Morgan Levine | On the Future of Aging

XHope Special with Foresight Fellow Morgan Levine

In a podcast given by Allison Duettmann and Beatrice Erkers for Foresight, special guest Morgan Levine discusses findings regarding understanding the language of the epigenome, alongside implications of epigenetics on healthy cells. Being the founding principal investigator at Altos Labs, as well as an assistant professor at Yale, her current research on epigenetic mechanisms of cellular and systems health provide great interest into the future of aging, disease reversal, and technological advancements across the field overall. The following discussion provides further insight into current advancements for scientific research and data collection, as well as other pieces of information regarding what it is like to be spearheading these advancements.

Allison Duettmann: Welcome to our podcast! We are really happy to see so many of you here. Today, we have the wonderful Morgan Levine joining us as a guest. Being the founding principal investigator at Altos Labs and an assistant professor at Yale, your expertise in researching epigenetic mechanisms of cellular and systems health is undeniable. Let us start with a quick introduction. Feel free to introduce yourself, what you are currently working on, and how you came to commit yourself to this specific focus.

Morgan Levine: Of course, I am excited to be a part of this and thank you so much for having me. My lab is working towards better understanding molecular changes that cells undergo, which we believe to be a part of the aging process. From the framework that the epigenome is the operating system of the cell, as it gives the cell its phenotype, traits, and functioning ability, we focus a lot on epigenetics. Truthfully, I did not think that I would be a scientist growing up. It was not my plan from an early age, but I found it to be my calling right after my undergraduate studies. Regardless, I had always been interested in aging since my father was in his 30’s when I was born. I used to be very concerned about him being a bit older, until I got exposed to the idea that we potentially have the power to intervene in the aging process. From that point, I became quite interested in figuring out why we age, how this can be slowed down, or even reversed to an extent.

Allison Duettmann: That sounds wonderful. Was there a particular moment in your life that felt like a determining point to shift to this current track? Or was it more so a gradual progression of individual steps throughout university that got you more interested in the specific field?

Morgan Levine: I give a lot of the credit to my husband, as I met him right after my undergraduate career. He was in a physics PhD program and we had many conversations around related topics. While he was not working on aging or anything of that nature at the time, our intellectual discussions got me quite interested in pursuing a scientific career for myself. He truly motivated me and I figured, if he can do it, so can I! I soon enrolled at USC and their aging program to pursue a PhD of my own. From there, the simple exposure to the faculty members themselves really solidified the decision as being a true fit for me and my interests.

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Allison Duettmann: What a journey! Could you provide some color as to what exactly you are now focused on? Furthermore, feel free to give some behind-the-scenes insight as to what it actually means to be a scientist day-to-day and what your job entails.

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Morgan Levine: Of course. So we are truly focused on whether we can understand the kind of language of the epigenome and how those changes differentiate what we consider to be a healthy cell. We think that dysfunctional, unhealthy cells accumulate with age, so we are curious as to what drives those changes. Is there any way to reverse them? Or is it more so a stochastic error that is too difficult for such reversal? Additionally, my current day-to-day at Yale will change in the near future as I am transitioning to the Altos lab soon. For the past few years, I run a team of about 11 to 12 scientists within the labs. About half of them are traditional scientists, which we consider bench scientists, sitting in the lab doing a lot of cell culture and rodent work. The other half of our team are computational scientists. Given my current academic position, I do not necessarily spend too much time in the lab, other than visiting. I still do my best to run data and do a lot of analysis when possible. Most of my time is taken up with meetings, administrative tasks, and brainstorming ideas. Once I transition to Altos, I hope to have more direct interaction with my team, alongside others in the field that will be close by, for a more developed, collaborative environment overall.

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Allison Duettmann: When you mention this process of change you are currently undergoing, can you share a bit about that upcoming transition? How is that transition from academia into your new career role going? Is there anything you can share about this process?

Morgan Levine: Yes, so the lab is structured in a unique way as a private institution, moreso like a university. In my lab, the day-to-day dynamics will not necessarily change too much. I will still have the same team size working on almost exactly the same types of topics. The biggest change is that I will not be preoccupied with academia-related responsibilities, such as administrative tasks or grant writings. This shift will allow me to really absorb all the scientific discussions taking place, as opposed to time consuming tasks like committee meetings and so forth.

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Allison Duettmann: Of course. We recently interviewed Clarice D’Aiello from our biotech group. She mentioned spending about 30 hours per week writing grant proposals, which I found mind boggling as I did not know it is time consuming to that extent. I am really happy to hear that you are getting to feel that shift in schedule soon in order to have more time with the scientific process overall.

Could you provide a bird’s eye view of the field? Also, given how outspoken you have been on Twitter, could you elaborate a bit on what you mean when you say you are not as excited for the snake oil that has seeped into the field as well? I salute you for speaking out on it as much as you have so far. It is a true need and I think it is really inspiring given how you are doing your best to make sure the community is flourishing in a positive manner. Also, for an outsider, what does the space and focus on aging entail? What gets you excited about it?

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Morgan Levine: We are at a really unique point in the field. Aging has always had snake oil as we are naturally opposed to our own deterioration and mortality. TIn other words, the realm of these discoveries is attractive to those engaging in pseudoscience because it is very easy to tell someone “Oh, I have a solution for what is probably most people’s biggest fear in life.” Additionally, as science is accelerating more than it ever has, it is becoming difficult to distinguish real, rigorous truth and valid science. A lot of the snake oil and pseudoscience will throw vague terms around to make their discoveries or products seem like valid findings to where people do not know any better. It is tricky because you can find research from one source and then contradictory research from another. I would recommend for people to look at who is selling a product. Are they independent academics or more so financially invested in it? Ultimately, I recommend just being as cautious as possible in those situations as the field is inevitably becoming more saturated while findings advance.

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Allison Duettmann: I think that is especially important to keep in mind in the space of this research. In your previous biotech and health extension seminar with Jamie Justice, we focused on biomarker standardization. I feel as though that is definitely on par with the quest of figuring out what exactly we are trying to do as a field. Perhaps you could bring people up to speed a bit on why biomarkers are interesting and relevant, and why standardization is something to focus on? Why are we trying to hone in on the metrics here?

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Morgan Levine: Yes, biomarkers are critical to anything related to the field of aging, especially human aging. In the past, we always relied upon animal studies for answers around mortality or disease, which in the timescale of human study is simply unreasonable. As a result, we need to have biomarkers that can highlight possible therapeutics worth implementing, as well as assess in real-time how these interventions are going. With that being said, all of the different subfields in aging research are inevitably plagued with some pseudoscience surrounding biomarkers. It is very easy to sell someone a biomarker that may be invalid or unreliable because there is nothing for anyone to check against it. For instance, if someone gives me a biological age estimate, I have no ground truth to say whether it is true or not. For that reason, I again think it is truly important that we have standard criteria in place. The criteria I work around include incorporating variables that correlate with chronological age.

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The tricky component is any sort of divergence between chronological age. Let’s say you are chronologically 50. That difference as you divide should actually be biologically meaningful. We can test that in a variety of ways. For instance, you can question whether people with the same ontological age differ in terms of disease incidence or mortality risk given their biological age. So that is sort of how we go about validating these biomarkers. Even more so, another important thing that I believe has been somewhat overlooked in the biomarker field is that of the reliability of biomarkers. If I measured the same biomarker twice in an individual within a short amount of time, would I get the same answer? It ends up not being that meaningful if it is plus or minus five or even ten years. All in all, I think these are all really important criteria for evaluating biomarkers, in order to ensure the correct results with what you are using. And, of course, these will improve with time as well.

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Allison Duettmann: Thank you. I think it is really establishing an entire field from the ground up, so setting this foundation is extremely important. Thank you for paving this path forward! You provide a great vision for folks that may not know why this is something worth caring about. Next up, we have Beatrice Erkers with a few more existential focused questions, which is a special twist we like to include in our podcast. We are truly trying to inspire people about why the long-term future for themselves, and civilization as a whole, matters and is an exciting topic. I will now hand the questions over to Beatrice.

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Beatrice Erkers: Hello, and thank you for your input thus far. To preface, these are more philosophical questions than you might be used to! We were particularly interested in hearing your perspective as a scientist on these questions, since the concept of the podcast is to get differing viewpoints. Firstly, if you think about the concept of existential hope, do you have any? Or can you envision any potential futures of existential hope? If so, what do they look like, as compared to a vision of existential angst for example.

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Morgan Levine: Of course. If I am understanding your question correctly, for me it is the realization that we have this power to learn whatever we want. With an exponential growth of science and technology, we now have the tools, alongside our imagination, to strive for these goals. Humans have shown that we have amazing potential to achieve things that once seemed impossible, so I feel that maintaining this optimism, while remaining realistic, is important.

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Beatrice Erkers: Yes, that fits in well with what I wanted to ask you next. To make these goals happen, we probably need new technology or further advancements in the field of science to reach this future. I am assuming on your end of antiaging, that may seem irrelevant. How does that fit into this future? Also, do you envision any other technologies you think that are important to get there, as well as any potential risks?

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Morgan Levine: Yes, I think to be able to do this it comes down to computational sciences too. From my perspective, to realize the goals we have for aging, we also need to be able to model and predict how to intervene in this complex process. That will require strong computational infrastructure and computing, alongside mathematics and data science. Humanity is already amassing huge amounts of data, but just having the talents and abilities to analyze this, as opposed to getting what we need out of it, requires a major leap forward.

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Beatrice Erkers: And do you see any risks with that data as well?

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Morgan Levine: Definitely. Data science is not perfect, so we need to ensure that we do not take everything coming out at face value, remaining critical throughout the process. We are also still injecting concepts, such as morality, to make sure we avoid any possible risks. For me, the thing that worries me most about successful aging intervention is that it may cause increased disparities, more so than what we see today. The biggest differentiator in lifespan today includes socioeconomic status, so I am a bit worried about that growing as we move forward. Making sure we are keeping these things in mind, and considering advancements to biotechnology, is important.

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Beatrice Erkers: That makes sense. Would you describe yourself as optimistic about the future? If so, what makes you optimistic and why do you think that is?

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Morgan Levine: Yes, I am very optimistic about the future. I feel as though ever since I have devoted myself to this field, the number of exciting discoveries to come along is huge. These advancements will only grow with time. It is very hard to speculate where we will be in the future, but I can imagine that there are huge discoveries on the horizon for aging and other related fields. I believe these have the potential to transform medicine, maintain health, and impact how we view life overall.

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Beatrice Erkers: Of course. I think one thing we often come across in this group is that people find it hard to think of the long-term future in ways that are concrete, because we simply do not know what is going to happen. There is a lot that can affect what direction our world takes, both good and bad. Do you have any thoughts on why you think it is rare to think positively to the future and have that outlook instead?

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Morgan Levine: I think we have to do just that. There are always going to be current events and things which could possibly go wrong that are not necessarily within our control. However, I think simply realizing what is within your control helps to create this positive outlook towards the future, doing what you can even when not-so-positive events are occurring. As opposed to dwelling on the negatives, figuring out how you can create a better future and focusing on what you can do is important.

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Beatrice Erkers: That is a nice way of looking at it. If we sort of imagine someone new entering this field, is there anything in particular that you would recommend they dive into or where they should focus first? For instance, any recommendations for inspiration regarding a book, a movie, nonfiction, fiction etc?

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Morgan Levine: There are truly interesting books that are not necessarily aging books. There is one that is in regards to biology and life that does not directly talk about aging, but so many topics you can extrapolate to some degree. I am drawing a blank as to the author's name but it is called Antifragility. It is fascinating for understanding the complexity surrounding these topics and rethinking life as a whole. I always think of aging as in line with the overarching questions regarding what is life, what makes life complex, and what maintains complex life. I recommend simply looking for any books that touch upon this overarching concept.

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Beatrice Erkers: If someone new read these books recommended, what do you think they should specialize in? Is it something particular within the longevity movement that you think they should specialize in?

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Morgan Levine: I truly think data science is going to be a major player in dealing with the future of how we go about science. We need true molecular and cellular biologists to make sense of data science. However, so much of what we see with this transition to big data, machine learning, and complex topics will require not only modeling and tracking, but also proper intervention. In understanding these phenomenons moving forward, it is really going to require strong computational tools.

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Beatrice Erkers: I was quite interested when you mentioned benchwork scientists being a part of your team, alongside computational scientists. Kearney, for example, is cutting a workshop later in the year on enabling tools for biotech. There is not only the software automation, but a lot of this physical lab automation. Are you looking into one as well within your lab? Or is it mostly, “Okay let’s get the software angle right first, before we start thinking about physical lab automation”?

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Morgan Levine: Altos lab is definitely looking into these sorts of things. I am not personally relying on the infrastructure offered there, but I still think that it will really accelerate our science in due time.

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Beatrice Erkers: I talk to a few people who are actively working on it. They usually say that one big problem is trying to figure the physical automation out within individual labs as opposed to with students. All of the financing and boutique work required can be tricky. Nevertheless, if we could have great templated solutions later on, then maybe it could drive greater potential forward for getting this right. You mentioned earlier the vast amount of data analysis we have to get better at. Do you think that there is a particular bottleneck that you often run into? For instance, one thing that comes up at our competitions is that there is not the best data standardization, and differing metrics throughout. Are there any specific bids? If someone could solve this, could it unlock a lot of progress on your end?

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Morgan Levine: I think this is a huge issue in the field. There are so many labs around the world collecting data, but having it harmonized into usable formats that people can use with open sides that works is where the problem lies. You touched upon it. The other thing that always worries me is that the only data or papers that make it into the public sphere are things that worked or had positive results. This can bias science when you’re using really advanced computational tools because these samples are only experiments that showed a positive result. This poses a risk as you might not be getting the real answer as this bias is built into the data being analyzed. For me, I think the bottleneck is having true, open science like what you are thinking. In which people put up data of all experiments to make the bias sounder as it is ultimately about searching for the truth. It comes down to the way science currently incentivizes people which is unintentionally creating this skew in the scientific community.

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Beatrice Erkers: Right. If you can learn from mistakes, fixing this could unlock great potential, however these mistakes are sort of hidden up till now. I think what you mentioned about open science is accurate. We just did a decentralized science track at a Web Suite conference in Denver and there’s now a ton of tool building within the more crypto-leaning spaces trying to move into science. I personally believe the two are still quite different. Are there any specific open science projects or efforts you are currently aware of? I feel like there is a lot cooking right now. What do you think?

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Morgan Levine: I mean, there are good open science data resources online that I think have really influenced how we see these things. We get a ton of data from our gene expression omnibus, which is all open science, but not well harmonized. People can put up whatever data they want, and half the time I feel as though there are some not putting up all the data for personal gain. However, things like TCGA, such as the Cancer Genome Atlas, is a good example. There are some for Alzheimer’s disease, UK Biobank, and so forth. I am truly excited about all of the private sector involvement, but I do worry that this will change the move towards more open science. There are potential companies that are slightly less open than academic labs per say, however, I may be wrong on that, and I hope I am.

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Beatrice Erkers: Wonderful. It sounded like when you said that much of the work you may be doing looks a lot like university-based work. I do think that oftentimes founders, I have met at least, of private companies have an enlightened view of what it is they are doing. I believe that more long term bets that I have seen in the public sector and organizations tech is really exciting given people stepping up. Do you have any advancements coming out of Altos that you are able to share with us?

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Morgan Levine: The thing exciting me most about Altos, which was profound enough for me to be willing to leave my academic position, is that there are not really stated goals in terms of discoveries. The set up is more of a bell labs model where we ask the most interesting questions we can think of, such as high risk problems to work on. There is no assumption as to what could come out of it in terms of something true and translational. With that being said, most great discoveries that have gone on to impact human health or technology came out of basic science. So I think that this is something that made Altos truly intriguing to me as opposed to them chasing specific discoveries. We more so just want to understand the problem, and will most likely discover things we never knew of. Take CRISPR for instance. There was never a goal to discover it, it just came out. This is the most basic science you can imagine. The idea that there will be discoveries similar to that magnitude from doing what we currently are is truly exciting in itself.

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Beatrice Erkers: I think that is a great way to look at it. Also, those are the sort of bets that haven’t been taken very much previously, and now people are willing to take them. I think this is an extremely exciting time to be working in such a space. To segue back into the more existential hope: This part of the podcast is inspired by this one paper on existential hope that Toby Ord wrote which references talking about a term eucatastrophe. It practically is the opposite of a catastrophe where the value of things increase for the better. I wonder if there is an event that you could think of, especially right now, in which after that moment the world looks a little brighter than before? For instance, is there a specific scientific event that you could imagine in our human future that would create for a much more hopeful reality. Is there such a switch point?

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Morgan Levine: I do not want to be a pageant person and say world peace, so I will just stick to science for now as it is what I have. What would be hugely monumental for me in the aging field is to find that we can extend life through treating diseases and slowing their progressions, and even possibly reverse it some time down the line. It is difficult to exactly note how that progress would look like, as many can disagree, but I would think a 10 year age reversal is very substantial. Simply giving people more years of healthy life allows for the ability to keep doing all of the things that make us want to stay alive. That would be a big hope from my perspective.

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Beatrice Erkers: That sounds like a lot to me! I know that you are outspoken on Twitter, as Allison mentioned, regarding the more immoral list. I feel as though you ground people back to the reality of what these breakthroughs can feasibly entail. I think those having the massive, unreachable expectations of the aging field will only lead to a lot of failed hopes down the road even though it is truly magical. I hear 10 years and I think, yeah I would take that. It seems pretty ambitious to me! Do you have a specific vision or a way to color in what it would look like to live in a world with those possibilities? I know this takes a more creative writing form, but I think it would be nice to kickstart people's imagination to the very real possibility that could lie ahead.

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Morgan Levine: Let’s say we imagine this happening in 30 years or so, but who knows how long truthfully. Whatever the case, by that time I would be eligible for Social Security. While we stereotype that age range, elderly are still very functional. Say I would not be too different in my physical capacity than where I am today. I would not have developed any major conditions yet, keeping in mind that most people that age have developed at least one major chronic condition. In the worst case, say I would have, but it would be able to be reversed to some degree. That to me would feel like I haven’t lost any vitality that I have today. While I may not look younger, I would feel younger and healthy nonetheless, which is more than enough. I believe that aspect in itself would diminish the dread many of us have towards aging, as opposed to the chronological component itself. If we can completely disentangle those aspects, we will not be dreading our next birthday because it would not entail an inevitable loss of functioning. I think that would be amazing and I feel that we would be able to enjoy life further with less of that sort of existential dread to some degree.

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Beatrice Erkers: I also think that there could be a lot of collateral benefits for many societal issues we face down the line when we are just kicking the can down the road. I think one thing that is really exciting is that added time with friends and family, right? That seems like a motivating factor worth it in itself. Also, I found what you said about the disparities at the beginning to be quite interesting. In my mind, I saw how it could also decrease disparities in the sense of decreasing the costs that come with treating conditions found out later rather than sooner because there would be interventions and reverse pathologies present. It could possibly become a cheaper alternative to allow people within lower income brackets to have longer, healthier lives. I wonder if that also sounds plausible at all?

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Morgan Levine: We always talk about extending maximum lifespan and aging as if that is the ultimate goal. However, there is so much we can do that will make significant differences in lifespan. Actually, the greatest increase in median life expectancy would come from saving all the individuals who are aging at a much more accelerated rate, making them look more like what we consider the exceptional ages in today’s world. That is probably going to be easier than just figuring out how to live to 160, 180, or even 200 per say, or whatever these expectations may be. In the end, it will be hugely beneficial to society, especially on an economic scale as you mentioned, given the accumulation of chronic diseases that are expensive to treat. Research shows that centenarians are actually much cheaper to treat in their last few years of their lifespan as opposed to people who died much earlier. That, and simply the societal benefit in terms of the ability of the population to continue working and contributing to society longer, for instance.

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Beatrice Erkers: I think that extrapolating a little bit down the line, the varying types of technologies needed for that require more specializations for such complexities. Do you see any potential areas where you feel like different technologies or areas you are focused on will, or should intersect? Do you have any hunch as to what technologies may be like? What different types of scientists do you look forward to collaborating with soon?

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Morgan Levin: I completely agree with this. I feel like when I structure my lab, I try to get as multidisciplinary a group as I can possibly find. That multidisciplinary aspect has also benefited me most, when thinking about my own training. I have never necessarily been a specialist in anything. I find myself to be more a jack of all trades and an expert of none, and it has served me quite well. I can listen to people in very diverse fields, take all of that information, and integrate it into my framework. There is a lot to pull from and it is sort of a sampling landscape in terms of information and science. It is hard to say which things will be best in terms of intersection, aside from biology, data science, and mathematics. There are all kinds of complex system tools out there that can bring huge potential when being applied towards biology.

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Beatrice Erkers: We just had a truly fantastic nanotech researcher in our biotech group and I was blown away by the types of screens we can come up with, as well as the effects different types of quantum states could have to produce different biological states down the line. I think you will discover there are so many possibilities in these intersections. Well, that is it for me. I will finish up with a last philosophical question to close this meeting. It is a jump, but I think it is a great way to collect some wisdom nuggets for people. What is the best advice you ever received? If there is a story around it, feel free to elaborate on that as well!

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Morgan Levine: For me personally, it has sort of been the idea of not letting your current state dictate where you want to go. Coming from not knowing I wanted to do science, I was very self-conscious entering the field that I did not have the right expertise and so forth. I felt as though I couldn’t take classes because people would be much further ahead of me, but moving forward I have just forced myself to not get fixated on those fears that come to the forefront. I am always surprised each and every year when I look back, seeing just how much I have learned and developed. Just do not let anything, especially yourself limit you. Sure I am going to mess up, not always know what I am doing, or be insecure in what I am thinking but not letting those inevitable moments hold you back and diving head first will do wonders. You will come out on the other side better off.

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Beatrice Erkers: I think that is great advice and applicable in society on a much larger scale. We do not necessarily have to be defined by what we currently are. It is very hopeful. I think those were all my questions. We could take a few audience questions. I think we had one from Walter wanting to know whether having the trim trials already demonstrated persistent multi omics age reversal.

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Morgan Levine: To me, I don’t think it has proven age reversal. I think there may be hints of it, but we need a lot more rigorous testing, which goes into the issues with these biomarkers. Not that they don’t work, as I am a huge proponent for them. However, I think we can keep making them better, as opposed to simply taking them at face value given assumptions, biases, and potential confounders that need to be considered with something like reversed age. I do not have the best advice on how we should do this yet, but I think there are always traditional, primary outcomes to take into account as well. I am optimistic that we can have a reversal, but I do not think it has been proven yet.

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Beatrice Erkers: We’re definitely on the right track. Great, thank you so much, Morgan for taking the time to join us here. Also for taking the opportunity to think about these philosophical questions and sharing your thoughts.

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Morgan Levine: It was really fun and my pleasure, thank you.

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Beatrice Erkers: Thanks for experimenting with us and for your inspiration to so many people in the field. We appreciate you giving us a small personal look. This is very useful for new books as well and I love what you said about the experience angle. Thanks again for joining us and have a wonderful rest of your day.

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Morgan Levin: Thank you guys, that means a lot. Thank you.

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