Decoding Aging: The Science Of Cellular Rejuvenation With Dr. Vittorio Sebastiano

It was a career-defining (and perhaps life changing) moment when Dr. Vittorio Sebastiano, a reproductive biologist by training, realized that because we are able to create life, that same body of information could be harnessed to create youth – that is, radically reverse our biological aging process to a younger time point without losing cellular identity.

In 2014, he and his lab began unpacking this epiphany. They made the radical decision to conduct their investigations in human cells and tissue rather than in rodents, with the expectation that such a start would be a better bridge to human clinical trials.

Flash forward a decade and Dr. Sebastiano and his team stand poised to begin trials in humans. Dr. Sebastiano is, in my opinion, one of the most extraordinary scientists in the longevity space today who flies under the radar of most of us in functional medicine.

In this podcast – which is actually two-in-one because I continued the conversation with him on a second date – you’ll hear about the remarkable work they’re undertaking at his lab. For example: They’ve created a biological clock that encompasses the whole genome consisting of millions and millions of CpG sites. They are able to clearly demonstrate the reversal of bioage using their methodology – a cocktail of Yamanaka factors plus, with clear time limits – which changes the epigenome first, and in so doing influences all of the hallmarks of aging. Teaser: they’ve identified one intervention routinely used in clinical practice that influences their bio age clock in the same way that their cocktail does. What is it? I was riveted with this conversation, as I am sure you’ll be. Leave a review if you like it, and – Yes – let me know what you think. I know this will prompt deep questions for you, as it did for me. ~DrKF

Decoding Aging: The Science Of Cellular Rejuvenation With Dr. Vittorio Sebastiano

As the world becomes increasingly focused on the subject of aging and longevity, we are left grappling with questions of precisely what the aging process is, its causes, how it can be measured, and how to slow down or even reverse the process. Today, I am beyond excited to engage in not one, but two enlightening conversations with the visionary Dr. Vittorio Sebastiano, a trailblazer in the realm of epigenetic rejuvenation. Join us as we delve into his groundbreaking research, unraveling the mysteries of ERA technology—a powerful tool designed to reprogram human cells and promote epigenetic rejuvenation. Imagine the possibilities: resetting the aging program, unlocking age reversal, revolutionizing cancer treatment, and more. It’s a discussion that takes us into the future of medicine, where the tools being developed offer transformative potential. Prepare for an fascinating exploration of what lies on the horizon.

 

In this episode of New Frontiers, learn about:

Dr. Kara Fitzgerald (00:00:02) – Hi, everybody. Welcome to New Frontiers in Functional Medicine, where we are interviewing the best minds in functional medicine, and of course, today is no exception. I am thrilled to be bringing Dr. Vittorio Sebastiano to the world of functional medicine. Let me tell you a little bit about who he is, his background, we’re going to jump into what I hope to be quite a far-ranging conversation around some of the amazing, amazing science that he’s up to. Dr. Sebastiano is an associate professor in the Department of Obstetrics and Gynecology at Stanford School of Medicine. His lab has developed a new technology named ERA, that’s Epigenetic Reprogramming of Aging, which repurposes the conceptual idea of reprogramming with the goal to promote epigenetic rejuvenation of human adult cells, leaving their identity untouched. This new technology was patented and is being implemented by Turn Biotechnologies, which Dr. Sebastiano co-founded and where he serves as Head of Research and chair of the Scientific Advisory Board. He’s also a member of the Dior Beauty Reverse Aging Scientific Advisory Board. Dr. Sebastiano, welcome to New Frontiers.

Dr. Vittorio Sebastiano (00:01:20) – Thank you so much for having me. I’m flattered and I look forward to this conversation.

Dr. Kara Fitzgerald (00:01:26) – Well, you know, I have had the honor, or just the pleasure of finding your work and listening to you speak, and you’ve just got lots of really interesting, provocative stuff to not only say, but what you’re demonstrating in your lab. I want to just ask you, like, go back to the beginning and hear what you think aging is.

Dr. Vittorio Sebastiano (00:01:48) – Well, that’s a very difficult question. I mean, ageing is a lot of things that are happening, you know, with time. The scientists have been trying to tackle this problem for a very, very long time. But I think that really, right now we are at a kind of an inflection point where for a number of reasons, most importantly, the fact that the right technology is developing actually to answer these questions. We are at an inflection point where I think there’s going to be a really significant, massive revolution in the field of aging.

Dr. Vittorio Sebastiano (00:02:35) – So, historically, and I think this has been in part kind of the reason why we have been so “slow” in understanding what aging is, was the fact that scientists have been looking at this problem through a very narrow lens. So, if you think about how in the past we have been thinking about this problem, we have been thinking about, for example, focusing on telomere attrition, which is the erosion of the telomeres in the chromosomes. Some other people have been only focusing on senescent cells, mitochondrial dysfunction. So, they have been tackling this problem through a very, very narrow space. What I think is happening right now is really the integration of all of these, what are now called hallmarks of aging, together with the implementation of cutting-edge technology that is really, really helping us at a very fast pace to understand what aging means. And let me tell you what aging is to me, or how I look at this problem.

Dr. Kara Fitzgerald (00:03:46) – Yeah

Dr. Vittorio Sebastiano (00:03:47) – Well, obviously, as I said, it’s a very complex phenomenon that still we are far from understanding. But fundamentally, what I believe is happening as we grow older and as we get older is the fact that the epigenetic program of the cells changes with time, and it becomes dysfunctional with time. Maybe we should spend a couple of words in saying what the epigenetic program is so that everybody understands it. So, you can think about that, I always use the analogy of a language. In every language there is an alphabet, which is the letters that we use, right. The alphabet in the case of the cells is the sequence of bases that make up the DNA in the cells. Then these letters can be put together into words. Now in the analogy, the words are the genes, right, the genes that are turned on or turned off in some cells. And so how do you turn on and off these words, these genes? Well, that is thanks to the epigenetic program, which is in a way, you can think about that as the grammar, as the syntax of a language.

Dr. Vittorio Sebastiano (00:05:10) – So it’s a set of rules that puts together in a meaningful fashion these words so that now you have an understandable sentence, for example. Okay, so let’s get out of the analogy and let’s talk about the cell. So, the alphabet is the DNA. The words are the genes, and so, cells that are genetically identical, meaning that they have the same genetic code, for example, the cells in the brain or the cells in the liver, they are dramatically different in their function. Why? Thanks to the grammar. Thanks to the epigenetic code that turns on in the brain cells a specific set of genes and turns off a specific set of genes, and in the liver turns on a different set of genes and turns off a different set of genes. So altogether, basically, this brings to the complexity of cell behavior. Now what happens with time? It happens that this grammar, this set of rules, becomes dysfunctional over time.

Dr. Vittorio Sebastiano (00:06:16) – And so it can happen that in the liver, in the brain, in the muscle, in the skin, genes that are supposed to be on are now silenced, and genes that are supposed to be silenced become active. So, to me, I think that the fundamental linchpin, the fundamental explanation of why we are aging, is because this set of rules becomes faulty with time. The good news, though, is that this program can be reset so it can be brought back to a functional, youthful state. Because the epigenetic program is a malleable, is plastic, is reprogrammable. And that’s exactly what we are trying to do.

Dr. Kara Fitzgerald (00:06:58) – It’s extraordinary. It’s extraordinary work that you’re doing. I look at changing epigenetics using diet and lifestyle. And you’re perhaps doing something similar with the volume turned up and we’re going to dive into it. So folks, we’ll link to a hallmarks of aging paper, actually one of the most recent ones to come out where the hallmarks are now expanded, and we have a blog on it as well. So, of the hallmarks, you know, cellular senescence, mitochondrial changes, dysbiosis, and chronic inflammation, it’s expanded. The driver, in your opinion, are these epigenetic changes that happen?

Dr. Vittorio Sebastiano (00:07:44) – Yes, they are the driver, in my opinion. And most importantly, I think that for the sake of this discussion and for the sake of what we’re trying to do, I think that they are hierarchically dominant over the other hallmarks. What does it mean? It means that since the epigenetic program is the fundamental program that controls a variety of different functions in the cells, if we can reprogram that program, then as a virtue of that, as a consequence of that, we can really impact most, if not all of the hallmarks of aging. And this is not just theory. We have proved this multiple times across many different cell types. So, it is not science fiction. It is reality.

Dr. Kara Fitzgerald (00:08:31) – That’s awesome. And there’s a lot of publications coming out of Doctor Sebastiano’s Labs and we’ll link to those as well so you can do your own drill down into this really bold statement that he’s making. I guess I have a couple questions. One question is- And then of course we’re going to spend a lot of time getting into your technology. Of the various epigenetic marks, what are the ones that really stand up as being drivers of the aging phenomena. So that’s question one. And then you can fold it into question two: Are we looking at the aging process, the changes to epigenetic programming occurring in a predictable programmed manner, which enables us to actually measure biological age by looking at DNA methylation patterns really reliably? Or are we looking at epigenetic drift or damage just due to the wear and tear of life or both?

Dr. Vittorio Sebastiano (00:09:34) – Yeah, well, those are two excellent questions. So let me let me unfold them.

Dr. Vittorio Sebastiano (00:09:40) – The epigenetic program is a collection of different types of programs in the cells. For example, one of the canonical epigenetic features, or epigenetic characteristics of the cells, is what is called the methylation of the DNA. The DNA can be or cannot be methylated in specific regions. And as a function of that, basically the gene expression changes in different cells with time. But there is a number of other epigenetic features. For example, the way the DNA is three dimensionally organized in the nucleus. The DNA is also wrapped around some proteins that are called histones that can be modified themselves and depending on the type of modifications, again, genes can be turned on or off. These histones can also slide on the chromatin, and depending on their position, again, they can impact gene expression. And there is a number of other things that I’m not mentioning right now. But collectively all these features are referred to as epigenetic program.

Dr. Vittorio Sebastiano (00:10:58) – That’s where basically, we are still far from understanding how these different pieces of the puzzle kind of altogether come into place to explain why we age. And I can tell you that right now we are at the dawn of this very exciting field. We are, for example, understanding very well how the methylation of the DNA is changing over time. And a brilliant example of this is the fact that there is a number of people and labs and companies that are developing the so-called epigenetic clocks. So those are ways to quantitatively measure how and where these methylation changes happen with time, both as a predictive tool to measure basically the chronological age. Well, chronological age is not so interesting because, you know, we all know, we are aware of our chronological age, but the biological age is what really matters.

Dr. Vittorio Sebastiano (00:12:12) – How far are we from our expected chronological age? Are we younger because we have a very good lifestyle, a very good diet, we exercise on a regular basis, we sleep well, and so on and so forth? Or are we older than our chronological age because again, our lifestyle, sun exposure, stress, and so on and so forth is actually accelerating our biological clock of aging. So those are wonderful tools that are being utilized as predictors of aging. But also, they’re starting to also be used as ways to really measure how a specific intervention, dietary supplementation, metformin, rapamycin, whatever it is, how that treatment impacts my biological age. So that’s kind of to answer your first question. There is a lot of things to look at. We are starting to understand it, and we have a very, very good understanding right now of the methylation profile. To come to the second question that I forgot, now…

Dr. Kara Fitzgerald (00:13:08) – So, some of these changes that are happening on the methylome, for example, are pretty predictable, but yet we think that aging is also random.

Dr. Vittorio Sebastiano (00:13:23) – Yeah, I personally think that it’s a combination of both. So the deterministic aspect that can really be predicted and can be forecasted in a way. And then on top of that, there is also a random accumulation of epigenetic errors that are driven by external factors, environmental factors. That could be again, inflammation, some of those could be genetic, some of those could be dietary, and so on and so forth. And that’s what makes it exciting but complex also because it’s kind of the integration of two very complex phenomena. One is developmental, so it is already preset in a way in our cells, which can be accelerated or delayed by the environmental factors that are kind of additive.

Dr. Kara Fitzgerald (00:14:15) – I think that our research looking at diet and lifestyle interventions, and we have shown some favorable influence on the methylome, is probably more in the camp of influencing those environmental exposures. Whereas the work that you’re doing is that you’re diving into the heart of what would be the program. And maybe you’re changing both, you know, the environmental- Well, you are. The influence of those environmental exposures, you know, plus this programmed aging phenomena. And in so doing, you’re really able to turn back the clock. And we’ll dive into that, and I want to. But before we do, I’m curious just given your background how you ended up here as a scientist. You’re teaching at Stanford in obstetrics and gynecology and I imagine this has something to do with the wildly exciting epigenetic time in embryogenesis. But yeah. How did you get here?

Dr. Vittorio Sebastiano (00:15:19) – Yeah. I think that I got here, I have to say, thanks to the training that I had in a field that seems to be completely disconnected from what I’m doing right now, but which it is not in reality. So, my training has always been in development and in reproductive biology.

Dr. Vittorio Sebastiano (00:15:44) – I have always been fascinated by how, for example, sperm and an egg come together and they make, you know, in this magic process, a new form, a new life. Of course, when I was younger, I was looking at that really from a hardcore developmental biology standpoint. So, I was really fascinated about how is it possible that these two specialized cells that come together all of a sudden and they become something completely different and they have all the information to basically develop an entire new body with trillions of cells that are coming from one single cell. That for me has always been really mind boggling and I’ve always been excited and fascinated by that. And so, I’ve been studying how sperm and eggs form, how human development unfolds, and so on.

Dr. Vittorio Sebastiano (00:16:58) – But then, at the end of 2014, I had this kind of epiphany all of a sudden, and I became interested in the aging field. And I said, “Wait a minute. Nature has already figured out how not to age. Why?” Well, it’s a very simple thing that was really in front of my eyes and I didn’t see it before. And I started thinking about the fact that aging doesn’t get vertically transmitted across generations. Right? I mean, as babies, we’re not inheriting the age of our parents. Right?

Dr. Kara Fitzgerald (00:17:24) – No. Right.

Dr. Vittorio Sebastiano (00:17:25) – At every generation, babies are born at age zero, and then they age over time. But then, their children are going to be, again, age zero.

Dr. Kara Fitzgerald (00:17:36) – Right, right.

Dr. Vittorio Sebastiano (00:17:37) – And if you think about that, you know, that’s not true only, within every single species, right? If you think about that in a more philosophical and holistic way, life hasn’t aged on our planet from the very first form of life that formed 3.6 plus billion years ago, all the way up to us.

Dr. Vittorio Sebastiano (00:18:03) – And so that means that nature has already figured out a way to prevent aging, broadly speaking, from happening in life. The question, though, is that it’s doing it through a form, which is reproduction, which is again, going back to where I come from, which is, you know, how egg and sperms come together and then they form a new life and so on and so forth. And so, to make a long story short, I really realized that nature has already figured it out, obviously from an evolutionary standpoint. What we need to do now is to understand those processes and apply them to cells that are not embryonic, that are not germ cells, but are the cells that make up our own bodies that are programmed to die, of course, to age and to die. But we can basically hijack those principles that prevent aging from being vertically transmitted and utilize those principles and apply them to the other cells of the body that do age and do become dysfunctional.

Dr. Kara Fitzgerald (00:19:16) – We know from Waddington, of course, like this is the ultimate epigenetic puzzler. So you must have been really positioned with your background in reproductive biology to be just- Of course, you’re going to be leaning into epigenetics as the answer to the aging phenomena, because that’s what’s happening, cell differentiation- I mean, first of all, we’re scrubbing clean the information from mom and dad via epigenetics and then laying down new epigenetic programming.

Dr. Vittorio Sebastiano (00:19:50) – Exactly. You’re actually absolutely nailing it. This wiping out of this epigenetic information happens at a massive scale in the embryos in the first 2 or 3 days of development and it also happens in germ cells as we as we grow older. And that rewiring of the information is required to cancel or to erase the information that is coming from the previous generation and to set up a new information in the new generation. So, it’s happening massively across the entire genome.

Dr. Vittorio Sebastiano (00:20:41) –  Now, the question is, now that we understand how aging happens, epigenetically in our genome, we can utilize that information that we are learning from embryos and from germ cells and we can just apply it to those parts of the genome that are changing and that are becoming older and epigenetically dysfunctional with time. So, it’s basically a matter of taking an incredibly functioning and performing machinery and just focusing it and repurposing it to very specific parts of the genome that are the parts of the genome that age and become dysfunctional with time.

Dr. Kara Fitzgerald (00:21:08) – Let me ask you, I just have to pick your brain. You know, I don’t have a reproductive biologist on my podcast that often. Just going back to embryogenesis and scrubbing it clean, I just have two questions. Three questions. One is, are we looking at methylation and demethylation as sitting in the driver’s seat of these? I’m curious just based on my own reading it seems to be. And according to HOR (higher-order repeat units), we don’t lose everything. There’s some information retained and this would be the heritable aspect of the epigenome. Right? We can and we’ve seen this in, like say, the Dutch Hunger Winter or the Överkalix cohort where there’s generations of information that have been transmitted epigenetically.

Dr. Vittorio Sebastiano (00:22:05) Yeah.

Dr. Kara Fitzgerald (00:21:06) – Okay. Yeah. I’m curious your thoughts there.

Dr. Vittorio Sebastiano (00:22:08) – There is definitely a component that is also epigenetically heritable. Absolutely.  But again, the good thing is that the epigenetic information, even though some of it could be heritable, can still be reprogrammed and be reset in the new generation and in the new cells. And that’s because the epigenetic program also is very responsive and it changes very dynamically in response to the environment. It was actually built for that reason. So the lower organisms don’t have an epigenetic program and that’s why they have a lot of capabilities in replicating, for example. But every time there is an environmental change, you know, they cannot respond very effectively to those changes. And then you may have some species that just vanish because of that, you know, starvation or UV exposure and so on.

Dr. Vittorio Sebastiano (00:23:09) – The epigenetic program was built evolutionary in our cells to be very, very capable of dynamically responding to those environmental changes that can happen very frequently in nature. And so, by virtue of that, they are very dynamic, but they can also be reprogrammed, you know, very, very efficiently if we know how to do it. And that’s exactly what we’re trying to do here.

Dr. Kara Fitzgerald (00:23:33) – Do you think that of the epigenetic marks that we’ve been discussing, I mean they all are hugely important, but again, methylation and demethylation are pretty front and center during that time.

Dr. Vittorio Sebastiano (00:23:48) – Yeah. For two reasons. Well first of all is because methylation is the epigenetic information for which we have the better understanding. And so of course we can also understand much better the consequences of changing that profile. As the technology grows and as we develop new technology that can actually give us information about the other epigenetic features, of course, those are going to be integrated in the future.

Dr. Vittorio Sebastiano (00:24:19) – And those could also be opportunities actually to develop even new technology that are actually tackling other types of still epigenetic reprogramming technologies, but of course, that they tackle different angle.

Dr. Kara Fitzgerald (00:24:34) – A different angle. It’s ridiculously interesting. Well, I can imagine in 2014 your head was on fire with that epiphany that you could begin to, like, tease away.

Dr. Vittorio Sebastiano (00:24:44) – It was absolutely on fire. At the same time, you know, every time, unfortunately, that you have something that has an enormous potential and, you know, nobody had really thought about before, it also comes with a lot of challenges. Unfortunately, because there’s, you know, at the beginning, you’re kind of looked at as kind of a weirdo who’s coming with this, you know… But few years after I can say that, you know, the idea and the hypothesis was correct. And I’m pleased to see that it’s actually exploding.

Dr. Kara Fitzgerald (00:25:19) – It is exploding. So were you at Stanford at that time?  Yeah? And so, you were able to actually begin to tease apart aging as an epigenetic phenomenon back in 2014? That, I guess, would have been the beginning of the development of ERA. What you’re now calling ERA is that correct?

Dr. Vittorio Sebastiano (00:25:43) – That is correct.

Dr. Kara Fitzgerald (00:25:45) – So can you talk about what ERA is now? Of course, I know you’ll talk about this in a minute, but you’re using some kind of Yamanaka variation. When did Yamanaka (Shinya Yamanaka, PhD)- Where does Yamanaka fall in the timeline?  When were those [Yamanaka factors] characterized and when did we realize we could reverse- But I’m curious about- I mean, just talk about what you did. I guess I’ll just leave it open.

Dr. Vittorio Sebastiano (00:26:20) – So, yeah. So Yamanaka published his seminal work in 2006 in mouse, and then the year after in 2007 in human cells. And basically, to simplify what he did, what he showed was that it is possible to take any cell of the body, for example, a skin cell and by expressing in this cell a set of factors, a set of proteins, you can basically change that skin cell and make it become an embryonic-like cell. So this was a remarkable finding that, of course, received the Nobel Prize in 2012. And why is it so important? It’s very important because now you can really create, from any cell of the body, you can create this group of cells that are embryonic-like. Instead of using embryos to make them you’re using somatic cells, so the cells of the body to make them. And now these cells can be grown indefinitely. But most importantly, they can now be redifferentiated into any cell of the body. So, you start from a skin cell, you end up with an embryonic-like cell. These cells are called IPS. And now these cells can become the skin cell you started with, but also any other cell of the body: brain cell, liver cell, skin cell, muscle cells and so on and so forth.

Dr. Vittorio Sebastiano (00:27:58) – So why is it so important? Because now you can create virtually any organ ex novo. And these organs now are genetically matched with me because I utilized my skin cell to, you know, to derive the IPS. And so, Yamanaka utilized the cocktail of factors. He didn’t discover the factors themselves, but he boiled down, basically, this process to a subset of four factors: Oct4, Sox2, Klf4, and c-Myc. So, these are the canonical Yamanaka factors that again can make this transition happening. What he did not realize right away was the fact that by making the IPS, these embryonic-like cells, yes, now they can be used to generate any organ in the body, as we just said, but they are also youthful. By all means, they are almost age zero.

Dr. Vittorio Sebastiano (00:29:07) – So by doing this process of reprogramming, he was changing basically the identity of the cells. So again, turning a skin cell into an embryonic-like cell. But he was also making an aged cell into a very, very youthful cell because embryonic cells are youthful by all means. So in 2014, again, thanks to the fact that I was working with iPSCs (induced pluripotent stem cells) among other things, the hypothesis and the question that we had was, well, maybe these two processes that are happening simultaneously, maybe they can be decoupled so we could achieve rejuvenation without changing the identity of the cells. So, what does this mean? It means that maybe I can, simply by tuning and tweaking that process of reprogramming, and we do this through dosage, duration and so on, we can start with the skin cell and end up with a skin cell again. So not an embryonic, but a skin cell. But a younger version of the skin cell. So that was exactly the question that we had. Is it possible to tweak and tune the reprogramming process so that we change the age, but we don’t change the identity of the cells? And now, almost ten years after we can say yes, absolutely.

Dr. Vittorio Sebastiano (00:30:29) – It is possible. We can rejuvenate the cells. We still have the same cell type, but it’s a younger. We have a younger version of that cell type.

Dr. Kara Fitzgerald (00:30:39) – I want to just, you know, exclamation point and just underline the extraordinary achievement of your epiphany and your work and diligence. And this is very, very, very exciting. So, Yamanaka took the somatic cells, everybody, and brought them all the way back to inducible pluripotent stem cells that are completely dedifferentiated. And I know when they were experimenting with sort of creating, you know, growing from these stem cells, that cancer occurred. There was some pretty negative fallout from taking them all the way back there and then attempting to create an organ or- I mean, you know better than I do, but I am aware that the fallout was tumorigenesis and some pretty crazy stuff. And so it certainly makes sense that you would be thinking, you know, could we actually do this, you know, less extreme.

Dr. Kara Fitzgerald (00:31:41) – And I also think you guys were the first to demonstrate this in human cells. Right. And are you still? I mean, you were the first, but has it been done elsewhere?

Dr. Vittorio Sebastiano (00:31:55) – Yes. We were the first to show that it works in human cells. There was a paper before us that actually showed it in mice, and he showed it in a genetic model of accelerated aging in mice. But yes, absolutely, we were the first ones to show it in human cells. And I have to say that we are still probably among the few. There are really very few people that are working with human cells. Most of the work is being conducted in mice and in other animal models. But honestly, I’m a big believer, although I often make my life miserable because, of course, working with human cells is much more complicated for a number of reasons.

Dr. Vittorio Sebastiano (00:32:45) – But I actually want to make sure that what I see is potentially or directly implementable in the clinic. What does this mean? It means that I have seen way too many studies and instances where something phenomenal that was working in animal models then doesn’t translate in human. And I’m not saying that those studies shouldn’t be done. Those studies are absolutely fundamental to understand the biology, the complex biology. But there’s plenty of examples of things that work greatly in animal models and then they don’t work in the human context. I want to accelerate this process and I really want to make sure that whatever I’m doing really has an impact for the life of people. And I think really that the only way in particular- Because now the technology allows for that, because we have learned how to culture the human cells, we have learned how to make organoids from human cells. So there is a lot of human models that, of course, are not perfect, but they are much better, for example, than many other animal models.

Dr. Vittorio Sebastiano (00:34:05) – And so what I’m trying to say here is that we decided to take the long path, but we decided really to develop something that could really be concrete and tangible for clinical translation. Because at the end of the day, what I really care about is really making this affordable, accessible, and, you know, for everybody. I want this to be a democratized form of medicine that can really impact the life of people, which is what I care about. And so, yes, it’s difficult, it’s challenging, but I think it’s the only way to do it, in my opinion.

Dr. Kara Fitzgerald (00:34:43) – Well, just bravo. Just extraordinary for sticking to it until you were able to demonstrate it. And you took, I think, skin cells of somebody in their fifties, I believe, and reversed them to an equivalent of twenties. Was that what you did? Yeah. Talk about what you did. And I just want to circle back for my listeners to say that this was when you demonstrated epigenetics were, in fact, influencing all of the hallmarks. Right? This would have been teasing that out. Okay.

Dr. Vittorio Sebastiano (00:35:16) – Yeah, I know. So, we worked with a variety- We published our work in 2020 and then we have now dramatically expanded our studies. We always try, when possible, to work with older cells. In the paper that we published we have worked with skin cells, we worked with other cell types, chondrocytes, which are the cells of the cartilage, the muscle cells, and we have always tried to work with cells that are at least over 65 or coming from people that at least over 65. In some cases, even 80 or 90 years old.

Dr. Kara Fitzgerald (00:35:56) – Wow. Okay.

Dr. Vittorio Sebastiano (00:35:58) – And again, since then we have worked with a variety of other cell types: eye cells, muscle cells, skin cells, mesenchymal stem cells-

Dr. Kara Fitzgerald (00:36:07) – All in humans.

Dr. Vittorio Sebastiano (00:36:08) – All humans, all humans. Yeah. And again, as much as we can, we try to work with older cells because again, the aging process that happens when you are forty or fifty is very different from the aging process that you experience when you are seventy, eighty or ninety, as I think most of the people are very aware of.

Dr. Vittorio Sebastiano (00:36:34) – And so yeah, we have been working with very old cells and we always try to work holistically, again to go back to one of the earlier questions, we always try to look holistically at every single hallmark of aging. So, every time we do our intervention we try to see in as many ways as possible to prove that the cells are still the same cells you started with, but youthful and more functional. Because again, cells age and they age across most of the hallmarks of aging. Of course, you know, they are very different in this process depending on the cell type you are dealing with but they don’t age only for one single hallmark. They age across many different hallmarks. And we always consistently see that when we do our approach, so when we bring in our ERA factors, the cells are youthful now, not just because of one hallmark, but because of every single hallmark that has changed in that specific cell type with time, with age. Which is again, speaking about the remarkable power and potential of this technology, and also about the fact that the epigenetic program, again, can be a fundamental kind of tune that we can use and utilize to rejuvenate the cells comprehensively and holistically.

Dr. Kara Fitzgerald (00:38:07) – Really interesting. That’s just so exciting to me. I mean, it’s just beyond- I was listening to you recently talk about addressing cancer by reversing the biological age of T cells and then they can get busy in eliminating the cancer process. I mean, the implications of your work are crazy. You’re starting with skin and anybody who’s getting older is excited about that. You think about that sort of from a surface level, but you’re doing all of this. You’re looking at this in many different cell types and the implications of all of them are just kind of breathtaking.

Dr. Vittorio Sebastiano (00:38:59) – Yeah, because I think that ERA is agnostic when it comes to cell types and tissue types. So, in principle it can be applied to any cell type or any tissue type or any organ type in the body.

Dr. Vittorio Sebastiano (00:39:13) – Obviously the challenge is to identify that window of intervention that is crucial for retention of cell identity, but for rejuvenation. And in the case of what you were mentioning, like in that specific instance we are dealing with immunotherapy, which is a technology that is being implemented by many companies. Basically, immunotherapy is a way to take your own blood cells, the T cells, engineer them so that they can now recognize the tumor and kill it selectively. And this is a function of age for sure, but it’s not necessarily a function of chronological age. What happens is that during this process of isolation, expansion, engineering and manufacturing of the cells, the cells become aged, they become exhausted. That’s the term that is used in the in the field. So, they become fatigued, and once you reinfuse them back into the body, they are not as powerful and as fit and as functional as they should be in killing the cancer.

Dr. Vittorio Sebastiano (00:40:31) – So they have an enormous potential of doing it. But again, they are in a way exhausted in doing so. So this is a perfect example of where ERA can kind of orthogonally intersect. Since ERA “impacts” the aging phenomenon of cells and can bring back the age of an old dysfunctional cell back to a youthful one, it’s a perfect example of how ERA can really be nicely applied. And so, now you can make these exhausted cells youthful and functional again. Now you have two things that are coming together: their ability to recognize and kill the cancer cell, and also their ability to not be exhausted and aged so they can just go and kill the cancer more effectively. And that’s exactly what we’re working on as well, as a way to really bring this amazing technology to fruition. Not just to the fruition of very few people that use it as a last resort, but as a first line opportunity that could really wipe out and could really impact, you know-

Dr. Kara Fitzgerald (00:41:51) – Quality of life.

Dr. Vittorio Sebastiano (00:41:52) – Cancer biology, broadly speaking.

Dr. Kara Fitzgerald (00:41:55) – Yeah yeah. We could look at potentially prevention before the need for this kind of immunotherapy when the cancer is present, and you’ve talked about that. And I would like to talk about prevention, but before we get there, just understanding a little bit now that we’ve talked about Yamanaka factors and some of the challenges. And ERA is a different take on that. If you could distinguish them, I would like that. You know, it’s not like we’re going to all go out and take an ERA cocktail today. I mean, there’s some challenges there. Cells respond differently and the dosage and the duration, and- There’s massive variables, and so talk about that as well: what ERA is and what some of the challenges to translating this to real time medicine are.

Dr. Vittorio Sebastiano (00:42:50) – Yeah. So yeah, the biology of ERA is really this idea of reprogramming the epigenetic profile. How do we do it? Basically, what we do is to bring inside an aged cell a cocktail of mRNAs that then can encode for a specific protein. These proteins now go into the nucleus of the cell, they reset the epigenetic landscape, and they bring it back to this youthful and functional state. This is the biology of the of the process. The real challenge is how do you bring this cocktail into the cells. And you can think about these in two ways.

Dr. Kara Fitzgerald (00:43:33) – Yeah.

Dr. Vittorio Sebastiano (00:43:34) – The first way is, I first isolate the cells from my body. Right? I treat the cells in a petri dish, so in the laboratory, and then reinfuse the cells back into the body. This would be the idea behind the immunotherapy that we just discussed. But our vision is to be able to rejuvenate the cells inside the body without prospectively isolating the cells and culturing in them outside of the body. But this comes- The potential here is enormous, because, again, we can go into the liver and make it younger.

Dr. Vittorio Sebastiano (00:44:09) – We can go into the brain, hopefully one day, and make it younger, and the same is true for every organ, every tissue in the body. But the challenge is how do I make sure that I specifically target some cells in that organ or in that tissue. And that’s exactly why Turn is not only working on ERA, the biology of this process, but is also working on developing new ways to specifically target and deliver this cocktail of mRNAs inside the cells. To make sure that we are targeting only one specific cell type, or maybe more than one, but in a very, very efficient, and specific way. And this is a very challenging question-

Dr. Kara Fitzgerald: (00:44:54) – Really challenging.

Dr. Vittorio Sebastiano (00:44:55) – Again, the technology is now developing, so I think there’s going to be a lot of remarkable findings in the near future because there is a lot of people that are working on this.

Dr. Vittorio Sebastiano (00:45:14) – The delivery is really the challenge here and we are working actually on making that precise and specific. We are developing our own lipids that can encapsulate and protect the mRNAs until they are outside of the cells and then being efficient in delivering the cargo, which is again is the mRNAs inside the cells.

Dr. Kara Fitzgerald (00:45:33) – Into the correct organ.

Dr. Vittorio Sebastiano (00:45:35) – Exactly. Yeah. And from a safety standpoint- You were alluding about there are always obviously some safety risks associated with this. Yes, absolutely, there are. And the risks come from the fact that if you don’t know how to control in time and in dosage the expression of these factors, some of these factors may become “carcinogenic”. But really the key here and that-

Dr. Kara Fitzgerald (00:46:00) – Would that be because of too much dedifferentiation? They would just go too far back.

Dr. Vittorio Sebastiano (00:46:06) – Exactly. You would go too far back. And that’s where the delivery technology, together with the understanding of the biology of the cells, kind of come together nicely. Because if you know how to deliver the cargo in a specific cell type, you already know the biology of that specific cell type, and you know that cocktail, in that amount for that number of days, is sufficient to rejuvenate but not lead to cancer, that’s basically where the solution is. And that’s why we’re working hard on that problem to, on the one hand, target specific cell types in the body, but also at the same time, understanding very nicely and deeply the biology of those cells so that we can make sure that there is no loss of cell identity happening in this process.

Dr. Kara Fitzgerald (00:46:58) – You know, Sergei Young is a is a friend and colleague of mine who talks about the Longevity Bridge. And he’s a proponent for all the things you mentioned: eating right, getting enough sleep, exercising, you know, all of the things we can do today as we walk this longevity bridge and we get to what you’re proposing. Because there’s some time involved before anybody- You know, it’s exciting to listen to David Sinclair and to see what he’s doing over at Harvard with his various animal models playing around with aging, and I think I may have heard him actually say one time that he might take a Yamanaka cocktail, but it just doesn’t, you know, make any sense.

Dr. Kara Fitzgerald (00:47:46) – Yeah. There are some really clear hurdles and yet the potential is extraordinary. So, epigenetic rejuvenation or biological age reversal is going to perhaps look different than, say, Aubrey de Grey, who thinks the first person who’s going to live to 1000 is- You know, that we’re going to just take this cocktail and become 30 years younger. Like, that sounds, listening to you, you know, like it’s science fiction. Or is it not? This is the first step, what you’re talking about. Yeah.

Dr. Vittorio Sebastiano (00:48:19) – No, I don’t think it’s science fiction, honestly. Of course, I think we need to also be a little bit down to earth and not be, you know, too bombastic about our, you know- What do I mean by this? First of all, I think that ERA, not alone, but together with many other types of interventions are actually going to get us there one day. I don’t know exactly when but are going to definitely get us to a point where we are really going to be able to live, yes, longer lives, but most importantly, healthier lives. Okay. This is what I think is really the point of what we’re trying to do. We’re not impacting lifespan for the sake of living longer. We are impacting healthspan for the sake of living longer, healthier lives. Okay, so this is what I think, at least for me, is important. I don’t find it so useful to live until 150 years of age if my last 50 are going to be miserable because I am frail, because I have all sorts of issues, right? That’s not the point. The point is-

Dr. Kara Fitzgerald (00:49:37) – I mean, and that’s really what we’re seeing. Now we’re not going to 150, but we’re spending upwards of our final twenty years, many of us, with significant disease, significant quality of life issues, you know, across the globe.

Dr. Vittorio Sebastiano (00:49:56) – Yeah. So yeah, the whole point, task, and goal that we have is really, for now, trying to impact the healthspan of our current lifespan. Making sure that if I am at risk of developing heart disease, just as a function of age, of the function that I become older and maybe I had a horrible lifestyle, maybe I can fix that or I can prevent that from happening. And of course, I’m going to impact the lifespan, for sure, because if I’m not dying of a heart attack, of course I have a longer expectancy of life. But really, what matters here is to make sure that the quality of life is impacted, and so, I don’t develop frailty, I’m not at risk of pulmonary disease, dementia and so on and so forth.

Dr. Vittorio Sebastiano (00:50:55) How are we going to do it? I think that it’s going to be in many different ways. ERA is definitely one of the ways. And so again, to go back to your question, I don’t think that it is science fiction in the sense that it’s not going to happen. I think it’s going to happen at some point that maybe we’re going to have a dietary supplementation of some sort that is going to really “reboost”, kind of systematically and systemically all our cells in the body. I don’t think it’s going to be the Yamanaka cocktail. Honestly, I don’t think that’s going to happen. But I think that, you know, again, ERA, together with many senolytics and many other interventions are going to get us to a point where we’re going to live significantly longer and significantly healthier lives.

Dr. Kara Fitzgerald (00:51:49) – Isn’t ERA kind of a next generation Yamanaka- I mean, you invoke- You’re leaning on the Yamanaka factors in what you’re doing.

Dr. Vittorio Sebastiano (00:51:59) – Well, right now we are using the canonical Yamanaka factors plus two other factors that, together with the other four, elicits the highest degree of rejuvenation in the shortest amount of time. Again, to go back to the safety issue, if I can make sure that I can treat the cells for just a very small number of times and days, but by using an expanded cocktail, I can actually get a higher degree of rejuvenation with a minimum number of doses. That impacts the efficacy, of course, but it also impacts safety dramatically.

Dr. Kara Fitzgerald (00:52:34) – Are some of those other factors helping to just shut it down? Are they-

Dr. Vittorio Sebastiano (00:52:38) – All the factors are shut down because again, we are bringing in the mRNAs. So, the mRNAs have a half-life, so they hang around in the cells just for 16-20 hours. Not more than that.

Dr. Vittorio Sebastiano (00:52:49) – You can prolong the expression of these genes if you keep giving these factors to the cells. But if you give them just one time, they are expressed for 16-20 hours and then they’re gone. But that time is sufficient for the proteins that they are encoding for to go into the nucleus and reset the epigenetic landscape. Okay. The cocktail that we are using right now gives us that opportunity to really get a remarkable rejuvenation in a very short time. That doesn’t mean that the same cocktail could and should be used for every cell type. You know, we can optimize that cocktail in a cell specific manner. But in addition to that, we’re also discovering other factors, that in response to these factors, are being turned on or off. And this is going to give us a lot of leverage about, you know, maybe we can implement, we can optimize this cocktail with other factors, or we could replace some of the current factors in the cocktail with some other factors that maybe are just even more potent in doing so. So there is a lot of discovery also that is happening that is super exciting.

Dr. Kara Fitzgerald (00:54:01) – So exciting. It’s really interesting. I would just want to say, you know, circling back to my community where we’re thinking about nutrition and things like that, if you’re going to rejuvenate someone, you need the ingredients to be able to do the rebuilding. So, our world is not going to go away anytime soon, but it would be really fun to sort of partner in helping, you know, something older, you know, have the ingredients to actually enact the information that your work is providing. It’s kind of a cool idea for me, in my world. You’re at clinical trials, right?

Dr. Vittorio Sebastiano (00:54:42) – Not yet.

Dr. Kara Fitzgerald (00:54:44) – Are you near?

Dr. Vittorio Sebastiano (00:54:45) – We are near. Yes. In the next few days we are going to actually have our first conversation with the FDA.

Dr. Kara Fitzgerald (00:54:55) – Wow.

Dr. Vittorio Sebastiano (00:54:56) – So you know, this is new territory for the FDA, so I think there’s going to be a lot of very crucial information exchanged that is going to help them understand what this technology is all about, but also help us understand how, from a safety standpoint and from an efficacy standpoint, we should start thinking about the clinical trials. We’re very excited about that because I think this is going to be, you know, a very, very interesting and very important conversation with the regulatory agency. And so again, depending also other things, for example funding, of course we’re not in a in a super friendly market environment at the moment. But yeah.

Dr. Kara Fitzgerald (00:55:42) – It’s got to be wildly expensive.

Dr. Vittorio Sebastiano (00:55:44) – Yes, but we are very optimistic and I think that if everything goes smooth, we could really get to a Phase 1 clinical trial, which is a safety phase, maybe by early 2025.

Dr. Kara Fitzgerald (00:56:01) – Wow. It’s just super exciting. All right. So let me just circle back to the work that you did in human skin cells and the fact that you’re with Dior. Are you thinking about topical delivery? I’ve heard you talk about microneedling once upon a time. Is that something that may move closer to use in humans? I mean, speak about that.

Dr. Vittorio Sebastiano (00:56:25) – Yeah, I think so, definitely. I mean, again, we have to also deal with the fact that there is some other technology that needs to be developed in the meanwhile that is going to complement what we are doing. But speaking about the skin, right now the way we’re thinking about this would be to deliver into the skin, for kind, of medical associated cosmetic issues to begin with. But maybe one day just, you know, cosmetically to really bring these factors inside the skin, for example through microneedling, because that’s the technology that has been developed. It has a lot of history. There is a lot of knowledge about it. So that’s the technology that we have available right now for the delivery, or for the route of administration, I should say.

Dr. Vittorio Sebastiano (00:57:16) – But yes, absolutely. We are also working on topical formulations that would not require any microneedling. It would just be a cream of some sort that could be topically applied, for example, in wound healing, for example, you know.

Dr. Kara Fitzgerald (00:57:32) – Or burns.

Dr. Vittorio Sebastiano (00:57:34) – Yeah. Burns. Exactly. Those are all phenomena or indications that are severely impacted by aging. The healing capacity of aged skin is dramatically, dramatically impaired. So, if we could accelerate the process, if we could make sure that the healing happens much faster, and that also by doing so that the thickness of the skin becomes, you know, thicker. And so, the skin becomes more resistant to pathogens, it becomes more resistant to wear and tear. That has a lot of repercussions also on the future. Right? Because at that point the skin becomes more resistant to a variety of things, like inflammation, it becomes more resistant to pathogens.

Dr. Vittorio Sebastiano (00:58:16) – So that means that there is no inflammation happening and that means that there’s no accelerated aging. So, the consequences of this could really be endless.

Dr. Kara Fitzgerald (00:58:27) – Where are you at in that journey? Has that moved into any clinical trials?

Dr. Vittorio Sebastiano (00:58:34) – Not yet. But again, we are actively working on preclinical studies right now, and we are developing- To go back to the challenge of the delivery technology, where we are developing topical formulations that are going to be actually used for the delivery of mRNA into the skin. Again, it sounds simple. It’s not simple at all because the skin is one of the most complicated tissues in the body and it comes with a lot of challenges from a chemistry standpoint. But we’re trying to solve those challenges. And again, these can have a repercussion on a variety of different things because you can even think about delivering other types of genes in the skin to make it again, more functional.

Dr. Vittorio Sebastiano (00:59:17) – And you could even at some point start thinking about genetic correction of some skin diseases, for example.

Dr. Kara Fitzgerald 00:59:23) – Interesting. You have talked about ovarian rejuvenation as well. And this is an area, I think, of particular interest for you. Speak about that and where you see ERA.

Dr. Vittorio Sebastiano (00:59:37) – Yeah. So ovarian regeneration and rejuvenation is actually one of the things that really is at my heart because I think, personally, I want to really impact women’s longevity and women’s healthspan. And again, we have to think about the problem of aging in its complexity. To go back to what I said before, ERA is going to be definitely one of the solutions, but it’s not going to be the only solution. One of the things that my lab is working on is to really show that we could regenerate and rejuvenate the ovarian tissue through ERA, yes. By going in with the same cocktail of factors and bringing back the ovarian tissue in time to the point where it’s youthful and functional, but also through generating new ovarian tissues, ex novo, for example, from IPS cells.

Dr. Vittorio Sebastiano (01:00:35) – Why is this important? For a very simple reason. The age of entrance in menopause is inversely correlated with the life expectancy and healthspan. What does it mean? It means that the earlier a woman enters in menopause, the more likely it’s going to be that the lifespan is going to be shorter and the healthspan is going to be impacted from a cognitive standpoint and from a health standpoint.

Dr. Kara Fitzgerald (01:01:07) – I mean, just going back to the original conversation about, I’m sorry I interrupted you, but say that this programmed aging phenomena, like menopause seems like the classic evidence that this change will push us towards death in a very predictable way.

Dr. Vittorio Sebastiano (01:01:28) – Exactly, and it’s an accelerated aging phenomenon that happens postmenopause. But in addition to this, I think there is quite a significant number of women that enter menopause, not when they are in their late forties, but they enter menopause when they are in their early forties, or maybe in their thirties or in their twenties-

Dr. Kara Fitzgerald (01:01:48) – Yes, yes.

Dr. Vittorio Sebastiano (01:01:49) – because of premature ovarian failure or premature ovarian insufficiency. So now we have a number of women that are very young that experience accelerated aging because of loss of functionality of the ovarian tissue. So, we can make an impact. We could potentially make an impact. And if we could extend the functionality of the ovarian tissue for much longer, we could actually give them an opportunity actually to at least age in a physiological manner, right, and not to accelerate their process of aging. But again, broadly speaking, you can apply this potentially to any woman and you could really make a significant impact on the healthspan.

Dr. Kara Fitzgerald (01:02:36) – Yeah, extraordinary. I mean, that’s a key leverage point in women, because what the ovaries do is so impactful globally. I mean, the central nervous system, brain health, heart health, bone density, muscle… I mean and on and on. It’s extraordinary. So, starting there could be a really appropriate entry point into bringing ERA. Wow. And having just really a global rejuvenating effect by only needing to address a single organ.

Dr. Vittorio Sebastiano (01:03:12) – Yeah. And that’s actually interesting, what you are saying, because at least in the short term, I don’t think that we necessarily need to think about having the long-life elixir, you know, that we are going to drink to become younger. Maybe just by working on a number of subsets of tissues we can have this systemic global effect. By just by doing one simple thing, which is targeting one organ at a time. Yeah.

Dr. Kara Fitzgerald (01:03:41) – That’s very cool. I want to just- We need to wrap up here, but I have about 20 more questions. But no. I just I wanted to talk about telomeres. So, telomeres are one of the hallmarks- Telomere attrition is one of the hallmarks. But what you’ve seen in your research is that if you’re elongating telomeres, you’re actually hitting cell dedifferentiation. It’s like it would be a bad sign in your work. And think that you’ve said that our focus on telomeres may be misdirected. Can you just speak to that? I mean, it’s one of the things that comes to mind first and foremost when we’re thinking about longevity.

Dr. Vittorio Sebastiano (01:04:25) – So yeah, it’s a good question. Let me clarify what I mean. For example, there is an existing technology right now that is thinking about, for example, through the mRNAs, to bring inside the cells the gene that is responsible for the elongation of the telomeres as a possible solution to aging. I think that’s definitely one of the weapons that we have in our arsenal to tackle the problem of aging. So, I don’t mean that we shouldn’t be looking at that and it’s dangerous on its own.

Dr. Vittorio Sebastiano (01:05:04) – For our factors, I think that if you can control that process and you can make sure that you just temporarily elongate the telomeres, but then you don’t overdo it, because if you overdo it, then the cells become, you know, carcinogenic, I think that that’s a splendid idea. And I think that people should be pursuing and following up with that idea.

Dr. Vittorio Sebastiano (01:05:28) – What I mean, though, is that the telomere attrition is just one of the many different things happening with age, and alone doesn’t explain why we age. And telomere attrition is a phenomenon that primarily impacts cells that become senescent, which is, again, a subset of cells that is only maybe explaining 1% to 5% of the cells that we have in our body as we age. And so, solving the problem of telomere attrition is important, but again, it’s going to affect only a small number of cells and it’s not going to have such a dramatic impact comprehensively on the process of aging. So that’s what I mean.

Dr. Kara Fitzgerald (01:06:17) – So there may be a subset of people for whom that would yield benefit worthy of intervention.

Dr. Vittorio Sebastiano (01:06:26) – Exactly. And to explain why, in our case, we do not see telomere elongation and why we think it’s good for us.

Dr. Kara Fitzgerald (01:06:35) – Yeah.

Dr. Vittorio Sebastiano (01:06:34) – During the process of reprogramming, the gene that is responsible for elongating the telomere becomes active when you are far away in the process of reprogramming, so when the cells are almost about to become IPS. The reason why we don’t want to see telomere elongation happening in our case is because if we do, that would mean that the cells would have lost their identity and they would become carcinogenic. But that doesn’t mean that together with our cocktail, we can’t bring in, again temporarily, the gene that is responsible for telomere elongation, but just making sure that it’s expressed for a very short time and not for much longer, if it makes sense.

Dr. Kara Fitzgerald (01:07:22) – Yeah, it does make sense. I guess I’m just not- I don’t know that I’m as convinced that would yield- You know, I mean it’s not my field. I’m just like an armchair opinion generator over here. Like it might not- I’d rather have my ovaries rejuvenated with an ERA cocktail. Anyway-

Dr. Kara Fitzgerald (01:07:43) – Although I guess we could do both. It’ll be interesting to pay attention to that as they actually do telomere elongation and to see what outcomes occur with that. Listen, it has just been a really great conversation. Thank you so much for your time and your ability to explain in really plain language and bring this field alive. And I appreciate your commitment to this work and your passion around making the world a better place for all of us and making it affordable. Thank you.

Dr. Vittorio Sebastiano (01:08:15) – Yeah. Thank you. Thank you for having me. And, yeah, absolutely. You know, this is really what drives me, what gets me up in the morning. I really hope that this is going to be really something that everybody can utilize at some point because I’m really a big believer of democratization of medicine and I really hope that this is going to be applicable to anybody with no distinction in terms of who can afford it or not.

Dr. Vittorio Sebastiano (01:08:46) – Yeah. So, thank you actually for giving me this opportunity because I think it’s important that the information gets out there and people are aware of it.

Dr. Kara Fitzgerald (01:08:56) – Yeah, absolutely. All right. Well, Dr. Sebastiano, welcome again. Thank you for coming to New Frontiers.

Dr. Vittorio Sebastiano (01:09:04) – Thank you.

 

Transcript for Second Interview

Dr. Kara Fitzgerald – Hey New Frontiers listeners. So, when I finished my conversation with Doctor Sebastiano, I realized I had a lot more questions for him. I was grateful he was willing to hop on a call with me and chat through these additional thoughts. So, what follows is a deeper drill down into the science, but it’s incredibly interesting. For example, why did he choose to focus his research using human cell lines and human tissue rather than an animal model? Is this more translatable into human application? The answer, he believes, is yes, and he’s nearing FDA approval to start clinical trials. So, listen to that. The other huge question that we covered, among other things, was whether or not epigenetics is the root of aging, or is focusing on epigenetic changes, manipulating DNA methylation and so forth, the most effective entry point into reversing aging? So listen to what he has to say about this. I think that you’ll be incredibly interested in it. I’m grateful for his time, and really, this is one of my favorite podcasts of the year.

Dr. Kara Fitzgerald – Thanks so much.

Dr. Kara Fitzgerald – So you’re a part of the Biomarker of Aging Consortium, which I’m excited about. You’re going to have your first meeting, if I’m not mistaken, in December at The Buck Institute. Obviously, DNA methylation clocks are in there because Horvath (Steve Horvath, Ph.D.) is a part of it, but what are you guys thinking about in terms of pulling together biomarkers? And any that you can mention?

Dr. Vittorio Sebastiano – Of course. Yeah. Well, the initiative of the Biomarkers of Aging Consortium was put together by a postdoc, actually in my lab. His name is Mahdi Moqri, Ph.D. and he’s really the heavy lifter and the spearhead of this whole initiative. And the idea came all about- He actually shares a postdoc between my lab and Vadim Gladyshev’s Lab, who’s also a PI (principal investigator) that’s working in the space of biomarkers.

Dr. Vittorio Sebastiano – The idea came all about by considering the fact that there is a lot of different clocks out there. I think there is now more than twenty, just methylation clocks. But there is a number of additional clocks that are being developed: transcriptional clocks, metabolomic clocks, proteomic clocks, and so on and so forth. So there is a lot of interest in the field by many investigators to really develop new quantitative methods to really assess in a very tangible and measurable way what aging means on the one hand, but also in particular now that we are at an inflection point, how any kind of rejuvenating interventions, for example, from exercise to diet to caloric restriction or metformin or epigenetic reprogramming of aging. What is the impact of any of those interventions on the biological age? What do they do to the biological age of an individual?

Dr. Vittorio Sebastiano – And so basically, we came to the idea that there is a lot of different clocks and they are all absolutely well, not all of them, you know, some more than others, but they’re definitely all very useful tools to measure aging at the cellular level. But they’re not necessarily always good at capturing the effects of regenerative interventions. Right? And we have demonstrated- So we have a study under revision and we have seen that if you utilize different regenerative interventions and you utilize the same clocks, you see that those interventions are actually acting on the epigenome in different ways. Some interventions affect some parts of the genome and some other interventions affect some other parts of the genome.

Dr. Vittorio Sebastiano – But the question is what that mean from a clinical standpoint? Does that really translate into enhanced healthspan, enhanced lifespan? What does that mean. To make a long story short, we really realized that- Well, first of all a lot of different clocks, and there was not a unifying consensus about which of those should be primarily used, should they be all combined into one super clock of some sort? And in particular, I think there is really right now the need to also inform the FDA and really make them aware that sooner or later these interventions are going to become practice somehow.

Dr. Vittorio Sebastiano – So how do you measure effectively and quantitatively the effect of any of those on the biological age of people. So, that’s the spirit behind the initiative and the consortium is doing great work in this regard. It’s trying to put together right now- All the people that are involved in this field to try to come up to a consensus. We published a review in Cell very recently to, first of all, come up with a consensus language about what aging means, what rejuvenation is. Because we still lack a common ground and different people think about this in different ways.

Dr. Kara Fitzgerald – Totally like, what is aging? And I know scientists get in a flutter when you say you’ve reversed it. Just using that term. And I think that Matt Kaeberlein is sort of a big advocate for- I could be mistaken, so I don’t want to- But that we haven’t reversed. Certainly, there are some scientists who come from that. But then you know what are you doing in your lab? I’m assuming this is something that you’re going to be grappling with, defining these granular terms, and then measuring. But we also know… Let me ask you this-

Dr. Kara Fitzgerald – I have two questions for you regarding the clocks. Clocks can behave differently depending on tissue type. So biological age, as you talked about in your own research, I mean, what’s happening in the brain versus what’s happening in an immune cell, etc., etc., that can vary. Are the clocks surrogate markers of what’s happening or are they actually capturing the aging phenomena? Are they just reflective? Yeah.

Dr. Vittorio Sebastiano – So you’re saying, in other words, are those changes that we see with the clocks correlative or causative of aging? Well, as I said, the clocks are very, very useful tools actually to measure aging today. Okay. But they have a couple of fundamental limitations, and that’s, I think, the reason why we need to develop new types of clocks. Or probably not clocks, you know, we have one, we call it Index. First of all, the clocks are pretty much algorithms that are trained on a specific cell type, okay. And they’re trained not only on a specific cell type, but they’re also trained on how that specific cell type ages over time.

Dr. Kara Fitzgerald – Yeah. Okay.

Dr. Vittorio Sebastiano – And so, what they do in simple words is that they try to extrapolate from those cell types, from the methylation of those cell types. They extrapolate, through machine-learning algorithms, a subset of bases in the DNA that change, meaning that they either get hypermethylated over time or hypomethylated over time. And so basically, they extrapolate that information and at the end of the day, what they do is just, they really end up looking at, in the best case, only maybe 400 base pairs or so. In the worst case just a handful of base pairs. And so basically what they do is just, you know, it’s like trying to simplify a very complex image and try to really kind of zoom in into a very tiny little pixel of that image. And that pixel, basically, is good in the sense that it really gives you a very remarkable and reproducible way to say, “Okay, this cell type is age X and the same cell type from an older individual is now age Y.”

Dr. Vittorio Sebastiano – But the problem is that it needs to be trained on a specific cell type and that means that when you use the same clock in other cell types, it may not work as well. Because again, it’s been trained on that cell type. So that’s the first limitation, and that’s the reason why there’s multiple clocks now that are being developed. The second limitation is that despite being very helpful, it’s looking at such a tiny little fraction of the information, you know, of the whole information that is really giving you a very blurred image, or of the whole picture. Right? It’s like looking at, you know, you’re in a museum, right? You’re in front of a portrait and instead of looking at the whole portrait, you’re just looking at one tiny little pixel of it.

Dr. Kara Fitzgerald – Right.

Dr. Vittorio Sebastiano – It can be very informative, but it doesn’t give you the whole complexity of… And so that’s the reason why I think we really need to develop new clocks because, sorry- The third limitation that I should mention is that since they have been built on aging, it doesn’t necessarily mean that now with rejuvenative (regenerative) intervention, we’re going to see a reversion of that clock in the same, you know, in the reverse orientation. Why? Because the different rejuvenative (regenerative) interventions may be maybe doing different-

Dr. Kara Fitzgerald – Yeah. Dancing around elsewhere.

Dr. Vittorio Sebastiano – And those parts of the genome that are changing may not be necessarily captured by the clock that has been built for a different purpose. And so-

Dr. Kara Fitzgerald – And so this could be why that CALERIE study that came out, it didn’t move any of the clocks. It only moved the pace. So that’s it. It’s not that those clocks are limited.

Dr. Vittorio Sebastiano – No. It doesn’t mean that it’s not doing anything to the genome. It’s actually doing a lot but the clocks cannot capture that information because they have been built for different reasons.

Dr. Kara Fitzgerald – Right. So, we don’t want to throw that intervention out by a long shot.

Dr. Vittorio Sebastiano – Exactly.

Dr. Kara Fitzgerald – Fascinating. Okay. What clocks are you using? What do you find work in your lab?

Dr. Vittorio Sebastiano – Yeah. In our study, originally we used the original Horvath’s clock. We actually use two different ones, and in both cases, we saw rejuvenation. But that’s an interesting question, Kara, because actually, when we start digging- And we did see rejuvenation, you know, by X number of years. But that’s an interesting question because when we start digging a little bit deeper into the data and we ask ourselves, to go back to your question, are these changes correlative of aging or are they causative of aging. So, can those changes in the clocks really tell us something about the biology of the cells? Or they just change with age but they have nothing to do with it.

Dr. Kara Fitzgerald  – Yes. Right.

Dr. Vittorio Sebastiano – So we started digging into that and we saw that the rejuvenation effect that we were seeing with those clocks were explained in both of the cell types that we looked at just by one single base pair in the genome. And that’s incredible. Because, you know, I was expecting again, really changes across the whole genome. And what the clock was saying was that the rejuvenation that I saw in my cells was due to the fact that the one base pair was changing and that that was so heavy in the clock. And I said, well, okay-

Dr. Kara Fitzgerald – Just one methylation site? Like literally a single red lollipop?

Dr. Vittorio Sebastiano – Yeah. That doesn’t mean- There were thousands, if not hundreds of thousands of changes happening in the cells, but the clock was capturing only that one. Okay. And I said, well on the one hand, great and exciting, but on the other hand it’s like I need to understand what is going on during this process. I need to understand the logic of this process. I cannot explain the whole rejuvenation by one base out of 7 billion base pairs of the genome that I’m looking at. I mean, that’s just impossible. And that’s the reason why we started developing new clocks that are looking at the whole genome now.

Dr. Kara Fitzgerald – Wow.

Dr. Vittorio Sebastiano  – And now in an unbiased way, we are trying to understand if there are features of the genome that are changing in a predictable way as we age and also as we interact with-

Dr. Kara Fitzgerald – So, you guys are in the middle of creating clocks because you need to actually measure the rejuvenation that you’re seeing.

Dr. Vittorio Sebastiano – Exactly. Yeah.

Dr. Kara Fitzgerald – That’s ridiculously interesting. Are you using the whole methylome or the whole genome?

Dr. Vittorio Sebastiano – Yeah. We are using the whole genome and we are not using algorithms. We’re not training the system in any way. We are just looking at the genome and we are extrapolating from the genome features, through machine learning, features that are invisible to our human eyes, but that a machine learning kind of approach can actually extrapolate because it can look combinatorial at a number of these. But it’s not trained. It’s just extracting information from a screenshot if you wish. A screenshot taken at different times. So, it’s extrapolating the whole information and is trying to make an order out of this mass and try to really come out with biological features that are changing. And just to make an example, we found that there is one feature that seems to be consistently changing over time across different cell types, so this can potentially lead to a universal clock, which is a particular part of the genome that is bound by a protein complex.

Dr. Vittorio Sebastiano – And we saw that this particular part of the genome keeps changing, keeps being hypermethylated with time. And when we come in with rejuvenation, for example, with the epigenetic reprogramming, we see that that same feature now is becoming younger. So, it’s becoming demethylated with reprogramming. So what- Yeah.

Dr. Kara Fitzgerald – What’s that protein about.

Dr. Vittorio Sebastiano – So this is a protein complex that is called the PRC2 (Polycomb response elements), excuse me, and it’s a complex that basically, generally speaking, keeps some developmental genes (turned) off in cells. So those are genes that are normally expressed when we embryonically develop, but at some point, they need to be turned off. We see that these regions that are bound by these repressive complexes become hypermethylated with time and this is associated with an aberrant expression of those developmental genes that now start becoming expressed as we age.

Dr. Kara Fitzgerald – Interesting.

Dr. Vittorio Sebastiano – And we don’t know if the binding of that complex now becomes loose, and so that’s the reason why these genes now are being turned off. Or maybe it’s because there’s something even at a higher order that is happening. And so maybe these genes not only are bound by this repressive complex, but they are also in the nucleus, they are in parts of the nucleus where they’re also being kept silenced. And by hypermethylating them, maybe they detach from those regions and they move into regions of the nucleus where they become active now. So we’re trying to understand the biology of this phenomenon and I think this is more interesting because at least we can start understanding the whole process. Yeah.

Dr. Kara Fitzgerald – It’s incredibly complex. It’s like that joke about epigenetics. I mean, it’s just so complex. It’s really interesting. But it seems like what you’re suggesting is that some sort of- It’s possible that later in life there may be aberrant expressions of genes that should be repressed because we’re only using them in embryogenesis. But as things maybe get sloppy or if it’s not just sloppy, it’s maybe some program phenomena that’s happening that’s allowing these to sort of relocate and turn back on. Am I getting it?

Dr. Vittorio Sebastiano – Absolutely. You’re right. Yeah.

Dr. Kara Fitzgerald – That’s interesting. Really interesting. Okay, so my next question is, you said to me on the podcast that you really thought that root cause aging, if you will, is happening in the epigenome. But you say it’s your opinion. And I just thought that’s fascinating that you’re saying it’s your opinion and yet in your research, you’re really demonstrating that. So why not put that stake in the ground a little bit more strongly? What’s the- Yeah.

Dr. Vittorio Sebastiano – I think that to clarify what I said the other time was I don’t necessarily- So, there are a lot of different theories about aging, right? There is the Disposable Soma Theory, there is the Accumulation of Damage Theory and others.

Dr. Vittorio Sebastiano – So what I wanted to clarify is that I am agnostic about what the theory of aging is. Okay, I don’t know- There is not a consensus as of yet of what’s really the root cause of aging and I don’t have a particular opinion about what is the most accurate theory. They are all inaccurate, but I don’t know what is the most accurate of all of them. So that’s why I don’t necessarily think that epigenetic changes are the causes of aging in that in that sense. I don’t know if that’s clear. But what I’m really strong and adamant about is that whatever the theory of aging is, you know, again, it can be developmental, it can be accumulation of damage, whatever that is, it results in epigenetic changes that are, in my opinion, and I’m really strong about this, across all the hallmarks are the hierarchically dominant hallmarks of aging. Okay. So that’s my my strong opinion.

Dr. Kara Fitzgerald – I got it. It’s what you’ve demonstrated, though, wouldn’t you say?

Dr. Vittorio Sebastiano – Yeah, yeah. And since the epigenome is hierarchically dominant and also reprogrammable, I think that by reprogramming the epigenome, we can, as a cascade, reprogram all the other hallmarks of aging because they’re just, kind of a second layer of importance.

Dr. Kara Fitzgerald – Got it, got it, got it. So regardless of the why, this appears to be the business end, you know, in terms of manipulating all of the hallmarks. Okay, cool. You had talked to me about purposely putting your attention on human cells and that being the more challenging but closer to being translatable than animal models, and we were curious about why that is. What is it about the human cell studies that make it so much harder than animals?

Dr. Vittorio Sebastiano – Let me start by saying that, I mean, I come from basic biology history. As much as I value the animal models, you know, across the spectrum from the simplest organism to the most complex organism, as much as I value those models, I think they are fantastic ways, actually, to expand and extend our understanding and our knowledge. When it comes to developing therapies I think that those models are largely insufficient for the goal that we have. In particular, if we want to have a goal that is in the short term, or not in such a long term, let’s say it that way… In a non-diplomatic way, what I’m trying to say is that I am a little bit sick of seeing potentially groundbreaking technologies and discoveries that work beautifully in animals, and almost all of the time don’t work in humans, because humans are so similar, but also so different from animal models.

Dr. Vittorio Sebastiano – I think that now the technology really allows us to start asking the right questions, using the right tools in the right models. For example, using human organoids, or human tissues, or some simplified version of the human organs and the human tissues. And I think I would rather spend a little bit more attention and time and efforts and resources on that, because I think that as imperfect as they are, like the animal models, they’re definitely a step closer to the complexity of the goal that you have in mind, which is treating human diseases and treating human aging. Okay. So that’s the reason why. But it’s difficult, of course, because of course, you have to rely on specimens that are often difficult to get, in some cases ethically concerning also to get, sometimes impossible because maybe you have to rely on tissues that are not available.

Dr. Vittorio Sebastiano – And so it’s very challenging, but I think it’s as challenging as the goal that we have in mind. Again, I have spent- The entire research that we did on aging was almost entirely done on human cells because at the end, I wanted to have something that could really have a potential for treating human diseases and human aging. And yeah, I don’t know. It was a long way to answer your question.

Dr. Kara Fitzgerald – Well, let me just ask you this, and I know this is not your wheelhouse, and it feels almost like a dumb question, but whatever. You know, as a clinician, we’re always trying to translate research. As a clinician in functional medicine we’re thinking about translating research. And actually, since science is sort of in the popular media now, especially longevity, and everybody’s hungry for what’s happening, people will extrapolate from animal studies and start experimenting on themselves.

Dr. Kara Fitzgerald – But when my colleagues and I think about it- If you were going to translate, which I don’t know that you would, but if you were going to make clinical decisions around cell studies versus animal studies, what would they be? Would you look at animal studies or would you look at cells? I-

Dr. Vittorio Sebastiano – Well, the animal studies are necessary. Absolutely. But what I’m trying to say is that the discovery, in my opinion, now that we have the tools and the technology, the discovery now should be done on human cells and human tissues. And then, of course, it needs to be reverse translated in a way to animals because you need to do safety, some sort of efficacy also. But the biology of the aging, despite there are a lot of similarities, of course, our aging, in a way, is very similar to the aging that you see in rodents-

Dr. Kara Fitzgerald – Mammals. Yeah.

Dr. Vittorio Sebastiano – But it’s also so dramatically different. It happens over the lifespan, which is, you know, eighty or ninety years old versus two years old. And it’s not just a matter of accelerating a process that is the same. It’s not just as simple as that. It’s not just a matter of extending that biological process over the course- No, it’s not as simple as that. The structural complexity of the tissue is completely different. The cells, the cell types, you know, they’re similar, but at the same time they behave differently. You know, the brain. How can you study the brain aging since our brain is so different from any brain of rodents? I don’t think it’s a fair comparison.

Dr. Vittorio Sebastiano – And again, up to now, or up to a few years ago, we didn’t have the right tools. Fine. You have to work with what you have, and you have to try to make the best out of it. But now that we have access to cells, now that we have ways to culture human organoids, we can make iPSCs, we can build all sorts of quasi-perfect tissues out of those cells, I think we should start working on those. And this would accelerate dramatically the pace at which, not only you discover drugs, but you also find candidates that really have a potential to be translated because they have been tested on human tissues and humans.

Dr. Kara Fitzgerald – Yeah, that’s right, I get it. Yeah. So, let me just ask you quickly, going back to the clock conversation, the mammalian clock that Horvath recently published on, is that still the pixel, right? You’re still looking at a couple of pixels even though it’s across mammals.

Dr. Vittorio Sebastiano – Yeah

Dr. Kara Fitzgerald – Okay. Now, just leapfrogging off of what you just said about the commitment to human and human organoids, where are we at in the clinical trial journey?

Dr. Vittorio Sebastiano – So I can speak for what Turn is doing? We are not too far, actually, from the clinical trial. We just had a very exciting first conversation with the FDA. We submitted an early preliminary INTERACT package, which is the very, very, very early conversation. We had some questions about our mRNAs, the cargo, the lipid nanoparticles, and so on and so forth and it was great, actually, because we got excellent feedback from the FDA. So, we had a press release last week on this. I can-

Dr. Kara Fitzgerald – Yes, please. Yeah. I’d love to see it.

Dr. Vittorio Sebastiano – And to the point that actually we didn’t really have to have a meeting with the FDA officers. Now our next stage is really to develop the preclinical studies and then submit a pre-IND package (Pre-Investigational New Drug Application) and an IND package (Investigational New Drug Application) after that. So, we are really accelerating it now dramatically because this first conversation was absolutely important for us to understand how the FDA is thinking about this, because it’s completely new territory for them. And it was very reassuring and pleasing to see that actually we are on the same page. So, now it’s just a matter of really starting to develop this technology and to bring it to Phase 1. If everything goes well, money, funding, and so on, I think we are we are really looking at Phase 1 that would start relatively soon. Hopefully early 2025.

Dr. Kara Fitzgerald – Wow. That’s incredible. Yeah. I would love to see the press release. Yeah. I don’t know that you- This is a little off to the right, but, you know Charles Brenner? He’s huge on Twitter, and he’s always, actually accosting David Sinclair. It’s like a kind of a humorous drama that those guys have going on. Or he has. But he really challenges Sinclair’s publications out of Harvard and does not think that the aging phenomena is actually happening and they’re reversing it. And I just wondered if you’ve been following that at all, it seems like you’re aware of it, and what your thoughts are on this, like sort of heated drama.

Dr. Vittorio Sebastiano – Well, yeah. Yeah, I’m aware of it. I mean, I’m not following it, you know, super closely. Of course, when it comes to science, like in any other discipline, every time there is something new, this obviously stirs a lot of egos.

Dr. Vittorio Sebastiano – Yeah. So any new idea comes, of course, with the potential, also with a lot of controversy around it because until it really gets either disproved or understood, which are, I think that the two sides of the same coin in a way. So I think, I mean, he has a point when it comes to, for example saying, well, is that paper really the proof that the fundamental cause- Or to go back to the our question initially, to really show that that’s really the fundamental cause of aging, I think he’s right in the sense that it doesn’t really necessarily prove that that’s really the fundamental cause of aging. Also, because again, the method that has been used is through induction of double-strand (DNA) breaks, which are obviously also impacting the sequence of the genes.

Dr. Vittorio Sebastiano – Again, I think it’s more a theoretical kind of controversy about the theory that explains aging, but I don’t think it- And I think he has a lot of reasons to really say that maybe it hasn’t been shown that really that’s the cause of of aging. But again, I don’t think that that changes the whole picture because again, it may not be the cause, but it’s the manifestation that is really what we care about when it comes to rejuvenation and resetting that program back to a youthful state. So yeah.

Dr. Kara Fitzgerald – Okay. Awesome. Thank you. All right. And so then my final question again, it might be a little bit outside your wheelhouse, but I’m just wondering if you have any thoughts- So for me being in functional medicine and thinking about nutrition, you know, Randy Jirtle has a kind of a godlike stature in my field, and the fact that he showed using methyl donors, this remarkable phenotype change in the Agouti Mouse Model.

Dr. Kara Fitzgerald – And I’m just wondering- For me, this suggests that nutrients are a potentially and exceptionally powerful influence on methylation, on the epigenome, especially when delivered during certain developmental windows. But we know from my diet and lifestyle interventions that we could change gene expression. I’m just wondering, do you have thoughts on that at all? It’s maybe a selfish question for me because it’s my area, but yeah.

Dr. Vittorio Sebastiano – Well, yeah, I do have thoughts in the sense that I absolutely think and firmly believe that nutrition, together with many other things, has a really fundamental impact on gene expression. And it has implications on gene expression, again, because it has implications on the epigenome. So I absolutely think that yes, nutrients can epigenetically impact our body, our cells, our tissues, and by doing so, they can either accelerate aging or kind of slow it down over time. I’m absolutely I’m totally- Not only the nutrients, but also, again, caloric restriction, for example, exercise, even the amounts of food-

Dr. Kara Fitzgerald  – Yes, yes.

Dr. Vittorio Sebastiano – And in our study on the Index, we saw that caloric restriction, like epigenetic reprogramming, has the same impact on the same regions of the genome. They are working through the same mechanism of rejuvenation, if you wish, in ways that again we don’t understand. But it’s exciting to see that’s happening.

Dr. Kara Fitzgerald  – Have you shown anything else to work similarly to epigenetic rejuvenation besides caloric restriction?

Dr. Vittorio Sebastiano  – No, but we saw that rapamycin treatment, for example, is not acting on the same region. It’s working on different regions, and again, we don’t understand why. Metformin, not yet because we didn’t have the data to look at. We were trying to mine existing data sets and there was not nothing available. So far caloric restriction and epigenetic reprogramming seem to be working, at least in part, through the same mechanism.

Dr. Kara Fitzgerald  – Oh, that’s super fascinating. What is this Index clock that you’re using?

Dr. Vittorio Sebastiano  – So we call it the PRC2 index and we have a publication under review now, but it’s also publicly available. I can send that to you, so maybe you can read it.

Dr. Kara Fitzgerald  – Yes. I would like to. Is this a clock specific for your research in your models, or is this something that people could use?

Dr. Vittorio Sebastiano – Anybody could use it. Yeah.

Dr. Kara Fitzgerald  – Is it available? Or the CPGs, the clock structure is available? So you could run it on like the Illumina or something.

Dr. Vittorio Sebastiano  – Yeah. The sequencing can be done on any platform. It can be done on Illumina, it can be done through Microarray, it can be done through any platform. And as I said, it doesn’t require any specific algorithm, so there is no code associated with it. It’s just a feature of the genome that you can extrapolate easily without any complex bioinformatic tool. So, it’s much easier to look at, because again, it doesn’t require machine learning training, it’s just focusing and zooming in into specific regions of the genome that have a specific behavior over time. Yeah.

Dr. Kara Fitzgerald  – So, it wouldn’t really be appropriate outside of a research setting.

Dr. Vittorio Sebastiano  – No, I think it would. But again, we go back to the question: what of the clocks, actually- Because the downside of our approach is that you need to look at the whole genome. It’s more expensive than that clock. And so that becomes a little bit more challenging. Of course, when it comes to, you know, can you for every single person? Well, maybe not because it’s very expensive and so is it worth using it? So that’s why I think we need to develop a real consensus about this. But on the flip side, the sequencing is becoming so cheap now that, you know, with a few hundred bucks you can have the information across the whole genome. And so instead of spending maybe a couple of dollars, you spend a couple of hundred dollars, and you get much more comprehensive information about the whole process.

Dr. Kara Fitzgerald  – Okay, so that paper and then the press release, if you could send those to me and that’s all I’ve got. Vittorio, thank you so much for making some more time. Okay. Ciao, ciao.

Dr. Vittorio Sebastiano: Goodbye.

Dr. Vittorio Sebastiano is an Associate Professor in the Department of Obstetrics and Gynecology at Stanford School of Medicine. His lab has developed a new technology named ERA (Epigenetic Reprogramming of Aging), which repurposes the conceptual idea of reprogramming, with the goal to promote epigenetic rejuvenation of human adult cells leaving their identity untouched. This new technology was patented and is being implemented by Turn Biotechnologies, which Dr. Sebastiano co-founded and where he serves as head of Research and chair of the Scientific Advisory Board.

Dr. Sebastiano is also a member of the Dior Beauty Reverse Aging Scientific Advisory Board.

The groundbreaking discovery of ERA has been covered by the press worldwide, including BBC, National Geographic, New York Times, France 2 Envoye Special. You can find a compilation of media coverage of Turn Bio here.You can find a list of scientific publications and presentations regarding Turn Bio’s work here.

EMAIL:

vittorio.sebastiano@turn.bio

vsebast@stanford.edu

WEBSITES:

https://www.turn.bio

https://med.stanford.edu/sebastiano.html

Phone: +1 (650) 2485693

Dr. Vittorio Sebastiano

Turn Biotechnologies

The Sebastiano Lab at Stanford University

Dior Beauty Reverse Aging Scientific Advisory Board

Hallmarks of aging: An expanding universe

FxMed Blog: The 12 biological hallmarks of aging viewed through a functional medicine and functional longevity lens

Scientific publications and presentations regarding Turn Bio’s work.

Shinya Yamanaka

Study: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors

Sergei Young

David Sinclair

Aubrey de Grey

Biomarker of Aging Consortium

The Buck Institute

Randy L. Jirtle, Ph.D.

Study: The agouti mouse model: an epigenetic biosensor for nutritional and environmental alterations on the fetal epigenome

Mahdi Moqri, Ph.D.

Review: Biomarkers of aging for the identification and evaluation of longevity interventions

Matt Kaeberlein

Index Biological Age Clock by Elysium

Study: Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial

The Disposable Soma Theory

Press Release: FDA Meeting Feedback Puts Turn Biotechnologies on Track to be First Longevity Company Taking Cell Rejuvenation Therapy to Clinic

Study: PRC2 clock: a universal epigenetic biomarker of aging and rejuvenation (Pre-print, under revision)

Illumina sequencing platforms

Gene Expression Microarray Platform

Yamanaka Cocktail

PRACTICE BETTER: Start your free trial and save 20% for 4 months on any paid plan with code KF20

 

NFFM Resources

FxMed Blog: The 12 biological hallmarks of aging viewed through a functional medicine and functional longevity lens

Podcast: Sergey Young’s Technological Innovations for Longevity and Biological Age Reversal

Podcast: The Epicenter of Epigenetics; Discussing the Agouti Mice Study with Dr. Randy Jirtle

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• Bio Age Self Assessment Quiz
• Younger You book
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