How Ketones Take out the Trash: New Research on Diet and Brain Aging

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 gonna 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 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 micro machines 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. Shapeling 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 salt water into fresh water 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 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 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 And this is because we're now showing that ketone bodies, which are compounds whose concentrations are determined by diet or exercise or by supplementation, 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 being published. And so I think at 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? So that was something that we weren't able to fully answer within our paper. And so I think it's gonna 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 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 autophagosome 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 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 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 is more targeted than say the hypothalamus. And I think at a broader level, another question that you can ask that, that I find really interesting is that what other metabolites are also causing the same mechanistic effect and what does it look like in a different tissue? So we showed in the paper that 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 other interesting inquiries that are going to come out of this paper. So thanks.