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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 absolutely thrilled to be here again with Dr. Joseph Raffaele. I’m going to give you his background and you’ll see why I am thrilled to be diving in and picking his brain today.

Dr. Raffaele 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, he’s 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 while 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 to the effect of oral telomeres 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 RaffaeleMedical.com and PhysioAge.com. Dr. Raffaele, welcome again to New Frontiers.

Dr. Joseph Raffaele: Thank you, Dr. Fitzgerald. Glad to be here.

Dr. Kara Fitzgerald: Yeah, it’s always good to get to talk to you. I think the only limitation is that we should talk more frequently, I think, is the conclusion. I really enjoy picking your brain. Last year we did a nice dive and, folks, you’ll find a link to our previous conversation on the show notes pages so you can listen to that podcast. In fact, if you want to listen to that podcast first and then tune into this one, this is really a part two.

We talked about testing and treating telomeres in our initial podcasts. Telomeres are one of the tried and true biomarkers of biological aging and we just took a deep dive into telomere biology, we talked about lab tests, about immune biomarkers, telomere length and the therapeutics available. We closed the podcast touching on DNA methylation and we talked a little bit about epigenetics.

Since our first podcast, tell me what’s new in your practice.

Dr. Joseph Raffaele: Well, there’s a couple of things that have been really exciting me lately. I think one of the things is more information and, I think, better understanding of what role DNA methylation and, particularly DNA methylation clocks have and its relation to epigenetics that has removed some of the roadblocks to there being useful tests.

I don’t know if you remember, we talked about them in the context of biomarkers overall and a lot of people have been, in the last six months or so, new companies coming out offering DNA methylation tests have been talking about how fantastic these clocks are because they correlate with age with what we call an R-squared, meaning how much of the variance between individuals is predicted by it, of upwards of 0.9 and even up to 0.98, which is a perfect clock.

Dr. Horvath has used the test in forensics for figuring out the age of somebody when they don’t have a documentation of it, so it’s great for that. But having been involved with biomarkers of aging for the last 20 years, you don’t want a biomarker that’s that perfect because otherwise you just look at your calendar and you get the same information. What you want to look for is the variation in age between two individuals, the physiological aging that’s taking place, so that there’s something to treat or something to monitor. A perfect clock like that, it doesn’t really give you that much information.

What has happened is since then, a number of studies have been published looking at different ways of training these datasets with the deep learning. That’s how they come up with these things. Won’t get into the mathematical details, probably because I wouldn’t explain them, but I’ll leave that to my data scientist who we work with. It depends on the dataset you train. If you train them to predict chronological age, then they will predict that as well as they can by looking at all these thousands of sites, what we call CpG sites, on DNA.

But if you train them to look for something else like to predict how biologically healthy someone is, then a different kind of information. It may not correlate with chronological age quite as well, although it certainly will, but will tell you more about propensity for disease and for mortality.

A number of companies, of one clock in particular, was published by Dr. Morgan Levine’s group when she was at USC and now she’s at Yale, that was trained on routine lab data that we all get from just chemistries, that would be albumin, alkaline phosphatase, creatinine, fasting glucose, percent lymphocytes, red cell distribution width, or RDW, MCV and high-sensitivity C-reactive protein. They fed that into the machine, into the deep learning software, and they came up with what’s called PhenoAge, which then they train DNA methylation to predict the PhenoAge, so a second step.

So this clock looks at a different type of epigenetic change that is predictive of biological change, and that then is something that could be potentially affected by therapies and alter disease outcomes mortality and, potentially, functionality, making these clocks much more useful, I think, at this point.

Dr. Kara Fitzgerald: Yeah, that’s a really good summary. Jeez, thank you Joe. That’s a great job. Yeah, but it actually still does correlate with chronological age, it’s just not one-to-one, as the previous clocks. Yeah, you’re right, it is changeable and it is quite extraordinary what she did. She was in Horvath’s lab, but yeah. The simple chem screen and CBC with additional, I think, just C-reactive protein, that’s it.

Dr. Joseph Raffaele: Yeah, the only addition was the C-reactive protein well and CBC with the lymphs, and RDW and MCV, and then a chemistry and then a CRP. Everybody has that data available to them, and you can feed it into the clock and it actually predicts … They have mortality predictions based on the NHANES cohort, and disease risk. What would be really interesting is to learn the molecular biology and physiology behind why each of those is contributing.

What we don’t know necessarily is if we make interventions to alter those, is that going to change the mortality? That’s an intervention trial that has not been done. But we know that the salutary direction for most of these things, we want your albumin to be higher, not lower. It’s usually important in the antioxidant system you want your creatinine to be lower, of course. You want your glucose to be low. RDW, you want them to be tight so you don’t have a lot of different sizes of red blood cells and C-reactive protein, of course, you want to be low. So it makes sense from what everything we know about it, but to put them all together in this way and then be able to predict outcomes is really pretty fascinating.

I think it also was great for me because it put to rest this misconception that people had, and particularly people when they’re marketing their clocks, which is, “These other biomarkers are passé,” in particular they’re talking about things like telomeres’ length, which I have a deep interest and, at this point, knowledge of. They’re saying, “Well, telomeres are passé. You just need to look at the DNA methylation clock because it’s so much more powerful a predictor.”

But, in fact, just predicting chronological age is not really that important and biomarkers that might only have an R-squared of 0.5 could well be very important. I use them all the time in my practice. Like we talked about central arterial pressure, I think, last time, which is a better blood pressure. That is an R-squared of just about 0.5, but is highly correlated with end stage renal disease mortality, coronary artery disease mortality, changes linearly over age, it’s a very, very useful biomarker.

Dr. Levin herself, and other experts in the biomarker field, have said, “None of these fancy new clocks, as important as they may be, are going to displace other direct physiological measurements. They’re going to be additive.

Dr. Kara Fitzgerald: Yeah, that’s right.

Dr. Joseph Raffaele: The more that you have, the better.

Dr. Kara Fitzgerald: That’s right, that’s right. Absolutely, yeah. They’re not going to supplant a blood sugar, they’re going to supplant just getting an old school blood pressure, yeah.

Dr. Joseph Raffaele: They can tell you other new and interesting things, but don’t think that if you know just that then that’s all you need to know because that’s just not the case.

Dr. Kara Fitzgerald: Listen, I just have to ask you for a second, I don’t want to digress too much, but are you prescribing continuous glucose monitors with your patients these days?

Dr. Joseph Raffaele: I don’t. I mean, I’m not against it. I’ve listened to a lot of Peter Attia’s stuff and other doctors that do that, but I have patients who … I follow the hemoglobin A1c, so if hemoglobin A1c is 5.0, then you don’t need to continuous glucose monitor. That’s really all there is to it. Now, if you’re trying to get, I mean, as a behavior modification tool there are those patients out there that are, “Well, I eat this and I eat this and it doesn’t do that. I don’t believe that bananas raise my blood sugar.”

Or there may be people where you’re trying to figure out maybe they have to eat some carbs and you’re trying to negotiate with them and we know that some carbs, in some people, raise their blood sugar, like bananas might in one person. Whereas in another person it doesn’t, but rice does.

So they’re useful for that, but most of my patients, I have a really pretty healthy population, and the average hemoglobin A1C is around 5.4. We just don’t need that information. It’s not that much fun to wear, let’s face it.

Dr. Kara Fitzgerald: Okay, that’s good. That’s good. That’s a good answer. I’ve been wearing one recently and I’ve been somewhat addicted to it. It is pretty addictive and it is a behavioral modifier, for sure, so I was just wondering what your take was.

Dr. Joseph Raffaele: Absolutely. I have some sitting here that I’ve hoarded, I just haven’t been able to put it on my tricep yet to do it. Now, if it gets really small and a tiny little patch with that lumpy thing that you can actually go do an arm workout or do a more intensive sweating workout where it’s not going to fall off and it’s just not going to get in the way, then I’ll probably do that just for the fun of it, as you said, and to see. Particularly if I’m doing … I do time restricted eating now. I don’t eat breakfast. Be nice to see what happens during the day. But again, we’re just looking at our devices so much.

Dr. Kara Fitzgerald: We are, we are. It’s TMI. It is. It is TMI. It’s fun, but to your point, I did knock it off the other day, so it’s not where it will be in a few years. I appreciate the background on what you’re thinking about the DNA methylation clock. That was just really nice, lovely intro. The fact that the other biomarkers are still useful, including looking at telomeres. There’s some pretty interesting research that you brought to my attention on thinking about telomeres in our current pandemic. So I want to ask you about that and just how we might use this knowledge to affect benefit with building resilience in our patients?

Dr. Joseph Raffaele: Yes. Well, so what has been fascinating, but also, I think … Trying to find the right word. It’s not coming right just this second, but really interesting that the kind of medicine I’ve been involved in for the past 20 years I’ve always thought of as preventative, functional, take healthy people, keep them healthy for as long as possible. But I don’t do acute care medicine, okay?

It turns out, and we’ve always known, that the number one risk factor for most of the diseases that kill 95% of people, the top four; cancer, cardiovascular disease, dementia or diabetes are the number one risk factor, that’s aging. And now we have this pandemic that’s come along that we find that the number one risk factor for having severe disease is aging, so that’s pretty fascinating.

And so, thinking about ways to turn back the biological clock on people who are chronologically old to help them not have a severe disease is potentially something that my field could offer to the acute medicine field to help reduce the burden of this disease because, whatever, 99% of the people have mild or no symptoms. But how do you know who doesn’t? Chronological age, is another thing that’s I think gratifying to find out, chronological age doesn’t exempt you. There’s not an absolute cutoff at 60 or 70.

I just heard of a terrible story about a 23-year-old yoga instructor, super-fit, died of COVID. I mean, no preexisting conditions that we knew of. That’s the thing. What’s lurking within us? Could it be potentially short telomeres or excessive numbers of senescent T cells because of a viral infection that they have that’s not SARS Covid two. In fact, I think we talked a little bit about CMV last time-

Dr. Kara Fitzgerald: We did, mm-hmm (affirmative).

Dr. Joseph Raffaele: … being a precursor to a cause of premature aging. Two really interesting papers came out. When I was thinking about this I run into two of the leaders in telomere biology and one in senescence, study of aging of immune system, Aviv and Moss. Basically are hypothesis papers, but basically saying that perhaps one of the things that is important in explaining why chronological age is the major risk factor, but also explaining some of these younger cases is that while they have younger age, in certain systems they’re not as young. They may well be like a 70-year-old. I have an example in my practice. A very healthy 40-year-old woman and she has telomeres that are about the length of a 74-year-old.

Dr. Kara Fitzgerald: Well, do you see that correlate when you do her … I mean, if you do a more detailed immune phenotype workup, do you see that in T cell status or do you see that reflected elsewhere in the biomarkers of that woman?

Dr. Joseph Raffaele: Yeah, I saw it reflected in two things. Well, one is that she had premature graying, which is part of her family and probably her telomere length, a good portion of it was inherited. I think we talked about it last time. About 70% of your telomere length is inherited and there’s quite a wide variability of three to four kilobases, which is just about as much as you lose over a lifetime. So at young adulthood you could be stuck with telomeres of somebody that’s 30-40 years older than you are because of what you inherited, not because of lifestyle or any other things going on.

So, I saw in her the premature graying, also she’d never smoked, and very athletic, and very significantly older lungs. You know that one of the areas that’s hit most significantly in people with telomere biology disorder are the lungs, idiopathetic pulmonary fibrosis, 3% to 5% of those cases have telomerase mutations. She did have some of those, but because she was relatively young, with telomeres it’s when you get to a critically short telomere length that you start to see manifestation, so hopefully this will not happen because we have her on TA-65 and we’re having her do lifestyle things, et cetera.

But typically what happens at a certain point her telomeres get too short and then a lot of disease start to happen prematurely, cardiovascular disease, pulmonary disease, potentially osteoporosis, dementia, all those things could happen, but they won’t show up when she’s in her mid-40s, not yet.

Dr. Kara Fitzgerald: Okay, okay. Just give me a little bit for people who aren’t familiar with TA-65 that you started her on immediately. Just give me a little bit of the background on it.

Dr. Joseph Raffaele: TA-65 is a virtually pure extract of a traditional Chinese medicine called the astragalus root and this particular species of astragalus root, which is astragalus membranaceus, that has been used in Chinese medicine, astragalus root, for immune enhancing and longevity-

Dr. Kara Fitzgerald: It’s been used in COVID in combinations, in TCM, actually.

Dr. Joseph Raffaele: Oh, is that right, yeah? I mean, that makes sense. I’ll get back to those other two papers in just a minute as well as to potentially why it might be beneficial in that. But so it has been shown … TA-65 is originally found by a company called Geron, which was a biotech named after the Greek for old man, which was what geron means in Greek. They were looking for things to treat the aging process because they knew back then in the early ’90s that the major killer of people is really the aging process and then it just picks the disease that happens to you first as you get older.

They turned away from that towards cancer therapeutics because the FDA is still, certainly back then and still is as of yet, won’t give an indication for aging for approving a drug. So they turned away from it and the rights of it were sold off to a company that was founded by Noel Patton. He started to sell it as a supplement to enhance, turn on telomerase. They did all the pre-clinical stuff. They did the molecular biology where they showed that it did turn on telomerase, which is suppressed largely at birth and did raise it about threefold, which is a moderate telomerase activator.

Then we subsequently had published paper showing the telomere length has been increased in a randomized controlled trial and has had beneficial effects in immune system, reducing the number of the senescent T cells that accumulate with age, and accumulate particularly in individuals who have been exposed to cytomegalovirus. This is where the COVID link is, basically.

The individuals who are too young to succumb to COVID-19, do they have immune systems that look more like 60 or 70-year-olds because they have a large accumulation of senescent T cells and things that would do that would be an infection with CMV from very early on? Because what CMV does is if you asked your regular doctor about it, it would be like, “Don’t worry about CMV, it’s benign. Nobody has it and it only causes disease in newborns because their immune system’s not functioning well enough, and immunocompromised individuals.”

That is not true. The fact is, is that to keep that herpesvirus, and it’s herpesvirus number five, at bay when that is latent, not causing disease, and we know what disease it causes from the AID’s epidemic, it causes retinitis, gastroenteritis, pneumonia. It can cause encephalitis and it can kill you. Your immune system has to work very hard to keep it from coming out. It has to divide, and divide, and divide and each time your cells divide, those cells that are left behind so the memory cells that were left behind and then the CMV gets reactivated, they have to divide again to fight it off. Then they’re left with slightly shorter telomeres. That happens over and over again. The telomeres get too short and then its T cells become senescent.

Those senescent T cells not only don’t do their job, but they do two bad things. They take up space for naïve T cells so they can respond to new vaccinations and possibly respond to new tumors or infections, but they also secrete a lot of inflammatory cytokines. You all have heard about cytokine storm that happens when someone gets really bad COVID disease. The thinking behind this, and this is from this paper by Paul Moss, who’s arguably the world authority on CMV and immune system, is that individuals may have accumulated a lot of these senescent T cells at a younger age because they had CMV from an early age.

Other things, like being overweight, having high blood pressure, having glucose problems, all of those can conspire to cause your body to overreact to the virus. And what they’re suggesting is that perhaps in addition to age, looking at CMV status could be a way to stratify people for risk and for more robust protection in quarantining from other individuals rather than just saying, “Well, you got to keep your grandmother away from the kid coming home from college,” you also got to keep whoever’s CMV positive away from them because that could potentially worsen their response.

Now again, this is not meant as medical advice to anybody. This is hypothesis stuff, but it’s based in some pretty significant data that I think could be helpful to trying to get this pandemic under control. The underlying thing here, what ties it all together, is that it’s the shortening of the telomeres that occur. Not only do they secrete the inflammatory cytokines, but also with short telomeres those final effector T cells that have to divide, and divide, and divide massively with this onslaught of this virus, end up not being able to divide anymore because the telomeres get too short. Yet, we know that people with severe disease get lymphopenia, in other words a low number of lymphocytes.

Dr. Kara Fitzgerald: Yes, I mean that’s been shown in COVID. That’s been shown-

Dr. Joseph Raffaele: Right, in COVID. That’s what I’m talking. I mean COVID. It all makes sense, as they say, as to what hypothesis is about, what’s going on to cause disease in some individuals where other ones … I had a patient that came in, didn’t even know she had it. I’m doing SARS antibodies on anybody whenever I do blood all, because I want to know whether they’ve turned positive, whether that’s going to be explaining long haul symptoms. We know that 40% of people are asymptomatic. This is a very healthy patient of mine, she’s been a patient for 10 years, 55-years-old, didn’t even know she got … Didn’t know where she got it. She didn’t even know she had it, but she’s SARS antibody positive.

So, why does she not get any symptoms whereas that 23-year-old yoga instructor died? That’s the real question.

Dr. Kara Fitzgerald: That’s a really good question, yup.

Dr. Joseph Raffaele: But telomere biology and looking at immunosenescence and look at biomarkers that can help us really stratify things could lead to pathways for getting this thing under control.

Dr. Kara Fitzgerald: Yeah, it’s an important question. I mean, it’s a head scratcher, right? We can say there’s the classic comorbidities, right, that we see commonly, regardless of age. We see diabetes and pre-diabetes, et cetera, hypertension, obesity, so you can see that, yes. But what about these otherwise really healthy individuals? That’s a good theory. Certainly when we look for antibodies in cytomegalovirus, and I want to ask you about Epstein-Barr as well because we can see really high Epstein-Barr titers and reactivation, et cetera, et cetera. Would that be similar? I mean, that would lead to T cell exhaustion.

Dr. Joseph Raffaele: Yeah, so the most powerful effect on the immune system comes from CMV. It’s been looked at, but there’s also been an interesting study that was done that looked the number of herpesviruses. The greater the number of herpesviruses you have, and there’s seven or eight depending on how you do the count, the shorter your telomere length is.

Dr. Kara Fitzgerald: Wow, so do you test them all in practice. Do you look for all of them?

Dr. Joseph Raffaele: I’ve started doing that now just this year, particularly HHV-6 which causes, I believe, roseola. Yeah, I think it’s roseola. Is basically asymptomatic, but I have patients whose telomere length and immune function lymphocyte subsets look like they have CMV, but they’re CMV negative. It’s turning out that those individuals have three, four, five herpesviruses just not herpesvirus-6.

Dr. Kara Fitzgerald: So there’s just background infection? There’s a background-

Dr. Joseph Raffaele: Background stress on your body to keep-

Dr. Kara Fitzgerald: Yeah, fascinating.

Dr. Joseph Raffaele: …. I think to keep these viruses latent.

Dr. Kara Fitzgerald: Right. Oh, my goodness.

Dr. Joseph Raffaele: Which explains the whole concept of the virome, I mean, we all know about the microbiome and the microbiome’s importance in metabolism, in cognitive function, you name it, we’re looking at microbiome now. But the virome is actually, I think it could end up being just as important, if not more important-

Dr. Kara Fitzgerald: Yeah, that’s right. That’s right. That’s right.

Dr. Joseph Raffaele: … and we’re going to start looking at those things. And actually, that’s probably going to be a little bit easier to study because there aren’t quite as many of them and they can study in blood rather than the other way.

Dr. Kara Fitzgerald: Well, we have a ton of them in our gut though too. I mean, honestly-

Dr. Joseph Raffaele: We do, for sure.

Dr. Kara Fitzgerald: … and have a pretty cool podcast if anyone’s interested in discussing bacteriophages with one of the premiere scientists, Paul Turner, who’s at Yale. And so speaking of interesting viruses, those guys are actually potentially good guys, but I digress. I think you’re on to something really pretty cool here regarding just having this high viral load that your immune system’s working at keeping at bay. It makes so much sense to me.

These folks, for this 40-year-old and for the other patients who you are suspecting of this, or you’re measuring the various herpesviruses and seeing activation, you’re using TA-65 with them, obviously, because you’re thinking about short telomere. I know you’re tested telomeres as well, but for somebody who’s not, they could consider using this intervention, especially because it has demonstrated benefit in a number of studies where positive CMV participants were included.

Is there anything else besides TA-65 and how do you dose it?

Dr. Joseph Raffaele: Yeah, well so there’s what we know from biology and pharmacodynamics, then just other practical considerations. I’ll start with the practical considerations. TA-65’s not inexpensive and so you want to try to use the lowest dose that’s effective. That’s where telomere testing, I think, is important. Now, you could just take 250 ius, which is the standard capsule size or half of a tablet size, which is 500 ius. You take it every day and you may well benefit. Our studies show that in a large group statistically significant benefit occurred at the 250 iu level.

But I’ve seen in my practice that it may take more, it may potentially be a little bit less too, but I never look at a lower dose to get a reduction in senescent T cells, which I look at as a major marker of knowing that you’re getting a blood level. But in the absence of being able to test of telomeres, I think that you can’t go wrong taking the 250.

Would 500, if you can afford it, cover you? But then, at that point, if you’re going to spend the money for the extra 250 ius, you might as well spend the money on telomere length test because you only have to do that once or twice a year and if can save you money, then that’s the better way to do it. But that’s the practical consideration.

The other test that you could do if you really want to see whether you’re in dire … Not, dire need, but, I think, a very good candidate, let’s put it that way, for TA-65 is to look at the CD4 to CD8 ratio, which has been shown in a very, I think convincing, eloquent series of studies in older individuals in Sweden.

And now has been replicated in other, slightly younger populations in other countries where that ratio fits under one, which we call the immune risk phenotype or the immune risk ratio. If it’s under one, then your mortality levels rise quite significantly. Your short-term mortality levels rise if you’re above 80 and, potentially, cardiovascular disease and longer term mortality risk could increase if you’re 60s and above.

If that level is below one, that means that you have an accumulation of senescent T cells because the denominator is the CDAs and that’s where the T cells get senescent in that population, the cytotoxic T cells. So when they accumulate and take up immunological space, the denominator gets bigger, the numerator, the helper cells, doesn’t change that much with age, and so it’s going to be a bad thing when the denominator goes up and it goes under one. If you have somebody in that circumstance, then I would put them on TA-65, maybe recheck the ratio in three to six months. If it’s going above one, then you’re doing good things.

Dr. Kara Fitzgerald: Okay, all right. Nice. Good. That’s good pearl. Listen, just as an aside, what COVID antibody test are you using?

Dr. Joseph Raffaele: Oh, right now I’m using the ones that Quest and LabCorp offer-

Dr. Kara Fitzgerald: You are? Okay.

Dr. Joseph Raffaele: I think they are … I mean, I say that they’ve gotten better and the current one I think are highly sensitive and specific. I can’t give you the exact number, but I think it’s in the 99.97 for the specificity and 99.9 for the sensitivity, something like that. So that’s a very useful one if there’s not cross-reactivity with other coronaviruses to any significant extent, and so I think that they’ve gotten that part down pretty well.

Dr. Kara Fitzgerald: Yeah, good. Okay.

Dr. Joseph Raffaele: The rapid COVID tests are still a little harder to get than we’d like them to be, but that is what it is.

Dr. Kara Fitzgerald: Let’s see, where else do we want to go here?

Dr. Joseph Raffaele: I want to mention…..

Dr. Kara Fitzgerald: Yeah, go ahead. Mm-hmm (affirmative).

Dr. Joseph Raffaele: I wanted to mention one other thing because I have things that are exciting me and we got pulled aside just for a second. Besides, the DNA methylation thing that I wanted to talk about, but I also wanted to talk about it because there’s another new biomarker kid on the block that maybe your listeners have heard about or haven’t heard about, the new kid on the block in the biomarkers.

Dr. Kara Fitzgerald: Do tell, do tell.

Dr. Joseph Raffaele: It is a GlycanAGE and it is a measure … That’s G-L-Y-C-A-N-A-G-E. I was introduced to it a couple of years ago by a company who was going to offer it in the US, a US company, and for some reason they moved away from that and they didn’t end up offering it. And then I have this company, PhysioAge Systems, which is a biomarker software. It’s more than that, it’s health analytics. We put almost 600 different markers into it to analyze where you are in the aging process, but also in overall health and functionality.

And so, one of my licensees in Warsaw, Poland, The Longevity Center, is run by a really fascinating woman, Joanna Bensz, who is involved in health and medicine in the EU, and put together a biomarker roundtable that I was invited to with David Sinclair and, actually, the founder of this company, GlycanAGE, and she started using it and she wanted to add it to my software.

So I, about six or seven months ago, started doing the test. It’s available now in the US. What it is, is a biomarker who’s R-squared is probably between 0.5 and 0.6-0.65, so we might say, “Well, that’s pretty good, but not that impressive.” But again, the point is, it’s not so much how it correlates with age, but how it correlates with other things. What this test is, is a measure of the pattern of the sugar molecules that are attached to your immunoglobulin-G, the predominant antibody in your blood.

What’s fascinating to me is that this has opened up a whole new field of information in signaling glycans, which are sugar molecules not only attach to IgG, they attach to virtually every protein-

Dr. Kara Fitzgerald: Everything. Yeah, that’s right.

Dr. Joseph Raffaele: … They are all over your cell membranes and your lipids-

Dr. Kara Fitzgerald: But how is this different than an A1c?

Dr. Joseph Raffaele: Okay, very good question, but also the answer is very different and patients ask that too. It’s not about what your sugar control is, this is signaling that’s controlled by your body. It’s not a shift-base like an A1c is, it is covalently attached to the protein through usually an asparagine or, I believe, it’s a threonine amino acid that’s right in the center of the antibody where two arms attach. They can vary between … And they’re different sugars, it’s not glucose. Glucose, I think, is not even one of them. I think it’s, maybe one of them

Dr. Kara Fitzgerald: Okay.

Dr. Joseph Raffaele: … is a lactose, fucose, mannose, many other -oses.

Dr. Kara Fitzgerald: Okay, so it’s a bunch of -oses’.

Dr. Joseph Raffaele: Yeah, they’re basically all of those saccharides in a certain pattern that are attached to it. The fascinating thing about it is that they alter the functionality and the signaling of the molecule. And in IgG, they change the inflammatory behavior already, so if you have a certain pattern which is found in younger people, this is what’s so fascinating with regard to the COVID, in younger people the IgG is much less inflammatory. It turns on complement much less, turns on the cytokines much less, does its job and then gets out of the way. That may be why people can have an asymptomatic disease because they don’t have the cytokines stored.

As you get older the pattern changes, it turns out that you lose the galactose typically on there, and some other changes take place, a fucose may be lost as well, and then you become a little bit more inflammatory. And then it changes even further and you become even more inflammatory so that they can correlate it with age, but also correlate it with now … The founder of the company, I just spoke to him recently, has looked at people who have had COVID disease and those with younger glycan ages have had less severe disease.

Dr. Kara Fitzgerald: Oh, interesting. Is he going to publish on that?

Dr. Joseph Raffaele: It’s in review now, I believe.

Dr. Kara Fitzgerald: Hmm.

Dr. Joseph Raffaele: His name is Gordon Lauc, L-A-U-C. Put him in PubMed, he’s got a large number of publications. Really nice guy and a really brilliant researcher bringing this field. I think I’ve talked about this in the past, maybe not on your podcast, but it takes the commercial availability of a test for a biomarker to become really important. What’s the quintessential example of that? Is the other weird Greek word other than telomere?

Cholesterol. We knew about cholesterol, but until there was a good assay for it, it wasn’t going to be studied that much, it wasn’t going to be used for that much, and now Gordon has brought to the world, through his lab, Genos, G-E-N-O-S, this technology to measure in a really easy way, it’s a blood spot on a card.

Dr. Kara Fitzgerald: Is it really?

Dr. Joseph Raffaele: Yeah, and it’s available basically worldwide and he’s rapidly accumulating data. He has a very highly characterized datasets that he’s looked at these in, like the UK twin study, I think it’s UK, 8000 subjects. So when he gives you a GlycanAGE it’s not just based on a small dataset, it’s based on a large dataset. What’s fascinating about that is that, in my practice is how I got to know him, besides the roundtable, was that we kept on sending results back. We sent about 60 of them back at this point and we have many more cooking. He was noticing that in my patients, the average male glycan age was 27-years younger than average chronological age. The average female was about 14-years younger.

He sent me an email and then got a call, “What’s going on?” And we’re trying to figure it out. As you asked me earlier before the show to talk a little bit about what I do in my practice, what therapies I do, and boy a lot of them, and so I don’t know just yet what it is. We’re getting now to the point where we’re having the numbers to look at it and analyze and see if we can tease out what it is that’s doing it.

Now look, we know that being good shape, exercising regularly, not being overweight, having a diet high in fruits and vegetables, all these things that are good for you make you less likely to get COVID. I mean, those are the antithesis of the comorbidities, right? And all my patients do all that stuff. They’re on our supplement packs. But they’re on other things too, so we have to try to figure it out because we don’t know yet, but if his study gets confirmed …

I’m 61 and my glycan age is 22 or 23. Does that mean that I may get less severe disease? We don’t know, but so far I’m still SARS negative and antibody negative and I haven’t been exposed to it, but this biomarker is very, very useful because is also correlates with mortality and correlates with osteoporosis, diabetes risk, hypertension. It is more like Levine’s PhenoAge than the original Horvath clock. So, it correlates with age, but it gives you much more interesting biomarker. This is not just a biomarker, these are effector molecules

But what’s also interesting is that my DNA methylation age is not that great and I have patients whose DNA methylation isn’t that great, but their glycan age is really good.

Dr. Kara Fitzgerald: So what clock did you … Just out of curiosity, what Clock..

Dr. Joseph Raffaele: Right now I’m still using Zymo Research’s clock, which is licensed from Horvath

Dr. Kara Fitzgerald: Yeah, but they don’t use Horvath’s anymore. They springboarded long-

Dr. Joseph Raffaele: Yeah….

Dr. Kara Fitzgerald: Yeah, so they’re not … It’s their proprietary clock. I mean, it might be interesting to see what you are using a Levine clock or something.

Dr. Joseph Raffaele: Oh, I have behind me a PhenoAge kit that I’m going to spit into when I do my next quarterly biomarkers, so I’ll let you know.

Dr. Kara Fitzgerald: Good. I want to know. I just want to tell folks, because we’re talking about so much interesting stuff, first of all, we will do a roundup of the myriad studies that Joe has just mentioned and we’ll pack the show notes with all of these studies. The GlycanAGE, we’ll get a link to that for you. Just a lot of these cool topics that he’s covered today we’ll just put on the show notes.

Just really interesting. There’s a proteomics clock out there too. I mean-

Dr. Joseph Raffaele: Yup. I’ve heard-

Dr. Kara Fitzgerald: Of course you know.

Dr. Joseph Raffaele: … things about that one too. I mean, this is the take home for me for the past year since we last talked, is that we’re talking about systems biology and to think that one biomarker or even one clock, no matter how much data it puts into it, that it tells you the whole story is silly. We should-

Dr. Kara Fitzgerald: Yeah, that’s right. That’s right.

Dr. Joseph Raffaele: … know that in retrospect.

Dr. Kara Fitzgerald: Well, listen. When they have this biomarker roundtable, I don’t know if you’re able to sneak a guest into this virtual world. I really want to go. It sounds so fascinating.

Dr. Joseph Raffaele: Yeah, we had it already. It was supposed to be in-person in Lichtenstein, and they’ll do one next year actually in Lichtenstein, so-

Dr. Kara Fitzgerald: Well, 2021.

Dr. Joseph Raffaele: Right. Keep your fingers crossed, right?

Dr. Kara Fitzgerald: Yeah, that’s right. Well, if it’s virtual it’ll be easier to sneak me in. So listen, it’s just a blood spot? All right, we’ll link to it. I have question about it. If it’s pricey, I’m really curious about it. I’m thrilled with this hypothesis that you’ve posited to us today on why extremely healthy people could be really developing severe COVID-19 as well as it’s just a logical collection of interventions or way to think about addressing COVID in older patients and helping with immune rejuvenation. I think that’s the name of the game.

Dr. Joseph Raffaele: Yeah, that is.

Dr. Kara Fitzgerald: So, where else do we want to talk here? You sent me another pretty cool study that was published in August. It’s an animal study, but looking at infertility and kidney dysfunction, again, using TA-65. Any comments on that?

Dr. Joseph Raffaele: Yeah, so I just saw that fairly recently, that’s why I added it to because I was looking for new stuff that I came up with then the last time we spoke.

Dr. Kara Fitzgerald: I think it’s actually … They accepted it, but it’s not going to be published until November. But yeah, so I was looking at the date. Very new, but yeah.

Dr. Joseph Raffaele: Yeah, so two things about it. One, it wasn’t … I should say just parenthetically that in Dr. Aviv and the paper on COVID-19 and telomeres talks about potentially TA-65 as something that could be helpful, but then makes an aside about it being funded by the company that the studies that he was mentioning. This study was not funded by the company. There have been other studies that are coming out are just people interested in-

Dr. Kara Fitzgerald: Molecule.

Dr. Joseph Raffaele: … what we have is the telomeres, telomere biology and what is probably the best and most well-validated telomerase activator. So, what they did was they took young rats and older rats and gave them TA-65. Oh, wait. They didn’t give it to the younger rats. They measured, they looked at their testicles, they looked at their kidney size, they looked at their kidney function, they look at their hormone levels and what they found was that …

And in older rats, following from 10 months to one year, they gave them TA-65 at 500 milligrams per kilogram along with pomegranate extract at 250 milligrams per kilogram. I know you were interested in that, I’m sure, from a functional medicine standpoint and all the polyphenols that are in pomegranate. With the hypothesis being that either … They didn’t really mention telomeres per se and they didn’t measure telomeres, and certainly for pomegranate that wasn’t part of the hypothesis, but just as antioxidant in its potential youth-enhancing and longevity-enhancing benefits.

What they found was that the control group in the older mice did lose fertility, they had abnormal morphology, motility, and numbers of sperm produced in their testicles on histology looked older and different. And then the kidneys shrank, their GFR decreased by close to 50% and their uric acid levels went up, so all things of aging kidney that they would expect to happen, happened.

But in the older … I mean, they’ve gotten to equivalent of humans about 60, these rats then were given TA-65 orally, in an oral gavage, so just how we basically would take it, except squirted down their throat rather than taking it as a pill with some water. And virtually all these changes with age were reversed to a large extent.

I mean, the testosterone levels didn’t go back up as much, didn’t go back to youthful levels, but they improved. But LH improved, the signal from the pituitary, so it affected the pituitary, FSH improved. That would explain why the sperm and the Sertoli cells responded better and made better and more healthy sperm. Creatinine and GFR improved. Uric acid levels came down, so a rejuvenation of these animals.

Now, the caveat on that is they didn’t have any molecular mechanisms for how this happened, and they didn’t measure telomere length, which would have been great. It happened just to a certain extent in pomegranate, but more it was a better response, except in the hormones, but everything else was better response with the TA-65. And then, yeah. So we really didn’t know why it took place.

The other caveat was that 500 milligrams per kilogram is a lot of TA-65 in a human. It’s about, I think, 10 times what we’d normally dose people with, so super-expensive. But-

Dr. Kara Fitzgerald: How long was the study? How long did they do the intervention?

Dr. Joseph Raffaele: Two months of intervention.

Dr. Kara Fitzgerald: Okay, two months. All right, go ahead.

Dr. Joseph Raffaele: But they didn’t do a lower dose. We don’t know that a lower dose wouldn’t have been effective.

Dr. Kara Fitzgerald: Well, you’ve been using TA-65 for more than a decade in your patients. Do you see some of this? You see some of this rejuvenating-

Dr. Joseph Raffaele: Well, I certainly see telomere lives getting longer in many of my patients and-

Dr. Kara Fitzgerald: Well, what about kidney function and some of the other? I mean, I know you’re doing a lot, so you can’t tease it out, but-

Dr. Joseph Raffaele: Right, so I haven’t looked specifically, longitudinally at change in kidney function, but I … not systematically.

Dr. Kara Fitzgerald: You could do that really easily.

Dr. Joseph Raffaele: That’s on the list.

Dr. Kara Fitzgerald: Yeah.

Dr. Joseph Raffaele: I’ve got a data scientist working with me that’s at the level of a Morgan Levine in terms of his knowledge of this stuff, so hopefully we’ll be producing some of these analyses and I hope be publishing some. But you know how that is when you’re seeing patients all day long too.

Dr. Kara Fitzgerald: Yeah, it’s hard. Yeah, it is. I know. I get it. You’ve done a lot. You’ve done a lot.

Dr. Joseph Raffaele: What we do see, though, is either increased or I have many patients where I’ve shown them their trend and, over the past 10 years, they’ve had no loss of telomere length. That’s not the natural history. The natural history is lose at least a half a kilobase, which is much more than the fluctuation of the test. We see that. I can say just anecdotally, that I have some males that have fathered children in their 70s and so that’s maybe something going on there, I don’t know for sure. But yeah, I don’t have anything more.

I just thought that that kind of rejuvenation, now that kind of rejuvenation is the kind of rejuvenation that was seen in some of the studies I mentioned last time where they’re doing gene therapy, they’re lengthening telomeres by 30% and you’re seeing testes rejuvenated, kidneys rejuvenated, brain rejuvenated, skin rejuvenated and they may be, if they looked the telomere length, have gotten something like that. Who knows? They didn’t look at the telomere length.

But it’s really pretty fascinating that it mirrors the gene therapy studies to a certain extend with oral dosing, albeit at a very high level.

Dr. Kara Fitzgerald: Really high level, yeah. Fascinating. God. Well, you know what? We’re running out of time. I could continue to pick your brain on this topic, it’s so interesting. Let’s see, you’re going to reveal, the title of the podcast as you see, folks, is The Best Biomarker of Aging, so you’re going to, of the many that you’ve talked about, you’re going to reveal that to me. We talked about the DNA methylation testing that you’ve been doing in your patients. You’re going to give me a follow-up on that. Then the women’s expected longevity linked to age at birth of last child, that’s a pretty interesting paper.

Those are three things that maybe we can just bang out in our next few minutes here. What do you think?

Dr. Joseph Raffaele: When I was thinking about the title, I want to get people interested by saying, “What’s the best biomarker of aging?” But the truth is there isn’t a best biomarker.

Dr. Kara Fitzgerald: It’s click bait, it’s definitely click bait. It worked for me. I’m like, “Oh, do tell.” Okay, there’s no best …

Dr. Joseph Raffaele: And again, that’s really I want to say to the DNA methylation people out there who keep on saying that their biomarker’s the best biomarker for aging. People who have invented DNA methylation aren’t saying that anymore, so you shouldn’t be saying it-

Dr. Kara Fitzgerald: Well, let me tell you something. You just posited, you argued it very elegantly. I mean, you just did a really good job today on that.

Dr. Joseph Raffaele: I think that money aside, the best biomarker of aging is the more the merrier. That’s my approach in my practice and I’m, of course, I’m trying to be cognizant of patients because virtually none of these biomarkers are covered by insurance. They’re not hardly expensive, but they run between $200 and $400 or $500 depending on the biomarker. But then I would say, “Look. If you’re thinking about doing a whole body CT scan,” which I think is a waste of time and too much radiation, “Spend your money on a biomarker panel instead.”

But in my practice, I do telomeres, I do the immune lymphocyte subset panel which we then give them an immune age. We have a new kid on the block for a different kind of an immune age, which is the GlycanAGE. I do the DNA methylation age. There’s going to be a proliferation of clocks available that, I think, will be used for different things, trained on different things and we may use a number of different methylation clocks. They may not even be called clocks at that point, they’re just going to be called predictors of various things. That, I think, is going to be something we’re going to see in the future.

I think that the easy one, which we’ll have available through our company fairly soon, is to just put in the routine markers that I mentioned and give you a pretty good clock based on data that you probably have already.

Dr. Kara Fitzgerald: Oh, thrilled. Yeah, perfect. Okay, well jeez. Why don’t you let us know and we can link to that?

Dr. Joseph Raffaele: I certainly will. Then the women’s expected longevity, that’s another one of those things like the best biomarker of aging. My take on that is that you shouldn’t home what you think you should take home from them, which is people are like, “Okay. If I have a child late in life then I’m going to live longer.” No. The causality is not there. We don’t know that that’s not … It’s possible that that might have to do something with it, but what is more likely is that … This is a follow onto a smaller study that was in done in 2017. It was a larger study, I think was close to 1000 subjects.

But basically, to just quickly sum it up, if you have longer telomeres you are likely aging more slowly, you are physiologically younger. And therefore, even if you’re in your late-30s, you’re really like you’re in your late-20s and so you’re likely to have a longer lifespan, a healthy lifespan, and that’s what this study did. They looked at the telomere length and women that lived into their 70s and saw when they had their last child and, in fact, the ones that had the latest child had the longer life and the longer telomeres, because they were all in their 70s.

I think it’s really more, a generally more healthy woman is more fertile.

Dr. Kara Fitzgerald: Yeah, their fertility is longer lasting, just like the prior study in the animals. Well, yeah. Just good fertility, although that those guys were using TA-65. Yeah.

Dr. Joseph Raffaele: Yeah, I see that in my patients. I actually have patients that come in who are still menstruating in 54-55 and they have typically longer telomeres. Some of them may have … I haven’t looked at it systematically, but I wouldn’t be surprised if some had children later in life because they were able to. So you don’t want to say, “Look. I’m going to delay childbirth for career reasons and it’s going to help me to live longer.” That’s not the way

Dr. Kara Fitzgerald: Not a good way to interpret that study. All right, let me try to get pregnant now.

Dr. Joseph Raffaele: They did the same thing with the title that we did with the best biomarker of aging. Keep people interested thinking that’s what it is, but that’s not what it is.

Dr. Kara Fitzgerald: Right. Very interesting. Gosh. Well, I just want to make one comment and then we’ll wrap up, but you talk about none of these tests, these really useful biomarkers of aging, being covered by insurance and as you started our talk today pointing out that the number one risk factor for COVID-19, for severe disease and mortality, is aging. And, of course, aging is the number one risk factor cancer, for cardiovascular disease, for diabetes, for dementia, as you pointed out also.

And so at some point the powers that be need to get that this is, in fact, a very wise investment to look at these biomarkers. Because if we just turn back the biological hands of time a little bit, we improve outcome, we improve health-span, lifespan, just remarkably. I think there needs to be a revolution in how we’re conducting research and stepping away from being so siloed into really, as you say, embracing the systems’ approach.

Dr. Joseph Raffaele: Yeah, and I think that revolution’s about to occur. The Cain trial, which is looking at the effect of metformin on mortality, is the first anti-aging trial that hasn’t yet started, but will start fairly soon. One of the former FDA commissioners was on that call and they will likely start to think about approving a drug for aging. And if they approve a drug for aging, then they’re going to have to approve the biomarker of aging.

Dr. Kara Fitzgerald: Yeah, yeah. The floodgates are going to open.

Dr. Joseph Raffaele: It’s going to open and the bastions of stodgy academia are now making people, like Morgan Levine, professors at a young age to study aging and bioinformatics around aging, so that means the sea change is starting to take place.

Dr. Kara Fitzgerald: Yeah, that’s right. That’s a really good point. Yup, absolutely. She’s here in Connecticut at Yale. Yeah. Well, I think that’s a great way to end. It’s always nice to connect with you. Yeah, I look forward to visiting your clinic. We’ll put links to the clinic and links to Dr. Raffaele’s various websites and just make all of this rich content that he’s shared with us today available to you, everybody listening to New Frontiers.

Again, Dr. Raffaele, thank you so much for joining me today.

Dr. Joseph Raffaele: You’re welcome, Kara. Have a great day. Wish you had more time.

Dr. Kara Fitzgerald: Well, to be continued.

Dr. Joseph Raffaele: Yeah, I look forward to having you coming down here and then giving you a … We’ll get you your overall PhysioAge.

Dr. Kara Fitzgerald: I know, I know. Well, I’m hesitant, as I’m sure most people are, but I’m also really looking forward it. It’s-

Dr. Joseph Raffaele: Oh, I’ve met you in person. You’re a pretty healthy specimen, so I’m sure it’ll look …

Dr. Kara Fitzgerald: Great, all right. So to be continued. Thank you. Take care.

Dr. Joseph Raffaele: Take care

Dr. Kara Fitzgerald: Bye.