Transcription
Ryan, welcome to the podcast.
Yeah, thank you so much for having me.
Today we're here with Ryan Smith. Ryan Smith is the founder of True Diagnostic, a certified lab and health data company specializing in epigenetic methylation data. Since starting in 2020, True Diagnostic has created the largest private epigenetic database in the world and algorithms to interpret and predict aging phase, telomere length, inflammation, disease risk, and more. Their pioneering clinical trials investigate the best ways to reverse aging markers through diet, lifestyle, and prescription interventions. True Diagnostic is working in collaboration with the leading universities in health and science, including Duke, Harvard, Yale, and more. And before True Diagnostics, Ryan co-founded Tailor Made Compounding, an advanced peptide formulation company that grew to 80 million in revenue within 3 years. Ryan also consults with pharmacies internationally, sets up pharmacies, develops supplements and cosmetic formulations and is the go-to expert in peptides, aging blocks and novel regenerative therapies. So for people listening, we are literally learning from the person now who brought most peptides into the market as well as third generation biological age tests making a significant impact on the longevity and wellness space. Ryan, does that sound about right? And did I miss something?
No, I think that's perfect. I think it described my journey from peptides to sort of aging and and epigenetics and excited to talk about everything.
Great. So, today I'd like to discuss what are peptides and what's their legal status and what are their benefits and can we use them for anti-aging and longevity and if we have time we can also cover biological age testing. Sounds okay.
Yeah, sounds perfect.
Perfect. So, as I mentioned before, you've been a pioneer in the anti-aging space, which are major innovations in diagnostics and treatment. So, if I got it right, you got into med school, you passed the USMLE step one, a very difficult high stakes exam, and then you left medical school to pursue the biomedical field, specifically peptides. So, how did that come about?
Yeah, you know, uh, my my undergrad in biochemistry was really focused a lot on peptide and protein synthesis. Um, so I was, uh, you know, transfecting E. coli cells with, uh, proteins and plasmids that, uh, then I could express and grow and purify. So I had a lot of protein specific work and was always a little bit interested in this space. Uh, but but when I left med school, I was a little bit disillusioned with healthcare a little bit. Uh, didn't didn't want to just uh keep uh, you know, treating illness in a very formulaic way. Um, and so I was very lucky to uh to meet a business partner of mine and we decided to create a compounding pharmacy that was really focused on new and innovative peptides as drug molecules. Um, and so as you mentioned, we were able to really be the first pharmacy to really start educating in a big way on the products that were out there and bringing them to market.
Right. So that's very interesting. I think there is still a very common misconception that peptides are risky, they are synthetic or they are just for gym bros. So firstly where do you think that comes from and can you also break down how peptides are made and how they are used in health and why they are so beneficial?
Yeah, absolutely. So, so, uh, peptides just generally, I should mention, are, uh, more and more frequently found in approved pharmacological ingredients. You know, improved medications. You know, some of the best examples now, or at least the most common examples are things like the GLP-1s. Um, you know, these are peptide-based molecules, um, which, uh, obviously have some really good effects and helping reverse metabolic dysfunction. But, uh, peptides generally, um, are mimicking the natural infrastructure of our body. We've had peptide signalers um in everything that we do. All of our sort of hormone specific products like growth hormone releasing hormone, luteinizing hormone. Um, all of these things are are peptide signalers within the body. And so, uh, really the the peptides that we know from, uh, popular, uh, usage maybe from some of those gym bros. Um, they're all just mimicking natural products. They're mimicking natural products and the the the ability for the body to do its own sort of natural signaling. Um, over time, some of those peptides have been tweaked and or modified just a little bit to be even better for what we want them to be. That might mean that they have longer half-lives or durations. It might mean they're more specific for certain tissues. It might mean we make them more bioavailable. Uh, even the GLP-1s were once a daily injection, now they're once weekly injections by how we've modified these peptides. And so, the peptides themselves are not, you know, illegal or legal. Uh, they're just sort of formulas or or sequences of amino acids that are mimicking our body's natural signaling. Um, and we can take advantage of that, uh, in a lot of really cool ways. Um, and so, unfortunately, I think a lot of these peptides have had really good effects for a long time but haven't been FDA approved. Things like the thymosin beta 4 or the BPC. These are products which, uh, people have used like those gym bros because they know that they have really good effects but they're not yet, uh, FDA approved. And so they sit in this really, really weird category. Um, what we were trying to do with Tailor Made Compounding is bring that under prescription infrastructure where we'd receive prescriptions from physicians, um, and on a patient-specific basis, um, and then, uh, they'd be able to offer them to their patients and we saw some really, really good results but, you know, the regulatory category of peptides is always changing on a really, a peptide-specific basis.
Right. So from that regulatory standpoint, how does the FDA classify and approve peptides and what does it actually mean for clinicians and consumers when a peptide is FDA approved versus it's not?
Yeah. So whenever we started even Tailor Made, we were doing peptides that were in the various stages of the approval process. That means, you know, really before it is an FDA approved drug. Um, the reason for that is that compounding pharmacies have a little bit more leeway on what they're able to make. Um, that's because, for instance, if someone has an allergy, um, and you can't include a, you know, an off-the-shelf product for them, you have to make an exception to that so that they can actually use the medication. Or if you have a pediatric dose, a really, really small dose that needs to be made for a child, you can't use an off-the-shelf product. And so, compounding pharmacies are given a little bit of leeway. And we were using that leeway to be able to do really interesting non-FDA approved products. Um, and so, uh, but but generally the FDA approval process is a long and arduous one. It takes around $2.3 billion dollars to take a drug from conception, uh, to FDA approval. And so that is a lot of money, uh, that most people wouldn't have. Um, and there are a lot of products that are that are on their way to approval through various approval stages. Uh, what we were really doing is taking ones that were in phase two, you know, clinical studies, already had documented safety, documented use cases, and were on the way to, to sort of FDA approval strategies. So, a lot of peptides we started with, even in the pharmacy, weren't approved at that time, but now are FDA approved. Um, and so, uh, generally, if it's not FDA approved, most people don't use it anymore. But in the compounding space, uh, there's a little bit more leeway, as I mentioned. So, as long as it's not on a certain list of products you can do or products you can't do, um, then usually there's a little bit of flexibility there. Um, and unfortunately, that's sort of what happened to Tailor Made is we grew really, really quick. Uh, but we also unfortunately had the FDA step in and tell us we couldn't compound some of those peptides. That was about now five years ago, which is crazy to believe, but in that time, the regulation around peptides has gotten a lot better and more compounding pharmacies are now back into doing more innovative products.
So given your background and your interest in preventive health and longevity, do you think we'll ever see FDA approved drugs or peptides specifically for anti-aging and disease prevention, not just for treating diagnosed conditions?
You know, that is a great question and I, I, I, I want to say that the answer will be yes. Um, you know, I think we're starting to see some really good trends toward this. Um, you know, one of the biggest trends that I think is most exciting is in the US, there's a dog company called Loyal who's now had the first FDA approved clinical trial for aging or longevity. Um, which is super exciting. It's an IGF-1 blocker, um, that, uh, has been, uh, making sort of a history in how it's regulated and how it's handled by the FDA. And so it gets me excited to see things like that. Unfortunately, um, you know, the, the World Health Organization even recognizes aging as a, a disease classifier with an ICD-10 code. Uh, but in the United States, we do not have that yet. And so, um, you know, I think that unfortunately there hasn't been the framework up until this time to really have a drug approved for preventive health or or to treat the biggest risk factor for every chronic disease, which is aging. Um, but, uh, but I think we're starting to see some trends in the right direction. Uh, there, there's also this idea called, uh, of intrinsic capacity, your ability to recover from certain types of insults. I think that might be one of the first ways we actually get an FDA approved test for aging approved.
Okay. So that's very interesting. We definitely hope that that's going to be the way that's going to be the future that we're going to be preventing more disease than treating them. Um, one more question that I want to ask or clarification about the peptide. So actually the most Googled peptide with the word peptide is collagen peptide. So when people hear peptides maybe they think of collagen peptides, the white powder you stir into your coffee, which is basically a structural supplement. Um, but these are not the same as therapeutic peptides, uh, right? So can you break down the difference between oral peptides like collagen and the injectable or bioactive peptides that we are talking about here?
Yeah, absolutely. So, as I mentioned, you know, our bodies are making all different types of peptides all the time. Um, some of those are are peptides which make collagen. You know, it's the same reason that we have great connective tissue or our skin looks really, uh, great or, you know, all those different things. And and so collagen, um, can be actually broken down into multiple different peptides. And that's actually what we're taking with some of those supplement collagen peptides, is just collagen that's been fragmented into all of its different sequences. Um, and by using those, sometimes they can act as signaling molecules for a lot of things that we really like about collagen, right? Like improving our skin or helping repair from, you know, a shoulder tear or, you know, an Achilles tear in my, uh, my recent experience. Um, and so, uh, so they're they're just sort of a, a mass spectrum of all the different peptides that can be created from the much larger protein of collagen. Um, however, you know, when we're talking about the other peptides, we're taking a very, very much more specific approach. We're talking about individual amino acid sequences that are designed for a particular effect. Um, and those are a lot more specific. Um, sometimes they can be a lot harder to take. You know, they're not as just multiple times per day orally. Um, a lot of these have to be injected because they're not orally bioavailable. But, um, but really we're talking about the same biochemistry, just sequences of amino acids. The difference is just, uh, what those amino acids are and how they're programmed to work, right?
Okay. So, we know that peptides can be incredibly beneficial, but it's like, as we have covered so far, the landscape is a bit messy. So, most people don't know which ones are actually worth paying attention to. So from your perspective, which categories of peptides show the most promise for improving health span and longevity?
Oh, that, that's a hard question too. I think there are a lot of peptides out there that could be on that list. Um, I certainly have a couple I think that are certainly the most exciting for me. Um, to start, I would say that I always like to discuss my favorite, uh, peptide, uh, which is the SS31. Um, this is a mitochondrial peptide which improves mitochondrial function. Um, and as most people know, uh, they've probably heard, you know, the mitochondria, uh, uh, is the powerhouse of the cell. Um, and, uh, and because it, it, it really creates the power for everything that we do, its importance in every cell can't be understated. And so, if you're improving that process, you can improve every different type of of function, uh, within the body. The, the studies on SS31 with aging are really, really impressive. And they, there's studies in everything from Alzheimer's to metabolic disease to, you know, repair and recovery of injuries. Um, and so it's a one product that can do quite a lot, right?
So how do the mitochondrial peptides actually work? Moti is another one, right? The mitochondrial, quite popular one. What do they do mechanistically in the mitochondria to improve their functioning there?
So, uh, the mitochondrial peptides have very different, um, methods of root of action, I should say. Um, you know, my favorite in the SS31, um, what it's actually doing is as we get older, um, we have a mitochondrial membrane that has two parts. Uh, you've probably seen this in the classic drawings of mitochondria. We have the outer membrane, but on the inside, you have an inner membrane that's really curved. Um, and and, uh, that curvature in the inner membrane, um, unfortunately, as we get older, starts to really get farther and farther away. So it's like a little bit like a, a t-shirt you wash too many times where the neck starts stretching out. Um, that's essentially what happens. But as that happens, all of our electron transport chain starts to get farther away from each other. Um, and as they get farther away, energy is just less efficiently created. Um, and so it's a little bit like, you know, if you, if you have to hand someone, it's very, uh, you know, a product, it's very, very easy. But if you have to, you know, go 5 feet, it becomes more and more, uh, inefficient over time. And so what happens with SS31 is it restructures that inner membrane to be very curved and tight. Um, and that improves all of our energy production. Um, and it just improves mitochondria efficiency. So it's like, uh, uh, just improving the efficiency of, of the biggest power creation mechanism we have. Um, and so as a result, it improves almost everything. Um, so that's why it's one of my favorites. And, um, with the mitochondrial peptides, it's, there is no like clear sort of, um, how would I put it? So if someone has obesity or is overweight, it's kind of clear you need to lose fat and you need a fat loss peptide, for example, simplistically. Um, or if you can't sleep, some sleep peptide. But with mitochondria, it's sort of like it has so, so many benefits. And I think most people are fatigued. So, do you think this is a peptide that would suit most people? Um, or is there some specific type of a person or a target audience or target user that that would be the most beneficial for?
Yeah. So, so, uh, because the thing that SS31 is fixing is is really a result of age and a result of oxidation. Um, the older you are, generally the better candidate you are for the improvements found with that product. And so, it really does help everyone. And and, uh, as I mentioned, if you look in the literature, that it's almost irregardless of of medical condition, we see improvements. Um, and and so that's really the why I think it's the most exciting is that it works for everyone, has very, very little, uh, downside, almost no side effects, um, and can help almost any process within the body. And so, um, so for those reasons, it's one of my favorites. Uh, you know, the MSC is is another one, obviously, that's a mitochondrial peptide. Um, you know, interestingly enough, we have two genomes in our body, right? We have our, our genome, but our mitochondria also have their own genome. Um, which is really, really interesting. And they've sort of co-evolved with us to be the energy producers of the cell. Uh, but one of the genes that they actually have in there creates the peptide, the MSC. Um, which increases basically energy production. Um, and, uh, and so it is also a way to, you know, help, uh, it increases AMPK, which is sort of that master regulator of, of energy. Um, and, and basically increases the mitochondria workload. And so it's another thing that can help improve the mitochondria. Um, generally though, I'm not as big a fan of MSC. A lot of people, uh, are always surprised I think when I say this because it's so popular out there and we brought it to market. Um, but unfortunately, I think with the MSC, there, um, you'd have to use it at such high doses, uh, for it to be really, really effective that it becomes really cost prohibitive. Um, so I, I certainly love the mechanism. Um, I think it's a great product, but I think that in practicality, it becomes a little bit less efficacious because you have to do it at such high dosing, right?
And have you used both of them?
So, um, I'm actually not a user of, uh, of the, the MSC anymore. I actually have other peptide or, or now small molecule products that I really like instead for that. Um, uh, but, but I use the SS31 frequently. Um, and I will use that at about 5 milligrams twice a week. Sometimes people will do up to 10 milligrams twice a week. Um, and the clinical studies have been up to 40 milligrams per day in really, um, you know, harsh conditions. Um, but I think 5 milligrams twice per week is really effective.
So you also mentioned some other peptides that you are very excited about and, can you share something about these peptides?
Yeah, definitely. So, um, you know, I, I, if you don't mind, I want to take a little bit of a step back and talk about peptides versus, uh, you know, the other most common type of drug, uh, which is a small molecule. Um, you know, peptides are amino acid sequences sort of put together piece by piece. And usually they say that it's a peptide if it's under, you know, either 40 or 50 amino acids. You usually anything above that in size is called a protein. Um, and the small molecules, uh, they are other drugs that that are also meant, and oftentimes can hit the same receptor. So they can have the same, uh, mechanism of action. Um, but usually they have a couple benefits that peptides don't. Mainly, they can be more orally bioavailable. Um, and they also usually have longer half-lives. Um, and so sometimes, uh, there are products that that started out as as peptide products, but then the mechanism of action looked much better as a small molecule product. Um, and, uh, one of the products I'm really, really excited about now is called the OS01, or, you know, also called ATX304. Um, it's a product which, like MSC, stimulates the mitochondria by activating AMPK. Um, so it's sort of like exercise in a pill. It is, uh, sort of the same types of, uh, molecular signaling you'd get if you did a lot of exercise. U and this is a product that I'm really excited about now. Now, and although it's not a peptide, it's a small molecule, it has a lot of the same actions as what we would expect MSC to do, right?
That was very interesting actually. You linked me some of the studies and some of the, um, information about these small molecules. So it activates AMPK independently of the body's traditional AMPK signals, as you mentioned. Can you explain or walk us through the significance of this AMPK pathway for longevity?
Yeah, certainly. So, so this is, uh, you know, the, the AMPK pathway is sort of a master energy regulator. Um, and so it, it generally whenever we have low levels of ATP, right, the things that are made in that mitochondria, um, AMPK is stimulated. Um, and generally when AMPK is turned on, there are three major things that happen. The first is we, uh, improve glucose metabolism. So our glucose gets, uh, taken into our cells a little bit easier, get out of our bloodstream. Um, we also increase lipid metabolism. So we start to break down fat. Um, so we do what we call beta oxidation and lipolysis. Um, and then lastly, we increase mitochondrial metabolism. So we increase oxidative metabolism, we increase mitophagy and autophagy, which improves our mitochondria. Um, and so for all, all of these three reasons, basically you can think of it as, as just what exactly happens with exercise. We start using our glucose, breaking down fat, improving our mitochondria, production of energy so that it can supply that energy to the body. And so, uh, that's really what AMPK is meant to do. It's really that master regulator of things like exercise, right?
And so, just to sum it up, these small molecules like ATX304 basically mimic the effects of exercise or calorie restriction without actually doing those things.
Yeah, exactly. And, and, you know, in some of the early mouse trials, they saw that, uh, 95% of all the weight that was lost in the clinical trials were of fat mass. Um, and so, uh, one of the other really cool things about this, this small molecule, the OS01, is that in addition to just improving, you know, the ability to break down fat and, and to handle glucose, we also have a lot of other effects that are really, really positive. Uh, particularly, we improve muscle. Um, and that's something that oftentimes I think the GLP-1s are very, very popular, but they also come with some muscle wasting side effects where you tend to lose muscle as well. And the AMPK activator is actually able to stimulate muscle growth and muscle function, which makes it very, very unique in terms of mechanism of action. Um, and then lastly, you know, one of my favorite parts about it too is it also inhibits mTOR, which is, uh, something we see with things like rapamycin, for instance, which are these, these probably classical and really well-validated, uh, longevity treatment interventions. And so all three mechanisms sound great for aging. We improve our muscle mass so we're less frail. We're less sarcopenic. Uh, we're, we're getting rid of all of our fat mass, which is, uh, sometimes really detrimental to that aging process and can cause a lot of inflammation, and we're inhibiting mTOR, which has been shown in multiple animal species to have longevity benefits. So for all of those reasons, I think it's both a, a performance, uh, medication, which is really exciting, but also doubles as a product that's great for longevity, right?
So, if I understood correctly, these work a bit differently than, so some people use like berberine or metformin for tissue-specific activation, right? And this is more of a systemic one.
Yeah, exactly. You know, it really goes to the strength as well, uh, of AMPK activation. Um, and, and, you know, uh, uh, unfortunately, some things like berberine have some negative side effects, like it actually inhibits mitochondrial respiration through, uh, targeting the mitochondrial complex one, a little bit like metformin, for instance. Um, and so sometimes, uh, you know, the, even though it is stimulating AMPK, it might have some negative effects to the other pathways we talked about, particularly like mitochondrial function. Um, and so sometimes people can take things like metformin, um, and actually have performance decreases or rapamycin and have performance decreases because, uh, of some of the pathways involved. But with OS01, you're getting the performance increases while still getting all of that mechanism of action.
Right. Okay. That's very interesting. So I was thinking when you were discussing about the benefits of this, uh, OS01 peptide or the small molecule, is that could it be used for someone who is very sensitive to the effects of calorie restriction or exercise even? So for example, I had a discussion with Dr. Matt Cabralin, who is, um, proficient and eminent and very known in the longevity space, especially longevity nutrition and the calorie restriction studies, and he told me that when female rats are put into prolonged calorie-restricted diet, they actually lose all their reproductive activity. We also know many people who, you know, go too far with their calorie restriction or exercise, especially young women, and they start getting low hormones and, you know, no ovulation anymore, menstrual cycle messed up. So maybe this could be something that could support those benefits without bringing your body or taking your body into that overdrive.
Yeah, absolutely. Yeah. No, certainly, you know, um, caloric restriction is one of those longevity pathways because it sort of conserves energy and, and, and sometimes if you don't have enough nutrition, that can be a hard thing to do. Uh, but, but imagine this is having, you know, really optimal nutrition but still stimulating the metabolic pathways to have the best of metabolic function while also, you know, reducing inflammation by improving your muscle mass. Um, so, so it has, uh, basically a really unique mechanism that helps and, uh, inhibits the things we also want. Um, and so I think it can get around some of those restrictions. I mean, ultimately, I think, uh, you know, the amount of mTOR inhibition does sort of relate to caloric intake, but, but there are ways to to maybe, uh, help affect that that spectrum, uh, with dietary supplements or, or small molecules like this. And I think that the OS01 is a really good example of that.
Right. And, what if someone's already quite healthy and, um, exercising and intermittent fasting? Can peptides still provide additional benefits?
Oh, definitely. Um, you know, uh, we've talked about with OS01 its ability to, you know, uh, improve fat loss and improve mitochondria, but it can also do things like increasing autophagy, right? Like our ability to break down, you know, products. Uh, you know, spermidine is also talked about this way. Um, but, but being able to, uh, to to break down products which we don't want to stay around is another benefit. Um, and again, the OS01 can do that. But the peptides themselves are are really exciting because they're very, very specific in mechanism of action. Um, and so we can really, uh, be very, uh, precise about what we're trying to change within the body. Um, it's one of their, their best features is that they're very, very precise. They usually are very short-lived, but we can be generally very confident about what they're doing and the side effect profile is so low. So I think the peptides are certainly ways that we can, uh, um, choose what we really want to happen for the best and most optimal thing for our bodies.
Right. Well, that sounds very exciting. Uh, what's the current development status of this OS01? Are we still in early stage research or is it close to real-world use?
It's at, it's past now its phase two clinical trials, um, and moving on and so I think hopefully we'll see it, uh, in the real-world application here very, very soon. Um, um, but, but I'm certainly a big fan of the mechanism and I think that there are certainly other drugs like this that are coming out. Um, you know, new molecules of, uh, uh, designed a little bit better than rapamycin are on their way for mTOR inhibition. I think, uh, drug discovery and longevity is actually better off right now than it's ever been before.
So what is it actually researched for or what are the clinical trials concerning what it will potentially be FDA approved for?
Yeah. Well, that's, uh, goes back to, I think, one of our first topics, which is that the FDA does not have aging approved, uh, you know, end outcomes for these clinical trials, which is again, I'm hopefully going to change in these next few years with definitions like intrinsic capacity. Um, but right now, uh, these drugs that might have really great longevity benefits have to go for approval in something else. Um, and so the OS01 in particular, that one is headed toward approval for metabolic disease. Um, again, helping people, uh, lose some of that unhealthy fat while still keeping on muscle mass. Um, and so I think that if it's going to be approved, it should be for type two diabetes or, or metabolic disease, right?
Well, I mean, starting with that is going to be a major impact and it's going to make a major impact for people's health in general. I believe most people have some sort of metabolic disorder or at least overweight or obesity statistically globally, almost at least in the US and Europe. So it is definitely needed. Um, and actually talking about this obesity and chronic inflammation, these are major drivers of disease and we've seen like an explosion in fat loss peptides and growth hormone peptides like tesamorelin and CJC-1295, ipamorelin, semaglutide. So what kind of biological shifts can these peptides accelerate and do you think these can also be beneficial for longevity?
Yeah, you know, um, I, I'll start maybe with the growth hormone secrets because these are actually, you know, pretty controversial in terms of their impact on longevity. Um, you know, uh, often times we know that, uh, the higher the IGF-1 and the higher the growth hormone level, generally the shorter the lifespan, um, is what we've seen in a lot of correlated studies. And so, um, that can obviously worry, I think, a lot of people. Um, and that's also why the mechanism of action I talked about earlier for the dog aging, uh, drug is an IGF-1 blocker, actually blocks the effects of IGF-1. Um, and so, uh, with that being said, a lot of people still love the growth hormone secretagogues because of how they feel when they're on it. Um, you know, they have things like improved deep sleep. Um, they have things like, um, you know, increased repair and recovery, so they're not feeling as sore. Um, and, and for some people who have growth hormone deficiency, they really start to lose a lot of weight, particularly some of that bad weight like the visceral adipose tissue that surrounds our organs and is really dangerous. Um, and so growth hormone might have some significant performance increases, but it might have an overall detriment to the overall longevity. And so, so balancing this idea between health span and lifespan, um, is a difficult one. And I think it brings up one of the biggest problems that we have right now, um, just in in longevity medicine, is if we're really optimizing for health span or lifespan. I think growth hormone has the ability to maybe do both. Um, I think depending on how you use it. Um, one of the other things that is really exciting about growth hormone secretagogues is the ability to improve the immune system, to particularly, you know, regenerate the thymus, which is sort of that immune organ that shrinks as we get older. Um, and one of the reasons why, you know, older individuals get vaccines or, or, you know, are more likely to get sick. Um, and so I think that growth hormone certainly has its longevity or health specific benefits, but it might not be something we want to use all the time, um, in, in our longevity journeys.
All right. Um, you mentioned that the visceral fat, which is a major problem and it's a risk factor for many things such as non-alcoholic fatty liver disease. Can some peptides target visceral fat per se?
Yeah. Well, certainly if you have a growth hormone deficiency, the growth hormone secrets will absolutely target visceral fat. Um, and that's exactly why the tesamorelin was approved for AIDS lipodystrophy. Um, you know, in HIV and AIDS, some of the, the constellation of symptoms from, you know, both the disease process as well as some of the medications that they take, can actually build up that visceral adipose tissue. Um, and, and so in, in the case of, you know, helping with that growth hormone deficiency, once it's corrected, it can significantly lower that visceral adipose tissue. Um, and so growth hormone secrets are probably the most well-documented. Things like tesamorelin, you know, on average have an IGF-1 increase of 181 points, which is a massive increase. Um, they reduce visceral adipose tissue, they reduce subcutaneous adipose tissue, and they improve things like carotid media thickness, which is sort of a biomarker for cardiovascular disease. And so I think out of all of those that are reducing, um, the best mechanism for people who are growth hormone deficient is certainly with those growth hormone secrets. Um, but, but a lot of the other peptides we've talked about also decrease visceral adipose tissue. Um, so obviously the GLP-1s, the liraglutide, the semaglutide, the tirzepatide, all of those are really effective at reversing visceral adipose tissue and, and also even just, uh, things like the, uh, the OS01 that we already talked about can reduce visceral adipose tissue as well.
Which one do you think is the best growth hormone peptide?
Um, oh, it's a hard question. Um, you know, I, I would say tesamorelin, um, just because of its relative strength. It has massive increases in IGF-1, um, and, you know, it is FDA approved. However, if you want more constant stimulation, um, you know, maybe more frequently, but not as powerful, maybe you're a little bit worried about some of the big IGF-1 increases, then, uh, I would recommend at that point, uh, the Mod GRF, that 29 amino acid that's usually paired with the growth hormone peptide, like ipamorelin, right?
Which one is better for longevity, to have a milder effect that is more frequent or have one strong pulse every now and then?
Oh, I, I would say that that is debatable, but I, if I probably had to guess, I would say that you would want to mimic your natural growth hormone secretion cycles, which are really, you know, having the largest peak right after we go to bed. Um, and so taking those some of those growth hormone secrets at nighttime, um, like the Mod GRF and the ipamorelin can mimic that natural circadian rhythm and restore any growth hormone deficiency that we might have. Um, and, and so, uh, you know, I wouldn't recommend growth hormone secretagogues for everyone, but if you're certainly growth hormone deficient, you will have by far the most benefits. Um, and if you are growth hormone deficient, trying to mimic the body's natural rhythms are probably the best thing to do.
What about you mentioned also the semaglutide and that category of peptides. What do those specifically mechanistically do in the body?
Yeah, so they have a lot of different, um, effects, uh, within the body. Um, you know, the, the first products that came out were relatively endogenous things called like lixisenatide, for example. Um, uh, but, but these are known as GLP-1s. And so GLP-1 is a hormone that's produced in the small intestine that stimulates insulin secretion and glucagon secretion. Um, and so what generally happens is that it improves our response to insulin. Um, so when insulin is in the body, um, you know, we, we can then drive it out of our bloodstream and into the muscles, which then causes our body to to go through pathways to sort of burn energy. Um, and so, uh, so that is sort of the mechanism, but GLP-1s also, um, have some really unique mechanisms we're starting to learn as well. Even just last week, uh, they published an article showing that GLP-1s are able to even hit dopamine specific mechanisms. So that people who eat just for, uh, food and feeding behavior, right? The, the way that it makes them feel, are no longer eating for those, those reasons. And so I think that, uh, you know, as, as much and as, as exciting as the glucagon insulin secretion is, I think there are also mechanisms, uh, to sort of neurological functions that are also really exciting as well. So we can increase things like neuropeptide Y or, you know, uh, or sorry, inhibit neuropeptide Y, which increases satiety, and then also, you know, stimulates the POMC pathway, which reduces energy intake, which reduces hunger. So I think that not just the, the metabolic mechanisms, but even the neurochemical mechanisms are super exciting there.
Yeah, there was a lot of things that, um, I didn't know about. So thanks for sharing that. What about then the immune modulating peptides? So immune boosting peptides and also regenerative peptides, mainly like BPC and thymosin beta 4. What is the specific benefit of these kinds of peptides?
Yeah, definitely. So, um, I'll start with the immune because probably my second favorite peptide right after the SS31 is the thymosin alpha 1. Um, you know, the thymosin alpha 1 even had an orphan, uh, FDA drug designation, um, you know, early in 2013 because, uh, uh, it was being given as an adjuvant with, uh, other types of, of drugs within, uh, melanoma to help have our immune system fight cancer cells. Um, and so I love the thymosin alpha because it's an endogenous product. It's something that our body already makes, um, to help increase the immune system. Um, so one of my favorite anecdotes about thymosin alpha 1 is that, um, it's one, its production is massively increased during pregnancy for women, um, in order to help protect the fetus and protect their own immune system. Um, and so, but with that being said, you know, it has lots of different immune modulatory interactions. Um, it sort of, you know, promotes T helper cells, it promotes cytotoxic T cells. It increases B cells and antibody production. It's just an immune stimulation product across the board. Um, and with that, you know, it can help with cancer, it can help with recovering from viral illnesses, it can help reduce senescence, even, some of these other longevity pathways. And so, uh, by just activating the immune system, but not making it too active, where it can be harmful, I think it's, it's a really, really amazing peptide with great safety and tons of tons of benefit.
Uh, how does that compare to the thymosin beta 4?
Yeah, unfortunately, they don't compare at all. Um, other than being, you know, relatively similar in amino acid size, um, they are, are, are remarkably different, um, in their mechanism of action. Um, and so the thymosin beta 4 is certainly more of a repair and recovery product than it is, uh, an immune modulatory product. And so most people know it as, you know, with terms like TB500, because it's been used in, in the sports performance world for a long time to help with soft tissue repair and recovery. Um, so people who are getting out of surgery, people who are working out really, really hard. Um, you know, it is a product that that can help with with all of those repair and recovery functions. Um, and as a result, uh, is, is, is often considered, uh, with some more of those gym bro type of, uh, of usage.
Right. So, if I go jump back a little bit then to the immunity category, is there anything else that could maybe counteract some of the inflammaging that everyone's talking about at the moment?
You know, I, I think that, um, nothing nearly as, as broad-scale and direct as the thymosin alpha 1. Um, I, I know that, you know, if people are going through individual viral, um, illnesses or things of that nature, I think that there might be other products that I might suggest. You know, one of the big categories, one of the biggest categories in peptides right now is antimicrobial peptides. Um, you know, peptides that can help, uh, reduce bacterial loads, etc. Um, but, but generally, I think that thymosin alpha is the one that's by far the best.
All right. Um, okay, then I'll jump back to the regenerative, the thymosin beta 4, and I guess this is commonly used together with BPC 157. Um, what do you think about these peptides for someone who is, um, trying to improve their longevity?
Yeah, you know, I, I think that the, the, the BPC and thymosin beta 4 are amazing peptides, uh, that have plenty of clinical uses. However, I don't know that they're, uh, I would say I put them in the longevity category per se. Um, you know, I think that they're mainly peptides that I would use for, for, uh, I would say illness-specific effects. Uh, so obviously the thymosin beta 4, as we talked about, can help repair soft tissue. Um, you know, it's being really researched to help, uh, repair sort of the cornea and the eyes, which is probably going to get FDA approved with, um, but it also, you know, has, uh, ability to help with hair growth, angiogenesis, promotes wound healing, but it's also very anti-inflammatory, so it decreases all those inflammatory cytokines. Um, so, so it's really good in specific use cases like recovery from surgery or an injury, as I mentioned, I just tore my Achilles and think beta 4 was fundamental in that repair and recovery. Um, however, I don't think it's something that you, you want to use daily, um, necessarily for longevity. I think there are probably other compounds that I would say are, are, are more likely to help on a daily basis.
Right. What, what are these other compounds? The ones that we talked about before.
Yeah, certainly some of those. You know, I, I also tend to be a big fan of, uh, of other mechanisms. Uh, you know, there's a, a really famous trial called the ITP trial at the University of Michigan where they're trying out some of these compounds. Matt probably talked about it on his podcast as well, but there are some products there that I think are really exciting. Um, again, other products which have been used to treat metabolic disease like the SGLT2 inhibitors. These are sodium-glucose cotransporter inhibitors that help you just basically pee out your glucose, your extra glucose. Um, and they've been shown to have some longevity benefits in that ITP trial, but I think that they also, you know, help reduce senescence, improve kidney function, improve metabolic function. I'm, I'm very excited for some of those products as well.
Well, that's one of the products I'll take on a daily basis as well. So, you mentioned several times, like, um, this peptide is good for daily basis, this I wouldn't use on a daily basis. How much do the peptide protocols differ? Can you use peptides indefinitely on a daily basis or do you always need to take breaks?
You do not always need to take breaks. I think there are some peptides which you can take forever. Uh, SS31 included. Uh, even things like the BPC, you know, I think if you're getting benefit, uh, you can certainly keep using them. Um, and, but, but there are some that need to be cycled and usually those are the products which are hormonal in nature. Um, you know, products that are acting at signaling on a really large scale, because our body has adaptation mechanisms to that as well. So if we start simulating things that are a little bit too high, our body will naturally downregulate. Um, and, and so, so anything that would be a hormone-specific peptide product, that's mimicking those natural products like the growth hormone secrets, or even things like the kisspeptin, which might be increasing, you know, LH or FSH, then, then we want to probably cycle those a little bit more, right?
Okay. Um, you also previously mentioned hair growth. I think it was thymosin beta 4. Um, is there any other? This is actually a big thing that also many of my listeners ask about. What can we do to regrow out our hair and also enhance skin?
Yeah. So, so hair is, hair is very interesting. Um, you know, uh, uh, generally there are many different ways that we can lose our hair. Um, and that's going to be differing.
Uh, by by, you know who you are, and in that process. But for men, um, which is obviously the most common type of hair loss, the male pattern baldness that we talk about, is because, uh, DHT sort of, that the testosterone gets converted to DHT. DHT causes hair follicle miniaturization. Um, so, so slowly those hair follicles start to just, uh, shrink and then ultimately they, they die. Um, and so, uh, there are some really exciting peptide products which can actually directly impact that process. Um, my favorite of which is a combination of a peptide and a small molecule. Uh, the peptide is called PTD DBM. Um, and, uh, and what it does is it sort of goes and, and, um, inhibits the inhibitor of this process. I sort of, uh, you know, if if we're talking about hair growth as a car, um, this sort of cuts the brakes, uh, it sort of prevents the, the, the process of hair growth from slowing down. Um, but we also want to step on the gas, right? We also want to activate it, and for that we use valproic acid. Um, and that combo is really, really effective topically, uh, for, uh, improving DHT related hair loss. It's one of my favorite combos. Um, although there are other products that have different mechanisms that also help with hair loss.
Right. Okay. Okay. What are these?
Yeah. So, probably the, the two other most common products that are peptide products used for, for hair regeneration are going to be the GHKCU, um, uh, and the, the thyulin, um, uh, product, another sort of thymus derived product. They both have, you know, very different mechanisms of action. Um, but with that being said, uh, you know, the GHKCU is, is really extending the hair cycle, um, so to speak. Uh, so it is, uh, particularly prolonging that antigen phase of hair growth. Um, and, uh, so it's making sure that we're retaining more of our hair follicles. And so, uh, because of that mechanism of action, it's actually good for almost any type of hair loss, uh, male pattern baldness included, but also women who might be losing their hair or having hair thinning with age, right? So it could be beneficial for someone who is going through perimenopause or menopause. We, many, many women get hair loss at that, that time, that hormonal shift. And, and the, the thyuline is, is almost the exact same. It's just, um, in increasing that antigen phase of active hair growth. Um, and by doing that can make the hair thicker. Um, certainly, um, and so usually those products, the GHK and the thulin are both combined as well.
Right. So the GHK, can that be beneficial for hair growth and skin? Um, is it only beneficial topically or would you use injections as well?
There, there. Um, so theoretically, I, I would say I would use injections. Uh, you know, the GHK has a lot of other benefits than just hair. Um, you know, it has anti-cancer properties where it can suppress some of the genes involved in metastasis or tumor growth. Um, it can help with wound healing. It can help with, you know, sort of antioxidant effects. But most people know it for its ability to help with skin. Um, and, uh, you know, that, that is used topically, uh, to help, you know, stimulate the, the synthesis of collagen and elastin and, uh, glycosaminoglycans and reduce the, the turnover with metalloproteinases. Um, and so it has a lot of longevity skin specific benefits, and so there are reasons it should be used, uh, or it could be used systemically. Um, however, in my experience, um, I would say that it's one of those products that's really hard to inject, um, to get that formula right. Uh, often times it can cause a lot of bruising and redness. Um, and so, uh, I, I think that that generally topical is where you're going to see the most effect.
Right. So, how does that work? You just kind of rub it into your scalp and maybe microneedle or something.
Yeah. You know, it's, it's relatively bioavailable, right? It's a really small peptide. Um, it's just three amino acids. Um, and so it, it's relatively easy to get into the skin and into the cell, um, to act as a signaling molecule. And so, um, you know, it's actually, if you look in any cosmetic over the cream, uh, counter. So go to any drugstore and pick up a beauty brand, you'll usually see, you know, copper tripeptide or GHK, uh, or, you know, it's in almost all of these different products already. Um, so it's been widely recognized by the cosmetic industry as a, as a great product for many years. Um, and so topically, you can apply it to your face, you can have a serum and apply it to your scalp. Uh, but it has relatively good bioavailability, right?
All right. Exciting. So what is your peptide protocol? What do you use?
You know, uh, I always experiment. So I'm always, uh, trying new things. Um, you know, most recently, as I mentioned, I did tear my Achilles. So I've been doing a lot of repair and recovery. I've been doing things to, to help with, you know, protein synthesis, doing things to help like the, the BPC and the thymus and beta 4. Definitely doing the OS1 along with a multitude of other things. As I mentioned, I'm a big fan of the SGLT2s and, and the SS31. Um, so my, my, my protocol can be, um, quite complex, but I think that if I had to pick some of the things that I, I just couldn't do without, it would certainly be the SS31. Um, it would be the canagliflozin, uh, or the empagliflozin, is SG, LT2 inhibitors, um, and, uh, and, and really again, I, I will do like a five milligram daily tidal. I'm a big fan of some of the mechanisms of, of, you know, increasing, uh, VEGF and some of that vasodilation. Um, so those are, you know, not just peptides, but generally, uh, the major products that I will use on a daily basis.
Great. Awesome. Um, okay, let's discuss biological age for, for a little bit. Uh, we have a little bit more time. So most people will know their cholesterol levels or fasting glucose, but not their biological age. So with your work at True Diagnostic, you've been focusing on this concept, per se, and speed of aging and even reversing biological age. So could you break down what biological age actually means? What is speed of aging, and how these organ-specific clocks tie into disease risk? Maybe we go into the organ-specific clocks in the next question, starting with the speed of aging and biological age. What are those?
Yeah, definitely. So, so, uh, as you mentioned, people might know their cardiovascular risk factors, uh, but sometimes they're ignoring the biggest risk factor period, the one that makes the most difference, and that is the biological aging process. You know, um, uh, aging dwarfs even risk factors like smoking and obesity in terms of the relative risk and, and how it makes us likely to get sick. Um, and so if you're doing one thing to, to really measure your preventative health capability, I think it really is biologic age. Um, and, uh, and so we know that this has been important for years. And, and there have been really crude measurements to predict someone's biological age. Like your chronological age plus one pack, uh, one year for every pack per day you smoke. Really crude measurements. Um, but in recent years, we've developed molecular mechanisms to measure this process. Um, and, uh, and that's why we can sort of differentiate now between this relatively arbitrary process of, you know, how many times you've gone around the sun, uh, versus, you know, your, your body's age or, or how likely you are to develop some of these negative outcomes of aging. Um, and so that's the process that we do here at True Diagnostic, and, and it really started for me because, uh, we were using a lot of these peptides for longevity, as you mentioned, we were using the growth hormone secretagogues, we were using peptides like epitalon, um, you know, we were using, uh, senolytics even at that time, NAD products, um, and trying to figure out what works. And unfortunately, we don't have 40 years to try and figure out an answer to this, right? So, we can't wait 40 years to see if people are, um, living longer or, or dying more frequently due to each of these different drugs. And so, um, I was really excited to find surrogates for this process. And, and these biological age clocks really started, um, uh, the first ever clinical trial happened in in 2019. Um, and that was the, the one that for me got me really excited about being able to use these to test things like the peptides for their, their longevity benefits. Um, and so, uh, so starting in that time, uh, we created True Diagnostic, which now has created multiple ways to measure this process. Um, and so we've worked with some of the best universities in the world. Our, our three main algorithms, uh, as you've mentioned, uh, now are, we've created an OMIC age clock, uh, based off of a lot of big data with Harvard. That clock can actually predict death with a 92% accuracy within a five-year time period, which is pretty incredible.
We've created, which is pretty scary as well.
Yeah. We don't report out on death. Um, but, uh, but ideally, hopefully, we're being able to pick up a signal that we can prevent. Um, which is why it gets us excited. Um, but in addition to that, we've created the, the rate of aging, as you, you mentioned. This is one that's been created by some researchers at Duke and, and now Columbia, that can tell you how fast you're aging at a single point in time, almost like a speedometer of aging. Um, and then we've also created a, a clock with Yale, we call Symphony Age or Systems Age, which tells you the age of 11 different organ systems. Um, and, uh, so these clocks have gotten much, much more specific over time, and this is great. So now with things like OMIC Age or Symphony Age, we can actually tell you what organ system might be aging the fastest and therefore, what should we focus on in order to have the best benefits. Um, uh, which is really, really exciting. And, uh, and so I think we're starting to get a resolution into treating the aging process that we just previously haven't had. And, and now we've done over 120 different interventions, uh, and measured their effect on these aging clocks to see what actually works. And that's helping us hopefully create better protocols to increase and improve health throughout time.
Yeah, I, I mean, I respect this approach so much because I feel like there is a lot of confusion for people, uh, in the longevity space, especially when there is so many interventions that you could do. You should optimize your metabolism and cardiovascular health and brain health and kidney health and liver health, and, you know, if you were to focus on optimizing all of those all the time, it would take more than one day. So you wouldn't have time for anything else. And with these clocks, you can kind of see like, okay, this is my, uh, bottleneck which prevents me from getting to my optimal whole body health. So I, I really like these reports that you have. Have you seen any surprising or exciting patterns when targeting biological aging to these specific systems, any specific interventions that, oh, this works super well for that organ system?
Yeah, definitely. You know, we're starting to build those maps, but, but the answer is yes. Uh, you know, some of the first five interventions that we looked at, um, were, we hypothesized would have some organ-specific effects. So we did things like, for instance, gastric bypass, where we know we're having an effect on the metabolic system, right? We're decreasing food intake, uh, we're improving insulin sensitivity, and sure enough, whenever we did gastric bypass, we saw metabolic age was improved. Um, you know, whenever we had people stop smoking, this might sound really simple, but we saw reductions in cardiovascular age and lung age and in kidney age, which makes perfect sense. Um, and then even when we did things like, uh, kidney dialysis or kidney transplant, we saw improvements in kidney age. Um, and so, uh, there, there are a lot of things that behave exactly like we would expect, and we're starting to get some organ-specific, um, features over a lot of interventions. Um, you know, for instance, we, we just did a hyperbaric trial, which had really good results. It was probably actually one of the best results across the multiple interventions that we did. Um, but we saw improvements in lung as well as brain-specific organs as well, which I think makes perfect sense, as a lot of people have been using hyperbaric as a way to improve optimal cognitive function for a long time.
Right. Oh, that's interesting. Um, you also, uh, I saw like an early trial on semaglutide and its impact on epigenetic aging. Do you already have some data on that one?
We do. We have two trials that we've done, um, with semaglutide. Um, one is a, a big double-blind randomized placebo-controlled trial we did with Cornell and Harvard. Um, and in that one, we saw some very interesting effects. In particular, we saw, um, sort of an age-leveling effect. Um, so people who were already pretty advanced in age, um, showed significant improvements, but people who were already doing pretty well, um, didn't see that much improvement at all. Um, which I think is, is super interesting because we're seeing that, uh, um, differential responses according to where someone is at in their, in their relative health span. Um, and so I think that that was super interesting. We also, um, one of my favorite things to mention is we also did this with our, our healthy cohort. You know, one of the things about True Diagnostic patients is that they tend to be very healthy, um, and very health-conscious, much healthier than some of the biobank data sets we might get from a Harvard or, or other group. Um, and whenever we did semaglutide in these patients, we almost saw no significant age effects, but we did see something really interesting, and that was that those people who were on hormone replacement while also on the GLP-1s, um, hardly lost any muscle mass at all. Um, and I know that as we talked about earlier, that's one of the bigger fears about the GLP-1s is they might lose fat mass, but also make you a little bit more frail or likely to lose muscle mass, which is this metabolic currency as we age. Um, and so, uh, the good thing is on hormone replacement, we didn't see any of that muscle loss.
Okay. What, what other, um, exciting patterns have you seen? Let's say, uh, we were discussing previously about the organ-specific age, but let's jump into the speed of aging. Um, so yeah, can you clarify that concept and what have you seen works to reduce that?
Yeah. So, so that, that speed of aging is really exciting because it's, it's more likely to change quickly. Um, and, and it can register change in really short intervals, while sometimes, you know, we've accumulated our overall biological aging process over many, many years, and sometimes it's a little bit harder to change that one. Um, so we like the Dunn pace because it gives us more feedback, uh, in, in a shorter time interval. Um, so we can actually know what's working and what's not. Um, and we found a lot of things to be responsive to that Dunn needed and pace marker. Um, you know, just even talking about some of the, the popular trials we've done in diet and nutrition. Um, there was a Netflix documentary on vegan versus omnivore diets where we had 20 pairs of identical twins, and one twin went on a vegan diet, the other one went on an omnivore, sort of typical American diet. Um, so again, it wasn't the most optimal omnivore diet. Um, but we saw that comparatively, the vegan diet had significant age reductions, um, compared to that omnivore diet. And, and, and one of the great things about that is we're using genetically identical individuals. Um, so it's a great control to get really good signal. Um, you know, but as I mentioned, we've seen improvements with things like hyperbaric. Um, you know, as people, I would say a lot of the things we've seen are not too surprising. They back up what we already know, which is things like caloric restriction work. Um, but we're also seeing some things that, that we think should work, also work now. Things like senolytics, like the dasatinib and quercetin, ways to kill those zombie cells, have been really effective as well.
All right, that's exciting. I've imagined you've run a few tests on yourself too. Uh, what have you noticed personally worked for your biological age or speed of aging?
Yeah, I've definitely done a lot, and, uh, you know, I think that, uh, for me, I'm always surprised by the impact of just even the psychosocial things going on in my life. Um, you know, you hear about this often, you see it in, in the literature, is, you know, the number of close relationships, the ability, you know, with mindfulness to help with inflammation and cardiovascular risk factors. Um, and, and always I'm surprised that, um, that when I pay attention to my mental health, try and do things like mindfulness, um, uh, it actually plays an impact on, on a lot of my, my different, uh, features. Um, but, you know, I, I think, uh, in addition to that, you know, diet and exercise is, is super important, sleep is super important. Um, and then, uh, just, uh, you know, with that being said, also all those medications we've already talked about, I think have all been for me pretty effective.
Thank you so much, Ryan, for sharing everything. This has been a hugely informative podcast and very relevant, and I've learned a lot. Could you please share all of the links where people can find you, your work, um, True Diagnostic, anything that you want to share so people can learn more?
Certainly. Uh, you know, I'm not big on social media, but I do have a LinkedIn. Uh, you can find me. Uh, just search Ryan Smith at True Diagnostic. Also, uh, our True Diagnostic account puts out a lot of content. So as we find some of these unique associations or we develop these studies, people can can learn, uh, how to, to improve their own health. So, uh, True Diagnostic is also able to be followed on all platforms, or just go to truediagnostic.com to find us.
[Music]