252 ‒ Latest insights on Alzheimer’s disease, cancer, exercise, nutrition, and fasting

hey everyone welcome to the drive podcast I'm your host Peter attia Rhonda it is so great to see you especially on that awesome remote setup that I almost shouldn't have said to people was remote because it really feels like we are in person about as close to in person as we've been in a few years it's really great it's really great to see you Peter it's it's been a minute yeah well we'll meet together soon in a couple of months so I'm looking forward to that um there's a lot to catch up on over the past few years we've obviously exchanged a bunch of emails about things that we each find interesting um and I think in the last couple of years well let's just pause it in the last five years was the last time we did a podcast just going back to that point I think both of us have evolved a lot in our thinking uh and I think we've done so unapologetically that's the nature of science that's the nature of what we do and we're trying to learn so um in thinking about our discussion today I think we both agreed it would be most enjoyable to at least spend some time talking about areas where your thinking has evolved but I think first we wanted to start with I don't want to put words in your mouth but maybe that which you're thinking about the most right now would that be a safe assessment if we were to start to talk about dementia specifically Alzheimer's disease and maybe the change in how you think about that it would um so you know I for me personally I have neurodegenerative disease on my mind quite a lot because Alzheimer's disease and Parkinson's disease both run in my family so and I have a genetic predisposition so for me you know understanding everything I can do you know with my with my diet with my lifestyle just you know exposure to or limiting exposure to certain things Etc becomes Paramount right because I don't want to get Alzheimer's disease and Parkinson's disease so um like as you know Peter the the Alzheimer's disease field has been it's been quite a roller coaster in a way like I mean we've had this dominating sort of I think um hypothesis this amyloid hypothesis as it's called so there's you know one of the major pathologies of Alzheimer's disease are amyloid plaques in the brain and there are other pathologies Tau Tangles also glucose hypo metabolism so you know glucose uptake into the brain is impaired and also uh perhaps even the utilization of glucose as well so uh these are like three major pathologies of Alzheimer's disease and it seems as though the majority of targeting you know how how Science And scientists have decided to Target you know Alzheimer's disease is through this amyloid anti-amyloid you know hypothesis and as you know we've had quite a few failed trials although of recent a little bit more I would say you know possible success maybe but um generally speaking it's been it's like we need to go okay like are we just are we just trying to treat a symptom here or are we too far Downstream like what what's the deal and I started reading some Studies by at USC and axel Dr Axel montane who was trained with um Dr slovovic and now has his own Lab at the University of Edinburgh in Scotland and I recently did a podcast with him on my on my podcast and uh Axel and it was really like when I started to read some of this literature and I'm going to talk about like what you know this sort of new I don't know it's not even necessarily new but like you know it's not a new way of understanding it but it is in a way because in in the public opinion the public mind it's a new way um and this is sort of like okay well what are the underlying causes of you know of dementia and so there's you know three major types of dementia Alzheimer's disease being like the most common there's uh um small vessel disease cerebral small vessel disease and then vascular dementia those are the three most common forms of dementia but like is there a common underlying denominator between those and on top of that like what what sort of Lifestyle factors and genetic factors do we know really increase the risk of Alzheimer's disease and dementia well we know having an apoe4 allele so this is a version of a gene that is known to increase the risk of Alzheimer's disease if you have one of them it increases the risk twofold if you have two if you got one from Mom and one from Dad it could be up to tenfold and this isn't like an early onset Alzheimer's disease it's it's more of what's called late onset which is the normal sort of age-related you know progression of Alzheimer's disease but that Gene really does play a role in in in you know in someone's risk the other thing we know is type 2 diabetes right I mean so I mean that over I don't know somewhere between 50 to 80 percent of people with Alzheimer's disease also have type 2 diabetes like that's a lot there's definitely something going on right I mean yeah this is where you hear and let's sort of pause there for a moment because I want to go back to sort of the premise of your interest which is you are at increased risk so just even if you just think about this personally and therefore presumably you're interested in quote unquote prevention and as you've probably heard on my podcast you know prevention is still a word that doesn't quite resonate within the field which is in other words up until very recently I think the NIH didn't even acknowledge the idea of prevention as a strategy within this field and in fact preventative neurology or preventive neurology I suppose um is is really something that is still kind of on the outskirts most people are thinking about what to do when you have Alzheimer's disease not as many people are thinking about the question that you're asking and that a few other people are asking which is what's in our control because yes you alluded to APO E4 which I'm sure we'll talk more about but what you just said about type 2 diabetes would suggest that if you believe you can prevent type 2 diabetes wouldn't that at least suggest you have the probability or possibility of preventing or delaying Alzheimer's disease sorry so I didn't mean to interrupt you but I want to highlight the important implication of that statement exactly exactly the it's so important I think that um looking at Alzheimer's disease and understanding sort of the underlying cause of it opens up you know these new avenues for prevention and also treatment you know um and of course there are people that do get Alzheimer's disease early in life I mean these are these are people that could come down with it in their 40s or 50s that's sort of an app you know people are outliers in that in that case but it does happen and um so obviously there's not there there are there are things that um you know you might do everything right and still like have that terrible genetic combination right so um but with respect to the apoe4 um and type 2 diabetes understanding again is there something like common going on here that we can sort of understand as a foundation to what is the what are the initial like things going wrong to lead to Alzheimer's disease and um and that is where vascular dysfunction particularly the blood vessels and capillaries that are lining the blood-brain barrier seems to be a really really early event that is common between all types of dementia and between Type 2 diabetes and apoe4 so people with type 2 diabetes as you know can I interrupt for a second Rhonda tell folks what the blood-brain barrier is I think it's it's obviously going to be an important part of this discussion and I and not everybody might understand what it is or why it's so important so the blood-brain barrier and um you know this is again you know I am not a neuroscientist I'm just you know I am a Scientist but I have I have an interest in this and so I've done a lot of reading in this in this field um the blood-brain barrier serves a couple of functions I mean one is it is providing it's it's there's a combination of different cell types that make up the blood-brain barrier and a lot of vasculature right and so um blood flow you know things things are brought to the blood-brain barrier and oxygen glucose other nutrients and they are you know transported across the blood-brain barrier but it also as the word implies barrier provides a barrier to things that you don't want to get into your brain so you know we don't want red blood cells getting into our brain you know we don't we don't want a variety of other molecules proteins that are floating around in our circulation to get into our brain and so when the blood-brain barrier begins to break down and it's kind of an people like think are a lot more familiar with when the barrier the gut barrier starts to break down I think it's a it's a sort of become more of a common theme that people are focused on gut health and so you'll hear the word um mostly you hear the word leaky gut I don't really like that term I think it's intestinal permeability but you know the tight junctions these proteins that are holding endothelial cells together in the gut when those open up you you get that term you know leaky gut or as it really should be called intestinal permeability well in the brain you also have endothelial cells and you have tight junctions and when those tight junctions also break apart and we can talk about like what's you know at the root of that that leads to permeability of the blood-brain barrier and therefore two things happen you know one you are allowing then things from circulation to get in the brain cause which you know wreaks havoc on the brain and sort of leads to this vicious cycle of neuroinflammation inflammation in the brain but also you're disrupting the transport of important nutrients oxygen you know glucose I mean blood flow is disrupted to the brain as well so um the blood-brain barrier and and maintaining that Integrity is very important and both apoe4 and type 2 diabetes lead to permeability of that and so with um type 2 diabetes you know people people have hypoglycemia right they have elevated blood glucose levels and that over time leads to Advanced glycation end products these are basically like the cross they cross-linked proteins and you know a variety of other things that you know in in the vasculature and that basically damages the blood-brain barrier and leads to permeability um apoe4 it's a you know there's a variety of other mechanisms that happen but essentially you can measure the permeability of the blood-brain barrier looking at a variety of biomarkers and proteins in cerebral spinal fluid but also in plasma and these have been shown by Dr slovovic Dr montane to occur I mean it's like decades before the onset of you know cognitive impairment and it's literally you can find it in more than 50 of all dementias so it's re and it's happening independent of of amyloid accumulation Tau Tangles as well so uh it's you know either something that's happening before well before and in fact blood-brain barrier permeability is also um the blood-brain barrier is essential for removing toxic compounds from the brain and a variety of different processes you know happen to allow this to occur so for example you you activate the lymphatic system during sleep right and a lot of people are aware of this your brain sort of swells during sleep and the lymphatic system is pushing the cerebral spinal fluid through the brain clearing out debris amyloid plaques you know things like that well that doesn't you need the blood-brain barrier to be intact to occur yeah so I mean that makes sense that basically if you have blood brain barrier permeability happening that you would start to have the accumulation of amyloid so it's sort of like um and accumulation I never thought of that by the way Rhonda that's that I never thought of what you just said which is if your blood-brain barrier can't hold the back pressure which is what would be the case if it were permeable you would not have the back pressure to maintain glymphatic flow that never actually occurred to me until you said that so very interesting mechanistic tie to that problem right and there's also like the other types of and I'm not familiar with all the types of ways the brain like there's other like parenchyma and stuff that are like you know cleaning out the brain all of those things are not happening as good when your blood-brain barrier you know is dysfunctional right and then another point is the ability of things to interrupt and get into the brain that shouldn't so one of the things you know everybody learns in Pharmacology or medical school is that there are certain drugs that penetrate the blood-brain barrier there are certain drugs that do not the implication being certain molecules can pass through certain molecules cannot well presumably the leakier that barrier is the more things that maybe we evolved to not have across that barrier do indeed cross and perhaps that's a part of what you just said right which is this increase in inflammation that is now coupled with an inability or a decreased ability to to clear out debris exactly in fact um you know so work from Dr montane has shown that fibrinogen which is you and I are familiar with this protein it's something if you are measuring your if you're doing an inflammatory biomarker panel right I mean so so that's it's it's an it's it's a protein that's involved in blood coagulation but it's also something that is a marker of inflammation you know and fibrinogen is not supposed to be in the brain but it's found in the brain in people with a leaky blood-brain barrier and not only um so what's it doing in there it disrupts a cell type called oleodendrocytes these are a cell type that make myelin um that sort of fatty white structure that's important for you know electric signals being fired throughout the you know brain and it it's basically toxic to them so you basically start to have these in you know lesions and stuff in the white matter part of the brain white matter hyperintensities as you're probably very familiar with a very common in small vessel disease also you can see that in people with Alzheimer's as well but you know um getting that fibrinogen in the brain like that that's happening because it's allowed to get in there and that you know so so the the permeability of the broad brain barrier again like as you mentioned you know basically preventing stuff from getting in your brain that you don't want in there that's number one but also the trans support I think you also alluded to this you're not getting things like glucose into the brain and in fact all these Transporters they're they're in the endothelial cells they're in these these these cells that are that are making up the blood-brain barrier and when you start to disrupt that blood-brain barrier those Transporters like are dysfunctional um you know so you're for example one of them is the glute one transporter this transports glucose into the brain as you start to get a disruption in blood-brain barrier function glucose Transporters they go down and and so you're talking about like not getting enough glucose into the brain which is again that's one of the you know pathological features of Alzheimer's disease right not getting enough glucose into the brain that's actually an interesting explanation because a very subtle point you made that might not be picked up on everybody is you mentioned the glute one transporter as opposed to the glute4 transporter and if my memory serves correctly the brain has glute ones as opposed to glute fours and glute ones are insulin independent is that correct yeah for the most part I mean it they're insulin independent I mean that's that's my understanding um and why that's interesting is because it seems a bit counter-intuitive that a condition that leads to insulin resistance of course type 2 diabetes is the essence of insulin resistance it seems counterintuitive that that would produce a hypometabolic state in an organ whose glucose Transporters are insulin independent except when you explain it the way you did which is it's not the insulin resistance of the glute one transporter that's the problem the way it is for the glute4 transporter in the muscle instead it's the actual mechanical disruption if I'm understanding you correctly of that transporter because of the way it's no longer presumably held in place by the barrier itself that allows glucose to get across is that did I did I understand that correctly okay 100 correctly and then this is you know this isn't like Dogma like this is like this is definitely known it's definitely where I'm heading it's my opinion but there is evidence of it and I think I'm I think it's time to explore this evidence a little closer and a little deeper because um type 2 diabetes and it you know you hear that the term type 3 diabetes and I think people think about it in the way of the brain being insulin resistant and you know maybe there's something to that but I you know I don't know if that's exactly what's going on I think the type 2 diabetes is disrupting the blood-brain barrier through a variety of mechanisms including you know the the advanced glycation end products and the vascular I mean the vasculature disruption in type 2 diabetes is well known I mean they have all sorts of you know problems right retinopathy that you know the the neuropathy like all this I mean they're they they're disrupting their vasculature including these tiny tiny little blood vessels that are like smaller in size than are like the diameter of a hair those things are like disrupted at the blood-brain barrier and when you disrupt them your their blood flows decrease and the Transporters are going down I mean there's all sorts of problems and so I think um you know fixing the diabetes obviously would be like the you know Downstream thing to do but like it's kind of a new mechanism right it's kind of a new way of understanding it and um you know so right in other words it explains the observation so there's an observation that is unmistakable which is type 2 diabetes I don't know the number but I think it approximately doubles your risk of Alzheimer's disease so in other words even if you're sitting there walking around with two copies of the APO E3 allele having type 2 diabetes means you might as well have a copy of an E4 allele from a risk perspective and what this is saying is well it's not entirely clear at the surface why type 2 diabetes would impact the brain through the lens of traditional thinking of glute4 Transporters which are insulin dependent in other words it isn't just an insulin resistance problem but I think these two other things matter right this what you said about the microvasculature again what I think a lot of people don't realize is how destructive type 2 diabetes is to the kidneys um right because those tiny tiny blood vessels right people are familiar with amputations and things that occur in digits because of that impotence right all of these things where blood vessel is essential in small blood vessels and so there's that which feeds into the vascular path that you've discussed but it's this also this disruption of glucose transport directly across that transporter so I think it's actually a very compelling thesis for how type 2 diabetes could be acting via those two prongs um to to ultimately result in high hypomatabolism I do too yeah and um and then of course the Cascade of inflammation that happens after that so um you know the other thing that's also very interesting is and again this so we're talking about type 2 diabetes and very big implications there for the prevention of Alzheimer's disease right I mean you there's a lot you can do as you've talked about you know to prevent and even you know treat you know with diet and lifestyle right type 2 diabetes but also um what's really interesting and you know I was sort of on this Trail years ago I published a sort of Integrative review on the role of the omega-3 DHA transporter mfsd2a in the brain and um what's really interesting that is that animal studies when you disrupt that transporter it causes like 50 you know breakdown of the blood-brain barrier and like like greater than 50 loss of Omega-3 in the brain so in my opinion it's sort of it's It's you know that's animal evidence of course there's human evidence where mfsd2a Transporters decrease with age particularly rapidly in Alzheimer's disease and with apoe4 it leads to so there are genetic you know abnormalities and mutations that occur in that transporter where people have less of it and they have microcephalies they have like smaller heads and they also have cognitive dysfunction um sort of cognitive impairment things like that as well um how do we know that Rhonda so that's um let's even put the pathology aside the the the sort of Latter category but let's just talk about um well again what you've said explains something we've empirically felt is true and the evidence suggests it but this provides a mechanism right which is APO E4 carriers need a higher level of EPA and DHA to get the same benefit that appears to be empirically correct that would provide an explanation something else you said is it's almost like you know we talk about amino acid or protein uh resistance basically um anabolic resistance as a person ages they need more and more protein to get the same effect it's almost like you're saying if you know aging itself could create some resistance to dietary EPA and DHA that might require more as time goes on do you think there are also just genetic differences within the variant of normal quote unquote I.E non-pathological where one person would need more EPA and DHA to afford them the same benefit of protection as another person I do I know there's at least a couple that are known um and and so like some people have certain Gene variants that actually they respond better to for example omega-3 supplementation and others don't um where they would actually need a higher dose and I think there's many more to be explored like we haven't unlocked all of that yet when I say we I mean the scientific Community not me not me personally um but I I do you know with the omega-3 and this again really hits home the preventative sort of role here that we can you know have in our Alzheimer's disease risk I so with the mfsd2a like this the these Transporters are actually lost um so there's a type of cell called parasites pair e with an i not to be confused with a parasite they um they back they basically have these like big feet that wrap around the endothelial cells at the blood-brain barrier and they serve really too important many important but two main important functions one is they are they're basically constricting and dilating and like helping squeeze like the flow of blood so they're like they're regulating blood flow to the brain but they also are very important for that barrier and they start to fall off with age these parasites and inflammation plays a big role on that um but the mfsd2a Transporters are concentrated on those cells too right and so you'll see like hot spots of where the parasites basically when Once those pericites start to fall off that is uh when basically immune cells and everything starts going into the brain it's like the start it's like the start of the vicious inflammation cycle in the brain of the leakage amyloid accumulation just everything Downstream right and so um those there's something there with those Transporters of Omega-3 that are right at the same site you know of where you lose those parasites which is also really interesting and again there's a lot of animal evidence that suggests the role of that transporter in blood-brain barrier Integrity also again you can kind of like Connect the Dots here where you think okay well this is a DHA specifically a d it's DHA and phospholipid form transporter so it's like okay there's got to be something here with the omega-3 and you know there's I know there's a variety of scientists that are investigating this but I'm sort of excited that I I am now going to be part of of a team so I I've joined the fatty acid Research Institute which is Bill Bill Dr Bill Harris's Research Institute and as a research associate associate and we are we've sort of secured a small Grant to look at the role of omega-3 with blood-brain barrier integrity and biomarkers and people a variety of different people that have small vessel disease that perhaps go on to get Alzheimer's disease and so I think there needs to be more research in this area because it really it the implications here I think are really important with omega-3 intake I mean it's one of like you know so there's two main lifestyle interventions I think that that are important with with respect to the blood-brain barrier three actually three so not basically not getting or fixing your type 2 diabetes and then the omega-3 intake and like defining that will be sort of tricky but you know full stop most people in the United States don't they're not eating enough fatty fish and they're not supplementing with omega-3 which is sort of an alternative and it was like I think it was like a 2012 study out of Harvard that identified omega-3 low omega-3 intake from fish so the Marine type of Omega-3 not not the plant AOA as one of the top six preventable causes of death so it was up there with basically like it was smoking and blood pressure and you know obesity and being sedentary low omega-3 was like it blew my mind and the the they calculate there's some you know I'm not a biostatistician but there was some calculation done with estimating the number of deaths caused by not getting in enough Omega-3 each year it was like the same as the same number of deaths it was like 84 000 deaths a year from low omega-3 intake from fish I wonder though if that's also just a marker for poor health I know that's the challenge of all of those studies right is totally in some cases with smoking it's pretty obvious that there's causality there I think there also is with blood pressure um I I but you know you could argue that never in the history of the world has there been a person who has you know I'm making I'm being a bit facetious who has you know a high omega-3 index who eats junk food and fast food all day right like those those can't co-exist I want to ask one clarifying question Rhonda certainly I know that when you're talking about Omega-3s you're referring to the Marine variant of which we have EPA and DHA but the transporter if I understood correctly is it a transporter only for DHA and it's phospholipid form and if so where what is the importance of EPA in this great question um so the mfsd2a transporter that I've been referring to is specific to DHA and DHA the form of DHA is lysophosphatidylcholine DHA and that you know so that that specific we make it and so we basically get when we take in DHA from fish or from a supplement uh our bodies the higher amount of DHA that we take in we add that lysophosphatidylcholine group to the DHA we also have DHA and free fatty acid form bound to albumin and albumin is not supposed to that doesn't get into the brain but it takes it to the brain blood-brain barrier and the free fatty acid can sort of diffuse passively across the blood-brain barrier as well same with EPA with respect to your question oh I see but because the phospholipids on the DHA it needs a dedicated transporter whereas the unphosphorylated we're not phosphorylated the one that doesn't have a phosphate a side chain phosphatidyl lipidine can diffuse without a transporter exactly yeah so there's that so it's free fatty acid Bounty albumin and it can just diffuse across okay brain yeah so that's how EPA is generally getting in the brain and then second question for you on that thread uh and feel free to go into as much depth as possible because I know this is actually a very important topic that is somewhat controversial what do you see as the relative importance of DHA and EPA the 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 um so you know my the way I personally think about both EPA and DHA so there there's a variety of metabolites and of DHA um that are involved in resolving inflammation so these are resolvins the marisens the spms protectants and EPA also has uh some of those metabolites as well and it also plays a direct role in inflammation through the sort of um I don't want to say inhibition but like dampening the prostaglandins and glucatrines and a lot of the other inflammatory processes so it's kind of like a an approach where your your affecting inflammation from multiple ways right it's like a multi-pronged approach and I mentioned fibrinogen earlier about like fibrinogen you know it's an inflammatory protein well it's involved in coagulation but it's a mar is something that we do measure as a marker of inflammation so um there's studies showing that people that are exposed to particulate air matter their fibergenic fibrinogen goes up but if they have a higher dose of Omega-3 or higher intake of Omega-3 it blunts that effect again through the inflammation right so you know both DHA and Pa are important in my mind for the brain as well I mean there's a variety of studies that have looked at even depression and like you can 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 millions of those in our gut in fact there's about one gram of lipopolysaccharide or LPS for short it's also referred to as endotoxin there's about one gram of that in our gut well you can inject people with a low dose of that something that actually would be somewhat 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 you know this is like this is a field that's again understudied underfunded but you know some preliminary evidence randomized controlled trials small randomized controlled trials that need to be of course repeated with larger sample sizes you know they're basically showing that supplementation with EPA can help with depression yeah this is such a frustrating thing for me and I obviously I know it is for you and for many others including Bill Harris um if you took the cost of one phase three anti-amyloid failed drug trial just take one of them right like 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 you know something that's really interesting like the optimal supplementation of DHA in the right patient population group we could have an answer and yet you know for obvious reasons there's an incentive to do a phase three drug tile on a candidate with an IND uh there's not an incentive from a financial perspective to study these other things um and I think for a disease like Alzheimer's disease that's particularly problematic because as I suspect we'll discuss you know unlike cardiovascular disease where yes prevention is still the best strategy you can come in late to the game and still make a difference I don't think the evidence is particularly compelling that that is true for Alzheimer's disease now I'd love to be wrong but I have yet to see compelling evidence that you can be a Johnny come lately to that pathology and have an impact it's hard to fix those leaks in the brain once they're started right I mean and that and that also is why I think there have been failed trials also with there have 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 like you you know patience with high triglycerides or cardiovascular problems four yeah I know at least four you know this is this something that has the safety of a nutrient but literally acts can act like a pharmacological drug you know it's you know higher Doses and so um I I agree with you I think it is much more challenging to fix you know when you when you have Alzheimer's disease and certainly like I'm talking about like the leaks in the brain but like then what happens after that the amyloid accumulation and like when you start to get to this level when you're you've got all of that I mean good luck it's gonna be it is going to be challenging and you're going to have to take it's not going to just be fixing the amyloid you're going to have to have a cocktail that are going multiple angles I think in order to get some improvement I think the amyloid and perhaps also fixing this the blood-brain barrier leaks as well maybe at the same time with the cocktail may help a little bit but prevention is the way to go I mean like it's so much better to not get Alzheimer's disease than to try to fix it once you have it because it's it is a very complicated disease with lots of things going on so um you know I think that the strategies that that can be done um and they're not that child they're not that difficult right so we talked about type 2 diabetes I mean there's there there's no there's no reason why someone should have it like right I mean like you you should be able to yeah it's I would I would phrase it as I do not believe for a moment the type 2 diabetes is inevitable to our species whereas I do believe atherosclerosis is inevitable of course I also think most people don't need to die of it so there's a there's a that's a very Stark contradiction the disease is inevitable as in as much as humans will have lipoproteins that carry apob we will get atherosclerosis but again we have the technology to delay the onset of that disease to the point where it should not be the cause of death we should be dying with it but not from it I would also argue that cancer is inevitable to our species I it you know it is simply a stochastic problem where if you live long enough and if you accumulate enough genetic mutations and we can do lots of things to reduce the risk of that and to delay the onset of that and to detect cancer early and be more successful in treating it but the incidence of cancer strikes me as something that is inevitable with enough age I actually don't feel that way about type 2 diabetes in other words I think I share your point of view which is it's not something that is necessary we don't have to eventually get it and I think that makes it all that much more tragic that you watch how many people are suffering from this disease and how much damage it's causing not just in the disease itself but as you said it's such an amplifier of the what I what I refer to as the horsemen right it's what it does to your risk of cardiovascular disease cancer and Alzheimer's disease is actually why the death toll for type 2 diabetes is so grossly underappreciated yeah it's accelerating the aging process right I mean like the the molecular yeah it's gasoline on the fire of Aging I don't I do I am I would I'd have to really reflect on it but I can't think of a process that accelerates aging more than type 2 diabetes right I mean maybe a morbid obesity but like they're probably also type 2 people I would argue only only in the context of insulin resistance which gets us right back on that path yeah yeah so right um so I mean I think the good news there is uh not that it's easy but it's like we sort of know what it takes to to treat it and prevent it um and it doesn't necessarily look like the strategies that are being deployed unfortunately at the level of the Ada I want to ask you one other thing that we haven't talked about but I I want to know if it pertains to the blood-brain barrier at all and that's blood pressure so hypertension and I guess hyperlipidemia also pose enormous risk for not just cardiovascular disease where they are two of the three biggest drivers of risk but they also pose a risk um in Alzheimer's disease and I I wonder do either of those act specifically through the blood-brain barrier it is another really uh important modifiable lifestyle factor that can affect Alzheimer's disease risk and you know so blood pressure maintaining good blood pressure so I mean basically you want to be systolic below 130 right I mean like once you get to 130 the Sprint trial would even say 120 120 yes yeah um and the the blood pressure itself so getting that blood flow to the brain blood brain Bearer specifically is so important um when you don't have you know that that when that blood flow doesn't you know basically isn't able to get to the blood-brain barrier well enough um those tiny little vessels start to like just fall off and it's one of the reasons why exercise also is so so important um so yeah blood pressure there's been a variety of studies that have looked you know of course as you mentioned you know the the observational data is is never able to establish causation but it's still an interesting point to look at in combination with many other types of data right but especially when it's always in the same direction I mean I think that's what always that's what differentiates the epidemiology around for example exercise and blood pressure from the epidemiology around nutrition the epidemiology around Nutrition a it has very low Hazard ratios and it's always changing the direction it's moving in suggesting that whatever's being studied probably doesn't matter yet when you look at you know the epidemiology of smoking blood pressure dyslipidemia exercise much bigger Hazard ratios virtually always pointing in the same direction so it strikes me that the latter is signal the former is noise right good point um yeah so blood pressure is associated particularly um so you know 50 of people adults in the US have hypertension and about 20 of young adults like we're talking people age 18 to 39 have hypertension like that's crazy right and and it's actually the the high blood pressure it's the cumulative exposure to high blood pressure that's really damaging the vasculature and so it's the younger people um it's the people that have it earlier in life that should be the most concerned and are the least right those are the ones that are like 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 you know the 50s like so when you start when you get it in your you know before the 50s or you know midlife once you start to get high blood pressure in older age like 70 80. it's not as much associated with you know the the Alzheimer's disease and dementia risk so um it really does seem like cumulative exposure is the the key factor there but um you know again one of those things that you know is a lifestyle Factor that's easily modifiable exercise improves blood pressure sauna improves blood pressure right those are two you know basically low-hanging fruit lifestyle and interventions some people do have Gene polymorphisms where they're very sensitive to salt intake instead of intake and and that combination of those people with like a higher sodium intake really seems to Skyrocket blood pressure it also I think is one like you were mentioning nutrition I think it's also looking at the combination of genes and diet most nutrition studies don't do that like they don't and there is an interaction going on and I do think that's why some of the sodium intake blood pressure literature is just a little more um yeah it's all over the place complicated yeah right I wanted to ask you a question about exercise but before I do that I want to actually pick up on something you just said how optimistic are you I don't know let's bracket this with let's say in the next decade that we will have more of a sense around what Precision Nutrition looks like as it pertains to genes and polymorphisms of them in other words people talk the talk like oh I did this test and it told me I should be eating this that and the other thing but the reality of it is there's nothing that's available today that's come close to offering that type of insight a do you believe that that type of insight is available you used one example which I would agree with you on which is that there are probably different levels of genetic susceptibility to sodium that might suggest one person needs to be eating two grams a day of sodium and another person needs four grams a day but do you think it will get further than that and How likely do you think we will be to extract that information I I do think 10 years we're going to know a lot more about you know Precision Nutrition um obviously Precision medicine as well uh because there's also an interaction between you know pharmacological treatments and genes as well as you know so um you know in 10 years we're definitely going to be a lot further than we are now the the problem is and this is this is always the problem we've already alluded to it a few times is the incentive for funding to study those things that aren't necessarily going to be super profitable um it's you know you the the the the government the NIH we get there's a certain amount of funding that you can get from them and and they often like to study one sort of thing you know it's hard for like the nutrition when there's like multiple things involved it's like they're just like too complicated you know um and so you know there's a lot of funding from Pharma industry for example and then they put in lots of money because they are incentivized to do that when it's a when it's a drug right so um that that's my one concern with the I would say gene diet interaction when it's more on nutrition but there there are people that are there's a there's it's a growing field of research for sure and I do think with there's technology is advancing too I mean so at the point that our technology is advancing with AI and stuff I think that's we're going to start to see an exponential there honestly so I am optimistic that in 10 years that's going to be a lot easier to sort of delineate what a person should eat based off of you know their the genetic makeup you know versus just what you know generally we think is healthy and and do you think that that will be at the level of macronutrients or micronutrients like what what do you think how much heterogeneity do you think there is among people as it pertains to factors like that I think both for sure I mean there there's there are there are differences in the response to macronutrient intake and the response to micronutrient intake and there are people you know like there's there's vitamin D polymorphisms right where people um you know for whatever reason they actually even so so maybe they they evolved in a place where they were so like there was so much um sun or something like I don't like I don't know what the cause is but like some people they have to supplement with high doses of Omega-3 to get uh you know to be able to convert the vitamin D cursor to actual the hormone right the steroid hormone um and and so and that's and like you know that's just one example there's selenium I mean there's there's magnesium there's a lot of different micronutrients that are off and there's omega-3 there's omega-3 as well exactly there's B vitamins yeah so I do think that it plays it does it will kind of more people are looking into it and again 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 you know that's how it works right so um yeah that's kind of where I think it's going and I'm excited about it I think that's where it needs to head I think it's going to clear up as you mentioned all the conflicting data with nutrition I mean nutrition studies are a mess designing the right trial I mean the part of the reason for that is because we have evolved these genes and when it's a drug and you don't have I mean with it with the exception of yes there's there's the the cyp enzymes and stuff that help us metabolize xenobiotics things that are not a vitamin or a mineral or essential amino acid or fatty acid rights I mean it's foreign to our body but by and large when you give someone a drug like they're starting with zero levels of that drug in their body and you give them the dose that you're giving them it's like clear you're giving them a dose and it's it's going to be different than people getting a placebo right it's going from zero to something whereas when you do this nutrition study a micronutrient you know you give them a vitamin or a mineral they're not they're not nobody's starting with zero for one your your placebo group could have high levels of that and unless you measure something you'll never know right so it's it's very different when you're in all the trials are sort of um they're trying to mimic that gold standard of a randomized controlled trial with a pharmacological drug and it's just you you can't you have to like put in so much more effort with nutrition with the drug you don't have to start doing blood samples of this and that and measure the drug and make sure people aren't deficient in that drug of course they're deficient in the drug before they start the trial they don't it's like a drug you know so um yeah it's such a good point Rhonda and I'm going to use two examples to highlight why this is so important and because it ties to two things we've been talking about right so if you look at how a blood pressure trial is done it is exactly what you say it's titrated meaning it's done the way a Pharma trial is normally not done so a blood pressure trial says let's just bring in a whole bunch of people with high blood pressure okay you guys on the placebo or on the low treatment arm we're going to manage you to a blood pressure of 140 over 90 but no lower you guys in the treatment arm we're going to manage you to 120 over 80 or better and by the way we're managing to the outcome not the drug so I'm agnostic as to whether this person needs a higher dose or a lesser dose we're checking the outcome here and so if we did a vitamin D trial that way it would be a very different trial and one of my biggest criticisms of vitamin D trials and why I think we don't have an answer as to whether supplemental vitamin D is valuable is they don't do this you take the people you divide them into two groups you give one group of placebo you give one group usually a very low dose somewhere between two to four thousand IU daily but we don't actually know what the level goes to in other words a better vitamin D trial would be we take a bunch of people whose vitamin D is below 30. in one group we give a placebo and in another group we give whatever it takes to get them to I'm making this up but 80. then we would see is there a difference between this group that's below 30 and this group that gets to 80 regardless of the dose it took to get them there because of course that may include part of the problem so I think your point is an excellent one and I think it's something that listeners need to be aware of when they're scrutinizing Trials of this nature which is a negative trial doesn't mean the thing doesn't work if the trial wasn't designed correctly right and it often it's I mean it's a matter of money too right like to measure all those things you know it's just 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 it's you know it says that vitamin D supplement supplements do nothing yeah it's it's it's a big problem and I do again I think as you know our Technologies are advancing that that's going to become less of a problem as well um so I mean at least I hope I mean I guess you never know but um yeah so I want to go back to something you talked about earlier which is you just touched on exercise and um 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 it's exercise but I think there's a reason for that right it's not just that I love exercise it's that the the evidence is overwhelming that a person who exercises especially at the right amount right like we're talking not just 30 minutes a week type thing but if you're really doing the work you're having a greater impact on the reduction of risk of Alzheimer's disease than any other intervention you can take now there are lots of interventions that matter sleep matters nutrition as we talked about type 2 diabetes all these things matter but but the risk reduction that comes from exercise is enormous what do you think are the mechanisms by which that is happening because I suspect there's many oh definitely um there's definitely many mechanisms happening and um I would I would first of all 100 agree with you like there's nothing better than exercise and I mean of course any exercise is better than none but for me because as I mentioned at the start of this this podcast I'm very focused on neurodegenerative disease I specifically sort of design my workout routine based off of what I think are going to give me the biggest brain benefits and what I've sort of come to the conclusion of is that intensity does make a difference with respect to the neurobiological effects exercise intensity and there are some mechanistic reasons for that but just talking about like what's moderate intensity exercise what's considered vigorous intensity exercise right if you look at some of the recommendations out there by the Committees that have you know there's a team of scientists Physicians that sort of analyze all this data and then make these Health recommendations based off of that data it's 150 to 300 minutes of moderate intensity exercise which I think they Define as like 50 to 70 percent of maximum heart rate vigorous intensity they they say you know 75 minutes I guess a week um and that would be more of you know you're getting above the like 75 to 85 max heart rate so um that's that's what they I think Define as something like that vigorous and they have a variety of examples you know there's there's the World Health Organization and um you know there's a variety of committees that are sort of they come to that same conclusion uh for me I like to go higher intensity and this is something I kind of was looking forward to talking to you about because it has to do with how do you measure like so there's the there's the Mac the estimated heart rate which is what I do I've estimated and again all sorts of problems with that based on your physical meaning as estimating your maximum heart rate to take a percent event okay right yeah right I mean so so basically you know like if the more fit you are like you could be doing a more vigorous intensity exercise but your heart rate like doesn't go as high as someone who's not fit right um and then people that are older so there's of course I would say problems with that but um generally speaking that's one way but I'm also very interested in lactate and I know you are as well um for me I I actually want to get my lactate levels high like High um and and the reason for that is the neurobiological benefits so lactate as you know was once thought to be this sort of and metabolic byproduct with no like it was like you know useless well not only just useless actually it was thought to be harmful right so um at least to Performance yeah right harmful to Performance with respect to people thought it was like causing their muscle soreness right and that's sort of you know as you know now that it's not it's not lactate it's the the proton buildup right so lactate is sort of in homeostasis of lactic acid and it's the protons that we're sort of responsible for that and neither of them are responsible for the soreness you feel the next day that's the micro trauma of course like the the soreness and the burn from the hydrogen ion is gone you know minutes after you stop exercising right yeah yeah exactly uh so the lactate that gets into so you're generating lactate when you basically are pushing your mitochondria inside your muscle cells to a point Beyond they can where they can generate enough energy in the form of ATP adenosine triphosphate then they sort of have to figure out another way like your cell has to figure out another way to get the energy right so this is where glycolysis comes into play so this is happening outside of the mitochondria and I'm sure your listeners have heard all this before but for those that haven't you know the the lactate generation is then from from that you know metabolism of glucose outside of the mitochondria and that's happening when again you reach that threshold of you know basically you're pushing your your your muscle cells hard enough and their mitochondria can't keep up with you know producing enough energy so the lactate itself and this is this I mean these studies date back to like the 70s uh it's been shown that lactate that it gets into circulation and it's used by other organs as a human source for one as a fuel yeah and the Brain being a big one and and this is now you know this has been you know Decades of of research but um Dr George Brooks has you know he was like one of the first to propose this lactate shuttle Theory and he's you know of course provided evidence for him for that as many others have as well where you know during exercise and after exercise the lactate that is generated you know from muscles that gets into circulation is consumed by the brain this has been shown in humans and animal studies of course but it's consumed by the brain and also not only is it consumed uh it's acting as a signaling molecule and increasing at the blood-brain barrier it lactate itself has been shown to be responsible for the production what's called veg F this is a it's a vascular endothelial growth factor veg F and what it's doing at the blood-brain barrier is it is growing new vessels and repairing damaged one so that brings it back to what we're just talking about right the damage the vascular damage at the blood-brain barrier lactate itself is a signal to increase that veg f it also increases brain derived neurotrophic Factor bdnf at the brain at the blood-brain barrier and in the brain as well um and so you know where is bdlf produced many places many places it's produced in it's produced in in in the capillaries and in the vascular system in the heart and muscle is produced in the brain um and so the brain so exercise increases brain derived neurotrophic factor in many different parts of the body in many different organs and tissues and it's really interesting because there's some evidence that the sheer force of blood flow so essentially like the more vigorous you are exercising your blood is just your heart's pumping right and your blood is just going faster right 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 but um it also increases bdnf you know in in muscle which it plays a role in repairing damaged muscle it's it increases in plasma brain Drive neurotrophic Factor although there's a little controversy controversy about this it can cross the blood-brain barrier and it also is produced in the brain as well so all of those things and brain Drive neurotrophic factor is a really important for many reasons I mean it's a um it's a it's it's important for long-term uh potentiation it's important for neuroplasticity so long-term potentiation is you know they're maintaining that can basically strengthening the connections um of the synapses that are connecting neurons it's involved in in basically long-term memory form uh retention but also um 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 and it's essentially I think a really easy way to think about it is uh your brains like your ability to reshape and restructure with the changing environment and like like as you're aging things are changing in the brain and like you have to be able to respond to that like your 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 Drive neurotrophic Factor plays an important role in that but I am going for higher lactate and um so I much to you like to your basically I based off of your recommendation I got the lactate meter the Nova the one that you have and I've been I've been using that to kind of try to get my lactate higher um than typically what I think you are doing with your um a completely different type of um training well we do we do kind of both ends right so on the one end of the spectrum what 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 the way I describe this to people is the way one of my coaches described it to me when I was a you know uh fledgling cyclist your aerobic capacity is a pyramid and the area of that pyramid is your total aerobic capacity and to have the largest area of a pyramid you need the widest base and the highest peak right a pyramid with a narrow base and a high peak yeah not as good a pyramid with a very wide base and a shallow Peak also not great you want wide base high peak well in that analogy the base is your Zone 2 threshold right it's how much work can you do while keeping lactate at that sort of threshold that George Brooks and you go saw Milan talk about of about two millimole so what differentiates the best aerobic athletes from someone you know say with type 2 diabetes which would be the opposite end of that Spectrum where you have real metabolic dysfunction or rather mitochondrial dysfunction we're talking a four-fold difference in watts per kilo output and you just have to train at that level you have to get to that threshold and train right there so you know this morning that was the workout I did right was a zone two ride where I'm just riding right at a lactate level of 1.9 millimole was where I was today but you do need to do what you're describing as well you have to do the pyramid building you have to build the peak of that pyramid those are the VO2 max sets and you know generally The Sweet Spot for building those is three to eight minutes of all-out effort for the respective um duration so obviously what you can do for three minutes and no more is harder than what you might be able to do for eight minutes or no more my favorite are four minutes so for example on Sunday that was my workout it was I actually did an hour of that zone two 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. and 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 so yeah long-winded way of saying you want both right you want to build that pyramid to be as wide and as tall as possible what I don't think I appreciated though was that the brain is getting a benefit from those lactate Peaks yes it's getting a benefit and they don't like you know it's cleared quite quickly yeah so I mean like you know I mean it's minutes if you do nothing it's yeah if you just stopped you know you'll I mean and of course athletes are even better at this right like an amazing athlete would clear lactate Within you know they'd go from 10 millimole to two millimole in minutes yeah for me um yeah like you know 20 minutes later I'm back to my 0.9 you know millimole Baseline but um you know that that lactate also is is it's it's important for neurotransmitter synthesis your your um making glutamate the major excitatory neurotransmitter of the brain it's it's important for making precursors to that norepinephrine I mean these are all been shown in human studies also animal studies um so for me I do a lot of Tabata training and um so that's even more intense because you're only doing 20 seconds on and 10 seconds off so that's that's really intense yeah it is I do um and I do 16 of those um so I do you know like eight and then separated by like a 30 second you know break and then I do another eight um and four minute blocks yeah and then well it's a total of about 10 minutes but um so the first minute I'm in like zone two and then by like the end of that minute I'm like zone three and then I go into zone four like you know so it's like what are you doing this on are you doing this on an air bike I'm doing it on a Peloton right and my Apple watch is is you know beaming my heart rate and my zones um on to my screen which is kind of they're all estimated of course again uh you know so but but I do that five five days a week it's again I think um you know the for me the efficiency also so I'm trying to maximize the the neurobiological effects for me with exercise and I really find um pretty compelling evidence that intensity is really important with respect to that for for the brain not that there isn't a benefit for you know lower intensity exercise uh but and it's certainly people doing you know moderate intensity like the more time you put in like the volume of training right is like you know you're gonna probably find some equivalent there right but with the lactate though that's the one mechanism I'm like that is really something I personally am trying to optimize for and I it it's definitely a consequence of intensity right um but and and the fact that uh it's it's cleared so quickly uh and it's transient like I'm wanting it on I'm wanting a lot of it like each day I'm wanting to keep doing it right like so I kind of I do those those types of training but you know there are there are other ways to do it that you might want to consider right so you might want to say look I'll do those tabatas two days a week I'll do some longer slower cardio and to be clear like when I'm doing that zone two it's still it's not trivial like I mean I'm still my heart rate's still 140 when I'm doing that zone two um but what you could do is use Blood Flow Restriction um when you're lifting weights on the other days and that will get your lactate through the roof so um four days a week you know I'll do Blood Flow Restriction at the end of every workout so uh two days will be upper body two days will be lower body and especially on the lower body days so you've got these huge cuffs at the upper part of your thighs and I'll do you know leg presses leg extension leg curl and finish up on an air bike and by the time you take those cuffs off all that lactate that's been pooling in your legs for 10 minutes will flush through systemically and your systemic lactate level surges so even though your levels get to what's your life oh I mean not as high as I would get on an all-out Sprint I mean like the highest I've ever had my lactate is about an 18 or 19 but I can still hit the mid teens doing um doing Blood Flow Restriction so that's incredibly High yeah point you know it's funny when I used to coach uh 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 you're lactate is 26 is is comical to me but he could he could finish a swim race like a something like a 400 individual medley which is you know probably the highest lactate generating race there is because it's all out upper body lower body assault have a lactate of 26 to 24 to 26 millimole and four minutes later jump in the pool again and do a race and and enter the pool with a lactate of maybe six it's pretty amazing that's amazing what um so so my point is like you could diversify the training a little bit and if you're still because again you'd still get that lactate hit but you'd also be diversifying the training um because I do think performance it's hard to make the performance gains if you're really doing an all-out Tabata five days a week I think that is hard 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 right you're you're trying to get as much power as you can in those 20 seconds um and that those are those are what we call match burning workouts like you're you're you're burning all the matches that day right those are yeah I'll tell you something that's interesting I started I don't have you ever tried doing an aerobic or a high you know high intensity workout with like mouth tape where you're just breathing through your nose um so I mean you're limited of course I mean at some point you're you're not going to get to your you're going to be limited by depending on you know for me at least I'm I can't do my all-out best without mouth breathing at the end once I reach 215 to 220 Watts I can't sustain maybe 225 Watts I need to start breathing through my mouth I need to at least every other breath use my mouth and I I would expect everybody sort of different there right exactly 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 like I'm I pr'd the first time I did it and I I didn't you know like I wasn't going as hard on my all outs but I think on my rests I was going harder on my 10 seconds off I was like not really bringing my resistance down have you tried doing it where you do nothing on the off a pure off what do you mean just like keep going don't don't yeah don't don't spin whatsoever so do the 20 seconds all out and then the 10 seconds you're not spinning at all oh I've never tried that give that a try well I think the goal is to make the hard as hard as possible and so being truly off for 10 seconds will make it more likely that you can deliver the maximum wattage during the 20 seconds okay I've been doing I've been trying to do the opposite where I'm like okay am I off I like keep I'm like you know zone three I like I'm I'm really like uh I'm still I'm still I'm still putting in quite a bit of um Power right like that that's good too I don't want to say just that there's you know those are those are we used to call that sweet spot workouts where you would go zone three zone five zone three zone five zone three zone five um but what you really probably want to be doing in a Tabata is zone six Zone one six one six one what's zone six it depends on the system so uh yeah yeah basically I mean so technically the literature on this would suggest that we are only able to hold full maximal effort for 10 seconds anything we do that's longer than 10 seconds we are applying some Governor to the system now so even so at 20 seconds you're true you're even if you don't realize it you're somewhat pacing yourself even if you're trying to go yeah I'm not doing maximum yeah I'm not I'm not for sure like my husband like he seems like he really gets to that all out but I'm not for sure I am I'm I'm definitely not maximum at my 20 seconds no way yeah that that makes sense because I don't think one could do that five days a week I think you would I think you would fry yourself you know it's also really interesting Peter is that though like by by like the fourth or fifth day um I'll still like I'll be I'll be pring so I'm always competing against myself and by what metrics by wattage oh the Peloton no no I'm not nearly as scientific as you okay so Peloton ranks you ranks you um based yeah based off of so but isn't it based on kilojoules or Watts isn't it based on average wattage it is yeah okay yeah but I don't know all those off the top of my head like you're writing everything down I'm not doing that yeah um but my lack but that doesn't surprise me Rhonda because the way to get maximum wattage is to hold your highest constant maximal 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 you are 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 it's what's that's actually what's called FTP functional threshold power which is what technically the Peloton is using to estimate your zones have you ever done the FTP test on the Peloton no so that's that's actually probably worth doing so if you go into the Peloton there's called 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 120 minute all out I prefer the 20 minute all out I think it's a better test it will take your average wattage over 20 minutes it will multiply it by 0.9 and it will say that is your functional threshold power which is defined as the maximum power you can hold for one hour and in cycling and Peloton uses this system that is the metric by which the zones are set so zones one through seven 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 right 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 you're using kind of a slightly different protocol where I think like 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 yeah it's definitely right no I'm definitely I'm definitely not doing it the way I guess uh and how high are your lactates and you check your lactate at the end of the both sessions after the two rounds after uh so it's a so the two round it's all like what continuous thing like it's you get like a 30 second you know rest period between the two eight you know sessions but like I'm again doing I'm not resting yeah you're going hard I'm going I'm like probably zone three yeah so um at the end of that now my lactate doesn't get nearly as high as as yours but I'm I'm typically like around seven to eight millimolar um so you know that could give you an idea of my maybe uh I you know I'm what I call a committed exerciser you know I'm not I'm not an athlete as I would consider you are I'm sure well actually it's it's it's actually quite different there's the best athletes in the world like world class right so both Michael Phelps and Lance Armstrong You could argue two of the greatest um 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 so it's not um it's it's not it's it's actually you know 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 it would be interesting to differentiate for sure I mean um you know but like I do know for example so when you are doing at least a high intensity interval type of training which I would say that this you know would you agree this yeah this type of thing definitely would fall into that um and of course there's a people generalize this term and stuff but that's a whole other issue um but like that does like you are sort of forcing adaptations on your mitochondria to make more mitochondria right because your your your body's like oh I no longer can use my mitochondria to make energy I gotta like 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 um in human studies right that you can you can increase mitochondrial biogenesis now also aerobic training does that as well but it's really a question of time I mean to me this is what sort of comes down to what you were saying earlier so if somebody says to me I've only got 10 minutes a day to devote to aerobic training what does it need to be well the answer is clearly it needs to be the type of training that we're talking about here now if someone says to me I don't want the minimum effective dose I want the maximum result then I'm going to say well would you be willing to give me 90 minutes a day in which case we could do we could build you the biggest pyramid basically right I need I need like an hour I need an hour a day to build you a mega pyramid um 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 um you know it I I get asked this question all the time um I think in 10 minutes a day of cardio and you know 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 like it's you know I'm sure when you're done that 10 minute workout there's no ambiguity about how hard you've worked um no not at all so it's not it has to be very vigorous yeah it does um and I do I do also use Peloton for my strength training as well and there's a lot of like paired sets and super sets and so it's like non-stop you know training where I'm I mean it's definitely like I'm putting effort in but it's not a long session either and um I do try to do that like it you know I'm I'm putting 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 and um I used to not do any you know so like even that's like um all right we have some we have some stuff we're going to talk about at dinner here because because there's 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 um do you dissociate in timing sauna from your exercise do you go right into the sauna after you work out how do you incorporate that it varies so I um I I do both a you know a regular what's you know dry sauna actually I don't use it as a dry sauna I I do a lot of steam um as well but but I do that but I also do hot tub so I do jacuzzi as well and both of those you know forms of heat stress have been shown to increase um you know heat shock proteins which is sort of a biomarker of heat stress and um both of them also been shown to increase brain Drive neurotrophic Factor as well so heat I think also plays a role in that like stress response but um I it depends on the day so I often will in this sauna I like to read scientific papers or listen to podcasts like like the drive or like I'll listen to like if someone's on Tim Ferriss issue like there's only a couple of podcasts that I ever listened to uh yours is one of them um so it's not like that's like my time or like because there's no other time like if I'm in the car with like my child like most the time I'm listening to you know Frozen music or whatever you know like it's not I'm not listening to to the drive so um uh so I so it's like what it depends on what I'm doing but also we I like to do do hot tubs at night so typically the sauna will be in the day so I do my workout in the morning I'll have this on a warmed up and ready to go and I'll get right into the sauna after my workout and I either have a paper in hand or I'm going over a presentation or something um I find it's really interesting I don't know if you've ever tried this or observed it but uh I've this goes way back to my you know days as a graduate student when I first started using the sauna I realized that like if I would go over a talk that I was going to give like a departmental meeting or whatever you know I was giving a talk if I went over it and thought about like what I was gonna say in the sauna man did I remember it better like it was like very clear that there was something going on with my memory and I mean 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 uh you know lo and behold there's like a very like there's like certain growth factors uh that you that you make um that in this in the sauna with heat stress that do affect like memory so um you know plausible plausible um you know hypothesis there but anyways so if I have something going on like a podcast or a presentation what's your protocol um what's your temperature and duration in the Sun so typically I like to it depends on how hard I went on my like my workout too or if I'm doing it like right after the workout or if I'm like midday just like I'm gonna take a break from what I'm doing at my computer and I'm gonna go read a science paper in the in the sauna so like it really all depends um generally speaking if I go in right after I'm I do my Tabata session I probably stay in about 20 to 25 minutes and it'll my temperature is like 175 degree Fahrenheit um if I am not going in right after a uh you know training session then I'll stay in longer I'll I'll stay in probably a little bit longer than 30 minutes um sometimes I'm pretty I'm pretty adapted too and my temperature will be you know 175 180 sometimes I also do the the humidity which makes it hotter feel hotter as well um so so I guess anywhere between 20 to 30 minutes and temperatures anywhere between 175 to 180. I find that I like I like I used to do really really hot and I just sort of like above like 190 like I was doing 190 and I it was giving me like my head I was getting headaches more easier and um and so I didn't you know I just didn't like it and I didn't feel good I was getting dehydrated how long did you sauna during your pregnancy how far uh did were you able to to and what do you what do you I'm sure women ask you this all the time and I I've never I don't I don't know that I have an answer to the question I didn't so I first found out that I was uh pregnant when I was um touring Finland and that like everyone was like it was like sauna right it was like we were going touring saunas yeah you're a son of VIP yeah I was and I'm like holy crap like what am I gonna do um so I I felt like at that early early stage I mean literally like I found out I was pregnant in Finland so um I I did do a lot of sauna touring and stuff and and cold and you know cold plunging and all that um at that stage but right after when I got on the plane come back home Sana was out and the reason I sort of aired on the side of Koch I mean you can I talked to women in Finland and I was and they were like oh yeah I sauna throughout pregnancy and like you know you'll you'll find those anecdotes and you know certainly certainly in that culture um but I you know there there is a body of evidence mostly looking at like hot tub um you know and it's this is common like it's common knowledge like pregnant women shouldn't get in the hot tub right I mean like like you go to any Spa like it's like um known but um there's there's a body of evidence that it can you know something might increase the risk of like sort of like a fetal alcohol syndrome sort of thing in Offspring where it's like or even neural tube defects so I was concerned that going in the sauna um perhaps could increase the risk of something like that and so I decided that it just wasn't worth it and and so I did not sauna at all like throughout pregnancy and I even waited a little bit like while um breastfeeding and stuff like I I waited probably like I don't know six months or so before I really got back into sawning now all the while I was exercising throughout pregnancy and so many benefits to that but um 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 I'm like we're in 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 right I mean it's like our time we're like out the Stars you know you know like dark sky like it's nice and um that is something that like my husband likes to do it like literally like he wants to do it every night because it helps his his sleep so tremendously um I don't have as much of an issue with like my latency or my sleep like in general um but he does like he falls like my natural bit like I'm asleep by 9 30 and it's like no like I can fall asleep within like you know I'm asleep in 10 minutes like I get in the bed and like I can be asleep in 10 minutes like he is not that way uh and so the doing doing the hot tub and he likes the hot tub that really helps his sleep so so I end up doing that a lot as well and sometimes I'll do like both I'll do the sauna and hot tub in the same day it just it all depends but exercise is the most important I mean like that's like like you know that 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 you know impairment you know you'll find all sorts of things but lit like I think the most common thing that is is pretty thematic is that the more effort you put in the more time you put in the the bigger the uh 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 proximately at a two-fold higher risk for Alzheimer's disease that's right super interesting but um so this is in women and they were studied for you know decades and I think it was like starting from like the 70s up until like 2010 or something and they came in um for a physical like they were like they were put on a bike exercise bike and they're like Fitness was measured like it was like empirical data okay and this was like I don't know five to seven times so like over the you know course of you know it was like 40 years or something exactly something like that um and and the and the women that you know were the most fit by their measurements on you know this like cycle test they did yeah it's probably VO2 max VO2 max um and I think yeah so it was cardio respiratory Fitness that's right and then um those those women that were the most fit had like a like they were like the reduction in um like Alzheimer's like Risk was like so robust I think there was something like um like there were nine times less likely to get or something crazy like that uh the ones that were moderate like so they had like a moderate cardio respiratory Fitness they were like four or five times you know uh like they had a four or five fold reduction but then you'll like look at another perspective study same deal where they cut like they they don't come in and get anything measured but they come in for a questionnaire or they get they get a questionnaire every you know whatever it was over the course of like 40 40 or 50 years or something and and it's like there's it's the 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 between physical activity and dementia risk and I'm like hmm like that's interesting because this other study where they're actually measuring something showed a robust reduction uh in dementia risk and so I again it go it hits home this like okay what study are we looking at like question you'll find questionnaire studies that also show you know a benefit like you know people that are physically fit and the more fit they are there's like a linear dose response effect right where you see you know people that put in more effort they're training for a longer period of time and they're um you know doing it more vigorate more vigorous or more volume both right like they have the greatest benefit with respect to dementia risk which isn't so surprising to me yeah but this the studies that are unambiguous as you said are the ones that actually measure VO2 max because there's no denying what you're measuring it's a very objective measurement and it basically takes out the training component because it captures that benefit it's the readout state of the training and it basically says look maybe it doesn't matter if you do five high intensity workouts a week or two high intensity five low intensity like what matters maybe more is the output I don't know if that's the case but but there's no denying that people who have a high VO2 max are doing something that people who have a low VO2 max are not and that's what's being captured in those studies and you know the numbers are astronomical uh you know I won't go into them again because people on this podcast have heard it too many times because I I can't I can't stop talking about the the benefits of having a high VO2 max um but I want to touch on something else you just said a second ago which is you you noted that that women are indeed at twice the risk of Alzheimer's disease to men um of course Parkinson's flips that men are at higher risk but focusing on Alzheimer's disease for a second is there any evidence that there are gender differences in response to exercise in other words are women more responsive to the benefits or more amenable to the benefits of exercise than men because they are at a higher risk genetically um it's it's studies looking at the response to exercise with respect to um you know the sex differences but like as you mentioned like there's definitely differences with respect to their you know Alzheimer's disease risk um so and I I do know like there are there are um different mechanisms that could you know like so women have different like there's different metabolic responses to exercise maybe also uh you know hormonally different I I'm just like this this would make sense right like I don't know that this has all been studied I haven't seen that data but like hormonally different responses to exercise that would be plausible immune system effects as well you know there's there's so many exercises affecting the immune system so we haven't even talked about like myokines like these are like you know these are molecules being secreted by our muscles we talked about lactate that's not a myokine that's a you know it's a metabolite but I mean we're physical activity when we force our muscles to work hard we're making something called a myokine sometimes it's referred to as an extra kind but like this is you know this is irisin is one il-6 is another um there's there's other ones as well but like these these are also affecting the brain and they're effective in cancer risk right there may be differences in in respect to like myokines that are being secreted uh with with respect to how um you know the stress of exercise how how that response is happening um let's dive into that let's talk about cancer because Rhonda while I think both of us are and and I think there are others who share this point of view completely convinced uh and I in fact I 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 right but I don't the data aren't clear right like you can certainly make the case that horrible sleep would lead to a weakened immune system a weakened immune system especially the cellular system more than the humeral system would easily lead to an increase in not necessarily cancer initiation but cancer propagation but again the data are are so much less obvious let's talk about this relationship between exercise and cancer right on the surface it should make sense exercise is good cancer is bad more exercise should mean less cancer how compelling are the data and I'll admit that I haven't gone as deep here as I have on cardiovascular disease and neurodegenerative disease so I it's also another area that I'm very very interested in because I mean as you start to get into your fourth decade of life you like you've you've now had a friend or a family member that has come down with cancer and you see just I mean I mean you're a physician so of course you've you've experienced it on you know at a different level but like you just see how terrible it is you know to get cancer and um in like and that it 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 I mean there there are definitely things that uh can modulate that risk that are a little you know genetic you know Wise that are harder to kind of move the needle but um overall so with respect to cancer incidents it's interesting if you look at like you you were talking about some of these elite elite athletes right I mean like people winning the Tour de France and uh people that are Olympic medalists or maybe that have even just entered the Olympics I mean you have to be quite an athlete to just get into the Olympics right and there's been a lot of interesting studies quite a quite a few um that I have seen and you know this is these are studies where um you know observational data again um so obvious obviously caveat with that looking at people um that have just entered the Olympics and you know over the course of like from 1912 to 2010 or something like that like you know just decades and looked at all cause mortality cancer-related mortality and compared it to like the general population so there's a couple of studies that have come out of the U.S and if you look at you know both of those studies one of them was actually looking at medalists and the other one was just looking at people that like were in entered the Olympics um they they saved about one and a half to two years like in in other words they were of life from not getting cancer and about five to six of just basically they they had a five to six year um what you could call lifespan extension compared to the general population same with like French uh French Olympians as well some very similar where it was like you know five years they lived on average five years longer than people you know than the general population and they were there it was attributed that they basically saved you know two years of life from not getting and dying from cancer um I guess I should say dying from cancer because they are two different things but that would be like at the elite level and it's interesting because you go well two years are just like that's it I mean that's kind of I that's how I see it I'm like really like two years um it's funny because I remember when I was a postdoc my my postdoctoral mentor Bruce Ames um he had said to me once or actually more than once um you know I once read you know there's of all the things that you can do like if you prevent cancer you really only save about two years of your life and I always thought I'm like no way no way um but anyways um so so that would be like at the extreme extreme end when you're looking at the the you know the actual athletes um they are they're definitely less likely to die from cancer than than general population people but when you look when you're talking about prevention so there's a difference between you know if you read a study and it says you know people that are Physically Active are X percent less likely to to you know die from cancer like cancer so cancer mortality is decreased that's not necessarily the same thing as not getting cancer right that just means you're not dying from cancer uh 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 you can find uh studies on you know strength training and cancer-related mortality but with prevention I really um it's it's sort of focused on for whatever reason on aerobic exercise and it does seem like there are certain types of cancer that are more responsive to exercise with respect to um you know basically having a reduced risk and some of those cancers are ones that that are we should care about so breast cancer you know what's the lifetime risk of breast cancer for a woman it's about one in eight it's pretty pretty high for the average woman right um of course many different lifestyle factors play into that and exercise you know is is one of those factors colon cancer is another one that seems to be quite responsive um lifetime risk of colon cancer for average woman is like 1 in 23 for a man it's like 1 in 25 or something like that the reason I'm mentioning as as you know Peter lifetime risk of can't like if you're talking about like esophageal cancer some cancer where it's like one in 500 I mean you're more likely to die in a car wreck than get esophageal like you know one of those cancers I think it was esophageal cancer but you get my point where the lifetime risk is is already kind of you know quite low for for the general person or the average person um so so breast cancer colon cancer and then uh there's a few other cancer types that are are quite responsive but those two in particular kind of stand up because with prevention um and also with like with respect to people that are diagnosed with cancer and have those cancers and then they engage in physical activity as well um it's very like you see a very robust response with respect to like reducing cancer mortality and also recurrence being you know being you know it's like 50 like so you see like you know cancer mortality is reduced by a 50 cancer recurrence is reduced by 50 in those individuals diagnosed with breast or colon cancer or colorectal cancer that are engaging in more physical activity so the question is well how much and you mentioned like you have a lot more knowledge with respect to cardiovascular disease and I would argue the data really I would say suggests that you actually probably need to do more exercise um to sort of reap the cancer preventative benef benefits then you do cardiovascular benefits you know even you know some of the metabolic benefits and I don't know why that is but um it seems as though you know like like getting more to that upper limit of what these you know committees are recommending so 300 minutes a week of moderate intensity exercise um or maybe 150 minutes more of like what they would Define as vigorous which actually I think is a little bit their vigorous is a little bit below what my definition would be but um anyway so so it seems like the the the amount of exercise you actually have to put in a little bit more time and effort for for the cancer but any any amount is beneficial so it's not like you know oh well I can't do 300 minutes therefore I shouldn't even care well that's not true because there is there are benefits you know even with like any type of physical activity uh so you know that's all the observational data and you can find anywhere between a 10 to 20 reduction in basically people are that you know they're less likely to get can't you know breast or colorectal cancer 10 to 20 again when you're talking about a type of cancer with a with a higher lifetime risk um it makes more it's it's more compelling right um so I'd be curious to see if the data line up with the cancers that are known to increase in Risk due to obesity so right after smoking obesity is obviously the second leading uh modifiable risk factor associated with cancer I've always thought that was an oversimplification because we use obesity as a proxy but I think it's probably insulin resistance that's the true marker that obesity is serving as a poor man's version of um it would be interesting to see because there are certain cancers including breast and colorectal by the way where obesity amplifies risk there are other cancers where obesity doesn't seem to play as much of a role it would be very interesting to align the exercise data with the Obesity insulin resistance data and see if exercise is disproportionately reducing risk in those cancers for which obesity is a risk such a good point Peter and I think there is at least some data to suggest that you are correct with that so um I mean what is there like 13 or so cancer types that like obesity is yeah it's either 13 or 17 something like that yeah yeah and um and and and breast and colorectal cancer are on that list and so um yes so it the aerobic exercise um it you know there's I think there's direct mechanism so like you know aerobic exercise is you know directly you're making those Maya kinds and like you know some of these myokines have been shown to to basically um decrease the production of like growth factors created from cancer cells and they're like they also like kill you know are killing cancer cells um uh you know through a variety of other mechanisms also the anti-inflammatory effect you know from from exercise as well so you're you're having a strong anti-inflammatory response but back also like there is a little bit of that okay well exercise is also like improving insulin sensitivity and it's you know your in combination is particularly in combination with dietary strategies weight loss you know your the weight loss itself is is basically a important component of the cancer reduced cancer risk so I think you're totally I think it's a combination of these things where it's like the the Direct effects from from exercise and there's also you know it's really interesting because as I mentioned people that even have cancer um the the the response like it it seems like you know physical activity like I am not an oncologist and you know many more oncologists than I do I don't know that I've you know I don't know how common it is for for oncologist to prescribe exercise as an adjunct um sort of treatment to you know whatever the person you know whatever type of treatment whether it's immunotherapy or radiation or chemotherapy or a combination whatever um I I don't know how common it is but um the the data is more and more compelling and I think it's become more and more compelling over the years that really uh exercising is it seems to be very important for reducing cancer metastasis and also dramatically and you know decreasing cancer recurrence and so a really interesting mechanism by which this is likely occurring is literally through that Shear Force mechanism I was describing for the brain well as you know you know cancer cells tumor cells sort of escape the site of the tumor and they make their way into circulation it's called a circulating tumor cell or circulating cancer cell depending on the study you read and you know these circulating tumor cells are like traveling throughout the vascular system to distance sites and they sort of take camp and then like it's like kind of seed of you know a new tumor forming in another tissue um well it's really interesting because these cancer cells cancer cells are so messed up as you know like they're just they're like they're completely wonky and very very sensitive to stress any type of stress they have these mechanical mechanoreceptors on their cell surface that are responsive to force Shear Force so when you get your blood pumping it's like it's like a hurricane that like just wipes it out they die because they can't they can't they can't stand just the sheer force of the blood flow through you know the vascular system and so so and this is where you'll see you know studies you can sort of pair it so you compare the mechanistic studies and they've been there have been some studies looking at circulating cancer cells and it's like people with those are like three times more likely to have cancer metastasis and um and so on but um they're they're again there are studies showing that like physical activity like dramatically decreases and this there's been randomized trials showing it dramatically decreases circulating cancer cells in people um compared to whatever their the other you know standard treatment that they're you know being given um and so like kind of pairing that data with looking at you know other data where exercises is being prescribed to to patients and it is beneficial with respect to their cancer metastasis reduction and also mortality reduction you know like 50 mortality reduction you know versus recurrence as well so I do think there is substantial evidence to suggest that being Physically Active is a good measure um for cancer prevention and you know I don't again there's also a lot of differences there are sex differences as well like I don't know why but in some cases women respond better um you know and there's certain cancer types that respond better lots of variables here like I'm I feel like I'm speaking in a general way but like but like there are lots of things to consider right there are cancer types and and there are sex effects and there are as you mentioned other covariates there's obesity and there's you know insulin resistance and age as well so I mean there are lots of nuanced as as usual but I do think that you can make the case that like if you like what can I do you know in my life to reduce you know reduce my my my risk of getting cancer reduce my risk of dying from cancer reduce my risk of getting Alzheimer's disease reduce my ribs from getting dementia reduce members from getting cardiovascular disease reduce my risk for type 2 diabetes like the only Panacea there is is exercise it's exercise right I mean that that is it is it is the case and um unfortunately it's the thing that you have to put the most effort in it's certainly a lot easier to take a supplement to take a pill I do think there is an argument that omega-3 is one of the it's up there I think I think getting yourself to a good omega-3 status and defining what that is is still like being investigated but um I do think that's a low-hanging fruit that should not be ignored but exercise as you've talked about many of times is the king is the king um and and that's that's the thing that you should focus on if you I mean any I mean obviously if you're obese weight loss exercise is part of that program and like like I don't think that anyone that's obese would be worrying about all the other things like they need to like lose weight and any personal trainer and Coach like probably is going to help you do that like just you eat less like that's calories and calories out it like matters to some degree like if you're not eating as much yeah but but as you said exercise matters not just on the energy balance side but exercise makes you for example more sensitive to satiety hormones so um you know look I I have kind of a belief here that the the person who is overweight uh the person who is obese and who is clearly eating more than they should be uh isn't doing that by choice maybe some are but 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 right um and I think that you know that's one of the challenges is why is it that a person who is not in energy balance is not responding to the normal satiety signals and I think there's a lot of reasons on the food science side we could talk about a whole bunch of reasons why our food has been hijacked our food is void of nutrients our food is hyper palatable it's far too available there's a whole bunch of reasons but I think one thing that doesn't get enough attention is this thing which is an exercising person has a better sense of nutrient requirement they have a better their body physiologically is more in tune with their repetitive needs and so even though I don't think exercise matters as much as intake purely on the energy balance side in other words I think it's more about reducing input than increasing output but a part of that equation is the feedback loop that exercise brings so yes exercise just matters and and I also think that you know especially in this discussion of cancer and breast cancer is the example you brought up you know so many women are so petrified of hormone replacement therapy because of this awful you know study the Women's Health Initiative which was completely misinterpreted but just to use one example of what we spoke about even the people who ran the study who to this day some of them at least a subset still maintain that conjugated equine estrogen plus MPA the synthetic progesterone increased the risk of breast cancer even those people will acknowledge it did not increase breast cancer mortality so even if you take the most favorable to the Whi the Women's Health Initiative study reading the reading is that conjugated equine estrogen plus MPA increased the incidence of breast cancer by 0.1 percent in absolute risk but did not increase breast cancer mortality so here you have basically a non-event that has most people panicked senseless most women panicked senseless when confronted with taking hormones during the perimenopausal period and yet at the other end of that Spectrum we have a treatment that has more than a log fold benefit in the other direction I.E in reducing risk and I wish I wish people would just allow their attention to be allocated proportionate to the size of the impact I'm I'm 100 with you and and with kind of to kind of just highlight or emphasize what you just said you know there are studies with women who are doing moderate drinking which I mean depending on the study you read it's like I mean for women moderate drinking is like it's like you know three drinks a day or something like it's a lot wow um and like that incr like that literally like translates to a lifetime risk of breast cancer it's like one in six or something like that where it's pretty significant but you don't hear about women petrified of like drinking you know like two glasses of wine a night um which I mean some people do like it's you know not it's actually not uncommon um and and so I it's like again it's one of those things that you were saying where it's like like looking at like what's 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 you know it absolutely impacts breast cancer um same with you know physical activity in the opposite direction has it I mean just really enormous benefits and then alcohol consumption um is another one even even a mild alcohol consumption I would say that like I don't want to go there because it's like so it's complicated and I like I can't even like begin like there's there's I've gone on there I've gone there Rhonda I've gone there I'm I go I go out on the limb and I'm gonna say it there is no amount of alcohol that is healthy um the J curve is a misnomer and what I think I would say is somewhere between zero and one there's probably that much there's not that much of an increase in Risk but there's not a reduction in Risk right so the for what for for mortality in general mortality yeah yeah yeah yeah yeah so in other words you know they talk about the sort of J curve where complete abstinence is a greater risk than you know one drink a day uh but but I think both the mendelian randomization makes that not makes it clear that that's not true and then secondly when you look at all the confounders of the people who are drinking zero drinks and what confounds their mortality um I I feel very comfortable saying that there is no dose of alcohol that is healthy but you know at a very low dose I got probably four to seven drinks per week it probably has immeasurable um or pardon me not immeasurable you probably can't quite quantify the harm um that that would be my take and and so I I I'm I'm comfortable saying that I really feel confident that that is the case um and that you know things like the French paradox have far better explanations as one example yeah I I I tend to think I mean there's the data is also a mess like you like I agree with you and um it does seem like you know like can you have your weekend you know glasses of wine like absolutely I think you can and you know with respect to the cancer risk and like that's that's considered you know it's mild I mean it's less than you're having less than one drink a day and the only evidence I've really seen against the the mild is on the National Cancer Institute site where they like it's one of those cancers where it's like one in 500 like it it increases your risk of a cancer that you already have a lifetime risk of one in 500 and it's still less than one percent of an increase like yeah to me it's like your life you can't you can't measure it you can't I can't measure it yeah it's a classic example of the dose makes the poison but don't confuse that the poison is a poison right so another example would be cigarettes if you smoked a cigarette twice a week literally one cigarette twice twice a week would your risk of cancer go up yes but you wouldn't be able to measure it that doesn't change the fact that cigarettes are harmful right to mention heart disease like that that is not a linear like that like yeah yeah no no I mean I mean it's it's it but but even just focusing on cancer right like it really comes down to kind of establishing causality right is tobacco causally related to disease yes it's it's it's a harmful thing to take but the dose matters right like again just being glib one cigarette a week is it's probably increasing risk but we don't live long enough to see that to see the separation of those kaplan-meyer curves right maybe if we lived 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 to nine cigarettes a day but you know what I'm getting at right and I think that's my point with alcohol it's it's it's simply just a question of of that but but I just want to make sure people aren't taking away from this that you know 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 well how do you feel about apoe4 carriers and alcohol consumption like our view in the practice is that they are indeed more susceptible um to the deleterious effects of alcohol um and 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 um you know I think poor sleep is 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 know you don't need to be Matt Walker to 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 um yeah and and so so through that lens I would just say you know if we have we have lots of patients with E4 in our practice including a number of E4 e4s we dispro you know even though those patients represent only two percent of the population they're probably about seven or eight percent of our patient population and [Music] um 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 um a couple of things just because you brought up the sleep and uh for one so I started wearing a continuous glucose monitor largely because of you um and 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 that can't be a good time to wear a CGM but but although it must have been interesting right it was extreme so here here I am coming into this like oh I'm going to learn about the foods I eat and how my body you know responds to those foods and lo and behold the biggest and most compelling and most important data point or many points because I had many of them that I sort of learned from wearing my continuous glucose monitor which I'm sure most of your listeners know about where you're measuring your glucose level like continuously was the effect that my sleep Interruption had on both my fasting blood glucose and my post print where I was like like I could get like pre like what we can be considered like pre-diabetic like I was like blown away I was like what is this is insane um and then what I also sort of gleamed from this was that when I like was on days and the effect lasted about I would say like about 48 hours or so when I did work out and 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 um that it almost completely blunted that effect where I even though I was dog tired last thing I want to do is go to my damn spin class I was just like this is like I can't it's going to be bad for me if I go that's how I felt like it's gonna be bad for me but it was completely the opposite where I mean like this crazy glucose you know dysregulation and whatever the causes for that I'm sure you know much more about that than I do um it was almost completely blunted and it was so profound and it was like the one all the food stuff you know I learned a little bit of interesting but really that was the thing that for me was like I have to work out no matter what no matter what like I have to no matter how I feel it doesn't matter it's beneficial and there there's also it was a really interesting study uh caveat observational data you never know like there's reverse causation all the problems with any study but it was it was looking at the um you know sleep habits and so people that had slept you know was poor sleep or interrupted sleep something of that nature I can't remember the all the exact things that were measured with respect to sleep but um people that you know didn't sleep as long or had poor sleep Whatever by whatever measurements had a higher all-cause mortality which is not that surprising but only in people that weren't physically active and to me I was like oh wow that's interesting it's interesting and it's like you know exercise can forgive a lot of sins in many ways it really can and you know so you're talking about your you know your patients with E4 E4 and I'm sitting here going oh my gosh I've got one of those and I'm already like it's like it's a lot it's a burden you have to like you have to calculate things you have to be very um you know specific in your the actions you take and like things that you don't do things you do right and and for me it's like okay am I gonna like I'm having a party we're gonna have some mimosas whatever like I'm gonna exercise no matter what like and that might take off some of the stress right I'm not saying I'd go out like I I personally um I hardly drink and mostly because I am E4 I have one allele and I have uh pretty much come to the conclusion that it my brain can't repair damage as well as my husband's who doesn't have any four allele um with that said um you know I occasionally will I'll have like maybe you know a glass or two of wine usually if that's my preference but uh you know a week but even I mean last time I had a drink was like Valentine's Day you know so it's been it's been a while um but at least I think with the sleep sorry with the exercise you know again it's like it does it seems to forgive a lot of sins honestly I like that way of describing it yeah yeah I think well I kind of borrowed that from Stuart Phillips I think I think he was the one that said it to me because I was like this is like yeah that's right I heard that that's right I remember him saying that on your podcast so he gets he gets all the credit um and that of course brings us into the whole like protein intake and muscles yeah yeah so so let's set this up for listeners because you know you and I have talked about this a lot in fact I remember probably the last time this is pre-covered because we were both in San Diego you and your husband were for dinner I think I cooked up some fresh venison that I had just killed and we were kind of talking about protein and I think at the time both of us were kind of struggling with two competing ideas in zeroscience um and those two ideas that seemed dialectical they seemed at odds was on the one hand there's this body of mostly kind of animal literature that suggests lower protein intake is associated with a longer life but on the other hand there's this literature that says lower protein intake is associated with more Frailty in humans and that's associated with a shorter life so how do we reconcile these two things and and we didn't we didn't have a great resolution on that I mean we both kind of felt like we were sort of scratching our heads thinking at least I don't want to speak for you but my thought thinking at the time this is again three and a half years ago probably was we just got to find the minimum effective dose what's the minimum effective dose of protein to not undergo mandatory catabolism and that's what that's what the dose is so and of course it's not clear how you find that dose theoretically you would use a metabolic cart and try to identify nitrogen balance and things like that but of course no one can do that outside of a lab so it was a bit of a head scratcher now I my thinking has evolved so much on this but I'd like to hear first of all I'd like to hear your formulation of the problem that I did I formulated the way you would and I guess more importantly tell me how you're thinking today yeah so you actually did a very good job formulating sort of uh my my mentality with respect to protein intake and Longevity um back in you know 2019 prior to that but like you know even even up until not even that long ago to be honest you know there's of like as you mentioned a large body of animal evidence but also like there was coupled you know this coupled you know epidemiological data where you think where you know people are looking at you know vegetarians are taking in lower amounts of protein and they're all cause mortality and they're cancer mortality and they just study after study after study and they have a lower all-cause mortality lower cancer mortality but but only in those individuals who are not obese not sedentary sorry are sedentary are smoking or you know they had some unhealthy lifestyle Factor so in other words the people taking in higher protein animal protein uh who were basically healthy had a similar cancer-related mortality all-cause mortality as these vegetarians okay so and similarly studies where they normalized for fruit and vegetable intake high protein versus low protein no difference in right in in in early mortality right so yes it seemed that a lot of the data that we're 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 had never like I wasn't really of the opinion that vegetarian diets were Superior to you know meat eating or I guess omnivore types of diets that were healthy omnivore types of diets like I I I like because of what you were saying like that data was you know it was nuanced and it wasn't just like you know so I wasn't that wasn't something I was that has shifted in my you know the way I've been thinking but with respect to you know a lot of the animal data in the you know the mechanisms and you can you can you know restrict a mouse of protein and make it live longer and not get cancer and you know all these things that you see study after study I mean it's just like the longevity science and that whole field is like dominated by that like at least was and there's now I think some pushback going on but there's still a large you know group of scientists that are you know still you know publishing a lot of animal data and and this is where I sort of started to look into some of these exercise physiologists people um that like Stuart Phillips I know you've had like um like exactly like these these like giants in the field that are doing the research and uh Brad schoenfeld is another one where they're they're looking at protein intake they're looking at uh you know strength training and its effect in humans right in humans um on muscle protein synthesis and also just like looking at data with respect to muscle mass and you know all cause mortality and you know Alzheimer's disease dementia we didn't you know talk about that but like strength training also you know can modify that risk um also cancer mortality and so um yeah strong grip versus weak grip monotonic change in grip strength 70 reduction in incidents and mortality from dementia I mean 70 reduction in Risk remember people don't understand you can't reduce risk more than a hundred percent 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 yeah it does it does and you're not like they're you know as you know and many of your listeners like there's two important signals for you know your your muscle of strength obviously a big component of that is like physically working them but you know protein intake plays a plays a role there as well and I think it was Stuart Phillips like phrased it this way where you know the the animals that were that that are being studied in these labs are in a sterile environment right you know they're in a sterile environment they're not being exposed to influenza and all these infectious diseases and you know like like any of us have we've had a parent or a relative or someone that has gone into the hospital and maybe had bed rest um and then come out and like like I had a grandparent who like I mean literally couldn't walk after a back surgery I it was like I mean for forever like that was it that was like that was their downfall it was like the trajectory just went down completely down and you know so losing that muscle mass you know when you're in older age um obviously building up a bigger Reserve in in youth like in in middle adulthood whatever like that's that's very important but like you know these animals that people are manipulating the protein restriction in them like they're not being exposed to that right they're not they're not losing like I don't know how what percentage like it's it's pretty intense like how much they you know you can lose from like three weeks of bad rest um and and also like you know as it's been pointed out by um people in your I think Matt kibberlin like these you know mice are dying from like cancer right like cardiovascular disease they're not they're not dying from the same diseases and it's not even the same type of cancer that humans get like human we get a lot of these epithelial like tumors solid tumors they're like dying from lymphomas you know like that's so there's a lot of differences there as well um where I you know I don't like there's a lot of interesting and I'm all the one to I've talked a million times about animal studies um and it's I think they're important mechanistic data like there's things you just won't ever get from humans uh you know but at the end of the day I started to realize that you know looking at this you know mice in a sterile environment where they're not really being exposed to the same stimuli as humans things are very different in terms of Aging um I don't I just I wasn't I was like this it was falling apart in my mind basically it was like all falling apart I'm like oh my goodness this isn't doesn't make any sense like this isn't what to be looking at if I'm if I'm wanting to really focus on healthy Aging for myself you know and forever for everyone else right so I think that's kind of what was the Tipping Point for me was just kind of that realization of the importance of muscle mass and how you know some of these animal studies you look and you're like oh they're they have you know they're a little bit of an improvement in their cardiovascular health and I'm like oh exercise okay is it better than exercise no um you know like the things that were improved I was like exercise does that exercise does that like this isn't convincing me that I need to like do that you know so um I think it was just kind of like the shift in the way I viewed the data like the lens I was seeing it through yeah I'm still waiting for somebody to demonstrate for me that if there is an increase in the risk of cancer associated with higher protein intake in humans I'd like to see that Quantified but I would like to see somebody demonstrate that if there is an increase in risk that quantifiable increase in Risk is greater then the offset of sarcopenia because that's something for which there is no ambiguity we have all the data in the world to point to the devastation of sarcopenia on an aging population and we know full well that two things have to be true to avoid sarcopenia adequate protein intake which as you age gets bigger and bigger that number goes up and up and up due to anabolic resistance coupled with strength training so here we have something for which there is no uncertainty you must consume increasing amounts of protein and you must do strength training to ward off sarcopenia as you age and if you don't here's your mortality trajectory and it's awful let's compare all of that to this questionable risk for which frankly I don't see data and I'll add one more point to what you said Rhonda which is I think this story got confounded by our good friend C elegans right so let's go back 29 years roughly call it 30 years directionally when some very seminal and interesting work was published looking at the daf 16 mutation in or maybe it was daf2 I can't remember if it was daf 2 first or daf 16 but it was the analog of the igf receptor and if you knocked out that Gene you could double the lifespan from roughly two weeks to four weeks or four weeks to eight weeks I forget what it was of uh C elegans this worm and the implication of that was profound I mean that I don't want to down play the most important takeaway from that which was lifespan was malleable that that turned out to be very interesting um I could go on my rant about why C elegans is not an organism or a or an animal model that offers any insight into us um you know based on its sell based on a whole bunch of things about its biology but nevertheless it somehow became knocking out daft2 or daf 16 was tantamount to dropping IVF uh igf insulin like growth factor one to zero is the key to longevity and the way to do that is to have no protein and I think that story is is so incorrect but somehow it's become part of Dogma so I think I think that's the other piece of this that just kind of won't go away um yeah it's it's funny because I I've done those experiments in with my own hands when I was at the Salk Institute and I was in Andy Dillon's lab who had trained with Cynthia Kenyon who made the discovery right back in was it early 90s or something yeah Philly was 93 or 94. yeah and you know like it was 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 the health plan was remarkable yeah they were youthful I mean like you could see them you look at a microscope and you see how they move around it is very apparent they were acting like a youthful young larva that had like not been born long ago right uh but then you also realize they go into this dour state where like in order to get that you know lifespan extension they're like like going into this like metabolic stasis and like this like this thing that we don't do like humans don't do doubt like we're not you know we we it's it's a completely separate um sort of pathway that is required for that lifespan extension and I think you know to your point about the igf-1 the insulin um you know like growth factor receptor um and also the insulin pathway they're kind of both like tied into that um you know the the fact of the matter is is that that is a growth factor and you know as we have talked about you and I have talked about this before you know growth factors in the context of a tumor can allow tumor cells to override cell death mechanisms so they can continue to survive when they otherwise might have been you know signaled to die right um and so there can be a problem with too much igf-1 in the context of a tumor and what causes that High hf1 Is Up For Debate uh but I think at the end of the day it's not that high igf-1 that is necessarily causing the tumor I think you know like there are things that you can do in your lifestyle like exercise actually causes igf-1 to go into muscle where you're repairing damaged muscle it's helping muscle repair it goes into your brain it's important for like neurogenesis a little bit of controversy there I know but like I'm in the camp that you adults are I mean like their studies showing multiple studies showing that you can take an older adult put them train them for a year and their hippocampus will grow by like one to two percent like there's multiple studies also another study showing this with the sub ventricular zone so these are two regions of the brain where it is my opinion I I believe data that says that adult neurogenesis or the growth of you know new neurons as an adult is occurring and do you think that part of the vehicle for exercise to do that is through igf-1 uh-huh yeah absolutely it is interesting I mean animal Studies have shown that again we you know we all know about the caveats it does does it translate to humans we don't know but you know often time you have to take the whole body of evidence the human evidence couple it with mechanistic data with animals and try to kind of put together a story to the best of your ability I mean that's that's all we're gonna get you know and so um yeah igf like you you always hear about I want to lower igf-1 but you you know it's actually like important for the brain and important for muscle and and the way to get it to the brain is through exercise like that's that's that's known and it's been shown again in human studies as well so um I think also part of the the problem here is in some respects um people that are doing I mean really impeccable animal research like you look at you know the data and it's like oh they're doing the study great like this isn't 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 like who are we talking to are we talking to an overweight obese person maybe they're probably getting enough protein they're getting enough you know they're like I don't know that they have to worry so much about protein intake I think they need to focus on losing you know losing that unhealthy weight but that's also really important and I think some some scientists and also Health uh you know and science communicators also sort of maybe it it's hard you have to like 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 they they read about some animal study where too much protein increases mortality right um so I mean and also I think age is such an important part of this again so if you look at that um I think it was Levine in 2017 had that study where they look at the relationship between protein and igf-1 but stratified by so they stratified by protein intake low medium high low medium high and then they looked at middle-aged people so 50 to 65 and then people over 65. and in people age 50 to 65 there was a relationship between protein intake and igf higher protein intake was associated with higher igf now it wasn't a huge difference this gets over stated constantly but it was statistically significant but what often gets ignored is the people over 65 there was no statistical difference whatsoever between protein intake and igf-1 again this is taken as Dogma that the more protein you have the higher your igf-1 and in people over 65 that's not the case now why do I harp on that I harp on that because it isn't exactly that population that I am most concerned with sarcopenia so If the message is somehow getting transmitted to somebody listening to this who's 65 or older that I shouldn't be eating protein and they might not even know that it's through igf but somehow high protein is going to give me cancer and you know that's because someone who telling them that is talking about 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 res 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 you know then the younger people eating more protein leads to more igf which is bad I would argue that the absolute risk of death is so much lower in that group that the absolute difference in mortality between the younger and the older in the presence of high protein is no comparison what I mean is higher protein across the board is going to save more lives than it would ever hurt in younger people even if you could convince yourself at higher protein intake was associated with increased mortality and so again I find these data unassailable um especially in the older population I think Matt cable and I did talk about this on a podcast once and I worry that you know as you do that that that information is is not making its way clearly to people of the susceptible age group right and I think also that the thinking about a lot of people are focused on the the recommended daily allowance of protein right like well then right like what is the what are these old ass studies that were not done correctly using the wrong tracers what are they like like what is that telling me about what how much protein I should take in and this is also another sort of change in my like it was a turning point for me because I didn't I knew nothing about the uh fault like you know the the errors the recommended dietary analysis I know I know everything about micronutrients and rdas but I knew nothing about the protein and um once I talked to Stu I mean it was it was clear he was like oh no those we we did we repeated those studies him and many others using different tracers and I can't tell you all this the tracers and stuff because it's you know it's a certain not my field but um it was like no we determined that the like the minimum was really more like 1.2 grams per kilogram weight not 0.8 and and to me I was like oh wow you know because you know well you you don't store protein so it's like okay well this is this is important because I mean that's a big difference um and then on top of that when you start to get into the Physically Active people or elderly population as you mentioned anabolic resistance where they're basically like their their muscle isn't getting that signal you know as well to increase muscle protein synthesis from the same amount of protein that they're younger self would right so they actually need more of a dose you know up to like I don't know 1.6 1.8 we're talking we basically tell people aim for one gram per pound which would be 2.2 grams per kilo um because the other thing that complicates it Rhonda is not all protein is created equal so you know if you're eating on if you're getting a reasonable amount of your protein in uh In from from Plants you're getting a lower bioavailable amino acid you're also not getting the same quantity of leucine Lysine and methionine which are probably the three most important amino acids anyway so um you know one of the things Don Layman talked about was if you really 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 leucine and lysine now again for a lot of people that's too nerdy but but you know you can go through the math a couple of times with certain things that you eat repeatedly and you'll realize that's probably more protein in aggregate than a person is used to eating and as you said when you start to factor in those two other categories of risk right more demand so when you're doing those high intensity workouts you are ripping apart muscle fibers when you're lifting weights when you're rucking when you're doing all these other things we have to do you're demanding more amino acids for the turnover and then of course anabolic resistance I think is the biggest issue and and something that truthfully up until two years ago I just wasn't paying enough attention to I I wasn't appreciating that my older patients had had an additional problem that younger patients didn't have with respect to that signal so that's a lot 2.2 grams per kilogram by way that's I mean I struggle like I to get for me to get 1.6 like I'm supplementing I'm taking whey protein like I I just can't it's like how many like so how many meals like typically four yeah because it's hard yeah it has to be and and one like so so for me it's really two meals and two snacks and the snacks are just protein snacks so so it's a it's a shake so one of them is just a whey protein shake and then one of them is I eat these venison jerky sticks so five venison jerky sticks has 50 they're 10 grams a piece um and they're really good they're you know super pure venison um it's you know Wild game amazing product and I I should disclose I'm an investor in the company that makes them by the way um I was gonna ask do you make them is it like no yeah but I I know that people say well I know everything about it and I know that the quality is there um so those are two snacks right they're otherwise they're relatively low in calories right like my whey protein shake doesn't really have anything else in it except some frozen berries and almond milk um and then the venison sticks are what they are and then and then two meals that are you know gonna have protein and for me again A lot of times like it's going to be an omelet and then you know protein dinner so yeah it's um not gonna deny it it's work it's it's not um it probably consumes more of my dietary planning and dietary attention than anything else I I don't pay any attention to how many carbs and fat I eat anymore uh I'm just paying attention to protein intake it's something I never really paid attention to at much at all um you know until and I would say like last June or July is when I really started focusing on strength training you know both for my muscle mass and also bone mineral density like I mean yep like like that's another thing where it's like you want you want to like that's you want a reserve of that as well especially as a female right like so that that those are like folks focusing on the strength training and also the protein intake and it's been quite challenging I've always sort of focused on micronutrients and I and it is you know it's still a focus of mine and like making sure I'm getting enough of those and I do supplement as well um you know in addition to trying to eat like leafy greens and getting some you know some of the veggies and stuff it's either going to be roasted veggies for me or like salad but um the protein intake is like it's been it's been challenging and I find I typically do three meals um one of them is is like a a protein meal snack so it's like some salmon or like a homemade turkey burger or something like that but then the protein shakes also is where I I just have to do I guess that I don't really consider it a meal but it kind of is and um you know it's it is like it's it's satiating the protein like Shake is definitely satiating and I'm already it's even kind of hard because when you work out like as you mentioned your your satiety you know hormones go up like you're like I'm not hungry like I don't like necessarily want to eat like it it takes a while before I can actually like even get an appetite you know yeah so there's all these like competing things where I'm like trying to get the protein but I'm like I'm not really hungry and I'm like I know I need it and you know so all these little um important factors and yet again um important to sort of you know highlight that you know I don't know that someone who is overweight or obese necessarily needs to focus so much on that right I mean would you agree right that's right yeah I mean 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 um and and then we can come back to it but but yeah now that said for people so it depends on the strategy right depends on the dietary strategy so for people who are using tracking kind of the caloric restriction way we would still set a protein Target that is at two grams per pound because of the satiating benefits that you said right also you have the thermogenic effect and the benefits of protein over fat and carbohydrate from a thermogenesis standpoint but when you have people that are going about it via dietary restriction or time restriction as their strategy for cutting calories it can become a little overwhelming and when you force high protein you sometimes end up getting high calorie with it so that's where we would say just don't pay attention to it as much just focus on the the drtrtr approach The Other Place Rhonda where we do pay a lot of attention to protein is in the few of our patients that are taking glp-1 Agonist so I've been a pretty public uh critic might be too strong a word but I've certainly expressed my reservations about the ubiquitous use and the liberal use of glp-1 agonists especially in people you know just trying to lose 10 pounds right like it's one thing if you're 100 pounds overweight and you've tried everything by all means the benefits clearly outweigh the risks but you know the um I got to get my Beachbody on for the wedding this summer I'm going to lose 10 pounds let me fire up some semi-glutide or terzapatide I think that's a net negative personally and in those patients not that we're giving it to those patients but in any patient who's on a glp-1 Agonist we feel it is so essential to hammer home protein because those drugs are so effective at squashing appetite that I mean we've seen people who basically just want to drink alcohol when they're on it and they'll lose weight like crazy because they're you know not getting that many calories but they're like yeah I just like wine yeah I'm just losing muscle drinking wine um yeah so yeah I totally like I've I've got um some acquaintances that are of that category where it's like you know a stay-at-home mom wants to lose 10 pounds has the the means to to get it and does it and um there they I mean I have we haven't measured muscle but I look at them and I'm like you look like you're wasting your like your muscle is wasting like you know you're not if you're not eating you're not taking in proteins I mean like that makes 100 sense and it also I don't know 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 yeah um I know you've kind of no you don't do as much at least of the long you know long fast and boy we could I would love to get into that um you can decide whether we should do that do that next time or we could talk a little bit now but um but yeah that was also like like the biggest you know there was another shift in my um understanding of you know fasting and time restricted eating a lot of people use time restricted eating they they sort of practice it by skipping meals um and I don't know necessarily that's the way to do it but people do that um it's just you know what people do and when you're skipping a meal you're skipping your protein right and so you're not getting as much as you're basically becoming uh you know losing muscle mass because you're not you're not getting that that important signal especially if you're not doing resistance training right then it's like kind of a disaster and that was also something uh that I hadn't thought about a lot and I know you've helped you've got a lot of experience in it on both personal and clinically uh but um I mean I'll I'll share with you briefly how we think about that so so on the on the time restricted feeding part we we agree that that the greatest drawback is that the patients get protein deficient so so time restricted feeding as a strategy for weight loss vis-a-vis caloric restriction is very effective with a small enough feeding window so you know a 16 8 you can eat your way into obesity with a 16-8 but once you start getting down to a 24 or a 22 too basically just doing one meal a day really getting restrictive um for the most part you're going to lose weight um the problem is by definition you're not going to 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 right there they're literally not coming on the toilet they're coming out as via vis-a-b urine right coming out the urea cycle so um the um the thing that we would counsel people on if they're going to use time restricted eating is they have to have protein snacks outside of their feeding window so if they're going to say look I'm gonna I'm going to only have kind of a 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 but oh my God that's like outside of my feeding window will that impair autophagy to which I argue you're not getting any autophagy doing a single daytime restricted feeding anyway it doesn't matter but if people are getting gut benefits from taking that time off then yeah they're going to miss out on those because you're I just don't see how you can get the gut rest if you're trying to get those amino acids so you might have to really start to cycle those things um but yeah long-winded answer to why I think fasting can really be at odds with the adequate maintenance of muscle and as we get older you know I think that I'm I'm just entering my sixth decade this is a very high priority for me oh really wow you look great Peter I didn't so you're you're in your life no six decades so I oh yeah yeah so you just so yeah yeah gotcha yeah um well but I love that I love that you thought I was 60. that's awesome well you know you know I think Joe Rogan's entering that and that's kind of what I was thinking and he looks I mean like you know that you can you can definitely see the people that like put in the work and work out and and you know they do aerobic they do strength training like you look at them there was like a study published on that too like a bunch of Bio biological markers of aging and biomarkers of Aging were measured and then like there was like people looked at pictures and like ranked their their age and their their you know quote-unquote biomarker biological age so like according to all these biomarkers that basically say they're chronological age maybe older than their biological age where they looked like their biological age not their chronological age you know so that that's 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 exercise is done outdoors and of course uh Sun can play a horrible role in that um well so we've been you know we've we've I've taken up more of your time than I said I would but I want to ask you kind of just one last thing is there any other just sticking with this theme of things that you believe today that you didn't believe three or four years ago or things that you believed three or four years ago that you don't believe today is there anything we haven't touched on because we've we've talked about some really good ones um I think those are the the really important ones off the top of my head um I definitely don't want to get into the whole covet thing at this point but I've my view has changed on on things as that has progressed and changed as well um so I don't want to like not mention it but uh yeah so but um the the most I think the most important things would be um muscle mass protein intake also I like fasting and I think the effects of time restricted eating on weight loss specifically when you're looking at that outcome being attributed to caloric restriction I think that is something that I've it's it's you know I wasn't always you know buying into that but I do it is still my opinion there are benefits to eating within your circadian rhythm I mean so like you know eating eating late at night when you're making melatonin two to three hours before bed you're basically inhibiting insulin secretion and I don't like there's data showing that you will you know your glucose levels will be higher with the same exact macronutrient intake as if you eat it earlier so I do there are benefits circadian benefits and I also think you mentioned the the gut rest and like digestion um you know resting like how having that rest period like your body can't so DNA repair mechanisms you mentioned autophagy like those things happen when you're not digesting so like in that process like isn't happening so you have to have like a rest period um for repair processes to occur and I don't know that I necessarily I think autophagy is as good as the the markers that we are sensitive assays that we have to measure it and I don't know that it's settled with respect to how long I personally think there's probably even in between meals there's some amount of autophagy a topologies are happening in us it is yeah it's not like we're not but is it clinically significant right or more so than say exercise would induce yeah no right exercise like no like extras nothing like the exercise is like that's my point like how long would you need to fast to to get the benefits how long would you need to fast to get the benefits of an amazing workout and what my thinking is right probably a long time um you know you might have to go a full day without food or a couple days without food to get the benefits of that but but you're right I think without biomarkers a lot of this stuff is very difficult to speculate on because we can't really extrapolate from mice on this stuff I I think I I don't it's so non-linear that I don't think I could and I've never heard anybody offer a very compelling argument either for what the quote-unquote answer is I I agree we can extrapolate from Ice and um the way I view it though is more of a cumulative effect where I'm thinking you know like I think it's better to just eat within a circadian window and do I think that's going to have a cumulative effect on you know metabolism and yes I think that it's better that I'm not eating you know within a 15-hour window like eating you know with which most people in the United States they actually do eat like they're eating from start to finish like a lot of people are eating like you know within a 15 hour period And so um is that going to like if you're exercising maybe it maybe it doesn't matter maybe you're right maybe they can't even a 15-hour window we don't really know but um I tend to think probably the Circadian component like does play some role um but the question is is it is it significant you know is it significant uh I am of the opinion it probably is cumulative if for no other reason I think it just is on sleep right I mean if on sleep yeah exactly like if you just look at the benefits of risk nighttime food restriction in terms of as you pointed out the where you know we're least insulin sensitive and the negative impacts probably of thermogenesis and other things on on sleep you know that that's probably the most compelling reason even if nothing else mattered if we couldn't measure it but but those those day those are so abundantly clear right like you you know that's that's as clear as how alcohol impairs sleep you know a late night meal is a is a great way to destroy a good sleep absolutely right and most I think most people have but it's anecdotally like people realize that as well yeah um so yeah I think I think I think we covered uh a lot of the the things that of my my perspective has shifted as any scientist that's following data should you know I mean some people argue oh you change you know how can I yeah yeah you know follow you you're you know change your mind it's like well like when new data comes out like you have to reassess things like I recess the supplements I'm taking I mean the supplements I take Now versus five years ago you know totally different not all of them they're certain base things like that I like vitamin D omega-3 like those are like super important I think but you know like you have you have to reassess things because new data comes out and you know you might have a new understanding of things that we didn't know we have new tools we have you know it's it's always getting better so you have to kind of reassess things so Rhonda for folks to follow you obviously your podcast found my fitness great way to follow amazing content also you put up a lot of content I think Instagram is probably where you're putting up most of your content right is that is that safe to say that if folks reach if folks follow you on Instagram that's where you're doing kind of really sort of thorough analyzes and stuff like that would you recommend people also check out Twitter where should people be going to see your thinking on a frequent basis well it depends on what they like to consume so if they like to consume like in-depth articles we publish them on my website foundmyfitness.com we have like topic articles that we cover we cover blood brain barrier for one is one um you know like so we cover that more in depth some people like to read they like to like nerd out on that um so that would be the place for that and then some people just like short little to the point like what you know and that is where if they want like the sort of uh quick thing like the Instagram um would be you know so found my Fitness on Instagram and also Twitter as well I do like a lot of it's it's kind of like a short I mean you only get so much time on Twitter and um you know you can't go into in depth and nuance and then I sort of have a love-hate relationship on Twitter but um but it is kind of a fun a fun place to also like there's other scientists on there as well and so yeah I'm I'm on Twitter and Instagram but and it's all the same handle right it's awesome yeah I found my fitness and then in the podcast as well which is Andrew Andrew huberman and I were talking a little while ago and we were sort of singing your Praises as as truly the the OG Health podcaster when did you start was it 2014 yeah I start that was when I started the podcast when I it was a weekend um I was doing my post-doc in in Oakland and I just started like Ron Krauss down the hall um George Brooks so I have a podcast with George Brooks on lactate like he was like I don't think I've heard that I need to go and listen to that one yeah we went all into that I've been into that like that whole podcast like kind of shifted my thinking of like intensity of exercise and the importance of lactate because you know 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 like I I was a mitochondrial metabolism you know researcher in grad school you know and so I was looking at my the role of mitochondria in cancer um and so of course like lactate I mean I was thinking about it in a completely different frame of mind right as opposed to I mean we now know it's such an important signaling molecule in addition to all those other things we we talked about um it is you know we've had at least one guest suggest that George Brooks uh is deserving of a Nobel Prize I mean I think you know he his lactate shuttle Theory it's called a theory and I kind of hate that it's called that because people hear that and they're like oh it's not proven yeah yeah but it but it's been but it's been proven um 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 in the getting in the brain uh in response to physical activity and um and and it's like beta hydroxybutyrate it's a signaling molecule it activates bdnf like beta hydroxybutyrate they go through the same transporter monocarboxylate transport of the MCT transporter to get into the brain um and there's also those in mitochondria but it's so funny because there's a lot of similarities the effects on TBI so you know George Brooks has done some studies um USC looking at you know some of these victims of TBI and I'm giving them lactate and it's like improving whatever their Glasgow rating scores yeah whatever the things that they're looking at but like I think beta hydroxybutyrate there's some wasn't there some evidence I think we with TBI I remember Dom talking yeah Thomas talked about this yeah yeah so it's like it's so interesting because also you know with respect to like Alzheimer's disease and like through some really preliminary data that of course needs to be repeated probably won't because you can't get funding but like giving beta hydroxybutyrate BHB to people with Alzheimer's disease um can like help improve like there's some small clinical studies looking at improve Improvement in like cognition and um you know so lactate lactate's like I think similar so 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 right so it'd be interesting like there's you know if there's Synergy there uh but like the the the trying to get the lactate and the beta hydroxybutyrate the neurobiological effects of them to me is is like it's so important it'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 listen to your podcast researchers Physicians so it's it's it's good to kind of like spread ideas I mean that's part of what the podcast does right spreading ideas it's not it's not just like I'm a communicating you know the the health ideas inside it's like scientists are listening to this and they're they're outside of their like you know lens where they're only thinking about the thing that they research and they hear this and it's like creativity right they start to go oh like and I've I've seen that happen like that like scientists like doing experiments you know based off of like listening to podcasts and stuff and so I think it's really I think it's really great um but thank you for the OG yeah I did that and it was a it was a weekend thing for me and um I loved it it took off I just I love it so much like I know you do as well I mean it's like and by the way um phenomenal podcast like it's funny um I don't listen to podcasts much at all as I mentioned but there's there's a few people that I trust to really be vigorous in their you know research and to be critical to really like dive down and like get into the root of things and and you are like one of those people and so like people will come to me you know and say oh Peter ortia said this I'm like oh okay I should like this is like like you know this is something I should consider or you know oftentimes it'll be oh yeah Peter also said that and so I'm like oh good you know so so I'm always like I'm always like okay what is Peter thinking what is Peter what is Peter thinking so um it's nice to have you as a colleague as a friend request I'm glad we've reconnected um thank you so much for inviting me on your podcast can't wait to to speak with you again uh soon on your amazing book which I can't wait to read and uh discuss as well in a couple of months well thank you very much Rhonda I can't wait to uh to see you in person even though it's been pretty awesome to see you in video your setup is as I said exceptional so we've we've treated the people who are watching this to a world-class view of what a home podcast setup can look like amazing thanks Peter all right see you around [Music]

Channel: Peter Attia MD

Views: 512,708

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Id: zkp0DRUQ33g

Length: 173min 27sec (10407 seconds)

Published: Mon May 01 2023