Dr. Tommy Wood: Can Cognitive Decline Be Reversed?

23:50Dr. Gabrielle Lyon:We should link to that paper. So we know that because aerobic type exercises, particularly if you increase intensity, that drives production of things like brain-derived neurotrophic factor. That seems to help the gray matter, seems to help memory. Resistance training seems to release things like insulin-like growth factor one, IGF-1, which is really important for white matter, which is kind of like in the middle of the brain, really important for fast connections between different parts of the brain and the brain and the body. And so resistance training improves the structure and function of the white matter, again, even in older adults.

24:24So, yes, some aspect of physical movement is going to help drive brain structure and function. But similarly, we know that the food environment, the sort of unrestricted access to hyperbalatable foods in animals and humans is a life shortening scenario. And that's a quote from Charles Brenner, who's one of the great longevity scientists. And so I think, coming now down to cognitive stimuli, I think we're now at risk of some of the same things. Because what is it that drives brain development in the first place? It's the development of motor skills, social skills, language. But then it's also these core complex skills that humans have been doing for millennia, like dancing and moving and then teaching and music.

25:20These kinds of things are the primary determinants of how our brains, or even the accumulation of knowledge, right? Whether that's in a formal education system or not. These are the things that drive development of the brain. And we know that if we continue to engage in these later in life, that helps to maintain the structure and function of the brain and slows the rate of decline. So if we end up in a scenario where we're not having to develop these skills, we're not having to use our brains in the same way, of course, like that becomes potentially really concerning.

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27:24Dr. Gabrielle Lyon:And this was really surprising to me. Obviously, you do cognitive testing and you do physical testing. And part of the job of a fellow is to run a memory and aging clinic. So you see individuals come in with vascular dementia, with Alzheimer's dementia. And I'd love for you to touch on those. But I will never forget this guy. He was a gym teacher. He was super fit. And he had really bad Alzheimer's dementia. It kind of blew my mind at the moment because it wasn't like it was just APOE4 or genetics. It just seemed to happen. This is one of the issues that I've certainly faced and a number of people have faced when we talk about this idea that Alzheimer's and dementias in general are potentially preventable.

28:13So right now, depending on which analysis -

28:15Dr. Gabrielle Lyon:Do you believe that? I do believe that. Hence the book. Hence the book. Even though actually a lot of the book is about cognitive performance today, right? Which is actually what I loved about it and why I started with this idea of friction. I didn't call it friction, but this idea of being able to operate in this austere environment as opposed to predictable planning to win. Yeah. And we can definitely come back to that even more. I think there's a ton to unpack there. But knowing that, depending on which analysis you read, somewhere between 45 and maybe 70 plus percent of dementias may be preventable.

28:51If we think about those different types of dementia, so you already mentioned Alzheimer's disease, that makes up something like 60 to 80 percent of dementias. The next most common is vascular dementia, which makes up 10 to 20 percent. And they actually have a ton of overlap. So the majority of cases of Alzheimer's disease have some evidence of vascular disease, like issues, disease in the blood vessels in the brain.

29:13Dr. Gabrielle Lyon:So which there's probably a component of that, which is a natural part of aging. Do you think those microvascular matter changes? Yeah. So yeah, one of the reasons why white matter is actually really interesting when it comes to cognitive function and cognitive decline is it's most susceptible to issues with blood flow because there isn't as much blood flow in those parts of the brain than in the gray matter. So if you have any issues with blood vessels, the white matter becomes particularly susceptible. The blood vessels are also thought to be one of the tissues in the body that age earliest and fastest.

29:47But we know a number of things that can help to at least slow that aging process, right? Many of which we've talked about already, like exercise. So between those two, they make up like 70 to 90 % of dementias. There are other types, frontotemporal dementia, Lewy body dementia, dementia with Parkinson's disease. But when we talk about preventable dementias they're probably in those two buckets right because we know they're related to the lifestyle and the environment genetics as well but genetics is largely a risk multiplier in most in most scenarios so when we talk about that then i understandably well people will give me examples like well you're telling me exercise you know decreases risk of dementia but i know this guy who exercised a ton he was super fit and he still got still got Alzheimer's um and this then like allows us to maybe think about the fact that this is not a single variable problem right um and there are tons of different risk factors that kind of interact and they interact differently within each of us based on our genetics and our environment and other things um and so there's this well-known quote in urology which says that once you've seen one case of Alzheimer's, you've seen one case of Alzheimer's, right?

31:02Because each person experiences it very differently, different trajectory, different changes in cognitive functions, right? When we think about Alzheimer's, often we assume it's related to memory, but it's also executive function and our ability to make decisions. So numbers, decision making. There was a paper that came out recently that showed that one of the best sort of early predictors of later Alzheimer's disease was people losing the ability to keep track of their finances right that kind of like complex overview of things those are some of the things that you that you you lose earliest but each of us experience that differently so then we need to think about like what are what are all the different risk factors that could be involved and how might they each of them be relevant to me right so somebody who's very fit exercises a lot that's unlikely to be the primary lever or their primary risk factor.

32:00So then you might have to look elsewhere. But like sometimes people struggle with this because they know people who've had dementia. And if I say dementia is potentially preventable, that could be interpreted as me saying, well, somebody got dementia, it's their fault, which of course is not the case. Because we're each doing the best that we can at any given moment in time.

32:23Dr. Gabrielle Lyon:What must they do? If you wanted to say, if you want to multiply your risk of dementia, here's what I would have you do. Yeah. Struggle with obesity. Yeah. Have a body fat percentage over, I don't know, 35%, whatever it is. Drugs and alcohol. Don't say sleep. I'm not a great sleeper. I'm trying. It's like my one kryptonite. Yeah. If you were to say, okay, here is what I don't want you to do. Yeah. Yeah. So I think that the biggest risk factors that we know exist are, yes, being sedentary. I'm not particularly concerned about as much about a specific body fat percentage. Actually, it's interesting when you look at population data sets, like for men, the best metabolic health on average seems to be like 20 to 30 % body fat, and women, it's like 35 to 45%.

33:21I don't think that has to be the target. But what I really care about is how that's affecting your metabolic health. So we know that the two biggest risk factors, the metabolic risk factors for dementia are hypertension and prediabetes or type 2 diabetes.

33:35Dr. Gabrielle Lyon:And how would you define hypertension? People define it differently. Also in an aging population, sometimes they'll say you want your blood pressure higher for cerebral perfusion. Yeah. Yeah. So the best sort of meta-analyses of all the data we have suggest that if you're above 130 over 80, so systolic over diastolic, some might say 130 over 85, depending on the criteria, then you have a significantly increased risk of dementia. Essentially, anything over 120 over 80 seems like risk starts to increase. And then by the same token, pretty much, the only pharmaceutical therapy that we know significantly decreases the risk of dementia from large randomized controlled trials is blood pressure medications for people with high blood pressure.

34:25Dr. Gabrielle Lyon:Have you seen any data with things like Cialis or Tadalafil for vasodilation? Again, the best studies are less on Cialis and Tadalafil and more Sildenafil, so Viagra. There is a study done looking looking at big sort of insurance databases here in the US. And there was a similar study looking at this in the UK until recently. And then in the UK, they changed it so you could buy Viagra over the counter. But they found that in both those large studies, those men who had Viagra prescriptions, and they mainly focus on Viagra because that was just the most common, you would think that inhibiting that pathway, improving blood flow would probably work for all of those for all those drugs but actually sildenafil is interesting is you is being tested as a neuroprotective agent separate from its effect on on blood flow because it might affect inflammation and neurogenesis and other things so maybe having other effects in the brain as well um and that seems to be associated with a lower risk of of dementia in the men who particularly those who had you were getting regular prescriptions so you knew you were using it regularly now i would argue that it's not purely an effect of the medication if that effect is true right This is not a randomized control trial compared to the blood pressure medications, which are sort of high-quality randomized trials.

35:45Dr. Gabrielle Lyon:And you could say this is the mechanism of action as to why this would potentially work. Yeah. But if you think about the things that are important for long-term brain health, physical activity. And when you say physical activity, both a combination of resistance and zone two, high intensity, where are we at? Yeah. So, well, let's let's finish the Viagra conversation and then we can come back to the next episode. Yeah. So all the men, all the male, actually and female listeners are now listening. As a random aside, the guy who helped to invent Viagra was knighted by the queen for services to chemistry.

36:25This is one of my favorite phrases. Anyway. So when you think about the things that are important for long term brain health and dementia risk, we know physical activity is important. We know that social connection is important when you are a man with erectile dysfunction Who goes to a doctor to ask for a prescription? You need multiple things right you need The likelihood of an active sex life you probably have your own kind of supportive partner Like the act of having sex counts as physical activity And so we focus very much sex

36:58Dr. Gabrielle Lyon:Any sex counts as any physical activity. Any sex counts as any physical activity. Right. Of course, more is better if that's your primary source of physical activity. But the reason why I'm saying this is that it's not just the fact that the drug changes blood flow that might be improving brain health. All these other things are required in a scenario where somebody is regularly using Viagra. So I think that's where some of that benefit is potentially coming from, right? Like having a partner or partners, having active sex life, which counts as physical activity, having some kind of social connection.

37:34All that kind of good stuff that we know is also beneficial for the brain. So that doesn't mean that everybody needs to go out and get a Viagra prescription. I think that it's the context of where it's being used that is important as well. So, like going back to the metabolic health thing and the things that we would think that would amplify our risk, right? So high blood pressure.

37:59Dr. Gabrielle Lyon:Which we define as anything over 120 over 80. Which is unusual for people because that is easily tolerated. Yes. Yeah. You wouldn't notice it. And also tolerated by physicians. They would say 120 over 80. This is perfect. Potentially lower, maybe a little bit better for brain function. Yeah. So it kind of looks like it's kind of the risk is kind of flat until 120 over 80. And then it starts to increase. And then it's like significantly increased somewhere around 100. So it's a systolic of 130 over a diastolic of 85. And then high blood sugar as well, we know, is really important. Like, so if you have prediabetes, your rate of cognitive decline is faster than somebody with normal blood sugar, right?

38:38So a faster blood sugar under 100 versus over.

38:41Dr. Gabrielle Lyon:Do you think that that number is accurate? This is just a hypothetical question. You mean like is lower better? Yeah, is lower better because I think we tolerate what we're seeing in the landscape in general is we have a tendency to tolerate these higher numbers. So we say pre-diabetes, but by the time they're diabetic, they have retinal pathology, they have microvascular disease. So probably if I was looking at a fasting blood sugar, you know, maybe again, we'd be lower would be better? It's a great question. And when you look at like meta-aggressions, right, so you get like a big data set of numbers and you kind of look at this as like a continuous factor.

39:20The risk really does start to increase somewhere around there. So if somebody's like high 90s versus 100, that's probably pretty similar. I think once you're into the low 90s, high 80s, that's probably just fine. Really, the strongest evidence is for like surprisingly, even though Although we might consider them or some people might consider them not ideal, really the biggest evidence is for just avoiding the components of metabolic syndrome, right, which is actually a potentially fairly low bar but is also incredibly rare. Like less than 10 % of the adult population can say that they don't have any of the components of metabolic syndrome.

40:03Dr. Gabrielle Lyon:Which would be elevated triglycerides, elevated blood glucose, elevated blood pressure, wide waistline and a low HDL so below 50 and females and below 40 in males and so like if you tick those boxes right then then I'm then I would say the metabolic health is not going to be your primary risk factor right so then other things where we already talked about being sedentary low cognitive stimulus and cognitive engagement low social support low social connection How big of a percentage does that play? It will depend from person to person, study to study. When I, so a couple of years ago, maybe it's three years ago now, my colleague Josh Turknit and I, he's a neurologist, we wrote a paper together sort of hypothesizing that the primary driver of cognitive decline in sort of modernized societies was the way, changing the way we use our brains.

41:01As we get older, we stop doing the things that we know help to develop and maintain cognitive function, like learning new skills, social interaction, that kind of stuff. And then I spoke to a friend of mine who's a retired palliative care physician called Jupiter Nabel.

41:16Dr. Gabrielle Lyon:That's tough. That's a very tough field. Very tough. Very tough field. Very tough job. For those who don't know what that is, it's end of life. I did that for a couple of months on rotations. and you're seeing 30 patients that are getting ready to die a day. And like a lot of Julian's work is really important because it talks about dying with dignity, like death isn't failure, which is often what we kind of assume as physicians, right? I need to keep this person alive as long as possible when that's not even necessarily best for them, let alone for other people in their lives. But work that he's done has focused on the building of what he calls compassionate communities.

42:00And so the first example of this was in Froome in the UK, where they, around the primary care practice, they built this network of people so that every patient coming in with a chronic disease had a social network built around them. That's amazing. They sort of interviewed them, like, what do you need, what do you want, what do you want to do? and what they found was that in that area they significantly decreased emergency room admissions whilst all around it, the counties around it they significantly increased over a period of time this has now been repeated in multiple cities and places around the world and so when I spoke to him about this idea he was like, yes this is true but basically all of this is driven by the human need for social connection, like his idea is that our connection to others is the primary driver of this idea of cognitive stimulation and and and cognitive skills and and how they build and maintain the brain and that doesn't make sense right you don't usually learn a skill or a language um so that you can do it at home by yourself right you're usually using it so that you can go out into the world and express it with other people, be that, yeah, music, sport.

43:16And we know that of all the different types of social connection, something that seems to be particularly beneficial is pro-social behavior. So it's not just like interacting with other people. It's having the opportunity to do things for others. And that actually activates the vagus nerve, like downregulates a bunch of stress responses. Like you know, like it just feels good.

43:35Dr. Gabrielle Lyon:Isn't there a stress response, tend and befriend? Say that again. So there, you know, we talk about fight or flight as if it's the only stress response. There's other documented stress responses like the courage response. You know, many people that are able to modulate that initial, oh my gosh, and then go right into action. And then there's also tend and befriend, which is very much about community. What can I do? There's a stress report. What can I do for you? Yeah. And so that's when you look at. So not all of this is related. Not all of these data related to dementia risk, but also this like overall mortality But we don't necessarily know that because, again, a cognitively impaired brain could be one in isolation, doesn't do things for other people, isn't moving, is maybe only connecting on Zoom.

44:20Dr. Gabrielle Lyon:Those nervous system connections are probably not as dynamic or real as the human pro-social connection. Oh, yeah, definitely. So just to say that there's a ton of evidence that suggests that one of the primary reasons or one of the primary drivers of the benefit of social connection is pro-social behavior. So it's not just like interacting with other people, but it's taking those opportunities or having those opportunities to care or help others. And we know that the way that we connect with people or are disconnected from people changes inflammatory responses, changes baseline stress responses.

44:53There are some super interesting things.

44:55Dr. Gabrielle Lyon:Are you convinced by that? I mean, have you seen convincing data? So, for example, there was this scientist and he was talking about rheumatology-related disease. So rheumatological-related disease, elevated levels of ANA, and these markers. And basically, what they saw was as interpersonal—I don't know if it was just trauma, but really stressful just thinking of shame—would increase the actual thought, the cognitive top-down process of feeling shamed increases or would increase these autoimmune biomarkers. Do you? So I think the way I think about this and that this like the shame. But doesn't that sound a little crazy?

45:41It does. It sounds completely insane.

45:42Dr. Gabrielle Lyon:For those that are physicians or just they're like, I'm evidence based. What do you mean if I shamed you in some way in that moment and then took your blood? Would you have that immediate response of beyond cortisol, but increase in autoimmune markers? And I don't know. So there was a recent study that actually looked at something very similar in terms of weight shaming and saw a similar thing. So in individuals who are obese, if you put them in a scenario where you increased the sort of shame around their body weight, they saw inflammatory responses in the short term. And so all of this fits into this idea of how our body responds to changes in social status and social rank.

46:29So all of these are social stressors, right? Humans are social beings. Our complex social structure was one of the primary drivers of human brain evolution.

46:42Dr. Gabrielle Lyon:Meaning, what do you mean? So when… The truncated version. Yeah. Well, now I'm going to go back to Darwin because you are. So when Darwin first wrote On the Origin of Species, right, that's where we think we got a lot of this idea of evolution. And we also came up with this idea of survival of the fittest. right um 12 years after he published on the origin of species he published um a series of like a collection of thoughts about evolution of the human species in particular called this the descent of man and he did that because he realized that survival of the fittest as an idea didn't explain human evolution.

47:32And where he ended up was that the collection of beings that were the most, what he called sympathetic towards one another and looked after one another were the group that would survive and dominate the environment.

47:45Dr. Gabrielle Lyon:What he called sympathy, we would probably call empathy now. And basically there's now a ton of evidence that suggests that it's our complex social structure, how we look after each other and behave in a group, plus changes in nutrient availability, omega-3 fatty acids all that kind of stuff contributed as well but that seems to be a primary driver of how our brains evolved and so then the one of the primary determinants of our overall well-being is our is our social status and our social rank and um like very quickly before i get into that a little bit more we we can see from studies of social isolation and this has been done experimentally looking at um individuals um like it like simulated trips to mars so nasa have done studies like this we we see looking at the brains of people who do like arctic exploration like you're on your own at the top of the world for months the parts of the brain that are most evolutionary recent evolutionarily recent in human humans part of the prefrontal cortex parts of the lateral parietal lobe the the temporal lobe that are responsible for some of our most complex cognitive functions these areas of the brain are most susceptible to um aging and most susceptible to periods of social isolation.

48:59And these are the things that explain, you know, us having our human brains. And you can see that in short-term and long-term studies. And they've also done studies looking at prisoners in solitary confinement. And you see the same thing. So the structure and function of our brain seems to be driven by the social environment. Yes, all these, like nutrition, physical activity, all critically important as well.

49:20Dr. Gabrielle Lyon:But the structure and function, the architecture is really based on the interpersonal connection. That's unusual to think about. Yeah. And you can see it in very short term, where you put somebody in socialization for a couple of weeks, cognitive function declines because of the lack of stimulus and sort of connection you're getting from other people. And so in like a bigger picture sense, so anybody who really wants to dig into the research, Julie and I, who I mentioned earlier, we recently edited an edition of a journal, the journal Lifestyle Medicine, on compassionate communities and social connection, why it's so important to health.

49:55One of the papers was written by George Slavich and Steve Cole. They're at UCLA. They've done a ton of research in this area. And one of the ideas is that any time we experience a social stressor, and that could be social isolation, but it could also be changes in perceived social rank. So that's where shame comes from.

50:16Dr. Gabrielle Lyon:Which now also is happening much more rapidly, getting back to the blood level connection. now we can with the velocity of the connection you could be shamed on I mean you and I both know someone who was went from status over here and in one second completely shamed within moments to millions and we see this all the time and it happens even like on a much smaller scale to each of us like anytime you're on social media and you see people who are richer more beautiful more jacked more successful than you are right you're all always like trying to put yourself into place in like the the bigger world of society around you and so these kinds of things can drive social stress and what social stress does is it triggers uh an evolutionarily um conserved shift in immune function and stress response so when you take somebody and that and you socially isolate them so um if i'm in my you know and set one of my ancestral homes of iceland a thousand years ago and i get separated from my group i'm on like lost on some mossy lava field in the middle of nowhere what happens is you see a shift in the immune system that you change from more of a like adaptive immune response that's that's particularly important for like um uh like handling viruses flus and colds and things because that's what you get you get exposed to those when you're in a social group it shifts to become more of like an amplified innate immune response so you see a bit of wound healing um and higher low grades of inflammation because right you're no longer going to be exposed to these kinds of things that you get when you're exposed to in a group but if you get injured and you're by yourself like you're stuffed you have to be able to survive so you can measure these shifts in the immune system in response to social stress and so in the short term that's a good thing right it actually improves survival in the short term because you have this shift in the immune system and the sympathetic nervous system but if that's activated chronically you have higher baseline levels of stress you have higher baseline levels of activation of the sympathetic nervous system which then seems to contribute to the progression of chronic disease so all of this driven by all these potential ways that we can feel socially stressed, which historically was around social isolation.

52:43But now there's a ton more ways that we can experience that.

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54:26Dr. Gabrielle Lyon:Would you say if you were kind of circling back to what you wouldn't want people to do? What would you not want them to do? Yeah, so be sedentary at home alone. Eat a calorie-dense, nutrient-poor diet. Because we know there's a ton of nutrients that are critical for brain function. What are your top? So the ones that we have the most important evidence for are vitamin D, omega-3 fatty acids, the B vitamins associated with methylation. Vitamin D ingested orally, meaning through foods or just the exposure outside? Either. If you need to supplement, I think there's very good evidence for it from a cognitive standpoint.

55:20And that's in terms of mood disorders, but also potentially in terms of dementia risk. But then also we know that it's important for like athletic performance, right? So that's something that we're very cognizant of with the athletes we work with. So vitamin D, omega-3 fatty acids, B vitamins related to methylation. So B12, folate, B6, riboflavin, which is B2. And the market that seems to be most important is homocysteine. So elevated homocysteine that we know is associated with significantly increased risk of dementia. And there are randomized control trials where if you lower homocysteine, particularly in the context of adequate omega-3 status, you see slowed brain atrophy, slowed cognitive decline.

56:02And then iron, particularly critical. I think there is—

56:08Dr. Gabrielle Lyon:Even post-growth. Even post-growth. So there are so iron is critical for the development of the white matter in in babies. And then it's also important for maintaining the structure and function of white matter later in life. So there are several studies that suggest that anemia or low iron status, particularly in women, as they enter sort of the perimenopausal transition, one of the reasons they experience cognitive symptoms is because of issues with iron status. And that is even very common. in people eating a sort of a, and what you might consider an adequate diet. So that's something, that's something definitely to take care of, take care of or look at.

56:50You can see that you see this kind of bell-shaped curve between cognitive function and hemoglobin levels, right? So if you're anemic, you have low hemoglobin, we know that's suggesting poor iron status. That's not going to be helpful for the brain, but at the high end, high hemoglobin is usually, the most common cause is obstructive sleep apnea right you become hypoxic during the night the body makes more red blood cells in response so it's not then the high hemoglobin that's the problem it's the fact that you have sleep apnea and you're you're not it not sleeping properly and you're becoming hypoxic during periods at night so that's another reason why that's that's a useful market to look at um then other things that we have some reasonable evidence for um might include magnesium zinc um uh choline in certain scenarios um and then uh like the the antioxidant polyphenols that you get from berries um the roasted um skins of nuts and seeds coffee tea um you know the sort of uh yellows and reds lutein and zeaxanthin from like you know peppers and carrots and things like that.

57:56And then astaxanthin, which you get from is what makes salmon and shrimp pink. Those higher intake of those associated with better cognitive function, lower risk of dementia.

58:07Dr. Gabrielle Lyon:Is it over a lifetime or could someone come in? Because these are all fixable deficiencies if someone is deficient. How over what period of time do you think that there's impact? So I think that... So essentially, as soon as you can address that, the better. But so something like vitamin D, we know that there are some vitamin D trials or like studies looking at like population intakes of vitamin D, vitamin D supplementation is associated with lower dementia risk. You know, once people are into their like 60s and beyond. So even like later in life, if you're starting to address this, this, you could potentially change that.

58:48And most of the studies that look at vitamin status and dementia risk are again sort of like in individuals in their 60s and 70s. And there are randomized controlled trials of omega-3 fatty acids and B vitamins, again, in individuals.

58:59Dr. Gabrielle Lyon:I am absolutely sold on that data for omega-3 fatty acids in the brain. The most interesting thing to me, though, is this interaction between B vitamins and omega-3s. So the original study that looked at this was the BioTacog study run out of Oxford in the UK. and they found that lowering homocysteine at least below 30 at least below 13 ideally below 11 was associated with slow rate of cognitive decline improved cognitive function um but only in individuals who had adequate omega-3 status that is that is i mean it's just interesting yeah because what food has both omega-3 and b12 naturally what's the highest natural food in Cydines, small fish have both.

59:49And this has now been replicated in multiple other trials. So the bee-proof trial did the same thing. The omega-AD trial came from the other side. They supplemented with omega-3s, but they found that it mostly benefited those who had low enough homocysteine. So there's a really interesting interaction there. And this is particularly interesting to me because you'll have seen dozens of trials where you give one nutrient, And then it doesn't affect cognitive function. And they're like, oh, it doesn't work.

1:00:15Dr. Gabrielle Lyon:Absolutely. But it also doesn't make sense to supplement with something if you weren't deficient in the first place. And most of these trials don't measure nutrient status initially. And then it's silly to think that just like one nutrient is going to solve all the problems. But it also goes back to this whole food matrix. Yes. Eating over time. Yeah. People have estimated that we only really know about 10 % of what's in like whole foods. Right. And so the other 90 % is doing something. And there's a reason why seafood intake is associated with more of an effect on dementia risk than supplementing with omega-3s.

1:00:52Like from the trials, we know that supplementing with omega-3s can be beneficial. But seafood has a whole bunch of other stuff in it, right? So if it's salmon, you have astaxanthin, you have selenium, you have a whole bunch of other, like salmon has some B vitamins in it. So there are a whole bunch of other things you're getting at the same time.

1:01:09Dr. Gabrielle Lyon:How often do you recommend eating fish? At least two or three times a week. I think the goal is to sort of get something like two to four grams of long chain omega-3s on average per day. But it actually doesn't have to be daily. I published a paper with a colleague of mine, Rory Heath, a few years ago, looking at how the body handles long chain omega-3s. And basically, if you overeat them, right, so if you eat like a massive plate of salmon one night, your body will store the extra omega-3s in your adipose. And then it will access that later. And it gets sent to the brain, say, if it needs it.

1:01:48So you don't have to eat it every day. But just like regular consumption will then make sure you've got a bit of a depot.

1:01:54Dr. Gabrielle Lyon:I mean that. So we had Tom Brenna on. Do you know Dr. Tom Brenna? I don't. He was responsible for the last three dietary guidelines. His expertise is in fat. saturated fat, long-chain fatty acids. And he said that the idea that women, pregnant women should reduce their fish consumption, whether it was tuna or anything else, he said is completely wrong. Yeah. This is really interesting to me because it brings up some of the most counterintuitive studies that you might ever read when it comes to this kind of thing. Firstly, I think it is interesting that women seems to be better at converting shorter chain omega-3s to longer chain omega-3s because they're so critical to infant development, to the fetus.

1:02:40That may be upregulated even more during pregnancy. So women may be more likely to be able to get short-chain omega-3s like alpha-lilonic acid from chia seeds and walnuts and things. I still think they should eat. Yeah.

1:02:53Dr. Gabrielle Lyon:And Tom would say it's not really bioavailable, the conversion is still off, and we're not going to have a good job. It's better in women than in men because it's important for the fetus. But that doesn't mean that it's enough to like not consume them. But when you look at studies of infant development and then some studies of like what's going on in the brain individuals who experience Alzheimer's disease or not, what you see is that there is a net benefit for seafood consumption, even if that comes with increased mercury consumption. And that's true in terms of. Exactly what Tom said. He said there's no reason.

1:03:28Dr. Gabrielle Lyon:He said those that are eating more omega-3 fatty acids and fish, their offspring are they are better off from a cognitive standpoint. Yeah. So there's studies done in the UK on this, studies done in the Seychelles on this because the Seychelles is obviously an island nation that really a ton of seafood. And this I think is really important because so often we get caught up in this side. We focus on like one negative thing in this food. And we think that offsets all of the benefits. when actually all the evidence suggests that the net benefit is much greater than this one thing that we might like to focus on.

1:04:04And we can think about it in terms of lots of things. We can think about it in terms of grass-fed meat. We can think about it in terms of seafood. We can think about it in terms of like mycotoxins in coffee, right? All the signal says these foods can be beneficial. And like the net benefit is much greater than to outweigh some of these other things.

1:04:19Dr. Gabrielle Lyon:What about alcohol? Alcohol, drug consumption? So alcohol is important. But I want to say about this one study in terms of... So like there was a study that looked at mercury, the mercury content of people's brains. And they found that those who had more mercury in their brains have had a lower risk of dementia. And like that doesn't make any sense. Makes no sense. Right. Right. Unless you think about the fact that this mercury is coming from seafood. In seafood, you get selenium that helps offset some of the negative effects of the mercury. And you get all these omega-3s and all these other things.

1:04:53So it's not that the mercury is beneficial. Right. It's just this signal for people having consumed more seafood. So like all that again to just say that I think that eating the seafood is much more important than worrying about some of the things that come along with it. And of course, yes, if you want to eat more sardines, mackerel, smaller fish, anchovies, great. But we shouldn't be scared of seafood because -

1:05:15Dr. Gabrielle Lyon:Which we have been. Yeah, absolutely. And women, pregnant women, even myself, but through my pregnancies I was like, oh, you know, I don't want to have too much fish. I was really concerned. Yeah, yeah. Whereas the, so when you were pregnant, then your body would have sacrificed your own DHA stores for your fetus. We know that. It's very tightly regulated. You will offload those stores because the baby's brain needs it. So then coming to alcohol, this is another thing that I think is really interesting because whenever anybody asks me about alcohol, it's usually because they want to be able to justify their current level of intake, regardless of what that is.

1:05:50um you know everybody wants to think that they're that what they're doing is okay particularly when it comes to alcohol um i think what the evidence suggests is that um i i don't agree with some of the more recent studies that say that any alcohol you ever drink is bad and you shouldn't ever drink it um most of those are based on this really weird methodology where you use reported alcohol intake to generate a polygenic risk score for alcohol intake and then And you use the polygenic risk score to predict.

1:06:21Dr. Gabrielle Lyon:That's complicated. It does affect sleep architecture. Absolutely. So like, I am not saying that like alcohol absolutely has downsides. It impairs REM sleep in particular, causes a REM sleep deficit. It messes with thermoregulation like during sleep. So we know that it's not great for your sleep, of course. But when you sort of look at overall outcomes, brain volumes, cognitive function, it seems like as long as you're averaging less than half and the reason why I say half is because in the UK one standard drink is about half what a US standard drink is well okay so in the UK you're saying yeah so in the UK it's eight grams of ethanol in the US it's 14 grams of ethanol for a stand for a standard unit or drink so if you're if you're on average consuming less than half uh standard u.s drink per day on average there seems to be no net effect on on the brain so what that means is you have a a beer or two once or twice a week or a glass of wine once or twice a week that's probably fine um beyond that then we start to see changes in brain structure the physical incognitive function increased uh risk of dementia so like the occasional drink with friends is fine Is it the effect on B12 status or the B vitamin status or is it something else?

1:07:42I don't think we know. At least I haven't seen studies that have kind of, they may just look at alcohol intake and then they look at health outcomes. I don't think they've looked at mediators of that effect. I would certainly expect sleep to be a big part of that.

1:07:54Dr. Gabrielle Lyon:Can we talk about that? Okay. Sleep is important. I understand. I just think if I do all the other things that are right, then maybe I can offset the fact that I'm not a great sleeper. And then, you know, when you have little kids, they sleep in your bed and read all this stuff about how there's a close connection for them and it's important. So tell me how I need to kick my kids out of the bed and sleep more. So but don't tell me too much because that I think we've gotten to the point where we We now understand sleep is important, right? But in many respects, I'm worried that we've taken it a little bit too far.

1:08:37Because of course sleep is critical. We know that people who consistently sleep for less than six hours a night have an increased risk of dementia, for example.

1:08:45Dr. Gabrielle Lyon:And they probably have other bad habits. Yeah. No. And these things come together. I'm just trying to justify it. Yeah. And so like— To be clear. I'm backing you up here. So we know residency and graduate school and being pregnant. It's miserable sleeping. Yeah. And there's actually good evidence to support that that's not a net detriment. So there's a ton of evidence that shows that those who are physically active offset some of the negative effects of sleep deprivation. Potentially, because you're doing other beneficial things at the same time, you're offsetting some of the negative effects of sleep deprivation that might be related to blood pressure or blood sugar or inflammation, right?

1:09:28We know exercise helps with that. If you exercise more, we know your sleep quality tends to be better, right? So maybe you're getting less sleep, but it's better quality sleep because you're exercising. So exercise seems to be one way to offset inadequate sleep, whatever that is for that individual. We also know that at least in the short term, how we perform is based on how we think we slept rather than how we actually slept right there are multiple really interesting studies where you manipulate how how long somebody think thinks they slept or how well they think they slept by like manipulating data unawareable and actually you perform if you think you didn't sleep well so are you ready for this not to interrupt you but

1:10:11Dr. Gabrielle Lyon:i just want to tell you this story because my husband just found this out we had our friends over, the Seal Future Foundation had this event and some of the older seals were over and one of the guys, Robert, he is, he's like the OG BUDS instructor. Yeah. And so he was sitting with Shane and a couple of the other guys and he's like, you know, I just want to tell you, we told you, you guys slept four hours. Yeah. We let you fall asleep for four minutes. And the guys were like, what? You know, in this many days, but they were told, they were like, all right, we're going to let you fall asleep for four, for four hours.

1:10:45Dr. Gabrielle Lyon:Anyway, and it just blew everybody's mind, whether it's true or not. I don't know. Well, so they've done this in the lab, five hours versus eight hours. And this was done by Ellen Langer and Steve Lockley at Harvard. And people go into the lab to sleep, and they either get to sleep five hours or eight hours, and then the clock gets manipulated. So that when some of the group who slept five hours wake up and they think, oh, eight hours have passed, I've slept for eight hours. And some of the group that slept for eight hours wake up and only five hours have passed. So they think they've only slept for five hours.

1:11:15And so then how they felt and performed the next day was better determined by how well they thought they slept rather than how well they actually slept. And people have done something similar with wearable data. And in the short term, the brain actually adapts. The network shifts slightly so you can maintain function when you're sleep deprived. So the thing that is affected more is your mood is affected more than your performance. So you perform the same, but you're just a little grumpy about it. Of course, like the more sleep you lose, like hours lost multiplied by number of days, right, the worse for your cognitive function.

1:11:50But in the short term, actually, we deal with sleep deprivation fairly well. But we get ourselves in trouble when we think we're not going to perform well because we didn't sleep well. And then we don't perform well because we thought it rather than because we didn't sleep well.

1:12:01Dr. Gabrielle Lyon:Is there recovery? Can we recover brain function? Yes. so there's um we know that you can um offset some of the effects of like um sleep deprivation during the week um by sleeping more on the weekend it's not the best for your circadian rhythm right because things get a little bit more out of kilter but you can get some of that back napping can get some can get some of it back um but i think that it's also worth right i don't want to downplay And I think that's why the focus on sleep, we know it's critical. But as it comes to parenthood, there's a really nice study that was done in the UK Biobank, where they looked at parents and later risk of dementia.

1:12:46And they found that the more kids somebody had, the lower their risk of dementia. And this was for both mothers and fathers. And I think this is interesting because when you first think about it, like you said, being Being a parent is terrible for your health, right? You don't sleep, you're stressed, you don't have time to exercise, you don't have time to look after yourself. You're so worried about this.

1:13:08Dr. Gabrielle Lyon:My kids were waking me up at 5 this morning. I didn't fall asleep till 1.30 because I had to put together a talk. And they're waking me up at 5 in the morning to read a survival book. But this and the thing. Like, guys. Yeah. And this is what happens, right? And but you think about all the things that come with having kids, right? Think about the social connection and the process of behavior and like the love and joy and all these other things that we know are really important. Just like with mercury and seafood, right? The net benefit of having children and actually the similar data on being like a pet owner.

1:13:43I was just thinking about that. In terms of how it affects cognitive function and dementia risk. But like there's this the net benefit outweighs the downsides. So yes, even if you slept terribly during like when your kids were young, overall, there seems to be this net benefit in terms of long term cognition. So all that to say that you're probably doing a lot of things that are offsetting some of the poor sleep, even if, you know, maybe if there's some point, oh, OK, so maybe it's important now to mention that you asked about recovery.

1:14:16Dr. Gabrielle Lyon:Meaning recovery from brain volume, recovery from, you know, they say that Alzheimer's is not reversible, that cognitive decline, prevention is the best metric or the prevention is the best measure versus once you have problems, you're in trouble. So as it relates to like just to sleep, and then we can expand out from there. There was a nice study done by Matthew Walker's lab where they looked at people and their their sleep as it changed over the over their lifespan so they asked them like did your sleep get better or get worse in different decades of your life and they found that even if people's sleep was improving not until they got into their 50s or 60s if their sleep did improve in that in that decade that was then associated with a lower like pathology burden in their brains and we know that one of the things that sleep is important for is clearing out proteins and metabolic waste and one of those things is amyloid, which is part of the process of developing Alzheimer's disease.

1:15:19So that even suggests that if you're in your 30s, 40s, you're not sleeping well because you're raising a family. Even if you start to then improve your sleep later in life, you will still see benefit from there. Once you've actually experienced some element of cognitive decline, whether that's fully reversible right now is controversial. There's certainly lots of evidence that you can improve some aspects of cognition and quality of life through dietary changes, through physical activity, through social connection, all this kind of stuff. So you can certainly change the trajectory of the disease.

1:15:52Dr. Gabrielle Lyon:This episode is sponsored by Branch Basics. One thing I've become much more aware of over the years is the impact of the environmental chemicals on our food and also inside our home. If you're a frequent listener, you know we spend a lot of time talking about nutrition and muscle health. But beyond that, we should be thinking about what we're exposed to every day through things like cleaning products. Now, I started using Branch Basics when I was pregnant to, of course, limit my exposure to harsh chemicals. Their products are made with plant and mineral-based ingredients, and their premium starter kit uses a single, powerful concentrate that can replace almost everything in your home.

1:16:35Dr. Gabrielle Lyon:From laundry detergent to bathroom cleaner and even, get this, produce wash. I like that it simplifies my cleaning routine and removes any concern of exposure for myself and my little ones. If you're also worried about the chemicals you are using in your home, I suggest you try Branch Basics. You can get 15 % off the premium starter kit at branchbasics.com with the code DRLYON. Again, that's 15 % off BranchBasics.com with the code Dr. Lion. Do you see that on imaging? For example, you might see, again, we image a lot of people's brains. We see microvascular, what do they call it, white matter changes.

1:17:24White matter, like hyperintensities.

1:17:25Dr. Gabrielle Lyon:Yes, that is. And it will say, you know, in alignment with the natural aging process. And it's like, well, OK, is it and do we see an acceleration of it? We certainly don't see a reversal of it. But is that indicative of brain function getting worse? So it's like that, like it's clinicians thinking, OK, so we fix these things. They believe they experience some improvement. But do we see the actual imaging change? Not all of the studies that have looked at, say, cognitive function have then, And especially in the setting of like already established progress of decline, we'll then do imaging as well.

1:18:08But so if we're still like early on in that trajectory, right, we know that, say, so we're talking about white matter hyperintensities, we see some of those resolve in some of the resistance training studies, right? So if you're improving white matter structure and function, you may improve the burden of white matter hyperintensities, which are thought to be part of the, yeah, the sort of the decline in white matter structure as you get older. Some of it very likely to be related to vascular issues. And the change in white matter structure and decline in white matter structure and function is actually one of the best predictors of future cognitive decline and dementia.

1:18:46In some studies, even more so than like amyloid and tau burden, even though they are related. So yes, some of that seems to be reversible through lifestyle interventions because we've seen that in some trials. Until you're at the late stages of dementia, the brain is still capable of experiencing neuroplasticity, which then means that structural changes are possible. So when you start to lose brain volume, the first thing that happens is not that you're losing cells. So neurons aren't dying early on. What they're doing is they're shrinking down. It's kind of like when you stop training, your muscles shrink.

1:19:34But if you start training again, you experience much more rapid recovery of previous function that you had. like you're more muscle satellite cells and like you're able to you're able to like get strength and muscle back faster because you had that because you had it previously and so i think there is capacity in the system to respond to these interventions either right so the you know cell bodies could could increase you also see changes in like the extracellular matrix and structures around cells um so the brain is capable of neuroplasticity basically until the until the late stages of dementia so if you if you were to engage those processes you would expect to see improvements in brain structure and function but um and so you should be able to measure that on an mri scan even in even in older adults how much of that is like definitely proven because you know is is debatable because they just haven't scanned that you know not that many studies that do this kind of large scale interventions then look look at brain scans um but some small trials um like dale bredesen's evanthea trial which which is not published yet but the preprint came out recently um and there's there's a lot that we need to know about the the structure of how that trial was run um how the control routes worked all that kind of stuff but they did they did seem to show significant improvements in multiple aspects of cognitive function i know they're tracking brain structure as well in individuals who are already experiencing some cognitive decline and early dementia.

1:21:03So everything that exists so far suggests that early on in the process, at least, there's still capacity in the system to respond. Maybe it's only going to result in improvement, like improvements in function and quality of life rather than full reversal. And whether you can fully reverse Alzheimer's disease, like I said, is very controversial. And I honestly don't know what the answer is. But the brain is still capable of responding to these inputs, which should result in changes in structure, even until sort of like early parts of that process.

1:21:38Dr. Gabrielle Lyon:I mean, I'm hopeful because for anyone that's ever seen Alzheimer's or any type of dementia, it is devastating. One of the things that they were giving in the cognitive clinic was something called axona. And it was medium chain triglycerides. There's also been some use of ketones. I don't know if you've looked at that at all. Yeah. So the medium chain triglycerides are actually one of the sources of exogenous ketones that because the MCTs get absorbed in an interesting way in the gut, they go straight to the liver and get converted to ketones. There's probably some of the best evidence for them in the setting of some cognitive decline.

1:22:21So these studies were done at large by Stephen Kinane. And what they did is they took individuals with early stages of Alzheimer's and they gave them MCTs and saw some improvements in brain metabolism and then also in cognitive function. One of the things that you see in individuals with Alzheimer's disease is a decrease in glucose uptake into the brain. So that's what it's like. The fancy word is pathognomonic. You see this in certain areas of the brain. You're like, OK, this is Alzheimer's disease. And you do that with an FDG PET scan, like a radio labeled glucose. You make it radioactive and you can see where it goes.

1:23:02And in Stephen Penane's study, they saw, right, DQ's glucose uptake into the brain. But then when they gave MCTs, they did the same kind of scan, but with ketones, with acetoacetate, and saw an increase in acetoacetate coming into the brain. So more energy was getting into the brain and that was then associated with improvements in cognitive function.

1:23:22Dr. Gabrielle Lyon:So is that just a fuel switch? They were switching fuels. It seems to be a fuel switch. So glucose uptake into the brain didn't change with MCTs, but ketone uptake did increase. We often think about glucose uptake decreasing into the brain in terms of like some kind of insulin resistance or some kind of metabolic disease manifesting in the brain. Some people have called it type 3 diabetes, which there are many other things that contribute to Alzheimer's disease. So I don't think you can just blame it on glucose metabolism. But it's interesting to look at what is actually happening when you scan somebody's brain looking at glucose getting in.

1:24:07because the glucose getting in, you can say how much is getting in, but it doesn't tell you, is that because the glucose can't get in or because the brain isn't asking for it, right? So the parallel is in muscle tissue, right? We know that your skeletal muscle is your best glucose sink, right? But if you want your muscles to take up glucose, you have to move them, right you have to create that demand for for the for the glucose to be to be drawn in and the brain is the same so there was one fascinating study where they took individuals with a range of different levels of cognition so healthy controls and then different stages of Alzheimer's disease and you scan their brains and you see how much glucose is getting in and as you expect right the the worse the stage of dementia the less glucose is getting into the brain but in the early stages of Alzheimer's, if you stimulated their brains with a cognitively stimulating activity, they asked for more glucose and more glucose came in.

1:25:05So I think that one of the reasons why we see decreased glucose uptake into the brains of individuals with Alzheimer's disease is because the brain isn't asking for glucoses. Those regions of the brain are not being used in the same way and therefore it's not asking for it. It's just like your muscles not asking for glucose if you're not moving them. So at least again, like early on in the stages of the disease process, the brain can still respond and ask for more glucose if you stimulate the brain. So this is one of the reasons why my core idea is something that I present in the book is that I think the health and function of our brains is primarily driven by how we use them.

1:25:44And if we continue to use and stimulate those areas of the brain, they'll keep asking for more glucose and they'll actually help maintain their structure and function. So we just need to think about both sides of the metabolic health side, but then also about like how are we using our brains and how is that determining what fuel source they're using.

1:26:01Dr. Gabrielle Lyon:And you're a lifelong academic and you're able to assimilate and recall and think and you're constantly improving and engaging in these activities. If someone is listening to this and they're like, I don't know, I sit down to read for 15 minutes and I'm tired, my brain is tired or I'm distracted by something else. How would you advise them? The most important thing that we can do in that scenario is anything that requires us to focus for an extended period of time because focus is a skill in its own right. And we see evidence that people who spend a lot of time focusing on anything then get better at focusing.

1:26:44So there's one study where this is done by Wendy Suzuki where they had people do a mindfulness Training so as mindfulness like 30 minutes of mindfulness like They did like body scans and breath work and within a few weeks they saw improvements in the ability to to maintain focus and attention because the one of the reasons why people struggle with mindfulness is because like you have to just like sit there and think about the same thing again, right for a long period of time and like Like people struggle with that. I know. That sounds great.

1:27:14Dr. Gabrielle Lyon:It's like on my bucket list. But anything that we can do that requires us to pay focused attention on one thing is going to help us build that muscle. So one of the best ways to do that is with something that's engaging and fun. So if you only struggle to read for 15 minutes at a time, yes, great. Maybe you could build it out, 15, 16, 17 minutes. It's very similar to a training program. right you start where you can and you slowly build capacity but equally you could play a sport or learn a language or learn a musical instrument or anything that requires you to just focus on one thing at a time because what we've become really less good at just because we spend less time doing it is just focusing on one thing at a time we know that there's this thing called learning to learn which is basically anytime you're learning something it requires your focused attention.

1:28:09And when you do that, you then develop the skill of focus that you can apply elsewhere. So if somebody is really struggling with their focus, pick one thing that you want to do more of that you can only do whilst not doing anything else, right? You can't play badminton while scrolling on Instagram. Completely impossible, right? Eliminate those factors because you have to pay focused attention if you want to do well. And if it's something that's fun and engaging and you enjoy, you're much more likely to stick with it. One thing that I've noticed, most of my work is on a computer. I've got emails, I've got Slack and Teams and people are messaging me all the time.

1:28:50I have to jump back and forth, like everybody. But very regularly, almost once a week, I have to go into the lab and I have to do one thing for three hours at a time. It could be surgeries. Yesterday I was extracting brains because I do it faster than the team in my lab just because I've done it so much. But you sit there and it's just like one thing. I've got nothing else to think about. I've just got to focus on this one thing. Same when we're doing surgeries in the lab. So it's having these, whatever it is, something that requires you to pay sustained attention for long periods of time will help you build that skill.

1:29:29Because then I can apply that same skill when I'm doing research or writing my book or, you know, having to, you know, have a long conversation, right, which some people struggle with because they're constantly reaching for their phone or something else. So that's where I would start. Pick something that you want to get better at that requires you to just like pay focused attention to it and slowly build that skill over time. And it will help you in other areas.

1:29:53Dr. Gabrielle Lyon:Well, Dr. Tommy Wood, this book, I encourage everyone to get it. the simulated mind it's so well written it has just great action oriented items and congratulations thank you thank you so much um i'm really glad you enjoyed it thank you again for for your help um getting it off the ground and getting out there i really really appreciate it well done sir well done