Advances in Alzheimer’s Disease: A Deep Scientific Dive into How to Protect Your Brain

Alzheimer's is one of the scariest diseases on the planet, at least for me. And given its slow and insidious nature and the complexity of its underlying neurobiology— and boy, is it complex— it's proven really hard to treat or prevent with any certainty. That's why I am so interested in the emerging science in this space. And in this compilation of videos to come, I want to share with you some of my recent learnings, some of my most fascinating learnings, so as to empower you with foundational biological knowledge that will keep your brain fit and healthy throughout your life. We'll talk about ketones, protein misfolding, healthy fats, the glymphatic system, sleep, light therapy, nanotunnels, and more. Please enjoy and, more importantly, learn something valuable. What causes Alzheimer's disease? This is a complex question without a linear answer. However, what I can say with relative confidence is that Alzheimer's disease is a metabolic disease characterized by dysfunctions in how brain cells, neurons, and their partner cells called astrocytes process and produce energy in the brain. And chronic progressive failure in brain energy metabolism can result in dementia, including Alzheimer's disease. Now, new research in the prestigious journal Science has identified a is a key node in brain metabolism that acts as a convergence point of the classical amyloid and tau pathologies in the Alzheimer's brain. And this new finding opens up an unexpected way to target this node to rescue brain metabolism from dementia. But to truly understand these exciting novel findings, why I'm so excited, I need to first arm you with some brain metabolism background. A moment ago, I mentioned astrocytes. These are a type of glial support cell in the brain which support neurons. And one way in which astrocytes support neurons is by providing energy substrate to neurons in the form of the molecule lactate. So simply, astrocytes turn glucose via glycolysis and fermentation into lactate, and then the lactate can be passed from astrocytes to neurons for energetic support. And failure of this astrocyte-neuron lactate transport shuttle undermines neurons' ability to generate energy and undermines their ability to carry out critical neuronal functions, which is simply put, not good. So now let's introduce that node I mentioned in the brain metabolism network. It's an enzyme called indoleamine-2,3-dioxygenase, or IDO1 for short. IDO1 is an enzyme that converts the amino acid tryptophan into a molecule called kynurenine, or kyn for short. Now, what researchers of the study find is that the classical amyloid and tau pathologies in Alzheimer's disease each converge on and increase the activity of the IDO1 enzyme, which increases Kyn levels, thereby inhibiting astrocyte glycolysis, decreasing lactate transfer to neurons, starving neurons of energy. And I'll repeat that because it's very important to understand, and I appreciate it's a little complex. The hallmarks of Alzheimer's disease, amyloid and tau, each can activate IDO1 enzyme in astrocytes, and this increases levels of a metabolite KYN, which leads to inhibition of lactate production by astrocytes. Therefore, astrocytes can't provide neurons with as much lactate, and this leads to energetic starvation in neurons and brain metabolic failure. And impressively, in this paper, they found that this pathway was relevant in 3 independent animal models of Alzheimer's and has parallels in human brains, in human brain cells, where human astrocytes from patients with the most common form of Alzheimer's disease, late onset Alzheimer's disease, also had lower tryptophan in higher kyn levels, and that inhibiting IDO1 normalized these levels, basically revealing that this pathway is active in the human Alzheimer's brain as well. And that brings me to the solution part of the video. It's quite possible to inhibit IDO1, and in so doing, restore normal astrocyte glycolysis and lactate production to feed neurons and support brain metabolism. Indeed, they found that inhibiting IDO1 restored astrocyte glycolysis and lactate production. It improved metabolic function in the brain, improved neuronal function and markers, functional markers of learning, like long-term potentiation, and improved memory. And these effects were replicatable across models. Granted, one can't actually do these particular experiments in live humans, at least not yet. Although the effects were replicatable in human cells as far as metabolic rescue was concerned. So really, the question now is, how could we today attack this pathway in live humans with Alzheimer's disease? And the answer is— there's actually already a cancer drug that targets IDO1, uncreatively named PF068 in this paper. But this raises the possibility of repurposing a cancer metabolism therapy for Alzheimer's disease. And what's more, the IDO1-KYN pathway is also involved in other forms of neurodegenerative diseases like Parkinson's disease, leading to the possibility that targeting this pathway could have positive effects on dementia and neurodegenerative diseases beyond just Alzheimer's. Now, that constitutes the thrust of what I wanted to share with you on these particular new data. That said, I am catching on, and in anticipation of a question I know I'll receive in the comments— what can I do to decrease my risk of Alzheimer's disease today?— here are my high-level suggestions for protecting yourself against dementia and Alzheimer's disease. First, exercise. What's good for the body is good for the brain. This is in part due to indirect effects of exercise and overall health, but is also due to direct effects whereby exercise can increase levels of certain brain protective neurotrophic factors like BDNF, which support good brain health. Two, and this is quite obvious but bears repeating, get adequate sleep. The amount needed varies from person to person, but generally 7 to 9 hours is adequate for most. Sleep is really important for clearing the metabolic debris out of your brain, the debris that built up over the course of a day. Third, get long-chain omega-3 fatty acids in your diet. EPA and DHA. Personally, I like consuming these from fatty fish, the SMASH fish: salmon, mackerel, anchovy, sardine, and herring. You can get some from supplements as well, but there may be benefits beyond the omega-3s of actually eating real fatty fish, and this includes the presence of certain potentially neuroprotective forms of selenium. And if you want more on that, check out this video linked below. Furthermore, for those specifically with the APOE4 risk allele for Alzheimer's disease, the literature continues to suggest eating a lower carb, higher fat, and potentially ketogenic, although not necessarily, diet might be particularly beneficial. I'll link to more resources on that below because it's something I've done quite a deep dive on. And finally, enjoy life. While I'm by no means a socio-neurobiologist, it really appears that social connection and life purpose have powerful effects on lifespan and healthspan. So don't forget to enjoy the ride. It might just help you not forget. A new paper was just published about ketones Alzheimer's disease, and brain health that's so fascinating my synapses nearly short-circuited while reading it. The elegance and specificity of the mechanism described is so amazing that it almost seems like magic, but it's not. It's science. I'm going to walk you through the findings at a high level because it's quite technical. And at the end of the video, I almost guarantee If you don't do a ketogenic diet or intermittent fasting, you will at least try one of these interventions. Oh, and if you stick around to the end, you'll get to hear some thoughts from one of the authors themselves, so make sure to watch to the end. Okay, now for some necessary background. Alzheimer's disease is one of many different horrifying neurodegenerative diseases. Others include Parkinson's disease, Lewy body disease, Huntington's disease, ALS, other forms of dementia, and and so on. Most are related to aging and characterized by the misfolding of proteins, kind of like bad origami. Now, this is biology 101. Proteins are the micromachines that govern how the body and brain works. And a protein's structure, how it folds, determines its function. Structure determines function. And if a protein misfolds, disease can ensue. Especially neurodegenerative diseases like Alzheimer's disease. In fact, you may have heard of some of the products of these misfolded proteins, like amyloid plaques and tau neurofibrillary tangles that choke the brain into dementia. Okay, now some more background on ketogenic diets and Alzheimer's disease. There is already a body of literature supporting the use of ketogenic diets for Alzheimer's disease. This includes mouse models where ketogenic diets extend cognitive longevity, data showing that ketones can protect against amyloid toxicity and reduce amyloid plaque burden in the brain, and even a human randomized controlled trial showing the benefits of ketogenic diets in persons already exhibiting the signs and symptoms of Alzheimer's disease. Additionally, on first principles, ketones could help in Alzheimer's disease by providing an energy substrate when brain glucose metabolism is impaired, by reducing neuroinflammation, and by rewiring metabolism through changing how genes are expressed via histone deacetylase inhibition or altering protein function through post-translational modification. I know that's a lot of jargon, but the point here is it's all very cool and exciting and provides a framework for how ketones can help in Alzheimer's disease, but this research goes a step beyond all that. In brief, what they find, the researchers find, is that ketones can target specific pathological misfolded proteins and help them transition from a soluble to an insoluble state, which we will elaborate on in a moment, and ultimately help clear them out and clean up the brain. In the author's own words, ketone bodies are janitors of damaged proteins, chaperoning away molecular waste so organisms can operate at peak molecular fitness. Pretty cool quote, right? But let's unpack this a bit more because it is complicated. You see, when proteins misfold, they can be soluble meaning they are dissolved in the fluid in and around cells, or insoluble, meaning they are clustered up discreetly. And transitioning from soluble to insoluble is almost as if you could reverse dissolve salt from saltwater into freshwater in a salt cube. But is this good or bad? And if it is good, why? Well, certain misfolded proteins, when they're in their soluble form, can spread more easily from cell to cell and seed disease, progressing diseases like Alzheimer's disease. That ketones help transition misfolded proteins from soluble to insoluble could be thought of as a kind of defense mechanism to stop spread of disease. However, if the insoluble fraction accumulates, that's also a problem. Luckily, the researchers show in the study that ketones also help with the clearance out of the brain of the insolubilized proteins. So by way of analogy, it's like if you had a huge misfolded protein mess all over your apartment. The ketones not only target the trash and bring it to the trash bin, but then they kindly take out the trash bin for you and dump it down the garbage chute. In terms now of what they actually did in this study, to talk about some of the specific data, well, they did a lot, but among their experiments, they took brain tissue from Alzheimer's mice and older monkeys, specifically rhesus macaques, and confirmed that treatment with ketones increased the insolubilization. Think picking up the trash from your apartment and putting it in the trash bin. They also looked specifically at the amyloid protein in Alzheimer's and found that physiological levels of ketone bodies increased the insoluble fraction. They also showed that ketones protected against cellular toxicity of the misfolded amyloid Alzheimer's protein. And they present data that suggests that the most insolubilized aggregates get cleared out of the brain. Think about it like taking out the trash and throwing it down the garbage chute. Okay, now pause, because I'm guessing only a small percentage of you at this point are really appreciating what stuns me about this paper, why I said my neurons almost short-circuited when reading it, and the physiology to which this paper is speaking. Think about this now. How do ketones know how to target specifically misfolded proteins? Why wouldn't they just insolubilize proteins willy-nilly, non-specifically? Somehow the simple molecule that is a ketone body can select the bad apples out of the bushel. But how? Well, proper folding of proteins requires careful and specific conditions. When this occurs, the protein takes a particular shape and has a particular function. However, when the conditions are suboptimal, the so-called unstable folding conditions, proteins can misfold and get damaged. And this misfolded structure opens up particular binding sites that ketones can target. And then ketosis then promotes the clearance of the highly insolubilized proteins. Which depends on different cleanup mechanisms, including the proteasome and autophagy. And if those terms are novel to you, they're just different cellular cleanup and recycling systems. And this also makes sense from an evolutionary perspective, since ketosis is historically associated with fasting and nutrient deprivation, which would be an ideal time window to clear damaged and misfolded proteins to enhance cellular and organismal health and fitness. It's all super interesting and, in fact, represents a whole new frontier of cellular biology insofar as this effect, whereby ketones shift the soluble to insoluble protein fraction and alter overall protein balance, it's likely generalizable to other simple molecules. Like lactate made during exercise. In unpacking how different molecules have different effects on protein balance, this will give us deeper insights into the mechanisms by which different metabolic states—ketosis, fasting, and otherwise—fine-tune metabolic and physical health. That's pretty freaking cool, right? With that, stay curious.

And now, some thoughts from one of the authors. These data are really exciting because, uh, it gives a new level as to why ketone bodies are really interesting gerotherapeutic molecules. There's a whole host of energetic and non-energetic reasons as to why ketone bodies are really relevant to the aging field, but this paper gives a new layer as to why ketone bodies are really relevant for neurodegenerative diseases like Alzheimer's disease. And so this is because we're now showing that ketone bodies, which are compounds whose concentrations are determined by diet or exercise or by supplementation, uh, that these compounds, these ketone bodies can travel to the brain and interact specifically with misfolded and damaged proteins that are relevant to neurodegenerative diseases like Alzheimer's disease, as well as aging in general. And so I think this adds like a really nice new level of complexity to an already outstanding toolkit that's possessed by these ketone bodies. And so I think the big question that's on everybody's mind is what's next? So I have a couple, I think, avenues that I think are really interesting, but I think there's a whole number of opportunities that can come out of this paper. Are being published. And so I think at the molecular level, the first burning question is what exactly is the mechanism by which these ketone bodies are interacting with these misfolded and damaged proteins? That was something that we weren't able to fully answer within our paper. And so I think it's going to be interesting to see exactly what the interaction between these ketone bodies and the misfolded proteins are. We know from the paper that it's not it's due to pH. And we also know that it's not due to a post-translational modification. But beyond that, we aren't really sure exactly how these ketone bodies are coming up to these proteins and influencing their structure and relative solubility. I think secondarily, the big question is how are these misfolded proteins that are interacted with by the ketone bodies, how are they getting from their normal area to an phagosome or the proteasome in order to be degraded. And so I don't know if it's whether the ketone bodies themselves are touching and tagging a chaperone to take care of the business, or once the ketone bodies interact with the, the misfolded protein and change its relative solubility and structure, that chaperones are then able to recognize that protein. But that'll be a really interesting level of inquiry that'll show up hopefully in some next new papers. I think at a larger level, another question that you could ask is which cell types are most targeted by this mechanism? Is it glia? Is it neurons? And which brain region is most targeted by this mechanism as well? So we know that ketone bodies are associated with positive phenotypes, like improvements in cognition. Improvements in working memory. And so it'd be interesting whether the hippocampus, uh, is more targeted than say the hypothalamus. Um, and I think at a broader level, another question that you can ask, uh, that, that I find really interesting is that what other metabolites are, are also causing the same mechanistic effect and what does it look like in a different tissue? So we showed in the paper that, uh, other metabolites that have carboxylic acid structures like lactate, like succinate, that they possess similar activities to ketone bodies like beta-hydroxybutyrate. And so it'll be really interesting to kind of see whether, um, the proteome changes at a large level in elite athletes versus sedentary athletes, um, when lactate is, um, coming into the muscle, uh, during exercise. So that's just, uh, some of the first questions that pop into my mind, but I'm sure that there's gonna be a whole lot of, of other interesting inquiries that are going to come out of this paper. So thanks.

I have a personal reason to want to know a thing or two about Alzheimer's disease, on account of the fact that I carry not one but two copies of the major risk gene variant for Alzheimer's disease, APOE4. It's actually something that me and Thor, Chris Hemsworth have in common. But Marvel references aside, and I am a big MCU fan, when I found out that I'm one of these unlucky ones who is vulnerable to Alzheimer's disease, I decided, you know what, these genes won't be my fate. And instead, I'm going to use this information about myself as motivation early on in my life to pull all the levers at my disposal to prevent Alzheimer's disease and keep my brain healthy well into my 100s, or in Thor's case, about 1,500 years old. Anyway, I went on to do a PhD in neurometabolism at Oxford. I've written papers on Alzheimer's disease, Alzheimer's prevention, and aim to stay up to date on the literature. And a new paper just published in Cell Metabolism has me giddy with excitement since it provides a potentially accessible an actionable added tool in my Alzheimer's prevention arsenal, one that I want to share with you. So first, for some very high-level background, it's well established there's a strong link between the gut and the brain. Specifically, microbes in your gut, bacteria in your gut, make specific mysterious, I'll elaborate on that in a little bit, metabolites. And these metabolites influence brain health, including cognitive longevity, in different forms of neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Now, what they did in this research study is first look at microbiome patterns that differentiate Alzheimer's mice from control mice, and also confirmed that these same patterns held true in human patients with Alzheimer's disease versus healthy control patients. Indeed, they found patterns, including one I'll highlight: diminished levels of a bacteria called Bacteroides ovatus, or B. ovatus for short. Here you can see the human data, where B. ovatus are diminished in Alzheimer's patients, and the same is true in mice. And impressively, in the mouse model, in the animal model which you can use to show causality and dissect mechanisms, treatment of the Alzheimer's mice with this B. ovatus bacteria rescues those mice from the signs and symptoms of Alzheimer's disease. This included a tremendous reduction in amyloid beta accumulation. You can see that here in figures 1i through k. Here you're seeing a hallmark of Alzheimer's disease in green, amyloid beta in the brain, and you can see that treatment with the B. ovatus makes it disappear, or almost disappear. It also, BioVadis, rescued synaptic function. Here you're looking at the excitatory postsynaptic potentials of neurons, basically how they talk in the brain, and you can see BioVadis treatment restores cognitive function of the Alzheimer's mice to wild-type function. The BioVadis treatment also protected against neuroinflammation, and what you're seeing here are markers from activated mature microglia, brain immune cells, and astrocytes. This is all a proxy for gliosis or neuroinflammation. Again, the point is not the jargon. The point is that treatment with the bacteria B. ovatus improves this hallmark of Alzheimer's disease, neuroinflammation. And the B. ovatus improved cognition in functional behavioral tests. Here you're seeing the results from what's called a Morris Water Maze test, and again you can see B. ovatus treatment restores cognitive function in the Alzheimer's mice to healthy wild-type function. Again, understanding the exact methods isn't super important, and if you want to, you can go to the paper. But it's important that you comprehend that at multiple levels, what we're seeing here is that this bacteria has serious beneficial effects on many levels of Alzheimer's pathology and ultimately cognitive function. But that is actually not the important part, at least not in my opinion, because what you really want to know is what mysterious metabolite are the bacteria B. ovatus making that is mediating, that is executing the beneficial effect on the brain? You really care about that because if you can identify it, it's the easiest thing to add back into the body for metabolic benefit. Now, to cut to the chase, the metabolite they identify is so-called lysophosphatidylcholine, or LPC for short. B. ovatus makes lysophosphatidylcholine, LPC, and then LPC is what executes all these beneficial effects we just talked about: reducing amyloid beta accumulation, rescuing synaptic function, reducing neuroinflammation, and overall restoring, improving cognitive function and cognitive longevity. It's the lysophosphatidylcholine that does the work. And they also show how LPC works. LPC has a special transporter called the MSFD2A transporter that transports it across the blood-brain barrier where it binds to a receptor on cell surfaces, GPR119, leading to activation of a protein, NRF2, which inhibits cellular death processes, specifically ferroptosis, which is driven by iron-dependent damage to lipids and membranes. So in high-level summary of the mechanisms discovered in this paper, a bacteria, B. ovatus, makes lysophosphatidylcholine, LPC, which passes into the brain via the MSFD2A transporter, binds to receptors GPR119 to ultimately inhibit ferroptosis and cell death, reduce amyloid accumulation, protect against neuroinflammation, and restore cognition, or protect cognitive longevity. Now, the kicker is you can actually access lysophosphatidylcholine in food, in particular krill oil, which has a particularly high level of omega-3 lysophosphatidylcholine. To a lesser extent, fish roe and fatty fish also have lysophosphatidylcholine, but krill oil really stands out as the high LPC supplement. Now, given these preclinical data, these mechanistic data, I can't, of course, claim that this will prevent Alzheimer's. But the thing about studying Alzheimer's prevention in humans is it's super, super hard to do rigorously and in a controlled manner because of the nature of the disease, how it takes decades to manifest. You can't really do an easy RCT. So, in my opinion, the best thing you can do to reduce your risk of dementia is to gain an understanding of the metabolism and physiology and neurometabolism, and then use the levers available to you, and of course, common sense. In truth, nothing beats the fundamentals: exercise, including resistance training and cardiovascular, sleep, a good overall diet that maintains metabolic health with emphasis on omega-3s from fatty fish and possibly krill oil, stress reduction, and social connection. But if you're like me and particularly concerned about your cognitive longevity for whatever reason, Well, I find it really reassuring that we are learning more and more about Alzheimer's neurometabolism, and through this knowledge acquiring means by which we can develop protocols to potentially reduce our risk. And these new data, in my opinion, are one major point in favor of upping lysophosphatidylcholine intake, possibly through krill oil or other supplements to be developed now and in future. So anyway, all this is to say I'm really excited about what we're learning about the brain. We're starting to unpack what appears to many to be a black box, and through that, gaining knowledge that can be really practical and useful. And to me, it brings a lot of hope. Actually, to get a little sentimental for a moment, one of the things I think about curiosity about metabolism is it does bring forth hope. It brings forth hope that you can always improve, that your genes are not your fate. And also, it can be kind of fun if you find people with the right energy to engage with you and be like, guess what, your metabolic health journey, it's not a chore, it's a privilege. Which is why I love doing these papers, bringing them to you. I hope that enthusiasm passes forward, and I always appreciate feedback, questions. I hope you found this paper interesting and all the ones that I cover on my channel. This video is going to illuminate your mind. Literally, because we're going to be talking about how light, and specifically red and infrared light, can alter your brain biology and maybe even improve cognitive longevity. I know, that's a tall order, and I get that you might be skeptical, but we are going to construct a case together, starting at the cellular and subcellular mitochondrial level, and then zooming out to discuss some controlled human trials on photo- photobiomodulation, which is the fancy word for light therapy, photobiomodulation on the human brain. And then we're going to close by talking about the future of the field of light metabolism and practical takeaways, things that you can use today. So let's start with the mechanistic. How? How can red light change brain activity? Well, it's first important to acknowledge the brain is a super energetically expensive organ., and it relies on its trillions, and I did say trillions, of mitochondria to make energy. And mitochondria themselves are actually photoreceptors. They receive light as a signaling molecule, almost as if light were a hormone. That said, light signaling works a little bit differently than a true hormone. You see, mitochondria make energy using something called the electron transport chain, which is a series of protein complexes that are in the inner mitochondrial membrane. And these protein complexes harvest energy from electrons as electrons are passed along the chain to generate a potential energy gradient of protons. It's kind of like building up a waterfall, and then this proton waterfall can flow through a rotor called ATP synthase in the membrane, generating ATP energy. Now, red light is really, really good at exciting the fourth complex in this chain. So-called cytochrome c oxidase, and in doing so, it has a couple of really cool effects. First, red light can increase the membrane gradient, like making the waterfall of protons taller, and this ultimately leads to more energy generation as the taller waterfall flows through the ATP synthase rotor, so you get more ATP energy, which is really cool. Second, red light can actually cause the release of a volatile true hormone, nitric oxide, from complex IV, and then the nitric oxide can go forth from the mitochondria to cause vasodilation, or the opening of blood vessels to enhance blood flow in the brain. And indeed, this isn't just theoretical. I'm not just speculating. We will show later that red and infrared light can indeed enhance brain blood flow in human controlled trials. But before I get to that, I want to reveal some more light brain metabolism mechanisms because they're just so freaking cool. Alright, there are also data showing that photobiomodulation can increase levels of brain-derived neurotrophic factor, or BDNF, which helps neurons grow and survive and participates in neuroplasticity, which is essential for learning. Furthermore, it's been shown that infrared light therapy can increase levels of certain longevity proteins in the brain, at least in the brain of animal models, including SIRT1, a sirtuin, which is a well-known longevity protein, and PGC-1α, which is the master regulator of mitochondrial biogenesis. Furthermore, infrared light therapy has been shown to reduce the generation of harmful levels of reactive oxygen species in the brain under periods of severe brain stress. So I know that's a lot of jargon, so let's pause, zoom out, and take stock of the mechanisms we just went over for how red and infrared light therapy can enhance brain function. First, red and infrared light can enhance the function of mitochondrial electron transport chain proteins and increase energy—ATP—production in the brain. Second, it can cause the release of nitric oxide, which helps with vasodilation and enhances blood flow and oxygenation to the brain, which is a really good thing. Third, it can increase levels of brain hormones like BDNF that help neuron growth and survival and learning and memory. Fourth, it can increase levels of proteins important in cellular longevity, like SIRT1, and mitochondrial renewal, like PGC-1α. Which is all really cool. Isn't that just like a cool physiologic foundation? But really what we want to do is show that it actually translates into beneficial human clinical effects. So with that as our foundation, what do the human clinical trials say? Well, let's go through a couple. In one blinded human-controlled trial, researchers shone 1064-nanometer laser light through the human skull onto the brain and then measured the redox status of that mitochondrial complex IV that we were talking about, along with measuring levels of oxygenated hemoglobin. And what they found impressively, and in line with the mechanisms we just went over, is that light therapy altered the C4, complex IV, redox status significantly, along with a post-light stimulation jump in oxygenated blood flow to the prefrontal cortex where they were shining the light. These are super interesting data, and it's also worth adding, while an effect was seen in both young and old adults in this study, the effects were more pronounced in the older adults, and this makes complete sense because mitochondria function and cerebral blood flow tend to decrease with age. So older adults are as a population and on balance less metabolically optimized and have more room for improvement. Importantly, other controlled trials have found complementary and consistent results, such as this trial in 30 older adults without dementia, which found that 633 and 870 nanometer wavelength light, red light, improved cognitive performance with respect to frontal brain functions. Or this other trial, which also found infrared light treatment for 5 weeks improved psychomotor vigilance, reaction time, and elements of memory, and that this was further associated with changes on brain monitoring via EEG, changes that are themselves associated with enhanced cognition. So you see how a picture's coming together here. I could keep going on. There are actually a whole bunch of studies consistent with the idea that red and infrared light therapy can enhance cognition or measures of brain function. But I want to get on to what I think is most important for you to know today. Number 1, I really hope I've made the case that light has material impacts on brain function and very likely influences your overall cognitive health and cognitive longevity over the long term. So it's super important to mind light. Which brings me to point 2, while there are many innovations being made in technology, especially red light technology, your best source of light is the sun, and it's free. I could throw out all the biological jargon and randomized control trials in the world at you, but at the end of the day, if you want to boil this down to how can I, I being you, get the biggest bang for my buck, I'd say simply try to get morning sunlight and as much natural sunlight over the course of the day as you can, and also try to reduce your exposure to artificial light as is reasonable, especially in the evenings. The way I think about it is it helps to optimize your quote light ratios. And with that, if you'll indulge me in a little analogy. You probably hear a lot about omega-6s and omega-3s in the diet, where people say you're getting way too much omega-6, maybe you've heard the term linoleic acid or seed oils, and too little omega-3. And this imbalance can lead to ill health. Well, I think you can think about blue and red light much like omega-6s, blue, and omega-3s, red. We actually do need both. They're both essential nutrients. But our modern environments are typically overflowing with blue light, and omega-6 fatty acids, and deficient in red light, like omega-3 fatty acids, so it generally pays to be mindful to reduce your overexposure to blue and potentially augment exposure to red. And of course, I'll caveat all this as within the limits of practicality, because being truthful with you, my light protocol is so far from optimal. And I'll totally claim that. It's something I need to work on. So, to be honest, right now I kind of feel like a cashier at Dairy Queen holding a Blizzard and telling you to cut out dairy and sugar. Little hypocritical, but it is what it is. We all have room to improve, and actually by making this video and communicating facts about light to you, I'm hoping to motivate myself to improve my light habits. Okay? With that, moving on, 3. This topic is hot and fascinating, but it's also understudied. That means while I wish I could give you the quote optimal biohacking parameters for say using red light devices to boost your brain power, I can't. At least I can't with any degree of great certainty. But what I can say is I'm looking at the literature closely and speaking to a lot of people in the field with clinical interest in light and metabolism. For example, today I was speaking with Dr. Alexis Cowan, a PhD from Princeton, who was telling me that she finds 810 to 850 nanometer wavelength light is best for transcranial applications, through the skull applications to the brain, which is actually great because it falls right within the range of my EMRTEK Inferno device. And on that, if you do have the means and desire to get your own, you can use my discount code in the link below, Nick20, and get one of these devices. I'm really loving my experience with it. I'm going to be doing some spicy experiments. So sunlight first, but in addition to that, if you want to biohack with photobiomodulation or red light therapy, I do really recommend EMRTEK. Why is sleep so important? It's a deceptively simple question with surprisingly complex answers. But one leading theory is that sleep is the brain's deep cleaning cycle, clearing out metabolic wastes that accumulate throughout the day. And brand new research just revealed how this process works. Along with an alarming connection to a popular sleep medication that might, well, constipate the system. Yes, I said that, and we're going to break it all down. But before we get started, I have one quick little favor to ask you. If you like these breakdowns of the latest metabolic health science, please hit subscribe to support me. I can't tell you how much this helps and snowballs to help me get you voices from the primary research teams, which will also be included at the end of this video, and kick up initiatives, like continuing medical education credits, programs we have going for doctors, physicians, as well as going multilingual, including Spanish. Acaban de publicar un nuevo artículo sobre cetonas, la enfermedad de Alzheimer y la salud. In Hindi. Which we're going to be rolling out in 2025 on this channel so more people can have access to metabolic health science. I really hope you can help me out by clicking subscribe. Anyway, with that, let's get on with it. First, I need to arm you with some brain biology background, starting with defining something called the glymphatic system. Which is the cleaning system for your brain that activates during sleep. Here's what you need to know. Throughout the rest of the body, there's a series of vessels called lymphatic vessels, or the lymphatic system. However, your brain, despite being among the most metabolically active organs, actually lacks a lymphatic system to get the waste out of the brain. Interesting, right? And this is because your brain is so packed full of 86 billion neurons, not to mention the billions of support cells called glia and a complex network of blood vessels, that there physically isn't any space for another vessel system. This is where the glymphatic system with the G comes in, named for glia, the brain support cells, and lymphatic. And it solves the problem. Unlike the lymphatic system without the G, which is a series of tubular vessels throughout the body, the glymphatic system is a set of channels that expands as blood vessels constrict. Think about it this way: imagine you have a blood vessel running through brain tissue, all bathed in cerebrospinal fluid. When the vessel constricts and it shrinks in diameter, it creates a space between the vessel and brain tissue, allowing more cerebrospinal fluid to flow through and wash away waste. This is the glymphatic waste removal system in the brain. And because the brain is less metabolically active during sleep, and especially deep sleep, it allows the prime opportunity, deep sleep, to constrict blood vessels and turn on or upregulate the glymphatic system, clearing out metabolic waste from your brain. So simply, deep non-rapid eye movement, NREM sleep, is peak time for cleaning up the brain. But how the fenestrated capillaries does this work? That was the key question answered by this exciting new research. Now hang in with me for a moment because there's going to be some jargon coming up, but we're going to boil it all down after that. Through an elegant series of experiments conducted in mice, the researchers were able to show that the neurotransmitter norepinephrine is responsible for glymphatic flow. Specifically, a group of neurons in the brain, in the brainstem, called the locus coeruleus. It bathes the brain in norepinephrine pulses while we sleep, particularly during NREM sleep, this deep phase of sleep. Norepinephrine is a vasoconstrictor, and these pulses therefore generate waves of blood vessel constriction that enhance glymphatic flow and metabolic waste removal from the brain. By way of analogy, think about your gastrointestinal system. Your intestines, they use rhythmic contractions to move out waste, move it along your intestines and out the other end. And if that process gets impaired or stops, you get constipated. Now imagine if your brain had a similar waste removal system, the glymphatic system, but instead of food, it's clearing out toxic metabolic byproducts. And if something blocks that process, you get brain constipated. And that's exactly, or likely, what happens when norepinephrine pulses in the glymphatic system aren't working properly. So, the researchers then ask the provocative question: What do certain sleep medications, specifically in this study they use zolpidem, which acts on the GABA system, do to norepinephrine pulses in glymphatic function. In brief, they find shockingly that the sleep medication zolpidem impairs the normal oscillations in norepinephrine and decreases glymphatic flow. The implication is that long-term use could contribute to a buildup of metabolic debris in the brain and possibly long-term negative consequences like cognitive decline. Indeed, long-term human studies have linked zolpidem to higher rates of dementia and Alzheimer's disease. But fortunately, this does not appear to be the case for other sleep medications that are often used to help with sleep. I guess that's what a sleep medication is. Like the atypical antidepressant trazodone. In fact, there are suggestions in the scientific literature that this medication might improve sleep architecture, and is associated also with lower rates of dementia and Alzheimer's disease. And as a critical caveat and aside, I'm not a sleep scientist by trade, but I have reached out to a few, and if I acquire any new specific insights, I'll add those to the newsletter linked in the video notes. So make sure to check out that newsletter for more updates. So of course, an exciting frontier of research moving forward will be developing protocols to enhance this glymphatic flow system. For example, I'm currently enjoying playing with an acoustic neuromodulation device called EleMind, which has EEG sensors in the head device and sends acoustic pulses to interfere with alpha waves and accelerate the onset of sleep, help you fall asleep faster. Currently, it's only approved to help get sleep faster, but this sort of non-invasive technology may soon be able to alter the microarchitecture during deep sleep, potentially helping to improve glymphatic efficiency and removal of waste from the brain. Pretty cool, right? And we could also ask how different exposures to different types of light at different times during the day might impact sleep microarchitecture and glymphatic flow. And with advancements in technology, maybe we will soon be able to turn on glymphatics or turn up glymphatics and brain cleaning when we're awake but doing mindless tasks like watching a Marvel movie or a Harry Potter movie or Game of Thrones. Honestly, those are my nerd dreams— activating brain clearing while I get to watch Game of Thrones. Oh, the best. Anyway, what's the takeaway? Really, sleep It's not just about feeling rested. It's one of your body's most powerful tools for long-term health and brain health, but whole body health too. Keeping your glymphatic system running smoothly could mean sharper cognition, lower risk of neurodegenerative disease, and better overall performance, brain and whole body. And with emerging technologies from acoustic neuromodulation to light exposure strategies, we may one day soon be able fine-tune this process. But the fundamentals of sleep, they still matter. So sleep at a consistent time, minimize blue light at night, avoid eating too close to bedtime, and keep your sleep environment cool and dark. And seriously, if you're sleeping at 70°F or higher, we need to talk. But bottom line, sleep isn't just important, it's one of the best brain biohacks you have. So protect it, optimize it, and most importantly, get some. And now, words from the primary research team. Stay curious, and thank you so much for watching.

Our results are exciting because we uncover the mechanism behind clearance of waste from the brain during sleep. This knowledge puts us one step closer to answering the ultimate question: of why we even need to sleep at all. Knowing that the brain relies on this pumping mechanism to flush CSF through the system can hopefully help us develop new diagnostic tools and identify new drug targets to ultimately increase the efficiency of the glymphatic system. Although we are still not at the point where we have a pill we can take which will just boost our glymphatic system, we have data showing that we can do things to the brain to help this CSF flow a little bit. For example, studies in mice have shown that visual stimulation can entrain the synchronized activity of the neurons, which will promote CSF flow in the brain. Other studies made in humans have shown that deep breaths can also stimulate CSF flow through the ventricle and towards the brain. The next step in this project will be to dive even further down into the relationship between sleep and the glymphatic system. For example, we don't really know the role of REM sleep in the whole mechanism yet. In addition, we can use the knowledge we have now to look into other types of sleep medication and also different diseases to see how they interact with the slow oscillations that drive glymphatic clearance.

What if a specific form and frequency of light therapy could help clean your brain and even protect against Alzheimer's disease? Well, breaking new 2025 research reveals how this might actually work and how you can take advantage of this new science today. Now, I'm going to get to that, I promise. But first, I need to arm you with some brain biology background about the brain's cleaning system the glymphatic system. The glymphatic system is a set of channels in the brain that expand as blood vessels constrict. Imagine you have a blood vessel running through brain tissue, all bathed in cerebral spinal fluid. Well, when blood vessels constrict, generally during sleep, but not exclusively, as we'll find out, when they constrict and shrink in diameter, this creates space between the vessel and brain tissue, allowing for more cerebral spinal fluid to flow through and wash away— rinse out waste from the brain. I've reviewed this topic with a bit more detail in a prior video, so if you want more on glymphatic regulation, I'll refer you there. But a big question that I left as a cliffhanger to that prior video was: How? How do you increase glymphatic flow and clearance of metabolic waste out of the brain? Okay. Let there be light! 40 Hz blue light, to be more specific. 1 Hz equals 1 cycle per second, so 40 Hz just means 40 cycles or 40 flickers per second. Now, prior work has shown that 40 Hz light flickers can actually improve cognition in human Alzheimer's patients and in animal models. But How? Well, returning to glymphatics, this waste removal system is impaired in Alzheimer's disease, which means metabolic majunkus accumulates in the Alzheimer's brain, including amyloid oligomers, amyloid particles, and this can lead to a cascade of events precipitating cognitive decline, dementia, and progression of Alzheimer's disease. Now, there's one more nibble of neuronal knowledge I need to give you before we can get to the data. Glymphatic flow is regulated in part by water channels on brain support cells called astrocytes sitting around blood vessels in the brain. These water channels are called aquaporin-4, water pore 4, and to put it simply, more water flow through aquaporin-4 channels allows for better flow and more rinsing of metabolic debris out of the brain. Okay, on to the experimental results. What they did in the study is the researchers exposed mice, or a group of mice, a group of Alzheimer's mice, to 40 Hz blue light flickers for 1 hour per day for 2 weeks, and then tested their cognition on validated cognitive tests like a Y maze and novel object recognition test. The specifics of these tests aren't super important, but I named them in case you're interested and also provide more details in the newsletter associated with this video, which you can find in the video notes. Anyway, what they found, what the researchers found, is the blue light treatment improved memory performance on both tests closer to that of non-Alzheimer's control mice. And to chase the hypothesis that this improvement in cognition in the Alzheimer's mice exposed to blue light was related to enhanced glymphatic clearance—glymphatic clearance of waste from the brain—they injected a dye into the mice's brains that could be traced as it drains through the glymphatic system and out of the brain. So what you're looking at here—this is Figure 2C from the paper—is red dye in lymph nodes outside the brain. More red means more successful drainage and better glymphatic flow. And what you see here is less red in the middle panel, which represents the Alzheimer's mice without light treatment, as compared to control mice without Alzheimer's disease on the left. Then what you see on the right is Alzheimer's mice who were treated with blue light at 40 Hz for 1 hour per day for 2 weeks. And what you can see very clearly is more red, more dye, in these mice. Compared to the Alzheimer's mice that didn't get blue light treatment, suggesting more waste clearing, better glymphatic flow out of the brain. And in addition to that, they observed decreased levels of amyloid oligomers—this is Figure 2E—that are associated with Alzheimer's disease. So simply put, high level, the blue light 40 Hz treatment made the brain better at taking out the trash, taking out the metabolic waste. And, as a nuanced note, they did indeed show in this study that blue light treatment, the 40 Hz blue light treatment, increased levels of this aquaporin-4 transporter that I mentioned earlier, which provides a mechanism by which the blue light flicker increased glymphatic flow. So, I know that was a lot of jargon. Let's pause, collect, zoom out, and summarize. Lymphatic clearance and brain cleaning, they're impaired in Alzheimer's disease in human patients and animal models of Alzheimer's disease. But lymphatic flow can be enhanced by 40 Hz light flickers, which increases the expression of water channels, these aquaporin-4 channels that help with the lymphatic flow. And this system, this cascade causes improvements in amyloid levels, reduction in amyloid levels, and improved cognitive performance in at least animal models of Alzheimer's disease. Now, some people might have noticed I did emphasize "causes" because what they did next in this study was block different parts along the pathway I just described, like suppressing aquaporin-4 expression, and then exposing mice to the 40 Hz blue light flicker and seeing was there functional benefit. And at a high level, they showed that blocking parts of the pathway erased the benefits of the 40 Hz blue light. This is how researchers show causality in a mechanistic pathway. And for kicks and giggles, and if you really want a jargon bomb, brace for this. They found this system was dependent on something called the ventrolateral geniculate nucleus intergeniculate leaflet nucleus reunions circuit. You don't really need to know that detail. Certainly you don't. But don't you feel smart now? I know I do. Anyway, I mentioned at the beginning of this video, if I didn't just lose you there, that you can take advantage of this science today. You can actually buy 40 Hz flicker light bulbs and lamps commercially. They're readily available. Now, after reading this paper, I just happened to do some internet snooping for my own selfish purposes, actually, and ended up deciding that Gamma Light Therapy provided the best all-around spectrum of options. And then I reached out to the company to get a discount code for me and for you. So you can use my discount code NICKNORWITZ, just my name, one word, by following the link in the video notes and get 15% off any product. And now an aside and a moment of transparency. For those of you who are just interested in how brand deals like this come together. I don't hear a lot of influencers talk about these things, so I want to. Here was the sequence of events. Last week, I got all excited reading about new science of the glymphatic system, glymphatic system regulation, which I covered in my prior video. I really hope you watched that. Anyway, my exchange with the first author, who incidentally works in the same department at Oxford as I got my PhD in, well, Conversation with me got me even more enthused. Thereafter, I decided to do more digging on the topic based on tips she gave me and came across the new research that I covered in this video just now. Now, these data, they're relevant to me personally because I'm at high genetic risk for Alzheimer's disease. I have two copies of the APOE4 allele, and sleep, which is when most glymphatic clearance occurs, is a weak point in my health routine. So the idea of enhancing glymphatic clearance is really meaningful to me personally. So then, after drafting notes for this video, composing the title, thumbnail, etc., on February 12th as I was flying back from The Cholesterol Code movie screener in Vegas, which was amazing by the way, you should totally see it, it's gonna come out in September, probably on Amazon or Netflix, not sure which, I spent some time on the flight snooping around on the internet for quality devices with reasonable price points and reached out to a couple companies. Gamma Light Therapy seemed to be the best all-around, and they agreed to offer us—me and you—a 15% discount. I'm not sure if this disclosure is helpful. Let me know in the comments. But I do want you to know—this is important to me—that 100% of the time if I promote a product, it's genuinely because it's one that I value and would use myself or recommend to family members or friends or otherwise think has value, genuine value for you. So I hope this is received as it's intended, transparent and authentic. You can let me know in the comments. But in conclusion, what does this all mean for you? Well, while this research is still in its early stages, it shines a bright light on how something as simple as flickering light might help protect brain health by enhancing the glymphatic system's ability to clear out waste from the brain. And if future studies continue to confirm these findings in humans, we could be looking at a non-invasive way to support cognitive function and potentially reduce the risk of Alzheimer's disease. Of course, there's still a lot to illuminate. That's one of the great things about science. There always is. But one thing is clear. Our understanding of brain health is evolving rapidly, and discoveries like these could spark new breakthroughs in neurodegenerative disease prevention. Could microscopic tunnels in your brain hold the secret to preventing Alzheimer's disease and Parkinson's disease? It sounds like science fiction, right? But it's real, I swear. I'm referring to new data that has sent me into a state of just awe. At the beauty of biology. Let's dig into it and explore this breaking science and how it may inform solutions to keep your brain healthy as you age, and maybe as you dream too. Anyway, this new study was just published in Neuron and builds upon prior research about the fascinating topic of— wait for it— tunneling nanotubes. Literal tunnels between cells, including cells of different types, that allow them to exchange internal components. To me, this is as cool as if I could reach out and just touch my friend Dave and transfer literal energy from me to him, energy and information temporarily becoming one being, and then separating and going our separate ways. Now, why is this important for brain health? Well, in this study, the researchers look specifically at tunneling nanotubes formed between neurons and a cell called microglia, which are the resident immune cells in the brain. Simply, you can think about microglia as the cleanup crew for the brain. But as we will find out together, they are also much, much more than just simple cleanup crew. Anyway, now what they found first is that microglia can form tunneling nanotubes with neurons, reaching out and forming cytoplasmic connections with neurons, and through these nanotubes suck up harmful protein aggregates that play roles in Alzheimer's disease, like tau, and Parkinson's disease, like alpha-synuclein. The microglia use these nanotubes to suck up these toxic proteins right out of the neurons and then destroy them. That's pretty amazing, right? Isn't that just incredible? But that's not all. You see, these misfolded proteins that I just spoke about, they wreak havoc on neurons, contributing to oxidative stress and damaging mitochondria, the powerhouse of the cell that neurons need in tip-top shape so they can do their job and your brain can function normally and healthfully. Indeed, mitochondrial dysfunction is a hallmark of neurodegenerative diseases like Alzheimer's and Parkinson's. And these misfolded proteins, the tau and the alpha-synuclein, cause mitochondrial dysfunction. So in removing misfolded proteins through nanotubes, microglia are providing a great service. But that's only half the story. The microglia also replenish the mitochondria, donating healthy mitochondria from microglia to neurons through these nanotubes. So at a high level, imagine microglia extending one nanotube arm to suck out poisonous proteins harming mitochondria and extending one other nanotube arm to supply new, fresh, healthy mitochondria. How incredible is that? That's why I said I'm in awe of how beautiful biology is. And indeed, the researchers then show that this has functional consequences, with nanotubes formed between neurons and microglia leading to improvements in neuron metabolism. Reduced oxidative stress, and better overall mitochondrial function when the neurons were metabolically challenged. Again, I, I'm sorry I sound like a broken record, but this is so incredible. And I'm now sure you want to know, well, how do you increase the formation of these nanotubes in your brain to improve your brain health? Well, admittedly it's a bit complicated. First and foremost, the formation of nanotubes seems to be part of a stress response. In other words, it's the presence of things like alpha-synuclein and tau that provoke the need for nanotubes in the first place and provoke their formation. And you definitely don't want more misfolded proteins. That's bad. Furthermore, it's not just about quantity of mitochondria transfer, but also about quality of the mitochondria. Indeed, in this study, they show that a common mutation in the LRRK2 gene that contributes to Parkinson's disease in humans, it doesn't decrease mitochondrial transfer through nanotubes per se, but more likely decreases the quality of the transferred mitochondria such that neurons end up getting less metabolic support. The lesson here is you want to do what you need to do to keep your mitochondrial pool healthy. And fundamentally, this is everything you should do to maintain overall good metabolic health, like exercising regularly, including a mix of resistance training and cardio, eating a whole food carbohydrate appropriate diet for your activity level and metabolic state. For the brain, at least occasional bouts of ketosis may be beneficial, achieved either through carbohydrate restriction ketogenic diets, or intermittent fasting. And for those with insulin resistance, keeping your carbs low to ensure your brain gets a healthy energy supply from ketones. These are all things you can do to support brain health and metabolic health. And of course, I'm not going to leave it out, sleep. In fact, some research even shows that melatonin, the sleep hormone, increases the formation of nanotubes. Now, I'm not suggesting you should supplement melatonin to look for the benefit of nanotube formation, but I am saying this is one more reason to prioritize sleep and a healthy circadian pattern. If it's a helpful image for you that will inspire positive behavior change, imagine getting in bed at a reasonable hour, reducing exposure to blue night light, or getting sunlight in the morning as interventions that may help form these microscopic nanotunnels that maintain a healthy brain. And on the topic of sleep, I do want to give here a quick plug to this really cool device that the kind folks over at MIT let me have to test. It's called ELOmind, and it uses built-in EEG sensors and bone conduction sound wave pulses to help you get to sleep faster. For more details, if this is something that interests you, click on the link to my newsletter in the video notes below. It'll direct you more information. It's really cool tech. Now, the discovery of tunneling nanotubes in the brain— really, it's nothing short of mind-blowing, at least to me. Tell me in the comments if you feel the same way. These microscopic bridges between neurons and microglia, they act both as cleanup crew and energy support systems, removing toxic proteins and delivering fresh, healthy mitochondria to keep our brains running optimally. It's a breathtaking example of biology's ingenuity, almost like a science fiction repair system operating at the cellular level. And while we don't yet have direct ways to increase nanotube formation, at least not great protocols, what we do know is that keeping your mitochondria healthy is essential. So as you reflect on this fascinating discovery, let it be a reminder that your daily habits shape your long-term brain health. Small choices, whether it's movement, exercise, diet, or sleep, could be helping these microscopic tunnels work their magic, keeping your mind sharp and resilient for the years to come.