Telomere Biology in Regenerative Medicine

Matt Cook, M.D.

Yes, oh, that’s a good one. I went into anesthesiology, it’s an amazing sort of opportunity to take a deep dive into biochemistry and physiology, and at the time, I was really into expedition climbing and rock climbing and so I thought I was gonna be a team doctor for going to Everest, and I thought I need… everybody told me, “You need to have a job, where you can take six months off, and if you become a internal medicine doctor”, which I kind of would, I wish I had all of your knowledge, but they said, “If you do that, all of your patients are gonna leave by the time you get back from the Himalayas”

Joseph M. Raffaele, M.D.

No question, you don’t get to get away from your patients in internal medicine, that’s for sure.

Matt Cook, M.D.

So then I went into anesthesia, but then I kept kind of having this cognitive dissonance, that surgery is… they say surgery is a chance to see a chance to cut, a chance to cure, but it’s also a chance to cry. And so I started to feel that there were probably better, less interventional ways to help people with problems, and as I was sort of doing this, the thing that I evolved into spending most of my life doing in anesthesia, was doing ultrasound-guided nerve blocks. So then I would put the nerves to the shoulder or the hand, or the foot asleep, and then I would do basically, orthopedic surgery with sedation. 

And then about eight years ago, we started to find out that if you used something other than numbing medicine, a lot of times we could improve pain. And so that included everything from dextrose, to exosomes, to stem cells, to placental matrix, to peptides actually, and so then I started treating a lot of peripheral nerve pain and as I got into an interventional pain practice that was integrative, we ended up picking up a lot of people with complex illness because there’s so much pain in that population. And because I was doing nerve hydrodissection with peptides, then I started to deal with a lot of neuropathic pain and the whole time I was doing that, I was realizing, oh, no, if you start taking care of these fairly significant problems, I’ve got to go back to the beginning and become an internal medicine doctor like you, and then try to do that, and so then I went back and did a fellowship in integrative medicine, and so ever since then, I’ve been trying to put those, the interventional and the integrative, and sort of the functional medicine worlds together.

Joseph M. Raffaele, M.D.

Yeah, that is a really fascinating journey, you finally came back to what your real passion was, and we’ll get back to whether you actually got to do some climbing at some point, but yeah, so you… just blocking the nerve is one thing, but then ultimately trying to figure out what’s the inflammatory processes, is what’s the physiology behind it, it sounds like that’s what’s fascinating and what brought you to this field of peptides, and treating chronic pain, and chronic illnesses. I know we talked a little bit earlier about perhaps doing a little bit of a primer on peptide therapy and how you use it in your practice, and then moving towards potentially how you integrate TA-65 and some other, and telomere biology in general, into your practice.

Matt Cook, M.D.

Yeah, that’s a good one. So then I’ll take you on a little story about the history of how peptides have been used and this goes back to a famous Russian doctor, Dr. Khavinson, and he really did groundbreaking work, and he used both a combination of injectable peptides, which are synthetic versions of peptides that are identical to what are in our body, but then he also had extracts of basically, glandulars, so an extract of the pineal gland, and then they would isolate that extract and concentrate it in the actual peptides that were in that organ. And then what they found is, is that there are small, two, to four, to five amino acid peptides that regulate every organ. 

So there’s a couple for the brain, there’s one for blood vessels, there’s one for the heart, and the idea was, is that people would take these bioregulator peptides, and they used it as an anti-aging strategy, and one of their… and so they, this goes way back to 20, 30 years ago, and so they started to measure telomere length and they were using the pineal gland extracts, and so that would be like… the name would be epithalamin, and so then they were using these extracts, and so there’s a whole bunch of different protocols, but like one common protocol was to combine the pineal gland extracts with thymic extracts. And the thymic extracts are immune, and they had evidence that as we age, the amount of the… and I think this might be hypothetical, but maybe not, that our thymic proteins and our thymic levels go down, and we kinda know that just intuitively, because the thymus tends to involute as we age.

Joseph M. Raffaele, M.D.

Oh, no, they certainly do, yeah, I think they do and then Trex go down, and all sorts of indications of thymic activity declines with age, and by age 50, there’s not all that much going on there.

Matt Cook, M.D.

Which is when we start to have problems.

Joseph M. Raffaele, M.D.

Right, interestingly.

Matt Cook, M.D.

I’m getting in gear ’cause I just turned 50.

Joseph M. Raffaele, M.D.

There you go!

Matt Cook, M.D.

So then that was a protocol, and so then they have all kinds of research of… and I got the reprints of these in English, of protocols where sometimes we, people were on protocols, where they’re just taking a couple like the pineal extracts and the thymic ones, but then there are other protocols where people were taking a host, basically a bioregulator for almost every organ. And so then they correlated that people tended to have less cancer, less aging, and tended to have… and in their trials, they found a reduction in all-cause mortality. 

And so then this research fundamentally, we need to re, kind of continue on along that line and then, and reproduce it here, and so there’s gonna be work to be done, and then the testing, that was… it was amazing that they were able to do that and they were able to prove telomere-like thing, all the way back in that time, and I was telling you in the pre-call that we had, what we really wanna do is probably repeat this with some of the new diagnostics that I think you’re probably the smartest person that I’ve met up until now, in terms of knowing about that stuff. So anyways, the 1.0, was this whole Russian literature. And so then what happened is, is all of a sudden, they figured out, oh, okay, well, we know what the amino acid sequence is for Epitalon, so then let’s give that. And initially what they did, is those dosing algorithms, were based upon the concentrations that were given from the glandulars from Khavinson.

Joseph M. Raffaele, M.D.

Oh, okay.

Matt Cook, M.D.

And so then people were taking 10 milligrams a day, for 10 days. And so then that dosing ended up… and so then people were doing that twice a year. And so then it’s gonna have an epigenetic effect, it’s gonna go into the DNA and then affect the transcriptome, and so as a result of that, people… there was this idea, okay, we’ll do that a couple of times a year, and then that’s gonna be part of our anti-aging strategy, and so I did that, and a lot of people did that, over the last, I would say, year and a half, there’s been an evolution where people realized, oh, okay, what Khavinson was giving, was actually a full glandular with more stuff in it, than just Epitalon.

Joseph M. Raffaele, M.D.

Probably less Epitalon.

Matt Cook, M.D.

Less Epitalon, yeah, exactly. And so then there was some evidence that the amount of Epitalon in there, may have been significantly less, like 100 micrograms. And so then what people started doing, is they started doing low dose Epitalon, in the ballpark of like one milligram a day, and then doing that for 10 days a month, and then doing that… doing a 10-day a month sort of bioregulator stack, so then doing that, and then doing that either once a month, or a certain number of times per year. And so then there are some people that would do a bioregulator stack for one week a quarter, every other month, or even every month as a 10-day protocol. And then when people do those stacks, typically they’re using some combination of a number of bioregulators, just not only the pineal gland extract.

Joseph M. Raffaele, M.D.

So that’s really interesting, I’ve had a couple of other guests on that have had scientific research done in other countries and languages and journals that haven’t been translated in English, and then finally see the light of day in English through somebody discovering them and then that information starts to explode, I’m just curious about maybe for our listeners and for me as well, the term, let’s dig a little bit deeper in the term bioregulator ’cause that’s… what do we mean by that exactly for each organ, what’s sort of the physiology around that? What’s known about the physiology around that, I guess?

Matt Cook, M.D.

So then there’s the, not an enormous amount of data here in the west on those bioregulators, the idea is that the Epitalon is a bioregulator of the pineal gland. So there’s like a… and there’s one called cerluten that’s a bioregulator for the brain, there’s one called the vesugen that’s a bioregulator for blood vessels. And so then these are small peptides that are found in those areas, they seem to have a regulating influence upon that organ. So there’s some for the liver, some for the prostate, one for the bladder. And so then the idea is, is that these are… and so then you could imagine that there would be a host of things that could then regulate what’s happening in an organ, including small peptides that are gonna have epigenetic influences upon that organ, including hormones, including vitamins, including minerals, and so then they’re just gonna be one small, but potentially interesting influence that’s going to be impacting an organ.

Joseph M. Raffaele, M.D.

So it could be endocrine… it sounds like it’s almost like endocrine signaling, LH signaling the testicles, but maybe it works in different receptors, someplace within those organs that aren’t necessarily working in an endocrine fashion, whereas direct changes in gene transcription, I’m not sure, but in any case with Epitalon though, what sorts of… just sort of clinical benefits are seen with it and how do you know, is it… so the big question is how do you know if it’s working, I guess, kind of thing?

Matt Cook, M.D.

So then the… what we have seen clinically, pineal gland, I think, melatonin and I think, circadian rhythms, we’ve seen people definitely will say, “Oh, I’m sleeping better when I take Epitalon”, and then we’ve seen a lot of people who’ve said, “Oh…”, and interestingly, they tend to do better if they take in the morning, than if they take it at night. And so it may be that it’s regulating and enhancing and turning back that circadian rhythm into kind of a functional state. Then you say, is that truly and actually, turning on telomerase and lengthening telomeres? And so then, I think that I’m gonna be probably with you, what I wanna do is take a real serious approach to like using one of the newer laboratories that are using FISH to kind of assess the length of telomeres and then take some people in some specific populations, and then do before and after testing, where you run people through dosing, and potentially, what I think you’re gonna need to do is you’re gonna have to run people through low dosing and high dosing and then compare that. And so then a low dosing would be like a milligram a day, a high dosing would be like 10 milligrams a day, but just for a short period of time, and then compare that and start to suss that out because there’s been a lot of conversation about it, but I don’t think… I think we need to really build some great data on this.

Joseph M. Raffaele, M.D.

Yeah, I think that… I mean, the issue would be in some ways, if you’re improving sleep, you’re improving circadian rhythm, you may have a beneficial effect on telomere length, not necessarily to increase it but certainly to keep it from getting shorter, through just that, whether telomerase is being activated or not, I guess, I mean, the way in which, say, something like TA-65 is shown to be telomerase activators is in the TRAP assay in vitro where you just put it in it micromolar, one micromolar, 10 micromolar concentrations and see if telomerase is actually turned on, and that could be even a first step, I mean, there’s places that do TRAP assays, perhaps Bill Andrews would even be interested in testing, I don’t know whether they’ve tested Epitalon or not, perhaps they have, and maybe it doesn’t work that way, maybe it works in some other way to turn on telomerase, not directly, but that’s one way that you could test it before you even embarked upon a clinical trial, looking at telomere lengths to know whether it’s gonna be direct or indirect, that’s just a thought I had about it.

Matt Cook, M.D.

I’ve heard that he’s skeptical of it, which is why… we’ve had a lot of people tell us they feel really good taking it, but I’m somewhat skeptical also in part because of some of the stuff that I’ve heard on how much of an effect it has on telomeres. But then I think the telomeres conversations also, like for example, TA-65 is gonna activate telomerase, but it may also have some benefit of decreasing senescence, and then…

Joseph M. Raffaele, M.D.

Yeah, I mean, there are definitely potentially off target effects of any molecule, or any drug, anything that you’re putting into the body, if we have not for sure, proven that it’s through telomerase activation, that that reduction in senescent T cells, that our listeners have heard about in other episodes occurs, and likewise, it may be that Epitalon has an effect in through another mechanism, but that would be an interesting thing to do. I know did you talk to Ed Lee about his study that he did?

Matt Cook, M.D.

Which one?

Joseph M. Raffaele, M.D.

I think…

Matt Cook, M.D.

I know him, I like him.

Joseph M. Raffaele, M.D.

He did one with Epitalon, but he looked at DNA methylation rather than telomere lengths, as far as I recall, I mean, I’m not sure if he sent it off, certainly he didn’t tell me whether or not telomere length was… and they’re still analyzing data as far as I know, but he used Epitalon in a subset of patients for a while. So it could be having beneficial effects through multiple different ways, the people that say they sleep better, do they sleep better for months after taking that low dose, or is it while they’re taking the Epitalon?

Matt Cook, M.D.

So then that one is an interesting one too. So if you look at, if you hear the Khavinson research, they will say that there were people who were put on a protocol for like two years and then they stopped the protocol, and then they can continued to get benefit for like 10 years. 

Which is, I mean, kind of amazing, but then, it’s kind of, you’d like to see that repeated, I would say that I see benefit on sleep more real time and so it’s like, “Oh, when I take it, I feel a lot better”, and so then that has led to an emergence of people more taking these lower dosing, and so then there’s a part of me that wonders, okay, well, people were, and this is… and I thought I would just kinda tell you this story, because this is sort of where all this came from, and it’s a little bit soft from kind of a science perspective, but it’s also gives you an understanding of this one corner of kind of the peptide conversation, how it started and where it’s going, but you start with 10 milligrams and then all of a sudden you realize, oh, people are getting almost the same benefit, whether they take 10 milligrams or one milligram, and so then maybe they could take 500 micrograms and they could take that. I will tell people, I will say that when we have people who are like real stressed, they will… or going through an illness, they’ll also say, “Oh, if I take…” taking that seems to boost how they feel and it’s almost like… it has a stress reduction and emotional support, and I imagine that that could happen through supporting those areas of the brain.

Joseph M. Raffaele, M.D.

Is there any… I guess that Khavinson didn’t do it, but is there any reason not to take it everyday?

Matt Cook, M.D.

Well, so then the interesting thing is that the… my understanding of it, is this, that the… so then understand A, you have injectable peptides and so then there’s this experience in the west of like, let’s say, high dosing and low dosing, but then what they’re doing over there is they have like organically grown cows that are then from those cows, they’re taking their organ or gland, isolating that, and then concentrating, almost like a glandular, and that has been done forever in Chinese medicine. And so then these glandulars, now it makes sense if you eat protein, you’re just gonna digest that, and then that’s why most peptides, if you take most peptides, you take a 15-amino acid peptide, it’s gonna be hard for that to have a lot of effect orally, because your gastric juices are just gonna digest that. 

However, what’s happening on the , the bioregulator, is the bioregulator those are all small; two, three, four amino acids, and so then you can absorb those. And so then those protocols, will have people taking that bioregulator everyday, and so people will take a pineal bioregulator everyday. So I’ve been, to be honest, I’m actually doing it right now as a test, so I feel pretty great, but I’m generally doing a lot of stuff so I always feel great, so…

Joseph M. Raffaele, M.D.

Being in the biz, that’s what happens. So, let me see, so that’s what you… you have a division between oral and injectable Epitalons, is injectable, what’s the relationship between Epitalon and melatonin? I mean, is there some idea that it helps the melatonin secretion, or you give melatonin along with it, or you don’t have to, or, I mean, there certainly are assays that you can do with the saliva testing that’s available to see whether melatonin, or I thought , urine metabolites as well, whether you’re increasing that, has any work been done in that area?

Matt Cook, M.D.

I don’t think… if it has, I don’t know. So if Epitalon’s bioregulator of the pineal gland, then hypothetically, it would have a benefit on melatonin, we see a lot of people who will take melatonin and enjoy it, at a diversity of doses. So traditionally people were using real low dose and now there’s people doing all kinds of stuff out there, for people who take melatonin, I would say we’re in the low to moderate range and dosing, and then for people who do that, some people will do that as a regular thing, some people, I know it can be fairly helpful in big periods of physiological stress and illness, and it’s the central nervous system anti-oxidant, so if I have patients with neurological Lyme or mold, I think it’s a great adjunct, and then how I think about either oral pineal gland extracts, or how I would think about an injectable Epitalon, is a support to that system, but the science and data on that needs to evolve.

Joseph M. Raffaele, M.D.

And hopefully it will, with some of these things, I’m looking at the telomere lengths in those studies and see what at least study produces in the end. Other peptides that you work with regularly that have beneficial effects? You talked about some of the immune-modulating ones…

Matt Cook, M.D.

So the immune-modulating peptides are gonna be pretty interesting. The two most famous immune peptides, one’s thymosin alpha-1 and thymosin beta-4, and we have quite a bit of experience using those as support for people with kind of complex immune problems, think, Lyme, mold, long COVID, Epstein-Barr, CMV, and all of those conditions have the hallmark of a dysregulated immune system. Something comes in, wrecks havoc, it may or may not be there anymore, it may have come and gone, but then it continues to wreck havoc in one way or another, and then each one of those, if you want, I can kinda go through and talk you through my thoughts of what’s happening there.

Joseph M. Raffaele, M.D.

Yeah, I am particularly curious about those two, I understand, what is it? Thymosin 1-alpha is, or alpha-1, is it alpha-1 or 1-alpha…?

Matt Cook, M.D.

Alpha-1

Joseph M. Raffaele, M.D.

Alpha-1, that that’s going to be less available at this point?

Matt Cook, M.D.

Yeah, so then that’s what I… Well, they’re both fundamentally, or they’re both not available in the United States anymore, which, and you wonder is that just because a lot of people were marketing them for… they’re helpful, kind of on immune side, and so then people were marketing for COVID and so then, and there was such a push to get everybody vaccinated, which I’m supportive of and despite that, and there are people who were… some people are still finding ways to get them, but then there are… what happens is with these peptides, there can be a fragment, an active fragment of the peptide that can do something, and so then there are fragments and other versions of these peptides that are sort of coming out and so then what you’re gonna have is, it’s a little bit of a cat and mouse game on that conversation of continued… there’s a evolution of what we have available, but then also, the audience for this is worldwide, and so then I think that, my hope would be that at some point, some of those things come back to the United States because we had a lot of people who really benefited from those.

Joseph M. Raffaele, M.D.

So they’re generally considered as a supplement, they’re not… not a drug because they’re natural-occurring peptides, or is that, or how does that work?

Matt Cook, M.D.

I think the FDA is gonna consider them as drugs, and so then there’s a effort sort of underway in a variety of different countries to try to get normal regulatory status for peptides, it’s gonna be, it’ll be interesting to see how the evolution of that is, basically for people who are sort of new to that part of the conversation, the most famous peptide that you ever heard of is insulin. So…

Joseph M. Raffaele, M.D.

Yeah, right, exactly.

Matt Cook, M.D.

Protein, it binds on to a glucose channel and it opens up a… opens it up and allows glucose to go into a cell. And so then there are… and then there are some peptides that have multiple little signaling aspects to it, and so one aspect might help a muscle, another aspect is anti-inflammatory, and so then what people are finding is if you chop that peptide up and just have this, the active version of it, then it’s a smaller version, so there’s gonna be an evolution of peptides that come out over the next five years that are smaller versions of other active peptides that we know about.

Joseph M. Raffaele, M.D.

And do you think that’s gonna be pharma that’s doing that because of… or, if it’s gonna be a drug, I mean, do any of these have USP monographs?

Matt Cook, M.D.

Some of them do, yeah.

Joseph M. Raffaele, M.D.

One that I use in my practice, well, let’s, even though it’s not available, I’m curious about what response you’ve seen with the thymosins, and what you think the mechanism is, is it related to inflammations, synthetic effect, or what?

Matt Cook, M.D.

So the thymosin alpha-1 is primarily immunoregulatory and immunomodulatory, although it will boost antibody production, it will boost certain cell types, it will increase gamma Delta T cells, and I have found it to be regulating. And so we think about that in terms of like an immune system that’s overactive and overstressed, has too much on its plate to handle, then it can’t focus on something new that comes up. So then when you do something that, whether that could be a stem cell, or that could be exosome, or… but peptides will, to me, thymosin alpha-1 will work in a similar way, where the immune system will become a little bit more balanced, people will, people who are very sick with complex illness, a lot of times will feel a lot better when they take them. 

So it’s almost, I would think the thymosin alpha-1 almost like, if you imagine somebody that you see for hormone replacement, where their body stops making testosterone, and they don’t feel great because that’s a hormone that has been in their body, that they’ve been used to having, and you replace it and suddenly they feel better, and so then imagine that there are peptides and proteins coming out of different glands and organs, that probably are going to fade in a similar way, like hormones and many other things, however, they’re probably gonna fade more quickly in people with complex illness and problems like that.

Joseph M. Raffaele, M.D.

Huh, that’s a good analogy way of thinking about it, have you found with… I mean, I certainly I’ve been doing hormone optimization for years, and I’m sure you do some of it as well, I’m always still struck even at this point in my career, how amazing the effect is that a small molecule, like estradiol or testosterone can have, on somebody who’s either frankly deficient or even partially deficient, do you see those kinds of clinical changes, are they more subtle with peptides?

Matt Cook, M.D.

Well, yeah, I think so, yeah. I think even with small amounts and then the dosing, we go back to the dosing conversation that we had earlier, but even with small amounts, you can see… we’ve seen profound effects for some people. And then everybody responds a little bit differently, but everybody’s got different stuff going on and obviously, this is the decade of the immune system, regardless of whatever decade we thought we were living in.

Joseph M. Raffaele, M.D.

Oh yeah, I mean, I call it the decade of the virion, but it’s really because of the virion’s effect on the immune system, but it’s absolutely gonna be about the immune system and inflammation and we know that senescent cells have caused disease in other post-mitotic organs, so I absolutely agree with you about that. All these peptides so then, so your analogy was that these are peptides that are floating around in the blood in a healthy body, but then for whatever reason, illness, or infection, or stress, start being produced at a lower level, and that puts the person into a state of less ease. And so in some ways, there’re kind of replacement therapies that you’re doing as well, to a certain extent, it sounds like.

Matt Cook, M.D.

Yeah, to a certain extent, yeah. And then what I would say is, is that if you think of the big immune problems that we’re dealing with right now, are situations where there is an amount of physiological stress that’s too much for the body to handle. And now, that physiological stress may be from an acute infection that’s going on, and like on the one side over here, or that can be from an overactive and inflammatory response, both at kind of at a genetic and at a physiological and at a cellular level, that basically puts the body in a dysregulated state, and then it leads… the body becomes dysfunctional in terms of its ability to deal with that. 

And so then you’re dealing with those two things, and so then the question is, how do we, A, fight the infection on the one side? And so then I think peptides are not a 100% solution for that, but they are a supportive replacement idea, kind of that you could think of almost as an analogous to testosterone, and then on the other side, the question is, using these two, using peptides and a variety of other modalities, to regulate basically that total inflammatory state that the body was put in.

Joseph M. Raffaele, M.D.

Yeah, I mean, that’s… I was just thinking about, you’re talking about peptides and we now have technologies to do the proteomic analysis, we can do, look at all the proteins that are being produced, peptides as well in the body, and whether there’s a general decline with the aging process or within particular conditions, so that then you could even pick up which ones are declining and then replenish those, the whole idea of one drug, one illness kind of thing has gone out the window, we know we need multiple approaches to things, and that made me think about young human plasma transfusions, and maybe what’s happening partly in those, is that you’re getting back those peptides that you’re talking about that are getting lost, and they don’t know exactly what they are, some people have talked about GDF11 being an important one, but I’m sure it’s, when you have the whole plasma being transfused from a young person to an older person, there’s a whole lot of things going on there that needs some parsing out, to really understand the exact mechanism of what’s going on. 

But I wanted to move just a little bit to a molecule that I do some work with, and that’s… and you’re in musculoskeletal as well, is the BPC-157 and what’s your experiences with that, how that works, whether or not, I know that you can take it orally, you can take it in by injection, some people are injecting into the areas of where there’s the problem, is that your experience with, or…?

Matt Cook, M.D.

Oh yeah, so BPC-157 is got a good one and it’s an interesting molecule. So it is secreted actually by the stomach, and then do you know the story, the Pavlov story?

Joseph M. Raffaele, M.D.

I don’t.

Matt Cook, M.D.

Oh, so that’s a good one. The idea is, is that Pavlov had these digestive juices, which were kind of the tonic of the day back in Russia again, and so then… and they helped people, and so then one of the theories, this is that there was BPC-157 in those juices and so that was like the first peptide therapy that was ever done.

Joseph M. Raffaele, M.D.

Where did they get the juices from? From actual humans, or they put an NG tube down?

Matt Cook, M.D.

I don’t, they had like some kind of an NG tube down and I think it was from dogs.

Joseph M. Raffaele, M.D.

Oh, so Pavlov’s dog again!

Matt Cook, M.D.

I think so, but I know that he was involved in that. And so then BPC-157 is something that people will use orally, and so then, it makes sense that you could give it orally since it’s something that is secreted in the digestive system. And there’s two conversations around that. One is, is that there’s some short acting preparations and then there’s some long acting preparations, hypothetically the idea is the long acting preparations are gonna digest slowly, and so they’re gonna make it to the colon and the short acting ones would then have a systemic effect. 

Now, if I called 10 of my friends and pulled them and said, “Hey, what do you think about oral BPC-157”, I’ll tell you that five of them are gonna tell me that, “Oh yeah, they’re great and people get a systemic effect and we really like them”, and then another five are gonna tell me, “That’s a waste of time and money, we noticed that people haven’t gotten that much of a benefit from it”. So you’ve got that to contend with, but I have noticed benefit with BPC-157 orally, and then there are some people that will combine KPV, which is basically an antiinflammatory fragment from growth hormone…

Joseph M. Raffaele, M.D.

KPV?

Matt Cook, M.D.

KPV, and they’ll combine that with BPC as a supplement, and that’s a small one, and so then it has a good mechanism of action in the gut. In terms of systemic, so then the next thing that you could do is you can inject BPC-157 subcutaneously. And so then you can inject that subcutaneously in your belly or your gluteal area, and that can have a systemic effect and I’ll tell you, that people will have benefit gastrointestinally, from systemic dosing of BPC-157 and so we’ve definitely seen that. And we take care of a lot of patients with SIBO, leaky gut, and inflammatory bowel conditions, and in general, both with oral and with the subcutaneous dosing, we’ve seen benefits. In terms of musculoskeletal, what I like to say, is I like to think of kind of these five compartments of pain, so there’s the nerve, there’s the ligament, tendon and fascia, there’s the joint, there’s the subchondral space, and then there’s the systemic blood situation. 

What I’ll tell you is, is the BPC-157 is incredibly anti-inflammatory and helpful for connective tissue problems. Some people will take it as a connective tissue subcutaneously to try to have a systemic effect, which on a scale from one to 10, if you’re trying to treat a tendon, I would call that a two on a scale from one to 10, it’s not gonna be that helpful, but sometimes you’ll see real high-end athletes, that are real, super tuned, and they’ll be like, “Oh yeah, I got a benefit from that”. 

But so then I’ve got two strategies for how I do that, and one is, is that I just pinch a little connective tissue and I go subcutaneously right over the area. And so then I will… I’ve done hydrodissections with BPC-157 of fascia, everywhere from the neck, to the back, to the groin, the… everywhere in the body you can do hydrodissections, I’ve done with BPC-157. And I found it to be quite helpful, I like to do combinations of it with other peptides, and so the traditional thing that a lot of people did was they combined thymosin beta-4 and BPC-157 for nerve hydrodissection, and so the other thing we can do, is remember what I told you when I was an anesthesiologist doing… putting fluid around a nerve, we used an ultrasound and put a needle right by the nerve and put fluid around it. So then what you can do is, you can do the same thing, but instead of putting ropivacaine, you could put BPC-157 around nerves. And I’ll tell you, people will have a lot less… it’s a very good analgesic medication for peripheral nerves. Now, thymosin beta-4 is as well, and there’s actually a patent out for peripheral neuropathy and thymosin beta-4.

 And I found people do better with a combination of BPC-157 and thymosin beta-4, and then we’ve even used some of the fragments of thymosin beta-4, like fragment one to four of thymosin beta-4, so most anti-inflammatory fragment, and so we’ll combine that with BPC-157. Now, then you say, oh, okay, what else connective tissue wise? I love what my friend, Barb, who unfortunately, about once a month, will burn herself cooking in the kitchen, and then whenever that happens, she’ll look at me and she goes, “Time for another BPC miracle”. And so then, I’ve given her about 25 different injections for burns, where I’ll inject subcutaneously around the burns and then pour right topically over, thymosin beta-4 are also very good for burns. And so, and it’s kind of shocking, like we have pictures where we’ll do it, and it’ll be like, it’ll heal quite quickly. 

Ed Lee did a trial with BPC-157 injecting it into joints, and I’ve had a good experience injecting it into the joints, I’ve had a very good experience with back pain, and so using both combinations of thymosin beta-4 fragments and BPC-157, and what my group of people, anesthesiologists do, is if we think that somebody is having pain in their facet joint, we do something called the median branch block, where we go in and we put a needle right by the nerve, that goes to the facet joint and then if that works, then we say, “Oh, well, they’ve got pain from the facet joint, and so the thing that we do, is we do an ablation to try and kill that nerve. 

The good thing is that can be helpful, the bad thing is, they walk around for a couple of years, and then once the nerve comes back, then the pain’s worse. And so then what our approach is, is to treat the median branch and then treat the facet capsule with BPC-157 and other other peptides, that are going to tone inflammation down and start to regenerate and heal the connective tissue there, and then once those joints start to work better and function a lot better, force can move more freely through the spine, and then that’s gonna lead to less impingement of nerves…

Joseph M. Raffaele, M.D.

Oh, yeah. Well, so those are sort of your top peptides that we’ve been talking about, any other ones in that the, in your… I mean, I know there’s quite a few peptides that you have the most familiarity with and have, wanna share with our listeners before we turn to another subject, which, I mean, just briefly, ’cause I know we’re running out of time a little bit but…

Matt Cook, M.D.

Yeah, I’ll kind of leave it there, but one thing that I had a great… we just got back from FRM and it was nice to see you and get a chance to talk to you there, we’ve been… and I was talking to a lot of people about Lyme and mold and big neurological problems, which might be, allow us to dovetail into that segment of the conversation.

Joseph M. Raffaele, M.D.

Yeah, sure, .

Matt Cook, M.D.

But interestingly, when you think of chronic mold, one of the strategies that people are doing, is they’re trying to regulate and balance those patients, and improve them, and then what they’re using to ultimately regulate genetic expression of inflammatory genes that have been turned on, is a peptide called VIP. And so then I was talking to my friend, Kent Holtorf, who also is using some other bioregulators, so the bioregulator of the spleen, and then the pineal bioregulators, to start to treat the patients with real inflamed central nervous systems. 

And so then I could talk to you about that, but let’s go on, but then know that I think that what we’re gonna see, is a constellation of a whole bunch of problems, that are basically are all brothers and sisters and cousins of each other; chronic Lyme, chronic mole, DBV, CMV, and I was, maybe we could kinda go into the TA-65 conversation, because I also have seen TA-65 be quite helpful for those patients. And I’m not sure if it’s because you’re decreasing senescence in T-cells, which was some of the work that you guys just did, which I just like, I saw it and I was like, I totally get it, that, you ever read something and you go, oh, this is exactly how I thought it was gonna be, because I had that experience that I’ve had so many people get better. Tell me about that study, and then maybe we can dive into that ’cause I think that that’s just amazing work that you did.

Joseph M. Raffaele, M.D.

So it was a study looking at the effect of TA-65 at varying doses in 500 patients that had levels, basically the ages of 50 to 70 something and what we found, for a year, sorry, nine months, and what we found was that the way in which we defined a senescent T cell, is no longer expressing the CD28 molecule, which is very important for a brisk proliferation when the T-cell hooks up to the antigen presenting cell, and so cells that have a, lack CD28 are really considered senescent, they don’t divide anymore, they secrete a lot of inflammatory cytokines and accumulation of those is a very bad thing that occurs, I mean, it increases your risk of cardiovascular disease it’s been associated with, that one of the reasons we think that CMV is such a bad actor, even though most doctors consider it a benign virus, because it doesn’t cause any major life-threatening acute illness except it can cause congenital problems if you get it coming through the birth canal, but what it does, is it makes your immune system continue to work very hard to keep it latent. 

Remember all the herpes viruses are, once you get it, they never go away, they sit latent and then they can get reactivated either as a cold sore, as genital herpes, as shingles for varicella, Epstein-Barr can come and go, the herpes virus five though, well, it causes a small amount of… 10% of the actual clinical mano, it’s mostly when you get it, you don’t know it, you might feel a little crummy, you don’t know when you’re shedding the virus, but it’s actually the most challenging foreign infection in human bodies in terms of the amount of the immune systems needed to keep it from coming out. 

And so, year after year, keeping it latent in your endothelial cells and in your monocytes, your body has to use up T-cell reserves and particularly CD8s, cytotoxic T cells, and then the cells divide, divide, divide, they lose telomere length to get critically short, they become senescent, they accumulate and cause all of this senescence-associated secretory phenotype. So the idea was from our original cohort study back in 2011, when we saw that there was an effect on reduction of senescent T-cells, but a greater effect in those who were CMV positive ’cause there was a greater accumulation of them, that was just a cohort trial, we didn’t know whether there was an actual improvement, but we saw about a 20% reduction, and we also saw an increase in naive T cells, which can be reduced because of lack of thymic activity, but also because there’s taking up of what we call immunological space, which is the… it’s basically, if you have… there’s just a certain amount of space for immune cells, and if your body senses that the space is getting too filled with one type senescent T cells, then the naive T cells can’t increase. 

So when we saw that there was both a decrease in senescent T cells and an increase in naive T cells in this population, it was about 50, 60% CMV positive, the company then decided to do a randomized control trial to look to see, if this actually was repeatable and remarkably, it was almost the exact same amount, a 20% decrease in senescent T cells as measured by lacking CD28, and about a 10% increase in naive T cells in the CMV positive, but also reductions in senescent T-cells in the CMV negatives, as well as increase in the naive T cell population in the CMV negative, in addition to the CMV positive. 

So a remodeling of the immune system towards a younger type of immune system, that was really pretty fascinating, now, we don’t know exactly what the mechanism, to your point, whether it’s because those cells have been rejuvenated to a certain extent, although as we talked about earlier, it wasn’t because, we didn’t measure an increase in CD28 positive cells, so were they just removing senescent T cells? It’s hard to say. But definitely TA-65 had that effect, are there off target effects? We know telomerase can go into the mitochondria, we know that it can do, has other effects on gene expression, the telomeres do, so it’s hard to know, but definitely, that CMV bring it up along with Lyme, with mycotoxins, et cetera, anything that stresses the immune system to have to proliferate, to deal with an issue and then eventually cause senescence, is sort of really the, where we’re… that’s where we’re at war in chronic disease, really. So that’s kind of what happened and we saw that, it actually, some effected 100 units, 250 units, 500 units and then 500 twice a day, or 250, twice a day, we saw some effect at all the doses, it doesn’t necessarily mean that you can definitely get an effect at 100, just that was that patient population. So you’ve had experience with TA-65 where probably, it was reducing senescent burden, particularly of the cytotoxic T cells, reducing IL-6, reducing TNF-alpha, potentially improving the ability to create interferon gamma, so I think that would be interesting to do as well, to see whether or not in a trial with your patients being treated for those things, and I have Lyme patients, I got them all on TA-65 ’cause it is a stress to your immune system, no question about that. That’s just in a nutshell, the study.

Matt Cook, M.D.

And the, all of the… fundamentally, all of those patients, my experience is that the killer cells are low.

Joseph M. Raffaele, M.D.

Yeah, so that’s really interesting. Natural killer cells numbered, tends with the aging process, to go up, and that’s what we found in the baseline and that’s what I see in my fairly large database of natural killer cells, that with age, they slightly go up, but the reason they go up is because, and it’s been studied by Janet Lord and other people that look at the innate immune system, is the per cell activity decreases the ability for granzyme B and perforin to work to kill, is decreased and they think there’s some upregulation for that reason. And what we actually saw with TA-65 in the original cohort, was a slight decrease in natural killer cell function in the cohort with that remodeling, and it was, that’s back to a more useful thing, but I know in the Lyme literature, they think of natural killer cells differently in that, do you see that they have low natural killer?

Matt Cook, M.D.

They tend to, you’ll see a lot of people come in with very low and so then you wonder, are they out on the front lines or are those…

Joseph M. Raffaele, M.D.

Oh, right.

Matt Cook, M.D.

Within that population, is there more senescence in killer cells in these patients with… that are basically fighting a constant fight for their entire life?

Joseph M. Raffaele, M.D.

Right, yeah, I don’t think we know the answer to that, that would be interesting to see. So in terms of mycotoxins, which I don’t know, typically just briefly for my own interests, how do you measure that, and then you treat, you support around or you can actually treat the mycotoxins, or you can…?

Matt Cook, M.D.

So then this one’s a good one, it’s a little bit, this one’s another one that’s somewhat controversial and so there’s a variety of sort of luminaries out there, but I’ll just give you sort of the highlights in the lay of the land. The current sort of up-to-date thinking on mycotoxins is that there’s water damaged buildings. So then imagine that there’s water, the Sheetrock is bad, and so then there’s going to be an opportunity there for infections to exist and when they exist, then they’re gonna start to secrete an aerosolized plume that we could breathe in. 

Now, initially it was thought that there was just mycotoxins, and now Shoemaker, who’s probably one of the top luminaries in this field is basically, and Hammond Haman, are saying that there’s actinomyces, which has gram-positive rods mycotoxins and gram-negative rods. And so then, and they’re correlating basically, from their most recent data, and I spent the entire dinner that we had together talking to Eric about this, Eric Gordon, who’s a very smart sort of… like I always like to, if I could sit and talk to him for like 10 hours at a time, just going through the stuff, so anyways, so then the theory is, is that the people who tend to be quite susceptible to this water damaged building, are people that have biofilms and that could be a biofilm in their gut, but most likely, that’s a biofilm in their nose, so they start to breathe in, and then they start to have mold that’s living within a biofilm in their nose, or also could be the actinos, and so then instead of having that plume, that’s secreted into the air that we’re breathing, it’s happening in your nose. 

And so then what happens, is that leads to mycotoxins living there that are secreting in, now, there’s a few schools of thought about what to do, one, is that people will do a nasal swab and try to figure out if they have a biofilm in this, from this bacteria MARCoNS and then if that’s positive, then try to treat that. Other people will say, if you’ve got the symptoms, just treat it. So there’s some ideas back and forth there. In terms of the gut, try to do a workup and to see if there’s GI biofilms in a lot of gastrointestinal things or not, and then some people would say that doesn’t matter, it’s just the nose. And so then you’ve got both of those at play. In terms of testing, there is antibody testing, and so you can do IgG and IgE testing to see if you’re making antibodies for mycotoxins, and Andrew Campbell’s kind of a luminary who has a lab called MyMyco, and so you can do that to try to work that up. 

There’s a research lab that Shoemaker and these guys are starting to work with called the GENIE, and basically what that does, is that looks at a whole bunch of inflammatory genes and will give you an assessment of kind of low, medium, high of how toned on they are. And so then in that population, you see these genie reports, and so they’re all bright red. 

And so then epigenetically, you walked into this water damaged building, you’re breathing it in, you’ve got a biofilm and the molds living there, and so then your brain goes, “Oh, holy crap, this is end of days”, and so it starts to print fight or flight inflammatory aspects of your genome, which is just gonna hypothetically help you respond to this insult, but the reality is the response may be out of proportion to the insult and may be causing more damage than the insult. 

And then finally, with respect to that one, then there’s, people will do an assessment of urinary mycotoxins, and so then the urinary mycotoxins, there’s a couple of labs, Great Plains and RealTime, and if you wanna have controversy, just go find a bunch of mold doctors and ask them which one is the best and even ballot. So a bunch of them are gonna say, the urinary mycotoxin testing is totally invalid, and some are even gonna say the antibody testing is invalid, but, it exists and what I will say, is that you will occasionally see people with significant mold problems, that will have unbelievably high levels of certain neurotoxins, like leotoxin, for example. And it seems out of proportion that you could pick that up from food. 

And so that I think that there’s probably a space for all of this testing, and so then the question is, well, what are you gonna do about it? And so then one thing is, is that there’s… if you wanna have more controversy, go ask the mold doctor, what binder should you use to help these patients? And so then there’s gonna be a whole bunch of different ones, zeolite, and bentonite, and Cholestyramine, and all of these charcoals, but basically what happens, is you’re taking something that is… Chris Shade has one too, you’re gonna have to take something that’s a binder that’s gonna bind onto that mycotoxin. And it could be, it’s gonna hold on to that, and that binder is part of a big molecule, it’s gonna pull that out of the body. 

So then the idea is… the idea is 1.0, fix MARCoNS, and so then there’s an anti-microbial peptide called LL-37, and so we mix that with the xylitol nasal spray, and then have people do that, and that can help from MARCoNS. You can do colloidal silver, you can even do like Betadine rinses, and then there’s the traditional thing that most people did was a long approach of anti-microbial, antibiotic combinations, classic one BEG spray of putting antimicrobials up in the nose to try to break down those biofilms and eliminate where the mold’s living in the body, so then, but so then traditionally, you’re trying to work on that, remediate the house, and then work on binding, and then once you get people, 70, 80% better, then the ultimate kind of of… at a genetic level of regulating the… out of the inflammatory genes, back into kind of a more homeostatic situation, was done with that peptide that I told you about, VIP. 

And so then my sense is that some of the bioregulators will really help this population feel better and particularly, the brain bioregulators, the pineal bioregulators, the spleen bioregulators, and so then the problem is, is that VIP, if you give it to somebody that’s really sick, they get worse. And so there’s been a… the whole thing in the mold community, was to basically try to treat people and then, I first found out about this 10 years ago, and I had people that were, had been doing it for like two years and they were like, “I’m waiting to get to VIP, but I’m…” and then I even knew some people at that point, who did VIP, but they did it too early, and then it was like a catastrophe. 

So then it kinda made me nervous of the whole mold thing, and I was like, “I don’t think I’m gonna do that”. So it’s like so kind of tricky to handle, now I think we do a lot better because they tend to respond quite well to the immune peptides, they tend to respond to the bioregulators and even Holtorf is telling me that he’s using the bioregulators orally, for a lot of these patients, and there’s a big overlap between Lyme and mold. And then what happens, is within that, there are a host of basically symptoms that come out, that these patients will have, so they’ll have dysautonomia. And so they’ll stand up and they can’t vasoconstrict their blood vessels and so they get lightheaded and pass out, and so they’ll have mast cell activation. And so then basically, all of the symptoms are somehow related to immune system dysregulation and the different aspects of the body not working together to do whatever it’s supposed to do, because it’s in a state of constant inflammation and stress. 

So then the idea is knowing that, you can kind of build a model of how you can think about mold, within mold, to kind of circle back to the answer, I think you got to figure out all of these other things, and what I think is that they did incredible work on mold, but the reality is, mold is not mold, to go back to the beginning of my answer, but mold plus these other bacteria, and so then, oh, if it’s mold plus these other bacteria, what do we see a lot of in our practice? Mold plus a couple other bacteria, plus Epstein-Barr and CMV, like if you start to test in this population, you’re gonna start to see everybody… everybody that’s with those symptoms, has four or five things.

And then what’s gonna happen, is if you have somebody that comes in and they’ve got catastrophic long COVID, usually, I look and I find several of those things, and so you wonder, did COVID trigger those, or did they just, did COVID trigger all of this all by itself? And I think they’re basically all in a family, and so then we’re gonna begin to understand them, and then what do we have to do? We have to do things to regulate their immune system, we have to do things to tone down these inflammatory mediators, tone down IL-6, tone down TNF-alpha, and then what is that? Then interestingly, TA-65 actually comes back, I think, as something that could be kind of a home run at having a variety of different mechanisms, protecting our DNA, and then supporting people, as they go through fairly big immune problems.

Joseph M. Raffaele, M.D.

Yeah, it’s interesting. There was a hypothesis by Abraham Aviv about the overwhelming of the immune system that COVID does in severe COVID cases and that may be because of shortening of telomeres and that TA-65 could potentially help and that’s an acute version of sort of the longer version that maybe from a chronic infection with Lyme or mold and it all goes back to basically reserve and then when the reserve is lost, the senescence causes this dysregulation of the immune system. So it’s, yeah, there’s a lot more work to be done, but what’s always fascinating for me is how, and particularly doing the Telomere Summit, is talking to people about their disparate areas, but there’s common physiology, common mechanisms that come together to sort of make the whole thing kind of makes sense, and that’s what’s been really kind of fun and also good for patients. I really wanna thank you for this really interesting conversation, I know that… so you have a practice called BioReset, anything you wanna tell our listeners about that, how to get in touch with you if you have…?

Matt Cook, M.D.

Yeah, thanks, go to bioreset.com, and so then we do a host of things, we take care of these complex immune problems, we try to do an integrative approach, we do everything from plasmapheresis, to peptides, to supplements, and so a diversity of different things, what I found is everything that is helpful and works well for really, really sick patients, will help healthy people do better. So we do a lot of concierge wellness around similar modalities, which I think is fun, and then we take care of a lot of complex pain and sports medicine problems.

Joseph M. Raffaele, M.D.

I’m curious, just as a last question that popped into my head, in terms of sort of assessing these patients with these chronic immune inflammatory disorders, do you use GlycanAge at all in your practice?

Matt Cook, M.D.

No, no, tell me about it.

Joseph M. Raffaele, M.D.

Yes, so GlycanAge is something that would be really fascinating for you, it is based on the glycosylation of IgG, the sugar, non-glucose, saccharides, polysaccharides that are attached to IgG and the sort of the fourth signaling way in the human body, there’s a whole area of glycosylation of lipids, so if you think of the glycocalyx of the arterial system, that’s all sort of the same thing, but within the immune system, Gordan Lauc, who’s from… where is he from? Not the Czech Republic, Croatia, sorry, he has, he’s the world leader on this, I’ve had him on the Telomere Summit, but he has a test called GlycanAge, which is based on a large database of looking at how, what the pattern is on these, on the IgG of these saccharides, and it turns out that that pattern changes quite characteristically from young age, to middle age, to old age, so you can give them a GlycanAge, which is a pattern that’s equivalent to a 55-year-old, versus a 35-year-old, and what they… so in your patients, I would think that there’s probably significantly older GlycanAge because of their immune dysregulation, people that have, it’s not just a marker, people that have that more, the older pattern, their immune system is much more inflammatory, they can activate more easily, they cause more inflammation, and people who have older GlycanAges, have worse COVID outcomes than people have younger GlycanAges, for their chronological age. 

So it’s a test of , just like glycanage.com, definitely something that would be interesting to see, what therapies, one thing that we’ve seen in our practice, which is really fascinating, is that hormone replacement therapy, both in males and females, testosterone in males, in estradiol in females, causes a massive reduction in GlycanAge in patients. 10, 15, up to 25 years of reduction in their GlycanAge, because of the changing of the pattern that the hormone replacement therapy does and which is why perhaps hormone replacement therapy is anti-inflammatory in women. So just another thing to think about in terms of testing, and I’d be happy to offline, tell you more about it.

Matt Cook, M.D.

Yeah, I would love to, I went to a lecture on it at a forum, and…

Joseph M. Raffaele, M.D.

Who gave that? Not Gordan, it wasn’t Gordan, I don’t think.

Matt Cook, M.D.

No, I didn’t know who it was, I didn’t catch their name, but it’s… so then basically, it’s almost kind of analogous to you don’t want too much like glycosylation of your hemoglobin or anything basically.

Joseph M. Raffaele, M.D.

No, it’s not that, so that’s the interesting thing, now, people think that that’s what it is, and that’s perfectly reasonable, but it’s not about… they’re not glycation end products, this is actual… these are supposed to be on there, and the pattern is determined by post-line translational modification of the IgG, and so, it’s actually not about… diabetics obviously have that, it’s not about sugar molecules, the glucose molecules being attached, it’s non-glucose molecules, fucose, mannose, cyanuric acid, there’s a whole literature on it, and I bet you, you’re gonna be fascinated when you dig into it.

Matt Cook, M.D.

Okay, well, thank you so much, it’s super nice to talk to you.

Joseph M. Raffaele, M.D.

Yeah, you too, and thank you for taking the time, hope to catch up with you again at the next meeting fairly soon, and thanks again.

Matt Cook, M.D.

Awesome.