How do I Know How Well Am I Aging–and What Can I Do About it?

Joseph Raffaele, M.D.

I’m doing very well, Sanjeev. Nice to be on your summit.

Sanjeev Goel, MD, FCFP (PC), CAFCI

I’m so thankful that you were able to get you in at the last moment, but I think it’s so important with the work you’re doing and your expertise in this whole space of aging that we couldn’t have, not had the summit without you. So I’d like to, maybe before we can get into this, if we were to understand your background and how, you know, why you even went to this aging field because there’s no, like, there’s no specialty of aging, I think, you know, necessarily, so it must have been something that kind of pushed you down this road.

Joseph Raffaele, M.D.

Yeah, so it kind of- Looking back on it at this point, it’s kind of a long journey, but I was trained in internal medicine at Cornell here in New York and then went to practice primary care internal medicine up in New Hampshire at the Dartmouth-Hitchcock Clinic. This sort of got my doctor legs, and I saw patients for five years, you know, in an outpatient setting, but also saw patients in the hospital and saw a whole lotta patients, so the whole gambit of things, but I guess, at the same time, toward the end of that, both my parents were getting older. They were a little bit older when they had me, and they were starting to ail. One of them was developing Alzheimer’s disease. 

I was also starting to feel like I was just really kind of filling the holes in the dam and not really trying to, you know, sorta create a new way of holding water back. So I was looking around for other things to do, and it was a time of my life personally that I could sort of step back from internal medicine. I went to a few conferences in the field of what they called back then anti-aging medicine and saw that there was a lot of research going on in the field, I mean, not just do you have a disease or don’t you have a disease, and what do you do about it, but what’s the process, the sort of prodrome that leads up to a disease in an organ system before it’s detectable sort of at the subclinical level, and I got really interested in that because that’s what’s you wanna do for Alzheimer’s disease, you know. 

Once you have full-blown Alzheimer’s disease, it’s kinda like trying to unscramble an egg. That doesn’t work so well, and so I decided to switch my field. I came down to here, to New York, and you know that movie, “Field of Dreams,” “Build it, and they will come.” I opened up along with my partner at that time Anti-Aging Medicine Associates of Manhattan and said that we’re gonna try to sort of look at you, even if you’re healthy, and try to slow down your aging process with the technologies that were available. The thing that was happening at that time as well, which’ll tell you how old I am. 

This was in 1997, six, seven, I made the decision, eight, ’98, when we opened up, the internet was really coming into its own, and so you know, that fabulous thing, PubMed, was becoming available, and we could start to do our research rather than having to go to the library and, you know, ask for the journals, and so I just ravenously went at the material and started offering a program of hormone optimization, diet, exercise, supplementation, you know, with vitamins and other nutrients, and you know, at first, the phones did not ring much, but they eventually did. I did some moonlighting at Urgent Care to sorta pay the bills, and but eventually, they started to, and we started to see doctors- I mean, sorry, patients doing better, got a little bit of a, I would say, notoriety, I guess. 

The field was getting some media attention, so I was on some of the major, you know, national news outlets, talking about slowing down the aging process, and I was invited by Bob Butler, the founder of the National Institutes of Aging, to come to a round table, and he sort of wanted to know sort of what these practitioners were doing, and there was other geriatricians there, which remember, geriatricians are people that take care of the problems of old people, and then there was gerontologists there, who are the people who study aging, which I hadn’t known that was even a field, and little did I really know I was kinda being invited as a sacrificial lamb, to say, “You know, you’re practicing snake oil. What are you doing?” But it turned out that we had, actually, a pretty good conversation. 

They were receptive, the group, and Bob said to me, “Look, Joe, sounds like your patients are doing well.” I mean, at the same time, the NIA was undergoing a series of studies looking at trophic factors in aging, and they were trying to determine whether estrogen in women, testosterone in men, and growth hormone in women and men could help slow down aging and have improved outcomes, so they were interested in it, and what my clinical experience was with it, but ultimately, Bob said to me, “You know, look, you seem like a relatively smart guy.” Well, I’m not sure whether he said relatively or not at the time, but he said, “Look, you call yourself an antiaging doctor. You know, what are you doing to measure the aging process? You know, what are you doing? You measure blood pressure if you’re giving an antihypertensive. You’re giving this stuff. What do you do?” I’m like, you know, scratching my head. I don’t know. My patients are doing great! So that really started me in 2002 to look for biomarkers of aging and to try to practice the kinda medicine that is objective but personalized to look at what the effects are of what I’m doing on them, and that’s been my journey over the last 20-odd years.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Wow, you know, and certainly, you’re really one of the pioneers in this whole field. Let’s just dive right in to those biomarkers ’cause I think you spent, you know, probably the last decade working on your finding or understanding of this. Do you wanna take us through what is the current knowledge base on what are the top biomarkers, you know, I guess traditionally, and now what’s, you know, up and coming, and then you can kinda go through each one.

Joseph Raffaele, M.D.

Sure, so a biomarker in general is a measurement of a physiological or biological property in a body that gives you information about that organ system or that part of the body. People know what cholesterol is. That’s a biomarker for, you know, the lipids floating around your blood that could potentially cause cardiovascular disease. High blood pressure’s a biomarker, hemoglobin A1C, measurement of your blood sugar. Biomarkers of aging are those measurements that can be done with an instrument, either a, you know, a non-blood or a blood test that correlate with chronological age, you know, relatively well. We’ll call Pearson correlation about 0.2, which is, you know, a correlation of one is a one-to-one correlation, so it absolutely goes in lockstep. A very good biomarker would be 0.5 or so, but if it’s 0.2 or above, it does correlate with age. So biomarkers of aging are those measurements that can predict sort of, if you did that measurement on somebody, plus or minus a certain number of years, how old they are based on that kind of marker. They also then put together-

Sanjeev Goel, MD, FCFP (PC), CAFCI

Yeah, a quick question on that. You said a 0.2. Like, so a one, a one would basically mean a right-on, bang-on, it’s an exact correlation with age. Something like a 0.8 or whatever would be much closer, I would assume, so 0.2 all the way down close to almost zero. Like, zero would be no correlation.

Joseph Raffaele, M.D.

No correlation, right.

Sanjeev Goel, MD, FCFP (PC), CAFCI

So we’re saying we’re accepting even a 0.2, which is not a, doesn’t seem like it’s very far away, but even that slight correlation is considered-

Joseph Raffaele, M.D.

If it’s an important one, right. So there are biological measures that are very important, like for instance, hemoglobin A1C, the control of your blood sugar that doesn’t necessarily track with age. You don’t have to have that get worse with age ’cause not everybody gets insulin resistant or overweight or inactive or get early, you know, diabetes, but because it’s so important, you know, at whatever it is, 0.2 or so, it’s still gonna be, you know, useful as a biomarker of age, but it’s not a great one. So the ones that are very good are sort of in the nonblood category, things like, we think about blood pressure, but what blood pressure really is is a measure of your arterial stiffness and specifically the large arteries in your body: the aorta, the carotid arteries, the ones that go down at your legs called the iliacs. 

Those arteries, when they get stiff, they cause problems. They cause cardiovascular disease, stroke, heart failure, because the function of the arterial system is to dampen the pulsations of each time the blood is being pushed outta the heart in this pulsations. You have the top number systolic and the bottom number diastolic, and in between is that sort of pressure dampening stuff. That’s correlated around 0.5, that marker, which is done with a specialized instrument. Blood pressure’s pretty good. Systolic blood pressure goes up. It’s correlated around 0.3, 0.4, and so then, there’s pulmonary function, how fast you can blow out air in that first second when you’re doing that violent maneuver called the pulmonary function test, where you’re taking a deep breath and blowing it out real fast. 

There’s huge databases showing that that’s highly correlated with age, but also correlated with pulmonary disease and other diseases as well as death. So if you have those two, you have a pretty good idea about what people are doing in terms of the aging process. When you put those two together, then you can add onto that cognitive functioning through a battery of tests. We use a company called CNS Vital Signs that does an online 25-minute series of sort of like video games that you have to do with memory and how fast you process and scanning, tapping, et cetera. Things that used to be done in a manual fashion can now be done in a sort of a quick, computerized test. Then we look at skin elasticity, both from sort of an un-sun-exposed area and also from a sun-exposed area. Those are sort of our biomarkers of aging that are non blood, and they’re sort of in that mid-range of correlation with chronological age but are measuring very important functions, right?

Sanjeev Goel, MD, FCFP (PC), CAFCI

If it’s not that important if it measures to chronological age, it’s more important that it measures to actual biologic age.

Joseph Raffaele, M.D.

Right.

Sanjeev Goel, MD, FCFP (PC), CAFCI

I was thinking does it really matter, like, if it measures to chronological age?

Joseph Raffaele, M.D.

And that’s kinda the point. So up until 2013, we had those four biomarkers, and we had added to them telomere lengths and immune function, which we can talk about in more detail, and we put them into a panel that gave an overall what we call the physioage, which is our way of thinking about physiological age. So you, you know, you may be 60 years old, but physiologically, those markers are all saying you’re functioning more on average like a 50-year-old or like a 70-year-old, and then 2013, Steve Horvath came along and kinda threw a wrench in the whole thing by doing his DNA methylation seminal studies, where he looked at, and I know you’re interested in epigenetics and so, but he looked at blood and subsequently many other tissues and found that the pattern of methyl groups attached to your DNA, or what we call your epigenetics, changes highly characteristically with age such that, you know, you can predict within two years how old somebody is just by looking at their expression pattern in their DNA, or their epigenetics. 

So some of those biomarkers are coming in at 0.9. I’ve seen some as high as 0.95. You have to understand, though, to your earlier point, if a marker is correlated at 0.95, and it’s correlated with chronological age, you might as well just use chronological age, right? You’re not learning anything, and people don’t understand. They say, “What was the best biomarker of aging?” And I say, and I say, “I’ve heard there’s high correlation,” the ones that understand the Pearson R or the R squared, and I say, “If it’s, you know what, you need to have spread on either side of that correlation of chronological age versus the marker to know whether you’re doing better or worse. If it’s exactly along that bisection of that square, you’re not getting any information.” The original biomarkers in epigenetic age, DNA methylation age, were trained against chronological age, and subsequently, now they’ve start to train them against other markers like the kind of biomarkers that are important, and I think that they become more useful markers other than just in forensics.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Which ones are you using? I heard about the GrimAge as being, I guess, trained…

Joseph Raffaele, M.D.

Yeah, GrimAge is trained to a mortality, and the PhenoAge is the one that is, and Morgan Levine, originally at USC, I believe, and now is a professor, or associate professor, at Yale. She is a sort the biostatistician that was in Steve Horvath’s lab and has sort of been working and producing a lot of great papers on this. So PhenoAge is a number of tests that you can get in a routine CBC and chem panel as well as, and the addition of a CRP, which people may know is a C-reactive protein, a marker for inflammation. Probably if you’ve been to a doctor, and you’re over 40, you’ve had that measured in you, and you know, very fascinatingly, if you put those into what we call the sort of AI deep learning neural network kinds of things that smarter people than I understand, but you know, the data scientists tell us, you know, this is real stuff. 

It spits out, you know, high correlation between these eight to nine markers in mortality, like the GrimAge, and can give you an age that is, you know, in R squared of around 0.7-ish, 0.6, 0.7, so that’s really interesting to me. So when that came out, we sort of had to start incorporating those things into our overall software package where we measure these things and tell patients how well they’re doing, and the way I look at it now is there’s no single best biomarker of aging. 

Each one looks at different aspects of the aging process that are important, and I can tell you, having looked at hundreds of, you know, biomarkers of aging for some biomarkers, and thousands for other biomarkers over the years, there is a wide interindividual and intraindividual variation in those. So you can, for instance, have one biomarker that, you know, let’s say you’re 50, that shows you at 30, and another one in the same person that shows you at 60, and people will say, “Well, you know, what’s up with that?” Right, they’re like, I have patients sitting across from me going, “Should I believe, which one should I believe?” Of course, I wanna believe the younger one, right? But, but what it tells you is that people age differently in different tissues at different rates based on lifestyle, genetics, nutrition, epigenetics, many, many different factors. We all have our weakest system. We have our strongest system. We have our in-between systems, and it’s important to know what all of them are doing.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Does that vary amongst people, or is there like a general progression that, you know, first a cardiovascular system aging markers begin, then the respiratory, and then the immune system? Is there a certain progression that happens, or do you think it, is it, you know, depending on your genetic backgrounds?

Joseph Raffaele, M.D.

Yeah, so that’s a great question, and that brings up the concept- All right, that screen keeps on going off when I click through these things without touching it, sorry. That brings up the general concept of rate of loss versus what you inherited. So any time you measure a biomarker, you’re looking at what has happened since birth to that biomarker, and then also what you inherited in that biomarker. So you might, for instance, like I have a patient that has this big, barrel chest, and he was a swimmer when he was younger, great, you know, two max, but now a cigarette smoker, and he’s losing faster, as tracking him over time, FEV1, or pulmonary function, because of inflammation from the cigarette smoke, but he inherited a huge reserve, so his pulmo-age, what we call that number that is that how fast you can blow that air, is still 15 years younger than his age, but if you just looked at that one snapshot, you’d say, “Ah, no worries,” but no, you have to have tracked him over time. The same thing goes for many other biomarkers. 

So which systems start to age? Yeah, some don’t start to age, like cognitively, mid to late 30s, even a little later than that. Hand grip actually continues to go up into your 40s and then starts to go down after that. Things like the arterial stiffness, though, that does start to decline at your peak, sort of what we call your peak reproductive age. Around age 25 or so, you reach your peak level of arterial elasticity, the adverse of stiffness, and you lose about, you know, 1% per year. On average, most biomarkers of aging, you lose about a half to one, sometimes 1 1/2% of your inherited function per year, so that’s usually more in certainly the younger population, that’s more what determines what your biomarkers will look like is your inheritance, and then as you get older, it’s more what you’ve been doing with that inheritance that is gonna be the determinant of it. 

So you know, you have to look at them all, and you have to track ’em over time, but you’re absolutely right. There are certain systems that start to age earlier. Lungs also may reach a peak at about 25 or so and start to decline after that. Varying aspects of that whole process that goes into blowing air out really fast start to age, and that’s, and so if you want to sort of prevent lung aging, you wanna know early on how much inheritance you had. So I love to have patients come in at 25, 20 to 25, and I say that because most of my patients, so my average age of my patient is around 48 to 52, and so when they come in, they get started on a program, they oftentimes, learning all this stuff about themself, say, “Oh, would it be good if my son or daughter came in?” And I say, “Yeah, it’d be fantastic.” Get that baseline when they’re at they’re peak function, and we can know what’s going on, and sometimes you’ll find things, like particularly in telomere biology, which we’ll perhaps get into, inheritance is a big part of that. 

You know, you can inherit, it’s about 70% inheritable, so if you don’t choose your parents wisely, you could be, you know, on one end of the telomere lottery versus the other, and so, and knowing that early on allows you to do things to- People, when people have information, it really changes their behavior. So if you have really short telomeres, I mean, you don’t wanna smoke anyhow, but you really don’t wanna smoke if you have really short telomeres.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Well, let’s just move right into talking about telomeres ’cause I definitely wanna get into that, and immune system and all, and even hormones after that, but let’s maybe just for the viewers, just give us like a, you know, 30,000-feet view of these, of the value of the telomeres, why we think they’re such an important biomarker, and then go on from there.

Joseph Raffaele, M.D.

Yeah, so telomeres are the caps on the ends of your chromosome. Your chromosomes are the packaging of your DNA, and human chromosomes, and all mammals, have linear chromosomes, and so the ends of the chromosomes, they are not kind of protected. The DNA repair system, DNA damage repair system will recognize them as a broken strand of DNA, and they’ll try to go in there and fix it. So telomeres have to be, they’re these repeats of noncoding DNA. So remember those DNA codes for proteins, and then it’s turned into RNA, and it’s turned into proteins. If you have the ends of your chromosomes are noncoding, it’s this repeats of TTAGGG, which doesn’t make any proteins, they’re about 10,000 or so, between eight to 10,000 at young adulthood in length. 

The very ends of them is no longer a double strand of DNA. It’s a single strand of DNA that curls back on itself so that it doesn’t, it’s not exposed as a naked end that would cause a DNA damage response to occur. So being folded up like that protects them, and that whole structure of the proteins that bind it up into that little cap is what a telomere is. Now, each time cells divide, right, you have to replicate your whole DNA, make another set of DNA, but the problem is the ends of the chromosomes, the enzyme that, or the molecule that duplicates them called DNA polymerase, can’t do it at the very ends. It falls off the end of, so you need this enzyme called telomerase. It is an enzyme that puts the ends onto chromosomes, and that is what keeps the telomeres from getting shorter when remember, you go from a single cell at conception to 13 trillion cells at mid-adulthood. If you didn’t replicate the ends of those chromosomes, you quickly run outta those 10,000 base pairs, right? 

So it’s rapidly reproducing the telomere ends during, in utero, and then at birth, telomerase is suppressed, and that starts the gradual erosion of telomere length of about 50 base pairs per year or 0.05 kilobases, and that’s sort of the average rate of loss. Why is it important that you, besides preventing this DNA damage repair? Because if the DNA damage repair mechanism goes into work, then it stops the cell from dividing. If the damage is bad enough, and if telomere damage gets short enough, then the cells will no longer divide. They become what’s called senescent, which, you know, is the sort of the Greek word for old person, getting old, and they don’t do their job, and they secrete a lot of inflammatory molecules, so there’s, the telomeres are sort of that molecular clock for how much you can repair damaged tissues by having the stem cells that reside in each of your organ systems divide and replenish those cells. 

Other things that happen is that besides just, you know, replenishing cells, once they, particularly in the immune system, once they become senescent, they don’t just sit there quietly. I’d like to analogize it to a watchdog. A senescent cell is not like a healthy, young watchdog that knows when a burglar is coming, goes after him, bites the burglar, and gets rid of him. A senescent cell is like an old, blind, nasty watchdog that doesn’t get the burglar, doesn’t do his job, but also is sniffing at the neighbors, causing problems, and biting his own owner by secreting what we call these inflammatory cytokines, or these molecules that cause inflammation, which has been coined inflammaging. So that’s sort of a 50,000-foot view of what telomeres are, and they’re really at the very top of the list of things that are sort of the hallmarks of aging. You’ve probably heard of, and maybe you’re, some of your other guests have talked about the nine hallmarks of aging, and I think of that as our biological equivalent of the unified field theory in physics. In biology, we now have sort of broken it down into the various things that occur, and one of the major things is loss of telomere.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Mm-hmm, yeah, I’ve heard that before. This, the telomere part, again, they’ve basically shown that longer telomere lengths are associated with a longer life and a delayed cancer, less mortality, and so on.

Joseph Raffaele, M.D.

Right.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Yeah, is that correct, and short telomeres, critically short telomeres are associated with adverse and negative outcomes, is that correct?

Joseph Raffaele, M.D.

That’s absolutely true. There’s been hundreds of studies looking at telomere length, and know very well that you lose that 50 base pairs per year, and also, there’s studies showing, a very large study showing that the shortest third versus the longest third of telomere length at, say, 60 years of age, is associated with significantly increased risk of death and of cardiovascular disease and of cancer. It’s been sort of repeated in other studies, a large study out of Copenhagen looking at individuals between 45 and 75, up to 22 years of follow-up. 

They’ve seen that if you are in the bottom tenth, bottom decile of telomere length versus the top decile, you have about a 1.5 times or 50% increased risk of getting cardiovascular disease and of dying, and that’s sort of, with each decile increase, it gets worse and worse and worse. So I think, you know, the data is very strong, large datasets looking at longer telomeres being associated with better health and healthspan in addition to longevity, lower disease burden, and shorter telomeres being associated with the opposite. There are also models of disease that are very rare called the telomeropathies, dyskeratosis congenita being sort of the initial one, which was thought to be a skin disorder but actually is the skin manifestations are really sort of just the tip of the iceberg. 

What it really is is they have 50% activity of telomerase. Not gone, they just have 50%, and the first generation of that mutation can live to be about 50 but not much longer. Then their lungs give out. They get pulmonary fibrosis and die. If they pass, if they, you know, have children before they pass away, that next generation, they have shorter telomeres and less active telomerase, so then they will make to maybe 30 and die of bone marrow failure because the bone marrow, of course, has to keep on dividing to make new cells, so after three generations, they pretty much don’t make it outta uterus, and that ends that lineage. That is then recapitulated in mouse models, in other, and it’s, you know, if you have critically short telomeres, you don’t live very long. Likewise, yeah, go ahead.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Interesting is that it looks like it’s not just your life, what you do in your life, but also what happened to you in utero and what your parents gave you.

Joseph Raffaele, M.D.

Yep, yep.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Correct, I’ve seen that that’s almost a huge amount of the impact of your telomeres is what’s happening in the other generations or trauma that happened to your parents or something like that.

Joseph Raffaele, M.D.

Yeah, I mean, for sure. I mean, it’s things that happened in utero, but also, almost even more importantly, well, so what you’d inherit from them is very important. That’s that 70% number. You know, I have patients that come in, and yeah, there’s a range usually between eight and 12 kilobases at age 20, 25, so but you only lose about three kilobases over your whole life, so let’s say you start out at 12, and you get to nine, you’re still great. You’re like a 25-year-old. I have some patients that come in with telomeres that long. Likewise, I had a patient that came in at 40, and her telomere length was less than five, so she doesn’t have that much room to lose telomere before they get critically short. 

So inheritance is huge. Early childhood stress causes shortening of telomeres. Virtually, this is what I love about telomere biology, virtually everything that we know that is good for your health has been shown in studies to be associated with longer telomeres, and everything we know that’s bad for you: smoking, being overweight, being inactive, is associated with longer telomeres, and if you do things, like if you have a lotta stress from taking care of an older patient or an Alzheimer’s disease patient, your telomeres are longer, but if you exercise, it mitigates that stress, and your telomeres aren’t as short, and what’s even more fascinating as a physician studying this stuff is that, you know, we know that stress is associated with bad outcomes and shorter life. Well, how is that? We know that cortisol is bad for you too, right? Too high a cortisol, chronic stress, thin bones, the, you know, the Cushing syndrome, which is the disease state, is a very bad thing to have, but lo and behold, cortisol inhibits telomerase. It is the molecular link from between stress, shorter telomeres, and bad outcomes. So it’s really fascinating how it’s all coming together.

Sanjeev Goel, MD, FCFP (PC), CAFCI

I just wanna jump in there with this question about what has been shown to actually lengthen telomeres? I know exercise, I heard, and the study came up about hyperbaric oxygen therapy.

Joseph Raffaele, M.D.

Yeah, so that’s a great question. So you have to, I think, be clear about things that have been shown to lengthen telomeres versus things that have been shown to keep them stable versus things that have slowed down the attrition. A lotta the lifestyle stuff does that because besides having to divide, oxidative stress, free radical damage, causes telomeres to be shorter faster, not just when cells are dividing, but even when they’re just sitting there, they can go in and cause shortening. So if you do things to get rid of that oxidative stress, like diet high in fruits and vegetables, a Mediterranean-type diet or supplements, et cetera, those kinds of things can slow down the loss, but they’re not gonna lengthen telomeres ’cause the only thing that lengthens telomeres is telomerase, right? 

Now, there’s another way that telomeres can be, you know, for the molecular biologists out there, that there is another pathway for lengthening telomeres, but we’re not gonna get involved, and that’s a small part of it. So telomerase itself is what lengthens. There has been gene therapy in mouse models that have, and in vitro, that, you know, there’s a sort of same thing that they’re looking at for other kinds of gene therapy. You take an AAV or you take a virus that carries the gene into the DNA, and it turns on telomerase. Those things have definitely been shown to turn on telomerase and lengthen telomeres. 

The natural product molecule derived from astragalus membranaceus, a traditional Chinese medicine that goes by the trade name TA-65, has been shown in studies that I’ve been fortunate to be involved in to lengthen telomeres in a randomized control trial. Part of my computer keeps on going off here. Okay, sorry about that. In a large, randomized control trial, telomere lengthening. So and there’s, so exercise itself doesn’t lengthen telomeres. The hyperbaric oxygen chamber study you’re referring to was really a fascinating study that has shown some increase in telomere length and a decrease in senescent cells, which is associated with shortened telomeres. It’s a big increase. 

They’ve been reporting, like, I think 20% or something like that, which is pretty incredible. I’m not certain that the telomere length measurements were, like, you know, they didn’t use the exact same technique that I typically use in my office and that a number of studies have used, but so I’m waiting for more corroboration on that, but theoretically, what they’re doing with that is they’re giving a stress of hyperbaric oxygen and then pure oxygen and then taking oxygen away, and almost like exercise, I mean, this is how the human body gets stronger. You get a little stress. It repairs, recovers, and it’s a little stronger, and you keep doing that, and the protocol was, like, 50 sessions of an hour or so or more of this kind of protocol, so I could see how it might do it. I just would like to see a bigger dataset before I’m sure that that does that. So right now, you know, this small molecule telomerase activator, a gene therapy, I mean, and so far, I mean, there’s a couple other supplements that will claim it, but they don’t actually have the data that I’ve seen to back it up.

Sanjeev Goel, MD, FCFP (PC), CAFCI

For TA-65, this telomerase activator, do people actually notice, like, an improvement, like I mean, you said that person came in with, you know, five kilobase shortening. Did she notice anything? Do people, you know, can you see something?

Joseph Raffaele, M.D.

I don’t think you necessarily notice the increase per se, and so telomerase, TA-65 turns on telomerase, and the main function of telomerase is to lengthen telomeres. Lengthening telomeres is good for allowing the cells to divide. You know, you have a reduction in senescent T-cells, which we showed you in a study, and I’ll talk about in a little bit. Those can have beneficial effects, but telomerase itself, by reducing this DNA damage response, can increase mitochondrial biogenesis, meaning increase the number of mitochondria and the efficiency of mitochondria through these sort of what we call noncanonical, that is, things that aren’t about lengthening telomeres but are other functions of that telomerase enzyme within the cell, and so those types of things could cause things that you could feel by taking TA-65. 

I have patients that report, you know, top athletes that report, endurance, you know, master’s athletes that report better times, better recovery. That could be related to the improvement in mitochondrial function, perhaps reductions in inflammation to take place ’cause there’s fewer senescent cells. Some patients report improved vision. Certainly that could occur because of the, the retina have these cells called retinal epithelial cells, which divide a lot, and if you can help them divide more like when you were younger, perhaps you could get crisper vision. I notice that myself, and I’ve been on TA-65 for 14 years.

I have noticed that myself. Some patients have noticed improvement in farsightedness, which is the ability to read closely. You know, go figure, . So that’s some of the anecdotal things. Some people notice improved energy. There’s no studies that have sort of documented that yet, but there are reasons why that could happen, but again, you know, if you’re taking, if you’re doing a dietary measure, or you’re taking cholesterol-lowering medication to lower your cholesterol, you’re not necessarily gonna feel that, but you are gonna decrease the likelihood that you’re gonna have a heart attack or a stroke, and so that’s beneficial. 

I think, like with hormone replacement therapy, you know, besides the immediate getting rid of the hot flashes and night sweats, over time, you see, I mean, I’ve been doing this for 20, 25 years now, the patients telling me that their friends were like, that are their age, they’re saying, “Hmm, you just, why are you looking better than I am now? What are you doing?” And I think these kinda gradual, these numbers, 1% per year that you’re losing in function and appearance, these kinds of gradual things are what happen. So you’re gonna have to be in this for the long term. I call your telomere length your biological 401k. It is sort of your savings plan that you have for ability to divide, ability to keep yourselves healthy, as you get older, you know, to fund your retirement, which is what your healthspan is, the time that you’re alive and free of disease and functioning well.

Sanjeev Goel, MD, FCFP (PC), CAFCI

I think you’re right about that. I mean, it looks like we have to do this over some time to see the type of phenotypic changes. Maybe, you know, it hasn’t been long enough ’cause you know, maybe the TA-65’s been around for what, 10 years or so?

Joseph Raffaele, M.D.

You know, 14 now. I mean, well, actually available to the public about 14 years. That’s the other thing about TA-65. People ask me about it, why I think that it’s safe and a good idea to give as a supplement ’cause it’s not a drug, but it was originally discovered by a company called Geron Corporation. Geron is Greek for old man, and they were looking through a natural product strain about 5,000 molecules to find one that turned on telomerase ’cause they knew that telomerase, that was an important thing to do, and they got, like, three hits in this stream from this traditional Chinese medicine, a single molecule that’s extracted through a patented process, and they were moving it through the new investigational drug pathway, so they did all the safety testing that a drug is gonna go, become a pharmaceutical, and then they pivoted a few years later towards cancer therapeutics and sold off the rights, so it has a lot of safety built into it because of all these studies that were done. 

It’s generally regarded as safe ’cause it’s been in the Chinese medicine for a long time. So I think, you know, it’s a pretty safe supplement that’s been around for a while. I’ve been giving it to my patients for many years. I’ve been lecturing about telomeres and telomere biology and the effect of TA-65. There’s, I think, nine studies published now, three randomized control trials or more showing that it A, lengthens telomeres, turns on telomerase, reduces senescent T-cells in a randomized control trial fashion, so I think that, you know, that’s why that’s the one I use.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Yeah, yeah, let’s talk right about your study ’cause that one actually blew me away, and that’s why I was, like, I wanted to reach out to you. That basically showed people randomized to take TA-65 or not. There was a difference in the immunosenescence. Is that correct, that that was what the finding of the study was?

Joseph Raffaele, M.D.

That is correct. So the study was looking at 500 individuals taking TA-65 in varying doses from 100 to 500 IUs, and a typical dose is between 250 and 500 IUs, and looking at this population of cells called senescent T-cells, and they are, you remember, your white blood cells you have, and then you have your granulocytes and your lymphocytes. The granulocytes are sort of the grunt forces to hit the ground. They’re not smart about it, and the lymphocytes are sort of the part of the immune system that knows exactly what to attack, and so it’s more educated. These cells, part of them are T-cells. They become older if they have to divide and divide and divide because they’re fighting off infections, particularly a certain type of herpes virus infection that is very common, and they lose that ability to divide, and they become senescent, and as I mentioned before, they secrete all these inflammatory cytokines, and so that’s a bad thing. 

What they also do is they don’t go away, so they accumulate. What they’re supposed to do is go in there, knock out the enemy, being either a virus or a tumor, and then, you know, in order to do that, that one that’s uniquely designed to fight off that particular virus or that particular tumor expands into millions and millions of cells, so it divides and divides, and then once the job’s done, they die, and a few cells are left behind called the memory T-cells, which then are ready to fight that off if it comes back. Herpes viruses are, you’ve heard the phrase, the gift that keeps on giving, right? Once you have them, you have them. When you’re under stress, comes out from your trigeminal ganglion. 

If it’s a cold sore or a herpes virus-1, and it comes out on your lips, that’s a repeat thing, and every time that happens for a herpes virus, this whole process takes place. The cells, telomere lengths, get shorter and shorter and shorter. Once they get critically short, they become senescent. Giving TA-65 to this population that had this virus called CMV, cytomegalovirus, which is herpes virus number five, not all of them had it, but about 60% ’cause about 60% of people in that age group will have it, and they don’t even know have it. They don’t even know they have it ’cause it’s benign. It doesn’t have any symptoms. On it, we had a 20% reduction that was a highly significant reduction, and not only did we have a reduction in the senescent T-cells, but we had an increase in the naive T-cells. 

Those are the ones that can fight off new infections that we have a lot of ’em were young, but they start to dwindle as we age, which is one of the reasons why older people don’t respond well to vaccinations, like response to flu vaxes in an older population is 50% or less, but if you have an increase in those numbers more like when you’re youthful, another reason why individuals that are younger don’t have as adverse an outcome to COVID as us older people do, so it was really a complete remodeling of the immune system from an older immune system to a more youthful immune system.

Sanjeev Goel, MD, FCFP (PC), CAFCI

At the eight, CD28, is that correct?

Joseph Raffaele, M.D.

Yeah, so CD8, CD28, so you have to, all cells when you’re younger, all your T-cells express CD28, and that molecule helps it to really divide briskly and mount a great response. If you don’t have that, if it’s CD28-negative, then it doesn’t, it mounts an anemic response, it’s not as good at fighting off the infections, but again, sits there and secretes these inflammatory molecules that cause cardiovascular disease, osteoporosis, cancer. I mean, CMV infection has been associated with many of the chronic diseases of aging. 

Herpes viruses in general are stressors of the immune system, and there’s a whole theory of herpes virus-1 being an important factor in increased risk for Alzheimer’s disease because it causes the cells to support the neurons. The cells called the glial cells, they divide. Neurons don’t divide, but the glial, they do a little bit, but the glial cells divide, and when they get senescent ’cause they’ve been having to fight off these viruses, they don’t do their job. 

They don’t support the neurons well and then the neurons start to malfunction, producing the beta, the amyloid beta plaque that we talk about in Alzheimer’s disease, so there’s companies that are formed looking at turning on telomerase to help treat and prevent Alzheimer’s disease. So the immune system, you know, we think about it as being important for infection, but it really is a major factor in every disease of aging, every degenerative disease because again, it’s a stressor, and- But that’s really the key, is keeping inflammation at a low level.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Basically, our innate immunities becomes less as we get older. That’s what happens, immunosenescence, as the aging of immune system, and we end up because of all this lifetime exposure to, I guess…

Joseph Raffaele, M.D.

To various pathogens.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Yeah, and just basically stimulate our immune system. So something like you’re saying, the CD28-negative, is that correct, that ends up increasing as time goes on? Is that correct?

Joseph Raffaele, M.D.

Yep. Yeah, so for instance, we’ll just get back to the aging. The innate immune system does age and does get less functional, but the adaptive immune system is actually the one that suffers the most with age, and that’s the one that is, you know, the lymphocytes attacking in an orchestrated fashion, not just going out there, guns blazing, trying to kill everything. So what happens is it, the CD28 molecule then, if you count them, it’s about 99% cells express it. As you get older, it can be as low as 20, 30% or even 10% express that, or the adverse being 80 to 90% or CD28-negative, which takes up lots of space. So in the study, people with CMV had about 220 cells per microliter. 

Same age, CMV-negative, 60 cells per microliter. Huge difference, I mean, the statistically significant, and that was in a randomized control trial. Looking at it in the same group, their numbers were almost exactly in that cohort that came through my office, where we originally looked at TA-65 and those same cells. But what is the major thing that causes it? It’s chronic stimulation of the adaptive immune system, particularly the CD8 cells, and really the major actor is the herpes virus, particularly CMV, but even if you don’t have CMV, the more herpes viruses you have, good studies showing an association between the higher number of herpes viruses, the shorter your telomeres are because telomeres are that marker for how much stress the cells are undergoing as they are required to divide to keep the herpes virus from coming out. So that is, you know, one of the major aspects. 

Now, there’s other aspects of aging in the immune system, the thymus glad, which it sits behind your heart, or in front of your heart, where your T-cells go to learn and be educated and that they create these naive T-cells. That shrinks to almost nothingness at age 50. There was an interesting study that you’re probably aware of, the TRIM trial, where they gave growth hormone, metformin and DHEA. They saw some increase in thymus gland. That’s the other side. I call that intrinsic immune aging because that’s not from external forces, viruses, et cetera. It’s this sort of loss of that thymus gland production of the T-cells. Extrinsic aging is when you get exposed to these viruses or certain head and neck tumors. 

Any chronic stress of the immune system, though, is gonna have this effect on it. HIV has that kind of an effect. It’s not on the T-cells. It’s not on the CD8s. It’s on the CD4s, the helper cells, but now that we’re seeing, you know, people with HIV living longer lives with low viral loads, what’s causing them problems is CMV and an increase in those T-cells, and so we have to start, I mean, it would be fantastic if there were a vaccination for CMV because it is robbing people of, I think, quality years of life toward the end of life, when it’s caused more shortening of their telomeres, a greater increase in senescent T-cells than they would otherwise have to have. I call it a super-super-slow HIV.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Do you think that if we have less exposure to these allergens or things that stimulate the immune system, we’ll live longer?

Joseph Raffaele, M.D.

Yeah, so that’s a really interesting question. I mean, there’s a whole kind of a debate, research in immunology about what level of stimulation is good versus bad. I think if you live in a bubble, then, you know, your immune system then doesn’t get educated about certain things, and increases in autoimmune disorders have occurred. There’s been very interesting books written about that, and I think that’s true. You have to educate your immune system to certain pathogens, and you know, everything we know in biology, there’s an old phrase, “Nothing in biology makes sense except in light of evolution,” and that’s Theodosius Dobzhansky, who was a famous biologist, and it’s true. 

We evolved in an environment where we lived to be 30, 40 years old, maybe not even, and we died from infection, privation, starvation, next door neighbor trying to, you know, take over your plot of land. We didn’t die of natural causes. We didn’t die of old age, and so our immune systems evolved in that environment. CMV was probably, you know, relatively helpful then because it caused a little bit more robust, this is a theory that’s been written about in immunology journals, a more robust immune response that may have been helpful for parasitic infections that we were, you know, were rampant in us. So it might have had a beneficial effect, and that’s why CMV has got somewhat of a symbiotic relationship in the human body. It’s been in humans for a long time, but in the past 5,000 years, we’ve gone from living to 30, 40 on average to 75, 80. It is now having deleterious effects that weren’t showing themselves because we weren’t living that long, and that’s a theory called antagonistic pleiotropy, where there’s a beneficial effect youthfully, a response, so that increased inflammation to fight off infections that may have given those ancestors the ability to fight off that infection and get their genes into the next generation, but then the price is increase in senescent T-cells as we get older. 

So if you asked me would it be better to CMV-negative or CMV, I’d say negative because if you wanna live a long, healthy life, I mean, you can still do it. I’m not gonna say that, but I think your chances of doing it are better if you’re CMV-negative. Now, what can you do about it? Look, you know, we’ve all learned germophobia since COVID came around, wearing masks, washing your hands, putting all sorts of stuff on. You know, that probably is helpful for not getting it, but I have patients who are married, been married, good marriage, regular sex, 25 years, one CMV-positive, the other CMV-negative. So you only spread it when you’re shedding the virus, you know, just like when a cold sore, and most of the time, you’re not doing that. 

I think there’s probably some people that have a little bit more innate resistance to it than others. So you know, if you’re in a subway or you’re shaking a bunch of people’s hands, don’t stick ’em in your mouth right afterwards or don’t rub your nose or your face. Wash your hands. You know, there’s been a massive drop in flu since COVID because of people wearing masks and doing that stuff. Same thing would go with CMV. The interesting thing about CMV is that it, zero conversion rates are, you know, some technical medical term for who got infected and mounted an antibody response. It’s about 30% at age 10, and you get about a 1% conversion rate per year so that between 10 and 90, you basically get to 90-year-old’s are about 90% CMV-positive. 

That confused them about these senescent T-cells ’cause they thought that, you know, this was just a normal aging process, but if you’re CMV-negative, I got patients in my practice, if you’re CMV-negative, they’ve got 15 CB28-negative cells, not 220, and yeah, their telomeres are a little bit longer, taking into consideration whatever they inherited. They have more naive T-cells ’cause there’s room for them. They’re not being crowded out by the senescent T-cells. So, that’s sorta the short version of the CMV story. You know, it’s important. I don’t tell people to go crazy about it, but I think it really helps us understand the general concept, which is any stressor stresses a cell. In this case, the immune cell has to divide. 

Telomeres get shorter. That tissue, which is the immune system, gets older and doesn’t function as well. That could be a cartilage cell in your knee. You’re running 50 marathons a year, I heard some crazy guy did one marathon a week for a year. I mean, God bless him, that takes some guts and some skill, but the stress on your joints, undoubtedly, the chondrocytes, the cells that make cartilage, the stem cells that replace them are going through some stress. The telomeres are getting shorter. So you have to remember, you know, the phrase in the UK, “Mind the gap.” You gotta mind your telomeres, and I think you wanna do what you can to keep them from getting shorter. You want to then potentially do things that can lengthen them, possibly TA-65, you know, if that’s something that you wanna try. 

I think there’s gonna be genetic therapies for it in the future. There are some companies looking at that right now. Potent increase in telomerase activity that causes a 30, 40% increase that perhaps happened in the hyperbaric oxygen chamber. I’m not saying it didn’t, but if it did, that’s a thing that I’m a little bit skeptical about. So in the study from Harvard that Ron DePinho is now, you know, he was at Harvard and now at MD Anderson. He turned on, first he knocked it out in these mouse levels, and they aged more rapidly. They got gray. Testicles shrink. Their spleen shrunk. Their brains got smaller. You know, they just, they look like old mice. Then he was able to turn it on through this little genetic trick that he did, and then their fur grew back. 

Their spleens grew back. They de-aged, they almost did a “Benjamin Button,” you know, the movie where he went from old to young, and it was, like, 30% increase in telomere length. So if we, in fact, saw that, I would think we’d see more on the outside and the inside in terms of people just looking a lot different if that actually took place, which I think it will. I mean, I’m at the point now where I think that aging is a technological problem. It’s not a theoretical problem to cure it.

Sanjeev Goel, MD, FCFP (PC), CAFCI

I will do that, to ask you that exact question. How hopeful are you that, you know, we’re gonna be able to solve this aging problem, disease?

Joseph Raffaele, M.D.

Yeah, so I mean, I’m very hopeful. There are people like Aubrey de Gray, who, you know, I’m sure you know, the head of the SENS Foundation, you know, who talk. These are very legitimate, very smart people, talk about 150 years or what’s called longevity escape philosophy, where you live long enough that we get enough technology such that you just don’t age anymore. There are species who don’t age. I mean, we know that. I mean, tetrahymena, and some species of shark, they just, they have active telomerase. They have strong tumor suppressors, so they don’t get cancer, and they just keep getting bigger and bigger and bigger and don’t age, and what kills them is unnatural causes, you know. 

A boat hits them, or you know, they get an infection or something like that. So I think it’s possible within humans. I think that, you know, in the short term, with current technologies, we could see people living to 120 with a very robust level of health, depending on how soon and how early they start, and imagine that, you know. I get another 60 years of life in this or a better condition. I mean, that’s a pretty big deal. 150, 200, or you know, the vampire-type thing, I don’t know about that yet, but you know, it’s funny. 

In science, you just can’t predict. Back when I was growing up, they started the war on cancer and the mission to put a man on the moon, and people were, like, “Cancer will be cured, no problem. The moon thing, forget about it.” What happened? The other way around. So you just don’t know what technology comes along that can really change things, but it’s a very exciting time, I think, to be in the field and to be a part of this, and watching this, it’s made my career in medicine just fascinating, and I get to see it in my practice, the things I do for my patients, the various things I apply, improving their health, as you do as well.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Just one last question. I know that we’re just wrapping up, but I want to ask you right now. Maybe when I was just going through med school, like, the whole idea of antioxidants was really big, and I remember watching a documentary by way of Chris Robbins, taking like 15 pills. I asked him, “How can you take 15 pills?” He said, “I’m not gonna die, right?” But I want to get your thoughts on this ’cause our viewers are probably here inundated with, you know, antioxidants that supposed to be good for you. Where is the research at? What’s your thoughts on them?

Joseph Raffaele, M.D.

Yeah, so the free radical theory of aging, you know, from Denham Harman, posited that, you know, reactive oxygen species produced by the mitochondria and other inflammatory processes was a major driver of aging, and that if you took antioxidants and quelled those reactive oxygen species, then you would fix the aging process. I mean, that’s been largely debunked because aging, as you can imagine, is much, much more complex than that. These reactive oxygen species are actually, some of them are very important as signaling molecules, but that’s not to say that they weren’t onto something. 

I mean, inflammation from a, you know, attack from free radicals is definitely still a major part of the aging process, but what we understand now is that the damage taking place, the more important thing is to repair the damage. Being able to repair the damage, replace the damaged cells, this is where the telomeres come in. So just flooding yourself with antioxidants isn’t, you know, there have been studies that have shown benefits in various things. You know, vitamin C and vitamin E combination, slight reduction in cardiovascular disease. There have been a lotta null studies as well that have shown no benefit. There’s been some studies showing a worsening effect like beta carotene in lungs, lung cancer, because just one antioxidant being thrown in there, or even two, isn’t really working. 

Now, in mouse models, if you give a cocktail, like sorta the cocktail that you and I prescribe in our, you know, so various types of complementary antioxidants that regenerate your vitamin C, your vitamin E, alpha-lipoic acid, I think there’s a role for that, and I use them in my practice, but you need to… Aging is a more complex process than that. You need to look at the regeneration side. You need to look at the senescent side. You need to look at those nine hallmarks of aging. You know, mitochondrial dysfunction is one of them. That’s the major generator of reactive oxygen species. So for the listeners, don’t just willy nilly take a whole bunch of supplements and antioxidants. 

You want to make them targeted to do, there goes my computer again. Sorry about that. I gotta get that fixed. You wanna do it in a targeted fashion, I think, under the guidance of at least a nutritionist or a physician or somebody that knows about the complexity of the aging process and then measures what’s happening. I mean, if you want something to help your cardiovascular system, you wanna measure things like your arterial stiffness. 

You wanna measure, I mean, there’s a whole bunch of supplements that I have my patients take, and I thought I wouldn’t be, but I am taking somewhere in the range of 20 pills a day, but they’re all there for a reason, and I’m measuring to see whether they’re working, and I’m adjusting dose with my patients and with myself, that, you know, we talked before we became live, I practice and you practice, and what we all should be practicing is the N-of-1 medicine, where each of us is unique from a genetic, epigenetic, lifestyle standpoint. to apply the results of one theory or one study, you have to be exactly like the average person in that study to really make it applicable to you, so you need to know what all the markers are doing, and you need to track what you’re doing to those markers, and see if they’re going in a beneficial direction.

Sanjeev Goel, MD, FCFP (PC), CAFCI

That was perfect. Thank you. I really appreciate, we’re just running outta time, but I think where can our viewers learn more about the work you’re doing and should contact you?

Joseph Raffaele, M.D.

Yeah, so I have two places where you can learn. One is PhysioAge.com, P-H-Y-S-I-O-A-G-E.com, which is where our software that can measure aging is there particularly for doctors who wanna use that in their practices, and then at RaffaeleMedical.com, where I blog about things. That’s R-A-F-F-A-E-L-E-M-E-D-I-C-A-L, and then I try to put content up on Instagram weekly or at least sometimes twice a week @RaffaeleMD, and keep my followers abreast of things that are happening in the aging and occasionally some exercise fiasco that I’m involved in, but that’s where they can find me.

Sanjeev Goel, MD, FCFP (PC), CAFCI

Okay, that’s awesome. Thank you so much. I really appreciate your time today.

Joseph Raffaele, M.D. 

Great talking to you, Sanjeev. Thank you very much.

Sanjeev Goel, MD, FCFP (PC), CAFCI

No problem.