#040 Dr. Eric Verdin on Ketogenic Diet Longevity, Beta-Hydroxybutyrate & HDAC Inhibitors

Fasting as a longevity tool: insulin, mTOR, and the pathways that regulate aging

Fasting lowers insulin signaling and activates protective pathways. Ketosis begins around 16 hours; 14-hour fasting is the minimum.

"He is a professor of medicine at UCSF and is currently the fifth president and chief executive officer of the Buck Institute for Research on Aging. In this podcast, we talk broadly about many interesting areas of inquiry in aging, especially the areas that Dr. Verden and his colleagues are involved in. But of special interest is his lab's recent publication on a cyclic ketogenic diet. In other words, a version of the ketogenic diet where they rotate a normal diet and a ketogenic diet periodically. Particularly interesting is that it reduced midlife mortality and also memory decline. We also discussed some of the current research, including Dr. Verdin's, regarding the role of NAD plus in the aging process, a topic made especially popular due to the research surrounding nicotinamide riboside, a precursor to NAD plus as a potential anti-aging supplement. A few words about this episode. This podcast I would rate as a six or maybe seven in terms of technical difficulty. In other words, relative to my other podcasts, there are some that have greater technical depth, but there could be a few stumbling blocks in this one too. So let's talk about those. The three stumbling blocks for this podcast, if there are any, are probably the discussions surrounding mTOR, PPAR-alpha, and a family of enzymes known as HDACs, or histone deacetylases, and the compounds and enzymes that inhibit them, which are known as HDAC inhibitors. So let's talk about these things right off the top of the list. The first thing I just brought up was mTOR. mTOR functions as a master regulator of cell growth and metabolism. mTOR activity is increased when we eat protein and it's activated by essential amino acid intake and thus protein intake. When we take in amino acids, we boost the IGF-1 signal, which then triggers protein synthesis and cell growth through the activation of mTOR. mTOR is interesting because on the one hand, most research in the field of aging suggests that we should try to limit the activation of mTOR, which is why we often talk about fasting, caloric restriction, and also in some cases protein restriction as strategies for delaying aging. There's also a lot of interest in the aging community in inhibiting mTOR pharmacologically. One candidate particularly well known for its ability to inhibit mTOR is known as rapamycin. Maybe some of you have heard of it. On the other hand, sometimes we want a little boost in cell growth and metabolism, and it isn't a bad thing. If you're a bodybuilder, you probably want growth, and to do that, you probably eat more protein than someone who is sedentary. In this case, you might be deliberately, whether you know it or not, activating mTOR and its upstream signal IGF-1 when you're consuming amino acids in the form of protein. Additionally, we know that frailty is actually a predictor of mortality in the elderly. So what is a person to do? Questions like these are ultimately what make the field of aging and even nutrition very difficult. The answer is almost always it depends on many factors. It could depend on your age, where it's known that elderly actually have a lower all-cause mortality if they consume more protein, perhaps helping mitigate the approximately 10% muscle mass we lose per decade starting in midlife. It could depend on whether or not you're physically active or not, because physical activity might affect what tissues these growth signals end up concentrated in. Or it could depend on the existing health of your tissues and the amount of DNA damage and inflammation they have been exposed to, which might have the quality of creating an environment of cells just damaged enough that they are just looking for an environment that is rich in growth signals to begin the formation of a cancerous mass. These are all really important things to consider. The truth is, it may be a while before we have all the answers to all of these questions. So that's IGF-1 and mTOR in a nutshell. Caloric restriction, prolonged fasting, intermittent fasting, some anti-aging drugs, and even certain versions of the ketogenic diet that are low in protein, which is the version we're usually talking about if we're talking about aging research, all have the quality of suppressing mTOR. And this is almost certainly an important part of the cellular milieu associated with any type of healthspan extension that these strategies might confer. Now onto the next potential stumbling block you might find in this podcast, which is PPAR-alpha. The first thing you should know about PPAR-alpha is that it is absolutely critical for ketogenesis. It is activated by caloric restriction or fasting and nutrient deprivation, especially carbohydrate restriction, and plays an important role as a transcription factor in the promotion of the uptake, utilization, and catabolism of fatty acids. It does this by upregulations of genes involved in fatty acid transport, fatty acid binding and activation, and peroxisomal and mitochondrial fatty acid beta-oxidation. What we learned from Dr. Verdon in this episode is that activation of PPAR-alpha might play a special role in some of the beneficial effects of the ketogenic diet, at least in mice, because as Dr. Verdon explains, this is one of the biggest differences that his lab has seen between the ketogenic diet fed to mice and a high-fat, low-carb diet that was not ketogenic. What's interesting about the PPAR genes is that there are several well-known polymorphisms found in human populations, and some of these have been included in the raw data a person can get from certain genetic providers like 23andMe. Evidence suggests that these polymorphisms can actually have a pretty significant effect on the way in which fat, especially the ratio between saturated fat and polyunsaturated fat, influence blood markers of cardiovascular disease risk. This is a topic all on its own that we don't actually get into in this episode, other than a brief mention. But you can learn more about that by visiting my website at foundmyfitness.com forward slash genetics. Once again, that's foundmyfitness.com forward slash G-E-N-E-T-I-C-S, genetics. Finally, we get to the third potential stumbling block of the three I mentioned, histone deacetylases, otherwise known as HDACs, and histone deacetylase inhibitors, otherwise known as HDAC inhibitors. HDAC inhibitors, by virtue of inhibiting enzymes that go around removing acetyl groups from histones, actually increase the expression of certain genes. Dr. Verdon's work has shown that beta-hydroxybutyrate, a ketone body we produce a lot of during fasting and when we are under a carbohydrate restriction can function as a class 1 HDAC inhibitor to increase the genetic expression of a gene known as FOXO3. This gene is well known for its role in the protection from oxidative stress and involvement in delaying aging. Not mentioned as a potential stumbling block is also some pretty deep conversation about autophagy, a very important cellular cleanup mechanism that is activated when we fast. But if anything, that part of the conversation should just be a refresher for any of you that heard the discussion with Dr. Guido Kramer. If you're drawing a blank, head back a few episodes and listen to the episode with Dr. Guido Kramer. It's a great one and really gets into the nitty gritty of the biology surrounding cellular autophagy, an important topic, especially when we're talking about fasting and health span. Okay, that said, you are now equipped with a brief primer on mTOR, PPAR-alpha, HDAC, and HDAC inhibitors. This concludes the official Found My Fitness intro. Now, away we go to the podcast. Hello, everyone. Welcome back to another episode of the Found My Fitness podcast. I am sitting here with Dr. Eric Verdin, who is the president of the Buck Institute for Research on Aging. Now, I recently saw a quote from you that said you stated that a child born in the year 2007 had a 50% chance of living to be 104 years old. First of all, yes, you did. Can you explain what you mean by that? Because that's pretty exciting. I think it says what it says. It's based on the projection of where the progression and lifespan that has happened during the last 100 years, which has been about two years per decade. I think scientists at Berkeley, have been able to, this data comes out of a book that was based on data from Berkeley suggesting that a child born in 2007 has a 50% chance of living to 104. After reading that quote, I was thinking, well, maybe some of these lifestyle interventions that we know to regulate the aging process that we know that can have a positive effect on health span. Can you maybe tell people a little bit about what are some of the main lifestyle interventions that are known to regulate the aging process, at least in animal models? Yes. And in humans as well. I think there are, you know, four broad categories of things that are being considered by the aging field. One is exercise is to this day, the surest, best intervention that we have to increase healthspan and lifespan. The second one is nutrition. And there's a lot of research going on today trying to understand what is it about nutrition. Is it carbohydrates versus fat versus proteins? What is the relative role of all these nutrients in your lifespan and healthspan? The third one, which is actually an active field of investigation, is the identification of molecules that mimic either exercise or sort of exercise mimetic or mimic restriction in terms of nutrients, so what we call calorie restriction mimetics. And finally, the last part of the whole aging field is the idea of rejuvenation. So the first three approaches are geared towards slowing down the process of aging. Rejuvenation takes the approach that once the aging has occurred, how can you repair it and how can you fix it? So I think, you know, we have programs here that are studying all four different approaches. I think you're probably familiar with Jack Malayne, who was one of the gurus that started the American sort of infatuation. And he said he lived to 100 years old, and he said that exercise is king, nutrition is queen. Put them together, and you have a kingdom, which I think is really true. So I think for me and many of my colleagues, I think exercise and nutrition is the cornerstone of what we're trying to do today until we have better drugs. That's a beautiful quote. In terms of the nutrition, when I think of nutrition, and you mentioned the macronutrient content and trying to understand the ratios of carbohydrates and protein and fat, I often think of the micronutrients when I think of nutrition. I trained my mentor for my postdoc was Dr. Bruce Ames. And he, of course, you know, he's very focused on micronutrients, vitamins, minerals, essential fatty acids, and amino acids. But, you know, in the past, you know, couple of decades, the research has seemed to shown that, you know, limiting these certain macronutrients, you know, protein couple of decades, the research has seemed to have shown that, you know, limiting these certain macronutrients, you know, protein, fat, carbohydrates, you sort of tweak the amount that you take in. You can alter the way an animal ages, at least in terms of the way their tissues are aging. You're not necessarily going to, you know, increase their maximum lifespan, but you may increase their average lifespan, which is... Yes. I think in the last 20 years we've learned a lot. And a lot of this research has been actually causing a re-evaluation of some of the public policies that have been enacted in the last 20 and 30 years in terms of what should you eat, when should you eat. So a lot of work is ongoing today and actually generating lots of really interesting data. Along with this, the basic science of aging, I think what people have studied is trying to understand what are the pathways that control aging in C. elegans, in Drosophila, the fruit flies, in the little nematode, or in mice, one of the major pathways that has emerged is the insulin signaling pathway. That was the work of Cynthia Kenyon back in the 1990s, showing that the insulin signaling pathway is one of the major pathways that controls aging. Well if you know this, you can already sort of backtrack and say, well, what does insulin do? It's the major hormone that allows you to utilize carbohydrates. And so the implication of this is the more carbohydrate you eat, the more you activate the insulin signaling pathway. And the prediction would be that the faster you age. And I think real data really suggests this model. Now, it flies completely in the face of what we've assumed to be correct. You can walk into any store and find low-fat diet and low-fat products. It turns out that we really believe that the culprit is more carbohydrates. And a recent paper just came out, which is really remarkable, showing analyzing in thousands of humans a fraction of their total calorie intake that is represented by carbohydrates. And they were able to, just by interviewing them and asking, what do you eat? And what they showed in this paper is the all-cause mortality was directly correlated to the amount of carbohydrate that one eats. So the people who ate the least amount of carbohydrate showed the lowest all-cause mortality. Wow. Did they differentiate between refined carbohydrates and, for example, vegetables, which are carbohydrates? They did. They didn't. And I think, you know, this is obviously not all carbohydrates are created equal, but I think... Possibly a confounder. Irrespective, irrespective, total carbohydrate was a very strong predictor. Wow, yeah. But obviously, you know, your total carbohydrate intake is, it's very hard to eat a high amount of carbohydrates that are all sort of a low absorption type of carbohydrate. So typically, the people who eat a lot of carbohydrate will eat a lot of the bad ones as well. Yeah, most people that are eating that are probably eating more of a standard sort of American diet, you know, where it's chips and crackers and cookies. And I think people that are following more like of a Paleolithic type of diet, where they're eating, you know, whole foods and meat and nuts, probably would eat their carbohydrate intake. The bulk would be from vegetables and things like that."

Three meals and three snacks is the worst possible way to eat for longevity

Standard advice of 3 meals + 3 snacks keeps insulin high all day. Restricting eating windows lowers insulin, mTOR, activates autophagy.

"What dietary authorities today are recommending is three meals and three snacks. I think this is the worst possible way that you can possibly eat."