Well, 45 to 70% of dementia is preventable through lifestyle. Is that a defensible statement?
45% comes from the most recent edition of the Lancet Commission report on dementia prevention, looking at different risk factors that have a consistent relationship with dementia risk. And there are other studies, like there was one big study done from the UK Biobank data by Professor Yintaiu that estimated that up to 72% of dementias were preventable.
Tommy, Tommy, Tommy, nice to see you.
Nice to see you. Thanks for making the time.
Thanks for having me. Absolutely. And as mentioned before we started recording, this is just going to be like our last conversation because I wanted to reach out to you because cognition, cognition, cognition, boy oh boy, is that on the mind, and pun intended on one level. But we are going to bounce all over the place, and I hope to give people, including myself, a lot of tactical, practical recommendations. Also being clear where the science is solid and where the science is maybe a little thinner ice, right?
Yeah. Or something is plausible but not yet proven out.
And you've got me chewing xylitol gum. You got me looking at air purifiers. But I'm skipping ahead. Let's go back to the beginning, and I want to give the good old Dr. Chattery a nod here because it came up in a conversation you had with him, and I was like, 'Wow, I never would have thought of that.' Why are human babies so plump? Why are they so fat compared to other species? If you look at human babies compared to pretty much every other mammalian species, we are the only species that's born fat, even compared to other primates. And it's thought that the primary reason for this is that that fat
is a repository for things that the brain needs in order to develop. And the two that are probably most interesting to you and seem to be particularly important are DHA, the omega-3 fatty acid, and fats as a source of ketones for the brain. When the brain is developing in particular, and I think this is also very relevant to recovery from brain injuries and other states, the preferred synthetic precursor, as in the thing that the brain uses to make structure like fats and cholesterol and that kind of stuff which makes up a significant chunk of the brain, ketones are the preferred source, particularly in the developing brain, but I think also later on in, you know, various states as an adult. And so in order to support that very hungry brain, which it is particularly in humans, we're born fat so that we can generate a bunch of ketones to support that brain developing for the first, you know, especially for the first few weeks, but maybe even for months after that.
Mhm. We also have lots of, as I understand it, beautiful brown adipose tissue.
Keep those little hairless monkeys warm.
All right. So, we're going to talk about, because I think the, in a sense, the extremes inform the mean, but not the other way around. So, we can talk about certain maybe edge cases, things that people might not view as immediately relevant to themselves. But since we're talking about newborns, I'm curious. You've looked at therapies, various types of research into brain injury in newborns. What do you do? What can you do? I mean, what's the state of the art when it comes to treating brain injury in newborns or in infants?
There's two main brain injuries of babies that I study, and they're probably also the two main brain injuries that are most broadly studied just because of their impact. And so the first is preterm brain injury. So that's a baby's born early. The earlier you're born, the greater the risk of neurodevelopment impairment or, you know, some other kind of neurological disorder, cerebral palsy, other impairments later in life. And the other is something that we call hypoxic-ischemic encephalopathy, which is essentially you get to normal full term, something happens, not enough oxygen.
Exactly. Not enough blood flow, not enough oxygen get to the brain.
Something happens usually during childbirth, and people think about, you know, the cord is wrapped around the neck, or you can get placental abruption, right? The placenta kind of tears off the inside of the uterus, or like the uterus can completely rupture. But sometimes we don't know what happened; the baby just comes out and like something has happened. In that scenario, the second one, HIE as we call it, those babies are cooled down. So this was something that I studied a lot in my PhD. You take that baby, and as long as you start within a few hours of birth, you cool them down to 33.5°C for 72 hours. And that significantly reduces death and disability.
That's 92.3°F for you Yankees out there.
Although even in the US, many of the cooling machines are made in Europe, so they still run on Celsius. So those babies get cooled down, and that's really the state of the art. Although now we're starting to figure out that there are still a whole bunch of injuries where that doesn't help, including preterm babies. So if you're born preterm, cooling doesn't help. Actually, it can be detrimental. And in that scenario, one of the things that they found recently, which is probably most beneficial, is caffeine.
Yeah. Caffeine is not given for neuroprotection. It's given because babies who are born preterm don't breathe as well. They have this thing called apnea of prematurity. So they don't have like a normal respiratory drive.
So you give caffeine to stimulate that. But the trials that used caffeine to treat apnea of prematurity saw significant improvements in cognitive function.
And those were durable improvements or just during treatment with caffeine?
When you do these kinds of trials, usually you follow those babies up to something like 2 or 3 years old. That's mainly because an NIH funded trial or an NIH grant lasts five years. So if you're going to do a full trial in five years, then you have a year or two to enroll and treat, and then you have two or three years to follow them up. And so they see significant improvement at that age, but then also, you know, going into childhood, which is ideal. You really want to look out as far as you can. So then there's now renewed interest in caffeine in other brain injuries in babies, and that's something that we've tested in my lab. There are some trials now starting in other brain injuries. But beyond that, in both groups, really the biggest impact on later outcomes is the home environment that kid goes back to. So yes, my colleagues who are practicing neonatologists do a whole bunch of amazing stuff to keep these babies alive and keep their brains in good shape as much as they can when they're in the intensive care unit. But actually the home environment is where the biggest impact happens. And so then that means that even if you have an imperfect start to life, there's probably a lot that you can do as a parent to help that brain to develop and grow, you know, as normally as possible.
All right, we're going to continue to talk about brain injury for a little bit, and then we're going to talk about a whole lot of sort of multifactorial prisms around cognition and whether or not you can intervene with the fates to preserve or enhance cognition as an adult. Right? So, we're going to get to that. But if we make the hop from infant to adult, right? And if you slipped on the ice and hit the back of your head and suffered a severe concussion, what would you personally do after that?
There are a few things that I think we can probably do, and we actually wrote a paper about this, came out last year, that covered various nutritional strategies, and most of the strategies would be nutritional supplements I would probably lean on. And assuming that I didn't have any control over what happened beforehand, ideally I'd do lots of things to improve the health of myself, right? Because I think that's going to affect how my brain and body then respond to the injury. But after that point, then there's a couple of things that I would do. One is I would manage fevers. This goes back to the hypothermia that we talked about in babies. Lots of trials have tried hypothermia for traumatic brain injury in older humans and adults, and they haven't really shown any benefit. What does seem to be beneficial is preventing hyperthermia. So if you have significant trauma, one of the things that happens is the immune system gets activated, is you get a fever. And that fever increases this gap between the metabolic demand in the brain and the supply of energy because the mitochondria become damaged during the injury. So if you increase that gap because the, you know, higher metabolic rate because you're hotter
that seems to make that injury worse, and this has been found in some animal models but also in some human data. So the most important thing to do is to prevent fevers.
So get your flu shots, etc. Other things?
In this scenario, you know, if you need to take Tylenol to prevent a fever.
I see. Take acetaminophen.
Yeah. Acetaminophen, paracetamol, depending on where you are in the world.
Maybe even there are some devices where you can do some neck cooling or head cooling. They probably don't have as much of an effect as some people think they do. But whatever you can do to maintain your body temperature, and so antibiotics, so things that help prevent fevers are going to be helpful. I would then also manage blood sugar. The main thing being probably avoiding things that are going to cause large glucose spikes. So avoiding refined carbohydrates.
Why does that matter acutely after you whack your head?
You see again in multiple studies, and we have to do this experimentally. So some of this comes from animal models, but if you create diabetes or the hypoglycemic during the injury or immediately afterwards, and some of it is driven by the injury. If you have an acute injury, you're going to get higher blood sugar. So some is cause, some is effect, but it seems that these high glucose spikes are again stressful in that setting of an acute brain injury. So just minimizing that as much as possible. That doesn't mean that you shouldn't eat carbohydrates, but just like I would avoid refined carbohydrates when I sort of worked with athletes at high risk of concussions. Like if you're being taken off the field, a low-risk thing is just to not chug Powerade as you're being like taken down the tunnel.
Other things that are going to become important with varying degrees of evidence, but still good enough that there's a high sort of positive asymmetry, right? High possibility of benefit with low risk. Creatine supplementation. Creatine is probably more beneficial if you have it on board beforehand, but there's at least one trial in pediatric TBI that showed creatine enhanced recovery. Omega-3 fatty acids, the same would certainly include those as well. And then the next thing I would do is I would take exogenous ketones.
I have them, you know, at home. There are things I've played with. I don't use them regularly.
But in this setting, again, I think there's enough promise, right, to suggest that they're worth taking. I didn't include that in this paper because we don't have good evidence for it, but if I was, if I had a brain injury, I would take those ketones.
Yeah, I would. I would, too.
And then there are a few other things that have an increasing amount of evidence for them. So, there's some studies on some B vitamins, particularly riboflavin. Branched-chain amino acids seem to be beneficial.
And that seems to be by improving sleep. Then if you have sleep issues, melatonin has some evidence for it as well. I would avoid caffeine actually in this scenario. There's a little bit of evidence that says that again it's probably due to increasing brain metabolic rate in that sort of early, early window similar to high temperature. So I would avoid caffeine particularly early on. And then probably the most important thing that we have evidence for is early return to physical activity. So low-level aerobic exercise as soon as you can tolerate it at a level that doesn't make symptoms worse, and then increasing that over time as you get better. That's going to be an important part of recovery as well.
What's the supposed mechanism of action with the return to physical exercise and the impact that has on the recovery from say concussion?
There's probably a few different mechanisms. And to be honest, I don't think anybody really knows, right? Again, the evidence is best in pediatric brain injury, particularly pediatric sports-related concussions. That's where they've done most of these like randomized control trials. But there's a few things that are going to be happening. You're going to be improving cerebral blood flow. Probably going to get a whole bunch of myokines, exerkines during physical activity. We know many of those can have a beneficial effect on the brain. And then you may also see improvements in sleep, right? We know that physical activity helps support sleep. So many of those could be going on at the same time as long as you're not doing a level of activity that's then making symptoms worse.
All right. So, we're going to take a moment, not for a commercial break, but just for a topical break to ask a very important question, which is when you came in second at Washington's Strongest Man in 2024, and then when you came in the top 20 in the world's first ever fully off-road Ironman triathlon, what were your weights? What was your body weight in both of those cases?
Those two competitions were more than a decade apart, I will say. So, in 2012 is when I did the world's first fully off-road Ironman. It was initially called X-Man, and then Marvel sued the company. So, it ended up being called XTR 24. So, when I did that, I think I was probably something like low 80 kilo, 82, 83 kilos. So, like, you know, 185 pounds, something like that.
And then fast forward a decade when I was competing in Washington as the Strongest Man, I was in the middleweight class, and to get into that class, I had to basically diet down and then do a water cut to get under 198. So I was just under 90 kilos on the day. Although you normally, I'd hang out like 15 pounds higher than that.
Okay. Super interesting. We may come back to that. We're certainly going to talk about your own personal routines and tricks of the trade that you apply. Before we do that, I want to tie up a couple of loose ends. Specifically, infant baby, this thing you mentioned, DHA and why that and/or omega-3s more broadly speaking are important. Right. And I, for instance, I'd say one meal a day is probably right now two cans of sardines or chub mackerel mixed with some type of oil, like olive oil or MCT oil with a splash of apple cider vinegar. It's shockingly good. It sounds like cat food. It's actually better than it sounds with some salt. But could you explain why this DHA, etc. is important? You also mentioned the omega-3 in the context of recovery from brain injury. So why is it important and what is the prescription so to speak? Like how can people translate that into something they actually do?
When you think about again sort of the structure of the brain?
And you're trying to develop the brain in the first place.
Big pile of fat. And a lot of that fat is DHA. And actually, brain, if you don't mind eating brain, brain is a great source of omega-3s.
I tried it. I tried sheep brain in Turkey. I'm going to tell you, the presentation could have used some work. It was just like straight out of the formaldehyde jar, popped onto a plate. It was a bit much for me to be honest. But yeah, continue.
You can fancy it up if you want, but equally brain consumption is not required. So, DHA tends to concentrate in the synapses of neurons. It seems to be really important for like helping to regulate the release of neurotransmitters, like being part of the structural component of those synapses. It also tends to accumulate in mitochondria, and the DHA content of mitochondria is like positively correlated with their like capacity for energy production. Some of it could be due to some weird like physical, as in physics, properties of DHA, like how electrons move through it differently from other fats. But anyway, it seems that particularly for mitochondrial function as well as synaptic function, DHA is critical. And so it sort of preferentially accumulates in those areas. Very important during brain development. So much so that the mother will sacrifice her own DHA stores so that the baby gets enough if you know she's sort of borderline in terms of DHA levels. And it's also why women in general tend to be better at converting shorter-chain omega-3 fatty acids like ALA to DHA and EPA. It's thought that that's because that's going to be needed for a baby one day more so than in men.
So, eat brains or find someone you can breastfeed on. Am I hearing this correctly?
Are those the only two options?
I'm not sure. I'm kidding. Oh, wait. I forgot about the fish. I forgot about some fish. Optional third. Then we also know that DHA in particular, but also EPA, and these are both the long-chain omega-3 fatty acids, they're important precursors for various signaling molecules that are important as it pertains to brain function but also recovery from brain injury.
What is an example of a signaling molecule?
Actually a lot of the various molecules that have various functions in our body, activating receptors, turning genes on and off, are derived from different fats. And so in this setting the ones I'm thinking about are called like resolvins, maresins, protectins that are derived from these unsaturated fatty acids. And so neuroprotectin D1 is one that people are very interested in. It's being tested as you give it exogenously after different brain injuries. We're not at a point where I would recommend that people take it, but that's something that's being studied right now. And neuroprotectin D1 is derived from DHA. In the setting of brain injury, these resolvins and protectins seem to be really important for regulating the immune response. In particular, switching off the immune response, right? The immune response is important, but we also need to be able to switch it off. And that's probably part of the role that they're playing. When you look at long-term omega-3 supplementation, there was a study that was done in football players where they randomized them to different levels of DHA across the season, and they found that those taking 1 to 2 g of DHA a day saw less of an accumulation of a marker of brain injury in the blood called neurofilament light across the season. The thought being that, you know, all these small sort of subconcussive impacts that the kids experience on the field is generating this sort of low level of injury that accumulates across the season, and omega-3s or DHA seem to protect against that. So all of those to say that if you want, you know, to maintain brain function, and we see if you're omega-3 deficient, you're at higher risk of dementia, cognitive decline, that's dependent on other things like methylation status, but it's going to be an important component of maintaining brain structure and function. So, I think that kind of level, you know, 1 to 2 grams a day on average at least, this is going to, you know, if you get two or three good servings of seafood a week or a reasonable supplement, that's going to be probably enough to consistently hit those levels. The other part of it is that your body will actively sequester extra up to a point. So, when people are talking about different forms of DHA, right, should you take your omega-3s as a phospholipid form or a triglyceride form? And the triglyceride form is more common in seafood. The studies that look at these over long periods of time, what happens is if you consume a lot of the triglyceride form from seafood, your adipose tissue is used as a storage place. So it cycles through the adipose and then it gets released and the brain can use it afterwards. That probably requires you to spend periods of time where you're accessing your adipose tissue, right? You're not constantly eating. So exercise or periods of fasting may help you access that depot. But that depot, you know, allows us to then use these other forms of DHA that can sort of accumulate in our bodies over time and then we use them as we need them.
All right. I'm wondering if there's anything else, and it may end up circling back around as well. But is there anything else related to omega-3 specifically that you'd like to comment on? And am I, I could be hallucinating here. It's not just AI that does it, but omega-3, does that have... Oh, no. It was B complex which you brought up before perhaps, or maybe there is an interaction with omega-3 and homocysteine. I'm trying to figure out where homocysteine fits into the picture with respect to cognitive health.
There absolutely seems to be this interaction between omega-3 status and B vitamin status, particularly the B vitamins that are involved in methylation. So they affect the level of something called homocysteine, and this is something you can get a blood test for. And those who have inadequate B vitamin status or inadequate methylation status have an elevation of homocysteine. There have been multiple trials that happened sort of two or three decades ago, you know, maybe even in the last decade, where people thought, oh, omega-3s are going to be the answer to dementia prevention, or B vitamins and homocysteine are going to be the answer to dementia prevention, and then they would give people B vitamins or omega-3s, and then they didn't see much of an effect. What we found out later, I mean the, you know, the scientific we, was that both are required in order to see benefit. So this was probably first seen in the VITACOG trial which was run by David Smith at Oxford, and they found in individuals with elevated homocysteine, so that was a level above 13, giving B vitamins to reduce homocysteine significantly improved rate of brain atrophy and cognitive function only in those who had an adequate omega-3 status. And the same thing was seen in the B-proof trial subsequently, and then the opposite, which was seen in the OMEGA trial where they gave omega-3 fatty acids, but they found they only saw benefit in individuals who had a low enough homocysteine. It's thought to be because if you want DHA to be in a membrane in a cell in your brain, it needs to be attached to some kind of phospholipid, right? Fats don't just like float around. They're part of these phospholipids that sit inside the cell membrane, and that requires it to be attached to a head group. These head groups are usually derived from choline or an ethanolamine, although those can be converted from one to the other. And in order to do all of that kind of biochemical attaching and placement requires methylation, that is very methylation dependent. So, it's thought that in order for DHA to do its job, you need adequate methylation status so that all those processes can run. And if you only have one or the other, then you won't see benefit.
Got it. Yet another reminder for long-term listeners, this will come as no surprise, but you got to get blood tests, comprehensive blood tests, and really track this stuff with trend lines over time. But that's a much longer conversation, but suffice to say, you need the orchestra, right? Where you need multiple legs of the stool. It's not just one leg of the stool.
All right. So, let's maybe return to, I'm going to use a term, it's a little dangerous to throw around, but kind of first principles or fundamentals maybe is a better way to phrase it. I'm terrified, as many people are, of this thing called Alzheimer's disease. And you could throw in dementia, cognitive decline in general, right? And conversely very interested in extending health span. I'm not totally convinced that, you know, we're going to get to 150 years, 200 years.
Like all the tech billionaires might want to have us believe, but it does seem certainly if I look at my own health span kind of local maximum right now for myself, it's not really low just capacity right now compared to prior generations. I feel very good about it. So I feel like I can extend that runway, and cognition for me is just one of the most, maybe the most important pillars of that because having seen multiple people disintegrate cognitively, they don't just lose their ability to remember, they basically lose their identity, right? They lose their ability to emote. It's a loss of the self. I mean it's a death before death almost in a way. So really would love to do anything possible with the right risk benefit ratio to avoid it. But fundamentals, should we talk about, I'm going to [__] this up. August deer. Augusta Dita data. How do you say this name?
There we go. Yeah. All right. Who is this person because I'm guessing most folks will not recognize the name. Certainly, I didn't recognize the name. Hadn't seen it until I got a couple of notes from you prior to hopping on.
So Auguste Deter, or if you read some of the original papers, Auguste D was Alzheimer's index patient. So Alois Alzheimer, that Alzheimer's disease is named after, was a psychiatrist in the early 20th century, and he took a particular interest in individuals who had sort of rare or unusual cases of presenile dementia. So what we now call, or what now most of us call, Alzheimer's disease, which is sort of a late-onset dementia, or what was called a senile dementia, which just meant that it occurred after 65 years old. That was not what Alzheimer studied. He studied unusual dementias where people who were quite young, sort of in their, you know, 40s or 50s, experienced significant cognitive decline and dementia, and Auguste D was one of them. He then, after studying them as a psychiatrist or working with them as a psychiatrist, after they died, he then looked at their brains under a microscope. So he was the first person to see amyloid plaques and tangles that are now sort of pathognomonic. They're like what we consider to be sort of required as part of Alzheimer's disease. But it's just interesting that what we have now is not what he studied. Though over time people thought that the brains of individuals who had this sort of early-onset Alzheimer's or these early-onset dementias that Alzheimer studied and those who had this late-onset dementia that we now call Alzheimer's disease, those brains looked very similar under a microscope. So they were kind of lumped together, although we do still have two kind of broad forms: the early-onset Alzheimer's, which is usually a single genetic mutation in something like a presenilin gene or the amyloid precursor protein gene, that then, you know, creates a picture that's much more like what Alzheimer studied, or the late-onset Alzheimer's, which is what most people think about when they think about Alzheimer's disease, is probably somewhere between 95 and 99% of cases of Alzheimer's, and there is a genetic component to risk, but it seems to be much more tightly tied to lifestyle and the environment and other lifestyle factors that we have some control over hopefully. And the reason why Auguste is interesting to me is because I don't think she actually had Alzheimer's disease as we would now think of it. So there have been groups that have taken sections of her brain from like, you know, Alzheimer's old collections, and they've done genetic studies, and she didn't seem to have any of the genes that cause early-onset Alzheimer's disease or any of the mutations that cause early-onset Alzheimer's disease. She wasn't an APOE carrier. I think she was 33 if I remember correctly. So she didn't have any of the genetic risk factors. What caused this and caused this so young? I think she was in her 50s, right, is still actually unknown. Some people think there have been some like recent retellings of the story. Some people think that she may have had neurosyphilis, and neurosyphilis actually causes amyloid accumulation. It looks very similar to Alzheimer's disease.
Neurosyphilis meaning she had syphilis and
And that can look very similar under a microscope, especially 100 years ago or more than 100 years ago when we were just sort of first starting to look at brains under microscopes. And then others have suggested that it could have been more sort of psychiatric. Nutrient deficiencies certainly very common, could have been, you know, just like the other components of her environment. She was by all accounts a sort of like a downtrodden housewife that maybe didn't get, you know, sort of much engagement or stimulation or she wasn't particularly well treated at home, and that could have sort of precipitated a bit, and we don't actually know, but many of these things kind of, it just seems interesting that it's probably quite likely she didn't have Alzheimer's disease at all.
Wild. All right. So, I'm going to take this in a few different directions and as per usual, turn it around to be self-serving for yours truly. But I'm going through some of the notes that I had for our conversation. And I'm sure I will have mentioned this in the bio and intro at the very top of this show, but I have this bullet in front of me and I just want to make sure this is something you feel is defensible. 45 to 70% of dementia is preventable through lifestyle. Is that a defensible statement?
Yes. As far as we think it can be defensible.
Yeah. I'm not trying to put you in the hot seat. I'm just saying like I don't know where that number comes from.
I can tell you where that number comes from.
That sounds great. I mean that seems very, that seems like a ray of sunshine in a pretty gloomy possible conversation, right? Where people think you're just like, 'Okay, there's genetic determinism. You got this thing. You're screwed. If you have a bunch of it in your family, you're also screwed, etc.' But it seems like there's a lot you can do to right the ship for a period of time. Okay. So, where does 45 to 70% of dementia is preventable from lifestyle? Where does that number range come from?
45% comes from the most recent edition of the Lancet Commission report on dementia prevention, which is overseen by Professor Jill Livingston and brings together all these different experts in dementia and its risk factors, and they sort of scour the research for observational studies and then as much as possible interventional studies. So a lot of it is, you know, epidemiological data, looking at different risk factors that have a consistent relationship with dementia risk. And then you do these sort of statistical calculations to look at something called population attributable risk, which is essentially saying if I eliminated this risk factor entirely from the population, what percentage of dementias would I expect to no longer happen? That's essentially what it means. All of these different percentages add up to 45%. So it's a couple of percent for smoking. It's 7% for low level of early education. It's like a percent for alcohol. Then there's hypertension, hearing loss. Oh, sorry. High blood pressure. Hypertension is the fancy medical word. High blood pressure, hearing loss, obesity, low physical activity, and all these different percentages add up to 45%. There are some things that are on that list or that aren't on that list that I think should potentially be included. So like sleep loss or poor sleep and insomnia is not included. Late-life physical activity was discussed in the report but was not included even though there seems to be some good evidence there. So actually that suggests that there may be more than 45% that are preventable. And there are other studies, like there was one big study done from the UK Biobank data by Professor Yintaiu that estimated that up to 72% of dementias were preventable. If this was going to happen, this would require like a complete societal overhaul, right? Because a lot of this risk comes from low socioeconomic status, low educational and work opportunities, like all these other things that are kind of baked into societal risk for dementia. But others are things that we have more control over, like level of physical activity, whether we smoke, whether we drink. So some is directly under our control, that's probably something like 15 to 20% maybe more. And some is kind of driven by these maybe bigger kind of societal risk factors. But if you did all of that and we managed to completely change how everybody lives and all of these risk factors, the idea is that, you know, maybe even up to three quarters of dementia cases could be entirely prevented. Now, that's very different from saying that I could guarantee that you will not get dementia, right? That's not the same thing. We're talking about this stuff at the population level. And I have to say this because if I talk about, you know, physical activity or sleep or nutrition and these are really important for dementia risk, somebody will always say, well, my family member did all that stuff and they still got dementia, right? And so, we're talking about probabilities. We're not talking about I can definitely guarantee that somebody will avoid dementia, but I think we can definitely say you can stack the deck massively in your favor through a whole variety of actions that should you decrease risk long term.
All right. So, part of the reason that I make this very self-interested is because I'm self-interested. The other part is that I think the personal is very easy for people to concretize right for themselves.
So they can interrogate how they're behaving, what they might do differently, what they might add, what they might subtract.
So, let me tell you some of what I am observing and then some of what I'm doing. And I would love for you to identify or maybe speak to things that are low-hanging fruit or like reasonably accessible that are missing. Right. All right. So, few things. Lots of folks in my family currently caring for in one way or another deteriorating very quickly with what has been called Alzheimer's. Again, kind of a tricky diagnosis. Not sure how much they're actually looking at whether it's beta-amyloid tau or anything else. But certainly in some cases, these blood relatives are APOE33. So I'm like, huh? Also raises the question of is there an undiagnosed infection? Maybe it's an STI. Who knows, right? Like I don't know what the answer is to that. And it's kind of another line of testing perhaps. And so I've been trying to do a few things for myself, recognizing that if someone starts to really show obvious symptoms that can't be easily explained away in their 70s, let's just say the process probably started what, decades earlier, right? I mean, things have started like the cars have started to pile up, the machinery has started to break a lot sooner.
Yeah. So, it would seem like the earlier you intervene with better lifestyle changes, etc., the better off you'll be.
So, I've got the fasting and the ketogenic diet and all of that stuff, right? Which I do regularly. I've got the exogenous ketones, which like you I use sparingly. I don't use them all the time because particularly like before this conversation, I took 11 mil of a ketone monoester. But I think once all is said and done, it's basically 51% 1,3-butanediol. And I have some concerns around 1,3-butanediol specifically in chronic use.
Right. Or at sufficiently high doses, say 30 plus per day. I tend to use it for special occasions like this. You know, toast, have a glass of champagne, have some exogenous ketones, and off to the races. All right, so there's the ketone piece, which I think is non-trivial. There's the, by I would say for the most part avoiding crazy glucose spikes all the time, right? Occasionally I'll have like Christmas. Sure, I had a bunch of cookies. Like who cares? It's Christmas.
Had a bunch of pie. But I have a CGM on right now. I had a continuous ketone monitor on at the same time for about 28 days. I'm really interested to look at all of that. But I'm generally following like a slow-carb diet or Mediterranean-style diet. I am getting enough omega-3. I know that because of fish intake and also when needed supplemental intake. I do seem to be a poor methylator. So I'm taking like B vitamins, L-methylfolate, all of that stuff. Tracking blood once a quarter. So I've got super comprehensive stuff on that side. Zone 3 training. I do find it as boring as watching paint dry, even when I'm listening to a podcast or watching a Netflix miniseries or something, but probably doing two to three sessions a week of let's call it 30 to 60 minutes. Walking every day, lots of walking, and we'll come back to that.
Actually, yeah, I can't resist. We probably will come back to it, but walking 4,000 plus steps a day reduces dementia risk 25%, optimal 10,000 steps daily. And then reverses hippocampal shrinkage, 2% increase versus expected 1 to 2% decrease. That's the bullet that I highlighted. And then weight training a couple times a week. I could keep going. I'm not going to like bore people to death with this Dr. Evil life story, but I will say that I've also wanted to get a snapshot of what things look like.
So, I'm going to be having a call. I won't mention the company by name because I haven't done all of my due diligence. They have some scientific advisers who I think are very credible, but have done brain MRI. I've done the blood draws, the DNA tests, everything else. So, I'm APOE34.
And looking at the brain MRI. I mean, I'm a muggle, right? So, I probably shouldn't be allowed to sort of grab the wheel when driving on the MRI reading, but I wanted to look at the data. It seems like, and who knows how defensible this is, but my MRI predicted brain age based on hippocampal volume, etc., etc., etc., is 46 instead of 48. So, I wasn't thrilled about that. I'm like, well, all right. Not sure what else I can do. Maybe a flood dose of ibogaine. That actually is pretty interesting data around that from Nolan Williams, but not something I would recommend to most people, including myself. So, there's that. Did a whole battery of cognitive testing through this startup.
Now, that came in at brain age of 20 years predicted, 28 years younger than your chronological age, but you can kind of beat the test. Like there's some gamification, so I don't know how heavily to weigh this, right? So brain age of 20 years, man, sounds great. There are certain aspects that are
Harder to game, like reaction time testing. Okay, so I had like 267 milliseconds basically versus 406 milliseconds. Okay, great.
There could be some training effect, like learned training effect, but then there's like number span focus. I won't bore everybody with that. But word pairs, names, and face pairing with mnemonic devices, if you train yourself, you can really game the test. And TBD on like proteomics, I'm getting all sorts of stuff drawn to try to get an accurate baseline of where I stand now so that I can measure all of the effect hopefully of these interventions over time.
What would you say are like, there are 20 things I could mention, but like here are three or four that I would also pay attention to.
First, a couple of comments on all the stuff that you mentioned about what you're currently doing. I've already mentioned that I think that there's a lot of promise for ketones. I'm not sure that ketones necessarily have to have a place in prevention, and I'm not sure that you would necessarily need them from a prevention standpoint. There are some reasonably good data. So like the medium chain work from Stephen Cunnane's lab is quite compelling in Alzheimer's disease. Taking MCT oil seems to increase the C2 acetate uptake into the brain. This is associated with improvements in cognitive function, and this is overcoming what looks like an energetic deficit in individuals who have Alzheimer's disease. And this is something that again, it's one of those things that are pathognomonic, right? We think that we see this and this is kind of like part of the picture of Alzheimer's disease. We see that like this is Alzheimer's.
Can I pause for one second? Real quick, don't lose where you are. We're talking about MCT oil. Number one, if people want to play with MCT oil, be close to a bathroom when you start. And if you combine it with double espresso and creatine, definitely have some Depends around. The second is the ketogenic diet for me, just to briefly provide a little more context, is also for its I think plausible anti-cancer effects and just to kind of all-cause mortality plus mental acuity. I just think a lot faster when I have more metabolic flexibility with something like intermittent fasting. That's another thing I do a lot of, where my body has just got the machinery to produce ketones. But yes, I hear you. Okay. MCTs, the thought being here, right? There's a difference between what you find works really well for you versus what the listener thinks they should have to implement for themselves. And so I'm now going down the road of why I don't think we all need to be in ketosis to prevent dementia.
Yep. I think from a therapeutic standpoint it seems to be beneficial overcoming this energetic deficit that we see in Alzheimer's disease, particularly early Alzheimer's disease, or maybe it's easier to overcome earlier on. And one of the ways we look at this is with something called a PET scan, right? So you do an FDG PET, you give a labeled glucose molecule, you inject that, you see how much gets into the brain. In individuals with Alzheimer's disease, less glucose is getting into the brain. Now we've traditionally come at it from the point of that glucose can't get in, right? There's some kind of metabolic disease, insulin resistance. This is where the idea of type 3 diabetes has come from, right? Insulin resistance in the brain, that glucose isn't getting in. But a PET scan cannot differentiate between the glucose can't get in versus the brain isn't asking for that glucose in the first place. And there are actually some very nice studies that looked at brain activation and glucose uptake in response to cognitive stimulus in individuals with Alzheimer's disease. And what they see is that yes, at baseline, there's less glucose being taken up into the brain of individuals with Alzheimer's disease. But if you stimulate that brain cognitively, it can take up glucose just fine. And so you get into the range of a normal healthy brain in early Alzheimer's disease. Once you get to like advanced stage dementia, it's too late. But at that early stage, I think part of the reason why we're seeing less glucose uptake is because those parts of the brain are less active because we're just not using them as much. And just like glucose uptake into the muscles, which is demand driven, right? You work your muscles, they ask for more glucose, they take more up. The brain seems to be the same, at least early on. So I think we think a lot about the supply side, right, the energetic supply side, but I don't think we think enough about the demand side, how to create energetic demand in the brain such that we are maintaining glucose uptake, maintaining energetic state, and then doing that also maintains all the metabolic machinery that you really care about in terms of long-term function.
Can I just muggle translate for a second? All right. So, if I'm hearing you correctly, this is something I've, you know, chatted with Dom D'Agostino about, but I'm wearing this CGM, right? So, I've got this device on my arm that tells me what my glucose levels are at any given point in time with whatever 3-minute sampling or something like that. You got to calibrate that with a finger prick, by the way, folks. But if I eat a meal and then I don't go for a walk, right, my glucose spikes and I might conclude, wow, my muscles are really not accepting glucose. My muscles are bad at accepting glucose. But that's not actually true in my case, right? If I go for a walk or I do some light exercise, I guess it's like GLUT4 transporters or whatever, get all jazzed up and help that glucose to be better disposed into muscle tissue. And like you said, in the case of the brain and people referring to Alzheimer's as type 3 diabetes, it's like, wow, the brain can't use glucose or it's very bad at using glucose. But if I'm hearing you correctly, the additional question that they should be asking is, is it just that or is the brain not asking for glucose? Right. The equivalent of the GLUT4 transporters, right? Like is the brain basically offline? It's a car up on blocks, but if you take it down, like, yeah, it's going to use gasoline just fine. If that's the case, I guess it's just a call to action for more stimulation of the brain. Yeah. When I was first just coming across your notes that you sent prior to this conversation, I went on ChatGPT and I was like, what are the most glucose-intensive activities for the brain? And they gave me a bunch of mental exercises, which isn't exactly what I was looking for, but I could have prompted it better. And it said, but even still, you know, the sort of improvement or increase might be, you know, plus less than 10%, right? In terms of the total. And then I was like, well, are there other activities such as physical activities that might increase glucose uptake in the brain? And it gave me a whole list. But rather than regurgitate that, like are all types of stimulation created equal or are there some sort of 80/20 analysis like okay, there are some tools that are better for the job when looking at this purely in relation to glucose uptake?
Those data don't exist, right? So, we're going to have to extrapolate further than that. And I think that's important because a decrease in glucose uptake is just a signal that that area of the brain isn't as metabolically active, which means we're just not using it as much at the simplest level. Then if you think about various activities that we could use to stimulate the brain which do seem to be protective in various different ways, both they can enhance cognitive function in the short term and then protective against dementia in the long term. Actually this ties very nicely into the comment that I was going to make about your physical activity routine because this is where I think some things could be layered on. When you look at the different physical activities or exercise and how they affect the brain, different types of exercise affect the brain differently. So you certainly need a smorgasbord of all of them to kind of get global support for the brain. But something that seems to be particularly beneficial is coordinative exercise or open skill exercise. You plus or minus things that have a navigational component. And these are essentially sports or activities where you're constantly having to respond to the environment and adapt. That's what makes them open skill rather than closed skill or unimodal exercise like going for a jog or sitting on a bike or something like that. So when they compare sports or activities that have the same amount of physical challenge but different amounts of cognitive challenge because of the open skill nature, you see greater benefits in terms of brain structure, improvements in cognitive function.
And open skill just means high level of unanticipated variety or variety. What is that?
Both. It basically has a greater amount of complex motor skill required. Some of it can be learned. So, dancing is one example, right? So, because you learn the steps of a dance,
single strongest activity for dementia prevention. Am I overstepping there?
Yeah, probably. If you look at physical activity and the effect that it has on cognitive function and also mental health, or one of the stronger. Yeah. But in terms of both mental health, so studies in depression as well as studies looking at different activities that people do and their risk of dementia and studies where they randomize people to different types of activity including dance. Dance seems to have the highest sort of effect size compared to other types of physical activity, but there's multiple components to dance, right? So you have to learn the steps, but there's also a social component, there's a music component, right? All these things are probably like part of the magic sauce together. But open skill sports also include, you know, board sports or ball sports or team sports where you're having to like react to the environment and other people around you.
Do you say bull sports like rodeo? What are we talking?
Oh, okay. It's not going to be good for the TBI to get people on top of bulls, but okay, got it. Although, I think bull sports would probably be good if you could avoid the TBI. Actually probably right up there. Similarly, martial arts also good as long as you don't get punched in the head a bunch or kicked in the head a bunch or choked out too much.
Beyond the physical strain that these exercises have, they seem to have an additional aspect of, you know, requiring reaction speed, challenging processing speed, learned complex motor skills, they seem to have an outsized effect in terms of cognitive function. Yeah. Something else. This is kind of an aside, but just based on the physical activity component when you're looking at so more aerobic or you know even like closed skill unimodal running cycling kind of sports the benefit seems to be intensity dependent. So yes, if you're not doing anything, then going for a walk and walking a certain number of steps a day is going to be great, beneficial, decrease dementia risk, absolutely. But looking at hippocampal structure and function, for instance, which you mentioned, right, you're talking about measuring your, you know, measuring your hippocampus on an MRI scan, higher intensity activities seem to be better. Probably the longest study where they've ever did something like this. This is an Australian study where they had people do the Norwegian 4x4 protocol three times a week for several months. Oh my god. And so for anybody who doesn't know what this involves, it's four sets of 4 minutes on a treadmill at 85 to 95% of your maximum heart rate with 4 minutes rest. You do that four times. It is miserable. I mean, that's like pretend like you're being chased by wolves through the snow for four minutes and then take a four-minute rest and then doing it again. Yeah. Okay. Four times, right? But they saw significant improvements in hippocampal structure and function that were maintained for several years after the end of the trial. Several years. Several years after the trial, so a few months. Yeah. And then sustained for several years. Yeah. I think they followed them up for 5 years after the end of the trial. That makes it much more interesting. I think a lot of this is driven by lactate. When we talk about the various things that support the brain through exercise, we often talk about BDNF, brain-derived neurotrophic factor, which is increased with exercise. But the BDNF that you produce that you can measure in the blood that's produced by the muscles during exercise doesn't really get into the brain very readily. Most of the BDNF we have in the brain is produced locally and it's actually driven by things like lactate. So lactate does get into the brain. The more lactate you have in the blood, the more gets into the brain and then that acts as a histone deacetylase inhibitor that activates the expression of BDNF. Ketones do the same thing. Osteocalcin which is released when we sort of load the bones structurally, right, released from bones seems to do something similar. So generating lactate seems to be beneficial because probably because one of the things it's doing is it's generating more BDNF that then is associated with improvements in hippocampal structure and function. So as long as you're doing sports that have some high degree of intensity so you're regularly producing lactate and then either in the same sport or separately doing these sort of high skill high reaction time open skill kind of sports. That's probably going to be beneficial from an exercise standpoint.
I'm still completely stuck on the three times a week basically VO2 max training, right? For a few months. Is a few months like 3 or 4 months or how many months was it?
The study was either six or 12 months. I can't remember the intervention period. It was one or the other.
And with durable effects over a follow-up period of 5 years or something like that. Like that is a great investment. That makes it a much more compelling sales pitch for me. And like I've done plenty of VO2 max training in the past, but like it's not necessarily fun, right? No. I mean, I will say if you can again avoid getting your arms snapped, exhibit A right here with my elbow surgery. But if you can avoid the breaking limbs and getting choked out too frequently, yeah, something like jiu-jitsu, right, is actually fantastic because you might have 3 to 5 minute rounds and then you take a break for a round and then you go back in and chances are depending on who you're rolling with, it's going to be pretty intense. Obviously depends on how competitive the gym is. But the durability is just remarkable. That is really, really, really, really interesting. Now is the threshold for sufficient intensity, I imagine it varies tremendously from person to person depending on lactate threshold, right? But like for you do you need to do something approaching the Norwegian 4x4 to cross the threshold sufficiently in your mind or does something less suffice?
The problem with having just one, I mean it's one very good study but just having one study on this is that we get really focused on the protocol. But I think that anything that is regularly producing, you're getting above your lactate threshold, you're generating significant, you know, several millimoles of lactate. I don't think people need to measure it but you know if you're getting 6, 7 plus something like that, right, you're definitely going to be in that range.
Is there something like a, people use a talk test for instance, Peter Attia talks about this for zone 2 training where you can kind of have a conversation and be labored short sentences, but you don't really feel like it as an indicator that you may be roughly sort of in zone 2. Is there an equivalent for that range of lactate?
