Integrative Protocols: Focus on Senolytics, Cell Senescence, and the Role of Telomerase Activation

Colleagues, if you’ve been following me for any time, you’ve heard me speak frequently about aging as the top driver of chronic disease. In today’s interview, I dive into evidence-based integrative protocols to slow down and reverse the aging process. My guest, Dr. Joseph Cleaver MD, is a Fellow of the American Board of Anti-aging and Regenerative Medicine, is board-certified in internal medicine, a rheumatologist, on faculty at A4M and MMI and has authored and published a wealth of research and scholarly articles. He founded Paradigm Wellness Medical Group in Dallas and Sonoma Valley, California, AND he is Medical Director at Boutique Wellness in Winston, North Carolina. Folks, you’ll want to be ready to take notes during this interview, as Dr. Cleaver shares his personalized senolytic protocols specific to patient phenotypes. Listen, share, and leave a starred rating, if you wouldn’t mind! Thanks for listening. ~DrKF

How do we approach aging throughout the lifecycle, including telomerase activity and cellular senescence? In this episode of New Frontiers, Dr. Joseph Cleaver discusses what he considers the “Holy Grail of aging” and shares how he combines integrative medicine with the latest research, diagnostic testing, and nutraceuticals to create personalized senolytic protocols specific to patient phenotypes. As a Fellow of the American Board of Anti-Aging and Regenerative Medicine, Dr. Cleaver practices regenerative aesthetics specifically relating to skin, face, scalp, and hair rejuvenation. He founded Paradigm Wellness Medical Group in Dallas and Sonoma Valley, California. And he is Medical Director at Boutique Wellness in Winston, North Carolina. Stay tuned as Dr. Cleaver dives into the most recent research on longevity medicine and shares his favorite integrative protocols to reverse aging in patients.

In this episode of New Frontiers, learn about:

Dr. Joseph P. Cleaver, MD is fellow of the American Board of Anti-Aging/Regenerative Medicine (ABAARM) and board certified in Internal Medicine (ABIM). As a faculty member at A4M and MMI he lectures both nationally and internationally in longevity medicine, sports performance, and regenerative medicine. He holds the position of adjunct clinical professor at George Washington School of Medicine where he has taught the exercise prescription component of the integrative medicine masters program

Dr. Cleaver lectures extensively on longevity, senolytic science, aesthetics and hair restoration and actively trains medical professionals for A4M, Locanda Renaissance Group LLC. He has authored and published research, textbook chapters and has written numerous articles for international sports and anti-aging magazines. While at the Cooper Clinic and Cooper Institute he has conducted Homeland Security NIH research.

As a Biologics expert with 15 years’ experience in regenerative aesthetics he applies this cutting edge regenerative medical science minimally invasive aesthetics – skin and face rejuvenation. Currently, he sees patients at his Paradigm Wellness Medical Group LLC with offices based in Dallas and Sonoma Valley California and Boutique Wellness LLC in Winston North Carolina.

• TA Sciences
• Telomere Science Library
• TA-65® Helps Support Healthy Immune System
• Paradigm Wellness Medical Group
• Nature study
• UCLA TA sciences test (must contact TA sciences)
• Dr. Joe Raffaele study: A Natural Product Telomerase Activator Lengthens Telomeres in Humans
• CMV research study
• Locanda Renaissance Medical Conference
• Dr. Joe Raffaele: Best Biomarker of Aging (New Frontiers podcast)
• Telomere Integrity (New Frontiers podcast)

• DrKF FxMed Clinic: Patient consults with DrKF physicians
• Clinician Professional Development: DrKF FxMed Clinic Immersion
• DrKF FxMed Nutritional Residency Program

Dr. Kara Fitzgerald: Hi, everybody. Welcome to New Frontiers in Functional Medicine, where we are interviewing the best minds in functional medicine. And today is no exception. I am excited to be speaking with Dr. Joseph Cleaver. If you are familiar with his work, you know he is a Fellow of The American Board of Anti-Aging and Regenerative Medicine. He’s board certified in internal medicine and he’s a rheumatologist. He’s on faculty at A4M, so a lot of you have probably learned from him. He’s on faculty at MMI. He lectures nationally and internationally. He’s a clinical professor at George Washington School of Medicine. His focus is longevity, senolytic science, aesthetics, scalp and hair restoration, and actively trains medical professionals for A4M and Locanda Renaissance Group. He’s authored and published lots of research, textbook chapters, articles for international sports and anti-aging magazines. And while he was at Cooper Clinic and Cooper Institute, he has conducted Homeland Security NIH research.

As a biologics expert with 15 years experience in regenerative aesthetics, he applies his cutting edge regenerative medical science to minimally invasive aesthetics specifically relating to skin, face, scalp, and hair rejuvenation. He founded Paradigm Wellness Medical Group in Dallas and Sonoma Valley, California. And he is Medical Director at Boutique Wellness in Winston, North Carolina. Dr. Cleaver, welcome to New Frontiers.

Dr. Joseph Cleaver: Well, thank you for having me. It is a pleasure to be here.

Dr. Kara Fitzgerald: I am focused on anti-aging interventions these days quite a bit. And it’s always fabulous to have an expert on the show that has a particular angle. We know aging is really the unfortunate root cause of the chronic diseases that we’re seeing every day in our clinical practice. You and I were dialoguing beforehand about cellular senescence. And as a root cause something to be addressed. It’s becoming popular in our world. I’m sure that you are teaching on it. We’re certainly hearing the term all over the place. Clinicians are talking about it. But just, please for our audience, tell me what cellular senescence is and why it’s something that we need to be paying a lot of attention to.

Dr. Joseph Cleaver: Absolutely. Cell senescence, it’s actually a fail-safe mechanism that we’ve inherited from ancestry for millions of years in evolution. That when our cells go through their lifespan… And this is related to some degree to the Hayflick phenomenon that was… Dr. Hayflick had identified and showed that a cell has a certain amount of ability to reproduce itself over a lifetime. And it’s about 50 times a cell can create a new cell. And then at some point in time, that cell reaches its end of life. And that’s the Hayflick phenomenon. And it’s really driven by, most importantly, is telomere length. And as our telomere’s shortened, the lifespan of that cell becomes shorter and shorter, also. But what happens is the human body is extremely smart. And if that cell, at the end of its lifespan… the body, it has the ability to destroy it through autophagy, apoptosis.

Dr. Kara Fitzgerald: Mm-hmm (affirmative).

Dr. Joseph Cleaver: There are times when that senescence cell becomes hung up. And it’s affectionately known as a zombie cell. Because it doesn’t want to die. And this body can’t kill it. And the reason it becomes senescent because the DNA damage over that period of time has created, also, an issue with that cell that may increase its chance of becoming a cancer cell. And it becomes a cancer cell. That’s the reason why it becomes the state of senescence. And it can’t reproduce. So the body’s ability to block that cell from becoming cancerous. So now, we’re stuck with this zombie cell that we can’t get rid of. It won’t become a cancer cell. But what happens is it starts to build up over time.

Dr. Kara Fitzgerald: Mm-hmm (affirmative).

Dr. Joseph Cleaver: In terms of number. And that senescence cell has the ability to convert or turn into something called a SASP cell. And that’s the senescence-associated secretory phenotype. And that SASP cell, is one of the… It’s the bad boy on the block. It’s the one that drives all the low-grade inflammation. It starts pouring out all these inflammatory substances in addition to something called DAMPs. And it pollutes the niche, the environment around it. And it starts recruiting other stem cells to become SASPs.

Dr. Kara Fitzgerald: Mm.

Dr. Joseph Cleaver: So as we build up more of those cells, we have more accelerated inflammation. We have premature aging. And as we go through our decades of life, we age faster because those cells are not being destroyed by our immune system. And that’s the crux. That’s the nexus behind senolytic medicine is cell senescence management.

Dr. Kara Fitzgerald: So we’re understanding that these suckers are at the heart of inflammation. And we need to remedy them. You talked about the Hayflick constant and telomerase in the beginning of this introduction.

Dr. Joseph Cleaver: Mm-hmm (affirmative).

Dr. Kara Fitzgerald: Are we thinking about telomerase activation to deal with cellular senescence?

Dr. Joseph Cleaver: So what we try and prevent cellular senescence through telomerase activation, actually.

Dr. Kara Fitzgerald: Yeah. Okay. Yeah. I’m sorry if I misstated that. But, yes.

Dr. Joseph Cleaver: Yes.

Dr. Kara Fitzgerald: Go.

Dr. Joseph Cleaver: No, that’s okay. And what a telomerase activator can do… Everybody over the decades is looking at, oh, telomere length and what is my biological age. That’s only a small part of the story.

Dr. Kara Fitzgerald: Right.

Dr. Joseph Cleaver: I call it a surrogate marker for stem cell health. In other words, if you have long telomeres, those telomeres actually have a cycle between telomerase activator, telomere length, and mitochondrial health and mitochondrial biogenesis. And one of the other drivers behind cell senescence is mitochondriopathy or disfunction of mitochondria. Those little power packs in our cells that make up over at least half our weight in body weight. So they’re very important. They make our energy. They make the fuel that we need to function. It’s called ATP. But the non-canonical, the other abilities of a telomerase activator, are not just to prevent and slow or maybe even reverse some of the telomerase length at the end of the DNA, but it also has the ability to transport or move into the mitochondrial DNA. And go into the mitochondrial DNA and start healing mitochondrial DNA. And protect that mitochondria from dysfunction.

Dr. Kara Fitzgerald: Wow. Wow. Okay. So fun- Yeah.

Dr. Joseph Cleaver: An important point of that is that we have… there’s a lot more mitochondrial DNA damage than there is nuclear damage in a cell. So telomerase activator, as we age, starts to decrease over time. And adding a healthy dose, if you will, a healthy amount of telomerase activator to that formula actually improves and preserves stem cell health and function. And prevents, in my opinion, a healthy cell moving into that senescence state.

Dr. Kara Fitzgerald: So we can’t necessarily expedite the removal of the zombie cells. But we can prevent the buildup.

Dr. Joseph Cleaver: Oh, well. We absolutely can. When we look at the science of senolytics, actually, you look down the pathway of a young healthy cell, to an aged cell, to a senescence cell.

Dr. Kara Fitzgerald: Mm-hmm (affirmative).

Dr. Joseph Cleaver: Somewhere in that process, telomerase activator is involved. And I believe it’s involved in preventing a healthy cell from becoming senescent. Now, when we get into a senescence cell and it turns into that, as I always refer to as the bad boy, because the SASP cell is the one that is really changed. It’s actually had an increase in its up regulation of its function. And that function is to make an enormous amount of inflammatory markers such as IL-6, and MMP-3, and MMP-9.

Dr. Kara Fitzgerald: Mm-hmm (affirmative).

Dr. Joseph Cleaver: That are responsible for the aging process and the development of those diseases that you mentioned before, prior…

Dr. Kara Fitzgerald: Mm-hmm (affirmative).

Dr. Joseph Cleaver: … that’s related to aging. Diabetes, stroke, and dementia, et cetera, et cetera.

Dr. Kara Fitzgerald: All right. So then how are we… Well, all right. So I have a lot of questions. We’re going to circle back to…

Dr. Joseph Cleaver: Sure.

Dr. Kara Fitzgerald: We want to make… I want to unpack what it is that you’re doing to address this in individuals. But I also want to understand senolytics, as a class of small molecules.

Dr. Joseph Cleaver: Right.

Dr. Kara Fitzgerald: And what they do. If they’re able… Why don’t you introduce us to senolytic agents and what their role is in addressing senescent cells. And improving, maybe, shutting down these SASPs. And pulling us from the precipice of the chronic diseases of aging.

Dr. Joseph Cleaver: Right. So really what happens is… At least in my approach to senolytics is prevention of development of the senescent cell. And that starts out… We’re in the developmental phase as humans, as a species, to we’re in our mid-20s. We’re really not aging. We really peak in our development somewhere around that age group.

Dr. Kara Fitzgerald: Mm-hmm (affirmative).

Dr. Joseph Cleaver: And then we move into our 30s, and we start seeing a few lines, a few wrinkles, and maybe we have a few aches and pains. We’re not slowing down. We’re still in our prime. But each decade of life adds more and more of senescent cells. And we start building up senescent cells at some point in time. And that’s keenly linked to our lifestyle. If we live a high inflammatory or a high risk lifestyle where we’re eating high inflammatory foods… We have a lot of stress that we don’t manage. We don’t get adequate sleep and restore our cells and our systems affectively. We’ll accelerate the aging process. A lot of this is self-inflicted. A lot of the diseases of aging are linked to premature aging and the build-up of senescent cells.

Dr. Kara Fitzgerald: Yeah.

Dr. Joseph Cleaver: So there’s two targets, if you will. One of them is prevention.

Dr. Kara Fitzgerald: Yeah.

Dr. Joseph Cleaver: Prevention of a healthy cell moving into a senescence state. And then when we have those senescent cells, managing those senescent cells. If and when they become a SASP cell, that secretory cell, that is really going to have that aging process take off and the disease process take off. And the recruitment of the stem cells around them through that paracrine effect of the substances they’re producing. Those are the two targets. So we want to…

Dr. Kara Fitzgerald: That’s interesting.

Dr. Joseph Cleaver: The pure definition of a senolytic is apoptosis or autophagy killing that SASP cell and moving it out of the body. So-

Dr. Kara Fitzgerald: Okay. So these are molecules that are going to just destroy the SASPs.

Dr. Joseph Cleaver: Yes. That’s correct.

Dr. Kara Fitzgerald: Okay. All right. Okay. So then talk about both. Well, why you got here. It’s an amazing field. It certainly makes sense. And I just read your bio and your bio is sort of in keeping that you would land here. But really, what got you here.

Dr. Joseph Cleaver: Yeah.

Dr. Kara Fitzgerald: And I want to hear your protocol. How you developed that.

Dr. Joseph Cleaver: Yeah. And I just gave you a little insight into how I approach things.

Dr. Kara Fitzgerald: Mm-hmm (affirmative).

Dr. Joseph Cleaver: And when you walk into a regenerative integrative medicine conference 15 years ago, and your whole mindset changes. And how you approach disease.

Dr. Kara Fitzgerald: Right.

Dr. Joseph Cleaver: And I started very early. I started my career early in Dallas at Cooper Clinic. And it was really one of the original functional medicine clinics, integrative medicine clinics. They didn’t really realize that. But it was all based on lifestyle and prevention.

Dr. Kara Fitzgerald: Mm.

Dr. Joseph Cleaver: And that’s the pure form of medicine. So if we even take it to the next step, we can look at lifestyle. Diet and exercise, all these things really are a form of senolytics. They’re a form of the ability to prevent senescence and actually kill these cells.

Dr. Kara Fitzgerald: Yes.

Dr. Joseph Cleaver: And create apoptosis. And that’s why people who are more fit and people who eat a Mediterranean Diet have longer telomeres and live longer. Rewind it back to 15, 20 years ago, everybody was talking about antioxidants and DNA damage. And how that ages us prematurely. And then we start digging in deeper. And I don’t want to get into all the epigenetics of it, but we realized that the result of lifestyle and DNA damage, and things we can’t control, UV light, and radiation, et cetera, have scarred our DNA every single day thousands of times. And the more our DNA gets scarred, the faster we’re going to develop these senescent cells.

But now we start fast-forwarding and about seven years ago, I started reading literature on cell senescence. And I was like, “Well, that’s the end game right there.”

Dr. Kara Fitzgerald: Yeah.

Dr. Joseph Cleaver: If we are able to manage our cell senescence, then that is where I want to focus my patient population or my therapies for my patient population. It’s still prevention, but now I think I have a kind of… We’re looking at the Holy Grail of aging.

Dr. Kara Fitzgerald: Yeah.

Dr. Joseph Cleaver: At least in current literature, what we look at, what is happening, or what is being the focus of research is cell senescence and senolytics. And how do we develop-

Dr. Kara Fitzgerald: That’s so fascinating.

Dr. Joseph Cleaver: How do we develop therapies…

Dr. Kara Fitzgerald: Yeah.

Dr. Joseph Cleaver: … that manage these cells that are causing this or shortening our lifespan, possibly. But equally, our health span. So prevention-

Dr. Kara Fitzgerald: So you were- Yeah. So you came from this sort of broad sweep lifestyle medicine, preventative medicine. Very important, essential. But it sounds like you had this big aha drilling down into the mechanism. And that was a real game changer for you.

Dr. Joseph Cleaver: Absolutely. When I started to… I almost felt like I was being a little reactive. Meaning, “Okay. We’re going to look at your…” We have this integrative approach. And we say, “Okay. We’re going to determine how toxic you are, how inflamed you are. What we’re going to do with lifestyle.” But it was almost reactive. What are we going to do with… Okay. We probably have some oxidative stress going on.

Dr. Kara Fitzgerald: Mm.

Dr. Joseph Cleaver: So we’re going to balance things out in life. And then we’re going to start giving you… recommending certain supplements and antioxidants to control these things. But… And that’s part of the program. But now when I peel the onion in senolytics and longevity, it’s like, oh, at the center of this right now… And we’re still scratching the surface. It’s very, very early. The therapies we have. But they’re focused on targeting the SASP cell. And that is the essence. That’s a pure definition of senolytics.

Dr. Kara Fitzgerald: So, I guess… I want to hear… So, three things. I want to hear what some of the top senolytics are, both natural and pharma.

Dr. Joseph Cleaver: Uh-huh (affirmative).

Dr. Kara Fitzgerald: And I would like to hear, of course, we all want to hear about your protocol. And then I’ll ask you questions there. Like how your… kind of tests you might be using to evaluate. And then if you have any cases tied to any outcomes that you can share with us. That would be interesting.

Dr. Joseph Cleaver: Well, if we break it down by… First of all, if we break it down by each system, we can trace, for example, hair loss.

Dr. Kara Fitzgerald: Mm.

Dr. Joseph Cleaver: We can trace hair becoming gray.

Dr. Kara Fitzgerald: Mm.

Dr. Joseph Cleaver: Lines and wrinkles. Maybe a little slowing of your cognition, your executive function. I just can’t remember where my keys are.

Dr. Kara Fitzgerald: Yeah.

Dr. Joseph Cleaver: Or what was that guy’s name or that girl’s name, I can’t remember. That is, in my opinion, each system has a senescent burden. And that senescent burden is creating a small amount of… It looks like aging, but that is a consequence of low-grade inflammation. Low-grade inflammation that we experience as we move through each decade of life.

Dr. Kara Fitzgerald: Okay. So we all have-

Dr. Joseph Cleaver: So-

Dr. Kara Fitzgerald: We all have some of that going on.

Dr. Joseph Cleaver: Yeah. We all… We do.

Dr. Kara Fitzgerald: And I want to know what you’re doing for gray hair. Just that’s my little self-absorbed curiosity going on.

Dr. Joseph Cleaver: I do have an answer for that, actually. I can actually target your melanocytes, your follicular melanocytes. I have cases where I have patients who are… Well, I don’t know if they’re prematurely gray. Let’s call them 50 and lost all… they’re totally gray, 100 percent gray. We can target those melanocytes and they become functional again. And they stop producing peroxide. And they actually can… you can create color in hair again with certain approaches therapy.

Dr. Kara Fitzgerald: Are you serious?

Dr. Joseph Cleaver: So I’ll tell you about that if you’re interested.

Dr. Kara Fitzgerald: I do want… yeah. I do. It’s totally selfish and kind of superficial, but I’ve got to know. All right. Keep going about senolytics.

Dr. Joseph Cleaver: Yeah. So as I mentioned, we are really scratching the surface. And how I approach my programs are… One thing that has come to light, and it’s a wonderful tool. And it’s through TA… I actually wrote a collaboration with TA Sciences and UCLA. And we can look at cell senescence burden in a lab test now. Prior to that it was, “Okay. I think you have inflammation. I think you have a lot of these senescence cells or secretory cells.”

Dr. Kara Fitzgerald: Mm.

Dr. Joseph Cleaver: “I’m going to look at marker…” I can do an IL-6.

Dr. Kara Fitzgerald: Right.

Dr. Joseph Cleaver: I could do a cytokine panel. I could look at inflammatory markers. And then I can look as a physician, and understand if somebody is pre-diabetic. Or somebody has pre-hypertension or hypertension. Or they’re… Those are markers of aging. So I know they have senescent cells in those organs. And a combination of those two, I can develop, certainly, a plan. And that’s based on, certainly, somebody who is 35 versus 55 who’s going to have a different cell senescent burden. And the approach to prevention and treatment is going to be different. And the aggressivity, how aggressive I’m going to be in using certain therapies, is going to, certainly, change based on those parameters I just outlined.

So initially, if I have somebody who is very focused on their health and they’re, let’s say, they’re 40 years old. And they’re very healthy. And they’re really into prevention. They’re really into balance in life, et cetera, et cetera. And all their standard assessments look great. The blood sugar’s controlled. The blood pressure’s controlled. And they’re… You do a whole battery of testing we do in integrative medicine. And say, “Okay. I don’t think there’s a lot of senescence here. I’m going to look at a preventive approach.” And when we have somebody in that group, we’re focused more on natural therapies such as the flavons or flavonoids. Such as Fisetin, which has come to light as a very potent senolytic. And it works both-

Dr. Kara Fitzgerald: Right.

Dr. Joseph Cleaver: It works both sides of that equation, that pathway I mentioned before. It has the ability to prevent cell senescence. So it maintains a stem cell health. But it’s also a senolytic. It has the ability to cause apoptosis and autophagy in a SASP cell. That’s a perfect match for somebody in that age group.

Dr. Kara Fitzgerald: Wow.

Dr. Joseph Cleaver: Now, if we kind of fast-forward or move to somebody who’s a little bit more… has a little bit more age on them. Let’s say a 60-year-old, for example. Still very young in my world, actually, as an anti-aging, longevity doc in practicing senolytic medicine. The evidence showed… If you do this long enough, the number isn’t that important. You look at what that person has done in their life and how they’ve taken care of their health. And you can have significant issues that in a 40-year-old that you see in a 60 year old, and visa versa.

Dr. Kara Fitzgerald: Right.

Dr. Joseph Cleaver: But just for clarity’s sake, we take a normal, if you will, aging path of somebody 40 and somebody who is 60. Now, we’re dealing with someone whose immune system is a little bit… we call it immunosenescent. So we have a certain amount of the immuno vigilance that is lost.

Dr. Kara Fitzgerald: Mm-hmm (affirmative).

Dr. Joseph Cleaver: And that is why as we age and get into later decades in life, we have more and more cancers. Because the immune system doesn’t have the ability to recognize a cancer cell, for example. It doesn’t have the ability to attack, or cause, or induce autophagy and clean out the senescent cells or the SASP cell, the secretory cell. So we have a 60 year old who is losing some energy, losing a little bit of their memory, if you will, their mental acuity, their sharpness. And they say, “Oh, I’m just getting old.” No, you have a lot of… in my opinion, you have a lot of the secretory cells that are wreaking havoc on your healthy stem cells and the function of your organ systems.

Dr. Kara Fitzgerald: Are you testing… Are you getting that cellular senescent assay on all your patients?

Dr. Joseph Cleaver: So UCLA and TA Sciences have a, certainly, the immune health test, if you will, that is… What I see now is we’re heading in a direction of this is probably the master switch, if you will, of aging.

Dr. Kara Fitzgerald: Okay.

Dr. Joseph Cleaver: It could be, let’s say.

Dr. Kara Fitzgerald: Okay.

Dr. Joseph Cleaver: Because there was just a study that was published in Nature about two weeks ago out of, I think, University of Minnesota. And showed, at least in animal studies, that there’s a direct correlation of immunosenescence. In other words, an increase of a CD28 cell, marker cells. And a decrease in naive cells, naive T cells, CD95s. And it spills over, if you will, in this lab in this study that showed solid organs are also affected because of that cell senescence. And then when you use a senolytic such as Rapomycin, which is a rapalog that has been tested and been shown to decrease something called mTOR. And mTOR works both sides of that equation, also. It helps prevent the onset of senescence. But it’s also a very potent senolytic. And when we clean up the immunosenescence in the animals and when they cleaned up the immunosenescence in the senescent cells in the immune system, it improved, also, the function and senescence in the other organs that are listed in the study.

Dr. Kara Fitzgerald: Wow.

Dr. Joseph Cleaver: And that was-

Dr. Kara Fitzgerald: That’s beautiful.

Dr. Joseph Cleaver: Brain, heart, lung, kidney, liver, et cetera.

Dr. Kara Fitzgerald: So they sort of just went after these general senescent cells. And kind of turned around organs, solid organs.

Dr. Joseph Cleaver: Right.

Dr. Kara Fitzgerald: Okay.

Dr. Joseph Cleaver: And to me, that’s a aha moment because…

Dr. Kara Fitzgerald: Big aha moment.

Dr. Joseph Cleaver: I’ve been working really hard, diligently, trying to customize and personalize my senolytic program based on… As I mentioned, we’re just scratching the surface on how… what we have at our fingertips to deploy for our patients and utilize. And which ones are system specific. And that’s been, certainly, a challenge. Say, “Okay. Well, you have a family history of hypertension, heart disease, et cetera, et cetera. I’m going to really work on your endophilia health.” And in addition to all the things we do in integrative medicine, nitric oxide, et cetera, pomegranate… other endophilia supplements that improve endophilia health. Let me take a look at the senolytic literature and match the senolytic to that organ.

Dr. Kara Fitzgerald: Hm.

Dr. Joseph Cleaver: And there are some matches, but they’re few and far between.

Dr. Kara Fitzgerald: Right.

Dr. Joseph Cleaver: So one of the early… These studies are very early, looking at repurposed chemotherapeutic agents, Rapomycin, Dasatinib, et cetera.

Dr. Kara Fitzgerald: Right.

Dr. Joseph Cleaver: Immuno-modulators. Quercetin has been shown to actually have more benefit killing endophilia SASP cells, secretory cells. So we’re going to focus on your endophilia health, in addition to all your other organs and your systems I know have senescence. But this one’s particularly a problem for you.

Dr. Kara Fitzgerald: Right.

Dr. Joseph Cleaver: So we’re going to make sure you’re on this natural therapy. And that’s going to be quercetin.

Dr. Kara Fitzgerald: Cool.

Dr. Joseph Cleaver: In addition to other therapies that I would normally use.

Dr. Kara Fitzgerald: So I just want to circle back for our show notes… We’ll get the Nature study into the show notes. And if we can get a link to that UCLA, TA Sciences assay, that would be amazing. So then… Okay. So I just want to make sure I’m understanding you. You’re using a senolytic, maybe, cocktail. So you’re doing some general interventions for whatever the 60 year old is presenting with. If it’s heart disease or moving in that direction. Hypertension, et cetera. So you’re doing general integrative functional medicine. Then you’re also putting together a senolytic protocol for them specific to their phenotype. Am I following you on that?

Dr. Joseph Cleaver: Yeah.

Dr. Kara Fitzgerald: You said-

Dr. Joseph Cleaver: Yes. That’s correct. And there is a, certainly, a template I use for just about every patient and age group. Is one of the most potent ways… And it’s lifestyle that I mentioned before that a lot of the things that we do in lifestyle are actually not… can be defined as senolytics. And if we use, for example, intermittent fasting…

Dr. Kara Fitzgerald: Mm-hmm (affirmative).

Dr. Joseph Cleaver: Or fasting mimicking diet, that’s the first step that I use to start a senolytic program. And the reason why is if we take a step back and we want to use everything we have at our fingertips to maintain a healthy stem cell… We use mitochondrial support. We use NAD. And all the other supplements we don’t have to go into. And we realize that if we’re supporting a healthy stem cell, whether it be supplements, or peptides, or NAD that improve mitochondrial health, there’s literature that you can really just base your next step on or your cautionary therapy on because if we are making a healthy stem cell healthier, we’re also making that bad secretory cell healthier and more functional.

Dr. Kara Fitzgerald: Hm.

Dr. Joseph Cleaver: So the first thing we want to do is eliminate that secretory cell. And one of the most potent ways… one of the most, honestly, inexpensive, easy, lifestyle ways to do it is fasting.

Dr. Kara Fitzgerald: Yeah.

Dr. Joseph Cleaver: And it’s been shown over and over again. Intermittent fasting.

Dr. Kara Fitzgerald: Yeah.

Dr. Joseph Cleaver: And intermittent… You know where intermittent fasting actually was discovered?

Dr. Kara Fitzgerald: You mean beyond Longo?

Dr. Joseph Cleaver: Yeah. Beyond Longo, yeah.

Dr. Kara Fitzgerald: Do tell.

Dr. Joseph Cleaver: Yeah. And I always… I don’t know why I always block it on this researcher’s name. This was in the… This was in a story, in literature somewhere. Anyway, right around the Depression, right at the end of the Depression, a scientist, a researcher, who had a lab and he had lab animals. And he was doing animal research. And let’s say he had 100 rats. And nobody had any money. The economy was trashed. And he was trying to keep his lab open. And what he did was he started rationing the chow for his animals. And he split up the animals he had. And one of them got full amount of food they normally would eat. And the other half, actually, he rationed them. And he fasted them.

Dr. Kara Fitzgerald: Hm.

Dr. Joseph Cleaver: And as a scientist, researcher, he actually realized after a period of weeks that the rats that he actually fasted were living longer.

Dr. Kara Fitzgerald: Isn’t it fascinating?

Dr. Joseph Cleaver: I know. And I wish I could remember his name. I don’t know why. I always blank on his name. But that is the story in the literature. If you look for it, you’ll find it. It’s like, “That’s where intermittent fasting, the concept, started.”

Dr. Kara Fitzgerald: Really started.

Dr. Joseph Cleaver: Published in the literature-

Dr. Kara Fitzgerald: There’s some-

Dr. Joseph Cleaver: Yeah?

Dr. Kara Fitzgerald: There’s some- There’s a-

Dr. Joseph Cleaver: It’s like, “Oh, my God.”

Dr. Kara Fitzgerald: Yeah. There’s the cohort out of the Netherlands where they showed the first generation of, not starving, but less food. Actually, offspring generations later were healthier.

Dr. Joseph Cleaver: Healthier. Yep.

Dr. Kara Fitzgerald: Yeah.

Dr. Joseph Cleaver: Yep.

Dr. Kara Fitzgerald: And so that’s… I know. It’s pretty amazing. So that’s a fundamental first step approach for you. I guess… So what I’m curious is you’ve got sort of phenotype specific, condition specific things that you’re doing. Your lifestyle things. But you also said in the beginning really clearly that cellular senescence is root cause.

Dr. Joseph Cleaver: Mm-hmm (affirmative).

Dr. Kara Fitzgerald: And as you… You talked about this Nature paper where they made a difference, sort of a system wide difference. So are there interventions that you’re using kind of across the board for cellular senescence? For most of the patients that you’re working with? And what are those?

Dr. Joseph Cleaver: Yeah. So I phase in the senescent steps, if you will. And the first thing is to wipe out the secretory cells that are causing all the inflammation.

Dr. Kara Fitzgerald: Okay.

Dr. Joseph Cleaver: And then you can do… I use several… There are theoretically peptides that are actually very potent senolytics that are able to deliver P53, which is a potent senolytic in the body naturally occurring, that can destroy mitochondria in a secretory cell and kill it. Thats FOXO4-DRI, it’s actually… You can find it. But it’s difficult to find. So Fisetin is started right away. Even the Rapomycin that is repurposed as a… is basically a chemo therapeutic agent in very low dose.

Dr. Kara Fitzgerald: How are you dosing it? Rapomycin?

Dr. Joseph Cleaver: It’s one to two milligrams every one to two weeks.

Dr. Kara Fitzgerald: Okay.

Dr. Joseph Cleaver: And in that dosing range, you see zero to very few side effects. You can see some increase in blood sugar. But it’s been shown in several studies to from brain to just general, as a senolytic, to decrease the senolytic or the senescent cell population. So it’s one of the most… It’s still very early. But it’s probably the most studied right now. And it’s probably one of the most widely used senolytics in senolytic medicine.

Dr. Kara Fitzgerald: Mm-hmm (affirmative).

Dr. Joseph Cleaver: And that is used… That’s basically used year round.

Dr. Kara Fitzgerald: Okay.

Dr. Joseph Cleaver: And the other basis for… So after we get rid of all the SASP cells, we want to create a senescent cell. We want to go for prevention of additional senescent cells. And we dump senescent cells all the time. I’ve read a lot of different cycles. Every couple of weeks, we’ll dump senescent cells. We’ll start building them up. And that cycle is dependent on how the original assessment, the initial assessment of that patient, how inflamed they are, the senescent cell burden. And now, I can rely on the UCLA testing looking at the breakdowns of the senescent cell buildup. Now we can see it through lab testing. Before we couldn’t.

Dr. Kara Fitzgerald: Right.

Dr. Joseph Cleaver: So that’s a huge improvement.

Dr. Kara Fitzgerald: Yeah.

Dr. Joseph Cleaver: A wonderful addition to being able to assess your patient.

Dr. Kara Fitzgerald: Right.

Dr. Joseph Cleaver: So after we clean up SASP cells, what do we want to do? We want to do everything we can to maintain healthy stem cells and system function.

Dr. Kara Fitzgerald: Mm-hmm (affirmative).

Dr. Joseph Cleaver: And one of the fundamentals that I’ve used for 10 years in my practice is telomerase activator, TA-65.

Dr. Kara Fitzgerald: Mm-hmm (affirmative).

Dr. Joseph Cleaver: And I knew it was working, but we didn’t really know how. Everybody focused on telomere length. And then I started digging deeper. And I mentioned those non-canonical ability of a telomerase activator to really resuscitate and maintain mitochondrial biogenesis and mitochondrial DNA health and preservation. That is where, I think, the real impact of telomerase activator comes into play, at least in my programs. And if we’re able to maintain mitochondrial health, we maintain healthy stem cells and we have less senescence. And I’d have to ask Dr. Rafael what his new theory is on how TA-65 decreases senescent cells. But looking at the science, I believe that’s where that rate limiting step is. We maintain healthy stem cells. And to me, telomere length is a surrogate marker of a healthy cell.

Dr. Kara Fitzgerald: Yeah.

Dr. Joseph Cleaver: But I know those telomere length in the literature says, “Oh, you have health mitochondria. If you have healthy mitochondria, those stem cells are going to function beautifully and not become senescence or minimize their ability to transition into senescence.

Dr. Kara Fitzgerald: So you do the cleanup protocol at the beginning for… it’s probably different depending on how far along the person is on their aging journey. But about how long do you do that first piece before you introduce the…

Dr. Joseph Cleaver: Right.

Dr. Kara Fitzgerald: …. TA-65.

Dr. Joseph Cleaver: Yeah.

Dr. Kara Fitzgerald: And I want to hear what else you’re doing, also.

Dr. Joseph Cleaver: So it’s about a one to three month cycle. Most of it is with intermittent fasting and the flavonoids, meaning… I certainly use a lot of Fisetin. You can use Quercetin. Apigenin is another flavonoid.

Dr. Kara Fitzgerald: Mm-hmm (affirmative).

Dr. Joseph Cleaver: That is more potent for prostrate health and actually rendering… and being studied right now in prevention and treatment of cancer, especially prostate cancer. So they have their own specific or particular characteristics. But Fisetin, when you look at it as a broad spectrum, if you will, senolytic, it is… first of all, it’s easy to acquire. It has… The highest amount of Fisetin in Mother Nature is in strawberries.

Dr. Kara Fitzgerald: Right.

Dr. Joseph Cleaver: But if you have a very bio available supplement, it works quite well. And you can pulse your patients for a period of time with Fisetin or Quercetin. And that senolytic affect will last for weeks.

Dr. Kara Fitzgerald: How are you dosing it? In a regular pulse.

Dr. Joseph Cleaver: So Fisetin, it can cause some GI distress at higher doses. If you’re on the mark, and Fisetin’s like 500 milligrams…

Dr. Kara Fitzgerald: Okay.

Dr. Joseph Cleaver: I’ll start out the 500 milligrams. And I will push them to tolerance. So say, “Okay. Take 500 to 1,000. Then 1,500 to 2,000.” And if I can get them up to 2,500 to 3,000 milligrams a day, I think that’s having a significant impact on killing the SASP cell as a senolytic, along with intermittent fasting.

Dr. Kara Fitzgerald: Yeah.

Dr. Joseph Cleaver: Then I want to bring in… If I want to bring in now… If I’m confident over a period of time… And this is based on really experience and understanding the markers of that patient. And you can actually see improvement of a lot of parameters just using the flavonoids. Then I start them out on… Now that I’ve cleaned up a cell that I don’t… a SASP cell that I don’t want to… can improve their health and function. Then I can actually bring in… using, for example, NAD. Using something like… The Methylene Blue is becoming very popular as a senolytic now. But it supports mitochondrial health. So I clean up those SASP cells before I get into some of these other therapies.

Dr. Kara Fitzgerald: Okay.

Dr. Joseph Cleaver: But the foundation, the fundamental long term… What I’ve coined and trademarked is Precision Senolytic 365 to impress upon the patient this is a lifelong endeavor. If you want to address your aging because everybody’s aging and you can, in my opinion, we can manage aging. And if we manage it affectively, we can reduce the onset of the diseases of aging quite effectively. And it all link back to that SASP cell.

Dr. Kara Fitzgerald: Yeah. That’s really exciting. So you can do this TA Science, UCLA senescence cell burden. You can also look at, like you said earlier, IL-6 or a cytokine panel. You can look at standard markers like CRP, et cetera. But any suggestion of inflammation. How are you looking at mitochondria health?

Dr. Joseph Cleaver: Well, there’s a lot of mitochondrial testing, and I don’t think it’s that valid.

Dr. Kara Fitzgerald: Mm-hmm (affirmative).

Dr. Joseph Cleaver: I know that if we have a lot of evidence for inflammation in SASP cells, I know that we have mitochondrial dysfunction.

Dr. Kara Fitzgerald: Yep. Sure.

Dr. Joseph Cleaver: You could use… I do it sometimes. We could use telomere length. In my opinion, I use it as a surrogate marker, as I mentioned.

Dr. Kara Fitzgerald: Yes.

Dr. Joseph Cleaver: And I think there’s literature that has this positive feedback, as I mentioned, between telomerase activator, telomere length, and mitochondrial biogenesis. So I don’t necessarily test mitochondria.

Dr. Kara Fitzgerald: Mm-hmm (affirmative).

Dr. Joseph Cleaver: In the office. I have some research going on right now that measures certain markers of aerobic glycolysis, et cetera. But that’s not ready for, certainly, prime time in a clinical practice.

Dr. Kara Fitzgerald: Okay. Okay. Well, I’d like to hear about that. All right. So then you finish the first arm of the journey, and then you’re just working in prevention and just improving stem cell productivity and telomere length. And TA-65 sounds like it’s a work horse. How long… So you start that, say, one to three months. Then you move them over to TA-65. How long are they staying on that? And how are you dosing that? And what else are you doing?

Dr. Joseph Cleaver: So TA-65 is… When I first started using it about 10 years ago, we were using 250 units. And actually, that was the only dosing that was available on the market. And the challenge was, “Doc, I’m spending money on this TA-65. Why… And I don’t feel any different.” You have to… In medicine, you have to balance between doing the right thing for the patient and making them feel good fast, so they believe in you and they trust you.

Dr. Kara Fitzgerald: Sure.

Dr. Joseph Cleaver: And it was a little bit of a challenge in the beginning to explain how TA-65 works. And how it’s a lifelong commitment. And after about nine months to a year, if I can get them out nine months to a year… And now I do it quite easily. It’s easy to do. Because I understand it so much more intimately. If they still question me then, if they don’t feel any difference, there’s a sense of… you know that your mental acuity seems to be better. Your overall physical performance is better. Your sleep is better. And if they don’t believe you, tell them to stop it.

Dr. Kara Fitzgerald: Right.

Dr. Joseph Cleaver: And when they stop it, they’ll backpedal. And they’ll go, “You know what? I think that was, actually… I couldn’t really put my finger on it. But when I stopped it, I don’t feel as good as I did when I was on TA-65.” And I’ve heard that over, and over, and over again. That’s what people experience in my practice. And I can tell you personally, I’ve used the product for over 10 years with a really significant success. But my patients, the skeptics, if they want to stop it, I encourage them. I say, “Stop it for a month and see how you feel.”

Dr. Kara Fitzgerald: Right.

Dr. Joseph Cleaver: And inevitably, they will end up back on it. And now I have so much more science behind the encouragement for them to continue it. It’s not just this telomere lengthening, you might live longer. We don’t know about that. Look at your biological age.

Dr. Kara Fitzgerald: Mm-hmm (affirmative).

Dr. Joseph Cleaver: But now that the fundamental, that senescent cell, we know it decreases senescent cells in that study that was published.

Dr. Kara Fitzgerald: Right.

Dr. Joseph Cleaver: By up to 14 percent over a nine-month, 12-month period.

Dr. Kara Fitzgerald: Right. Right. Right.

Dr. Joseph Cleaver: And that’s where I believe that sense of well-being and that sense of energy and ability to do an exercise. Go to the gym and do a workout. Or whatever exercise you embark upon. You do feel a different healthy edge. And now you can trace that back to a valid lab test.

Dr. Kara Fitzgerald: Yes.

Dr. Joseph Cleaver: You can say, “Here is your aging. Here is your senescent cells. And now, this is where we’re going with this.” I believe now that the next step in senolytics is we are going to see that. That immunosenescence is really the driver behind whether you age or not, or how quickly you age in other organ systems. So it’s very compelling. It’s a wonderful addition for a senolytics program.

Dr. Kara Fitzgerald: Very exciting. Yeah.

Dr. Joseph Cleaver: Mm-hmm (affirmative).

Dr. Kara Fitzgerald: I think what you’re saying… So what you’re saying, basically, is that this most recent study… We’re going to pop this on show notes, people. This is double blind placebo controlled randomized clinical trial demonstrates telomerase activator TA-65 decreases immunosenescent CD-8 and CD-28 T cells in humans. And Joe Raffaele, who I’ve podcasted with twice now, is an author on this study. And it’s really cool. And they used this UCLA test that we’ve discussed. So what this finding suggests… And this was just… This is hot off the presses. It was published at the end of last month. So they’re showing, basically, that you could use TA-65 on both sides of the road as you say. So you could use… You could start to use TA-65 as the cleanup for the SASP cells and that inflammation journey as well as on the rebuilding side. Do you think that’s a take home? That that’s a reasonable conclusion?

Dr. Joseph Cleaver: Yeah. And it’s a… That makes it one of the key foundational components to senolytics because this is one of the ongoing therapies that should be in place.

Dr. Kara Fitzgerald: Yeah.

Dr. Joseph Cleaver: Going forward.

Dr. Kara Fitzgerald: Yeah.

Dr. Joseph Cleaver: And-

Dr. Kara Fitzgerald: It’s a-

Dr. Joseph Cleaver: What’s fascinating is with this… whatever is happening in the world right now with these viruses and wherever that’s going. There are studies that show that patients that have longer telomeres actually are less susceptible and less likely to end up in a hospital due to a coronavirus infection.

Dr. Kara Fitzgerald: Right. Right.

Dr. Joseph Cleaver: What came to light, also, in that study which is also built into my programs is I started using… Well, some of the antivirals we use make sense for possible longevity. But that’s for another podcast. We see that patients who are CMV (Cytomegalovirus) positive…

Dr. Kara Fitzgerald: Yes.

Dr. Joseph Cleaver: … have a greater senescence burden.

Dr. Kara Fitzgerald: Yep.

Dr. Joseph Cleaver: Shorter telomere.

Dr. Kara Fitzgerald: Right.

Dr. Joseph Cleaver: And greater risk for susceptibility to infection and serious outcomes or death.

Dr. Kara Fitzgerald: Yes.

Dr. Joseph Cleaver: And that was a wonderful component to this study because now I test all my patients for CMV. And if we look at the prevalence in say 50 percent in this country, the population is infected with CMV. And by the time we’re 80, it’s probably 80 percent. And it is a huge burden on the immune system.

Dr. Kara Fitzgerald: Right.

Dr. Joseph Cleaver: So I’ll use certain… Now I’ll use antivirals when I see an unexplained acceleration of their immune markers, their CD-28 markers. That there’s probably an underlying viral burden on the immune system that’s accelerating the aging process.

Dr. Kara Fitzgerald: Yeah. So they’re basically creating T cells, after T cell, after T cell, after T cell to try to tend to this stealth infection that’s been around. And it’s just taking… It’s like the Hayflick constant, they’re just moving to the end of the line really rapidly.

Dr. Joseph Cleaver: Yep.

Dr. Kara Fitzgerald: Of their T cell…

Dr. Joseph Cleaver: Yeah. And I think immunosenescence, that I mentioned before, we’ll see over the next few years where this goes.

Dr. Kara Fitzgerald: Yeah.

Dr. Joseph Cleaver: But I think it’s going to lead the way in all organ system aging.

Dr. Kara Fitzgerald: Yeah.

Dr. Joseph Cleaver: And all systems are going to go as goes your immune system.

Dr. Kara Fitzgerald: Yeah. I think that that makes sense. I think that TA-65 is really kind of a badass molecule myself. I just think it’s pretty cool. It comes from astragalus, which of course has a long, long, long, long, millennial long, use history as an antiviral. And I think it’s like we focused on it as a telomerase activator. But what this study shoes from Joe Raffaele and team, and how you’re using it, the CMV study that you talked about, I think it’s a molecule we’re going to continue to learn is pleiotropic. It does a lot of things. A lot of really important things on the anti-aging and health span journey.

Dr. Joseph Cleaver: It absolutely does. I think the power behind it is really mitochondrial health, mitochondrial resuscitation, mitochondrial function.

Dr. Kara Fitzgerald: Yeah.

Dr. Joseph Cleaver: That’s where I focused on it.

Dr. Kara Fitzgerald: Okay.

Dr. Joseph Cleaver: And I’m able to… When I come across another colleague and they go, “Eh, telomere length doesn’t mean anything.” I say, “Well, I understand what you’re saying. Because you can have really long telomeres and that doesn’t mean you’re going to live that long necessarily. We can mark a biological age. But I think much more importantly is really the overwhelming positive benefit is mitochondria.” When you read the literature it says, “Oh, the shorter your telomeres, the faster you’re going to develop cell senescence.” I still believe that is just the surrogate marker for mitochondrial health.

Dr. Kara Fitzgerald: Yeah.

Dr. Joseph Cleaver: Because it’s mitochondrial dysfunction. And the more you read the mitochondrial literature, everything’s a mitochondropathy. Our post-COVID patients are mitochondropathies. Our CIRS patients, the chronic inflammatory response syndrome, are mitochondropathies.

Dr. Kara Fitzgerald: Yeah. Hm.

Dr. Joseph Cleaver: So that’s where we need to focus our therapies. And especially in longevity medicine and senolytics.

Dr. Kara Fitzgerald: Got it.

Dr. Joseph Cleaver: So-

Dr. Kara Fitzgerald: Go ahead. Say it.

Dr. Joseph Cleaver: It’s getting more and more just… So much to discover and so much discovery to be done. But just the few things we do have, the tools we do have now, are just so much more than we had just a couple of years ago. So we can affect a real change in our patient’s quality of life. And I think it’ll have a huge impact, significant impact, on prevention of diabetes, and heart disease, and dementia, et cetera.

Dr. Kara Fitzgerald: Mm-hmm (affirmative).

Dr. Joseph Cleaver: That’s where the real power is right now.

Dr. Kara Fitzgerald: So where can people learn more about your work? And if they want to train with you, how can they connect?

Dr. Joseph Cleaver: Oh, wow. I am… Let’s see. I’ve got a… I’ll be speaking at Cell Surgical Network in Las Vegas on the 4th. And then I’ve developed a regenerative medicine conference at my… I own a winery in California. And that makes it easier to have doctors come and listen to experts speak.

Dr. Kara Fitzgerald: Right.

Dr. Joseph Cleaver: In a beautiful setting. But it’s called Locanda Renaissance Medical Conference. And we started it last year.

Dr. Kara Fitzgerald: Uh-huh (affirmative).

Dr. Joseph Cleaver: And it was a huge success. And that’s coming up on June 11th and 12th. And it’s a very small, close knit group. We have wonderful speakers. Jim Lavalle is there. Andy Heyman. Myself. And it’s a combination of all things regenerative.

Dr. Kara Fitzgerald: Mm-hmm (affirmative).

Dr. Joseph Cleaver: And longevity. And we do some regenerative aesthetics in a two-day program. And it’s just a wonderful setting. So those… I’m very proud of it. Being able to put that together in a middle of this crisis we’ve been having and globally over the last…

Dr. Kara Fitzgerald: Sure. Yes. Well, we’ll get links in the show notes for everything that Dr. Cleaver’s up to. And where you can connect with him. You opened up a lot of… I think a lot of folks have questions on your protocol. And I’m not going to ask you now, but I’m definitely curious about the gray. We never did circle back. But I…

Dr. Joseph Cleaver: Okay.

Dr. Kara Fitzgerald: We will. I’ll find you. And then I’m sure some of the listeners are curious as well. But just I like what you’re doing. And I’m just excited about where science is heading. I’m with you. I think that our ability to see more using more sophisticated laboratory analysis and just kind of wrapping our brains around these senolytics. Which you’re ahead of me on, for sure. It just sounds like you’re just doing great work.

Dr. Joseph Cleaver: Thank you.

Dr. Kara Fitzgerald: I appreciate you coming onboard here and talking to us at New Frontiers.

Dr. Joseph Cleaver: Thank you so much. It’s been a true pleasure. I really appreciate you having me.

Dr. Kara Fitzgerald: Absolutely.