As humans, our cognition and self-awareness create a unique dilemma. Like other animals, we have evolved numerous biological responses that are driven to keep us alive, and much of our interaction with the world is oriented toward survival and avoiding danger. But unlike other animals, we also have the intellectual capacity to recognize that death is inevitable, and we are all operating on limited time, regardless of what we do.
We deal with any resulting existential anxiety in different ways. For example, great painters may create works of art that endure long after they pass away. Yet for most of human history, efforts at literally extending human life beyond its traditional known limits have largely been confined to science fiction. This is because our understanding of the aging process, and how to slow or stop it, has been woefully limited.
The mechanisms that underlie aging are very complicated (as I discussed with Aubrey de Grey ), and longevity research has historically not been taken very seriously. Fortunately, some very smart and motivated individuals are trying to change this.
In this episode of humanOS Radio I talk to Dr. Neil Copes. When Neil was trying to decide what he wanted to study and ultimately do with his life, he immediately recognized he felt there is perhaps nothing more important to study and understand than life extension. Consequently, he has spent the past decade studying aging, focusing on how to slow the various mechanisms that drive this phenomenon.
Beta-Hydroxybutyrate and Aging
To that end, Neil and his colleagues at the University of South Florida have been looking closely at beta-hydroxybutyrate. Beta-hydroxybutyrate is a ketone body that is produced in the liver as an alternative energy source when glucose availability is low, generally when an animal is fasting or on a very low carbohydrate diet. You can now also increase beta-hydroxybutyrate levels by taking beta-hydroxybutyrate supplements (for example, Pruvit, Perfect Keto, Ketosports, or Zhou Nutrition).
We know that caloric restriction prolongs lifespan in many organisms, from yeast to fruit flies to dogs. But it’s hard to deprive yourself of food for much of your life. Researchers like Neil are hopeful that the metabolic changes induced by ketosis might be able to duplicate the increased vitality and longevity that is often seen in caloric restriction studies. An important next step is figuring out whether beta-hydroxybutyrate can substantially increase lifespan in larger animals, like us, the way it appears to act in other animals used in research.
Neil is also CEO of Osiris Green, a company that offers a DNA methylation analysis service, that measures age-related epigenetic changes to estimate the biological age of an individual. You can take advantage of this service by simply sending a saliva sample through the mail.
Listen below to learn more about this emerging science, as well as how you can try to take advantage of it yourself!
Neil Copes - 00:06: There are so many different things that people are working on, so many different treatments so there’s a lot of stuff that has potential, but if you want to do something right now that could help the way you’re aging and extend your life span, there’s nothing better that you can do other than just eat right and exercise.
Kendal Kendrick - 00:24: Human OS. Learn, master, achieve.
Dan Pardi - 00:34: Neil Copes, welcome to Human OS Radio. Thanks for taking some time to join us. Tell us a little bit about yourself.
Neil Copes - 00:39: All right. I actually got my start in what I’m doing about 12 years ago when me and a very close friend of mine were having a conversation essentially about what we wanted to do in our lives. We came to the conclusion that the thing that we wanted to do the most in our lives was essentially to extend our lives. We thought that that would probably be the most important thing that we can work on with our time.
Dan Pardi - 01:04: Totally. You have more time to figure out what you want to do with your life.
Neil Copes - 01:08: That was the thing. We realized that we didn’t have enough time to do potentially everything that we wanted to do. We thought life extension is probably the most important thing that we could focus our efforts on. We thought, “Okay, that’s probably the type of thing that we might need PhDs for.” We literally went out immediately upon that decision and enrolled at the University of South Florida. We got our bachelor’s degrees at USF. We went through the graduate program at USF. We got our PhDs. It took me 10 years total from start to finish and that has been really my main focus the entire time.
01:43: The whole way through I spent my time studying aging in general specifically human aging and we got our degrees. After we graduated, we thought, “Okay, well we could go on and we could be postdoctoral researchers.” Essentially the experience of being a postdoctoral researcher is just sort of extension of graduate school. Generally, the path at that point is you take another five to seven years working as a postdoc in someone else’s lab, doing someone else’s research and then if you’re lucky maybe get a university research job as a professor. Maybe another seven years of doing research for the point of publishing papers in the hopes of getting tenure.
02:22: We thought, “Okay, well that’s a very long track with a lot of uncertainty in it.” So we decided at that point that maybe the better thing to do would be actually to just teach and then see if we could open up a business that would possibly let us do type of research that we’re interested in doing.
Dan Pardi - 02:37: I applaud you for sticking with it and being real.
Neil Copes - 02:41: I think so much of my life now has been spent focused on the fact that I am aging. It really solidifies in my mind how little time I potentially have. So any time I see a track in front of me that “Okay, well I can get maybe to where I want to go possibly in say another seven or eight years or I could just do what I can to jump into it now.” That sort of motivation to just jump into it now.
Dan Pardi - 03:05: The sooner people gain an appreciation and interest in it, the better able they are to manipulate some of the factors that are going to create more clear and present signs of aging doing that preventative daily maintenance that keep your body in good shape longer until some of the more powerful interventions that are created that can really extend lifespan.
Neil Copes - 03:25: Exactly. The best thing we have now actually is just health since there aren’t yet available any dramatic or radical life extension techniques. Just keeping yourself alive and healthy and going until there is a radical life extension technique is really the best strategy for just a daily life.
Dan Pardi - 03:41: It’s really possible to stay young with effort.
Neil Copes - 03:45: It is and right out of high school I got a job working as a framing carpenter building houses. The man who I started working for was 75 years old at the time that he hired me. At 75, he worked just as hard as me and the other people in the crew who were like late teens, early 20s, completely ripped, didn’t have any gray hair. As a matter of fact, I have to say when I first started he was in far better shape than I was. I think I was 18 and he was 75.
Dan Pardi - 04:18: How do I be like that person is when I’m that age?
Neil Copes - 04:21: Yeah. How do I still go out and work like I’m 20 years old when I’m 75?
Dan Pardi - 04:25: Tell me about the range of subject matters that you are interested in?
Neil Copes - 04:30: So the thing with studying aging is that you end up studying just everything in biology in general. There’s still no one clear explanation for exactly what is going on in the human body as we age. As a matter of fact, there are still several hundred currently seriously discussed theories of human aging. So when you start talking about human aging, it is everything from studying the buildup of things like advanced glycation in products and the extracellular matrix around cells. It is studying the way gene expression changes over the course of a person’s life. It’s studying the way your hormones essentially go out of balance as you get older. It’s called hormonal dyscrasia. So you really have to be an expert in the biochemistry aspect of it, the genetics aspects of it, the hormonal developmental. It is a little bit of everything.
Dan Pardi - 05:24: When Aubrey de Grey was on the show, I asked him the question, “Do you think that we will see incremental benefits as we make significant advances in one of the subjects and then synergistic advancement when we are able to address them all together?”
Neil Copes - 05:37: That’s very true. With biology, you have to remember that every single thing is connected. It’s like a carpet or a tapestry. You can’t just pull on one thread without pulling out everything else. So that’s one of the problems even with just taking any type of prescription drug. It’s very hard if not just impossible for a drug to just do one single thing in the human body. Any time you go in and you try to target one single thing in the human body, you always end up affecting a multitude of things oftentimes completely in unpredictable ways.
Dan Pardi - 06:08: That’s why I really like the work that Dale Bredesen is doing in Alzheimer’s disease. He feels that there will never be a drug that satisfactorily addresses Alzheimer’s disease because there’s so many different lifestyle influences that are actually affecting its progression, and we get much better outcomes when we can say, “How do we get people on the right diet, with the right stress management program, right supplementation?” You go down the list and you get them to doing as many things right and as many categories that matter as possible. I think that that’s how we should probably approach all aspects of health and disease.
Neil Copes - 06:37: Oh probably is. Yeah, be healthy to begin with and that’s going to put you in a much position overall.
Dan Pardi - 06:42: So tell me about some of the areas that you are working on specifically?
Neil Copes - 06:45: So currently the primary area that I’m working on is we are developing tests for average consumers to just sort of send in saliva sample or like a buccal cell swab of the cheek and gum area. What we can do currently is we can take that sample and we can isolate DNA from the sample. We can go in and examine the epigenetics of the DNA.
Dan Pardi - 07:14: So explain to the listener what epigenetics means.
Neil Copes - 07:18: So you have your regular genetics which are genes that are heritable, that can be passed on from one cell to another or one generation to another. Then you have what is considered epigenetics. These are essentially heritable modifications to genetics to your genes that can be passed on from cell to cell or person to person potentially. These are things like chemical modifications to the DNA itself specifically chemical modification called methylation which essentially can occur all over the genome. When it is occurring in the promoter region before a gene, it can change the way that gene is expressed.
07:57: You also have things that fall into the category of epigenetics at least depending on exactly how you define the term such as chemical modifications to what are called histones which are proteins that DNA is normally wrapped around inside the nucleus. As you make modifications to the histones, the DNA will either wrap around more tightly or more loosely and that can change the way genes are turned on or turned off essentially.
Dan Pardi - 08:23: So you have these genes in your body but they might be silenced or they might be active because of the way that this epigenetic functioning is influencing the transcription of the genes?
Neil Copes - 08:33: Yes. As a matter of fact, one way that this really strongly manifest itself is when you think about the fact that every cell in your body has all of the same genes. So all of the same DNA every cell but you have all of these different cell types that do different roles in the body. The way say that a cell knows how to be a skin cell as opposed to maybe being a bone cell or being say a liver cell is essentially the epigenetics of the cell. It is the chemical modifications to the DNA itself or to the histones that the DNA is wrapped around. They are essentially turning these genes on or off. It’s the pattern of the on or off that will determine what cell type the cell becomes.
Dan Pardi - 09:19: What is influencing epigenetics?
Neil Copes - 09:22: Normal epigenetics that control say cell type is going to be part of the natural programing of development. So sort of a natural evolutionary program thing. You have a multitude of other factors that can potentially affect the epigenetics of the cells in your body. Environmental factors such as smoking and that can change some of the pattern of epigenetic modifications in your DNA. As time goes on actually and cells develop say damage from oxidative stress or the DNA experiences things like double strand break, you get cell repair. It looks like the repair process itself can sometimes change the epigenetic landscape of the DNA.
10:13: To some extent there’s just a random epigenetic drift too. You have some enzymes that the role in the nucleus is to add methyl groups to DNA and to some extent you can view them as essentially just with time getting bored and they just are able to extend areas of epigenetic modification is a little bit of everything.
Dan Pardi - 10:32: Right. I know it’s a big subject.
Neil Copes - 10:33: It’s a big topic. I ramble. I feel like I could just go on for hours on anything.
Dan Pardi - 10:38: It’s all great. I ask the question that was the distraction from what you were saying. So I interrupted you to give a little bit of a definition about what epigenetics are but you were talking about that in the context of what you do. Continue please.
Neil Copes - 10:51: Well one of the things that people have seen is that just the general process of aging and the way things are changing in the body in general has an epigenetic consequence. Well you’ll see two things happening with time with epigenetics. You will see a large amount of what appear to be just random epigenetic changes that happen throughout the genome. There are also at least 400 different genes that currently that we know of where the promoters of those genes experience very clear, very consistent changes over the course of a person’s lifespan.
11:27: So essentially what we’re doing with the service that we’ve set up is we’re going in and we’re looking at just a few of these genes that are known to experience clear consistent epigenetic changes across a person’s lifespan and we’re going in and based on what we see when we measured the epigenetic state of these genes is we’re able to essentially go in and make an estimate of what the person’s chronological age should be as based on what we see in their DNA.
Dan Pardi - 11:56: So you might have been born in January 1, 1980 and therefore you’re 37 but actually because of the way that you’ve lived and the methylation state that you can see through your buccal swab, you can see if somebody might actually look more like somebody who’s 35 or 42?
Neil Copes - 12:12: Exactly.
Dan Pardi - 12:12: Interesting. What is that business called?
Neil Copes - 12:13: So the business is called Osiris Green Incorporated.
Dan Pardi - 12:17: Where does that name come from?
Neil Copes - 12:18: So the name actually goes all the way back to when my partner and I first got this idea of pursuing lifespan research in general. My friend by the way Dr. Clare-Anne Canfield, I’ve known her for 23 years now. So the name goes back to right about the time that we were coming up with this idea. She read a book by Dr. Michael West called The Immortal Cell. Dr. Michael West is a researcher out in California and has been studying specifically stem cells and their role in aging for quite a while now.
12:54: So he wrote this book The Immortal Cell and there is a chapter in that book called I believe it’s the green face of Osiris. That book was a large amount of the inspiration for motivating us to do what we’re doing. Osiris by the way, Egyptian God of resurrection who in mythology had either a green face representing spring and growth or by some accounts a black face representing the fertile rich soil of the Nile.
Dan Pardi - 13:24: A nice homage to Dr. West.
Neil Copes - 13:26: Yes since he sort of helped us start this whole thing at least inspiration from the book. We thought it would be nice to name the company after the book.
Dan Pardi - 13:33: Yeah. Glad I asked. Okay, so that’s what Osiris Green does. One subject that I know you’re interested in that we have some overlap in is beta-hydroxybutyrate which is a ketone. So let’s talk a little bit about that subject and like before perhaps you can tell the listeners what are ketones, how are they formed in the body and what are the conditions in which they’re formed.
Neil Copes - 13:54: So probably the primary condition that ketones are formed in the body is under conditions of starvation. So your body is experiencing essentially some type of nutrient deprivation and your body will switch over to metabolizing fat. So you get free fatty acids that are released in the bloodstream. They make their way to the liver. In the liver, these fatty acids start to get broken down. It’s through a process called beta-oxidation. As they’re broken down, there’s a chemical byproduct from the breakdown process essentially or it’s the end result of the breakdown process and that’s called acetyl coenzyme A.
14:32: So if your body is doing a large amount of this fatty acid breakdown, your liver starts to build up a large amount of acetyl coenzyme A. So you build up acetyl coenzyme A or acetyl-CoA and you have enzymes in your liver which can essentially start packaging these things together. It will package these molecules into acetoacetate and it will also package them into beta-hydroxybutyrate.
Dan Pardi - 14:55: I was going to … Acetoacetate and beta-hydroxybutyrate, those are ketones?
Neil Copes - 15:00: Exactly. Yes, those are ketones.
Dan Pardi - 15:03: Through this breakdown of fatty acids, we have liver conversion of a metabolite, that packages that metabolite together and produces these ketones?
Neil Copes - 15:13: Yes.
Dan Pardi - 15:14: So from a human health perspective, why are we interested in the production of these packaged metabolites?
Neil Copes - 15:22: Good question. So first of all they act as an alternative fuel source. So let’s say normally the cells in your body are burning a lot of glucose from blood sugar but if say you’re fasting or going through a period of starvation, blood sugar is going to be low but your body can still function as long as these ketones are being produced because many cells in your body can bring these essentially as an alternative fuel and of very strong importance your brain is able to use ketones as an alternative fuel.
Dan Pardi - 15:53: Why is that so important that the brain can use these as fuel?
Neil Copes - 15:56: So your brain is doing the bulk of the glucose consumption at any given time in your body. Your brain is this extremely energy demanding tissue. Actually one of the very first things that’s going to start to happen naturally as your blood sugar dips is your cognition is going to be affected. If you have beta-hydroxybutyrate in you system, you can essentially go through a period of low blood sugar where your brain still has enough fuel to function.
Dan Pardi - 16:26: So when people transition into a ketogenic diet, they tend to feel pretty terrible for a few days before the body starts to produce ketones which then make the brain happy again?
Neil Copes - 16:37: Exactly. When you’re doing this naturally there is a lag. You go through a period of feeling crappy. People generally refer to that as keto flu, that sort of the transition period.
Dan Pardi - 16:47: So I think that ketones are for weight loss and weight management is probably the most popular topic where ketone has been discussed but there’s other topics too that have a whole different orientation around why you would take them in terms of for health. So what is the range of subjects that the subject of ketones is currently being discussed and where there’s interest?
Neil Copes - 17:07: So there are numerous applications for taking ketones. So for one, some people report being able to essentially just think more clearly whenever the ketone level is fairly high in their bloodstream. Another aspect of this is actually from the blood sugar aspect of it. So let’s say you can keep your blood sugar low and you can maintain high ketones enough to where you can continue to function and having low blood sugar is potentially you could view it as an anti-tumor state of the body. Cancer cells are always going to preferentially do glycolysis. They’re always going to preferentially be taking in and breaking down sugar.
17:47: The thing with cancer cells and tumor cells is that they have high rate of cellular division. So these things are growing rapidly. They’re dividing rapidly. Any time cells are growing and dividing, they need to be taking in glucose and breaking it down for byproducts necessary for going through cellular replication. Essentially what it comes down to is that tumor cells are going to be very energy demanding cells. So if you can lower the blood sugar in your body enough to where essentially you’re restricting glucose from cancer cells but still function by having ketones in your bloodstream, you’re putting yourself in this anti-cancer state.
Dan Pardi - 18:26: Some of the theories around this that you need to remain in the state all the time or that you can enter into it periodically or for a little bit every day, what are the thoughts from what you know about how people think about that subject?
Neil Copes - 18:39: So from what I’ve read on the subject, the thought seems to be that just occasional bouts of this are enough to where you’re going to experience some beneficial effects from it. So things like occasional fasting, maybe just one good long fast maybe once a year. Some people do intermittent fasting where instead of going on a multiday fast, they just not eat for half a day or maybe like 20 hours out of the day. It seems like it’s not the type of thing that you have to be in constantly. It’s the type of thing that you can just do occasionally and still reap pretty nice health benefits from.
Dan Pardi - 19:12: We have a course on fasting that will launch soon with Human OS. We talked about that quite a bit and a lot of the questions remain unknown. Can you have a truncated eating window where you only eat your calories between let’s say noon and six? What about a longer periodic fast? Can you take in certain fats without some of the benefits that happen during fasting? Lots of interesting questions, lots of stuff that we have information on. A lot more coming out on a daily but that’s another interesting aspect to it. So lowering blood glucose, starving cancer cells of their fuel source that helps them grow and divide seems to make good sense to me.
Neil Copes - 19:47: Yeah.
Dan Pardi - 19:47: Great! So that’s one area. Why are also people interested in ketones and beta-hydroxybutyrate?
Neil Copes - 19:52: So it seems that even without doing the fasting, just taking exogenous ketones, so just taking these things in as part of your diet, seems to have some health benefits. So it seems to help prevent muscle loss if you’re taking in ketones. It seems to help some people with endurance. I’ve heard report from some people that they say that they feel that they can just operate fine on less sleep if they are taking in ketones as part of their diet. By the way, these are hard to find previously but currently there are supplement suppliers and shake suppliers where you can essentially buy exogenous ketones. You mix them up in a shake and just drink them.
Dan Pardi - 20:29: Yeah that’s an exciting advancement. Do you know how people take them? With the idea of taking in exogenous ketones as some sort of package that you include like you said in a shake then you don’t necessarily live in ketosis to get some of the benefits of having ketones in your body.
Neil Copes - 20:42: Exactly. I believe there are some suppliers now that are supplying these essentially a a ketoester form or it comes as a powdered shake and you just mix it with water and you can drink that throughout the day to keep your ketone body level high.
Dan Pardi - 20:55: Yeah I’m excited about that innovation. I have to admit I did try some of the earlier versions of the exogenous ketones. The worst tasting stuff I’ve ever put in my body.
Neil Copes - 21:05: Yeah same here. The early ones tasted like you were drinking a lethal dose of salt when you’re drinking them. Some of them tasted pretty wretched. I have recently had some of that were honestly pretty good.
Dan Pardi - 21:15: I’ve written actually quite a bit about the effects of ketones particularly beta-hydroxybutyrate on energy regulating pathways within the central nervous system particularly in the arcuate nucleus of the hypothalamus. I won’t go into too much detail but essentially the main idea here is that everybody wants to lose weight as you want to lose it and you want to sustain it but oftentimes that’s not what happens. There’s a certain amount of weight that’s lost and oftentimes within a year the person who lost the weight is right back to where they were.
21:42: There’s no successful definition of what successful weight loss maintenance is but oftentimes it is discussed as the maintenance of a 10% reduction in body weight. That can have real significant health benefits but people oftentimes want much more than that. What is really interesting to me is the work that’s been done that looks at whether or not ketone production can affect what’s called proliferative remodeling of neurons within the central nervous system. So that means that these neurons are reproducing at a faster rate and under the conditions of diet induced obesity particularly in animal models within a lab, you see that the regeneration of these neural tissues reduces to a much reduced rate than somebody that has a healthy brain.
22:20: What I imagine could be happening is that you have the reason why your body will then want to stabilize at a higher set point which might be well above what you would like to have in terms of the amount of stored fat on your body is because you have some sort of imbalance between what’s considered orexigenic signaling and anorexigenic signaling. An easy explanation of that is that one side of the seesaw is promoting you to take in calories and to reduce energy expenditure and the other side is doing the exact opposite.
22:48: You might have some sort of rebalancing with the condition of obesity where the brain then becomes settled at a set point where you’re holding 30, 40, 50 pounds of body fat. So what’s exciting to me is some of the work looking at endogenously produced ketones through dietary manipulation and calorie reduction. You see that you have greater proliferative remodeling of that energy regulating pathways which actually then might mean that you lose weight and you have a better time sustaining that weight loss. That’s really exciting to me. That’s really what we want.
Neil Copes - 23:19: As a matter of fact, I have experimented off and on over the last couple of years with going onto and off again from ketogenic diets. The very first time I went on to extended ketogenic diet, the pounds just shed off of me. I got down to a pretty slim body weight pretty rapidly and your right is the weight that’s easy to maintain and immediately my energy levels went up.
Dan Pardi - 23:42: I go into ketosis a few times a year. I’m excited about these exogenous ketones. I know it’s certainly exploratory and a lot more we need to know about them before you can really apply it therapeutically but it’s exciting times. I think exciting times with gained appreciation for the potential therapeutic uses and the variety of them. What I was so interested to talk with you about today is, why are these also interesting for those interested in effect in aging?
Neil Copes - 24:05: Yes. So besides just the general health consequences which are very positive from all of this, we did do some research several years ago in the lab that I was in where we looked at giving exogenous ketones to a model organism that we were working with. So we’re working with this model organism called Caenorhabditis elegans. It is a little microscopic worm. It has a very short lifespan naturally which makes it easy to work with from a lifespan research perspective, because you can do a lot of experiments very quickly with something that only lives in this case just about three weeks. So we went in and gave exogenous ketones.
24:44: We treated these worms with beta-hydroxybutyrate and saw how that affected how they aged and how long they lived. By doing this treatment, we saw a 20% increase in the mean lifespan of these C. elegans, these microscopic worms. So we went in and started looking at what possible cellular signaling pathways and metabolic pathways were being affected. So we saw a couple of really nice changes going on at the molecular level inside the worms. So we saw that application of beta-hydroxybutyrate was activating two really healthy beneficial signaling pathways.
25:26: One is called the FOXO pathway. Essentially it was activating production of this FOXO transcription factor, transcription factors by the way. Things in cells as it … essentially when they get turned on or activated or expressed, will make their way into the nucleus and on their own then they will change gene expression. They will turn on or turn off potentially additional series of genes to change with the cells is doing overall. FOXO seems to be a transcription factor that is oftentimes seen in research cases where you’re looking at things that produce life span extension. It seems to promote survival and essentially resilience at a cellular level.
26:08: So we saw activation of FOXO as part of this application of beta-hydroxybutyrate. We also saw activation of Nrf2, a transcription factor which is a transcription factor that appears to turn on a lot of antioxidant systems inside of cells. So essentially we’re getting lifespan extension through both of those mechanisms as well as activation of antioxidant capacity.
Dan Pardi - 26:35: I was at a conference a couple of weeks ago in San Diego at a functional medicine conference. Jeffrey Bland who’s the founder of the functional medicine was on stage and he was presenting and he said so many positive things happen with the activation of Nrf2 which we’ll just be spending more time figuring out ways to keep that active and ways to stimulate it but certainly a lot of great things happens for the human body when that pathway is getting sufficient attention.
Neil Copes - 26:57: Yes, absolutely.
Dan Pardi - 26:58: So you’ve got these two powerful systems that are dealing with oxidative stress in various ways, FOXO and Nrf2 and they’re both stimulated by BHB, how?
Neil Copes - 27:08: Well it looks like through two different pathways that overlap a little. So for the FOXO what we saw it appears to be the result of inhibition of what are called histone deacetylase.
Dan Pardi - 27:21: Okay, going back to the epigenetics. Right.
Neil Copes - 27:23: Exactly, the epigenetics. So histone deacetylases are these enzymes that come in and they remove an acetyl group from the histone which then changes the way DNA wraps around the histone changing gene expression. So beta-hydroxybutyrate actually acts naturally as a histone deacetylase inhibitor so just on its own it is potentially changing some gene expression. We saw specifically that it was this histone deacetylase inhibition that was … at least one of the steps that produced the activation of FOXO.
27:56: The other method that we saw that looks like it’s activating these two transcription factors it seems to be through the metabolism of beta-hydroxybutyrate once it’s in the cells and broken down. What it breaks down into will essentially feed into what is called the tricarboxylic acid cycle or the TCA cycle. It seems to be the flow of the breakdown product of BHB through the TCA cycle that can also activate FOXO. In the process by the way, you’re feeding things into the TCA cycle. You’re feeding metabolites in.
28:31: What you’re doing in the process is you are producing NADH which is a metabolite, essentially an electron carrying metabolite which can then feed electrons into what it called the electron transport chain which is the primary way that cells have producing this high energy molecule called adenosine triphosphate or ATP. ATP is really the primary energy molecule of cells. So you’re feeding in BHB. BHB is going to TCA cycle. You’re getting electrons fed into the electron transport chain. The thing is that when you’re feeding electrons into the electron transport chain and you’re producing ATP, one byproduct of that is always reactive oxygen species is that inescapable consequence of the production of ATP.
29:14: So you were feeding this in and what we saw was actually an increase in the production of reactive oxygen species. Most people view that as a bad thing because reactive oxygen species, very reactive molecules. In general, you can just look as the rule of thumb being that reactive molecules in the body are not going to be good. They’re going to cause unwanted chemical reactions and modifications. That’s exactly what antioxidants are designed to protect against reactive oxygen species.
29:44: There is actually a good side to reactive oxygen species that people tend to overlook often is that if you get just a small increase in the production of reactive oxygen species, that will actually trigger a lot of potentially beneficial cell signaling. It looks like it’s actually this increase in reactive oxygen species which is activating Nrf2 which makes sense because Nrf2 is a transcription factor that turns on antioxidant capability. So it’s like you start producing some of these reactive oxygen species, the cell says, “Okay, we need to boost our defensive capability.” So you get an activation of natural cellular antioxidant mechanisms.
Dan Pardi - 30:27: A while ago that really struck me as the better way to address health than to take large volumes of exogenous antioxidants which was very popular a while ago. There’s a paper by Ristow somewhere in the mid-2000s which really turned things on its head. They had is they gave people antioxidants, one group did six weeks of exercise. The other group did the same amount of exercise but with vitamin C and vitamin E. What they found is that there was no improvement in insulin sensitivity in the group that was taking antioxidants.
Neil Copes - 31:00: Yeah, exactly. One of the natural consequences of exercise is your cell start producing an increased burst of reactive oxygen species. So you exercise, you get this ROS so reactive oxygen species burst. It’s sort of the signaling resulting from the reactive oxygen species burst that produces a lot of the beneficial effects of exercise.
Dan Pardi - 31:23: Yeah and a lot of the analogous to the effects of exercise, the stress that exercise provides, the positive stimulation that that provides to the body. You also have xenohormetic compounds from plants that do something very similar. The body perceives them as slightly stressful but in response to that, it increases the production of phase one and two detoxification enzymes that then do a better job keeping you healthy than if you’re trying to manage it from external sources.
Neil Copes - 31:49: The whole concept is usually referred to as hormesis of it. You stress your body a little and that’s enough to trigger your body to strengthen itself, to boost its defensive capability. So a little bit of stress is good. A lot of stress, bad but it’s all about the dosage.
Dan Pardi - 32:03: Very questionable about the influence of lots of exercise on your health versus the right amount regularly.
Neil Copes - 32:11: Exercise is good for you but you do a lot of exercise and you end up just wearing yourself down. It’s all about getting everything right in terms of the dosage.
Dan Pardi - 32:18: Dan Buettner who wrote the book Blue Zones which looks at the longest lived societies on earth had a comment that none of the 30 longest lived societies on the planet exercises we think of it in the United States. All of them however have regular physical activity mixed into daily life.
Neil Copes - 32:34: You look at native populations, tribes of people in the South America and these are people who are living in very natural conditions sort of a little bit closer to probably how humans lived in the Pleistocene and you look at how they are in terms of their health. Oftentimes these people are completely ripped. They will look like world class athletes and you go down there and you look at exactly what they’re doing and it’s not like they’re on any type of exercise regimen or it’s not like they’re working out or anything, they just have constant physical daily activity as part of their daily life. It’s enough to keep them in extraordinary shape.
Dan Pardi - 33:10: That’s a useful diversion. I’ll do a quick summary. Beta-hydroxybutyrate which is this ketone that is produced by packaging acetyl-CoA metabolites in the liver that can then be used by cells, for energy especially in the brain and there’s two mechanisms possibly more but two very interesting ones that seem to have a positive effect on the lifespan extending effects observed in C. elegans or the roundworm, a common model for aging research.
33:36: One of those is the influence of beta-hydroxybutyrate as an HDAC, histone deacetylase inhibitor. It’s inhibiting that process promoting then basically the opposite of that which is histone acetylation. As a result of that, you see increased levels of FOXO activity which has broad widespread effects on oxidative stress in the body.
33:57: Secondly, you have the metabolism of beta-hydroxybutyrate which produces metabolites for the tricyclic acid cycle and those metabolites will also then influence FOXO activity but they’ll also increase through the production of reactive oxygen species in the mitochondria just that little bit of stress is enough to then produce the activity of this Nrf2 pathway that help the body stay strong and healthy. Both of those influences can affect lifespan. Were you able to challenge some of those ideas with knockout models etc.?
Neil Copes - 34:27: Oh yeah absolutely. So the way that we were able to pry apart all these pathways was two things really. It was by extensive use of mutant strains of C. elegans. So C. elegans where say one certain gene was just genetically inactivated. So you go in, you turn off the gene that way sort of permanently in the strain of C. elegans and you’re able to see then whether or not the beta-hydroxybutyrate treatment still has the effect that you’re looking at. So you go in, you turn off the HDAC enzymes. You see if you’re still getting the effect with them just already turned off.
35:02: By the way, also another mutant strain that we used was just a strain of C. elegans that is itself a model for dietary restriction. It has trouble eating. C. elegans have this pharyngeal pump that’s essentially the back of their throat that sort of force pumps food constantly into their system. Certain mutant strains of C. elegans have a defective pharyngeal pump. So they can’t eat as much. They tend to be long lived strains. By the way, these strains of C. elegans which were essentially calorie restricted C. elegans, the effect of beta-hydroxybutyrate treatment had no additional lifespan increase.
Dan Pardi - 35:37: Interesting.
Neil Copes - 35:37: Yeah. So you get sort of a life span increase from calorie restriction. You get a life span increase from beta-hydroxybutyrate. You combine the two, you don’t get any additional lifespan increase suggestive that potentially beta-hydroxybutyrate is working through the same mechanisms that calorie restriction is working through. Other way that we went in and modified the C. elegans to start prying apart different pathways is C. elegans are really good models for doing what is called RNA interference.
Dan Pardi - 36:10: Okay. What’s that?
Neil Copes - 36:10: So RNA interference is this interesting technique that you can do at research setting where essentially you can go in and by … in the case of C. elegans literally just feeding them custom designed double stranded pieces of RNA. If you design the little pieces of double stranded RNA just right, the C. elegans will naturally shut down the expression of certain genes. So extremely easy model for doing this. We essentially went in and for certain genes that we wanted to turn off but we didn’t have easy access to a mutant strain of C. elegans, we just used this RNAi or RNA interference method to turn off gene expression that way.
Dan Pardi - 36:53: So that’s the explanation of what that technique can do. What genes were you targeting and what did you find?
Neil Copes - 36:58: So specifically we did RNAi knockdown of two histone deacetylases and C. elegans that are called just HDA-2 and HDA-3. So knockdown of HDA-2 and HDA-3 extended lifespan in C. elegans in a similar manner as the beta-hydroxybutyrate supplementation. So once again, kind of suggestive.
Dan Pardi - 37:21: If you reduce histone deacetylase activity through this RNAi model, then you’re showing another way in which reducing histone deacetylase which then binds DNA more tightly to the histones preventing transcription of the genes that are there, that also had a negative impact. You didn’t see the extension of lifespan under that influence.
Neil Copes - 37:43: Yeah, exactly.
Dan Pardi - 37:44: All right. So we’ve got an interesting model. It’s been challenged a couple of ways. beta-hdyroxy seems to be a calorie restriction memetic. We know that calorie restriction is to this day still the most powerful influence on extending lifespan and now we’ve got a substance that might be mediating at least part of it by its widespread influence on all these other systems that matter too.
Neil Copes - 38:04: Exactly. Which by the way that brings up a tangent on my part which I always like to point out to people. So I’ve been studying human aging and lifespan extension for quite a long time now and there are so many different things that people are working on, so many different treatments and there’s a lot of stuff that has a lot of potential. When it comes right down to it, if you want to do something right now that could help the way you’re aging and potentially extends your lifespan, there’s nothing better that you can do other than just eat right and exercise. Just cut the number of calories that you’re getting during the day and get a moderate amount of exercise and that’s probably going to be just as effective if not more so than most of what the other things people are trying right now.
Dan Pardi - 38:43: I was at the Buck Institute for a conference on aging not that long ago that was sponsored by SENS, Aubrey de Grey’s foundation, that was the conclusion from some of the keynote speakers as well. There’s legitimate things you can do through diet and exercise that can have a meaningful impact on extending life.
Neil Copes - 38:59: Yeah.
Dan Pardi - 39:00: So maybe a few more years but if you live to the maximum of your lifespan potential and you reduce all the current disease and the disability that comes with it, yeah maybe through the exact application of these, you extend your maximal lifespan by a year or two, but think about all the other life you’ve gained in that timeframe. That’s really exciting and worth it. It’s worth the effort.
Neil Copes - 39:22: Honestly it’s worth it. Just small reduction on average of the caloric intake potentially has quite a big effect.
Dan Pardi - 39:29: What’s next for you? What are you looking at now?
Neil Copes - 39:31: So next on the horizon for us is we’re trying to develop as many more tests as we can do in association with Osiris Green for other aging related parameters. So we have the one up and going where we’re looking at epigenetics, but as I said earlier, aging is an extraordinarily complex process. There are many, many diverse things going on in the body as someone is aging. So we’re interested in seeing how many different biomarkers for some of these changes that we can actually identify in a saliva sample and measure.
40:12: So we’re trying to cook up right now some other myelin saliva type tests that we can do to look for things like signs of immunosenescence. So part of the natural aging and degeneration of the immune system. We’re trying to see if maybe we can identify some biomarkers for things like the accumulation of senescent cells in tissue. Senescent cells normally are cleared by the immune system but as you age, they do tend to build up in the tissue. Senescent cells naturally produce what is called the senescence-associated secretory phenotype which is a mix of different cell signaling molecules, a large number of pro-inflammatory cytokines.
41:00: So since you get this buildup of cells that are secreting very specific things, we’re hoping that maybe we can actually identify some biomarkers that would let us get sort of an indirect estimate of maybe how or to what degree senescent cells are starting to build up in the body. Essentially what we want to do is get as many tests as we can so that people who supply with us samples we can just give them a broad dashboard type of readout of how all the different systems in their body are starting to age.
Dan Pardi - 41:31: It’s a super important component to how I view a real solution for those who care what they can do and that’s my audience. These are people that care about how it’s not that you have to convince them of that, but it’s where do we focus our energy and the opportunity cost of time, where can we get the best bang for the buck, what are the things that have merit, but the idea that you can get deeper insight into what’s really going on in your body provides opportunities for you to potentially address it with therapies that are out there.
41:59: It’s a part of the model that I’ve developed for Human OS which is this four stages. Why should you do something? How do you do it? Are you doing it? Is it working? That, is it working ideas looking at that deeper insight? It’s doing test just like this to understand what’s happening inside you with better fidelity and that can be maybe not always but it can be actionable or it will become actionable soon.
Neil Copes - 42:20: Exactly. If it’s not actionable now, hopefully it is the type of thing that will be soon in the future. It’s wonderful to be healthy. It’s what everyone should be striving to be. You don’t really know that you’re doing anything right unless you go in and you actually measure.
Dan Pardi - 42:35: Yeah, right.
Neil Copes - 42:36: Actually I guess that’s a rule of thumb in science. You don’t know anything until you go and you take a measurement.
Dan Pardi - 42:41: This is so interesting. I could talk to you all day.
Neil Copes - 42:44: Thank you.
Dan Pardi - 42:44: I’d love to have you back on as you develop more tools and papers that help with our cause here that we’re all on. Better insights, better information, so I really appreciate your time.
Neil Copes - 42:55: Any time. This has been fun.
Kendal Kendrick - 42:59: Thanks for listening and come visit us soon at humanos.me.