling molecule in addition to all those other things we talked about. You know, we've had at least one guess suggest that George Brooks is deserving of a Nobel Prize. His lactate shuttle theory, it's called a theory and I kind of hate that it's called tap because people hear that and they're like, oh, it's a theory. Yeah, it's not proven. But it's been proven. And in fact, there's like studies like even like there were people looking at this like even before he proposed like they were looking at lactate getting in the brain in response to physical activity.

2:23:33And it's like beta hydroxybutyrate. It's a signaling molecule. It activates BDNF, like beta hydroxybutyrate. They go through the same transporter, monocarboxylate transporter, the MCT transporter, to get into the brain. There's also those in mitochondria. But it's so funny because there's a lot of similarities that affects on TBI. So, you know, George Brooks has done some studies, USC looking at some of these victims of TBI and giving them lactate and it's like improving whatever their glass -cow rating scores, whatever the things that they're looking at. But I think beta hydroxy butyrate wasn't there some evidence, I think, with TB.

2:24:07I remember Dom talking about that. Dom has talked about this. It's so interesting because also with respect to Alzheimer's disease and there's some really preliminary data that of course needs to be repeated probably won't because you can't get funding. But giving beta hydroxy butyrate, BHB to people with Alzheimer's disease can help improve. There's some small clinical studies looking at improvement in cognition. lactate is like, I think similar. There's a lot of overlap there. Now lactate you can make. Beta hydroxybutyrate you make from exercise as well. You like push yourself into ketosis. So to be interesting, like, you know, if there's synergy there, trying to get the lactate and the beta hydroxybutyrate, the neurobiological effects of them, to me is, it's so important.

2:24:51It's so interesting. And I just, I kind of want more research in that area. And so I like talking about it because I know scientists to listen to your podcast, researchers, physicians, it's good to kind of like spread ideas. I mean, that's part of what the podcast does. Spreading ideas is not just like, I'm a communicating the health ideas. And it's like, scientists are listening to this and they're outside of their like lens where they're only thinking about the thing that they research and they hear this at, and it's a creativity. They start to go, oh, like, I've seen that happen. Scientists like doing experiments based off of like listening to podcasts and stuff.

2:25:25I think it's really great. But thank you for the OG. Yeah, it was a weekend thing for me and I loved it. It took off. I just I love it so much. I know you do as well. I mean, it's like by the way phenomenal podcasts. It's funny. I don't listen to podcasts much at all as I mentioned, but there's a few people that I trust to really be vigorous in their research and to be critical to really like dive down and and get into the root of things. And you are like one of those people. And so people will come to me and say, oh Peter, Tia said this, and I'm like, oh, okay, this is something I should consider.

2:26:04Or oftentimes it'll be, oh yeah, Peter also said that. And so I'm like, oh, good. So I'm always like, okay, what is Peter thinking? Nice to have you as a colleague as a friend. Like us. I'm glad we've reconnected. Thank you so much for inviting me on your podcast. Can't wait to speak with you again soon on your amazing book, which I can't wait to read and discuss as well in a couple of months. Well, thank you very much, Ron. I can't wait to see you in person. Even though it's been pretty awesome to see you in video your setup is, as I said, exceptional. We've treated the people who are watching this to a world class view of what a home podcast setup can look like.

2:26:39Amazing, thanks, Peter. Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring you more in -depth, exclusive content without relying on paid ads. It's our goal to ensure members get back much more than the price of the subscription. Now, for that end, membership benefits include a bunch of things. One, totally kick -ass comprehensive podcast show notes that detail every topic paper, person, thing we discuss on each episode. The word on the street is nobody's show notes rival these.

2:27:12Monthly AMA episodes are asking me anything episodes hearing these episodes completely. Access to our private podcast feed that allows you to hear everything without having to listen to spills like this. The Qualies, which are a super short podcast that we release every Tuesday through Friday, highlighting the best questions, topics, and tactics discussed on previous episodes of the drive. This is a great way to catch up on previous episodes without having to go back and necessarily listen to everyone. Steep discounts on products that I believe in, but for which I'm not getting paid to endorse.

2:27:45And a whole bunch of other benefits that we continue to trickle in as time goes on. If you want to learn more and access these member -only benefits, you can head over to peteratia MD dot com forward slash subscribe. You can find me on Twitter, Instagram, Facebook, all with the ID Peter Atia MD. You can also leave us a review on Apple podcasts or whatever podcast player you listen on. This podcast is for general informational purposes only, It does not constitute the practice of medicine, nursing, or other professional health care services, including the giving of medical advice. No doctor -patient relationship is formed.

2:28:21The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay an obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take conflicts of interest very seriously. For all of my disclosures in the companies I invest in, or advise, please visit peteratia -md .com forward slash about where I keep an up -to -date and active list of such companies.

2:29:28I'm going to do a little bit of the same thing.