Ginny Robards
Professor John Newman, MD, PhD
58
Our memory is fundamental to us as humans. The remarkable capacity of the human brain defines us as a species. And variation in our minds is, to a large degree, what makes each of us different from one another. Without a robustly functioning memory, our ability to interact with the world – and to relate to one another – is shattered. We can carry on relatively well if we lose a limb, or even certain organs. But if our memory is erased, we are erased, in a sense.
Everyone knows this on some level. This is likely one reason why large surveys of the public often find that dementia is the most feared disease – because our mind and our memory so profoundly defines us.
But another reason why diseases associated with aging and the brain are so feared is because they are recalcitrant to treatment. For example, drugs developed to address Alzheimer’s disease have the highest failure rate of any disease area (99.6%). And the situation isn’t much better for other neurodegenerative conditions, or for age-related cognitive decline in general. We need a new approach.
And that brings me to our guest for this episode.
Guest
In this episode of humanOS Radio, I speak with John Newman. Dr. Newman is a geriatrician (a physician who specializes in the care of older people) at UCSF, as well as a professor at the Buck Institute for Research on Aging. He is chief investigator at the Newman Lab, where he is exploring ways to harness metabolic signals to promote health and resilience, particularly in older adults.
Dr. Newman’s research focuses predominantly on ketone bodies – molecules produced in the liver when glucose is scarce, either due to restricted intake or prolonged physical activity. So we tend to think of them primarily as an alternative source of fuel, particularly in the context of a low carb diet. However, they are also intriguing with respect to aging, because of how they function as molecular signals, and how they influence gene expression.
In this podcast, we discuss:
- How ketones are generated in the body
- Why most medical doctors tend to think of ketones as being harmful
- How beta-hydroxybutyrate influences gene expression – turning on or off genes
- How gene expression goes awry in the aging process
- How BHB functions as a signaling molecule to regulate inflammation
- Why animals on ketogenic diets live longer and exhibit better memory as they age
- Ketogenic diets and aging/longevity
- Why exogenous ketones are exciting but we need more time to fully understand their therapeutic potential
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Transcript
John Newman - 00:00: The take homes from that study were that as long as the mice didn't get obese on ketogenic diet, they lived somewhat longer. They definitely survived better into old age, and they definitely had better memory as they aged. Depending on how you did the ketogenic diet, they might have better physical function to be stronger as they age also.
Kendall Kendrick - 00:24: HumanOS, learn, master, achieve.
Dan Pardi - 00:34: Professor John Newman, welcome to the humanOS Radio.
John Newman - 00:36: Hi everybody. Hi Dan. Great to be here.
Dan Pardi - 00:38: Tell us about where you work and the type of work you do.
John Newman - 00:41: Sure. I'm a geriatrician physician scientist at the Buck Institute for Research on aging and also UCSF. I'm a medical doctor who specializes in the care of older adults. I mostly practice inside hospitals, and I'm trying to keep all the adults safe through hospitalization and avoiding some of the harms that are very common for older adults that can really impact people's lives and their independence, but most of the time, I'm a basic scientist studying the biology of aging and trying to learn about the molecules and the pathways that regulate aging in our bodies, and particularly how many of those were linked to metabolism and to the molecules in our bodies that help to generate energy.
01:13: My favorite molecules are ketone bodies and especially beta-hydroxybutyrate and learning about how ketone bodies and beta-hydroxybutyrate are living active molecules, not just sources of energy as we'll talk about, but actually doing really cool stuff, binding to proteins, inhibiting enzymes and actors in how things like fasting and exercise might affect your health.
Dan Pardi - 01:33: I would say there's probably no subject at the moment that is more popular to people that are looking into cutting edge strategies or techniques or inputs into health and beta-hydroxybutyrate. If you just simply look at search terms on Google, ketogenic diet has been around for a long time, but it's really become popular as more research is coming out. How did you first become interested in ketones?
John Newman - 01:55: Well, I first became interested in the aging science in general. Doctors are often very broad in what they learned and how their practice, but scientists have to be really narrow and pick specific topics to really dive deeply into. I wound up picking ketone bodies, and I was parked because I was interested in mechanisms of aging, and a lot of that has to do with metabolism and dietary restriction and fasting, the great granddaddy experiments in the aging biology world.
02:16: In science, we often wind up working on things related to what our mentors did. I guess as the career advice often give people is, especially if you're in science, if you're in an academic career, your mentors are really important in how you grow as a professional and as a scientist and really pick good mentors, people who are going to take time to help you grow, and so I picked my mentors first and then work on projects related to that. There's so much cool stuff in science and so much cool stuff in aging biology especially. It's not really hard to find a niche. That's super exciting and really cool that you can dive into.
02:45: I wound up joining my mentor is Eric Verdin who's now the president of the Buck Institute. At the time, there was this really cool study that was just wrapping up, which I came in on the tail end of, where a postdoc working with Eric showed that this ketone body, beta-hydroxybutyrate, inhibits a class of enzymes involved in gene expression. Cool study, and a great example of what we'll talk about the signaling activities of ketone bodies. I joined the lab to help wrap that up and then to start to explore what implications that has for aging, and everything took off from there.
03:13: Now, ketone bodies are my favorite molecules to study in the lab part because they're exciting, and part because I had a great environment to develop as a scientist.
Dan Pardi - 03:20: Perhaps you can give us a primer on ketones. How are they generated in the body? Just the basics.
John Newman - 03:26: Ketones are part of our normal metabolism. Even though we don't see them very often in modern life, ketones are how your body uses fat for energy. If you're fasting, if you're exercising for a long time, your body starts off relying mostly on carbohydrates for energy, but when you burn through those stores or if you're not eating long enough that your gut empties, you have to pick something else to use for energy, so our body starts to mobilize the fats in our fat cells. In part, we use those directly, but most of it goes to the liver and gets turned into ketone bodies, which are much easier for cells to burn for energy.
03:56: Ketone bodies are the currency, the way that our bodies burn fat for energy. I like to use the analogy sugar, glucose, tiny molecule is to carbohydrates, what ketone bodies, tiny molecules are to fats. They're how we use fats for energy. In modern life, we don't tend to fast a whole lot, and we don't tend to exercise a whole lot, so most of us in our day to day lives don't make a lot of ketone bodies. They're always there a little bit, but we only make a lot if we're fasting or exercising or not eating any carbohydrates, which is called a ketogenic diet. Then your body makes ketone bodies in order to use the fats in your diet for energy.
04:28: Why is that interesting? It's how we survive a fast, but what does it have to do with aging? Well, the thing is that the beginning of the field of how do you study aging and can you alter aging came from studying dietary restriction, feeding animals less food, and then seeing that they lived longer and often lived healthier. 100 years later, we have all of this evidence about various ways that things like fasting in the laboratory often can extend life and extend health and all of those different ways.
04:54: I'm sure that your listeners have heard about most of them, the fasting and intermittent fasting and time restricted feeding and fasting mimic diet. They all involve your body making ketone bodies. Our ketone body is just a bystander, just a way that we survive those things, or they're actually doing something contributing to the health effects of these fasting like states. The cool thing that we're learning more and more is our mechanisms by which ketone bodies might actually be actors contributing to the health effects.
Dan Pardi - 05:19: Ketogenic diets are commonly described in public media as extreme diets, and yet they are in some ways promoting a state that is more natural than one that is trickle today. It's interesting to juxtapose what is considered extreme and actually what is considered more natural. You also mentioned the ketone levels will typically fluctuate, so a natural state probably has a baseline, low-level micromolar concentration, and depending on exercise and the timing of the last meal, you're going to see those levels rise.
05:48: Do that last meal happen to be more than a day ago? Then you're going to see it rise even to millimolar concentrations. Usually, they are present, but they're present in different concentrations depending on the condition that the individual is in at that moment.
John Newman - 06:00: In a way, my thinking on this has definitely changed since I've been studying ketone bodies and ketogenic diets and learning more about it, and by just getting comfortable with the idea, I think like you're saying, it's just become outside of our normal experience in modern life, which doesn't mean that it's not normal, not a normal part of our bodies. On the one hand, our bodies are all adapted. Every one of us can make ketone bodies. When most people hear about ketone bodies, especially most doctors, it's in the context of people who are not metabolically normal, especially people with type one diabetes where that disease completely dysregulates how your body controls making ketone bodies.
06:31: It just goes crazy and that can be really harmful, but that's in our mind space. That's when we think about ketone bodies, we think about the problems in people who are not metabolically normal, but in most of us, it's just a normal part of our bodies. I'm not sure I would think about ketogenic diet as extreme anymore. You put that in the context of what does the ketogenic diet means? It just means less carbohydrates and a lot more fat, and so you're making some ketone bodies.
06:52: It's really just a mirror image of of what for a long time was the standard recommendation of fat restriction that you do a fat restricted diet, which means eating a lot of carbohydrates. That doesn't seem extreme to anyone. I'm not sure it's a mirror image should seem extreme either. It's just a different way of organizing your diet.
Dan Pardi - 07:07: Do we suffer from a ketone deficiency in modern life? Should we all be producing ketones more regularly both through dietary modifications and through restriction of mealtimes or extended fasts? Does that then help replicate a more natural condition for the body? Do we actually even need to even do a ketogenic diet in order to produce a sufficiency of ketones to be healthy? I don't know if you have answers to that now. I think they're bigger questions.
John Newman - 07:32: Those are fascinating questions to ask, and they're questions that we can start to answer now. We have the tools to begin to answer those questions in clinical research. We are going to try to answer those questions. Well, ketone bodies are necessary to life. The question is just having more ketone bodies at certain times and maybe in, like you're saying, an ancestral pattern, does that help to contribute to health?
07:52: I think we can find that out. Now, we have the tools to answer these questions and this is something that I'm doing in the laboratory. What do ketone bodies themselves do, and how do just ketone bodies alongside the ketogenic but also just ketone bodies, what effects do they have on health phenotypes and disease models in the laboratory? Then can we begin to understand what their longterm effects might be in people too?
Dan Pardi - 08:12: Much of my PhD work was on the compound gamma-hydroxybutyrate, which is structurally very similar to beta-hydroxybutyrate, which is the primary ketone of interest that we'll be discussing today. As I have been comparing these, there are remarkable similarities and yet they do very different things still, but speaking of concentrations, we know GHB, gamma-hydroxybutyrate, is heterogeneously distributed within the central nervous system and throughout the bias. We see it in the periphery, and levels will rise with fasting.
08:41: Just like with beta-hydroxybutyrate, the highest levels of nature are found in hibernating animals, and the highest concentration within the body is in brown fat. While I was at Jazz Pharmaceuticals, one of the most common spontaneously reported adverse events of GHB was weight loss. Is there a substance overlap that these two chemicals are having on regulatory circuits for body fatness? I think so. Much of this direct signaling we know occurs through epigenetic modification, particularly by inhibiting certain enzymes that interact with things called histone. What is epigenetics in histone?
John Newman - 09:13: In the broadest sense, epigenetics is everything about who we are and how our bodies act as people that's not encoded in our genes. We have our genes. They're set when we're conceived, and then those genes have to be expressed and regulated in order to create our bodies and for us to live and live our lives in the environment. How you regulate what genes are expressed when is really important to just about everything in our lives, how we get diseases, how we respond to stresses, how we respond to a changing environment. It's all about regulating gene expression.
09:41: For example, we're talking about fasting. If you're fasting, your body has to switch its metabolic program to shift away from burning sugars and carbohydrates for fuel and shift towards burning fats for fuel. That involves changing the gene expression of all the genes that encode the proteins and the enzymes that are required for burning fats. Genes have to be regulated. Epigenetics is the study of how gene expression is regulated, and diving really in deep, there's all of these enzymes that will transcribe genes and turn them on, but they have to be able to get at the DNA, actually get to the DNA, bind to it, and then start to transcribe genes.
10:13: One way that genes are regulated is how tightly wound up and compacted they are versus spread out and ready for something to come in and start to transcribe it. It's crazy to think about, but if you took the DNA in one of our cells and stretched it out, it would stretch about a meter, and yet it's wrapped up and compacted so tightly that every single one of our billions and billions of cells has a meter of DNA in it. How it's mostly compacted, there are these proteins called histones, which are the spools around which DNA is wrapped.
10:39: DNA gets tightly wrapped around histones, and the more tightly it's wrapped around histones, the less accessible it is for the genes to be transcribed and turned into proteins. DNA and histones, why do they make such good pair? In part, it's because they're both charged. Some of your listeners who've maybe had a little bit of biochemistry know that DNA has a phosphate backbone. The structure of DNA has these phosphates on which the bases are hung, and the phosphates will have a negative charge. Histones are proteins that have these tails hanging off of them with positive charges, so positive attracts negative. DNA gets wrapped tightly around histones and sticks there.
11:13: If you want to unwrap the DNA so you can turn on a gene, you have to disrupt that positive and negative interaction, so those histone tails can get modified. You can stick groups to cover up the negative charges, groups called acetyl groups. You cover up the negative charges. Negative and positive don't bind anymore, and the DNA gets a little more loosey goosey and free to wander around and free to have an enzyme jump on and transcribe a gene. Acetylation is an epigenetic modification to histones that affects gene expression.
11:40: It's really important. Essentially, all genes or acetylated at some point, and it controls the start of gene transcription and controls every element of gene transcription. There's cells of a whole bunch of specialized enzymes for putting acetyl groups onto histones and taking them off. It's all very tightly regulated, and it turns out that beta-hydroxybutyrate, the ketone body, inhibits the enzymes that take acetylation off called deacetylases. This is always a bit of a mind twister for me. Acetylation helps to activate gene expression.
12:08: Deacetylases take off the acetylation and help to shut down gene expression, so if you inhibit the protein that shuts down, in general, you help to activate gene expression. Histone deacetylase inhibitors including beta-hydroxybutyrate generally help to activate gene expression. This was one of the first examples of how a metabolic molecule regulates gene expression. The other one, I already just mentioned, an even bigger one, so acetylation comes from Acetyl-CoA, which is one of the key molecules right in the middle of how ourselves turn sugar or fats into energy.
12:39: It all becomes Acetyl-CoA first, and then the Acetyl-CoA gets burned to produce ATP. That Acetyl-CoA is what becomes acetylation on histones, and then it can get regulated by ketone bodies, beta-hydroxybutyrate, that's all connected to metabolism.
Dan Pardi - 12:52: I'll do a quick review. We have our genes, genes wrap around histones. There are things that sit epi or above the genes that will then determine whether or not those genes are accessible for gene transcription. When they're acetylated, that allows for enough room for transcription factors to get in there and to transcribed into gene products that become proteins. If there's not enough room, then they can't get to it, and those genes are essentially silenced.
13:19: Is this silencing pattern in some ways protective, or is it really just a condition of dysfunction? Is the epigenetic modifications or silencing of genes something that the body isn't doing intentionally, or is it because we're not providing the right metabolic conditions for proper genetic transcription to occur, or is it both?
John Newman - 13:37: Everything has a purpose in the right context. I think if you want to talk about what goes wrong with aging, a lot of it has to do with things starting to happen out of context, but everything has a purpose. Think about you often need to silence genes and you often need to activate genes. Stem cells are a great example of that. For a stem cell to turn into say a muscle cell or a heart cell, you have to first turn off the genes that make it a stem cell, and then you have to turn on the genes that make it a muscle cell or a heart cell.
14:02: It's all important in different contexts. You can just imagine how complicated this all is in real life. Biology is complexity on top of complexity on top of messy complexity. It's not too hard for it to get out of whack, not work right. Well, as we get older, all these complicated epigenetic changes that have to work to express the genes that we want when we want and turn off the genes that we don't want when we don't want them. That all starts to get messed up, and you can see that reflection.
14:25: This is getting towards in our cutting edge of science and watching how our epigenetic patterns change as we age. They do change in animals, and they even change in people. This is the source of the DNA methylation epigenetic clock that Steve Horvath and others developed. We can see that our epigenetics start to get out of whack as we get older.
Dan Pardi - 14:44: These products of metabolism ketones are more than just packets of energy that the body can use for fuel. They regulate epigenetics, turning on or off genes. They also can serve as signaling molecules. I'd like to talk about where it's acting as a signaling molecule. It seems to be affecting gene protein coupled receptors on cells, so things like the hydroxy carboxylic acid receptor and also the free fatty acid receptor three. Let's talk about the hydroxy carboxylic acid receptor or HCAR2 activation first.
15:15: What are some things that we know about what this receptor relates to in terms of our physiology and then how does BHB intervene to influence things?
John Newman - 15:24: Well, so both HCAR2 and FFAR3 are expressed on a bunch of different cell types, and what they regulate can differ based on the cell type. My focus in the lab is more on the epigenetic aspects. There are other people around the world who are doing really cool work on BHB and these receptors, but in different cell types, both of these receptors in different ways can regulate the metabolic function of cells and can also regulate inflammation, which is one of the themes of I think BHB signaling. There's a few different ways that it can control metabolism, inflammation and epigenetics.
15:51: I think of those is the three pillars of what we know about the molecular signaling effects of BHB. In the brain, HCAR2 is expressed on immune cells, and it can regulate how those immune cells are activated into a more inflammatory or less inflammatory state. In some neurons, especially in sympathetic ganglia, there's some really elegant work and animals that these receptors control the sympathetic tone in animals and control the whole body metabolic rate and reduces the whole body metabolic rate.
16:17: This lowers the heart rate of animals when you expose them to ketone bodies, and this is thought to be maybe the mechanism or one of the mechanisms through which our own heart rate and metabolic rate can slow when we're fasting, which is a fun thing to observe when you're fasting yourself.
Dan Pardi - 16:32: It would be contrary to what many people who do the diet for weight loss would expect. They have a decrease in sympathetic tone and heart rate. You also have a decrease in the release of free fatty acids. There are people talking about how the effects of GHB on weight are happening because you're releasing more fatty acids, but this actually shows that that's not likely the cause of weight loss if it occurs in somebody who's doing the diet.
John Newman - 16:56: I don't do clinical studies on ketogenic diets, but my impression from reading literature and hearing folks talk about the studies that have been done is that it can be hard to show big differences in metabolic rate on different diet macronutrients formulations. I think there's very little controversy at this point that different macronutrients combinations work roughly equally well for weight loss, and there was just a large diet study published a few weeks ago showing that carbohydrate restriction and fat restriction work basically equivalently for weight loss, but what the contribution of changes into metabolic rate is to that is still pretty controversial in part, because it is a hard thing to study in people very precisely.
Dan Pardi - 17:30: Related to weight and calorie excess, so many conditions of modern life are results of calorie excess. The reasons for that is just I think we have an ancient genome engineered to seek out food in an environment where its presence is fairly ubiquitous and its palatability is super normal, and so it's just a perfect storm for weight gain. One of the more interesting aspects of your paper in the annual review about beta-hydroxybutyrate was the effects of inhibiting the NLRP# inflammasome. This inflammasome mediated inflammatory response to nutrient excess is one that might be in some ways causative of some of the negative inflammatory effects of a high fat diet or a high calorie diet.
18:10: By knocking that out, you don't seem to have as many of the issues related to calorie excess, because BHB is inhibiting that inflammasome marker, then that might be one of the beneficial effects given the environment we live in to a more favorable metabolic outcome with the ketogenic diet.
John Newman - 18:26: That's absolutely possible. The work on NLRP3 in the laboratory and animals has been really elegant and really thorough by Deep Dixit at Yale. He's focused more on inflammatory diseases than on metabolic syndrome, but I think it's really, really interesting to think about how that would roll into the pathogenesis of metabolic syndrome, this syndrome of overfeeding that so many of us get in the modern world. If that inflammatory regulation has a role in dampening the effects of metabolic syndrome would be really interesting to see.
Dan Pardi - 18:52: In some work by Speakman and McNay, they were looking at the effects of the ketogenic diet amongst other dietary styles in mice. The first part of the study, they put all the animals on a calorie restricted version of a high protein diet, a high carb diet, a ketogenic diet, and then their natural diet, and they all lost weight, but then they observed them for a month after the calorie restriction. In terms of weight regained, the high fat diet had the worst outcome, but the ketogenic diet had the best outcome.
19:22: Then they put them on an ad libitum diet where they had the same dietary groups, high protein, high carb, ketogenic, high fat. The amount of spontaneous weight loss in the ad libitum diet was by far greatest with the ketogenic diet. When they sacrificed those animals, they looked at the energy regulating centers in the arcuate nucleus of the brain and found that diet-induced obesity will cause less neuron regeneration. In the presence of ketones, you see an increase of what they call a proliferative remodeling.
19:50: It seems like those cells become healthy again. We see that in other tissues as well with butyrate. Butyrate is produced by microbiota in the gut. They have an impact on the regeneration of beta cell function. There's something seemingly regenerative. Butyrate seems to help damaged tissue perform better.
John Newman - 20:08: Some effect of the ketogenic that's persistent maybe through ketone bodies and maybe through these signaling pathways that we're talking about in different cell types, I mean, that's something that I came out of my work in the laboratory is ketogenic diets and mice too. I was along with a group at UC Davis, one of the first groups to look at the longterm effects of ketogenic diet in rodents, in mice over their entire lifespan, looking at their survival and also looking at their phenotypes of aging, how healthy and active and functional and strong and smart they were as they got older.
20:33: There were a couple of really interesting things that came out of that [inaudible 00:20:36] what you were just talking about. The take homes from that study were that as long as the mice didn't get obese on the ketogenic diet, they lived somewhat longer. They definitely survived better into old age, and they definitely had better memory as they aged. Depending on how you did the ketogenic diet, they might have better physical function, be stronger as they aged also, but it was like a persistent effect of the diets. They didn't have to be eating the diet all the time and they didn't even have to be eating the diet when you did the testing.
21:01: When I did one big memory test on the mice, I really want to look for changes from aging over time and not just having ketone bodies available for energy to improve your brain function in that moment.
Dan Pardi - 21:12: Yes.
John Newman - 21:12: I've had them on the diets for a year. I took them all back onto a normal diet. Actually, they had been eating a normal diet for two months when I did this big memory test and they still did better. There really was evidence that you didn't have to have them on the ketogenic diet continuously, and the effects can persist for weeks, for months. It probably represents some change to cell types in the brain reflecting epigenetics or inflammation or proliferation. This is what we're trying to figure out now exactly. What is it that changed in their brains from half a life of ketogenic diet that made them have better memory as they aged.
Dan Pardi - 21:42: Did they perform equally well when they were younger or did they have an improvement when they were younger?
John Newman - 21:47: Almost as an aside, so that was looking at how well their memory was preserved as they aged. We did a longitudinal study where we tested the same mice IN middle age, randomized them to the two different diets, and then tested them again a year later in old age. The memory of the mice who'd been on the ketogenic diet for most of that year was better than mice who'd been on the control diet. It trended. Meaning, if you look at them on a graph, it was better, but it was not statistically significantly different. Trended to them actually doing better on memory as old mice than they did as middle aged mice.
Dan Pardi - 22:15: Oh cool.
John Newman - 22:16: I would love to do that in a bigger way and see if that's really what's happening, but almost as an accident when I was doing some other experiments in Alzheimer's model, so here, we study younger mice, and I just happened to notice that the controls, the wild type mice, the normal mice that are not Alzheimer's models that we're just using as a point of comparison, they actually were doing better on memory tests on the ketogenic diet than on a normal diet. Even in the young healthy normal mice, when they were eating the ketogenic diet, they did better on memory tasks.
22:43: This is one of the things about the ketogenic diet and ketone bodies. It's a complicated biological intervention. It does a lot of different things, and so some of those are immediate and maybe that has to do with having this energy available for the brain to burn. Some of it is more longterm and persistent, and we're going to try to figure out what all those different aspects are.
Dan Pardi - 23:00: Now aside from memory, did you notice any decrease or change? Dementia or Alzheimer's pathology, was that observed?
John Newman - 23:08: Mice of course don't get Alzheimer's disease. You have to create models of it, which are hybrids of human genes in mice to get some aspects of Alzheimer's disease, but we were studying one of these models to see if the ketogenic diet would have an effect on this model. The reason we were doing that actually, and this is interesting and most people probably haven't heard about this yet. Part of what goes wrong in Alzheimer's disease, and this comes from work of Lennart Mucke and Jorge Palop and many others at UCSF and the Gladstone Institutes and at other places around the country.
23:34: You get this seizure like stuff in the brains of these mouse models of Alzheimer's disease. I'll give you the answer upfront that it was the seizure stuff that got us interested in the ketogenic diet in these models because there's such a long history of ketogenic diets being used to treat epilepsy in kids. Maybe it would help with this epilepsy like activity in the Alzheimer's brains. It turns out that in Alzheimer's disease, your brain normally has this class of neurons called inhibitory interneurons, whose job is to put the brakes on so that when one set of neurons fires, it's only that set that fires.
24:05: It's the same idea of only doing what you want when you want it, and not spreading to things that you don't want it to spread to.
Dan Pardi - 24:11: Gabaergic.
John Newman - 24:12: Yes, these gabaergic parvalbumin positive interneurons, so when they die or when they lose function, then neuronal firing can spread from one set of neurons to another. People describe epilepsy as like a wildfire, just it spreads, and so it disrupts the activity of all of the neurons that can cause seizures. You can see this activity visible on an EEG in the form of these epilepsy-like spikes. It turned out that in the mouse models, if you can control this epilepsy-like activity, the mice do better. They have better memory, and so that's thought to be part of the pathogenesis of how Alzheimer's disease affects memory through this epilepsy-like activity in the hippocampus and the cortex.
24:47: If you look really carefully and you can even see this activity in people too, so we found that the ketogenic diet indeed worked to suppress these epilepsy-like spikes. That's probably one of the reasons if not even the most important reason how it improves memory in the mouse models, and so you can find this on bio archive and a pre-print but it's not published yet in a peer review journal. We even found that ketone body compounds, so not the diet, but just compounds that turn into beta-hydroxybutyrate can have the same effect on this epilepsy-like activity in Alzheimer's models.
25:15: Maybe that could be an interesting mechanism through which we could study how ketone bodies or Alzheimer's or ketogenic diets might be useful in the context of Alzheimer's disease.
Dan Pardi - 25:24: It seems that beta-hydroxybutyrate will nudge metabolism of glutamate towards gabba, and that might make the brain less excitable and give you a greater state of control over epilepsy. I'll mention something related to GHB. That's been looked at in animal models of Alzheimer's disease, so amyloid precursor protein, transgenic mice, so they have a hard time breaking down this amyloid protein aggregate which then leads to its accumulation and then they start to develop some of the hallmark characteristics of the condition.
25:51: One very interesting about GHB is its effects on slow-wave sleep, which is quite unique to other sleep inducing compounds, and so the work with Matt Walker and Bryce Mander over at Berkeley is thinking that sleep loss is not only a symptom of the condition, but it might be also causative to its pathophysiology because it is during that slow-wave sleep, particularly sub-1 HZ slow waves that the rain is clearing out those neurotoxic substances like beta amyloid. When you can promote slow-wave sleep, these areas that accumulated fastest might have an easier time processing the waste of metabolism that occurs in the brain.
26:28: One other interesting aspect of GHB is that it also will induce the brain protease neprilysin, which breaks down beta amyloid. It has a positive effect on slow-wave sleep. It also induces this brain protease, and similarly to beta-hydroxybutyrate, it can serve as a fuel for the brain by entering into the electron transport chain of the mitochondrial complex II. You've got all these possible ways more than just one whereby this butyrate-like substance, which is gamma-hydroxybutyrate is having an effect. Butyrates are all stars.
John Newman - 26:56: The sleep questions is really cool, and I've seen some really cool data about Abeta secretion converted dynamically with sleep state, and that's scary for someone who's been through a PhD or a medical residency to one night of just a good sleep, you can detect the higher release of Abeta. This gives me an excuse to talk about delirium. If you think of dementia as being the chronic disease of the brain, delirium is an acute brain attack. This is what I spent a lot of time in the hospital trying to prevent and treat.
27:22: It's when people are... Especially people in the hospital if they're sick or if things are happening to them, especially older people, especially people with dementia, but even if you don't have dementia, we're prone to getting this acute confusional state. It's really terrifying when you see it. People don't know where they are. They don't recognize their families. They're paranoid. They're hallucinating. It's very sudden. Unfortunately, it's often reversible just suddenly, but one of the big triggers is sleep disruptions.
27:46: The protocols that we use in the hospital to try to prevent this acute brain attack or delirium, one of the key parts of that is as simple as trying to let people sleep, minimizing nighttime interruptions, making sure that it's dark in the room. It's not loud noises, that they get natural light during the day to keep their circadian regulation intact. It sounds like such a simple thing, but it has huge clinical impact, and the biology behind that has got to be fascinating.
Dan Pardi - 28:10: We talked about memory, and we talked about how they lived a little bit longer. Where else has this been studied?
John Newman - 28:15: BHB and aging. It's pretty early days, honestly, in the field, and there's all this circumstantial evidence from the huge amount of data around dietary restriction and fasting patterns and fasting mimic and all that sort of thing, where BHB is a fellow traveler. It's there. We don't know if that's what's doing the business of the fasting and things. It was only our study and the study from UC Davis where the first longterm lifespan aging studies of mice on a ketogenic diet, which is a little crazy that that hadn't been done before, but this was really the first time that we could show that as long as you control for weights and don't let the mice get obese, that the ketogenic diet has these measurable effects on lifespan and phenotypes of aging.
28:53: The next frontier is getting deeper on what are the components of the ketogenic diet that are active like that. We both took an early stab at that and that we didn't just study a ketogenic diet in the mice, but we also studied a very low carbohydrate but not quite ketogenic diet, so carbohydrate restricted but there's enough carbohydrates there to suppress ketogenesis in the mice, and the mice that works out to about 15% of their calories from carbohydrates versus the ketogenic diet has zero. That carbohydrate restriction alone has health effects too.
29:20: Those mice trended towards living longer. They were in between the high carbohydrate controls and the ketogenic. They were in the middle. I didn't test their memory, but the group at UC Davis showed that in some of the tests, they also saw this intermediate effect. It wasn't as good as ketogenic diet, but it also was maybe better than the controls, so just carbohydrate restriction probably has important health effects on its own. We know that already, because we know that has big effects on insulin and glucose and even IGF. In this case, we also saw suppression of tora activity just from the carbohydrate restriction.
29:50: Good reasons with carbohydrate restriction alone. How do we tease out what ketone bodies do? Your listeners can probably guess. Now, we have some technologies to do this in the form of exogenous ketones. It's really hard to just feed beta-hydroxybutyrate or to eat a meal of it. I would not recommend that your listeners try that because it's an organic acid, and so you're eating a lot of acid. It's about the same PH as vinegar, or a lot of salt to try to neutralize it. You can't just eat a meal of beta-hydroxybutyrate, but you can use chemical tricks to create compounds that you can eat in a meal quantity, but then that your bodies will metabolize directly into beta-hydroxybutyrate.
30:25: Now, we can use these compounds to try to see if the effects on aging that we saw from ketogenic diet, do we see them just from ketone bodies, just from beta-hydroxybutyrate? That's the cutting edge right now. No one's done a lifespan study, for example, of an exogenous ketone yet. I'm sure this is going to happen sooner rather than later. In fact, there is one example of that already underway. The National Institute on Aging supports this interventions testing program, which is a multicenter clinical trial for interventions that target aging in mice.
30:54: There's three sites around the country that do these enormous mouse experiments to see if various drugs and compounds make mice live longer. Their most famous hit of course was rapamycin, but this is the program that identified acarbose and 17alpha-estradiol and a couple of others as compounds that as rigorously as we can tell affect aging in mice. They're testing one example of a ketone body precursor compound in the current batch. We'll probably find out in two or three years if it works or not to effect the life span of those mice. It would be really interesting to see.
Dan Pardi - 31:23: I hope that these studies allow us to see the detail of conditions of a fasted state promoted with beta-hydroxybutyrate but in a fed state. Do you end up with conflict where you're stimulating fasted state physiology but you have a normal or even higher calories? Does that actually put fuel on the fire, or does it make it a better situation? I don't know, but I hope we can tell.
John Newman - 31:50: We don't know, and we need to do the science to find out. You can reason it out in both directions and tie yourself in knots I imagine. For example, there are some cells that like to metabolize beta-hydroxybutyrate, and given the choice between glucose and beta-hydroxybutyrate, they will absorb and metabolize the beta-hydroxybutyrate, but there are other cells that don't have that preference. Dan Kelly at University of Pennsylvania has done some really nice work around ketogenic diets and ketone bodies and models of heart failure. He and some other folks who have tested this in humans too to show that heart cells prefer using beta-hydroxybutyrate.
32:19: If you give them beta-hydroxybutyrate even in the normal fed state, they'll use it for energy, and you'll presumably get the effects of the fasting state for heart cells, but not all cells are going to be like that. One thing that I think we've also learned in the aging field, this is true in every field of biology. It's not just about turning on or turning off enzymes, but it's also about the context and about the fuel and about the substrates, and everything has to be able to work together.
32:41: I think this has been one of the examples of the Sirtuins NAD field. I'm sure your listeners might be familiar with. Sirtuin's a group of enzymes that have been implicated in many organisms and regulating aging processes, but trying to turn them on and turn them off with drugs has honestly been a little bit disappointing. One of the reasons that people think that is is sirtuin's used as a cofactor for their work on metabolic molecule called NAD. It turns out that as you age, you have less and less NAD in yourselves. If there's not enough NAD around, it doesn't matter how hard you try to turn on Sirtuins that can't do their work without NAD.
33:13: Now, we're shifting to the idea of maybe you need to replace the NAD and plus minus also turn on the Sirtuins, but you'd have to make the whole context work. The same might be true for metabolism, so just having beta-hydroxybutyrate around even if it's helping to, for example, turn on fat metabolism genes or activate fat metabolism, how much of an effect will that really have if it's not in the context of a state where that fat's available to be metabolized? The rest of your body's trying to metabolize fat. We really don't know.
33:38: Probably, we'll find out that just ketone bodies alone like exogenous ketones will be useful in some contexts, but it's not really a ketogenic died in a pill. It's not really fasting in a pill. It's just one element of that. We need to figure out how that element can be useful, but some of these studies are underway now, so there are at least three good size clinical trials I know of, different centers around the country in the U.S. which are testing different forms of ketogenic diet in people with mild or moderate Alzheimer's disease. Super cool science, and really excited to see what winds up happening with those clinical trials.
Dan Pardi - 34:08: On humanOS, we have a guy that shows you how to do what we think is a good version of that ketogenic diets. If anyone wants to try it, we walk through the principles and then show you these are the foods to eat, et cetera. If you're interested in giving a try, you can take a look at it there, but thank you for your work, and I'd love to have you back on.
John Newman - 34:22: Same here. Thanks a lot, Dan. This was fun.
Kendall Kendrick - 34:26: Thanks for listening, and come visit us soon at humanos.me.
Other Episodes with the Buck Institute
