Claudia von Boeselager: So, initially trained in internal medicine, you have been exclusively practicing and researching applied geroscience, medicine and longevity for 25 years. Where did this interest in longevity stem from, and how did it lead you to becoming the expert in longevity medicine that you now are?

Joseph Raffaele: Well, I guess looking back, it's been about a 25-year journey. You know, I started in this field in 1996 or so, after I'd been practicing internal medicine for about five years up in the Dartmouth Hitchcock system up in New Hampshire. Academic, but primary care internal medicine, seeing lots of patients every day, sort of getting your doctors’ sea legs. And that's what I wanted to do after coming out of training in New York hospital in Cornell.

But, after about five years, I really started to believe that I was, kind of, just plugging the holes in the dam, and not really helping to make a better dam or a more effective one, not to take that analogy too far. But, I was also seeing both my parents who were a little bit older, starting to get ill, early signs of Alzheimer's disease, and looked into what could be done there.

And at that time it was just the very beginning of the movement that was called, at the time, anti-aging medicine. I was at a place in my life personally, where I could, kind of, change career, sort of, not mid-career, but make a big shift. And so I just said, you know what? I went to some conferences, started to see this whole science of aging that was really being developed but not being clinically applied to any large extent.

I went to the first American Academy of Anti-Aging Medicine meeting in Las Vegas. And got pretty excited about it. And so, you know, as they say in that movie Field Of Dreams, build it and they will come, I just sort of decided to head down to Manhattan with my partner at that time in the practice I was in, Ron Livesey and me started Anti-Aging Medicine Associates Of Manhattan.

And, it was a little crazy looking back in retrospect, but I was just talking to somebody about what are the seminal, sort of, really good decisions I've made in my life. And that was definitely one of them.

Claudia von Boeselager: Incredible. And with 25 years working in the area of longevity, you surely must be one of the longest-standing pioneers in the field, right?

Joseph Raffaele: Well, you know, I don't think of myself that way. I guess I was at dinner at a conference recently and some people that were coming to see my talk, we had dinner the night before, and they asked me how long I've been doing this, you know, and to say that 25-year number, sort of like, take a step back there for a minute.

And one of my friends said, oh, so you must be one of the pioneers in this field. And I said, yeah, I like to think of myself as one of the least well-known pioneers in the field, so. I've been plugging away at it because I love it. And, I guess, yeah, I mean, early on we were probably one of two practices in Manhattan, maybe one of a handful in the country that were looking at aging and medicine in a new way that, over the past 25 years has really, I think, become the future, and almost the present at this point.

Claudia von Boeselager: Yeah. It's really exciting. What are the pioneers in the longevity space that you admire most and why?

Joseph Raffaele: The ones that are doing some of the hard research and really, sort of, changing the paradigm, I mean, medicine is littered with difficult stories of mavericks looking at things differently and getting ridiculed. There's that old saying by, sometimes attributed to Schopenhauer, that truth is first ridiculed, then, you know, I think, widely criticized, then accepted as truth. And that's, I think, what happens in this field. Aubrey de Grey who's at the SENS foundation, I'm sure you've heard of him. A lot of that early work to lay the groundwork for thinking of aging as malleable, as something that is to be targeted, because it's really the bedrock upon which most of the diseases of aging occur, most of the diseases, period, occur, and loss of function that takes place.

One of my mentors is Michael Fossil, who, if you get a chance, you should get him on. He's a clinician, an emergency room physician, but also a neurobiologist, who's done a lot of great work in making telomere biology understandable, and a couple of great books about it.

So those are two people I think that are,sort of, big influences. Robert Butler, who was the founder of the NIA, the National Institute on Aging, called me one time in 2002 or so, when I was about five years into my practice, and asked me to come attend a roundtable of gerontologists and scientists who studied aging to, sort of, see what it was I was doing in this new anti-aging medicine that had gotten some publicity, I'd been on NBC Today Show and some other national TV shows. And I was flattered to be asked to be interviewed by this, sort of, major figure in the field, a pioneer, of course, who started the National Institute of Aging.

Little did I know, I was, sort of, being brought in as a sacrificial lamb. Somebody not necessarily doing what he should be doing. And, you know, there was a lot of criticism of some of our approach, but one thing that he did say to me, is, you know, look, Joe, you seem like a pretty smart guy. Your, you know, your patients are doing well. They feel well. And, in fact, they did, and our practice was growing at that point, but he said “if you call yourself an anti-aging physician, what are you actually doing to measure aging?”

And I thought to myself, hmm, you know, well they feel good. So, but just like somebody just treating high blood pressure, you know, how do you know if it's working? Until the person has a stroke, you don't know that it didn't work, so you have to measure the blood pressure. Well, you measure aging. And that started me on the journey that I'm still on and love, which is understanding and learning about biomarkers of aging, and how you have to, in order to really know whether something is doing something, you have to be able to measure it. That's kind of, I think, you know, the way in which you practice evidence-based medicine.

Unfortunately, in the aging field, a lot of the studies are done in shorter-lived model animals like mice, because the mortality endpoint is sooner. Two years or so, three years at the most.

But that is not possible in humans, okay, and it's not good for your career if you're going to wait for an experiment to last 25 years. It also is because those models aren't great models of actual aging in humans. So I learned about how these usual devices like a lung measurement device that's used to diagnose asthma or COPD, or a fancier version of a blood pressure cuff, can be used to measure the age of your lungs and your arteries and these other things that they're not officially approved for, but actually work very well with big literature basing them. And that has, that started me on the route to really know in the relatively short-term, whether something I'm doing is making an organ system younger or older, and then looking at a wide variety of them, to get an idea about what you're doing to the whole person.

So, you know, as they say, In God we trust, to the rest, show us the data.
And that's what my patients want from me.

Claudia von Boeselager: I love that. And I'd love to dive into PhysioAge, and exactly what you're doing there shortly. But first I hear you have a funny story on exercise can be hazardous to your health.

Joseph Raffaele: Yeah, it was fun, it was, it was actually very recently. And I'll tell you what happened was, I'm a reasonable athlete. I was a decathlete in high school and pole vaulted and played soccer, and I've done triathlons in my forties and fifties.
So I like to think of myself in pretty good shape. But COVID took everybody out for a while. And I wasn't seeing my trainer regularly, the gym wasn't open. So I happened to move into this new building, they had a new gym. A really nice state-of-the-art gym, one of the reasons I moved into it. My trainer visited me there and got me started on a new program.

One of the exercises in that program, that some of your listeners may be familiar with, is with a medicine ball or what we call a med ball, which is this big ball, 15 to 30 pounds. It doesn't have any bounce in it. You throw it down and just slam it into the ground, you throw it over your head and you just whack it down as hard as you can.

It's quite effective.

It's great. I mean, I had a tough day at the office, I was pretty ready to go and I wanted to get some of that aggression out. So, I love that exercise. It was fantastic. He showed me how to do it. And then when I went to do it three days later, I went back to the gym and had been doing some cardio beforehand, listening to music, went over to reach, to grab the ball, picked it up, whacked it down into the ground, as hard as I could. It wasn't a med ball, it was a bouncy ball. It came back at me like, like a Mike Tyson uppercut. Took me out. I mean, literally, I went back up into the air, down on the ground. Blood was coming out of my nose. The first thing I thought was, because I have some arthritis, I was like, did I just make myself into a quadriplegic? That would be very ironic given that I was there to exercise.
But, you know, I got up. I'm a doctor, so I knew where to put my finger on my nose to stop the bleeding, and, you know, after a couple of cups of blood came out into the sink, I was okay. And I did go back, just recently.

Claudia von Boeselager: I'm so sorry.

Joseph Raffaele: Very carefully grabbed the med ball, threw it down a few times to make sure it didn't bounce and I'm back at it again. I'm back on the, back on the horse.

Claudia von Boeselager: Wow. I'm so sorry.
I'm laughing, but I'm sure it was quite a dramatic event at the time.
Joseph Raffaele: I've broken my nose a couple times, so I don't think it got broken this time. It was swollen for a bit, but it's okay. For now.

Claudia von Boeselager: So that's a good warning to take care when you do exercise, right?

Joseph Raffaele: Yeah. I mean, the truth is, I was very embarrassed by it. There was hardly anybody there, but in a way, if there had been a camera or something like a security camera, it would have gone viral under that heading of Stupid Human Exercise Fiasco, that would usually get a pretty good laugh.

Claudia von Boeselager: What not to do at the gym. Exactly. I'm glad you recovered okay.

Joe, you are an expert also in the telomere biology. Can you explain for my audience who are not familiar, what exactly telomeres are? And what do they do, and why are they so important in the anti-aging space?

Joseph Raffaele: They are the caps on the ends of your chromosomes. You know, we have chromosomes in our cells that hold our DNA, it's all folded up into these neat little packages.

Mammalian DNA is linear so it has ends to it. And that's a problem because DNA replication machinery, if it sees an end it thinks it's a break in a chromosome and it starts to try to repair it. So the telomeres are, these non-coding ends of the DNA that are repeats of the nucleotides TTAGGG. They don't code for any proteins, so you don't lose anything when you lose them. And every time cells divide, they get a little bit shorter, because DNA polymerase, which is the enzyme that replicates DNA, can't replicate the ends of the chromosomes. So it's called the End Replication Problem in molecular biology. But they're kind of like essentially our molecular clocks. Once they tick a certain amount of times and a certain amount of divisions, the cell can no longer divide.

That actually was a big major development in the field of cell biology, when, prior to the 1960s, it was thought that cells and culture could continue to divide indefinitely and they were immortal. And that the problem of aging was really above the cellular level, in organ, or organism level. But Len Hayflick, uh, Dr. Hayflick who did the seminal experiment that showed that in fact, no, they don't divide indefinitely. What happened was when they changed the medium that the cells grow in, some new cells slipped in there and they were the ones that were then dividing and making this quote-unquote immortal population. So when he did this experiment very carefully, he found it was just 50 to 60 doublings and that, that was it.
And that really changed the whole approach to cellular aging on its head. Then Cal Harley proposed, he was a friend, and a colleague, a brilliant scientist who proposed the theory that it was the telomeres that were one of the major drivers of the aging process themselves. And, so, when they get critically short, they can't divide anymore.

So for instance, your stem cells, which reside in every tissue in your body, those are there, it's a very small percentage of the cells in, say, your liver or in your muscle, but they divide to replace degenerated cells that are cleaned up by your immune system. If they can't continue to do that, then they can't continue to, you know, regenerate those tissues, and that's a major aspect of the aging process. But not only do they not, they lose the ability to regenerate tissues, but once they become senescent, that's the term for a cell that can't divide anymore, they secrete these nasty inflammatory molecules called cytokines, that we all, sort of, are familiar with now because of this cytokine storm from COVID.

And particularly immune systems, when they get into that, immune cells, when they get senescent, they start to secrete these inflammatory molecules that then, not only make it a less effective immune system, but increase inflammation quite significantly.

So that is one thing that happens with the immune system, that's even more so than in other tissues, but it's also this idea that telomeres control the aging process from a relatively high level, what we call upstream medicine, because it's ultimately that ability to continue to divide that's important because it starts the inflammatory process, which we know is very much a part of the aging process, and then there's many other ways in which it's linked into the aging process.

Claudia von Boeselager: Thank you for expanding on that.
You founded several successful businesses. Can you talk about PhysioAge, and the incredible work you are doing there?

Joseph Raffaele: Yeah. So this was an offshoot of Bob Butler's comment. And then another thing that happened to me about four or five years later, when Noel Patton, founder of T.A. Sciences, Telomerase Activation Sciences, came to my office and said, what would you need to know about this new molecule that I have, which can lengthen telomeres, to offer to your patients?

And I said, you know, having done all this biomarker research, I said, look, I will offer it, if we study how effective it is. There was a lot of animal data and other preclinical data, phase one data on it, so I knew it was safe. But was it effective? That was the question.

So we started this year-long cohort of patients that came through my practice and were on the protocol of supplements that we use in TA-65, that was called the patent protocol. We generated a lot of data from that and learned that TA-65, this molecule, which we can talk about, was effective in rejuvenating the immune system. But we also looked at a whole bunch of other biomarkers at that time. And when we put them all together in an analysis, we found that it was a really good way to model the aging system.

And at that point, you know, the NIA had been doing lots of studies on looking at biomarkers of aging and they didn't find one. So they were thinking maybe panels of biomarkers would be helpful. So we put together a panel looking at arterial stiffness called CardioAge. So in this panel, we had CardioAge, PulmoAge for lung, for lung agings, CutoAge for skin aging, NeuroAge, cognitive aging.

And when we looked at those four markers with these instruments in individuals, it gave us an overall PhysioAge that closely correlated to the chronological age, so it was one of the first, sort of, biomarkers of aging that was not blood-based. And the software that I developed from that, along with my co-founders, data scientist from Stanford Jochem Kumm, and an MBA, Jerry Fortunato, we created PhysioAge to allow doctors like me to track multiple markers in their patients, to see whether the things that they're doing, like recommending changes in diet, exercise, supplements, hormone optimization, other stem cell therapies. And now we have doctors around the country and around the world using the software to practice objective longevity medicine, age management medicine, whatever you want to call it, which is, I think, you know, the future of medicine is to really get started early, to see what is happening with your aging process, and then track it. Treat, monitor, adjust.

Claudia von Boeselager: Exactly. I completely agree. And one of my other podcast guests was Dr. Dale Bredesen, who I'm sure you're familiar with as well, and, just seeing how many diseases are actually reversible, or you can even catch them on time, and completely preventable as well. And so I think it's really about testing, and knowing what to test for.

Could you talk about the full evaluation that you do with your patients in your practice, and discuss perhaps some of the success stories that you've seen?

Joseph Raffaele: Yeah, so, earlier on we were doing primarily hormone optimization, and the practice became very busy. Then the women's health initiative came out and they were telling all these women they shouldn't take hormone replacement therapy for anti-aging. But, in fact, you know, we've all learned that that, sort of, is not true. As time has gone on with the developmental biomarker system, and all the other aspects of longevity science that have been increasing our knowledge of the aging process. We look at multiple different things.

So, when a patient comes in, we of course do a complete history. I can tell you that I just saw a patient this morning for a two-hour initial consultation. And she had come in prior to that for about an hour battery of tests. The cognitive arterial stiffness tests. And then a bunch of blood tests.

So, we look at non-blood biomarkers. We look at body composition. We look at inelasticity, arterial stiffness, all these other things. Then we look at more esoteric biomarkers of aging, like telomere length. We have a panel of tests that are done at UCLA clinical immunology laboratory, looking at the aging of the immune system that are, sort of, markers that you won't get in a routine lab test.

We look at, of course, routine chemistries, the things that are important, like hemoglobin A1C, chem screen lipid panel, we do advanced lipid testing. I often send the patient off for a coronary calcium score because of cardiovascular disease, whenever I hear about somebody having a heart attack, I just think it's a failure of the medical system, because that's a completely preventable disease with a little cooperation from the patient until they're maybe in their 90s or 100.

I mean, if you can't get them to quit smoking, then, you know, that's going to be a problem. But we detect that disease very, very well. And the coronary calcium score picks it up 10 to 15 years before it's going to cause a positive stress test or 20 years before it's going to cause a heart attack. So we look at all the major systems, at both cellular level and molecular level, and then at a more macro level, and so, the organ function level.

And then we look at these other newer biomarkers, one of which you referenced earlier, the GlycanAge, which is looking at the pattern of sugars that are attached to your IgG antibodies. We look at telomere length as I mentioned, we look at, then, a whole other discussion, which is the DNA methylation. I don't know if you have anybody coming on who's going to talk about that, but-

Claudia von Boeselager: Not yet, but if you've someone to recommend...

Joseph Raffaele: I certainly do. I mean, of course you can have the father of the field, Steve Horvath, come on. There's Morgan Levine, who's one of his postdocs, who's now a professor at Yale, to talk about that. That's a very interesting field, I'd love to talk some more about that, but we add that, we look at the composition of the red blood cells and the levels of fatty acids in your blood, because there's a lot of data on the role of omega-3 fatty acids. In aging and, particularly, in cardiovascular disease.

I pretty much apply everything that has a good level of evidence behind it to track aspects of the aging system and aging in the body, now, other patients, should they want to avail themselves of it, can also do full-body MRIs, where they look to see if there's early cancers.

And I'm okay with MRIs because there's no radiation exposure there, I don't believe that full-body CT scans is a good idea. And then we put all that together and, through our algorithms, give you an overall physio age. We show patients what their strong systems are and their weak systems are. I mean, that's, sort of, a truth of longevity medicine is that we all age differently, each individuals, and then different organ systems within individuals, age differently. You have a strong system, a weak system. Part of that is based on what you've inherited. Part of that is based upon how well you took care of that system. Like the lungs. If you smoke, you're not taking good care of them. Your skin, if you're baking yourself in the sun, likewise. You know, the liver, obviously if you drink too much, all those things, but we look at all those and give an idea about where they are in the aging process.
I always say to patients, the first step to aging well is knowing how well you are aging. And that's, kind of, what we give a person. I just gave this woman, she was 70 years old. She, overall, is functioning like a 57-year-old. And which is great because, you know, she's but she's been doing a lot of the right stuff. She also has two 90-year-old parents, which, you know-

Claudia von Boeselager: Good sign.

Joseph Raffaele: And then, you know, some successes.

I mean, one of the successes that I see all the time with my practice is treating women who are perimenopausal and menopausal because estrogen is such an important molecule in them, getting rid of symptoms. We hear all the time from patients: "You gave me myself back". They thought that they'd lost who they, who they were really, because of the loss of estrogen and the loss of sleep, et cetera.

And then I was really gratified to see that, you know, I knew all the literature pointed to the fact that estrogen is important in almost every organ system, but when these GlycanAges, the test came out and the GlycanAges started coming back, as you know, from your talking with Nikolina, the CEO of GlycanAge, that metabolic health is very important and obviously you're metabolically fit if you're 11 years younger, not having diabetes, those are all important things, but having good levels of estrogen in both men and women is turning out to be extremely important. The average male in my patients is 25 years younger by GlycanAge.

Claudia von Boeselager: This is after treatment, though, right?

Joseph Raffaele: This is after treatment, right. Exactly. They come in and some of them are metabolically healthy. Some of them aren't. And we work on that. Recently just had a guy who came in, he was 58. He was a little bit metabolically healthy, he's at 56, went on therapy, and now he's down to 48. Women, likewise, menopause adds nine years to your life, the loss of estrogen. But if you give that estrogen back, not only in my practice, but in studies, that doesn't happen. So the average woman is about 15 to 16 years younger.

So those are successes, in fact, you know, that's how I got to know the GlycanAge people, is we started sending those tests in and they called me up and they said, what are you doing?

Claudia von Boeselager: What are you doing so successfully! Just shows the comprehensive test offerings in the therapy that you actually offer, because what I hear from some people, you know, you test and then what was going to help you? And you actually have the full streamline of the full process to actually get people to where they want to be. And are they then patients for life or how does it work? You give them the tools to survive on their own?

Joseph Raffaele: Well, we do give them some tools and I tell patients or prospective patients, even if you're not sure that you want to necessarily do a program, that's more than diet, exercise, and supplements, which would need ongoing medical supervision, getting a baseline is important. And that gives me a lot of information to target which systems.

You'd be surprised how someone is like, oh, you know, I'm smoking, I'm getting away with it, but, you know, when you tell them their lungs are 10 years older than their age, then that's real concrete information and changes behaviors.
So they don't have to become lifelong patients. But the majority of my patients do. We started here in 1998. I have a 95-year-old woman who's started me with 1998, still taking hormone replacement therapy, even-

Claudia von Boeselager: Wow.

Joseph Raffaele: -I tell her to quit it. So I have about a 10% turnover per year for various reasons, some are financial, some are, used to be moving, sometimes they just lose interest or, you know, but which leaves room for new patients come in, I'm always excited to see new patients, and try to figure out what's going on with them, and trying to, you know, expand the services. But it's mostly lifelong. The base of my programming, it's a stepped approach.

First lifestyle, stress reduction, diet exercise, then supplements as needed, and then hormone optimization, as needed. And then actual pharmaceuticals that are potentially needed. And then beyond that, you know, I might refer to colleagues for stem cell therapy, PRP, there's other modalities as well, that I'm not as much of an expert in, but I refer patients to.

Whatever it takes to get those markers, to not keep getting worse and hopefully, in many systems, get better, is my goal. And that's, what's great about it. I can look at the dashboard and that's what I give my patients, they have access to their dashboard, and they can see, you know, where they are, where they were last year. And then in actual systems that don't change necessarily that much with age, but we know where it's better to be versus worse to be, we'll give them a letter grade to make it easy to understand. So we give them a report card for their arterial health, a report card for their cognitive health and they know, I went from a B- last year to a B+ this year. We're making some progress there.

I see my mission as to keep my patients as healthy as possible, as long as possible. Full stop.

Claudia von Boeselager: Excellent mission. And incredible work that you're doing. Are you only seeing patients locally or do you have a service that's also global?

Joseph Raffaele: Well, you know, I have patients from all over the country, and all over the world.

I've been around for a long time, so word get's around. And New York happens to be a nexus so a lot of people have places here or come through here. I used to require that I see patients in person first. I would perhaps get them started, particularly a very symptomatic post-menopausal women, before actually seeing them, as long as they saw another doctor and got a physical exam.

But COVID has really changed that. And I think medicine has changed to telemedicine a lot. You can do the zoom call or whatever platform you want to use. You can get to know them face-to-face, so to speak, as we are.

So I do now see patients, even if I haven't and start treating them, as long as they have a documented physical exam and have other doctors doing their pelvic exam or their other evaluations, but eventually, most patients come in and, you know, to get the more esoteric biomarkers that we do that are non-blood. Like the arterial stiffness, and some of the skin elasticity testing and things that we have to do in the office.
And some of the blood tests we have to send from the office, the major labs don't offer them, and they will draw them at a draw center. I like for them to come in, but it's not an absolute requirement anymore, I think COVID has taught us that these things can be done virtually for the most part. And a lot of stuff is laboratory and diagnostic testing. That's a long-winded answer to your question that, you know, wherever you are, if you want to come see me, that's fine.

Claudia von Boeselager: Exactly. No, I just, if people listening around the world are interested in becoming so much younger when joining your practice.

You talked about estrogen as hormones, but I would like to talk a little bit more about hormone optimization, and why, in your view, is this such a critical area? And why is it also helpful for women and men? What are the differences in improving healthspan and longevity?

Joseph Raffaele: I want to first make a distinction between healthspan and longevity. Typically, to get really old, you have to have pretty good healthspan, but that's not absolutely necessary.

Conventional medicine has been very good at keeping people alive at a relatively lower level of health for many years. And that's not my goal. Hormone optimization in menopausal women, I believe that, all the politics and cultural discussions aside, if your estrogen level, in the first 50 years of your life, is around a hundred, and after menopause, it's 2, then that's a deficiency syndrome. And we know that there are a lot of things that go wrong when that happens. It doesn't mean that you can't continue to live. Many women live 30, 40 years after that. I think there's a better quality of life, the healthspan is improved, the disease burden is improved, if you bring those levels back up to not quite the same as when you were normally cycling, but around 50, 30 to 50, depending on various factors in the woman.

And, interestingly, that's about the level that a male has at that age. I tell women, look, if you're 55 and you're coming into my practice, and you're wondering whether I should be on estrogen, because it's going to cause problems, your husband's level is higher than yours might be. Four times higher. And that's why women start to catch up to men with disease.

And I know there's a lot of controversy about this, but I think the preponderance of the evidence is that mammals, not just men and women, but mammals need a certain level of estrogen in their body to maintain optimal brain, arterial, immune, now we've learned about immune system health, bone health. skin health, you pretty much name it. Of course vaginal health in women. So that's, sort of, the optimization takes place there. Now, there are other hormones that are important. I mean, testosterone in men declines. Testosterone in women declines. And I look at the testosterone level in women as well.

So, I look at all the hormone levels and I try to bring them back to a level that addresses the symptoms that might come from them. That is closer to youth. That's what we have to do now. Once we get further along in our understanding of stem cell aging and organ rejuvenation, ovaries might keep alive longer, so we don't have to replace the estrogen. The testicles will continue to work more effectively. The signal from the brain, because it's a more youthful brain, will work more effectively. At a higher upstream level, we'll be able to not have andropause or menopause, or the loss of growth hormone, the loss of DHEA, or the less effective thyroid secretion that takes place. These are all the major hormones that I address because, you know, I just see what improvements they make. And using the term optimization is important because medicine now is, sort of, what I call a normal range medicine.
They target a normal range in the laboratory. If you're not below it or above it, you're normal, we don't need to worry about it, okay? But that range, the top 2.5%, or the bottom 2.5%. In the middle, most biological variables are continuous. So there's a level down here that's, particularly in something like vitamin D, where 21 is in normal range, okay? Below 20 is deficient. But we have a lot of evidence that 30 or 40, probably a lot better, even less controversial, you know, numbers and it shows that it's starting to happen in medicine is that cholesterol and blood pressure.

You know, we used to think that if your blood pressure was less than 200 over 100, you're good to go. Now, maybe you'll have a stroke when you're 60 or something. Then we did studies, we found that, well, you know, it's really like 150 over 90, we did more studies, it's 135 it just went down to. Really there's an optimal blood pressure, you know, and that's the one that, you know, you're not passing out with, basically, the lower the better that top number, the thought number. Same thing with cholesterol.

I mean, they've done that with the major killers because they've done the studies to show that there's an optimal level and that's way down lower, you know, it's a risk factor for, like, blood pressure or cholesterol than previously thought. Likewise with hormones, I think that your endocrinologist will say, well, don't treat them until you have 12 months without a period or don't treat them if they don't have, you know, Addison's disease and they have no cortisol, don't treat them for testosterone unless their level is out of a field mouse, I mean-

Claudia von Boeselager: But that's too late.

Joseph Raffaele: It's silly to think about the logic of it, the cutoff is 300 on the laboratory form. One guy comes in he's at 301. Normal. Another guy comes in he's at 299. Abnormal.

One guy gets treated. The other guy doesn't get treated. They both have the same symptoms, I guarantee you. So that's where the optimization comes in, looking for what's the right level to treat the symptoms. not get any side effects, and optimize the function of that, of that organ system. And then look at the whole orchestra together.

And that's what I try to do. You know, we try to do it first by, so the testosterone level that declines in a male, earlier on, is accelerated by having too much fat on the belly and inactivity, and poor sleep. The signal from the brain is not enough. It's not really a testicular problem, it's a pituitary problem. Well, we can do we can do diet, we do exercise. We get them down, and their testosterone level comes up. They don't need testosterone, basically. Or maybe we give them a little testosterone to help them get back into the gym to feel better, feel better about themselves, work harder on their diet, and then we wean them off of them. As they get older, right now we don't have the technology for keeping that signal high into the 70s and 80s, and so we replace it at that point. That's what we mean by optimization. I mean, hormone replacement therapy used to be called hormone replacement therapy. Then it was sort of, well, we're not replacing it because it's not deficient because that's not politically correct because it's a universal phenomenon, but, so they call it menopausal hormone therapy.

I'd say the next step is hormone optimization, and that's why I call it that.

Claudia von Boeselager: Optimization, yeah. And I mean, who doesn't want to feel and look younger later in life and avoid so many diseases. So there's so many benefits.

I'd love to switch gears a little bit, we talked about some of the different tests that you do, but are there also other devices, wearables, that you advise your patients to wear to track on a day-to-day basis, be it for sleep or otherwise? What are some of your favorite devices and tracking mechanisms?

Joseph Raffaele: Well, yeah, I mean, you have to first sit across from the patient and assess what level of biohacker they're, that they have. You know, some come in with their Excel spreadsheets and all their labs and all their devices, and you're like, I haven't even heard of that device!

Claudia von Boeselager: Guilty as charged!

Joseph Raffaele: I don't, I'm more in that range myself, and some are like, you know what, I think I sleep well, I wake up refreshed, I don't need to know how long in stage three of asleep, but having made that assessment, I mean, there are ones that I think are very useful, particularly if people are, you know, very active athletically, or if they're having trouble with sleep.
I mean, I wear the Oura Ring, O U R A-

Claudia von Boeselager: I have it on, myself.

Joseph Raffaele: Which finger you choose, it's tough to know, but I went with this one. I think it's a very useful device. It allows you to know how hard you can push yourself the next day. It tells you, you know, yeah that glass of wine did mess your sleep up a little bit. It gives you a good quantification of, of your readiness for the next day. So I think it's a pretty good thing to use.

The Whoop, a little bit more on learning the strain that you're putting your body through. Other wearables, you know, we're all, got a wearable from carrying a phone around, so, you know, Apple Health stuff, there's companies that have apps that track all your activity. So there's those, I think those are quite useful.

We're looking to have an interface with some of those things to upload into PhysioAge, so patients can know what's happening. We can correlate changes in hormone levels or changes in antioxidant levels with various changes in their data that's coming up. If their sleep's improving, is their growth hormone level, as measured by igf-1 going up, that kind of stuff.

I have had some patients on continuous glucose monitors. I know Peter Attia's a big fan of those, and other endocrinologists will say, oh, that's poopoo, you don't need that stuff unless you have diabetes. But again, it's all about tailored, personalized, what I'd call "in one" medicine. If somebody is sitting across from you saying, well, you know, ananas, I really love bananas, and I put them in my smoothies, and I don't think they raise my blood sugar. If you put a continuous glucose monitor on, you can tell whether it does or not, it might be rice that raises them. And there's, there's differences between individuals. You just have be willing to wear that device for a while.

And, me, I look at hemoglobin A1C and it's 5.2, which is very good, that's a control that measures all your blood sugar in the past 4 months, I mean, they're doing really well. I don't think that they need to know necessarily exactly what their glucose numbers are 24 hours a day. One of the tests that we use in our office for arterial stiffness is in the near future going to become part of a wearable, which I think would be fantastic, so that you can know what's happening to your central arterial pressure, you know, on a sort of day-to-day basis. And really know what effect supplements that you're taking, like things that raise nitric oxide or what the effect of your exercise is doing. So I think we're moving towards more and more of these kinds of things from more data, but it has to be put into a format that is consumable easily and actionable, and it makes sense.

Claudia von Boeselager: Yeah.
I actually tried, I don't know if you've come across them, it's a Silicon Valley startup called Levels Health. So they use the Abbott Laboratories' continuous glucose monitor, but they have a great interface on their app as well. And, you know, I thought sweet potato soup, very healthily made would be fine.

And it's just that glucose response was just incredible. So I was like, okay, no more sweet potato soup for me, but was also really interesting as well between my Oura Ring, and then looking at that, and my blood glucose was dropping really low during the night, hypoglycemic, and I was having these awakening responses. So it was probably the cortisol waking me up to get my liver working to produce enough blood sugar during the night.

So I've remedied that, if you will, with taking some almond butter near bedtime, because I thought I'm doing great with these longer intermittent fast. Because of the hypoglycemia that, it was waking me up and I wasn't getting good sleep. So this is why I find it so exciting and amazing what you can do to optimize things.
But you just, you need to have the data, right? You need to know what's actually going on in your body.

Joseph Raffaele: Yeah, I think that's, you know, we're going to have implantable chips in the not-too-distant future. I'm sure, we already do, they're called pacemakers, but they're for more critical situations, like if your heart's not beating regularly, but the size of these chips is decreasing rapidly and battery life is incredible.


So I think it's just a matter of less than a decade before that's pretty common stuff. It'll be good behavior modifying stuff. It'll be good for data collection because ultimately you want to see, the best experiment is getting good data from free-living individuals where you're not controlling the data, you're not controlling all the variables, but you're measuring, so you know what's happening. You know how those variables are affecting things. I'm sure, with our computing power, that's coming down the pipe pretty quickly.

Claudia von Boeselager: Would you implant one of the chips in yourself?

Joseph Raffaele: I mean, the devil's in the details on that. It depends on what it's telling me whether it's worth it or not. I'm not a conspiracy theorist kind of guy, so I could be worried about that. I might, yeah, I mean, if it gives me the kind of information that I need. Right now, I don't think there's anything out there that I'd implant in me just yet.

Claudia von Boeselager: Yeah.

And I think, I mean, when I talk to people who are very anti-devices and tracking, et cetera, I think if you think about your car and your car will tell you well in advance when it needs something, yet we human beings, haven't actually gotten to that level of having the same precision of knowing what's happening.
So I agree with you. It's just a matter of time.

I'd love to change gears a little bit and ask some rapid fire questions. What are some bad recommendations you hear in your area that you have to correct when patients come to you?

Joseph Raffaele: Right. Well, I mean, I think, sort of, an easy one, and it's not happening as much anymore, but people used to say, you know, breakfast is the most important meal of the day.

It's just not true. Intermittent fasting is very important. I haven't had breakfast in two years, occasional brunch here or there the longer we're in fasted state, I think, the better in terms of not all the time, of course, but maintaining the repair and maintenance systems, I think is important. That's one thing, I mean, I, you know, the worst advice I hear is, we mentioned it briefly, which is that estrogen causes breast cancer, and it doesn't cause breast cancer.

How can an endogenous molecule cause breast cancer? The associations have been looked at, the risk, in the largest trial, turned out to be non-statistically significant in younger women and clinically insignificant. So to stop all the benefits because of that makes no sense. And yet you still hear that because of the disinformation that's out there.

So that's one of the most damaging things that I hear.

Claudia von Boeselager: So great that you can correct them as well.
What are some of the learnings or insights your patients, that you work with, find the most valuable?

Joseph Raffaele: I think the biomarkers of aging are often things that really make them sit up and wonder because they can be so variable. Oftentimes say, well, how's that possible? I'm 20 years younger and this system and 15 years older in this system, and that's 'cause they learn that you're, have a certain level of inheritance of organ function, and then you either chip away at that more rapidly or do the right things to maintain that. And a biomarker at that time is a snapshot of what's happening and then tracking it over time is what's really important for them.

And so, they often think that one system might be their good system, but when we measure it really isn't. Telomere length, it's something that can be a big eye-opener for them because that's 70% heritable, so, and the range is quite wide. The average telomere length that you, sort of, have when you're born is between 8 and 12 kilobases, or 8,000 and 12,000 base pairs.

But the average loss over a lifespan is about 4,000 base pairs, or that whole range of inheritance. So, you could be born with a silver spoon in your mouth, or, you know, a plastic spoon in your mouth, and knowing which one of those it is in terms of how long your health span can be supported by telomere length, and what you can do to abuse your telomere length before it gets too short, is something that I think people really open their eyes about.

And then just getting their overall PhysioAge and seeing what little things can do to improve that, are things that, kind of, make them a little bit wide-eyed and keep them coming back for more.

Claudia von Boeselager: Exactly, really exciting.
What are some of the daily or weekly routines and practices that you have that help you perform at such a high level?

Joseph Raffaele: Well, you're assuming something right there, but let's go with it.

Claudia von Boeselager: Well, you're doing a lot of things right, so there's definitely something in that.

Joseph Raffaele: So a couple of things I do, one is I don't eat breakfast anymore, and that really gives you solid energy straight through. It takes a while to get your enzyme systems in your body burning fat as a fuel, but to have that sort of steady state level, I mean, I often times get to lunch, and I'm like, I could still eat lunch, you know, it's time to eat.

Claudia von Boeselager: It's flexible, yeah.

Joseph Raffaele: Yeah, I mean, and it wasn't like that for a long time in my life. I was like, I had to eat every three to four hours because I would be taking in carbs because the previous time was making me hypoglycemic, and I was hungry, and I wanted those carbs. It was like a vicious cycle.

So I think that helps. And then taking that in the morning, some time to do a little 15 to 20 minute meditation. I love using the MUSE device. MUSE, I think it's one of the greatest-.

Claudia von Boeselager: MUSE, okay. I'll note that in the show notes for my listeners.

Joseph Raffaele: I have no financial relationship with them, but, for people that aren't, you know, sort of natural meditators, it gives you the feedback to know whether you're getting into the calm state. And so I've incorporated that into my morning.

Claudia von Boeselager: Does it measure brainwaves, out of interest?

Joseph Raffaele: It's a neurofeedback device, you put a little device on your head, and then it tells you whether your mind is active, neutral, or calm, and gives you immediate feedback into your ears as to which way you're going, and then you learn how to breathe into a calm state. And you don't have to wonder whether you're in a calm state, it tells you, so-

Claudia von Boeselager: And does it actually tell you which is like, you know, which brain wave you're at, is it theta, or alpha, or, can you manipulate it?

Joseph Raffaele: They don't tell you delta versus alpha versus, you know, but they give, their definition of it's active, which would be, you know, not alpha. And then they just give you those three ranges, and you know, when you're in the calm, you're in a good alpha state. It's a fantastic device. It's like you know, I tell patients if you do it and you get good at it, it's like taking a Xanax, and you're just really relaxed afterwards, it has long-lasting effects. And it takes a while, but it's really nice the way that device is set up to, you track how many, you know, how many minutes you've done, you know, how many times you, what's the longest one you've done. It has a nice reward system built into it.

So you get the benefits of meditation, but for, sort of, my metric driven, kind of high driving people, it's kind of a yin and yang, it's calming them down, but giving them what they want.

Claudia von Boeselager: The competitive side comes out aswell. I must try it. And you've probably heard of 40 years of Zen. It's from Dave Asprey. So it's a five-day intensive neurofeedback session as well, where you really learn about how to access the different brainwaves.
Have you tried it yet?

Joseph Raffaele: I have not tried that. No. I'd be interested to try, but you know, sort of, this I like because it's actual immediate data and, you know, some days, you're just so raw and you can't get into that alpha, you know, so you know that maybe whatever you did that day, try not to do that too much. I mean, people that are really good meditators, I've only been doing it about three years now.

One of my patients is basically a Buddhist and she sits for hours. She's 83. She's on a lot of hormones and other things too, but her GlycanAge is 37. So-

Claudia von Boeselager: Wow.

Joseph Raffaele: It definitely helps. We know, there's lots of data showing the benefits of meditation. I just find that when you have the feedback, it's good for people who want to know whether they're actually achieving it or not.

Claudia von Boeselager: Yeah, and I'm going to check it out. I mean, I meditate regularly myself as well, daily. And, I also feel, for creativity, for intuition, things like that, it's just incredible. So, but, you know, more and more research is coming out about it.
I was going to ask you what your most exciting purchase was in the last six months.
I'm not sure how long you've had your Muse for, so I'm not sure if that would be it, or is there something else?

Joseph Raffaele: Yeah, no, you know what, from a biohacker standpoint, what have I done recently? I mean, for me, this is kind of a cheap answer, is finding some of these new biomarkers of aging lately that I've gotten. The GlycanAge, but also TruDiagnostic has a DNA methylation age that is based on a study that I had known about the Dunedin longevity study in New Zealand, where they give you, not only your biological age, your DNA methylation age, but also your rate of aging, which is really, really important. And they can do that because it's a longitudinal study that they got that data. It's not just a cross section study. So that is a purchase, I guess, in a sense of, you know, why we purchased the kits from them and we're starting to use them on our patients. Our previous lab was good, but I think this is the next thing above that. Beyond that, my most exciting purchase is my Porsche, I got recently.

Claudia von Boeselager: Oh, congratulations!

Joseph Raffaele: My last internal combustion engine car, I promise.

Claudia von Boeselager: Well, they have an electric car now, as well, so you know.
Joseph Raffaele: Oh, their electric cars are fantastic, I mean, they're as fast and they're beautiful cars, but it's just that sound, still I, it just tells you how old I am. I grew up on those cars and finally I'll, at some point, give it up.

Claudia von Boeselager: Well enjoy, but you need to be in Germany in order to drive it properly, right? To actually drive at speed, so-
Joseph Raffaele: Yeah, that is true, and I want to get on the autobahn. Absolutely.

Claudia von Boeselager: Yeah. It's actually a tourist thing. There's Chinese tourists that, well, pre-COVID, used to come and book the trip to Germany just to drive on the Autobahn.

Joseph Raffaele: Yeah. What I enjoy about it is, just, that car is like an ultimate machine, and you become part of it, and, so that's one of the things. Function, as you get older, declines and being able to react quickly in a car, I want to continue to be able to do that for a long time.

I want to be able to do things, and that's what my patients tell me. They don't want to just be able to keep the score of tennis. They want to play singles, and then I don't want to have to graduate the doubles. It's maintaining their healthspan, maintaining, not being afraid to do what they used to do. And, you know, you have to test those things. I don't want to do anything crazy to kill myself, but that's what it's all about is having the most life in the years that you have.

Claudia von Boeselager: Correct. So one of my goals is at 94 to be out partying, having fun, dancing on tables, and skydiving, and doing all these wonderful things, and not let age actually get in the way, so. And maybe, I think, I think I'll live 'til 120, so we'll see how I get on with that.

What trends and developments in the longevity space do you find most exciting?
I mean, you just talked about the DNA methylation testing, but where do you see, maybe in the next two years, developments coming out? What really excites you?

Joseph Raffaele: Well, I think, well, there's so many of them, I mean, but a particular area of interest of mine is telomere biology. And there's a couple of companies that are looking at getting telomere length, turning on telomerase, so you can significantly lengthen telomere length to 20, 30, 40%. And testing the theory that that's a major controller of the aging process, so that if you reset telomere length, then epigenetics is reset mitochondrial function is reset, senescent cells aren't killed, they're just turned back into healthy cells.

That theory has been tested in mice, both in Maria Blasco's lab in Spain and in Ron DePinho's lab, when he was at Harvard. Dr. DePinho is at MD Anderson now, where they took a mouse and knocked out telomerase, just 50%. They had shorter telomeres. They had an aging phenotype that was more rapid.

And then they were able to knock in this receptor so that if they give them a certain molecule and turned telemorase back on again, and these mice reversed their age. I mean, every single organ system virtually got younger again. Not just didn't keep getting older, but got younger, with significant turning on. So there's no reason why theoretically, that can happen in a human and we're talking, potentially, a Benjamin Button-type effect.

But you have to deliver it to the right cells at the right time, transiently. And that usually entails gene therapy, which has, you know, a history of having difficulties. So just getting that right. But that could happen in the next couple of years. Well, Michael Fossil's company is working on that Telocyte's another company working on that as well. That's exciting.

In the larger field, what is both exciting, but also just, like, overwhelming is the amount of new information that's coming out, because of computing power and artificial intelligence.

We're able to model things now "in silico", as they say, meaning that we can do it experiment on a cell, just like we would in a Petri dish, except it's just on computers, because you're modeling every aspect of it.

And that's going to rapidly increase things. I think Ray Kurzweil, who you're probably familiar with-

Claudia von Boeselager: Of course, yeah.

Joseph Raffaele: He said that he thinks that most problems in biology will be solved, maybe not even just biology, but, in the next 10 to 15 years, because of the increase in AI and computing power. He's been right about a lot of things. I'm also holding out hope for myself that I can stay alive until we reach longevity escape velocity, or LEV in the lingo, which is staying alive long enough to the point where the technologies are there to keep you going for a while.

But I think those are, sort of, the, a little bit more theoretical ones. Although the, I think the telomere length thing is probably sooner. Stuff that's going on with NAD and David Sinclair's work. There's now some labs offering NAD tests, which we didn't have before. And, you know, a lot of us are taking NAD supplements. I'm sure you are taking Elysium, or Tru Niagen, or something like that.

Or maybe you're a little bit young for that actually at this point, we usually wait 'til forties or something where it starts to decline. But there can be some quite significant beneficial effects in that, and we can measure now whether or not we're adequately raising NAD levels. So, I just want the damn field to slow down so we can keep up with it.

Claudia von Boeselager: Yeah. I was listening to a interview with David Sinclair actually, and Sergey Young, the founder of the Longevity Vision Fund, and David was saying, I mean, I think he's 15 years in this space, that alone in the last three years, he's having trouble keeping up with all the advancements, what's happening.
It's just really going exponentially now as well, but some really exciting developments, so thank you for highlighting those.

For my listeners interested in understanding more about longevity, living. well, what online resources or books would you recommend they start with?

Joseph Raffaele: There's two websites, where I think there's really good, very cutting-edge, and you know, well vetted information, that's the SENSorg, which is Aubrey de Grey's organization, the Society for Engineered Negligible Senescence, they put out good information. And then longevity.technology, have you seen that website?

Claudia von Boeselager: Yeah.

Joseph Raffaele: That's sort of the industry where you just see, you know, from biotech to supplements to lifestyle. And I think they do a really good job as well. Lifespan.io does a very good job as well. Gerontology Research Group.

And then, as far as books are concerned, you know, for understanding aging, I think even though it was written, like, more than 20 years ago, Steven Austad, he's a zoologist that does a lot on aging. He wrote Why We Age. That was one of the books I read back when I was just getting into the field, and he talks about the need to use other models besides mice to understand aging because mice are optimized for short lifespans, not long lifespans.

And they're good for looking at certain diseases, and they're good laboratory animals, but they're not really that great for studying aging. But he also talks about evolution and the evolutionary theory of aging, which I think is very important to understand if you're really going to, kind of, go into aging. I mean, you can go into it as a biohacker and just say, look, I want optimum performance, but some people go into with the idea that, well, should I mess with mother nature.

And that's the problem is that when you understand that mother nature didn't intend, we're not selected or evolved to live to 50, 80, 90. We mostly died in our thirties of unnatural causes. And so there's no plan. It's like you used the analogy of the car or I use the analogy of the dentist. You know, the car is designed to work and have a warranty for 5 years, after that, want it you want to be running at 15 years, you've got to keep on checking it, replacing parts, doing your diagnostics on it.

We do that in dentistry. You know, we, we just don't do it in medicine. We're still just screening for disease, instead of screening for health, and health erosion starts a lot longer before disease. And so, you know, that I think is really important to watch.
Michael Fossil's book on telomere biology, Telomerase Revolution, is very good.
 There's a, of course, David Sinclair's book, Lifespan. Those are, sort of, the top ones. If you really want to dive into cell biology then Michael's book Cells, Disease and Human Aging is one of the bibles that I read. I would think those are, that's a lot of reading there, but you're always getting pointed to new stuff.

The quality of a journalism on aging is really increasing. You know, on some of these sites that I talked about. And I have patients coming in and teaching me stuff all the time, stuff that they've read that they point me to, and that's really fun, too.

Claudia von Boeselager: Yeah. Never stop learning, right?

Where can people learn more about what you're up to? How can they follow you, be it social media, website? Where's the best place to keep track of what you're doing?
Joseph Raffaele: Yeah, so the main place that I post pretty regular information is on Instagram at Raffaele MD, R A F F A E L E MD. We go through the hallmarks of aging. We go through latest supplements. We go through some controversies. And we're posting more and more there. My practice website, raffaelemedical.com, all one word, is where we talk about hormone optimization and, you know, what it means to become a patient here.

And then for doctors, or potentially patients, or consumers fairly soon, PhysioAge.com is the software company, web-based platform, to measure aging. Right now it's licensed to doctors, as I said, around the country and around the world, to help measure aging in their patients. But we are, I think, in the next six months, going to be offering a version of it for consumers upload their data.
There are biomarkers that you can get now from routine labs, so they can give you a biological age, and then you can add your other labs and get information about you know, what your lipid panel tells you. And I think that's going to be kind of exciting, too.

Claudia von Boeselager: That's very exciting. I'm glad to hear that because I've lived in 9 different countries in my life, so I have got blood results from different places and whatever, and I think that system is really missing where you can just feed it all in. And as with blood tests you want to see what developments are happening and not just the screenshot, right?

Joseph Raffaele: And tracking over time is the most important thing. And having a repository of things to show how you, in aggregate, are aging. We have up to 600 different markers that can be added in there right now, most of the very important ones, and then some analyses where you can see, we give you that report card and we give you that PhysioAge.

So hopefully a tool. And then if you want to get, you know, more extensive therapies and physicians, you'd have to go see one of our licensed people.

Claudia von Boeselager: Sounds like you've really felt through everything. Amazing.
Do you have any final ask, Joe, or recommendation, or any parting thoughts or message for my audience?

Joseph Raffaele: It's a very exciting time to be alive in medicine.

I think, I don't want to sound too grandiose, but I really think that right now we're at one of those, now the term inflection point is overused, I get it, but we are in biomedical sciences, just like it was promised in 2000, when we sequenced the genome, we thought everything was going to change, but we needed to learn a few more things.

But right now with this convergence of computing power, artificial intelligence, and our understanding of the aging process, I really think that we are going to be altering the landscape of medicine, disease, how we think about, you know, healthy aging. Like the internet revolution that took place, you know, in the late 90s, early 2000s. That was a seminal part of what changed the biomedical revolution, it's been responsible for it.

So I think that, you know, you should really start to get involved in this, go to some of those websites, don't accept aging as, you know, each year, being able to do a little bit less, feel a little bit less well. That doesn't happen, you know, I'm almost 62. I want to keep on functioning like a 40-year-old. My various PhysioAges are somewhere in that range, my hairline is a little bit less than that, but that is, that is the idea.

And the final word is that slowing aging is not a theoretical problem anymore, it's just a technological problem. Some of it's been solved, you know, maybe we're on the first iPhone right now, and we're going to get to some very sophisticated approaches. So save your money because you're gonna, you're gonna have a long life if you're under 40.

Claudia von Boeselager: At the cusp of it as well.
Thank you. This has been such a pleasure, Joe. Thank you so much for your time.
Joseph Raffaele: You're welcome, Claudia. Great to talk to you, and I love your podcast, the ones I've listened to, and look forward to hearing more of them.