Episode 69: Sponsored | Telomere Integrity: What Clinicians Need to Know with Dr. Joseph Raffaele

Are you thinking about age management with your patients these days? I am. And I’m thinking about it regarding myself, quite frankly.

To that end, I just had a tour-de-force conversation with clinician researcher Joe Raffaele, MD.

Can we halt, or even reverse, the biological aging process? There are an extraordinary number of variables to consider here, but the take-home appears to be YES. Of course, FxMed is our foundation, but layer onto that telomere biology, and telomerase activation using innovative approaches such as the astragalus-derived molecule like the one found in TA-65, and some pretty impressive outcomes are possible, as we discuss.

With over 5000 “N of 1’s” in his database, and principle investigator of a number of published clinical trials, Dr. Raffaele has plenty of experience on how we want to be addressing (and measuring) the aging journey. Generally, lifestyle interventions – such as those we’re doing in

FxMed – will slow biological aging. But what about HALTING or even REVERSING biological aging? Listen to our convo on New Frontiers, and PLEASE be sure to comment and share wherever you listen to the podcast, and let us know what you think! ~DrKF

Telomeres in the Aging Process

The role of telomeres and, in particular, telomere length, in the aging process has gotten a lot of attention recently.

Dr. Joseph Raffaele is at the forefront of telomere research and age-related medicine, and he’s today’s guest on New Frontiers.

Dr. Raffaele received his BA in philosophy from Princeton and his MD from Drexel University. He trained at the New York Hospital Cornell University Medical Center, and was formerly a clinical assistant professor of medicine at Dartmouth Medical School.

He’s a member of the Endocrine Society, is board-certified in internal medicine, and is a diplomat at the American Board of Anti-Aging Medicine.

In 1997, he co-founded PhysioAge Medical Group, where he practices age-management medicine with a focus on personalized hormone optimization and physiologic age assessment. In this podcast,

Dr. Raffaele talks with Dr. Fitzgerald about the web-based biomarker data collection and reporting system he developed to assess, monitor, and communicate to patients the effectiveness of their treatments.

In this New Frontiers podcast, you’ll learn about:

Joseph M. Raffaele, MD received his B.A. in philosophy from Princeton University and his MD from Drexel University Medical School in 1989.

Dr. Raffaele trained at The New York Hospital/Cornell University Medical Center and was formerly a clinical assistant professor of medicine at Dartmouth Medical School while in practice at the Hitchcock Clinic.

Dr. Raffaele is a member of the Endocrine Society, is board certified in internal medicine, and is a diplomat of the American Board of Anti-Aging Medicine. In 1997, he co-founded PhysioAge Medical Group where he exclusively practiced age management medicine with a focus on personalized hormone optimization and physiological age assessment.

In 2007, his co-founded PhysioAge Systems, a web-based biomarker data collection and reporting system now used by age management practices around the world to assess, monitor, and communicate to patients the effectiveness of their treatments.

Since 2009, he has been involved in clinical telomere biology research and published three studies of the effect of oral telomerase activators on normal aging adults. He has lectured nationally and internationally on the clinical application of telomere biology.

Dr. Raffaele has recently focused his clinical research interests on the role of telomeres in aging and the potential benefits of TA-65, a natural compound discovered to be an activator of their critical enzyme, telomerase. Since 2006, he has been a member of the scientific advisory board of TA Sciences, which licenses TA-65 from Geron, the biotech company that discovered it.

Dr. Raffaele recently conducted an observational study of 114 PhysioAge patients, collaborating with three eminent telomere biologists, and the results—the first human study documenting the beneficial effects of TA-65—were published in published, in the journal Rejuvenation Research.

Dr. Raffaele has been an invited lecturer at the Joint Conference of the National Council on Aging and the American Society on Aging; the Foundation for Anti-Aging; Age Management Medicine Group; American Academy of Anti-Aging Medicine; and Worldlink Medical. He has appeared on the

Today show, National Public Radio and the local news broadcasts of NBC and ABC in New York, and quoted in The New York Times, Vogue, Elle, New York Post, and France’s Le Nouvel Observateur, and has written for the journal Geriatrics.

Dr. Raffaele earned a degree in philosophy at Princeton University and his MD at Hahnemann University Medical School in 1989. He served his residency at The New York Hospital/Cornell University Medical Center.

He’s is a member of the American College of Physicians, is board certified in internal medicine and a diplomate of the American Board of Anti-Aging Medicine.

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 thrilled to be here with Doctor Joseph Raffaele. Let me give you his background, and you will see why I’m so excited to pick his brain today. 

He received his BA in philosophy from Princeton, his MD from Drexel. He trained at the New York Hospital Cornell University Medical Center, and was formerly a clinical assistant professor of medicine at Dartmouth Medical School while in practice at Hitchcock Clinic. He’s a member of the Endocrine Society, is board-certified in internal medicine, and is a diplomat at the American Board of Anti-Aging Medicine. 

In 1997, he co-founded PhysioAge Medical Group, where he exclusively practiced age-management medicine with a focus on personalized hormone optimization, and physiologic age assessment. And we’re going to be focusing on this today, in 2007, he co-founded PhysioAge Systems, a web-based biomarker data collection and reporting system now used by age management practices around the world to assess, monitor, and communicate to patients the effectiveness of their treatments. 

Since 2009, he’s been involved in clinical telomere biology research, and he’s published three studies of the effect of oral telomerase activators on normal aging adults. He’s lectured nationally and internationally on the clinical application of telomere biology. In 2015, he founded the Raffaele Medical Group and blogs regularly about telomere biology, hormone optimization, and biomarkers of aging on doctorraffaele.com, and physiogage.com. 

Dr. Raffaele, welcome to New Frontiers. 

Dr. Joseph Raffaele: Thank you, Doctor Fitzgerald. It’s a pleasure to be here. 

Dr. Kara Fitzgerald: Let’s just jump right in. I’m so excited to be talking to you with this really long-time focus you’ve had in age management medicine. You’re in there as a clinician scientist and have been doing this for forever. So, just give me some background on your practice and the kind of patients that you’re working with. 

Dr. Joseph Raffaele: Sure, yeah, in the late 90s I was practicing internal medicine for about five years or so, and just realized that we were putting our fingers and holes in the leaking dam, we just were not really going after the fundamental problem, which was to shore up the overall functioning of the human body as it ages. 

The vast majority of diseases that we treat in developed western societies are the result of the erosion of health from the aging process. And sort of a little light bulb went off in my head, and I had a … was at a time of my life when I decided to change my focus, moved to New York City and opened up a practice to do just that. 

What I do in my practice is I focus on assessing how far off of optimum health an individual is, and of course, the major thing that gets you off of that is the aging process, and bad lifestyle habits, diet, et cetera. Also, assessing genetic risk, because that can increase your risk of organ failures of certain types, and diseases of certain types. 

And so, I started that practice along with my colleague, Dr. Lissy back then, and we were doing quite well for a number of years, got invited [inaudible] in 2001 or so, when he wanted to see what this clinical age-management medicine was, because he was the founder of the National Institute of Aging, had undergone a research initiative to look for biomarkers of aging, and he asked me, he said, “You know, Joe, you seem to be making your patients happy, they feel better, their symptoms are gone; but, you call yourself an anti-aging or age-management doctor, how do you really assess whether, objectively, it’s actually doing anything?”

And I said to him, “You know, well, I don’t …I really hadn’t thought about that.” 

Dr. Kara Fitzgerald: Yeah. 

Dr. Joseph Raffaele: So, that set me off on a … It’s been a long journey now, a sort of a labor of love to look for ways to measure how healthy and how well someone is aging, what they call biomarkers of aging. Over the next few years, I pinpointed a few things in arterial aging, pulmonary aging, cognitive aging, and we put together the PhysioAge biomarker system. 

And patients come in to see me to pick up where their other physicians have left off. Basically, they go to their doctor, they say, “Well, you have either this disease, and it’s out of control, or you’re perfectly healthy, nothing’s quote unquote out of the normal range on your laboratory tests or your imaging, so eat right, get a little exercise, and come back in a year. I have a very sophisticated patient base, they search for information on the internet, they look for things that can help maintain their health as long as they can, and they know there’s growing body of evidence about things to do to improve function and prevent disease, so what I do for them is I help to vet what’s out there, I help to measure in them what are their weak systems, their stronger systems, and what the trajectory of their aging is, and that’s really been my focus for the last 20 years.

Dr. Kara Fitzgerald: It’s really interesting to me. Some of the things that you’re doing … I mean we’re practicing in very similar ponds. I am a naturopathic physician, I practice functional medicine, and I cast a wide net with laboratory analysis, but just when I was over at PhysioAge.com the suite of investigations that you’re doing, it looks broad and deep and exciting. Folks, on the show notes, I will include links, and any papers or links to abstracts that Dr. Raffaele mentions today. We’ll have those over at the show notes too, but I encourage you to head over to PhysioAge.com, and to just kind of see the breadth of testing investigation that Joe’s doing.

I guess it begs the question, when you were challenged to determine whether or not you could affect lifespan and along with lifespan obviously health span is folded into that. So when you were challenged to be able to do that beyond the other investigations that you were doing early in your practice, what did you start doing? How did you set out to prove that in fact you were actually practicing age management and making true changes, what did you do?

Dr. Joseph Raffaele: Well, so it’s pretty interesting. I was really surprised, very pleasantly surprised when I started to look for ways to measure aging in a normal healthy individual that there was a lot of literature tucked away in various sub-specialties. So in cardiology there was a whole literature about how the arterial system ages from a stiffness standpoint as well as from a arthrosclerosis, or plaque deposition standpoint. We’re pretty focused in Western societies on plaque deposition and what we call arthrosclerosis, but in fact a more fundamental aging process is the stiffening and our inability to cushion the pulsations of the cardiac cycle over the course of a lifetime, even in indigenous populations where they don’t have bad habits, they’re very active, they don’t smoke, they don’t eat high saturated fat diet, they still have aging of their arteries from that standpoint. So I was surprised to see that there was this literature and instruments that had been developed to measure these things for pharmaceutical trials for anti-hypertension medications, and that certain parameters that came out of those like the central arterial pressure numbers that we use correlate linearly with chronological age in both males and females starting at around age 20.

So that I found, and then I found obviously your listeners I’m sure are familiar with spirometry and FEV-1 being highly correlated with age, and a lot of spirometry instruments spit out a lung age, because you have to know what the age of the person is before you can say they have abnormal lung function, because everybody loses lung function half to 1% per year with just normal aging.

In every other system, the brain, frontal lobes capacity to process things at a rapid rate to make complex decisions, declines and has a very robust literature looking at not loss of neurons, but actually loss of synapsis that occur to help you understand that. So when I saw this in virtually every organ system, it was just a cornucopia of information for me to assimilate, but there were also papers looking at overall biomarkers. Biomarkers and panels of biomarkers. There were studies that were going on, the Baltimore Longitudinal Study of Aging. There was a lot going on in the field that nobody in clinical medicine be it internal medicine or even functional medicine, or even to a certain extent anti-aging medicine people were aware of. I thought it would be best to try to put together a system to help practitioners to measure these things and see in an objective fashion, without having to wait for the results of a long term randomized controlled trial, whether in that N of one, and this is where it becomes very personalized medicine, the therapy that we’re applying is affecting not only the organ system that you want to beneficially, but also it doesn’t have adverse effects in other organ systems. That’s kind of key.

One therapy may do something great like exercise. Everybody thinks exercise is fantastic, which it is, but it’s got to be the right kind of exercise. If you’re somebody that has bad joints, a lot of chronic repetitive aerobic exercise is going to hurt your joints, it may help your cardiovascular system [inaudible] that’s just one example.

But you got to look at the whole picture. That’s why as an internist I always like to look at the forest and the trees. Our medicine these days is all about the trees. I don’t care what the other trees in the other part of the forest are doing, I’m going to take care of this tree. That’s a real mistake, when you’re looking at what the patient wants, which is overall optimal health and function.

Dr. Kara Fitzgerald: It begs the question, I don’t know about folks listening, but I certainly want to know, you are working with clinicians, so clinicians can refer to you for this comprehensive and really kind of intelligent workup that you’re doing. Is that true?

Dr. Joseph Raffaele: What we have is we offer a software, a web-based software program and then a series of instruments to use to measure the biomarkers that they can adopt for use in their office to measure all the things that I measure in my office for my patients, and to interpret them. What it does is it spits out a very curated report, that both the physician and the patient can look at interactively that doesn’t limit it to normal abnormal it gives it if the biomarker aging it will give it an age, so we have something called the cardio age, the pulmo age, the neuro age, for telomeres, which we’re going to get to, the telomere age, and immune function, immuno age, and then we give a report card on other organ systems that are not necessarily as tightly correlated with aging but we know what is optimal versus really a disease state, but also all the gradations in between.

Biological variables are continuous, the vast majority of them. And to say that there’s a cut off, like let’s say testosterone, 300 or 301 your testosterone is normal you don’t need therapy, 299 it’s abnormal. That doesn’t make any sense. We give a gradation. We give a grade, people are familiar with those, and we have licensees around the country and around the world using this system to try to practice objective personalized N of one age-management medicine.

Dr. Kara Fitzgerald: That’s really interesting. Are you actually pulling … I mean you’ve got a massive database at this point, have you been publishing or at least blogging on trends that you’re seeing or is that something that you want to do?

Dr. Joseph Raffaele: That is definitely something I want to do. We have over 5000 subjects in the database now.

Dr. Kara Fitzgerald: Many N of ones.

Dr. Joseph Raffaele: Yeah, and then many of them with data points over 10, 12 years. Many of them, there’s certainly a number of them. And I do want to dig into it, but as you said, I’m a clinician scientist with more emphasis on the clinician part. This is great…

Dr. Kara Fitzgerald: It is good. We need you in the clinical trenches for sure, yeah.

Dr. Joseph Raffaele: It also helps me to understand how useful the software is that I’m grading, how it works in every day fashion, and I get feedback from my licensees, and that’s all great, but yes at some point we’re going to start looking at this data in a more comprehensive fashion, and at some point in the very near future, we’re going to offer just the software, so there’s not the barrier to entry of getting the instruments, and hopefully then we’ll have thousands of licensees, hopefully fairly quickly, so look for that in the next six months.

Dr. Kara Fitzgerald: Awesome. It’s really cool. You need a PhD student in there to start moving through your data, you need something. Listen, so you mentioned telomeres, and you and I were talking about that, telomeres assessing and obviously being one of the tried and true markers of biological aging, and this is a part of the overall investigation that you undertake. Talk to me about how important a part it is and just some of your thoughts around working directly with telomeres assessing them and so forth.

Dr. Joseph Raffaele: Sure. When I first read about telomeres probably 15, 20 years ago, I thought like a lot of doctors probably thought at the time, how could this really be that fundamental component of aging, because there’s so many post mitotic tissues in the myocardium, in the brain that decline with age, and it’s not about cellular division. I kind of put it aside until 2007 when Noel Patton came to my office, the founder of T.A. Sciences who makes T.A. 65 and is a company I’ve been doing clinical research with on their molecule and the effects of it. He said to me, “What would it take for you to consider offering this to your patients?” I at that point started to look again at telomere biology and really started to understand that there are supporting cells around these other non-post mitotic tissues that are incredibly important to the health of those. 

So you can still have a marker that is involved in cellular division and the loss of the ability to do that, that is going to affect post mitotic tissues and it turns out that it profoundly affects them not only from a cellular support standpoint, but also from gene expression. I know you’re very interested in epigenetics and that’s an interface with telomere, telomeres and epigenetics is an evolving and very interesting area, but also how telomeres affect mitochondrial function. They’re very important for mitochondrial biogenesis things of that through the PCG one alpha and beta master regulators in mitochondrial function.

So it turned out that telomere biology while not the only, obviously the only part of aging, and the only thing responsible for aging it is one of the most critical components of it. I don’t know if your familiar with that paper that came out in 2013, the hallmarks of aging, but if you aren’t and if your readers aren’t, it’s a seminal paper that should be read by anybody in medicine, and certainly anybody interested in treating aging adults. And it lays out the nine major hallmarks of aging.

Dr. Kara Fitzgerald: Yeah, give us a summary and we’ll definitely link to it folks.

Dr. Joseph Raffaele: Yeah, so it basically says that there are four major aspects, hallmarks of aging, one is genomic instability the second is telomere attrition, the third is epigenetic alterations, and the fourth is loss of cholestasis. Then there are responses to the damage that occur when those primary hallmarks start to incur, and that’s deregulated nutrient-sensing] mitochondrial dysfunction and cellular senescence and then finally the ultimate result of that, which is stem cell exhaustion, altered intercellular communication. All of these are sort of the main things to focus on in the aging process, but the first four are the primary hallmarks and telomere attrition is number two, and very a very good reason, because it really affects all of those. Genomics instability is caused when telomeres get too short. The DNA damage response is turned on briskly when they get past a critically short length, because the cellular maintenance and repair systems don’t like to see free ends of chromosomes, that’s what telomeres are all about is the brief review, telomeres exist because the ends you carry out of DNA, can’t just be flying out there. They have to be concealed, so it doesn’t look like a broken strand of DNA that needs to be repaired.

So they get looped up into what’s called the T-loop and analogized to the aglet of plastic covering on the tips of shoe laces that keeps it hidden from the DNA damage response. Every time cells divide though, that telomere length, which is humans between, at the end of life, four or 5000 kilobases at peak reproductive age probably 20, 25 around 10 to 12 kilobases, if it starts to get too short it can’t make that T-loop, and all hell breaks loose in the cell at that point. Can’t divide anymore, and it becomes senescent. Telomere attrition affects all the other aspects of it. I mentioned the mitochondrial dysfunction because of the lack of mitochondria biogenesis. I would say that of the hallmarks of aging, it probably is in my view, it’s the number one factor, and one of the reasons I say that is because there are examples in genetic mutation examples in clinical medicine, something called a telomeropathy, which is when you inherit even just from one parent, so you’re heterozygous for a defective gene for telomerase, which is the enzyme that can help to put the teleomere links back on to your telomeres. 

If you get that, you will not live a normal lifespan, and depending on what type of mutation it is, you can die in your early 30s, or 40s if it’s the first time in your family that you’ve gotten that mutation, it might be in the 50s a pulmonary fibrosis. Critically short telomeres early in life are not compatible with a normal lifespan, and there are math models that recapitulate all that data, and then there’s models where you turn it back on in those mice that have had their telomerase knocked out, and it recovers all of that longevity and health span. 

That’s a single mutation. that’s a point mutation in a gene for a critical enzyme that keeps telomeres from getting short too fast.

Dr. Kara Fitzgerald: Are you, listen I have to ask you, I’ll be remiss and I know some people will get annoyed with me, are you looking at these mutations in practice? Are you getting the evidence of it in history? I just want to sidetrack you there, and then I want to come back.

Dr. Joseph Raffaele: The mutations I’m talking about, and the reason I brought them up is they are proof of concept the telomeres are incredibly important for human longevity, if they’re not functioning well, you’re not going to make it to a normal lifespan. These mutations of the more severe cases of the first description of them was Dyskeratosis congenita, which is a rare, very rare childhood disorder that is not very common, but it turns out that those same mutations and the same complex, the telomerase complex is a lot more common than Dyskeratosis congenita. For instance, pulmonary fibrosis is a relatively… about 48,000 mortality per year in United States, and about five to 10% of those have mutations in the telomere’s complex, so it’s the most common presentation of a telomeropathy like that.

But I believe that we’re missing a lot of mutations that might be slightly less penetrant, or cause less telomere shortening, and so I think that we’re probably going to be measuring and looking for those mutations in the future. Tests are available for them now at genetics companies, like Amber Genetics does a telomere screen for quite a few of the mutations that occur. What I do in my practice, everybody gets their telomere length measured.

Dr. Kara Fitzgerald: Yeah, yeah.

Dr. Joseph Raffaele: I don’t check for telomere mutation if you have pretty normal telomeres even for your age, because you’re unlikely to have a mutation under those circumstances. If they’re in the bottom 10th percentile, or certainly if they’re in the bottom one percentile, then I would definitely consider that. I haven’t measured the first one in my practice yet, because we just became available in the last year or so, but there are quite a few people that I have, and if you start measuring telomere lengths regularly in your practice, you will see people that walk in your door that don’t have a diagnosis, that have telomere lengths under the bottom one percentile for their age.

The literature on telomeropathy is that’s almost 90% sensitive specific for some mutation. It’s very interesting at that point, how many people are out there with their challenged telomerase and having shortening telomeres.

Dr. Kara Fitzgerald: Let me just ask you this, and then I’m digressing a little bit, but what you’re saying is ridiculously interesting. If you did get the genetic testing that might alter your intervention with the patient based on what the mutation is and where it’s active? Like you mentioned pulmonary fibrosis being one of the main areas associated with rapid biological aging based on telomere length. Would you say that’s true? Would it help you hone in on an organ system, or would it guide your treatment in some way having this information?

Dr. Joseph Raffaele: Sure, I mean there’s an action in medicine, you don’t measure something unless it’s going to change your management.

Dr. Kara Fitzgerald: Yeah, right.

Dr. Joseph Raffaele: Is it going to change the behavior or change the patient’s whatever else they do in their life, and so it’s a couple of things, first of all there will be counseling, because there’s a good chance, 25% that it will be passed onto your offspring, depending on what your husband or wife, what they’re tested for. So if somebody comes in really low with telomere lengths often after we have a discussion they’re going to want their brother, sisters, and children tested to see as well. If in that point, a mutation is determined then things like … We all know we shouldn’t smoke, but somebody with significant telomere mutation should not even get near smoke, secondhand smoke or any of that, because their lungs are going to be very vulnerable.

Dr. Kara Fitzgerald: Right.

Dr. Joseph Raffaele: And then there is a lot of increasingly growing body of data showing correlations between telomere length and shortened telomere lengths and risk for cardiovascular disease and cancer. Very large databases on both of those where I would say, and I don’t think I’m too far off saying that if I had to choose between knowing a person’s cholesterol or knowing their telomere length to predict their cardiovascular risk, I would choose telomere.

In an interesting study done…

Dr. Kara Fitzgerald: That’s pretty fascinating. What about particles? What if you could throw in the full test?

Dr. Joseph Raffaele: Even particles.

Dr. Kara Fitzgerald: Okay, good.

Dr. Joseph Raffaele: With the exception of probably lipid protein little A (LPa)

Dr. Kara Fitzgerald: Oh, okay, isn’t that interesting. Okay, so just go ahead, continue.

Dr. Joseph Raffaele: That’s the most atherogenic one.

Dr. Kara Fitzgerald: Yeah, right, right.

Dr. Joseph Raffaele: I wouldn’t mind knowing that as well, but regular cholesterol it is important and all things being equal you probably want it to be lower. Obviously it depends on whether it’s oxidized and so many other things are involved, but in terms of one cross-sectional study and both prospective cross sectional and retrospective, the risk, the hazard ratio for the shortest third versus the longest third for cardiovascular disease was about 1.5 fold, so 50% increased risk. It’s not that much with cholesterol, or it’s just around there. The other thing about it is you’re also assessing your risk for cancer. The risk for cancer in one study done in Italy a prospective longitudinal study, looking at people between the ages of 40 and 70 and all cancers, free of cancer at baseline, if you’re in the shortest third versus the longest third you had a three-fold increase risk of cancer over the next 10 years, and you had a 11-fold increase risk of dying of cancer.

So those are pretty big numbers and pretty significant numbers, and there’s a lot of biological and physiological explanation for why that would occur.

Dr. Kara Fitzgerald: Yeah, I think…

Dr. Joseph Raffaele: They’re actionable, I think. And then from many different standpoints, from genetic counseling to lifestyle to being more aggressive about cancer screening, more aggressive about cardiovascular risk factor, you want to get the other risk factors under control, and then you want to see what you can do with telomere lengths.

Dr. Kara Fitzgerald: Yeah, right, right. It’s exciting. Obviously if somebody comes with the bottom 1% of the population for telomere length, that’s going to be really pretty anxiety provoking and disturbing, but you just unpacked a lot that we can do, just this full integrative functional approach, but yeah, so I appreciate your tour of telomere biology and the importance, the wide spread importance, and again folks will just link to everything that we can that Joe’s mentioning here. Let’s talk about it. They’re more than a surrogate marker, we want them to be long for their physiologic affect, so they’re not just suggestive of aging, there’s a lot of processes, that I guess a short telomere would induce. We want our telomeres to be long and robust, and you’ve been working on that in your world and measuring and getting all sorts of follow-up data, you’ve been doing clinical research and publishing on it, so talk to me about what you’re doing to keep telomeres in tip-top shape.

Dr. Joseph Raffaele: Telomere length is one of the integrators. I like to think of it as your sort of biological 401K, it’s the reserve that you have for maintaining a healthy, your health span going forward. The amount of times your stem cells can divide because they have adequate telomere lengths to support that, and the interesting and fantastic things about telomeres is that they integrate so many aspects of biology and medicine that we know. Every bad habit, smoking, obesity, sedentary lifestyle, stress, etc. all associated with shorter telomeres, and the opposite fixing those things improves that.

All the things you do in functional medicine help to decrease the attrition rate of telomeres, because it reduces oxidative stress, stress reduction self, reduces cortisol, increased levels of cortisol, inhibit telomerase, so the whole thing fits together very nicely. You want to hit all those aspects of those things, but none of those things will actually turn on telomeres to lengthen telomeres, and that’s where you come to telomerase activators, and there’s two ways to do that, one is through gene therapy and there’s some exciting stuff going on right now with telomerase induction with AAV viral vectors and hopefully we’ll be seeing some results and trials of those in the next year or two, but what’s available here and now, sort of side of things, there is a telomerase activator, TA 65, that’s derived from the traditional Chinese medicine Astragalus membranaceus. A specific species, and that specific molecule that is extracted through a patented process to essentially 98 to 99% pure extract.

What’s interesting about this molecule came about through this company in the late 90s called Gerum Corporation looking for something to treat the aging process. They screened thousands of compounds internationally to see what turns on telomerase in vitro, they got a few hits, and they got this one molecule that also was not at all toxic. They started it on the NDA root, with a lot of safety testing, a lot more than any typical supplement would get, and then the company changed directions, because the FDA was signaling that they’re not going to approve anything for aging alone. So they changed to looking at cancer therapeutics and sold off the rights to company TA Sciences in 2002 to sell a supplement, because it’s a natural product, it’s generally considered a safe, because it’s been in the Chinese diet for millennia.

And so I was lucky enough to be involved in the first cohort that was given TA 65 along with a supplement packet I used in my practice to see whether or not telomere lengths were affected or any of these major biomarkers that we looked at were affected, and we published two papers in 2011, and 2013 looking at the effect on some SNP cells which were significantly reduced in individuals on supplement for a year, and then on other metabolic markers in the subsequent paper so there was some beneficial effect on blood pressure, cardiovascular, risk factors, bone density, those studies then gave the company the impetus to do a randomized control trial, which was conducted in Spain, and I was part of that, the last author on the paper we published the first clinical study looking at the results of a telomerase activator on individuals 50 to 70 something years old and we did show an increase in telomere length, and certainly highly statistically significant on the 250 IU dose, in comparison to placebo who actually lost telomere length, which we would expect over the course of that year.

Those are the things I’ve been involved. We have a study right now pending peer review, looking at a large 500 subject randomized control trial, on the effect of TA 65 on senescent T cells, we’re hoping to get that published in the next six months or so. There’s been studies looking at TA 65s effect in the retina in macular degeneration, and there’s an interesting signal that takes place there with some improvement in the MAIA, which is a test looking at changes in the Macula.

There’s been some skin studies done that showed some improvement in skin cream. It’s an exciting area that continues to grow, and I’m happy to work in this area, because I think the company is looking at clinical studies to show the effectiveness, and I’m all about in God we trust, for the rest show me the data.

Dr. Kara Fitzgerald: Yeah, that’s right, that’s right. Okay good. That was a lot. You just said a lot and I just kind of want to know what’s happening.

Dr. Joseph Raffaele: Yeah, it’s a whirlwind, sorry about that.

Dr. Kara Fitzgerald: Let me go back a little bit. No, it was great. And again I’m going to assure folks that we’re going to get, as many, we’re going to gather together as many citations and my team is going to ping you to make sure that we get them all, because you just mentioned a ton over the course of our conversation. They’ll be there on our show notes page. 

So first of all, I just want to hit home what you said in the beginning because it’s exquisitely important. We know that our functional medicine that the workhorse, dietary and lifestyle changes that we do, shoring up nutrient status, all of that detoxification, cleaning up diets and so forth, that is going to halt telomere damage, it’s going to turn the volume down, that’s going to preserve the length that is present and reduce the accelerated loss that happens with the aging process, so that’s what you said clearly, you can correct me if I’m wrong in any of this in a minute, but this telomere activator, specifically this astragalus derived compound that’s in TA 65 actually increases length, so this is reversing. So there’s two pieces here. There’s halting, and then there’s actually reversing the aging process. And lowering the biological age. Do I have that right? Did I articulate that correctly?

Dr. Joseph Raffaele: Yeah, absolutely. It is definitely a slowing and in some cases the halting of the telomere attrition rate, but then to actually add on telomere length, you have to turn on telomerase, which is not normally, it was relatively suppressed in adults to turn on the enzyme, to express the enzyme to add length to telomeres, and that I’m not ready to say that reverses biological age, but what it does is it definitely lengthens telomeres to more youthful lengths, which are associated with much more youthful functioning. In those mouse studies that were done, when they turned on telomerase strongly, and got a 33% increase in telomere length, there was an actual cocoon like, you know the movie Cocoon if anybody’s old enough to remember that where they jumped into the pool, these old people and got young again, these mice have rejuvenation in the brain, and their spleen of their fur of their skin, they basically became younger mice. It was big enough news that it was features on 60 Minutes with a video of things back when those results came out.

So as a proof of principle, if you significantly lengthen your telomeres, there should be improvements in other biomarkers of aging, and I do see that in some of my patients. I have patients who have over the course of five years gradually added up to 20% of telomere length, and their biomarkers are at least staying stable, in most systems. It doesn’t mean we halt the overall aging process in every tissue, but absolutely slow things down and in some cases can turn them around.

Dr. Kara Fitzgerald: Just anecdotally with your 5,000 N of ones do you see … You’ve got to be seeing clinical improvement or you wouldn’t be staying here doing this research. They feel better, they look better, etc. would you say that?

Dr. Joseph Raffaele: Yeah, we definitely hear from patients, things like I have more energy, more resilience, more recovery from some workouts. One thing we heard quite a bit is improvements in vision. Optomically, whatever the word is, proven…

Dr. Kara Fitzgerald: Ophthalmologic, yeah.

Dr. Joseph Raffaele: Improvement in both near vision and far sidedness. So hyperopia and myopia both and their ophthalmologists are like I never see this happen.

Dr. Kara Fitzgerald: What’s the mechanism? If it’s actually improving vision, the lens keeps growing and the muscle control is sort of lost and that’s the mechanism of presbyopia so I got it, is there anything published on that? I’d be really curious?

Dr. Joseph Raffaele: There isn’t anything published on that. I’m not the only physicians that gets those reports. I’ve heard it from the company and when I speak at conferences. It’s exactly that. Presbyopia is the eye or ciliary body’s ability to change the lens. But you can imagine that if it’s going in there and it’s helping the cells to function better and perhaps clean up some junk in the lens itself, certainly with the myopia, improvements in the retinal epithelial cells can occur that’s a highly proliferative tissue that can run out of telomere length and that’s probably some of the reason that it’s improved the marker for macular degeneration. 

So we see that, some people see improvements in the [inaudible] I think that’s probably just overall improvement in their energy and feeling well, although who knows. I still, like you said, I have some deep dives to do, to put together the changes in telomere length in a large enough number of subjects to correlate with other biomarkers in a statistical fashion and that is on the list of things I want to accomplish in the next couple years.

Dr. Kara Fitzgerald: All right, so I have a couple more questions here from that. Is this taking the TA 65 product alone, or is this in concert with a full approach. Talk about both of those.

Dr. Joseph Raffaele: Sure, so the first two could be cohorts that have the supplement pack, and they were my patients in my practice doing other things like hormone optimization exercise, etc. The randomized control trial in Spain, there was none of that, they were instructed not to do stuff like that, not to change anything they were doing, so it was test the molecule as seen with the one that hasn’t been published yet, and same with the macular degeneration one.

So, you’re hitting just one side of the equation there as you mentioned earlier. If you’re hitting the other side, we would expect to see potentially more robust improvements.

Dr. Kara Fitzgerald: Now delivery for the work, the retinal changes is that oral or is in a drop formula?

Dr. Joseph Raffaele: Nope, it’s oral. The oral gets into the vascular system, and then gets to the eye. It’s not drops. The only one that is topical is the skin study that was done that shows some improvement in a number of markers of skin aging.

Dr. Kara Fitzgerald: Oh, is that right? Okay.

Dr. Joseph Raffaele: You could imagine seeing improvements in skin as well, which we do see, but they’re on a whole bunch of things in my practice. With oral, assuming it gets to the dermis and potentially the epidermis through the capillaries and it helps with epithelial cell division. I could see that happening as well.

Dr. Kara Fitzgerald: Do you use the topical in your practice?

Dr. Joseph Raffaele: I do. I use the topical in my practice, on myself, because I think you can deliver a higher concentration to the epidermis than you would probably be able to get with oral.

Dr. Kara Fitzgerald: So, what are the primary indications for the topical in your practice? Just wrinkles?

Dr. Joseph Raffaele: For me, it’s just any skin aging that you want to attack. I think it’s good for any skin, the skin ages. We all have damage that’s been done. I gave a lecture probably five or six years ago at the South Beach symposium, a dermatologic meeting where I was asked to speak about the potential mechanisms through which telomerase activation and lengthening of telomeres could affect skin aging, and there is a number of ways in which it can and the decent body of literature and that’s probably why we saw the positive results. So if you want to slow down skin aging, even if you have pretty good skin right now I think it’s a perfectly reasonable thing to do.

Dr. Kara Fitzgerald: Yeah, right, right. What about things like actinic keratosis and stuff?

Dr. Joseph Raffaele: In those, I think that this is theoretical, but I think that those can occur because of DNA damage. If you can shore up your senescent cells, I mean get rid of your senescent cells and if you can keep telomeres from getting shorter, because I think one of the biggest risk factors for cancer by far is certainly epithelial cancers, which is the majority of cancers that we treat and that kill people in Western societies. If you can keep those telomeres longer, then you don’t get that DNA damage response, you don’t get that aneuploidy and all the molecular disarray that occurs when the chromosome tips can then start to fuse because the T-loops are gone and they’re naked ends. I think the actinic keratosis could potentially be a weakness.

Dr. Kara Fitzgerald: Yeah, it makes sense mechanistically it sure does. I suppose one would want to try oral along with topical. So what about dosing in these studies and how are you dosing your patients in practice? Is there a variation or is there a one-size-fits-all?

Dr. Joseph Raffaele: Yeah, that’s a great question. The interesting thing about TA 65 is that its bioavailability is highly variable individual to individual. Company did a series of studies looking at the dose response in a group of subjects, and on one dose somebody had really nice Cmax, another one was undetectable. And I see this in my practice. Unfortunately there’s not a blood test to look for how much gets into your blood, so we have to use markers. The 250 IU which is the starting dose did work in that randomized control trial which showed telomere lengthening. But I see in my practice all the time patients that come in and get started on, I start everybody on that 250 dose, and then what I look at telomere length and I look at senescent T-cell count, because you see a pretty early signal in reduction in senescent T-cell count on TA 65 within the first three to six months, whereas your telomere length may not happen as quickly, so if I don’t see an improvement then I assume that they’re not getting as good a tissue level or blood level as I want, and I double the dose, and I keep on doubling the dose until I get that improvement.

Dr. Kara Fitzgerald: What T-cell panel are you getting? I’m sorry.

Dr. Joseph Raffaele: Yeah, so that’s part of the problem the senescent T-cells are not available through your typical Quest or Lab Corp or most any place else. They have to be ordered through a clinical immunology laboratory, we use UCLA clinical immunology laboratory. And they do T-cells, P-cells, break it down between helper cells and suppressor cells, but then suppressor cells we break down into senescent suppressor cells and naïve suppressor cells, and those are the two major things that can happen to your T-cells and they’re associated with in the case of accumulation senescent suppressor cells a lot of bad things. Increased inflammation and increased mortality in fact in a series of studies that were done in Sweden. The marker we look at is absence of C-28, which is the co-stimulatory molecule that lines up next to the T-cell receptor when it locks onto the energy presenting cell. 

So you’ll get a risk response that you need if your CD-28 negative net, also once that happens telomerase doesn’t get turned on in the cells and they’re effectively senescent. There is some controversy now in the literature about what are other markers that might be good for looking at a senescent T-cell but I think the literature is really pretty good to show that if you have an accumulation of those senescent cells your immune system is a little bit overwhelmed, it’s producing more inflammatory markers and if you have a significant enough accumulation such that the ratio of your helper cells to your suppressor cells goes under one, and healthy is where it’s about two to one, that’s associated with short term increase risk of mortality.

So you can as an easy marker just look at a CD4 to CD8 ratio, and you can get that in any lab, and as a screen, if that’s below one then you really want to go for the more mesenteric test and do it different.

Dr. Kara Fitzgerald: Okay, so you want to see at least the two to one for CD4 to CD8

Dr. Joseph Raffaele: I mean you want to see definitely above one and 1.5 to 2.5 is about perfect.

Dr. Kara Fitzgerald: Okay, oh okay, okay.

Dr. Joseph Raffaele: That’s what we like to see. 

Dr. Kara Fitzgerald: Well listen, so when would you start therapy? When would you do your follow-up test? About how long into it?

Dr. Joseph Raffaele: If it’s below one and I’m trying to get the dose right, and it’s an older patient with some common morbidities, I’ll do a follow-up testing in three months of the senescent T-cells. The more telomere length measurements you get, the better idea of what the trend is. People talk about it’s gone up, I went from 6.5 to 6.7 that shows it’s working. I’d love to think that, but in fact .2 kilobase is within the variation biologically, so you really can’t make much, you need three to four points over the course of a year, year and a half to really know what your trend is and to really know whether what you’re doing is affecting it, and that’s why I do measure them annually at least and sometimes twice a year if they’re on therapy and we’re trying to give out what’s happening with our therapy.

Dr. Kara Fitzgerald: Who are you using to measure telomere length?

Dr. Joseph Raffaele: Yeah, so I use a company called Repeat Diagnostics in Vancouver Canada. Peter Landsdorp is one of the world experts in his lab in doing this. They’ve doing it for me since 2007 and much longer than that. Dozens of papers are published and their database is published. All the children’s hospitals around the county and I think in other parts of the world send samples there for telomeropathies and bone marrow transplant screening. I’ve looked at probably 3,000 telomere length measurements from them, and rarely is there a problem, something that doesn’t make that much sense to you.

Dr. Kara Fitzgerald: Okay, fabulous, thank you.

Dr. Joseph Raffaele: There are other companies that I think do a good job as well, Life Link in Spain those are both looking at the type of florescence in situ hybridization or what we call fish technology. I would stay away from the ones … A lot of the literature on cross sectional studies is done using QPCR, because in an individual looking at longitudinal testing the N of one is a lot more variation, so companies that offer that technology versus the fish, flow fish with repeat diagnostic PHT fish with life link I would say it’s a good screen for a hundred bucks or something like that for telomeres, but to follow it over time, I think there’s potentially … I know that company offers them over time, and they can show me the data, then I’ll be happy to restate my position, but for right now my experience is pretty vast over the last 12 years with this company and I think particularly in the extremes of high really long telomeres or really short telomeres they do the best job in the world.

Dr. Kara Fitzgerald: That’s great, okay thanks. Again folks, we’ll link over there. I’m really, I think Joe you’ve gotten a lot of people pretty excited about the possibility of all of this. Just another handful of tools in our practice. I know you and I were talking before we hopped onto the podcast, that the rate of loss over time is probably the better predictor of aging, not so much your baseline measurement of where your telomeres are, but just the rate of loss. Although, I guess if you started with the baseline measurement and your telomeres were shorter than you wanted them to be for your age that would be alarming. So basically what I’m saying is that you want to do measurement over time, you want to stick with the same lab and the labs using the fish technology are in your opinion the better labs.

Dr. Joseph Raffaele: Yes.

Dr. Kara Fitzgerald: Okay.

Dr. Joseph Raffaele: And that’s absolutely right. It is the attrition that … That’s that paper we were also talking about before we went live so to speak is that there’s been some debate, even the Nobel prize winners Elizabeth Blackburn and then Carol Greider’s been said that single telomere length measurement doesn’t tell you anything. And she quotes the fact that you can do a blood test on somebody and their telomere length could be the equivalent to a seven year old level or a 40 year old level and they could be 55, and that’s absolutely true, but that’s because there’s a wide variation  of heritability, there’s a very strong heritability, about 70% and there’s a wide variation in the length that’s inherited. So you can start with pretty short telomeres from your parents, but through lifestyle, through diet, through exercise, whatever technologies you’re bringing to bear, you’re not losing as much.

Dr. Kara Fitzgerald: Yes.

Dr. Joseph Raffaele: There’s a paper that just came out is really important, and it showed that species lifespan, average species lifespan is highly correlated in a power function with telomere length attrition. People always say, “Mice have really long telomeres, like 40, 50 kilobases long.” And humans as high as 10 to 15, but humans live many fold years longer, what’s the deal here? Well, it turns out that mice lose 7,000 kilobases per year, 7,000 base pairs per year, and we only lose 50 base pairs per year, and they did it for elephants, for reindeers for bottle nosed dolphin, all the way out to moose moskalus the mouse. I wish they had a few more time points in more short lived species, but the data is highly correlative. It’s R squared of .7 and so what that tells me is that one last thing that made us wonder about whether telomeres are important is been shown that it’s the telomere attrition length, and it’s really through active biological mechanisms that it affects longevity lifespan and health span, because of the way in which it affects gene expression, which we didn’t dig that much into.

Dr. Kara Fitzgerald: Exciting stuff. So don’t freak, the other funny thing you and I were talking about was Scott Kelly who’s the astronaut who spent a year in space and for whatever reason … And he has an identical twin brother who was landlocked, he was in space, he came home and his telomeres were significantly longer than his brothers for about two days. So that measurement could have gotten him really excited, but then when they did a repeat, unfortunately for him whatever wildly beneficial thing, like a space-time continuum-collapse for about 24 hours there benefited him and then he’s back to normal. So yeah, serial measurements. Go ahead.

Dr. Joseph Raffaele: If we have time, I would like to address this, because that’s a really important point to make about looking at telomere length measurements. I don’t have the exact data for that, but if it did change that much, then that was probably an example of what’s called pseudo-telomere lengthening or shortening. We’re measuring telomere length in white blood cells in your peripheral circulation. Only about 2% of your total white blood cell count is circulating in your vascular system, but it’s typically representative of what the ratios are in your tissues. However, under certain circumstances like exhaustive exercise, or potentially space, a rich mix of white blood cells could be circulating at that time, and they have very varying lengths of telomeres. The senescent T-cells have really short telomeres, the naïve T-cells have really long ones.

If because of something that happened changes the relative proportions of those so that it’s not what they normally are in you, it can look like your median telomere length has gotten a lot longer, a lot shorter, but in fact the telomere length hasn’t changed at all.

Dr. Kara Fitzgerald: That’s fascinating. So if you spike an illness and you just dump a whole lot of white blood cells you might actually at that time, if you catch it early on have a different length than you would after you recover, is that what you’re saying?

Dr. Joseph Raffaele: That’s exactly correct, and that’s why I tell my patients and I tell our licensees and other people that I talk to, if a patient comes in with an illness or a relatively recent illness don’t measure their telomeres.

Dr. Kara Fitzgerald: Right, or likewise don’t do it after a marathon.

Dr. Joseph Raffaele: Right, don’t do it after a marathon, any exhaustive exercise, at least 24, 48 hours in a marathon it will be a week or two I would wait. And because you want their measurement in a homeostatic state. 

Dr. Kara Fitzgerald: Listen, I have a couple more questions, we’re just wrapping up here, so again I wanted to … So all things controlled, you’re measuring telomeres and homeostatic state, you’re getting repeat analysis, you’ve got them on lifestyle, but you’re adding in the TA 65 product, you’re seeing good outcome in not just telomere length, but clinical presentation and the other biomarkers that you’re looking at. It sounds like, I hope somebody jumps into your 5,000 N of one database there and publishes some stuff, but it sounds like you’re doing some really cool work and just getting some really lovely outcome with TA 65.

Dr. Joseph Raffaele: We are, it’s been a long, especially a 12-year journey now for me, with this molecule, it’s been pretty fascinating. My own telomere length has not changed in 12 years, it’s .2 kilobases. I have about 13 measurements, with some fluctuation. That’s why you have to look at the trend and sort of moving average, but I do have some bases that have gone monotonically up, some that are not going down too fast. So the information is gathered over time, I want to stress that, and as far as the single telomere length measurement, when you’re young if it’s really short that’s a big deal. If you’re older and it’s really short, it’s not quite as big a deal, but it’s still a big deal. In a young person to be in the bottom 1%, when I talk about young, I mean I’m talking about 20 to 40, then you’re much more likely to have a mutation. The older person, they just might have a faster attrition where they might not have inherited that much, but not had a mutation. 

Those are the ways in which to look at telomere length measurements, I think an individual measurement is important, in a single individual measurement much more information is gained by getting them over time, and then augmenting them with the lymphocytes subset panel, which looks at the varying types of lymphocytes that contribute to that telomere length that you’re measuring, because we’re measuring the white blood cells, and then looking at how it affects other organ systems, because it really does. All of your organs get regenerated by the niche stem cells, and those niche stem cells can do their job only to the extent that they have enough telomere length to continue to divide.

Dr. Kara Fitzgerald: I think this is a game changer for a lot of folks listening today. I’m very, very excited. I have one more question, if you’ll just humor me. You and I were kind of emailing back and forth a little bit, and you know I mentioned before I’m interested in epigenetics, particularly the Steve Horvath the epigenetic, the DNA methylation clock. And you’ve started looking at that, you started to use it in practice. You mentioned that you’d been looking at I think there’s 353 CPG sites. DNA methylation spots that they’re accessing in the biological aging clock, this new clock, and what have you been seeing and how has TA 65 influenced it?

Dr. Joseph Raffaele: I have just started, I probably measured 20 something like that. I have about five or six that I have a year follow-up tests on. I think that what I’ve seen is some patients have three to five years older, I had one patient that was actually 10 years, but there was a lot of things in their medical history, stress, lifestyle that could explain that. I’ve had some people be younger.

Dr. Kara Fitzgerald: How significantly younger?

Dr. Joseph Raffaele: The most I’ve had so far is five years, which is kind of interesting. I’ve had a couple on the upper end. Vis-a-vis telomeres, Horvath has published that the clock doesn’t necessarily correlate that well with telomeres, and I think the new maven in this area is Morgan Levine who was in Horvath’s…

Dr. Kara Fitzgerald: Right, right, yes, that’s right.

Dr. Joseph Raffaele: … Yale, she has what’s called the PhenoAge clock now that isn’t commercially available that more closely correlates because it was trained on a data set for health span markers. I think it would be more interesting to see what telomerase activation telomere lengthening does to that, because I would be surprised if that isn’t affected. But I think that this clock is fascinating. She has cautioned people in publications and interviews to be careful to focus on trying to move the epigenetic clock needle because we don’t get half the data to show that will necessarily result in favorable outcomes.

So right now I’m really looking at it with my super early adopter patients that want to track this thing and know that the interpretation is going to be an evolving thing, sort of like genetic testing right now. It is fascinating and I think that telomeres, the thing about telomeres is it sits right between DNA and epigenetics. 

Dr. Kara Fitzgerald: Mm-hmm (affirmative), that’s right.

Dr. Joseph Raffaele: Telomeres are the only part of your DNA that actually change with age, unless it’s getting mutated, they get shorter. Epigenetics is about how we express and how we look at our, how our DNA is basically expressed. It’s sort of an epigenetics, telomere, or what I call telogenetics, and then genetics. These are the three areas that we can focus on, but I think there’s more and more focus on the first two, and less focus on the fact that you’re not necessarily stuck with what your genes are.

Dr. Kara Fitzgerald: That’s exactly right, yeah. I think that’s a beautiful way to end. So folks, Steve Horvath is at UCLA, and he developed this clock. We’ll link there. I also want to say that I don’t think we can … There was one study suggesting that there was some opposition between the clocks, but I think that’s just a representation of our newness in this area of investigation. I think we’re going to find that they’re related. They’re clearly related. Yeah, go ahead.

Dr. Joseph Raffaele: No, I would agree with that. I think it really depends on which part you’re looking at. The technology is fantastic, I think the proof of concept is there, it just needs to be worked out further with larger data sets and more information.

Dr. Kara Fitzgerald: Very exciting. Exciting times. Thank you so much for spending some time with me and sharing your wisdom and your experience in relation to telomeres and the aging process. Just really a good conversation.

Dr. Joseph Raffaele: Yeah, it’s been great. Great questions. I’ve enjoyed it thoroughly. Thank you very much.

Dr. Kara Fitzgerald: You’re welcome.