Precision Health Club

Interview – Alex Trapp from Harvard Medical School

Rachel: But also just to let you know, we are going to record the call just a really casual conversation. But basically, it allows us to distribute it afterwards. It allow folks who maybe can’t make the exact event time to get access to the recording and also make a blog post. So it’s really kind of a distribution opportunity to share your research as well. 

Alex: Okay. 

Rachel: Awesome. Perfect. All right. I’m sure some more folks will trickle in, but let’s get started. Welcome, everyone. Thank you so much for being here. Today, we are chatting with Alex Trapp, who’s a research assistant at Harvard Medical School, where he works on developing new computational frameworks for assessing biological age using molecular data. He is currently interested in developing further approaches for integrated single cell multi modal evaluation of biological aging trajectories, particularly within the context of evaluating and validating longevity and rejuvenation interventions. Alex, we are super excited to talk to you. This is a community that is very interested in longevity and health span, and consistently kind of brings up the conversation around how do we think about biological age, how do we test for it? So we’re all very excited to have you here. 

Alex: Thank you so much. I’m really excited to be here. 

Rachel: I know that I did give an introduction, but is there anything else that I missed? What are you working on, and share a little bit more about your background? 

Alex: Yeah, for sure. So, I’m not sure if people are familiar with the concept of biological or epigenetic aging. But it’s a way essentially to track someone’s aging instead of chronologically, so the number of years that you’ve been alive. It’s more of a biological readout of how fast or how slow you’re aging. And so these methods have been around for a couple years now. But they’ve been limited in that they only assess both samples, meaning that you needed to get millions of cells either from a blood sample, saliva samples, something like that. But that really hides the heterogeneity that you have for individual cells, and how individual cells age along the course of one’s life. So what I developed as a method to enable really single cell resolution assessment that the epigenetic aging over so far in mice, and hopefully in humans. 

Rachel: So in terms of the single cell versus the box cell approach, what is the benefit of doing it that way, versus doing it the way that’s been done for the past couple of years? 

Alex: So the way that it’s been done gives you a pretty, I guess, it’s an aggregate measure of how one’s aging. So basically, you look at how compendium of cells is aging over time, and that usually just gives you a number of things via what we call your biological age. So say you’re 35 years old, and you happen to be very healthy, you don’t get sick very often, you have very good lifestyle habits, maybe your biological age will be 30, right? But you still have the exact opposite, right? You can also just not be very fit, not eat very good food, and be susceptible to disease. And those factors will influence your biological age, and they get higher than your chronological age. So maybe you’ll be 40 biologically, even though 35 chronologically, and so we can do that with these both approaches. But what we’re really interested in, and what we believe, is that the longevity and rejuvenation interventions that are being tested and developed, both academically and in biotech really changed the way different cell types age and not as an entire organism. And so we really want to get resolution into how individual cells and individual cell types are, specifically stem cells, progenitor cells, differentiated cells, maybe neurons in brain, things like that we really wanted to know how each of them age and how those respond to interventions so that we can better tailor them to really extend lifespan at the house, expand health span too. 

Rachel: So, it sounds like the research that you’ve done and kind of this, the single cell approach will allow a more targeted kind of experimentation or data collection on specific interventions. So if there’s an intervention on the kind of on brain health, you can target cells within the brain to see if it’s working specifically there. Does that sound correct? 

Alex: Yeah, that’s exactly it. Yeah. So for example, like the blood is a tissue where there’s literally hundreds of different cell types. You have immune cells, you have red blood cells, white blood cells. And if you just look at the blood as a whole, sure. Maybe you can get a pretty good estimate of how biologically you’re aging. But if you’re able to really discern the individual trajectories of each of these different cell types, and we believe that, in fact, the different trajectories are arranged differently based on these interventions. So maybe an intervention will help white blood cells age slower, maybe another intervention will help another type of immune cell maybe stem cells in the bone marrow, and other types. So really, I think there’s just a big revolution in biology right now, which is just to look at single cell instead of bulk because bulk just really hides a lot of heterogeneity that we know exists at the single cell level. If we’re able to better characterize the trajectories of aging, and conversely, the trajectories of rejuvenation upon interventions really at that high resolution level. That’d be very, very useful for a lot of people. 

Rachel: Definitely. And then how would you think about if there’s interventions that are meant to impact kind of like multiple types of cells? Would you then do kind of multiple single cell analysis? Or how would you approach kind of that specific question? 

Alex: Yeah, so we think that there are definitely interventions that do affect different cell types. I mean, we can tell. So one of the most common interventions, dietary intervention specifically is caloric restriction in mice. So basically, if you feed a mouse 60% of what you feed another mouse, that mouse will live up to one and a half times as long as the regular mouse. And so we’ve shown that in previous papers that that effects is very systemic, so across the blood across many different organs deliver, so presumably, many cell types, and each of these tissues are affected. But really, before we were unable to tell exactly which ones and to what extent that occurred. Because we think a lot of this aging has to do with stem cells, and if stem cells aged in the cells that they give rise to the differentiated cells, maybe they age faster, as well. And so we just have a more holistic view, more comprehensive view, I would say, about the aging process and its interventions. 

Rachel: It also seems like this kind of change of the bulk testing versus single cell testing would be easier and less expensive for people to do more often. Is that correct? 

Alex: So at the moment, I wouldn’t say it’s less expensive, because you need to isolate individual cells, as opposed to just getting like a blood sample that you can process directly. So at the moment, current technologies don’t allow for super cheap assessments. But what you can do with single cells, is have a lot of them. So there are multiplexing approaches where you can literally analyze thousands, if not tens of thousands of cells and sample at one time. And it’s just infinitely much more data points than you have with just the one bulk samples. But I think yeah, despite the cost, I think the cost will decrease, because these technologies are still very new. Single cell RNA sequencing just piloted a few years ago. And now it’s really, really big hype in the space. So eventually, it will be cheaper. But I think, in any case, it just provides so much more information than you have with just the bulk. 

Rachel: Okay, that makes sense. And then in terms of interventions, I would love to talk a little bit more about that. How often kind of, let’s talk about the caloric restriction intervention. How often would you be testing your kind of biological age through this methodology to determine changes over time? Is it something where you’re testing weekly, monthly, yearly? Like, what would that look like? 

Alex: So that’s actually a really interesting question, and very related to some recent work that we put out. So the problem with these epigenetic clocks, either at the bulk level or at the single cell level, is so far, they’ve been very expensive to apply, because you need to be able to get the methylation information from your DNA. And you can, there are a couple of methods to do this. Some use microarrays, others use sequencing. But in any case, you’re paying at least 2 to $500 per sample, right, which is prohibitively expensive, especially if you want to do this in a routine manner like you’re alluding to. So what we recently developed is a method that enables really cost effective epigenetic age profiling, so our lab and David Sinclair’s lab, maybe people in the audience know David, kind of a popular guy on Twitter. But we recently developed a framework, both experimental and computational, that allows really effective cost reduction for this. So instead of paying 2 to $500, we can get similar accuracy, if not even better, at only 2 to $10 per sample, and we’re trying to get it even below $1. So ideally, you would be able to do this routinely when you go to the doctor’s office or even just on your own, especially looking at the price point it is. 

Rachel: In terms of the calorie restriction kind of intervention, let’s stick on this. How long would it take to kind of see a change in your biological age? 

Alex: Yeah, so that’s another good question. So when we did this experiment in mice, for the first few months, you don’t see anything and then it becomes much more profound in later stages of life. So we can basically draw like two curves, regular curves for normal animals [inaudible 9:28], does, that increases steadily. And the curve for calorically restricted animals in terms of their epigenetic age compared to their chronological age, the slope will be much reduced, right? So at the later stages of life, the epigenetic ages or the biological age of the animal is significantly lower than the chronological age of their peer animals. So we’re now giving this intervention. So we’ve done this for calorie intervention, but there’s also a lot of other interventions being tested. Rapamycin is another big one. Metformin is being tried in humans now, the team Kyle, maybe you guys have heard of that. So we’re out of New York City. And then I guess the really big hype, and what everyone is excited about is music rejuvenation, or reprogramming approaches. So where you literally reset the biological age of cell from whatever it is to zero, or some intermediate state where it just becomes younger. 

Rachel: Can you expand on that a little bit more? What is that? What does that mean? What does that look like? What’s being done right now? 

Alex: Yeah, of course. So, for a long time, people thought that was just purely science fiction that you were just not able to have aging was irreversible, and you need directional, right? So you weren’t able to reverse it. Or maybe you could slow it down, which is what most interventions have been looking at. So far it’s slowing down or attenuating aging. But what’s come out in the last few years, some work from a variety of labs in Spain and in California, and from our lab as well, is that you can in fact reverse the clock of these cells. And so the idea is that you take a cell and you reprogram it, there are a couple of different methods to do this. But the most popular one is called Yamanaka Reprogramming, it won the Nobel Prize in 2012 but the discovery was in 2006. And this guy, Shinya Yamanaka in Japan, he gave the cells four transcription factors, so you can think about them as four genes. And he forced those genes to be expressed. And in any cell that he took, so the differentiated stem cell, for example, a fibroblast, he could turn it back to an embryonic stem cell, with this process, and it takes about three weeks. Now, of course, we don’t want to turn all the cells in our bodies into embryonic stem cells, because then we would just become embryos. But if we can stop this process at the right time, and modulate it correctly, we don’t lose the identity of the original cell. So whether it’s a neuron or stem cell, it will remain a neuron or a stem cell. But instead, we do reduce the damage that is accumulated in that cell. And so the damage is effectively translated into age. And so we reduce the biological age of that cell. So that’s literally rejuvenation. And some of you may be familiar with some of the biotech efforts that have been pretty prevalent in the last few months. But the formation of altos labs, for example, are backed by Jeff Bezos, several 100 million dollars directed at this reprogramming facet of aging biology, where we can literally turn back the clock. 

Rachel: What are the use cases that you’re likely to see kind of using this technology or using this rejuvenation approach? First, like, is it cancer research? Is it something else? Is it purely kind of a play on longevity and health span? Where are we going to see this come to market first? 

Alex: So I think it’s very multifaceted. A lot of people are starting to try to target aging itself. But for some reason, the government and a lot of investors have mostly been focused on diseases where you have more tangible endpoints. Because with aging, you can use these clocks, for example, to see what your biological age is. But if you really wanted to get a really robust metric, you’d have to wait out the entire lifespan of someone giving them an intervention or not giving them randomized clinical trial type of stuff. But instead of like for cancer, right case, statistics, couple years, because there’s unfortunately very deadly. With aging, it would take 40, 50, 60 years, depending upon where you started. So I think it’ll start with these other age-related diseases, cancer, arthritis, and all these things. And it will also start in more targeted fashion. So people have been doing these things on specific organ systems, so the lab of David Sinclair and all that recently had a paper in Nature, where we basically cured blindness in mice. So mice, they became blind as a result of becoming old. If you give them this reprogramming therapy, wait a couple of weeks, they not only had their vision restored, but their age, according to these epigenetic clocks is also lower. But that was only in the optic nerve and optic system. So, I think people will start doing that maybe for the liver, which is obviously a tissue that ages pretty fast, especially depending upon your lifestyle habits, maybe the heart. I think first, it’ll be tissue specific, and then hopefully, we’ll be able to find ways to make it systemic. So that I mean, this is David Sinclair’s vision, but the idea is that you would take an antibiotic, maybe like Doxycycline, and then literally rejuvenate yourself by a couple of years, in a matter of a few days. 

Rachel: That would completely change the face of medicine. And it’s so interesting. 

Alex: It’s a good idea. 

Rachel: Yeah, so interesting to kind of think about what the future of that could look like and what the impact across kind of the world would be for health. I’d love to kind of switch gears a little bit and hear a little bit more about kind of what you do. What does your lifestyle look like? What are you doing, specifically towards kind of anti-aging or as you think about your own longevity? 

Alex: That’s a good question. So I know a lot of people who do take a lot of things. I mean, David takes a dozen supplements in the morning. I’m not that far yet. But I do try to live pretty well. I mean I exercise, I rock climb a lot and I try to eat well as well. But I think most of what I do is mostly derived through my work, I think I just want to contribute. And I really just want to make these tools that enable people to assess these interventions. Because I think if you made these platforms and these frameworks that enable other people to make discoveries, it’s just infinitely more powerful than making a discovery yourself. Like I can find a drug, maybe, that attenuates aging a couple years. But if you can build a platform that enables 10 people to find 10 such drugs, I think it’s just way more powerful. So I give us the computational work. I was experimental, in college. So I just graduated college last year, I went to University of Rochester, I worked on the Naked Maura. It’s also a really interesting animal. It’s the size of a mouse, it’s endemic to Eastern Africa, but it happens to live so far, 37 years old, maybe even longer. And it never develops cancer. So it’s one of these aging, some people call it a non-aging animal. And it’s one of the only mammals that would be classified as such. And so we were trying to investigate the mechanisms that kind of underlie this longevity and this cancer resistance. 

Rachel: That’s very interesting. I had no idea. I’m writing that down and going to look up this animal afterwards. I know you mentioned on the kind of supplementation side, it’s not something you’re doing a lot of but in terms of diet, nutrition, or supplementation based on kind of what you’ve seen, or the folks that you’ve worked with, as you mentioned, are there any specific kind of longevity-focused supplements or diet interventions that you have seen people doing, or any kind of trends that you’re excited about or see in the future? 

Alex: Yeah, for sure. So actually, in our lab, one of our really phenomenal postdocs, Anastasia, she works on finding new longevity interventions. So we’re testing a couple of drugs right now. And a lot of them are very promising at extending both lifespan and health span in mice. Of course, the big problem with all these experiments that people have been doing for a couple years now is that it has yet to be translated to humans. So it’s hard to tell exactly which supplements or which particular lifestyle may be beneficial to aging. Metformin is a pretty commonly taken drug, David still takes that. A lot of his work is directed at NAD metabolism and some metabolites. And it’s involved in a lot of redox transport and things like that in the cell. And so he takes a couple of drugs to boost that as well. But there is I think, at this point is purely speculative. In his case, it seems to work. I mean, he looks pretty young, I would say. And a lot of people say that it does work, at least maybe it’s the placebo effect, or maybe it’s a really effective drug. But I think in the next few years, we’ll see really pretty robust studies coming out in human. Not just in model systems really in humans that can point to the efficacy of a few drugs that maybe would be useful for this. 

Rachel: And how do you think of the N=1 kind of testing and experimentation approach that the people are starting to do versus the more standard kind of randomized clinical trials? And how do you think those two types of kind of data sources and testing will kind of work together in this space going forward? 

Alex: I think these approaches are actually very complimentary, I think you need a bit of both. So I think the N=1 will really be kind of a proof of concept. People do this and they find particular drugs or drug cocktails, it’s likely going to be several drugs. And as well, not just like supplements and drugs, but probably also changes to the lifestyle and fitness and all these things. But I think once people kind of shed light on this for the N=1 experiments, I think that’ll in a way motivate regulators, especially the FDA and CDC, etc. to really do and commission some more large scale trials, like you’re talking about randomized clinical trials. We also think that some, not a lot, but a small fraction of longevity is genetic. So there’s a lot of work. It’s going on right now to kind of uncover the specific genetic variants that may underlie longevity. It’s really a mix of environment and genetics, and it’s much more of the environment than the genetics. We estimate the genetic factor is about 10 to 20% at most. So that’s a good sign. It means you can really modulate your longevity and your health span based on how you live. But I think yeah, these N=1 experiments and a lot of people are doing this biohacking. I mean, this group specifically, I think he’s into this a lot. I think that’s really setting the framework, the groundwork for a lot of these upcoming trials, which will really help to validate more robustly with statistical significance of these things to do anything. 

Rachel: I’ve been thinking a lot about how health kind of is going to work in the metaverse and web three, and it almost sounds like just from your explanation that kind of the N=1 is more on the kind of creator and community generated. So clinical trials, research, and the way that we look at discoveries, it almost sounds like it’s going to change to be a much more kind of community created and community-driven approach versus the more standardized and centralized approach of the past. 

Alex: Absolutely, I would totally agree with that. I think it’s a really good direction to be heading in. I think democratizing science and making it available to different people and helping them make their own choices and then sharing the results of these choices with the community, especially in this age of the internet and really rapid information transfer, I think it’s really key. That’s the problem with these clinical trials, even if you have these endpoints, like that’d be genetic aging and things like that. That same trial is I mean, it’s planned to take several years, if not even decades, to run. And so I think these are very slow. And so if you want things to go faster, I think it’s really important to have people like in groups, who experiment on themselves, if you report to the community, how things are going, and if certain drugs are good, or they’re not good, side effects etc. I think it’s really important for sure. 

Rachel: Awesome. I love to switch gears a little bit, and go to our audience questions. And for those of you listening, if you do have additional questions, please add them to the expert stage chat, and we will get them answered. So Steven asked if anyone records or post notes. Sorry, that is for us. So Steven, asks, are there any reset or even reverse protocols for those dealing with or getting over chronic inflammation? 

Alex: So that’s definitely a pretty big area of aging is called inflammation, I actually combine the word inflammation and aging. So a lot of people think that aging, either is caused or is a consequence of inflammation that occurs in the body. So there’s a lot of studies in mice that are looking at this specifically in the context of senolytics. So senolytics are molecules in selectively targeted senescence cells. So these are basically like old cells in your body. It’s not conclusively shown that just targeting these cells will make a person live longer, but it does seem to help in that regard. Yeah. Can you repeat the question? 

Rachel: Yeah. Says are there any reset or even reverse protocols for those dealing with or getting over chronic inflammation? 

Alex: Yeah. So at the moment, I guess the answer would be no. I don’t know, people have done the optic nerve with this reset reprogramming idea. Some people have done it systemically, but they haven’t looked specifically at chronic inflammation. I think it’s a very difficult thing to look at, actually, in mice, because a lot of mice don’t really develop this. A lot of them died from cancer in old age. So they don’t develop heart disease, they don’t develop these inflammation things that are very common in humans. So I think for that we’ll really need some human trials and at least cells in a dish first to find out if it works, but there’s definitely a lot of promise for sure. 

Rachel: Great. And then this question is from Ty, can you explain the pros and cons of different aging tests that are existent today? We talked a little bit about this. But he mentioned things like telomere length, epigenetic methylation, he’s saying he just read a manuscript detailing a new cost effective methylation sequencing for like, I guess, time sequence, and would love to hear any thoughts you have on those different approaches? 

Alex: Yeah, so I’m actually on the time seat paper. It’s my colleague, Patrick is the first author. He’s in Sinclair’s lab, and I’m the third. 

Rachel: Awesome. 

Alex: So he did, yeah, he developed the experimental approach, and then I complimented it with my computational tools. And it’s really gonna enable really cheap epigenetic age profiling. So, so far, they can do it between 2 to $5, which is really like 100 fold cheaper than current methods. So we’re really excited about that. I would say, if you’re interested in measuring your age, so far, the most accurate biomarkers are epigenetics, specifically DNA methylation based, so the things that we’re developing, there are couple companies that offer this at the moment. But again, it’s really expensive. So you have to be willing to pay like 2, $300 for it. At least for now, I think in like maybe one or two years once these technologies like tank seek are being developed independently as well, in a company setting. So once the company is able to offer them, I think it’ll be much cheaper. So yeah, I would definitely do epigenetics. There are a lot of different clocks that people are building some of the transcriptome, some using telomeres. Obviously, aging is super multifaceted. So you can measure a lot of biomarkers, but the consensus of the field is that this epigenetic change is really the most accurate way to measure your biological age. 

Rachel: And for the companies that are offering an intervention based on biological age from telomere testing, what is it? Is the science there around telomeres, is it not? Like why is that kind of on the market and why is that an intervention that people are talking about in your opinion? 

Alex: So telomeres actually were one of the first things that people looked at in regard to aging, because they’re basically the ends of your chromosomes. And they just happen to get shorter, at least in most mammalian species, they get shorter with time with age. And when they get too short, your cells undergo this senescence process and become basically useless and old. And they’re actually damaging to the other cells around there. And so as you accumulate these cells, you age as well. Now, I don’t know if yeah, it’s an interesting question. 

Rachel: But it sounds like that was kind of the earliest test. 

Alex: That was the earliest. But there’s, I mean, people have mostly deviated away from it. Some experiments still report some telomere length experiments and their figures, but mostly people. The thing with telomere length is that it’s kind of like one number, right? You get like a particular number. Whereas with other types of molecular data, like the transcriptome and metabolome, the epigenome, the proteome, you have so many more dimensions to it, which in my opinion, really improves the accuracy and the resolution of whatever metric you provide people. 

Rachel: Okay, got it. And then this question is from IJ. Is there any reason why African and East Asian natives seem to aesthetically age slower than the rest? Is it diet related or the amount of melanin? And then I’ll add on have you found that these populations kind of biologically age in a different way as well? 

Alex: That’s a good question. There might be some papers about this. I’m not totally familiar with the science. Again, I work mostly like fundamental method development in mice. It’s easier to handle them. But there are some papers that indicate that a Mediterranean diet, for example, so people like Italy and Greece and things like that, they seem to have a slower trajectory of aging, so attenuated aging, and then East Asian African populations will be very interesting to look at that for sure. I think there’s just not enough data at the moment, but if someone is willing to sequence I think you will need not only cross sectional sequencing, but longitudinal sequencing. So you will need to track people over time in these different ethnic groups and different localities and then find out kind of if there is an effect. There very well might be, and it could be linked to diet for sure. I think diet is a huge part of aging. So interesting question, unanswered at the moment, but interesting for sure. 

Rachel: And then within our lifetime, this question is from Emily, how long do you think people are going to live? 

Alex: Emily, this is a tough one. I mean, I guess it all depends on how much progress is made. This year, I’ve only been in the longevity space for a couple years. And this year, I’ve never seen as much funding pour into it. There’s literally like billions of dollars being poured from crypto billionaires, regular billionaires, as well as just regular, like, huge consortiums that are really like focused on these powerful reprogramming and age reset approaches. So if we’re able to get that done, either on an organ system specific or even on a systemic level, combined with some other interventions, such as attenuators slow down aging, I think it’s reasonable that people in our lifespan will live to 150, if not more, depending on how the world goes of course. 

Rachel: In such rapid intervention that’s happening, it would seem that it can push lifespan, but it will definitely be interesting to see over the coming years, kind of how far we get. And then the last question, this is a great one to end on. But I know we talked a lot about diet, but are there any other kind of easy interventions that people can start doing towards anti-aging that you would recommend? 

Alex: So there are a lot of companies that are kind of pivoting to the space and who are offering these molecular trackers of aging, and then they give you recommendations based on that. Again, at this at this stage, I think the science is not strong enough to recommend anything specifically. But of course, you can find a lot of people who are very interested in pharmacological and dietary interventions. I think, yeah, Metformin being one of them. Personally, I don’t take any of these drugs yet. I don’t think there’s enough backing scientifically to show that they work. But if the drug doesn’t cause any side effects, and if it makes you feel better, and if it makes you feel younger, that’s also a huge thing. There’s recently a paper from Alex Chatango, the CEO of Insilico Medicine in Hong Kong. And he developed the cloud based on someone’s subjective answers to a survey, so he calls it Psychological Age. And he shows that if people think about themselves as younger when they look in the mirror, they actually will exhibit a younger phenotype. So if taking these drugs help you to feel younger then they may in fact actually be making you younger even though they may not have the physiological effect that you would expect. 

Rachel: Please send that research to this group, I would love to read a little bit more about that. It’s such an interesting kind of take on it. 

Alex: Yeah, I’ll send it over very soon. 

Rachel: Perfect. Well, thank you so much for joining us today. This was very interesting and informative. I really appreciate you taking the time. 

Alex: Yeah, thank you so much.

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