The Underpinnings of Aging and What to Do About It

Kent Holtorf, M.D.

And you practice in Dallas and your winery in Sonoma, where we went to a conference mastermind to, it was great. But a little about Joe, it’s such an honor to have him. He’s a fellow of American Board of Anti-aging Regenerative Medicine. In addition, he’s board certification in internal medicine, he’s board certified in anti-aging and regenerative medicine, has achieved certification by the ABAARM. He has a lot of initials after his name, and advanced metabolic endocrinology specializing in bio-identical hormone therapy. He sees patients at Paradigm Wellness Medical group. He’s in Dallas, Sonoma, but also it looks like North Carolina. And I had the honor to be invited to one of his masterminds at his winery, Lou Conda, great wines, by the way. I don’t know if there’s any spots for the wine club, but, we’re similar, you know. He does successful wine. I started a beer company after medical school. 

We had a hangover free beer double-blind placebo-controlled studies, but as soon as we brought it out, the bureau of tobacco and firearms said, you can’t make a healthy beer. So, we got shut down. But then we came with an energy beer before anyone had it. But our business plan was not very good. It costs us $7 to make it, at that time you couldn’t sell it for more than five. So, we tried to make it up in volume. I’m a doctor, I don’t know these finances and it didn’t work. We kept losing money, but, it was a great fun experience, but he’s the real deal. Patients come from all over the world to see him. He is so generous with his knowledge. He trains doctors from everywhere, he does a lot of aesthetics with threads and a plasma pen, which scares me, it’s hotter than the surface of the sun, but in his hands he can work wonders. And it’s really neat. 

So, I’ve been to a couple of his masterminds, conferences at his winery, which is beautiful setting in Sonoma, that it’s just amazing minds on peptides, on longevity, Senolytics, coming together. And it was just a wonderful experience of like-minded physicians that, you know, they’re geeky on one end, you know, Joe’s Mr. Suave good-looking guy, but he’s also a geek. You can tell. He just researches like crazy. He’s on the cutting edge of, of everything. And again, everything from cosmetics to the sickest person, but it seems like his passion is really having people live better, longer. And he has a whole new way of looking at this longevity. We hear longevity or take this, take that, which really goes after, you know, getting rid of your cells that are causing the problem. So, thanks, Joe. Thanks for being with us. It’s an honor. And I just learn so much every time we get together.

Joseph Cleaver, M.D.

Well, thank you for that wonderful introduction. It’s an honor to be here and to be able to share just some knowledge and education with my colleagues and peers, and just thank you for inviting me. I really appreciate it.

Kent Holtorf, M.D.

Thank you so much. And yeah, so senolytics versus longevity, it’s kind of like, okay, everyone wants to live longer, but one, how do you achieve that? Or is that kind of the goal or how do you, how do you achieve that? What’s so important about Senolytics and what is it, I guess?

Joseph Cleaver, M.D.

Yeah, so the… as we’ve developed what used to be called anti-aging, and we think about the largest educational institution outside of medical schools and looking for integrative medicine programs, the American Academy of Anti-aging Medicine, you know, coined that term decades ago. And we’ve used anti-aging for a lot of years and that anti-aging foundation and the fundamentals of our endeavors to slow the aging process started and still are true today, with lifestyle, the purest form of medicine. It really is. And if we can prevent disease and live a longer life, that’s where I really kind of cut my professional teeth, if you will, at the Cooper clinic in Dallas, Texas, but you know, back in the nineties, we looked at we have the largest, you know, I worked on the database there for a lot of years, and we look at the impact of lifestyle on longevity and the mortality data, all cause mortality data is, you know, is compelling. It’s all the evidence is there. If we live a healthy, balanced lifestyle.

Kent Holtorf, M.D.

Instead of lifestyle, I want the pill we got, we got peptides that makes your body think it’s exercising, makes your body think it’s fasting. So…

Joseph Cleaver, M.D.

We’ve made a lot of advancements in integrative and regenerative medicine that apply to longevity medicine. So, you know, we’ve coined the term longevity medicine and the underpinnings of the mechanisms of improving health span and lifespan. When we drill down deep into the literature and the science of where we used to focus on, we have to control inflammation, we still know that we have to control that low grade inflammation and oxidative stress. And we were taking all these antioxidants and there’s still a very important role for it, but the, that lifestyle, first of all, lifestyle create some of that low grade inflammation. Some of our genetics creates the low grade inflammation. 

What we, you know, certainly what we eat every day creates low grade inflammation, stress, et cetera. And so, we would try to balance those things out with supplements, et cetera. But we’ve become a lot more sophisticated because we know the, one of the most important end results and important drivers of premature aging is something called a senescent cell. And that senescent cell is produced in greater quantities from healthy STEM cells, healthy cells in the body. If we do those things wrong on a daily basis in lifestyle, and we don’t pay attention to what we, this low grade inflammation everybody talks about, and we start getting genetic or DNA damage in our cells that accelerate the number and speed at which we create these cells.

Kent Holtorf, M.D.

Can you go back a minute, what is a senescent cell?

Joseph Cleaver, M.D.

So, a senescent cell is a cell that, is at the end of its lifespan in the human body. It’s no longer functioning. And every system in our body has, first of all, healthy STEM cells, STEM cells that reproduce skin cells, epithelial skin cells, so we don’t get wrinkles, in our heart, so we don’t get heart disease or heart failure, or our lungs, our brains that we don’t get Alzheimer’s, et cetera. And as we age our ability to maintain those STEM cells, they also age and over time, the senescent cell, or excuse me, a senescent cell, the healthy STEM cell turns into that senescent cell. And it gets stuck in a state of suspended animation, if you will. It’s one of the ways the human body prevents that cell from becoming a cancer cell. So, in one of the phases, G0 of the life cycle, of the cell cycle, it gets stuck. It does… we normally, a good healthy immune system can destroy that STEM cell through apoptosis and autophagy.

Kent Holtorf, M.D.

How long does it take in general for a STEM cell to become a senescent cell?

Joseph Cleaver, M.D.

So, in the literature supports about a 22 day cycle.

Kent Holtorf, M.D.

That’s it?

Joseph Cleaver, M.D.

That’s it. So, about every 22 days, we see this migration of STEM cells, healthy cells turning into, morphing into these senescent cells. And as we get older, as we go throughout the decades of life, our ability of our immune system to identify them and rid them and basically kill them through apoptosis, becomes less and less effective. So, we look at ourselves and, you know, we go from 20 to 30 and say, well, okay, that was 10 years, I aged a little bit. 30 to 40, we seem to increase that aging process. It accelerates. And it is because these senescent cells are building up in our body until we get to an elderly population where we’re in our older or our later years. And we have so many senescent cells, we have so much inflammation that our quality of life really starts to deteriorate. And those senescent cells really start to increase about after age 60, where our immune system starts to falter and those senescent cell numbers start to increase.

Kent Holtorf, M.D.

So, the senescent cells, when I switch to senescent cells, they’re not just sitting there, they’re actually causing problems.

Joseph Cleaver, M.D.

So, true. What happens is every place in our, every system in our body has STEM cells. And that has a ratio of healthy STEM cells to senescent cells. And those senescent cells become eventually, the worst case scenario, is they become SASP cells and they’re secretory phenotypes. In other words, they turn into a, basically a factory that produces inflammatory substances that also pollute in the environment around this healthy STEM cells and start recruiting those STEM cells to become more and more unhealthy and convert to senescent cells. Accelerate the aging process. I’m sorry?

Kent Holtorf, M.D.

So, everything’s a vicious cycle.

Joseph Cleaver, M.D.

It becomes a vicious cycle if we don’t know how to target them, those senescent cells, and to prevent them from becoming senescent. And then if we have them understanding the science, as we know today, and we’re just still scratching the surface, but we do have, tools at our fingertips to be able to prevent senescent cells from occurring. And then if we do have them, we understand ways to actually rid them from the body. And that is for me, my focus of approach to my therapy, my therapies with senolytic therapies, my longevity therapies for my patients today in 2020. That’s the most current literature and science that I know that has a significant impact on our endeavors to improve our longevity and our health span also.

Kent Holtorf, M.D.

See, I love that because, you know, you have, this is good for you, this is good for the cells, good for the cells, but you don’t want to be these senescent cells. You want to get rid of them. So, all your protocols, you don’t, it depends on the order of things, right. You know, just saying, oh, this is good for you, take it. No, you got to do this first, this second, this third. Could you talk about the timing of your protocols?

Joseph Cleaver, M.D.

Well, if we look at and understand that we have we have a group of senescent cells in the body, we have a group of healthy STEM cells, and if we try to nourish or feed or improve the health of a healthy STEM cell, the same mechanisms that are improving the health of a healthy cell, actually improve a cell we don’t want to improve their function. Now we can take a senescent cell and pull it back from, occasionally, we can pull it back from that senescent and make it healthy again, but more often than not, it’s this, that last step on the pathway of senescent cells, that SASP cell that we do not want to promote it’s health, because we do not want that cell to become more efficient and producing inflammatory substances that accelerate the aging process.

Kent Holtorf, M.D.

Yeah. It seems like you’re taking a step, so-called forward, but you’re causing a cell that’s causing problems to live longer. And you may be better for a bit, but it’s going to be one of the ones to go back to senescent. So, yeah.

Joseph Cleaver, M.D.

And that’s rare. So, the most important concept that I explain to my patients that I understand from, you know, the literature and research, which is quite frankly, been around a long time. Senolytics has been in the literature for decades. It’s just coming to the floor now and understanding that this is one of the most powerful imbalances. This is one of the most powerful, I think concepts that have identified human body that have been linked to premature aging. And that premature aging begets diseases of aging, diabetes, there’s no shortage of that, heart disease, Alzheimer’s, dementia, et cetera.

Kent Holtorf, M.D.

Yeah. It’s like, you know, with diabetic patients, and if people do like STEM cells, like bone marrow or fat, they find they don’t work, right. Because you just got these crappy STEM cells that are senescent and you’re just basically giving them more than that. And, you know, what’s interesting is that there is a lot of research on this, one is, and again, I don’t want to be doctor bashing, but you know, how many doctors, even you go to your standard doctor knows about senescence, you know, and senoyltics, or do they care? I mean, they’re in a model that if they did care, they’d be miserable because you know, they’re going to have to take 20 minutes to explain it. No, they already, that’s twice their time they have. And it’s interesting, and like, everyone looks for new research, but you may find this as well. 

You look back, especially on peptides, there’s that people go, oh my God, how do I not know about these hundreds of studies? Well, they’ve been around for 50 years, you know, and it’s just gets overlooked because there’s no drug rep tapping on their door three times a day, trying to get them to buy a drug. And so, it’s really the old literature. And I really think you could go back and look at the old literature, in any specialty except for surgery or something like that, for two months and be better than the specialist, you know. They’re just doing the same thing they’ve been doing in residency and because that’s what they need to do, you know, where you are on the cutting edge. And you’re always… it’s amazing, you know, you’re finding new stuff, but it may be old research that was done, but fascinating stuff, fascinating, you know. And this whole senolytics is kind of blown a hole in everything, oh, take this it’s good for you, good for you, good for you. Well, at what time? You know, do you want to feed these sick cells and make them better at making you sick? You know.

Joseph Cleaver, M.D.

Right, well said. And that’s the, what I’ve termed now is more precision senolytics. When the fact that we have to, if we look at all the, anything from a natural occurring substance in mother nature, whether it be a flavanoid such as quercitin or frisetin or long pepper, that all, all these substances actually are very powerful senolytics, and they can prevent healthy STEM cells from becoming, they can prevent senescent cells, and they also, in addition can actually induce apoptosis of a senescent cell and get rid of them. So, that’s where diet comes in and then there’s supplements that actually can enhance that. But the, what the science shows and that’s all I, I base my therapeutics on, the literature, and take clues from many, many decades of, not forgotten, but there’s so much literature out there that we have to go back and actually revisit some of the very powerful science that has been forgotten, such as, even in peptides, peptides are very powerful in senolytics and in many areas of application of regenerative and integrative medicine.

Kent Holtorf, M.D.

Oh, yeah. Now wait a minute, you’re an anti-aging doctor. You’re not supposed to look at the literature.

Joseph Cleaver, M.D.

And so much of that literature, so much of the science, so much of the basic science, that those mechanisms of action and the science supports the clinical application in many ways anecdotally, there’s so much science that supports how we approach longevity.

Kent Holtorf, M.D.

And it’s interesting. And again, I don’t like, kind of get on soap box with the whole healthcare machine. And, but it’s like, you get the less the doctor knows, the more adamant they are, like, okay, that’s wrong, you know, okay, well, how much have they read? And I’m like, you know, I read more in a day then they do in a year, you know. And I’m sure you’re the same. And that’s what you got to do, you know, and it takes a long time, but, and it used to be, I remember like, you know, going to the library and like picking out the journal and then going to the fax machine and then looking for other journals, not there, whatever, now it’s information overload, right. It’s so much stuff coming at you, with 80% of it is just, you know, whatever, just political stuff.

Joseph Cleaver, M.D.

And so much is hitting really the consumer, the lay person, the person and your patient who will, you know, contact you and talk to you through, you know, my patient satisfaction is, in my patients, for example, in Dallas are word of mouth, I do no advertising. I just do my best and follow my passion, taking care of my patients, but they will come in with so much literature, so many ideas that they see online. And I feel that one of the most important jobs that we do as integrative medicine physicians is to be the gatekeeper for them. You know, we have to be able to, you know, weed through, wade through all the potentially dangerous things that they find, that they’d want to try and find them the most effective, safest, and cost-effective therapies for them.

Kent Holtorf, M.D.

Yeah, I agree. I tell patients, go to the internet and get all the stuff. There’s great information. There’s misinformation. Bring it in. We’ll talk about it. So, many doctors I hear, go, oh, are you the doctor now? No, you have to be an active participant in your health now. And if a doctor tells you stop reading the internet, run. Because they can’t support their therapies. I think it’s great. And I get patients bringing in obscure journals, hey, look at this. I’m like, Oh, that’s interesting. Well, yeah, you know, and there is so much great information that is just bypassed because there’s not a patent on it, there’s no drug rep, and, you know, and that’s where all the excitement is. And I’m telling you the excitement in this, and I hate the term anti-aging or alternative. I hate that even more, you know, because they go, oh, there’s no evidence. Like, are you kidding me? It’s, you know, I’m very evidence-based, I’ve always been. 

And, but I was told, never go to this alternative, and I went, and I’m like, oh my God, they’re more evidence-based than… you know, and a lot of doctors rely on societal recommendations. And you look at levels of evidence. So, you’ve got your double blind, placebo controlled study. You got your meta analysis, you got your single blind, and you got case studies, you know, anecdotal and then below that are societal recommendations. And why is that they’ve shown to be wrong, you know, such a high percent of the time because they don’t change for 20 years. They’re very biased and only get one side and they’re terrible, but what do doctors quote, oh, the, you know, the American Academy or the Endocrine Society says go by the TSH. Okay, well, that’s, I got one patient that says it’s not true. That’s better evidence than the societal guidelines. You know.

Joseph Cleaver, M.D.

You know, all physicians, I think as a profession, collectively are some of the most dedicated professionals, you know, on this earth. And we’re all just trying to do a good job, just that our toolbox and our tools may be a little bit different. And our thought processes, the way we approach patients may be a little bit different and what we, our depth of knowledge and our understanding. We’re just trying to do the best for them. I just know that I’m compelled to get up at 4:00 AM in the morning and comb through… I know what you do, you, I can text you 4:00 AM and find out, what are you looking at in Pub Med, right.

Kent Holtorf, M.D.

I’m still up, I can’t get up early, but you see, there’s no incentive for these doctors because they’re in a system that they could find a cure to cancer, they can’t do it, you know, so why should they find these things? You know. And so, I get mad at the doctors but I used to because it’s so angry. But they’re in an untenable situation. They, if they want to, they’re going to make themselves more miserable, you know.

Joseph Cleaver, M.D.

Yeah, no, I… so true, well said. And I think the, that balance that is even more finely honed in longevity medicine and senolytics, is the fact that, we, as I mentioned before, there’s a lot of science out there, but we are just getting an early understanding, just scratching the surface on longevity and we can improve our, you know, just our quality of life. And, but it’s more fine tuned because we don’t have the luxury of waiting, you know, a whole lifetime to see how well our, our approaches work. We know that, you know, short-term the same parameters that we use in longevity, certainly improve lifestyle. Hormone balancing, if we take a closer look at balancing hormones in men and women, there’s literature out there that does support that, you know, the humans do live longer when you do balanced sex hormones, but, and then we dig a little bit deeper into basic science. You see that, that hormone balancing has a direct effect, for example, on mitochondrial health, and function, and efficiency. It’s like, wow, okay. Yeah, you can define hormone balancing as a longevity approach.

Kent Holtorf, M.D.

Yeah. And you look at, you know, the doctors will say, oh, don’t take hormones, they can cause cancer. Well, yeah, synthetic hormones do, if you want to give a woman breast cancer, give her synthetic progestin. If you want to prevent breast cancer, you give her progesterone. And, you know, and would you say most of the things work epigenetically or change that gene expression?

Joseph Cleaver, M.D.

Yeah. And I think there’s a lot of unknown Epogen epigenetic phenomenon occurring in all our therapies that just haven’t been discovered. And one of, when I give one of my talks on, presentations on longevity and peptides, and I love referring to the GHK-Cu or copper peptide because the Broad Institute at Harvard has over 4,000 studies looking at the impact that copper peptide has on genomic and genetic expression and resetting your human genome to a healthier reset, healthier set, and down-regulating cancer genes, upregulating anticancer genes. The impact it has on misfolded proteins and making a cell healthier. There’s so much knowledge, and literature on a peptide that is, I think, overlooked in senolytics, and I use a lot of it in my programs, just as a, just to improve skin health.

Kent Holtorf, M.D.

And so, yeah, GHK, for everyone out there, you know, it’s a copper peptide, a tripeptide. You’ll see it a lot for skin. It’s a little blue, or it should be, now are you giving it as an injection?

Joseph Cleaver, M.D.

I do. I use it systemically and topically.

Kent Holtorf, M.D.

I mean, it makes sense. It’s doing the same thing. And really anti-aging the whole body, or do you want to know just the skin? And can you talk about, like the so-called theories of aging and how senolytics fits into that?

Joseph Cleaver, M.D.

Well, I, you know, the end result of the theories of aging where we’re looking at, or excuse me, DNA damage, the end result is, is a senescent cell. We can, just as we mentioned copper peptide can actually reverse some of that damage. Telomerase activator actually can go into the mitochondria and help reverse some of the mitochondrial DNA damage, but fundamentally every day, our DNA is being scarred hundreds of thousands of times. I mean, depending on what literature you refer to, where our collective DNA damage results in, essentially our demise and how we protect our DNA and how we maintain and manage our senescent cells, because remember those senescent cells, I mentioned that all the inflammatory substances that are produced go back in the environment, in that STEM cell environment, cause DNA damage and accelerate the other cells to become senescent. So, it’s that vicious cycle you were referring to before. So, protecting DNA in an environment such as we have with pesticides and radiation in this world is one of the fundamental reasons why we age.

Kent Holtorf, M.D.

Yeah, I mean, I think we’re at a more toxic environment than we’ve ever been, you know, I mean, it’s, you know, yeah. Pesticides, plastics, pollutants, EMF’s, all this stuff.

Joseph Cleaver, M.D.

Pandemic stress.

Kent Holtorf, M.D.

Stress is a killer. And it’s interesting all the theories of aging, you know, you got your free radical, but they do all kind of come down to, they argue over all these things, but wait a minute, it’s all about the senescent cell. Like they’re arguing over here, but the common denominator is over here.

Joseph Cleaver, M.D.

Yeah. And that term coined “inflammaging” is the, is really the result of all those insults we were talking about. And that’s a term in the literature that has been used for many, many years and is adopted by many physicians in integrative medicine that talk about inflammation. And because we want to prevent disease, we need to address inflammation because that inflammation is linked to those diseases of aging, which are big, they’re everywhere. They are pandemics, diabetes, heart disease, et cetera, and cancer.

Kent Holtorf, M.D.

Yeah. And it’s all, it’s all about inflammation. You look at like diabetes, inflammation in the hypothalamus causes diabetes, you get insulin and leptin resistance, where, you know, the receptors are inflamed, they don’t see the leptin and the insulin, you know. And you lower that, and low and behold they’re better. Interesting. What types of things do you do or how do peptides play a role in this and the order of things? How does that work?

Joseph Cleaver, M.D.

Sure. Certainly if I start with, because I’m really not going to get into, there’s some very exotic peptides that are cell penetrating peptides that get into the DNA in the nucleus and can reprogram cells to become healthier, or we can target senescent cells through various mechanisms in the body, such as P53 and induce apoptosis, but if we want to swing back the other end of the spectrum in terms of prevention, and we always falls on a healthy immune system. One of the major reasons why we develop cancers and our demise later in life is the fact that our immune system starts to falter. And the thymic peptides are integral in maintaining immune vigilance and preventing immune senescence. And you can certainly, there’s supporting evidence and science shows that synergistically, if we restore thymus peptides to a more youthful level, that our immune system becomes more vigilant and can see a cancer cell starting in the body, for example, and to then be able to identify it and eliminate it. So, those are some of the most important peptides, you know, I think in the senolytic space, in the longevity space are the thymic peptides.

Kent Holtorf, M.D.

Yeah. It’s interesting. And looking at studies and you look at, and this is what I hear all the time, but let’s say someone gets metastatic colon cancer, and then they go, oh, you’re cured. And I’m like, you know, I don’t tell them this, but in six years, it’s going to come back. You know, a cure is five years, right. So, and what they have found is after chemo, your chance of relapse is totally dependent and directly dependent on the level of your immune system. For instance, natural killer cell, it’s monitoring your body for cancer. So, the chemo wiped that out, and now you don’t have anything monitoring. So, of course it’s going to come back, right. And, you know, you have a bunch of senescent cells that they could be there, which are showing even like with chronic fatigue syndrome, they found that 25% have low natural killer cell number. Okay. They’re there, most of them are there, but 75% have low natural killer cell function. 

So, it doesn’t work. The cells are just dysfunctional, you know, and it’s amazing that that’s not, not addressed, but it’s key again, that immune system. Well, and that’s on the, I agree. And that, that is one of the key components on the prevention side is to prevent senescent cells from developing and in identifying them, destroying them. So, it’s one of the fundamental cornerstones of longevity medicine and longevity therapeutics. The overview of senolytics draws on so many areas of therapy that are really quite different. I mean, as I mentioned before, there’s some very natural therapies that are very powerful senolytics. There are mitochondrial peptides. 

We get into peptides, we talked about the thymic peptides, but there are mitochondrial peptides, which I don’t use a lot of. And I, if I do, I use them after I’ve wiped out those senescent cell population in the body and think about how do I want to optimize mitochondria. Mitochondria, we talked about theories of aging before we talked about DNA, mitochondria DNA and mitochondrial function are, are the fundamental underpinnings of a healthy STEM cell and longevity. So, they… you connect the dots every single time from lifestyle, exercise, optimizing mitochondria, certain things we eat in our diet are helpful to mitochondria. Then we move into nutraceuticals that help improve mitochondrial efficiency, whether it be, you know, ALA, resveratrol and activating CERT1, et cetera, to optimize mitochondrial function. Then we get into mitochondrial peptide like, I don’t use, you know, the literature says there are, supports the function of certain peptides that improve mitochondrial function. 

So, you can even look telomerase activator, telomerase, activator it, lengthens telomeres, but when you look at the non-canonical functions of telomerase activator, it has the ability also, when we were talking about GHK-Cu before, but it has the ability to impact mitochondrial DNA and repair mitochondrial DNA. And that’s one of the reasons why telomerase activators are extremely important. I think telomere length is a surrogate marker of STEM cell health and longevity. But if you have very long telomeres, doesn’t mean you’re going to live the equivalent of the, you know, my telomeres are twice what they should be and I’m a 15 year old, I’m not going to live another hundred years. But it is a great marker of, I think mitochondrial health and mitochondrial DNA health. And how far that gets you in terms of longevity, no one knows, but the fact is when we improve mitochondrial DNA, mitochondrial efficiency, it actually has a positive feedback back to telomere health and healthy telomere ends on our DNA that help also to promote longevity or contribute to our ability to live longer or potential to live longer, I should say.

Kent Holtorf, M.D.

Got you, got you. And the mitochondria, you know, we’re taught in medical school, you know, that, oh, the mitochondria just for energy, but a sick mitochondria, they do so much more, you know, they sense danger, they go to the danger response and they start pumping out basically, you know, all this oxidation and sickness. So, yeah, you’re better off getting rid of that cell then, you know, trying to save it. Can you just mention real quick, like, what is a telomere?

Joseph Cleaver, M.D.

Telomeres are the end caps on our DNA. And they are identified or measured in units. And let’s say we are assigned when we’re first born, our telomeres are 10 units long, and each time a cell reproduces, we have to, you know, read our DNA, and when that happens, our telomeres on our end caps become slightly damaged. And the amount of telomerase we have in our body, which we have more early on in life, has the ability to go into that telomere and help heal that injury. So, it doesn’t shorten each time a cell reproduces itself, the telomere shortens a little bit, and it’s kind of like it’s a clock of aging. And when that cell….

Kent Holtorf, M.D.

Every time they replicate, shorten, shorten, shorten, shorten.

Joseph Cleaver, M.D.

That’s right. Each replication a telomere shortens, and when we reach three units, that cell can no longer replicate. And essentially we’ve reached the end of our lifespan.

Kent Holtorf, M.D.

Now, does that cell just sit there until there’s a signal to die? Or is it still functioning or the fact that it can’t replicate does it automatically go to apoptosis, does it die?

Joseph Cleaver, M.D.

I think there’s a parallel between the two, there are cells that will reach senescence earlier on because of DNA damage, but your telomeres may not be a short as cell death. In other words, that cell is still viable, is still alive, but it took, when it converts to a senescent cell and the body can’t, it becomes very resistant to death, actually. So, it’s still in a, it’s still a cell that’s living, but it’s not contributing to the health of issue any longer, it’s a detriment, and we have to get rid of it. And it doesn’t necessarily mean that telomeres have reached those three unit lengths and actually…

Kent Holtorf, M.D.

Go you. So, it’s not the defining thing, as you were saying, but it’s a marker, it correlates with everything. And I mean, there’s so many things that, you know, I think the theories of aging, there’s so many thing, but they’re all taking little parts of it. What do you like to do to, I guess, get rid of these senescent cells first, before you use your quote unquote longevity therapies?

Joseph Cleaver, M.D.

Right. To rid the body of senescent cells, one of the most powerful things we can do is intermittent fasting. We basically starve out a senescent cell. If we create protocols that integrates intermittent fasting periodically throughout a calendar year, for example, we can maintain a lower level of senescent cells because we basically starve them out. And I add the various senolytics to, for example, an intermittent fasting program and an exercise program, and all the things that we can repeat over and over again, at nauseum. But that is one of the most potent ways and most powerful ways to clean up senescent cells in the body.

Kent Holtorf, M.D.

I’ve actually done two hours once. Does that work?

Joseph Cleaver, M.D.

So, interesting comment. So, you know, in my… this is a topic of conversation in so many blogs and webinars, et cetera, et cetera. My experience with senescence and literature is there is a, there’s a cut point at about 15 hours that will improve metabolic health may impact senescent cells to some degree. I personally use a three-day fast on my patients, or I’ll use fasting mimicking diets over five days where they still get some, still get some caloric or calories, and they still have some food, but they do enter certain states that will create that cycle, or start that cycle of cell senescence, cell senescent death.

Kent Holtorf, M.D.

So, that fasting is it the lack of nutrients that, that kills them, or is it something else, or do we know?

Joseph Cleaver, M.D.

I don’t think we know. I think senescent cells do not like a ketonic state. But in simple terms, if I, when I speak to my patients, and say we’re basically starving out those senescent cells. They succumb to that state of, it’s not starvation, but that state of fasting where they can no longer survive.

Kent Holtorf, M.D.

Got you. And you said you do a three-day fast, so you actually not eating anything for three days, just water or what do you do?

Joseph Cleaver, M.D.

So, you know, my patients can do, we do water fasts, three-day water fasts. And you should do it under physician supervision, in my opinion, because we can have some concern about electrolyte imbalances. And if there’s any sugar issues, I mean blood sugar issues, or glucose issues and diabetes, we have to, certainly, we certainly need that medical management and intervention, but even healthy patients, they can become dehydrated. They don’t drink enough water. They become hyponatremic. The longer you fast, obviously the longer we can run into those issues, we can develop those issues. But three-day fast is pretty safe. And the science and the physiology in the human body shows that we start to really, that inflammation really starts to drop off after about three days. And same thing in one of the most studied diets is the fasting mimicking, five day fasting mimicking diet that has been shown to decrease inflammation dramatically on day five, improve cholesterol profile, metabolic health. 

And all the things that we see that improve when we wipe out a population of senescent cells, then we can come back and we want to start up regulating mitochondria with NAD. If you want to do NAD protocols, you want to use (Nicotin Mibriomoside), but whatever, you know, there is some benefit I believe to some of the oral supplementation that improves NAD in the body. As we age, our levels of NAD, which is a fundamental substance, we’ll call it, in mitochondria that mitochondria need to create or produce ATP and produce and maintain cell health and mitochondrial health. At age 60, we have about half the NAD in our bodies that we did when we were 20. And one of the things that is overlooked in my opinion, is there’s an enzyme in the body, as we age, naturally, we increase this enzyme called a CD38 enzyme, that just wipes out NAD. 

So, and NAD is a, you know, start a protocol whether it be subQ or you hang IVs in your practice. You want to control that CD 38 enzyme, because as fast as you give NAD, you’re going to be destroying it because of the CD 38 enzyme. So, to control that CD 38 enzyme, one of the natural flavonoids is quercitin and fisetin works also. These are natural flavonoids that are found in, you know, our cruciferous vegetables, but in supplemental form, in supplement form, they’ve been very integral in decreasing that CD 38 enzyme. That’s when I’ll start, after I wipe out senescent cells, give them quercitin, give them the fisetin, they have it onboard already, and that’s when I give NAD. That’s when you get your most benefit, your bang for your buck, if you will.

Kent Holtorf, M.D.

Yeah, because if you’re just chewing it up and you’re like doing these long IVs. It’s like, okay, you’re just fighting with yourself. Yeah. And it’s, it’s interesting with the flavonoids. I don’t know if you do a lot of genetics, but on my genetics it’s like, every answer was flavonoids. It’s like, okay, you’ve got a weakness in this gene flavonoid, flavonoid, flavonoid. I’m like, oh my gosh. Yeah, yeah.

Joseph Cleaver, M.D.

Yeah. But they’re potent. And they have a lot of, you know, they have a lot of, mechanisms of action in longevity. So if we, you know, certainly if we took all the science that we’ve been talking about for the last hour or so on senolytics, and we just look at the blue zones and how, you know, the most, the best longevity on this earth are driven by genetics, are driven by social networks, are driven by exercise, daily exercise and nutrition, what we put in our bodies every day.

Kent Holtorf, M.D.

Because I think there’s a misnomer. Everyone thinks that genetics determine the person, right. And that’s my knock on these genetic tests. Oh my gosh, I’m going to get this, but you get identical twins, and this person has this environment and this type of lifestyle, this person is totally opposite, totally different. So, what is it about 80% is, you know, basically malleable to lifestyle, nutrition, you know, environmental factors, where genes are okay, the hand you’re given, but it’s what you do with it. And you can turn them on, you can turn them off. You can… yeah. And that’s, I think the key, right.

Joseph Cleaver, M.D.

Those studies are wonderful. I always refer to a Finnish study that looked at identical twins and different lifestyles and compared telomere length actually, over a lifetime. And so, and compared their lifestyle with stress and what they have endured, if you will, in terms of that alostatic load on and how they’ve focused or not focused on healthy lifestyle. And you see shortened telomeres in the identical twin that did not take care of themselves versus the identical twin that lived a very healthy lifestyle with exercise.

Kent Holtorf, M.D.

Yeah. So, your genes, aren’t your destiny, you know, people freak out, they have a APOA4 gene, Oh my God, I’ve got Alzheimer’s, but there’s so many things that you can do now, you know, to basically prevent those things. But with the mitochondria, have you done five amino 1MQ, just curious, it’s hard to get, and I don’t know if you can get it nowadays, but…

Joseph Cleaver, M.D.

I do not. No, I really do a lot of mitochondrial peptides.

Kent Holtorf, M.D.

Got you. And do you like any of the brain peptides? Cerebroicin, cmax, clink, do you like those?

Joseph Cleaver, M.D.

One of the areas of interest I have in my practice is chronic inflammatory response syndrome, which is a, it’s an innate immune system imbalance we’ll call it, where our innate immune system, which is our first responder kind of like that ancient part of the immune system that’s, you know, responds real quick to try and knock out a virus or bacteria, but never gets handed off to the rest of the immune system and shuts the hole…

Kent Holtorf, M.D.

Oh, you just love taking the easy patients.

Joseph Cleaver, M.D.

Yeah, the inflammatory response.

Kent Holtorf, M.D.

Those are tough patients. Yeah.

Joseph Cleaver, M.D.

And so, getting to that senolytics or neurotropes, there’s a, we’ve done a, we’ve created a small database and followed some patients with some neuro testing, cognitive testing, short-term memory, or executive function, et cetera. And we use a, we get a baseline because of what I just described as a systemic inflammation, but we know that that same inflammation is also ongoing in the brain. They have neuroglial inflammation, so they start losing memory. They start losing their ability to function and their livelihood. So, we’re using a neuropeptide called Adhexa, which that is, through the mechanism of hepatic growth factor, we have the ability to increase BDNF, brain derived neurotrophic factor. And everyone knows that that is basically miracle growth for neurons. And we know we can grow neurons now, we can heal the brain and decrease that inflammation. And anecdotally in the short and this small database, we’ve had some very significant success. And I believe it’s, anti-inflammatory not just the BDNF that shuts down inflammation. And within 30 days we see their short-term memory improve. It’s part of a protocol that we use for our CIR’s patients in addition to…

Kent Holtorf, M.D.

Yeah, there’s Adhexa. Great studies on Alzheimer’s and it’s an analog of angiotensin 2A, and Angiotensin is amazing and ACTA, they make so many things, but, yeah, there’s a number of trials with it coming out and it’s amazing. All these trials I’m like, okay, when are they going to finish? You know. And there’s a lot of FDA trials and it’s always a moving target. I believe that, you know, the FDA is not fond of Cerebrolysin currently. But there’s probably more studies on that as a… Approved in 35 countries, no side effects, and they made it a biologic, you know. So, you can’t do it as an injection anymore, but you can get it orally now, which actually, EEG study shows that absorbs, and one capsule’s equal to about two CC’S.

Joseph Cleaver, M.D.

Well, I think that’s one of the promising new developments in peptides where we’re moving off the sterile injectables and moving on to oral peptides, intra-nasal, transdermal peptides that become more and more effective and we can use them to a greater degree in an integrative medicine practice.

Kent Holtorf, M.D.

Yeah. But they all, let me tell you, we’re doing a lot of studies on bioavailability and you think, you know, just a tiny peptide, tripeptide is absorbable, and it’s not, like they’re just throwing everything sublingually and saying, oh, it’s going to absorb. You don’t know, you know, you have to look at the chemistry and we we’ve hired a CRM that basically works with all the big pharma, to develop these ways to make these things absorb. And when you look at, I mean, big pharma has been trying to do it for 20 years, right. I mean, everything’s exponentially getting better and better, but it’s, it’s a lot tougher than, you know, putting something in a wafer and putting it sublingual, you know,

Joseph Cleaver, M.D.

And we have, you know, we have so many disease processes that have just a paucity of therapeutic success. We look at TBI for example, or post-concussion syndrome in the chronic state. And there’s, I think there’s probably some significant effective therapies in peptides. And, you know, one of the products that you know I work with right now that we’re, we’re looking at, you know, treating TBI where we have hypoxia in the brain, et cetera. And the current therapies are just, fall so short.

Kent Holtorf, M.D.

It’s go home and die.

Joseph Cleaver, M.D.

Yeah, right.

Kent Holtorf, M.D.

And sorry, I cut you off.

Joseph Cleaver, M.D.

No, no, it’s fine. It’s just that there’s a lot of TBI researchers out there that are, you know, are all ears looking for just a therapy that has the promise to affect an improvement on chronic TBI or post concussion. You know, the players coming out of professional ball, military, et cetera, that really need to improve those therapies.

Kent Holtorf, M.D.

Yeah. And it’s, I mean, not just the, you know, the football player, I was at a STEM cell conference, and it was actually NIH did a study with SPECT scans. They can tell what position the football player played by where his brain damage was. But it’s reversible and exome STEM cells, peptides. And I know you’ve been working with powdered oxygen.

Joseph Cleaver, M.D.

There is a, there is a product that is under study right now, we’re doing research in various settings that have been showing more and more efficacy to increase oxygen levels in tissue with a product that is actually has benefit by oral ingestion. So we, if you think about the possibilities of being able to drink oxygen and oxygenate tissue, effectively and in various settings, acute and chronic settings, the potential is enormous. And the potential benefit after we get these studies underway and human studies, et cetera, everything from just sports performance, to traumatic brain injury, to wound healing, et cetera, and even…

Kent Holtorf, M.D.

Diabetic foot ulcers. I mean, you can save limbs.

Joseph Cleaver, M.D.

Yes. Yeah. The, you know, the product’s been around nine years, been studied for quite a while, and it’s ready for, we’re really getting into more and more human studies that are going to have a huge impact on a lot of global humanity. The fact is if you can oxygenate tissue in a world that has a shortage of options such as blood to be able to resuscitate, you know, an injured human, injured body with powdered oxygen. When those studies are complete and they certainly come to fruition where I think we’re going to see a huge impact those, on those issues where we have those lack of blood supply in the world, for example. So, that’s a profound one I can think of.

Kent Holtorf, M.D.

No, it’s incredible. Because you know, a couple things, one, you need blood supply there and then two, you need the lungs working, you know. So, you need like, what about COPD patients? They can get off their oxygen and just drink it.

Joseph Cleaver, M.D.

Right.

Kent Holtorf, M.D.

That’s pretty amazing. Or altitude.

Joseph Cleaver, M.D.

Hypoxia, sarcopenia. There’s I mean, the impact long-term of hypoxia on the body is… and COPD. COPD is a long-term…

Kent Holtorf, M.D.

Yeah. Well, my God, my head’s just spinning on my thinking, all these different things. That’s very cool. Because I was like, how the heck, okay, under tremendous pressure you can make the liquid, but how the heck do you make it a powder? Well, leave that to the patent, but that’s awesome. It’s exciting. It’s exciting.

Joseph Cleaver, M.D.

It’s very exciting. And if we think about applications in regenerative medicine and even longevity, if we have the ability to improve mitochondrial efficiency, I adapt in the future at some point in time, I see it even playing a role in, as a senolytic or longevity to improve STEM cell health. If we put an injured athlete in hyperbaric, as you know, we accelerate healing in an acute injury because of the increased oxygen, oxygen tensions.

Kent Holtorf, M.D.

Yeah, and I think there’s going to be secondary pathways. It’s like, okay, then that makes nitric oxide, all the things it does. And I think it’s going to be like, yeah, pleiotropic effect, where you have more oxygen, you have healthier tissues, which stimulate good genes and, you know. Where I think as you get hypoxia, that’s what all inflammation, bad stuff gets secreted, right. Great, interesting. Yeah, love to hear more, more about that. So, kind of in summary, what peptides do you like in general?

Joseph Cleaver, M.D.

Certainly a large part of my practice is aesthetics, regenerative aesthetics. So…

Kent Holtorf, M.D.

And he’s, just to mention, on the cutting edge of all these aesthetics and new, FDA approved, but they’re from like Italy, these threads, I got some, I’m such a wimp, they’re so painless. I mean, everyone is, I remember they were clamoring to get at you like, treat me, treat me. I mean, you know, so, he’s an artist as well, really with face and I was amazing and picked out like exactly what someone needs. It was very interesting. Like I don’t, I don’t have that sense, and just always looking for new therapies as well.

Joseph Cleaver, M.D.

The applications of peptides in aesthetics actually been around quite a long time. And we kind of repurpose them a little bit into hair restoration. I’ve been doing hair restoration for quite a few years and we just dig into the science of the thymosin’s for example, GHK, BPC, all of them collectively can repair the scalp as an anti-inflammatory increasing subcutaneous fat with TB4, activating STEM cells, improving their migration down to the hair follicle bulb and moving a hair follicle into an antigen phase and starting hair growth again. So, peptides are key to aesthetics, just starting in the scalp. GHK has been around since 1970, and studied endlessly as a topical cosmetic. And if you look at it, how potent it can potentially be as a systemic peptide, not just for the minute things we mentioned before, but all those, all those mechanisms of GHK, they also work on the STEM cell, the epithelial STEM cell, the fibroblasts. So, it makes to apply it topically for, sure it works, but why not systemically if we have a, you know, a decreasing, you know, increasing, excuse me, a successive decrease in our GHK as we age.

Kent Holtorf, M.D.

Sure. Well, I’m in LA, so you could just have beautiful outside, but if your inside’s just deteriorated, they don’t care. I’m telling you every time I see you, your hair, you got more and more hair.

Joseph Cleaver, M.D.

I’ve never done a… not once, this is my hair. Thank God I’m blessed. But yeah, the hair restoration is a lot of fun. The thymosins are integral in aesthetics and in regenerative aesthetics practice. And not only as from a topical application, but we know that the ability to accelerate healing is a systemic phenomenon. So, we can use peptides. There is evidence that using systemic peptides, such as TB4, or even BPC, or an oral BPC 157 are very effective in restoring or accelerating that healthy injury that we use in aesthetics to restore. We restore skin, restore tissue, to a more youthful state.

Kent Holtorf, M.D.

Nice, nice. So, you take, you know, I love that you take the application, I think that’s just lacking so much in medicine, is doctors learn this, but they don’t take this and apply it over here, you know.

Joseph Cleaver, M.D.

We repurpose medications all the time.

Kent Holtorf, M.D.

Everyone’s in their own little thing, you have the gastroenterologists, you got the cardiologists, you got the neurologist. And so, patients go to all these different things and it’s like, you know, come in with, you know, 22 diagnoses. And I’m like, what do you think it’s likely, more likely you have 22 separate diagnoses that aren’t related, or there’s something, one thing underlying, you know. But I love that. Any new therapies on the horizon? I love this powdered oxygen. think we’re going to be looking at you know, one of the areas in regenerative medicine, obviously is biologics and whether we use decellularized growth factors that used to be called exosomes, STEM cells, there’s always a moving target as to their application and how you can use them and when you can use them, but more and more of those products are becoming, being reinvented if you will, or redesigned as topicals. 

So, looking at combining, for example, in wound care, as you mentioned before in diabetics, but just in the aesthetics, the post procedure healing time is extremely key to your success. And if we can combine a topical biologic with a, something like a powdered oxygen that supplies that wound and that healing with oxygen, and those growth factors, and all the things we need to accelerate the healing without dampening down that inflammation too much. Because we want to call on those STEM cells naturally to come in and heal. And I think we can find that balance and accelerate that healing and affect a great outcome. Taming those STEM cells with the peptides in addition, that tell that STEM cell to go down that path of healthy, healing, laying down the right collagen, collagen 3 and collagen 1, and not going off and creating scar tissue. So, for me, that’s the very exciting area of development going forward over the next six to 12 months.

Kent Holtorf, M.D.

Yeah. And I think with peptides they’re so synergistic with things, but especially, you know, STEM cells and I’ve given a lot of talks on the synergy, even with the latest virus that’s out. I want to say it because the, you know… With the Ovid K, whatever, pig Latin, but is that STEM cells are reversing that especially added with peptides and, you know, the STEM cells will secrete peptides, whether it needs to be antimicrobial peptides or actually thymosin’s and then all that, like the thymosin’s, BPC stimulate the STEM cells, you know. So, it’s, they’re really a nice combo. And I think you get, you know, one plus one equals five type thing when you use them together,

Joseph Cleaver, M.D.

Wonderful synergies there that need to be explored. And created into products then and utilized in all these areas.

Kent Holtorf, M.D.

Yeah. I, where the FDA is so, yeah, they’re really the enforcement arm of big pharma, but, you know. If you have something that’s exceedingly totally safe and works. Yeah, they’re probably going to try to take it away, but anyways, this has been fascinating. I just love all the stuff you’re doing and just your passion. And I’ve seen you work in person and lecture and appreciate your, just your basically generosity and sharing everything that you do. And yeah, just to see everyone huddled around you, and there’s no shortage of free models for you, but yeah., So, I mean, you’re still doing great work, keep it up. Again, all the mastermind conferences you have, please keep them up. I just learn so much and just meet so many interesting people that are very cool, but a little nerdy side, you know, and…

Joseph Cleaver, M.D.

So, far we’ve been very successful. Our next one’s going to be the end of February, and then we’re going to have, just the all things regenerative medicine coming up in May. So, we already have people signed up and we’re excited for the just, you know, put on the next conference.

Kent Holtorf, M.D.

Nice. And afterward you get some beautiful wines at La Conda. Do you have any more spots in your wine club?

Joseph Cleaver, M.D.

We, yeah, there were some spots left, just have to call the main number, my winemaker will set you up because the wines are, speak for themselves. You’ve been to the wine maker dinner at La Conda conference. And I think that’s one of the, certainly the big draws everybody says when they leave the conference, it’s like, I learned a lot and I felt I was on a mini vacation and just time to relax a little bit.

Kent Holtorf, M.D.

Yeah, a little touch of paradise. And you obviously use your, your power of geekiness to the wines too, in the scientific. And, you know, I can just see you in there, like, you know, analyze them and get that, that ultimate wine. And it comes through. But again, you’re just doing some great things for people and, you know, and I think some of the people that see you, they probably don’t realize, hey, I’m going to live 10 years longer and not in a nursing home. What’s that worth? Right. And when, well, what is it now? 80% of the money is spent in the last year of someone’s life, you know, and they’re just sitting there in a nursing home or ICU half the time, coming in and out, liver transplants, and you can prevent that.

Joseph Cleaver, M.D.

We endeavor to. And we endeavor to make sure that our patients don’t end up in those nursing homes, prematurely.

Kent Holtorf, M.D.

Yeah. So, you’re a godsend to so many people, and I thank you. I’m proud to say you’re a colleague and friend, and thank you for all that you do.

Joseph Cleaver, M.D.

Okay. Thank you for having me today. I thoroughly enjoyed it. Thank you.

Kent Holtorf, M.D.

Thank you. I know you’re just so busy running around, so, I do really appreciate it.

Joseph Cleaver, M.D.

Thank you. Thank you.