Telomeres & Telomerase Activation; Connecting the Dots

Ron Rothenberg, M.D.

Oh, thanks, Joseph, it’s an honor to be here. This is gonna be a lot of fun.

Joseph M. Raffaele, M.D.

Yeah, so, why don’t we start out. I know, you and I have talked over the years, many times at conferences, and we’ve heard each other lecture about things. Why don’t we start out by talking about your idea about the role of the relationship between telomeres, what we do in the rest of our practices, hormone optimization, looking at immune function, and then, you also like to speak about the role of environmental toxicity.

Ron Rothenberg, M.D.

Sure, telomeres, really you can look at as the central piece of everything we do, putting it all together. So, protecting telomeres, you’re protecting genome instability, you’re controlling oxidative stress, and controlling inflammation. You know, inflammation is related to everything, as we’ve learned more and more, you know, through the years. So telomere science fits right in the middle of all this, and then there’s other, what I like to say, connect the dots, which we can cover from environmental toxicity, lifestyle, nutrition, stress reduction, they all come together, and so, all the things we’ve been learning to try to keep ourselves and our patients healthy, we can say the telomere science fits right in the middle.

Joseph M. Raffaele, M.D.

Yeah, that’s absolutely true. You know of the nine hallmarks of aging, it’s number two on the list, you know, making instability being number one, I would argue that probably they’re interchangeable at the top of that list, and everything trickles down from there, not to use a phrase from the eighties in economics.

Ron Rothenberg, M.D.

Yeah.

Joseph M. Raffaele, M.D.

But in a good way, it trickles down to understand, what’s going on.

Ron Rothenberg, M.D.

And you know, all of this is documented in peer reviewed literature. It’s not just a nice idea, but every step along the way has been published independently. And that’s, you know, that’s what’s so important.

Joseph M. Raffaele, M.D.

Yeah, that’s, what’s fancy about it. I think I did look at the publications and the exponential increase in ones that had telomeres and telomerase in them since the nineties, and, you know, every aspect of it from molecular biology through cellular biology, and then up through large cross-sectional studies, looking at the relationships, it’s all been tied together. And then also many clinical trials in animal models, some of those things we’ll touch on today.

Ron Rothenberg, M.D.

Okay, great.

Joseph M. Raffaele, M.D.

So, why don’t you , and I know I love listening to your lectures when you sort of give that brief introduction to telomere biology, you know, why it’s important, and then also what telomerase is, the enzyme that makes them longer.

Ron Rothenberg, M.D.

Okay, well, okay, yeah, we can start, so again, we’re thinking the telomeres, this is the centerpiece. So, the concept of telomeres has resolved a lot of mysteries in molecular biology and DNA, what was called the end replication problem. And going back into the sixties the Hayflick limits. So Lennon Hayflick determined that, skin fibroblasts and cell culture would divide around 50 times and then stop. So the mystery was, where’s the counter? Who’s counting? And even some comments in his papers were, “I leave this to future generations to do determine.” And then Elizabeth Blackburn and her group won the Nobel Prize for understanding that the telomere is the counter in our cells. So each division, a section of telomere is lost, that’s the TTAGGG, and when telomeres become critically short, cell function is impaired and is end of the road, and so, in our germ cell line, telomeres are restored by the endogenous enzyme telomerase, or else life wouldn’t have continued through the eons.

Joseph M. Raffaele, M.D.

Right.

Ron Rothenberg, M.D.

But in our somatic cells, you know, the rest of us, our minds and bodies, they’re limited by, you know, telomere degradation, either in rapid, especially in rapidly multiplying cells, immune system, skin, epithelial cells, but also there’s a big role for this in post-mitotic cells too, and this is another mystery, that’s been unraveled in the past few years. So this TTAGG section is edited by telomerase, and the G for guanine is very susceptible to oxidative stress, and that is part of the connection since it’s mostly, you know, you got three Gs there. So oxidative stress from the mitochondria, you know, energy, power plants turning out ATP and having it’s waste products, they’re damaging the mitochondria, and damaging the telomeres. 

So, there’s a vicious cycle going in and back, but it can be prevented by a feed forward cycle to prevent this, and so, the telomerase, again, the endogenous enzyme that can be turned on by TA-65 is, the more you start learning about it, the more windows open, and it gets more complex from your presentations. The main components are TERT, telomerase, and TERC. So, the TERT telomerase, the TRC, T-R-C, is the RNA template, that the TERT puts on different TTAGGGs. And so I tried to make little ways to remember this. So TERC sounds like a turkey, and it’s an RNA template and turkey is ready in November afternoon. 

I know that’s silly, but I remember it that way, the telomerase reverse transcriptase, but the TERT is the motor that puts them on, and sometimes it’s written as hTERT or hTERC, meaning human, it’s a study with a mouse, it could be mTERT or mTERC. So we’ve got these components that restore telomeres, if they’re turned on, but also, as we can talk about later, there’s non-canonical actions, you know, like canon is like official body of knowledge for theology or “Star Wars” or in this case it’s telomeres.

Joseph M. Raffaele, M.D.

Let’s leave that for a little bit, as a little bit of a teaser for later, and sort of just a bit with the sort of the canonical if you will, activities of telomerase, you know, the reverse transcriptase and, you know, it’s repressed at birth, and so people often ask, you know, when does aging begin? And some people say at about, you know, peak reproductive health, which is in their mid twenties, but from a telomere length standpoint, since telomerase turned down, it’s really at birth that you start to see erosions of your telomeres, you’ll lose them pretty rapidly going from a single cell to, you know, whatever 13, whatever the number is, trillion cells that you wanna, depending on the size of your check or a tattoo, there’s a differential number of cells there, but so you lose them fairly rapidly in that growth period, and after that, there’s kind of a 50 base pair per year loss of telomere length because it’s turned on, but not sufficiently in these these cells. So that gradual loss is what is what we’re talking about with with telomere length, and you do, I know, you do some measurements of telomeres in your practice.

Ron Rothenberg, M.D.

Yes, there’s different methodologies that are available. We’ve used the Life Length company, I have no business or personal relationship with them to disclaim, who do the Q-FISH test, and so I think, there’s various methodologies, but it’s important to use the same one, so you can follow patients. And it’s a little bit quirky to get, because it’s a separate lab test, and some patients just wanna dive in there, and, you know, I try to encourage the testing, but if they don’t want to that’s okay as well, since, you know, clinician of the many patients we’ve tested over the years, I’d say a few have made outstanding improvements in their telomere length. 

Most have made a steady improvement, which may be plateaus at a certain point and may zig and zag, and a few have stayed about the same, but even that is a victory, because we know what nature has in store for us, you know, a constant loss of telomeres, right? As you were saying, aging starts at conception, you know, it sounds kind of silly, but we lose a third of that rapid cellular division at embryogenesis lose a third of our telomeres. So, testing has confirmed to myself and patients, as well as the literature, that this is really happening, that they’re really maintaining, improving their telomeres. And, you know, this is impressive.

Joseph M. Raffaele, M.D.

Yeah, I mean, when I have a conversation with patients, you know, sometimes they’re, you know, they’re sort of, what’s a telomere, and, you know, you give them that great explanation of what it is, sort of the molecular clock, and then they’re saying, well, you know, why should I care about it? And if you tell them about what their telomere length is, let’s say it’s average, and okay, so, then trying to slow down that rate is great, but some patients I’ve had have come in, and they’ve had telomere lengths, you know, they’re in their forties, of like a 70-year-old, and that changes their calculation, they’re all of a sudden like, oh, oh, that’s not good, and one of the reasons for that is partly lifestyle, but also, I mean, all of the things we’re gonna talk about that can affect telomere length, but also inheritance is a big factor of it. 

It’s about a 70% heritability of your telomere length, and so people don’t know whether they have, you know, no pun intended, and sort of a little bit of a ticking, or a ticking time bomb because they started out with kind of a short reserve of telomeres. Likewise, some people come in with really long ones, and, you know, I don’t tell them to start smoking in that situation, but, you know, I think, that’s what I try to encourage patients to get the measurement done, but you’re right. I mean, if they don’t want to pay for it, or are still doing whatever you can to improve telomere length or to keep them from getting shorter is, I think, a very, very important thing. So one of the things that you kind of employ to help besides direct telomerase activation to keep your people’s telomeres healthy.

Ron Rothenberg, M.D.

Okay, so we know all this staying healthy business affects telomere length, and, you know, you can start looking at it and then any direction and kind of hit a few of them, one by one, exercise, but we know, okay, every week we will, there’s nobody, there’s the elliptical in the back, I should be on them while we’re talking, but we know all the benefits of exercise, it’s free, the health outcomes obviously are, you know, very, very impressive and there’s studies now, that part of the mechanism of health improvement through exercise, maybe you telling me related concepts in mouse studies, mouse where they’re TERT minus minus, so that, you know, the reverse transcriptase enzyme is missing, you put them on a little mouse treadmill, and they don’t improve in VO2 max like the control mice. So, this might even be part of the process, that better telomeres in various other studies. 

Nutrition, there’s studies comparing, there are studies evaluating how Mediterranean is your diet, olive oil, legumes, et cetera, et cetera, and the better, this is part of the Nurse’s Health study, huge numbers, the more Mediterranean diet, the better the telomeres. In terms of environment, we know poverty is associated with short telomeres for all the reasons, nutrition, proximity to pollution and traffic is separate, distance from freeways is a factor. 

So, you know, so unfortunately poverty is a factor in telomere loss, and stress reduction techniques, independent studies of yoga practitioners versus non yoga practitioners controlling other variables that are telomeres, meditation, each little component has been looked at separately, and in fascinating studies, so, you know, all of this is feeding together. Nutraceuticals, we’re gonna talk about, we could throw in right now, and then there’s a newer study, they have a very vast nutraceutical mix probiotics, and omega threes and always, like this is the-

Joseph M. Raffaele, M.D.

Yeah, I was just looking at that, go ahead.

Ron Rothenberg, M.D.

Yeah, the study, anyway, each nutraceutical has been looked at individually, especially the ones, you know, that we have tremendous data on health outcomes, vitamin D I mean, what doesn’t it do? Better telomeres, omega threes, and having an adequate balance of all the antioxidants, I think is important too, because remember, it’s our struggle against oxidative stress, telomerase helps, but if you can come in from the side, and reduce oxidative stress, remember that antioxidant idea, you can reduce oxidative stress with coenzyme Q 10, okay, your mitochondria are in better shape. They don’t need as much of the telomerase. Then it can move over to the nucleus and protect the genome. And so all these little things come together.

Joseph M. Raffaele, M.D.

Yeah, that’s what I’ve always been fascinated about before I even knew anything about telomeres, which was probably prior to 2007, although I’m sure, I heard about them before that, you know, it was fascinating to me that everything that we knew was good for your body, help to keep telomeres longer, and everything that was bad for your body was associated with shortened telomeres, and it kind of all, you know, it all really kind of made sense, and then remember that test, which we still can do, is the 8-hydroxy-2-deoxyguanosine urine test, you know, and it was our test for oxidative stress, but what is that? That’s the GGG portions getting, you know, taken out of the DNA because they’re damaged and showing up in your urine, so, you know, when you see that kind of aha kind of stuff happening over and over again, when you’re reading as time goes on and telomere biology is really pretty fascinating.

Ron Rothenberg, M.D.

Yeah, that’s why the GGG businesses, is why, you know, the telomere is so sensitive to oxidative stress. So, it’s great how that fits in.

Joseph M. Raffaele, M.D.

Yeah, I always talk to patients about Seesaw, basically, it’s as simple as the things that stress telomere length, briskly proliferating cells, oxidative stress, you know, all the bad things, balanced by how much you can do to prevent those, and then telomerase activity, essentially.

Ron Rothenberg, M.D.

Right, and even, you know, mental stresses there, and now there’s quite a few reviews going through the connection between just, you know, stress and perceived stress and how this all fits in. There’s a study now recently published on this. So, you know, we gotta do everything, no one’s lifestyle is gonna be perfect, but obviously you do what you can, now adding a telomerase activator like TA-65 gives you a step, a leap forward on this as well.

Joseph M. Raffaele, M.D.

Yeah, you know, both my parents passed away from Alzheimer’s disease and there was a lot of stress around the family, and I always found that, you know, doing exercise took some of that stress off of me, and I was very relieved to see that actually exercise can mitigate the shortening of telomeres that occurs with perceived stress, so, you know, it’s all, again, born out in the biology, when you’re, what you’re seeing in everyday life, which is really pretty fascinating. You talk a little bit about, I mean, both you and I do hormone optimization, like a little bit about the role of hormones in telomere biology and telomerase activation.

Ron Rothenberg, M.D.

You’re right, there’s another dot that we connect. Oh, in terms of Alzheimer’s we know Alzheimer’s and non Alzheimer’s dementia is associated with significantly shorter telomeres, a recent study in a mouse model of Parkinson’s treating with TA-65 improves their actual behavior and performance, balance, and all types of things that a Parkinson’s mice can’t do well. So back to hormones, you know, the whole field of hormone optimization evolved from it was considered a great thing, and then due to some faulty studies, like women’s health initiative, which measured, you know, equine estrogen, and, you know, artificial progesterone, which was a progesterone, progestin, and all of a sudden it was bad, but then the wheel turned, and again, that bio-identical hormone optimization doesn’t have increased cancer risk, there’s tremendous quality of life benefits. 

So, this is often a reason why people will show up in a preventive medicine or anti-aging practice, because of a hormone deficiencies whether you have testosterone in men or menopause in women. So, of course we have ways of measuring, and clinical evaluation and then replacing. Now before I began, before I even really had studied much telomere science, I was doing this and lo and behold, this, the direct connection just about every hormone, and its telomere effect has been studied. Estrogen and progesterone in women, testosterone in men, growth hormone, when there’s adult growth hormone deficiency in both men and women, melatonin, that’s another one of this what doesn’t it do, a kind of interventions all associated to, you know, optimizing to youthful levels, not, you know, again, all we wanna do is optimize human physiology. We don’t wanna use doses that are outside physiological ranges. All of this is another branch to improve telomeres.

Joseph M. Raffaele, M.D.

Right, there’s also, you know, I’ve always thought, it was fascinating that there’s direct evidence, that estradiol is a modest telomerase activator, 5-alpha, sorry, DHT, creation of DHT from testosterone through 5-alpha reductase is a mild telomerase activator. IGF-1 is a mild telomerase activator. Maybe part of the reason why growth hormone, testosterone, and hormone replacement therapy with estrogen in women, part of the beneficial effect is through telomerase activation, and we’ll talk about some of the other non-canonical activities of telomerase. The other fascinating thing is that we were talking about stress, cortisol, telomerase inhibitor. So the molecular mechanism for why stress could be detrimental to your health, further evidence that these things are all interrelated.

Ron Rothenberg, M.D.

Right, so we don’t need a mystical explanation of what why stress does this. We actually can have a biochemical, you know, scientific explanation, and again, in testosterone, when you treat men with testosterone, you’re really treating with three hormones, because aromatase to estradiol and 5-alpha reductase to dihydrotestosterone. So you’re getting all three.

Joseph M. Raffaele, M.D.

Yeah, which is again why I always try to tell the doctors, that we educate, that you have to be careful with these aromatase inhibitors to try to keep the estrogen level down. It is always thought that it’s a bad hormone in the male. It’s not, you’ve got to keep it at level. Not too much, but not too little.

Ron Rothenberg, M.D.

Estradiol, when women need testosterone as well, and also on that subject, you know, I’m not a fan of 5-alpha reductase inhibitors because of, again, DHT and the associated cognitive dysfunction, depression, erectile dysfunction. So again, these hormones are part of our natural hormone profile.

Joseph M. Raffaele, M.D.

Right, and some of that may be mediated through to telomere biology and telomerase activation.

Ron Rothenberg, M.D.

Yeah, well that’s the fascinating thing, that the telomere biology is right in the middle of it all.

Joseph M. Raffaele, M.D.

Yeah, it really is. So, you were talking about the sort of non-canonical aspects of telomerase. I remember when I first started thinking about tumor biology and what effect it might have in aging, I was sort of like, well, you know, it’s about cells dividing, but some of the most important cells in the body, the neurons, the cardiomyocytes, the heart cells don’t actually divide, they’re post-mitotic cell. So, how could telomerase be that important for aging? Well, of course we know what some of the mechanisms are. Why don’t you talk a little bit about that?

Ron Rothenberg, M.D.

Yeah, so, right, so first, you know, in terms of the post-mitotic cells, cardiac myocytes, neurons, well, they’re really not completely post-mitotic, because there are stem cells in the heart and in the brain, and one of the non-canonical effects of a TERC is to preserve stem cell function, it takes us in a whole other, another direction. So we’ve got this, ’cause we are somewhat repairing our cardiac myocytes and neurons. So we know that you can better cognitive function, less depression, all the neurological diseases associated with longer telomeres, even if they’re not directly making the telomeres in the neurons longer versus supporting the glia in terms of the brain. You know, I think when I was in medical school, I think, what was the concept of glia something, always like packing foam.

Joseph M. Raffaele, M.D.

It’s like the styrofoam peanuts.

Ron Rothenberg, M.D.

And again, it doesn’t do anything, but now we know that the metabolism of the glia is essential to the neurons, so, and they are mitotic. So, preserving the telomeres in the glia plus, again, having the protection against oxidative stress for the neurons is big, and even if you, it’s not a matter of adding more telomere sections, protecting against inflammation, you know, fire in the brain, this is the cognitive dysfunction related to inflammation, protect against inflammation, protect against oxidative stress will protect these post-mitotic neurons, you know, cardiovascular, better telomere length, there’s a lot of studies. 

There’s one correlating with coronary artery calcium score, that’s better, others just with major adverse cardiovascular events, so even, again, it ended up the myocytes telomeres aren’t getting longer, something good is happening to the cardiovascular system. Endothelial function is preserved, and that’s another key thing in the cardiovascular system. So the endothelium, it needs to keep its telomeres lengthy, so you don’t develop diastolic dysfunction and that whole cascade. So again, post-mitotic cells need telomerase from the components needed to TERC, and now there’s some basic papers suggesting, the RNA template to TERC even has non-canonical functions as well. So in biology, again, opening one little window, now there’s a whole new world.

Joseph M. Raffaele, M.D.

Right, yeah, when we had the first cohort come through our practice that was taking TA-65, we found significant effects on the immune system and remodeling of it, which we’ll talk a little bit more about, but in a second paper that we published a couple of years after the 2011 paper, we talked about the metabolic things that happened, improvement in cholesterol, in blood pressure, and, you know, it was difficult to know, whether that was real or not, because it wasn’t a randomized controlled trial, and they were taking supplement packs that had potential beneficial effects, but then subsequently Fernandez at University of Connecticut, did a study looking at TA-65 in metabolic syndrome, and they found similar results in a crossover controlled trial, and one of the reasons for that is this link between telomerase, and sort of master regulators of the genome, p53, and PGC-1 alpha and beta. So, you know, even if the cell is not dividing, you get that improvement in mitochondrial function, and mitochondrial biogenesis.

Ron Rothenberg, M.D.

Yeah, I agree, and you need to speak p53 balance, because too much can be destructive and too little, take me, you lose protection. And in terms of, you know, my clinical practice, I think, the first thing people might say, oh, anecdotal, but this is how experienced clinicians learned through the years, and maybe we’ll talk a little bit about this later, but one of the comments and the observations on TA-65 is seeming without really other variables changing, that hypertension improves, and so typically a patient will say, well, GIF is started TA-65, you know, like I cut my whatever, you know, amyloidine in half and then, gee, you know, later I kinda forgot about it, and my blood pressure is okay. And again, everything we’re doing should help and, you know, weight control obviously, and stress reduction, but when it seems, even when that’s the only thing, not all the time, but it’s a change that I’ve been observing time and time again.

Joseph M. Raffaele, M.D.

Yeah, I as well, I mean, I have, as you, I’m sure, do as well have some relatively elite masters athletes in my practice, and you know, these are people that follow their metrics quite closely and they’ll see things like improvements in their times or recovery time for whatever distance they’re running or cycling or swimming, and that could well be, because they are increasing their mitochondrial biogenesis, the efficiency of their mitochondria, there perhaps is less, fewer inflammatory cytokines, because of the mechanisms that have been worked out with, you know, making sure cells don’t become senescent.

Ron Rothenberg, M.D.

Right, like, oh yeah, it didn’t mention, you know, the senescent, so the acronyms S-A-S-P, senescence-associated secretory phenotype, so you say, when you lose telomeres, you got a few, few bad things can happen, the cell, you can just have senescence where the cell roles over and plays dead, worse yet you can have the cell become a little inflammation factory, producing this SASP, and that’s the concept of a bad apple. So, the inflammation that the cell that’s lost its telomere is producing, is affecting all the cells in the neighborhood and then getting things even worse, now you can have genome instability, breakage, fusion bridge of the DNA, and this can lead to mutations that can become malignant.

Joseph M. Raffaele, M.D.

Right.

Ron Rothenberg, M.D.

So the piece of this is this that when you lose telomeres, the cells become inflammation factories, or SASP generators, and this affects the entire body, because we know like what’s a bigger lab test risk factor for cardiovascular events, more than LDL cholesterol, and C-reactive protein? You know, it’s your overall inflammation score.

Joseph M. Raffaele, M.D.

Right, and that the two markers that are part of the senescence-associated secretory phenotype or SASP, as you mentioned, IL6, TNF alpha are the cytokines that increase C-reactive protein. C-reactive protein then is the one that, you know, from the Ridker studies a couple of decades ago, showing its association in, through to the Jupiter trial, where, you know, people with normal cholesterols, if they had a high C-reactive protein, and you brought it down with a statin, you would see improvement in events. 

That’s where the inflammation is important. And I think that’s, you know, important, think to understand, you know, I think I often tell patients and when I lecture, I talk to them about feeling your life is as good a predictor and independent of other traditional risk factors as hypertension, cholesterol, and diabetes for cardiovascular disease risk in large prospective, you know, associational studies, but, you know, you often have patients come in, I do a coronary calcium score and all my patients, they don’t have risk factors, what’s going on here? Still have a family history, you don’t have a high cholesterol, the blood pressure is okay. They got super short telomeres, that’s part of it, and, you know, if you’re aware of the study going on, the tactic trial in UK.

Ron Rothenberg, M.D.

Yeah.

Joseph M. Raffaele, M.D.

Right. That’s the same sort of theory.

Ron Rothenberg, M.D.

Right, so that study, you know, underway, not results, not published yet, but looking at the relationship between inflammation with telomeres, inflammation, cardiovascular events and-

Joseph M. Raffaele, M.D.

Right, so in this way, I mean, Ioakim Spyridopoulos, it may be through an endothelial cell regeneration, but I think since it’s looking at person with an MRI within six months, angiographically demonstrated, and then seeing whether or not a year of TA-65 keeps them from having a recurrent MI, but mostly what they’re looking at is, whether it reduces senescent T-cells, because it’s the senescent T cells that are setting up that inflammatory milieu, which then changes the T regulatory cells, which they say is so important for those actual events, that that’s their primary endpoint, is a reduction in senescent T cells, and, you know, that’s sort of what we showed in that original trial in a cohort in 2011, we showed that reduction in senescent T-cells, fascinating how it figures into cardiovascular disease as well.

Ron Rothenberg, M.D.

Yeah, well, that’s what I’ve learned from you, how you got your naive healthy and senescence, and, you know, the CD8 positive, 28 negative, once you’re there, you know, the senescent T-cells, then not only that don’t work, but to quote Yuto, they crowd out the immune space.

Joseph M. Raffaele, M.D.

That’s right.

Ron Rothenberg, M.D.

There’s no room for the young upstarts, who wanna fight inflammation and infectious disease.

Joseph M. Raffaele, M.D.

Right, and not only are they not, not only are they not doing their job correctly, oh, oh, I got lost, my picture here for a second. Okay, but they’re like the old watchdog, barking at the neighbors and biting their owners, and they don’t get the bad guys, ’cause they can’t see them, but the people that are nearby, which is, you know, one of the major factors that happens with senescent cells, they adversely affect their neighbors, real nearby through these paracrine activities and cytokines, that you get adverse effects that way, so, yeah. I mean, I think that we think about cardiovascular disease now, I think more as inflammatory disorder than anything else, and so the immune system is so critically involved.

Ron Rothenberg, M.D.

Yeah, so this all fits together with, you know, the biology. It’s not just the LDL, it’s gotta be oxidized. What turns on the oxidation of LDL? It’s inflammation, and then what turns on the adhesion molecules that grab the monocytes into the endothelium? That BCAM, ICAM, and, you know, it all fits together. This hormone branches on that too, have hormones inhibited, but again, if you keep digging deeper, it seems like the telomeres, telomerase are in the center of the target.

Joseph M. Raffaele, M.D.

Yeah, I mean, I think they’re sort of the upstream kind of regulator of everything. You know, we also just published in April online, it’s not yet even in PubMed as far as I can check, real recently, but the results of the randomized control trial showing, and I’ve talked about it before, we talked about the QPS trial before, in which we looked at whether TA-65 could lower senescent T cells as defined by lacking CD28, CD8 positive 28 negs, and in fact, we did see a, without the 20% highly statistically significant, reduction in them in a 500 patient trial, so, you know, it does and I see it in my practice, I measure the senescent T cells and I see reductions, I’ve seen reductions up to 50% at times.

Ron Rothenberg, M.D.

And in the, I haven’t seen the published version, we’re in the preliminary version of your paper there, I never saw p-value with so many zeros before the one, I’m was counting one, two, three, four, five, six, well, talk about significance.

Joseph M. Raffaele, M.D.

Yeah, it was really gratifying to see, you know, that’s the fun thing about what you and I do. We could have sort of sit, we get to see in our practices the effect of cutting edge science on our patients in beneficial ways, and then also see it played out in randomized controlled trials as well. You know, you’re practicing good objective, sort of, what what do you call yourself? Longevity medicine, anti-aging medicine, age management medicine?

Ron Rothenberg, M.D.

It’s a field looking for a name. Some people don’t like the anti part, even though we have antibiotics, preventative medicine. I don’t know, how about that? And actually it kind of overlaps with primary care, because you can’t separate them completely.

Joseph M. Raffaele, M.D.

Well, yeah.

Ron Rothenberg, M.D.

the same thing, in terms of the senescent T-cells of course, in terms of viral infections, dealt with a CMV virus, but there’s even some papers in the past year, during the pandemic, discussing the COVID-19 relationship to CD8 positive 28 negative cells, and suggesting that TA-65 could be an intervention, and, well, the shorter the telomeres, the greater the mortality from COVID-19, and only the comorbidity factors, cardiovascular disease, diabetes as well, these are short telomere diseases. Age is obviously a big co-morbidity, that’s the short telomeres thing, so it really does fit together, and of course we said, it will be difficult to really study this, and come to some specific conclusions, but logically it’s got to help. This would apply to all kinds of viral, rapidly multiplying viral illnesses, all these , Ebola virus, even HIV. If you’re burning through your T cells, you’re gonna end up with senescent ones, and that is our chance to, you know, rehabilitate some of them to actually work for us.

Joseph M. Raffaele, M.D.

Yeah, I mean, speaking sort of regenerating things, and I was speaking at a conferences past weekend to regenerate physicians about, you know, potentially why they should think about telomere biology in their work, any kind of stress, be it the stress of a joint that’s undergoing, you know, too many marathons or too many cycles on a bicycle, any kind of stress.

Ron Rothenberg, M.D.

You have to surf.

Joseph M. Raffaele, M.D.

Right, exactly, but for me, it would be getting back up on the board after I’ve fallen off too many times, any kind of stress requires your system to then, you know, breaks down cells, then requires them to divide, and what we’re finding is that these chronic viral stressors, particularly in the herpes virus family, you know, you mentioned CMV, we didn’t talk about that in depth, but that’s herpes virus number five, that most of us, when we were first training, were sort of like, yeah, it’s benign, don’t worry about it. Then we lived through the AIDS resurgence epidemic, and then we saw that people were dying of CMV, when their immune systems weren’t working well. So, if your immune system has to work well to keep it at bay, but if you do have what’s, you know, sort of a subclinical infection, there’s your positive for it.

It makes your immune system work harder to keep it, and it makes you have an increase in senescent T cells, and shorter telomeres, and so when COVID came out, I saw those hypothesis papers that you’re talking about, where they, you know, the research of the leading researchers in the field were saying, why did this 40-year-old, seemingly healthy guy succumb to COVID? Well, you know, did he have CMV? Did he have a high accumulation of senescent T cells that were more like a 7-year-old? And therefore biologically, he was really like a 7-year-old. This is kind of stuff that it’s easy to have sera. 

They should look at it. I think they probably are gonna start to look at it, because then they did, as you mentioned, they did publish papers, Maria Blasco, and then I think a French group published papers about if you had shorter telomeres, you had more severe COVID and higher mortality, because you just don’t have the reserve. The term I like to use is a biological 401k, you know, you’ve got to keep that up so that you can keep on .

Ron Rothenberg, M.D.

Yeah, and I guess, just like a 401k, where the employer and the employee can contribute, your lifestyle can contribute and the TA-65 can contribute.

Joseph M. Raffaele, M.D.

Right, right, there’s some other stress, so any other strategies that you use to sort of educate people or to monitor them on it? And then I think we talked about protecting post-mitotic cells. Yeah, anything else, that you wanna talk, environmental toxicity, you said.

Ron Rothenberg, M.D.

You know, fortunately, a luxury of this type of medical practice to me is, I have time to really sit down and talk to the patients, and I really get to know them, I mean, some have been with me now 23 years.

Joseph M. Raffaele, M.D.

Great.

Ron Rothenberg, M.D.

I know, that they know me and this is the way medicine ideally can be practiced. So part of it is, you know, like explaining what we’re doing and why, in terms of everything, in terms of hormones, certainly in explaining the whole telomere telomerase picture, and from the lifestyle things to the TA-65. And there’s a lot of products or supplements that claim to be telomerase activators, but claim is the word, as far as I know, the only nutraceutical that has published data on this is TA-65, and so a lot of things, well, who knows, it might work, it might be in the category, well, it might help, probably doesn’t hurt, who knows, but why pick something from that category when you actually have literature that documents the effectiveness? 

So we go through it and again, trying to talk to patients, and let’s work on their program. Sometimes people will come in with a shopping bag full of supplements and dump them out on the table and say, so this is what I’m taking, and of course very often they’re redundant or who knows what, and I say well, let’s try to prioritize things in terms of benefits, and what we know about it, and let’s go through your list, and sometimes people, also in terms of supplements, there’s a burnout factor. So, you know, okay, I’ll take 5 or 10 or this or that. 

Okay, let’s for you, in your particular situation, let’s just decide what’s most important, and then we can discuss, how things fit together. And I got to explain why I think, you know, TA-65 is so important, and of course the question is, and this kind of practice as well, do you take it? And you know, the old bottle of medicine, oh, no, we’re loose, you can’t, you know, but no, because, hey, if it’s so great and you don’t take it, there’s a disconnect, and you know, I explain, yeah, I do. 

I’ve been doing it for, I don’t know, five, four or five years now, and I’ve had three or four Life Length tests along the way, some jumps, some steady, some a little zig and zag, but going up, so spending time to go through what are they doing, where do they, and you know, this whole, everything, ’cause money is not unlimited, and how do you want to invest your money in your health, and we’re calmly having a discussion like this and explaining the importance, people will, you know, I’m trying to convince them to do what I think will keep them their healthiest, and so I probably have, I don’t know, 50, 60, maybe 80 patients that say, regularly I’ve been taking TA-65.

Joseph M. Raffaele, M.D.

Yeah, and sometimes they ask, you know, it’s a supplement, it’s a little bit expensive. What do you tell them when they ask you, is it safe to take? Have there been a safety studies done on it? We know that it works to turn on telomerase because of the TRAP assay, which is the gold standard, but, you know, has there been animal studies et cetera? And I tell them about the fact that it started out sort of as a drug, even though it’s an extract of the traditional Chinese medicine, but, you know, it went through the initial safety drugs experiments, to make sure that it was safe, and now it’s generally recognized as safe. And what kind of conversation do you have with them about that?

Ron Rothenberg, M.D.

Yes, so it has this generally, GRAS, generally recognized status, I mean, that means you can make it a medical food, you get TA-65 protein bars or something like that. So that, and there’s really no reported adverse events linked directly to TA-65. And let’s see, so again, we’re all in on one thing, we’re all losing telomeres except for immortal animals.

Joseph M. Raffaele, M.D.

Right.

Ron Rothenberg, M.D.

And that, we will talk about that and I know it sounds funny, what immortal animals? And actually, well, I could sea anemone, well, it’s not immortal, you could step on it or eat it, but it’s immortal in the sense that its germ cells and somatic cells were all mixed together. So it reproduces by budding. So theoretically the first sea anemone ever alive is still alive, and how do they pull this off? They have a lot of telomerase. And then we talk about even sometimes the giant leatherback like sea turtles that live pretty much indefinitely 4 or 500 years. And again, they produce a lot of telomerase to keep going, when people sometimes ask me, well, how do they die? And I try to go, well, eat plastic bags, and the ocean thinking they’re jellyfish. So we know a little bit about the biology of other animals and telomerase, do we.

Joseph M. Raffaele, M.D.

Yeah, and also I talk to patients about the cases of telomeropathy, where people, in humans, and so people are like, well, what’s a turtle, you know, what’s a shark, you know, I’m talking about me as a human. If you have just a 50% knockout of telomerase activity, not the whole thing, but just 50%, you are gonna have a shorter life. I mean, these people, if they have severe ones or born with short, real short telomeres, if they’re second or third or fourth generation, then they die in their twenties. 

If it’s your first mutation to have 50%, then they’ll die of pulmonary fibrosis in their fifties, but a lot of them are dying of bone marrow, the tissues that need more, high turnover. So telomerase absolutely is important for longevity. We see that. And then the other thing that patients often ask is, you know, your quick discussion with them about, well, all cancer, 90% of cancer cells have telomerase active in it, is this gonna increase my risk of cancer?

Ron Rothenberg, M.D.

Right, and this is an important part of the discussion. So the concept is that for a cell to become malignant, there’s a whole series of mutations that have to happen, having to do with retinoblastoma protein, and many other things, but for a cell to be malignant, it needs along the way that mutation to express telomerase, because if it had a Hayflick limit, again, rolled over and played dead after X amount of replications, wouldn’t be a problem, metastasis wouldn’t be problem. So one of the mutations along the way has to express telomerase, also lots of contacted ambition is another example. So it’s like they clump together with their kind, and so they become metastatic, they go floating off, and so the question is, well, gee, could a telomerase activator boost cancer somehow? But okay, first the big, cancer, malignant cells already have it.

Joseph M. Raffaele, M.D.

Right.

Ron Rothenberg, M.D.

Now, maybe there could be some fine balanced in shutting off the telomerase to get rid of malignant cells and then turning it on again to protect the rest of the cells, this is something to be determined. And certainly in all the animal studies, monkey or mice, live a couple of years, they usually die of some kind of cancer, you know, other, you know, renal disease, but no increase in cancer risk, and no observed increase in cancer risk is humans. In fact, just about all cancers are associated with short telomeres.

Joseph M. Raffaele, M.D.

That’s right.

Ron Rothenberg, M.D.

And so on and on and on, and you can see why shorter telomeres, genome is not protected, all it takes is that one malignant mutation, could have been years ago for that cell line to start multiplying. So we’ve got very strong evidence that short telomeres are a cancer risk factor, that cancer already has it. So turning it on, telomerase in other cells to protect them, isn’t gonna give a cancer a boost.

Joseph M. Raffaele, M.D.

Yeah, that’s a key thing that I tell patients, they’re sort of like, you know, cancer cells have been turned on, we call constituently, and so if you turn on telomerase modestly and transiently, which is what a molecule like TA-65 does, it’s like a drop in the bucket. Whereas the long-term studies we have, Bruneck, Italy, and then the biggest one from Copenhagen, where they looked at thousands and thousands of patients from the bottom 10th percentile to the top 10th percentile, you have, you know, that is longest, longest being the top 10 percentile, shortest being the bottom 10 percentile, you have about a 1 1/2 fold increased risk of both cancer and cardiovascular disease. That’s the important data in real life, short telomeres increase your risk. 

And then remember in studies done by Harley et al in fibroblasts, you turn it on, even constituently, you’re right, it needs other mutations, these cells are immortal, but if they don’t have the other mutations, they don’t turn into cancer cells. So, I mean, that’s why I have been taking TA-65 for 14 years now and treating hundreds of patients like you with it and watching the beneficial effects of it over time. So, yeah, I mean, look, I’m looking forward to the results of the TACTIC trial, and then more papers coming out on the role of telomere biology. Do you have any closing thoughts about what you think the future is for you in the practice and telomeres?

Ron Rothenberg, M.D.

Just to getting feedback clinically, like I send an email to my patients taking TA-65, no suggestion, any observations, and the kind of more consistent comments are, well, first there’s a aesthetic thing, skin, you know, our practice is anti-aging but from the inside out, we’re not involved in laser treatments et cetera, I mean, did that for some others with their expertise, so comments like, well, gee, I didn’t see so-and-so in so many years and they just said, well, what did you do with your face? You know, why it looks, you look younger, okay, interesting. Another comment, again, not in everyone, but occasionally our visual changes. 

Now we know this, that study improving a macular degeneration, and so the theory is, that retinal epithelium is improved, but presbyopia, I have two patients, both physicians who comment was, I don’t need my closeup glasses anymore. And when I mentioned this in various lectures and seminars, a couple of hands go up, say, me too. Speaking to my ophthalmologist buddy downstairs in the building from us, well, do you think it could be the TA-65? No impossible, but what do you think it is? I don’t know, okay, and it’s not a very productive discussion.

Joseph M. Raffaele, M.D.

I had patients bring pre and post eye exam numbers, and you see connected evidence of it.

Ron Rothenberg, M.D.

What is the deck of like quote, “I don’t need “my close up glasses.” Energy level, and that’s pretty nonspecific, and so many things feed into it, but that’s a very frequent comment, feel more energy, and some people, interestingly, some people take TA-65 late at night and say, it improves sleep, some of my patients say, if they take it late, it’s harder to sleep, they’re kind of wired and they take it in the morning. So, mh, something’s going on, comments like peripheral neuropathy improving in a few patients, non-diabetic peripheral neuropathy, attention deficit disorder, got a comment, it was, “This is what I need to focus better.” And one interesting is, but I used to have to take 20 milligrams of tadalafil, but now five works and this is the only change, okay.

Joseph M. Raffaele, M.D.

That’s saving a lot of money, I think, paying for your TA-65 right there.

Ron Rothenberg, M.D.

That’s right. And so, you know, all the interesting comments and people vote, especially in a product that’s not inexpensive, people, you know, they’re voting with their wallets. And I’d say almost all the patients who started on TA-65 have continued, and so that’s, I mean, that’s an interesting observation, right?

Joseph M. Raffaele, M.D.

Yeah, no, I can second that in my practice as well. Typically, they do continue and particularly-

Ron Rothenberg, M.D.

capacity too, oh, that’s interesting, in my personal case, just as a surfer, when there’s bigger waves here in the winter, you know, we’re getting held down under water, coming up, gasping, a little oxygen now and then, it would help, and I noticed that, again, without anything else obvious, that when I started TA-65, six months later maybe I’m just getting through the bigger surf better. I kinda didn’t feel as oxygen deprived. I didn’t really measure my VO2 max, but comments like that in a lot of athletes are actually, we do, you’re right, some of the athletes that won all the numbers and they commented the VO2 max has improved. So there is all these clinical benefits that you can see in patients, so as a clinician, you want the theory, you want to publish papers and you wanna see, what’s going on in your patients, and then you put it all together, and you’re trying to keep people happy and healthy.

Joseph M. Raffaele, M.D.

Yeah, that’s, you know, you and I, I think we’re been doing, it’s just about the same amount of time, and I haven’t seen anybody necessarily stop because of adverse effects, and I’ve seen patients stick with it for the beneficial effects, you’re talking about, and also maintaining telomere length. I measure telomere length in all my patients at least once a year and watch them and have over the last 14 years, if you haven’t lost any telomere length, that’s key, because the critical thing is relative telomere length. If yours are shorter for you, then gene expression changes and all sorts of things change, mitochondrial function changes. So if you can keep it at the level that it is, then you’re pretty much doing a really great job of slowing down the aging process in the patient.

Ron Rothenberg, M.D.

Yeah, and that’s been my observation as well, that again, this varies from patient to patient and there’s some zigging and zagging, but in general, people have either maintained their own or increased slightly, or a few increased dramatically.

Joseph M. Raffaele, M.D.

Yeah, I would say that about measurements is that I have had people call me and say, well, look, I took, I had a patient on TA-65 and did a baseline measurement, then six months later, they’re up 0.2 or 3 kilobases, which, telomeres are around eight kilobases in young adulthood, and then around a 6-year-old maybe around six kilobases, five kilobases, five and a half kilobases. So 0.2, 0.1 kilobase is a significant, it’s about four or five years of aging, but there is that variation in the measurement. So one measurement, six months later, it could have been down 0.2, it could have been up 0.1. It’s not gonna to be up 0.5, but I think, you know, particularly in the people that are saying, oh, it’s gone down, and so I should, you know, it’s not working for me. 

You need about two or three, three or four measurements over a course of a year or two to really know what the trajectory of your telomere length is, because there is that up and down, it’s been called a pseudo telomere lengthening and shortening, ’cause it’s really about the characteristics of the sort of relative fractions of the cells, the white blood cells that are floating around. For instance, if you exercise vigorously in the morning, it mobilizes senescent T cells into your blood. 

They have shorter telomere lengths, therefore, if you did their telomere length measurement a few hours after that, you’re gonna get slightly shorter telomere length than you do the next day with no actual change in telomere length, just the population. So you got to watch out for that, if you’re measuring telomere length and just sort of say, you know, you’re not a day trader in it, you’re in it for the long run.

Ron Rothenberg, M.D.

Oh, we should do just about everything in this, we should always put it in perspective and not be obsessed with the exact number and look at the big picture.

Joseph M. Raffaele, M.D.

Well, Ron, it’s been great talking to you. I think we’ve been talking about it about an hour now, and do you have any final thoughts on it?

Ron Rothenberg, M.D.

Very well, I’m very fortunate personally to be in this field and it’s allowed me to continue, you know, being happy and healthy, and a big part of it is the TA-65 along with everything else, and I think the work you’re doing in this field is really great, and I really appreciate how you’re advancing the field, and bringing this information to everyone. And thank you very much for chatting with me on this.

Joseph M. Raffaele, M.D.

Well, thank you. It’s been great talking to you as always, you know, you don’t look any different every time I see the last number of years, keep on surfing, keep on keeping people healthy, and I’m sure I’ll see you shortly at the next conference.

Ron Rothenberg, M.D.

Okay, hope so, tanks a lot.

Joseph M. Raffaele, M.D.

Take care of, Ron.