Aging industry blindspots | S Arrison, 100 Plus Capital, K Pfleger, AgingBiotech.info, M West, AgeX

7:30AM Feb 12, 2021

Speakers:

Allison Duettmann

Lynne

Joe

Sonia

Tom

Creon

Keith

Robert

Jean

Karl

Mike

Matthew

Cosmo

Keywords:

aging

cells

tissue

age

point

area

measure

question

telomeres

problem

hallmarks

field

tools

quantify

put

proteins

technology

called

companies

senescence

Hello, everyone,

welcome to for science, biotech and health extension group sponsored by 100 plus capital. This is the first keynote meeting of this year. And we had one meeting already a month ago in which we just discussed general goals for this year. Now in this meeting, we're going to specifically focus in on the health extension industry and discuss what specific areas in the health assessment industry are left under explored where a new project on Alliance could make significant progress. And to provide you a little bit of a context for that, this year, during the first half of the year, we shine light on a potential area for radical progress that are still left under explored and such as Today's focus on industry. And then in the fall of this year, we will be supporting efforts for solving them by an accelerator like structure. And we have just opened applications for this accelerator. And you can review our mentors at the bottom of our keynote program, which is accessible via the foresight website. So I will quickly share my screen just to give you an understanding of where to look. And in case you want to apply. Alright,

so if you go on our website, under program so up here on biotech health extension on the program, you'll be directed to the biotech and health extension program. And here you'll get just a quick brief introduction of what this group is about. And then we have the January meeting already with goals. Today we're in the February meeting, we will discuss industry blind spot, and we'll have a variety of different meetings in which we discuss a variety of different areas in the first half of the year. And then in the second half of the year. Starting really in late August, we're going to be discussing and we're going to have a space in which different projects so this is all of you guys who are making progress on aging can apply and and to join our accelerator. What this means is that we have a variety of mentors including Steve Howard, Niels ragga, from Apollo etc are really great from sens Research Foundation, Andrew Scott, Jim O'Neill from cents reason from repair biotechnologies, to bed slacker and Tina Woods from Clara health, Morgan Levine from Yale University, Gordon Lau from the University of SIGGRAPH, Daniel Hall from Harvard Wyss Institute, Joe is down from the Max Planck Institute for aging. Kristen fortney, from bio age, Felix power from Cambridge, magnetical Angelo from longevity technology, and Peter Sonic from longevity tech fund, all of those will be mentoring projects. And you can apply it while application form right up here. And once you have applied, and we'll be accepting you, and if you are not already in the group into the group, as you are already in the group, then to take some time and during the September until December in which you get mentored by the mentors, we have some financial grants available as well for your project. And then in December, we're going to do a final report out and hopefully get you much more follow up funding. So if that sounds like something that your health extension project could make use of, then please apply now applications are now open. And yeah, I'm really looking forward to lots of protest certifications, I know that a few projects, already were forming the group, and but we want to cast a broad net. So please don't feel don't feel constrained by the topics that we'll be discussing throughout the next month. This is definitely just a few suggestions. But you know best I think with your local knowledge, what kind of project is needed, but not to make progress. So we look forward to your to your applications. And let's turn back now and to end the topic of today's meeting. Today we have one of many sessions through through the first half of the year in which we explore specific areas and shine light on specific areas in which perhaps a project could make significant progress still, and today we're going to be focusing on what areas specifically in the industry are under exploited for potential progress. And for that, we have Mike West calculator and Sonia Arison here to give three times about 10 minutes presentations answering the questions which are the top one to three areas in the industry that are significantly under explored for progress. And then we'll discuss as a group and to participate it would be fantastic if you haven't done so you want to take a look at the second document that I shared and that is I'm going to share it again just for those that are late and that I think you should have that in the Zoom Room now as well. So this one is the document on which we collect a few challenges so if you want to voice your opinion there as well then please do that on that challenge doc it will be the basis from which we will suggest that accelerators potentially pick areas from as well. Okay, so I already added mics and Sonia suggestion to that Doc, but I think we should hear from themselves. So I think, Mike West, welcome to four sides biotechnology and health extension group sponsored by 100 plus capital. It's really, really nice to have you here. Would you care to start us off? And then we'll move on to Sonia.

muted mic.

Now, now, can you hear me?

Perfect?

Sorry. Okay. So as I would propose that the there's several major unmet needs that we ought to be thinking about, and several technologies that could be brought to bear on those needs. First, in regard to the unmet needs. There's a growing interest in aging research dramatically increasing over the last few years compared to the last few decades. And a tremendous amount of that interest is focused on life extension. And arguably, that's a really exciting area. And you know, we have evidence now numerous species, that lifespan can be extended by various means, typically by metabolic and interventions. I would argue, however, that focusing on life extension is not in the best service of mankind. And I'm sure immediately everyone's going to misunderstand what I'm trying to say. So let me try to clarify, I'm 100% in favor of life extension, extension of human lifespan. And I think it's a very honorable goal. The concern I have is being part of the baby boom population. But regardless of whether you are part of that generation, the boomers represent some 76 million Americans, and they're already in old age. So, you know, extension of lifespan is not a particularly useful modality, I would argue that the largest unmet need that we have is for treating chronic degenerative diseases associated with aging. These are accounting for nearly 80% of the what over $3 trillion in health care expenditures in the United States. Why I mean, obvious, maybe, if you have chronic arthritis, or heart failure, or whatever, it's with you every day, it's a COVID, like experience that you cannot escape from. And typical current modalities, small molecule therapeutics and so on are ineffective. For they can't regrow your heart or regrow your cartilage. So what I'm saying is economically, and for the benefit of humanity who's suffering because of aging, these degenerative diseases are, by far and away the most strategic target economically and for to alleviate human suffering. Second, the I would argue that the most powerful interventions in aging will actually come from technologies that could have a direct impact on chronic degenerative diseases. We call this new technology induced tissue regeneration. And it just didn't. Two minutes I have left, I try to briefly summarize what I'm thinking here. Early in human development. Our bodies can regenerate scarless sleep. So if you're just one day old when you're born, for instance, and you had a heart attack, which doesn't happen, but if you did, based on all the data we have and animal models, mammalian models, and some data in humans, your heart will regenerate and heal itself scarless Lee, if you're 65, for instance, and have a heart attack, you have scar tissue, permanent heart damage that could lead to death and or heart failure. The same is true throughout the body. Skin heals scar lessly earlier in development. It's part of human biology. It's not something unreachable. It's something we all once had. That biology is now within our reach to induce in an adult human using Programming technologies these days is sometimes called partial reprogramming. Using transcription factors that can take a cell back in time, all the way back to the first stem cells of life induced pluripotent stem cells. similar technology can not only reverse all known markers of aging and human cells, but can induce that regenerative state. And the evidence suggests, at least in our minds, they could be for

virtually all somatic cell types or all tissue types, for heart failure for CNS regeneration. And the there's a significant amount of evidence in support of this, both in the laboratory experiments being conducted in the last couple of years, but also in various animal models, animals, like the naked mole rat that we all know can live, an extraordinary amount of time for a rodent is locked in this primitive state where it can regenerate. And so I would argue that a very unexplored and yet very powerful modality for intervening and aging for lifespan certainly, but most critically for inducing tissue regeneration, in the context of chronic degenerative diseases of aging, is the most strategic target and probably eventually will become the major focus of intervention of gerontology in the biotech and pharmaceutical sectors in the coming years.

All right, great. Thanks for your opening statement. And if there's a clarification question, and that is fair game now, but otherwise, I would say we would for the discussion, any clarification questions?

Not for me.

I hope so. All right. Thank you, Mike.

Call Do you want to go? go next?

Mike, nice job. You were like under time and everything. Okay, so

I thought some more than

Okay, go ahead.

If you want to know. Okay, so let me just put up first of all put in a plug for aging biotech dot info in terms of looking for what is under invested or under resourced terms of areas, though, one of the reasons I made aging biotech dot info grew out of my investing is I was looking at things like breakdowns of companies by hallmarks of aging or by sens area. And you know, that tool is partially specifically designed so that you can easily sort by area and figure out what areas don't have enough companies in them. And so, you know, people should use that as they decide what companies to form. And, you know, you could use that for an exercise like the sort of underexplored topic emphasis of this meeting. But I'm going to talk about something that sort of things that are under explored, not from sort of a typical aging category breakdown, like sense or hallmarks. I want to talk about primarily two things, but I'll mention a third real quick at the end, that I think, are underexplored, due to sort of systemic reasons that I and you know, this is sort of a wish list, not a, I have a good solution for it. So hopefully, we you know, we as a community will come up with a solution. There's a lot of work on this. So the first thing is, is sort of better essays or ways to look under the hood inside the black boxes, in, you know, in biological systems. So we have biomarkers and there's lots of, for good reason. There's lots of explosion in work on biomarkers. But most of that work right now in terms of aging biomarkers is is blackbox whole organism. biomarkers like methylome clocks, and that that area is relatively well resourced and researched at the moment. Slightly more under the hood are breakdowns according to those same category breakdowns of the field, like biomarkers or clocks that are that are actually aligned specifically to specific hallmarks or sends areas or other kinds of categorizations. And people are now starting to work on those that hasn't received as much work as sort of whole organism methylome clocks or aging clocks, you know, but people like Morgan Levine has research going on to sort of create methylome clocks tuned to different Hallmark areas and there's other people doing work in that area there are companies even exploring things like how do you measure senescence cell load and, and that kind of thing, I think will is the next level to accelerate. It's not just accelerating because you can do faster trials that read out without having to wait the lifespan of the of the species in question, but you can actually look at whether your mechanisms are correct. But even under the hood, one more level we need

better assez to sort of see what going on inside. And so if you look at like engineering disciplines, right? If there's a box that does some job and it's broken, you don't generally poke at it from the edges. And and treat it like a black box, you unscrew the panel and look inside. And you can much more quickly figure out what's wrong, or how do you make it do what you want it to do. And, you know, similarly in computer science, I'm a computer scientist by educational background. And you know, there's a big flood into this field and interest in aging from computer scientists. And of course, most computer scientists as they enter the field, they all can't biomarker, biomarker biomarker. And that's because computer scientists are very used to jumping into debuggers, or inserting print statements and seeing exactly what's going on in the middle. And in biological, biological systems, that's much, much harder, but we need more of that. So we need ways to track the intermediate variables in metabolic pathways in other biological processes, you know, intermediate and long chains of chemical reactions that are important for aging, because the interventions need that to be able to verify that they're even working the way we think they're working, or to debug quickly if they're not. So to just take some examples, for example, Unity's failed trial for osteo. arthritis in the knee, right? We don't even know the high level didn't really clear the senescence cells and then simply not have the follow on effect, or did it fail to clear the senescence cells enough, right, you know, and those kinds of questions need to be able to be answered faster. And that's going to require new technology and new techniques. And those advances will probably come from fields other than the aging biology, longevity field specifically. And in fact, companies to the extent to which they are created and can sort of satisfy those needs, will probably not specifically B longevity industry companies, they'll be able to serve lots of other pharmaceutical development and other biological problems and other scientific research and academic labs. So as an example, company, one of the company that came through sort of in the San Francisco Bay Area launched and I'm just playing around investor called corellia. biosystems is sort of a has a better has an assay for proteins that sort of better than Elisa in the sense that it requires much, much less blood by requiring much, much less blood, you can take protein samples from mice longitudinally as part of preclinical trials and actually figure out better what's actually happening and metabolic pathways than you could if you needed enough blood to kill the mouse completely. So that that advance of the way that they do that has nothing to do with eight, you know, trying to look for, you know, reversal of aging or extension of longevity or anything like that. But more techniques along those lines that allow us to sample biological systems better to find out what's going on inside our, I think going to accelerate all of biology, but are going to be especially important for longevity. Another example is I don't actually know much about the stem cell history. But you know, how long did it take the stem cell field to figure out that the stem cells were mostly dying and not you know, and signaling was actually a lot of the the way that their beneficial effect was felt right, if that had happened faster, how much faster but overall progress in the field? So that's my first. That's my first thing it's coming. And, you know, I don't know how to incentivize, I think there are big financial gains to be had if that technology comes along faster. But right now, the backward chaining incentive signal, in terms of economics is broken in the sense that it's very hard to take those future games which will be diffused across a lot of places and, and cause that to create a good opportunity for a new company to come along, because they're not going to necessarily directly find a way to reap all those financial beneficial rewards. So we need some other way to jog that system. Okay, so a second thing. I think we need in this field, a lot more emphasis on combinations of therapies, right. So, you know, opera used to talk about robust mouse rejuvenation, but nobody's really pursuing that anymore. And we have ITP, but it's not really exploring the full cross product space of combinations, we really need more work that combines significant therapeutics that come from different areas that address different sens damage categories, or really attack different hallmarks and start seeing how much we can crank. And it's just not feasible to do that directly in

humans first. And even in terms of things like dogs, which are shorter lived, it might be too hard to do that maybe mice there's some reasons why mice aren't so great. Maybe there's an intermediate I don't know where it's like short lived pets that are even shorter lived in dogs like hamsters dribbles types, I don't know. I'm not sure what the right way to jog that system loose, but we need some way to incentivize the combination things better. So that's those are the two that I mostly wanted to just mention. Just to throw off something a third pet peeve of mine that I would love to see more of, but I don't know how to make it happen is there's too much emphasis on chronic diseases of aging, which is really only start to become clinical, when you're pretty old, there's quite a bit of aging that makes life worse in, you know, after you get out of your prime of life, the sort of 20s and 30s and into the 40s 50s and 60s, but still, before you get the clinical chronical diseases, and you know, I kind of think this is probably going to have to wait in line behind making progress on the diseases that are actually killing people. But it would be interesting to see some companies or some research really focused on reversing some of the things that make life worse in your 40s and 50s. And, you know, giving you back and, you know, maybe there's some ways to capture money from, for example, the sports field for those kinds of things, because lots of professional athletes degenerate due to aging, to the point where they cannot no longer play. And I think there's probably room for companies to come along and use aging science to help therapeutically rejuvenate some of those professional athletes back to their prime competitive levels, you know, in ways that would also dovetail with chronic diseases, but might be, you know, fundamental in a different way. So that's my, those are my three.

Okay, three, three clear goals. And all of them quite ambitious, I think. And Sonia, would would you care to share yours?

Yes.

That's so that was a that was a really interesting series of thoughts that are curl with that, you know, I think actually sports, things like sports medicine and, and the reproductive area as well, reproductive technologies, those things actually tend to drive a lot of a lot of corporate incentives. So yeah, interesting to bring it up and think about it. There's a lot something like Fitbit, right? I mean, not that that's a longevity tech, necessarily, but it helps us measure where we're going. And that was, you know, directly aimed at people in the fitness industry. So, um, yeah, so I just picked sort of the top three things that I would like to see, as an investor, not as a scientist, of course, I know, there's a lot of scientists on the call, but, um, you know, the immune system, obviously COVID has hit, it's kind of slapped us in the face a little bit, that, that we should be really looking at the immune system. I mean, I think in the past, the immune system, to the extent the industry was focused on it was like, autoimmune diseases, because there were a lot of like, sort of middle aged people getting autoimmune diseases and why, you know, like, people didn't really care about the old people, of course, old people are getting immune problems, because they just go get old. And that's, that's just something that happens to everybody. But I think now with COVID, there's more people thinking about, oh, hey, you know, the immune system has a huge function in our body. And we really need it, and it really declines with age, and that's associated with everything, right? Everything that and we're all going to get it even if we're not old. I mean, we will be old at some point. And so it's, it's, it's our problem. And I think that that served was a bit of a wake up call. And so like, if you think about a couple of years ago, when intervene, immune got all that press the nature article, you know, for regenerating the thymus, and literally turning back the clock, at least epigenetically that was pretty epic, and that, I feel like that sort of a beginning. And so if we can have more people working on thymus regeneration, a different different strategies to do that. I think that would go a long way and probably get a great amount of funding, not only from, you know, maybe maybe in the corporate world if it could get to a, you know, a company stage, but at least for certain with the NIH and NIH A. So, so I think I think that's one area to be looking at.

I guess the second area I I'm always talking about his regenerative medicine, because I feel like I'm seeing this all the time. I feel like it really, it really looks so so promising, you know, five to 10 years ago, we, you know, new bladders were made new windpipes were made real human beings with their own stem cells like these were not lab animals. These were real people. You know, you saw the kid who got the bladder walk on stage at TED and talk about how his life changed from basically nothing to everything. And in terms of quality of life. And and what's happened since then I I feel like the the field has really stalled in the sense of a new innovations not hitting the market. And, and I'm not quite sure why I don't think it's a science problem. I think There's other problems. If I'm wrong, somebody please correct me. But, and and that goes to I mean, one of you had mentioned, you know, growing new hearts and, you know, and and things like that, you know, maybe Mike West mentioned that, you know, maybe we don't even have to regrow the whole heart, maybe we can just inject some factors in there and help repair the heart, maybe without so much scarring. And maybe we go along in that direction. And I do know that there's researchers working on that. But it would be nice to know, like, what happened to Doris Taylor with the making the new hearts, she was at the Texas, the Texas Heart Center, May, I assume she's still there doing it. I haven't talked to her in a number of years. But I would like to see more of that. I think that's, I still think it's promising to repair people. And, and we should, we should work on that we should still work on the systemic stuff, too. But the repair stuff just feels like it's a lot closer and maybe more, more low hanging, more low hanging fruit than the other stuff. And then the last thing that I would mention is a brain. You know, the brain used to feel completely off limits. It was just this complex thing that we couldn't even see, let alone try to touch and we didn't understand it. We couldn't, you know, and and so much work has been done now, you know, with the, with the mapping of the brain that Allen brain Atlas like Human Connectome Project, the Federal brand initiative. You know, I know there's a there's a researcher at Stanford who I personally support philanthropically, who's growing brain organoids, literally little brains in the lab, and he's doing experiments on them. And it's, it's really amazing. And I just the brain, the brain is something that is, is it's almost there. And I think we should have more people focusing on it. So I think I'll just, I'll end my my, my comments, there

is also quite the concrete laundry list. And for those who want to look, look them up again, at least Mike's and Sonia's points are already on the job that I shared. And calls we will get them afterwards.

Next week.

Perfect.

I forgot to say you didn't mention vitamin D.

That's a different log jam. I'm working on that one separately.

Okay. Everyone take your vitamin D.

He's still full. robot. org, you can go and read about it.

Well, maybe share the link again, in the chat, just so everyone's aware. But for now, I think we had a tom Kolya already with with a question. And you know, to everyone else, please collect both questions and comments in the chat. So if either if you have a question, or you want to follow up, or even or object to any, any of the things that's on your call, or Mike has said so far, please and do so in the chat, and then I'll take you on here into the discussion. Or if you want to open up your own bucket and drop drop some something into the head that hadn't been named yet, then please do so too. And we get that on the video as well. Okay, Tom, do you do you want to start?

Sure, yeah, this question was for Michael, but other people who have reactions as well, which is, number one. What do you see as the most interesting work going on in this area, both in academia and industry? And number two, Has anyone done a good job of articulating the open research issues? a more general point, which is, I think it's useful if we can not only say, Hey, we're, we're under investing in this, but to figure out whether there's some structural reason why that's the case. So a good example would be private companies will under invest in clinical trials that involve off patent drugs. Because so that might have a really high social return to repurpose them, but the private return may be low. So trying to figure out, you know, if you think people are under investing in a particular area, is there some underlying structural reason why that's the case? And then we can begin to figure out what are some of the levers for for addressing some of those structural barriers?

That was a question for me correct. The most interesting academic work so the I guess that this bears on both of the both categories of questions you asked the, the the, the fact that it was possible to reprogram you remember the old floppy disks, you'd put them in Carl, you remember, for the computer guy, you put in no floppy disk, you hit initialize, just sets it back to factory specs. I guess you can still do that with your laptop, right. The fact that a cell from the body could be reprogrammed back to be the beginning of life was incredibly countered. intuitive when Dolly the sheep was cloned back in 98, or when it was published in 98, the scientific community rebelled, said this, this is a fraud, it's impossible course was quickly shown that it actually can be done. So the, you know, if the genome is like the memory on a floppy or other kind of memory device, it like that it can be reprogrammed. And the fact that that reverses aging markers in cloning was in the year 2000. In IPS, where you use define factors to reboot a cell back to the beginning of life, the fact that that reverses aging using all known markers, to filter it in at various time points in 2010 2000, whatever the concept of taking cells, IPS reprogramming one gene, one Shinya Yamanaka Nobel Prize, so it was very quickly adopted, unlike cloning, by the scientific community is being factual. The idea of taking cells part way back in time to regenerate this regenerative state I was referring to or induced tissue regeneration, or ITR, or partial reprogramming Everyone has their own name for is just about five years old. I mean, indena was patent filings. And the just last year, David Sinclair, Harvard, that this cover article in nature on reversing aging using this technology, so I was having just weeks or months ago, the so you know, in terms of investment and why hasn't industry progress bar, it's, you know, it's brand new, to the point where, you know, there's these stages you go through where, at the beginning, people say it's not true, and then you adopt the truth when they say it's not important. And then you go through all those stages. And this is in writing the transition, I would say from, I think the majority of aging researchers are really in the weeds on things. I think they except I kind of informal poll with some of these individuals. And there's a consensus that this technology reverses aging, and probably induces this regenerative effect. There are companies forming, we've formed one called reverse. Stanford group is formed one, called turn by turn back the clock. And Sinclair has started one, I think it's called iduna. So you know, it's early stage.

Thank you. Carlos. When did you want to chime in? Or? Next question?

I want to push on that. If no objection, I think I'm, I think that partial reprogramming if we can call it that is really like a holy grail of sorts for aging. And that like, we are not going to make meaningful impacts, like the way I think most people in this room would like without being able to achieve it. However, I don't think that it's even remotely possible in situ, without substantial advances in synthetic biology. This idea that, you know, you can pull cells and subsets of Yamanaka factors, in addition, in push them to the just the right amount is great in a dish. But if you want to do this in a living organism, where you have, you know, your by distribution curves, not flat, the state of the cells are massively heterogeneous, like, and you need to have like really complicated control logic to get them back to the right state. And I think, if I wasn't obsessing so much on delivery, at the moment, I would probably be obsessing a lot more about synthetic biology and the control logic in the body in general. But I don't hear a lot of people talking about this. And I think that it's like, it's really what's keeping something in the dish right now, instead of going forward into into actual therapeutic or translational work.

What Why isn't that just a simple targeting rather than more complicated logic? Like, why can't you use, you know, the, you know, the stuff ocean is using in terms of targeting a particular expression pattern?

Well, to be clear, oceans technology is involved in some of these efforts. But the I think the main issue is that you have a whole bunch of different cells and a whole bunch of different states. And so the meal, I mean, think about it this way, how do you know from a purely genetic or transcriptional activity point of view, when you've reached the right spot? We look at how these things are described. If you look at you know, paper at Stanford guys, like when we post it for a few days, and we got it to the right spot, you know, this it turns out, you know, three days is good four days is not, you know, like, that's a that's something you control in a dish, but you can't do it. in vivo, so I do think this idea came about like, abusing the kind of Boolean logic approach is something we don't want to do. But it's complex, like an order of magnitude harder, like because it has to work for every cell that the particle can touch. And so I have done some work on this already trying to put things like this together, it's not an easy problem. And I think it could use some serious full time work.

Let me push back on your criticism, the from the other direction, you know, to rephrase what you said, like in a petri dish, when you've got a flat set of cells, they're all the same, you can tune your partial reprogramming timing to be the optimal level. But what about a loose, lowest common denominator, right? If you just do it, you know, the minimal amount, that's the that sort of doesn't get into doing the problem anywhere, for any tissue in the body, it won't be the optimal point for a lot of them, but it will still potentially reverse some degree of aging, in a lot of them.

I think it's an interesting idea, my first reaction is that, it's given the kind of exponential difference between like biodistribution of a vector in vivo, it's gonna be very difficult to do this, like it's a, let's just say we want the liver because you can hit the liver easy, the liver is gonna take, you know, orders of magnitude more of the particle than the next tissue. So you have to have a very low dose to make sure that the liver doesn't get turned into a tumor in this case. And by that point, you're not even gonna be the ballpark for other stuff. And that says the liver already has a lot of regenerative capability as it is, it's probably not practically the best target for that. So I think that the idea isn't irrational. I think that from a practical point of view, though, it's very difficult in a in a living organism. All right,

we have kind of the, the,

I agree with the the need for essays and markers. One that we've published is a POC 781. It's a marker of the transition, called the embryonic fetal transitions, a very effective marker in all cells, except for blood cells. As far as we know, it's for every cell type in the body. So I mean, there and there's others, which we don't talk about. assay development is certainly certainly critical. I agree on the delivery, the challenges of delivery, Sinclair proposed using adeno associated virus. We're a public company. So we don't talk about precisely what we're doing. But I think we have indicated that gene therapy approaches our first choice. And logically, what companies typically do is they target a serious life threatening disease, that is compartmentalized, so you're not doing a total body systemic treatment in the first clinical trial. And that's a typical logic and certainly one that's not escaped art, notice, and attention

series interesting, just a thought experiment. If we say put a build a construct that had the factors you want to express, you know, what some, you know, restriction enzymes built in that were relatively long, and then we put a, you know, homing mega in a nucleus under a promoter responsive to caulk 781. Can you basically cause its activation or deactivation to simply chop up your construct and have a break put on based on on that pathway specifically?

Does that make sense?

Yeah,

that's interesting thought.

So I've labeled these circuits a bit.

Yeah, I mean, we're, yeah, I mean, so obviously, we're trying to design a delivery vehicle. And then these essays would be not part of the targeting vehicle, of course, for the therapeutic city for human use.

I have a delivery vehicle for you.

West at HMC, calm. All right.

All right, we have a few more comments on that particular point from Lynn and from Java.

Okay. To start off with, I'd like to thank Mike because I am 100% behind the idea that actually what makes aging really miserable is the long term chronic conditions. And it's the non sexy ones. It's it's the incontinence. It's all the undignified stuff that you don't realize until you're actually caring for some very old people. And then you see it and think, really, I don't want that. So there's a quality of life issue, that there's a massive economic issue. So the last five years of life cost more than the whole of the rest of life put together in terms of health care costs. So there's a massive market. I mean, If you're an investor, it makes sense to invest in this market is vast. If you're a human being, it makes sense to invest in it because of the quality of life and the relief of suffering. So Mike, I'm completely with you on the quality of life stuff, and not lifespan extension for the sake of it, but healthspan extension, which will have the knock on effect of increasing lifespan. But in terms of the reprogramming, I put a comment on the chat about the real huge difficulties with stem cells, and at the moment being in the very early stages of understanding that differentiation pathway and going, treading that incredibly fine line between hyper proliferation and hypo proliferation and cancer. And I love the comment that when we can cure cancer, actually, we're not going to be bothered about that. But unfortunately, a moment, I don't think we're quite there. But there's one way of doing it for certain cells, tissues and organs, where you can get the best of both worlds where you do the ex vivo programming in dishes, and then you put the engineer tissue back in. So there's some work in the UK, Imperial College, you're doing band aid for the heart, essentially. So they're growing stem cells, they're putting in patches, you can actually have minor surgery put over the infarct repopulate. And that's one way of exploiting the regenerative properties without having the cancer risks. But that's not going to work systemically, I don't really know what is I've put in the chat, also linked to oxygen, which is a company has been out from the university, I'm not involved in it. So I'm not selling it from a personal point of view. But they're looking at small molecule reprogramming, specific to individual cell types, to try and tweak regeneration in vivo. So I, and then we have had the fields, that the whole waters have been muddied by certain people claiming things that turn out not to be right. So again, I put in the chat about the issue with regenerative medicine in the claims that you could regrow a truck here on a scaffold and implant it and the surgeon was so well looked out. At that, nobody did question the fact that actually more patients died than lift, and the scandal finally broke. And I think we have to be incredibly careful about the speed at which things move so that you don't let some stellar people get their own way and then create something that's going to destroy the field, put it back 10 years, like a genetic engineering did, when there were studies where people got cancer from from some of the genetic engineering stuff. So we have to move at a rate that's appropriate to the science and not push it too fast. But I think the science is, is getting there. And I love this idea of the ex vivo reprogramming and then being able to patch up certain tissues. So I think that's sort of covered some of the stuff I put in the chat. Thanks, Alison.

Thank you. And if anyone wants a view once a direct call Miko, Sonya, otherwise we'll

make one comment on that date. Yeah, I thought that'd be brought up earlier. The the report, you know, this idea of reversing aging using reprogramming technologies is a way to make two points. One, yeah, the, to me the challenge, and the the issue that we're gonna be facing is the concern about cancer. 100% sure of that. So because the, what isn't yet completely known publicly, is these same pathways are being used heavily by cancer cells. So cancer cells are sort of regeneration out of control. And a lot of that data will be made clearer in the coming months in the scientific literature. Now, but it's, it'd be guilt by association. If we therefore said, that that's a big problem. And in fact, many of these animals that have this profound regenerative potential, have almost no cancer. And the word the science is that right now, we actually think we know why that works. And so it addresses some of these issues of cell senescence, if a tissue can regenerate than the cells have, are senescent or have serious DNA damage. What we do is we keep them around and it causes us all these aging problems. That's the whole logic of psychoanalysis. You know, how do we get rid of these zombie cells? But if you're in this regenerative state, they just explode. They're a pitocin away. And so that reduces the risk of cancer. So no person number one, the big thing that the scientific community, I swear I agree, that we focused on is can we safely reprogram and reverse aging using this technology without increasing the risk of cancer and that's what FDA, I'm sure is going to have been their number one concern in the big burden.

Like in regenerative reptiles that a pop toasts the senescent cells so much better and avoid cancer. Is that is that immune system modulated or something else?

Yeah, there's some speculation that it is, but i don't think so i think it's just a form of a pitocin. South, you know, the P 53. pathway for those of you that are into all this nuance that, can you do senescence instead will induce apoptosis if you're in that regenerative state. A second point, which also was was brought up is the nonsense factor. We've never had the gerontology community, you know, medical research community as a whole. Now with a journal called nature, aging, you know, serious science talking about age reversal. And we're now entering that era, if we really think this is real science. The, if there was a lot of nonsense about stem cells and regenerative medicine, and believe me, there were laws, massive misinformation, about I will point fingers, but there's a lot of misinformation out there. Can you imagine what it's going to be when, you know, the snake oil salesmen start hearing about age reversal? So we really do need platforms like this and others to communicate where the real sciences and where the, you know, the schlock sciences, in the coming years,

ever been a good model of a sort of, like self regulation in terms of a group of, because you can also imagine a group of scientists just getting together and going, Oh, they look like they're gonna beat me. They're snake oil, you know? And, you know, like, you, but mica is such a good, it's such a good suggestion, because it is a big danger. How do we, and maybe this is a topic for another time, but how do we set this up so that we can help that?

I don't like these. They're these industry groups. And again, I'm not pointing fingers, but I mean, it, people love to form these industry groups, you know, the regenerative medicine industry organization, you know, some such thing you can imagine, and they'll set standards early on in the stem cell field at the International Society for stem cell research, right. And they would put an imprint on, you know, whatever they thought was real science or what wasn't, although they didn't really go after the nonsense all that much.

I don't know the answer.

To anyone. Have you ever looked at the aviation Incident Reporting System? It's an extremely successful system for anonymous reporting of anomalies in a cockpit, where there's no questions asked. And it is almost singularly responsible for the fact that commercial aviation is the safest form of travel when measured per mile or per seat.

Right. So maybe it's done on the consumer end, something bad happens and something's reported. Is that what you're saying?

Yeah, it's almost like you whistle blow on yourself. But get away with it, because it's anonymous, because the institution recognizes it's better to let them get away with it once then for it to remain a systemic problem in the system.

Can I also

accident reporting system,

I was gonna say that, right.

Sorry for interrupting

to publish negative results. We ought to allow people to publish negative results, rather than always saying that every cell in nature paper has to be the most interesting novel thing ever. If people hide their data, we don't have this anonymous reporting of things that go wrong, because he can't get it out there in the scientific literature. So I absolutely agree with you, David, I think that, that we're not safe because we don't report the negative stuff, because there isn't a vehicle for reporting the negative stuff. So I love what you're saying about the aviation industry. Sorry to have interrupted you.

I had something.

Yeah. And yeah. Yeah, go for it. And then Keith also want to chime in on this one, and then we're gonna continue with the questions.

Just because it has to do with reprogramming more on that topic more. So I'm a huge fan of reprogramming. It can have a lot of applications but I think it will fail in terms of reversing aging in an organism. I mean, you know, Matthew pointed out some of the reasons Why implementation would be very difficult. even think of how you might do that in the brain, which is even harder to access. And we might consider that to be an important Oregon becomes very difficult to imagine how it might be implemented. But beyond that, I think one of the main reasons that we'll fail is because it doesn't address a large fraction of the damage that accumulates with age, which is extracellular, which doesn't get turned over. So you can change gene expression all you want, and it won't reverse much of the damage that occurs outside themselves. So, you know, I think it could have some benefits for sure, as as Mike has pointed out, but in terms of reversing aging, or even, you know, significantly slowing, you know, the a lot of the damage that occurs to our proteins and carbohydrates that exists outside of cells, and that don't get turned over much in life and that contribute to the frailty of aging. I think, you know, that's a neat, we have to admit the limitations of the approach. I think

they you know, when you lob a leg off on my axolotl, Mexican salamander, you could have this tattered and frayed appendage. And what happens is, a family of cell adhesion molecules are pulled together and the tissue is remodeled as a blast steamer. And the whole blast the library grows with all of its complexities, all the articulations and tendons and muscles and everything else. The to say that this will not work in a context of turning over. Matrix, extracellular matrix. I think it's too early. I would argue it's too early to say we have reasons to believe that the early embryonic state

might give me example of the axolotl. It's all new cells, you're talking about existing cells, which is completely different. Tissue now I'm talking about replacing absolutely work. You're right. So replacing organs by regrowing will work.

I didn't mean to imply that it was a remodeling of existing tissue and axolotl. But my point is the, the if you think if you think about the complexities of what the tissue is doing, to recognize the damage, and then like I said, it's not a clean break, necessarily. It can be tattered and frayed. And these cells can recognize the trauma and reorganize matrix and other things to reorganize and generate a complete nearly completely normal limb. I think we ought to be slow to be quick to assume that it can't remodel ECM. In the early embryonic stages of development is when a lot of the last agenesis is occurring. For instance, you know, there's all these fibula ones and elastin associated proteins that are laying down in the elastic matrix, for instance, and some of the preliminary data suggests that ITR partial reprogramming can re induce an elastic genic state for instance,

I'm discussing this offline, I'd love to do that. But all these examples are very different than the adult unless you're talking about injuring and removing tissue and having it regenerate, which is, um, you know, I'm all for that.

I guess my

point is aging, but

very good question and jury's out. And we'll see. Yeah,

well, maybe. And, john, I bet you can address it in when you have your focus, talk and a few weeks from now. Yeah.

Does that sound good? Hope you're there.

And great. And okay, and lovely. So next up, we had Keith with a quick comment on this, and then we have a general question. Great.

Yes, I was actually on the previous topic about the snake oil stuff. So I'll be brief. But I just wanted to point out that there are existing models we can follow just in the normal world, for example, clear codes of journalistic ethics. I've been noticing that there's a lot of sort of emerging new sites happening in our field that really aren't following proper journalistic ethics, you know, diligent diligence in the stories before they're just sort of re communicating it out or not properly disclosing disclosing conflicts of interest, right. So one of the things that we're starting to, to to push out soon is basically writing up a tailored version of journalistic ethics for our field specifically with some additional things that should be met. So I think That will help to at least have a litmus test to be like, does this story hit that or not that to help sort of tamp down on, you know, irresponsibly shared information? It's not the whole puzzle, but it's a piece.

Right? Well, maybe you can share that with us. And we can add and discuss. Thank you, Robert, you had another question.

Yeah, thanks for inviting me to say your so I'm just wondering if there's any interest here in like technology platform or drug delivery, platform development. So there's a lot of discussion here about, you know, what's what can be done with existing tools and approaches. But as Lord Denning, for example, often points out, you know, maybe improving the tools is really what's needed to advance the state of the art in biology. And just a comment there. So the Paul G. Allen frontiers group, I think I emailed the, I sent out something off the mailing list, they have a $10 million ideation challenge exactly along these lines. So I'm just curious if there's any interest in if this would fit the accelerator goals?

Yeah, well, we, we kind of had suggested a few potential focus areas of interest. So instead of like, in addition to the more general meetings that we have, where we kind of serve a specific section, such as industry now, then research Next, we also do specific focus topics. So one of them is specifically on biomarkers, one is on biomarker standardization, and one is on platforms and tools. And so there we have, in total, I think six, false or false that fellows will be discussing their current data and AI research in health extension. And from that, we hope to extract a few more enabling technologies. But you know, if, if anyone has more suggestions for that, and to point them to the keynote, yes, Mike, you

have a few more time, I apologize, if I am.

Maybe my hoarseness is by by trying to tell me to shut up the, I really feel a really valuable tool could be accomplished, it just needs money, and would be a tool that would be used for millennia. Absolutely foundational. And that would be that is called age map, it would be to on a single This is all, you know, doable technology today, it would be to map every RNA transcript, which is the messages of life, right? Every mRNA by RNA sequencing, and the chromatin structure of on a single cell level of resolution. So you know, like a high mag, you know, picture on a single cell resolution of aging tissues in the human body. It would be then could be plugged into AI, and be used by researchers, and would be an absolutely incredibly invaluable way to study aging, because you could then query it for, you know, as we're talking about extracellular matrix, or anything else you could quickly look at, you know, is the type two numerous site in the lung, doing what during aging and wondering aging. If we had that map, and it's simply a matter of money, you could plug it into all these companies that do next generation sequencing and so on, you could generate this massive database. And that'd be the type of thing if they own Apollo and foundation or others would fund would be used by medical researchers all over the world for millennia to come.

And that's kind of like the Zuckerberg, human cell Atlas project has sort of started doing right just needs more money to make it more complete. Yeah,

we started a thing called lifemap, which was like map discovery in particular, which was mapping the cells and so they ran out of money.

More broadly, Robert, I think that you're the Allen ideation challenge on tools is very much in the same spirit of what I talked about first about, but but but I was talking about a specific subcategory of tools, namely ones that are sensing based, not just arbitrary tools. And you know, Paul, Allen has a lot of money, and it's great that he's going to put up 10 million in funds. But you know, I think the broader problem with incentivizing tool development is that it's not commercially a great investment. You know, it's not it's not a very lucrative way. So there's not enough commercial development incentive economically, to

what about Illumina sequencers? I mean, I agree you're

no great success story, obviously. And you know, you know, it would be interesting to see a business case study of them, right. Like, isn't That, you know, is it really a standout? Like is it the the one in a million company that it was so successful? as well, because the, you know, it happened to hit a Moore's Law kind of thing right at the right time and and had benefited from that, you know, but you know, how many illuminous do we not know about because they died and only the one that we successful? Do we know about? I don't know. But you know, lots of these other tool breakthroughs are kind of come opportunistically when the science and the technology make them available, but there's not as much funding driving toward them, I don't think.

Yeah, so that's another question. I mean, you know, how do the electron microscopy, electronics manufacturers and cryo, yeah, and, and all that kind of stuff, extremely expensive pieces of equipment for now. Right, and they're still being sold, and they're still being manufactured. So is there distortion in the types of investments that are made from from, you know, venture sources because of the need for strong profits, or, or not, it's just another point that I thought I would bring up.

You know, Google Earth.

And beef before you jump in, I just want to say it's now one minute past the hour. So in case anyone has to drop off, and with that, I mean, also called Mike and Sonia, I want to give you an easy out, I just want to not miss this. Thank you very, very, very much. I know that all of you have a very, very full schedule, especially right now. So thank you very much for making it today. You're welcome to stay on also via phone. And while And apart from that, we have our next meeting again in a month from now, and I'll be following up with videos. But please feel free to stay on. I just wanted to give you an easy way out and not not necessarily

to say goodbye. Thank you very much. All right, thank

you. And bye bye, Sonia. And Alright, so for those who want to stay on, and I would love to know, a little bit in more detail what kinds of platforms or or tools you were thinking about. Like, Robert, which, what kind of platform where you were envisioning this? I think it's easy to say in every technology, but like, Is there a specific one, you know, for example, like the one that Mike discussed, that you think would really, really help specifically in the health extension field, because we talked about enabling technologies and they and those kinds of platforms all the time, even in the molecular machines group. But is there a particular area, especially right now, in biotech and healthcare session?

That's interesting. Well,

here's an idea. Well, this is all you know, this sounds like an ideation discussion anyway. But here's an idea that I hadn't heard elsewhere, I'm just putting out that it's obviously not, these are technically very challenging things to to do. So, you know, one of the reasons why there might be less interest in in pursuing them is that they're just very hard problems. It's harder to develop a new instrumentation or planetology, than it is to pursue some kind of like, conventional therapeutic development, probably, even though the therapeutic development is incredibly complicated as it is right. It's so risky. But here's an idea. That may help certainly, in case of, of aging, biology, longevity, therapeutics, what about creating an artificial model? Something like an organized system? Of course, this is, you know, probably still the future, but one, which ages faster than normal? In other words, so that you can test all of the interventions on something, you know, you can compress? What what would normally be a year, you know, lifetime of aging into like eight months or something like that, right? And then it has like the the correct? correspondence. That would be very useful. Right? And I haven't seen any discussion, it

seems like it would be really valuable to make an organoid model with knockin progeroid jeans. That'd be one way of doing it.

It's too bad that Mike, it looks like left the call right before you said that. So I mean, part of part of his work, they're talking about manipulating the epigenetics, not only to move it in the youthful direction, but to move it in the faster aging direction as well. And, you know, that's not so much. There are other benefits of that, besides, as, you know, faster test cases to test anti aging, you know, it's a potentially a cancer therapy, for example. So you can make the cancer cells age faster than that might help kill them. I mean, we have

that it's called a mouse. But that's not obviously it's not human DNA. So we're wondering is it really a But then you can, you can take something like you could take stem cells from the Hutchinson Gilford progeria patient and throw them in culture. And that has some sort of assorted agent. But then you're still asking, Well, yeah, but is that really aging? And so I think in order to get something that is doing accelerated aging, you have to tell it to do something different from a normal cell, which means you have to think you know, exactly what aging is by like, making that thing happen. And then, then you're, if you're using it as a model to try to reverse the aging, you're basically trying to undo this thing that you already know the answer to.

I agree with Joe there. I think that we could put in a progeroid gene, and cause something to age faster. And then if we took out that 00 gene, we'd say we'd cured aging, but no, we just returned it to normal.

I mean, if I can just present a thought experiment here. It's this is science fiction, right. But if you could create a virtual human, right, that you can run in a simulation, then you can definitely run it faster than real time in the simulation, and still have correspondence to to what's going on. Of course, this is science fiction, right? This is far away. But like there, there are people working on this, I think the comp biomed.us very far advanced in this area, and this virtual rats as the open worm. But maybe maybe there's some kind of hybrid approach that uses organoids, or some physical model that can then be simulated that and if you can get the simulation to correspond to the properties of the physical system, then then you can certainly run a simulation faster. And

yeah, so I think it'd be easier to combat ageing, then to devise a model of aging, certainly 3d organized are better than cells and culture because you have those, but there's still a long cry from the mixture of, you know, post mitotic cells really mature and extracellular matrix. And, and, and cells, some of which are still proliferating, compared. So organoids are usually cells that are growing. So they're very different. So that wouldn't necessarily work. But But the bigger problem is,

is,

you know, biochemists have looked at the complexity of aging, like decades ago, right? And the different types of damage like, are is incredible. Just to proteins, for example, there's there's dozens of different crosslinks or covalent modifications that occur the proteins, nevermind DNA, fats, carbohydrates, and probably we only know a fraction of them. So I think modeling that where it's going to be exceedingly difficult. Maybe like you say, science fiction in the future. Oh, this will make more progress on aging before we make sufficient progress on that, for it to be really

Gail, any

comments on cosmo?

Yeah, the the the lab, I did my PhD and was working on protein modifications in skeletal muscle in diabetic and aging people. And I concur with the notion that simulating that is a total mess. I don't think that would necessarily be workable, then again, putting together a resource of a fairly sizable aging cohort of people. And getting that kind of proteomic data would be very valuable, I think.

What's the kind of tool that you'd like to see because

I'm always gung ho on maldi imaging, that's my, that's my current technological obsession. So my, my goal is to create effectively a core facility where tissue sections or sections of organoid tissue can be multi imaged, which would give you a a pixel wise determination of the full mass spectrum. So you could effectively quantitate metabolites in tissue at every single location in a tissue, and then compare that to age. I think that's very similar to what like recursion pharmaceuticals is doing, but they're doing it with optical microscopy with maybe four color channels at a time. But if you could do that with mass spectrometry and get 1000s of metabolites at a time, that would be hugely powerful as a resource.

Any comments with it?

The question is how do we incentivize? You know, if we had that, it would have so many applications, and it could capture so much, you know, if it were priced at a fair market value to recoup a reasonable profit margin relative to the value it brings, it could make a huge amount of money. But it's hard to, you know, how do we actually bridge that gap to because the huge amount of money would come from a wide variety of different places?

How about we help? How about we bridge the gap by helping Cosmo form a company and fund it?

Well, I'm talking more about the I be helping Cosmo form a company part is easy step, I'm talking about the how do we get the you know, the future potential income, if such a thing to actually make the investment attractive enough, I think there's a, there's a problem there capturing all those future gains. In tool companies like this.

I gave up on the business side A long time ago.

We need to know what we're looking for before we build a platform to look for it.

I'm definitely a fan of going fishing. So I tend, I tend to take the opposite approach.

When you're doing science, it's good to have a model, you know, biological understanding and have a hypothesis and stuff like that. But then when you're actually doing the work, you want to have the broadest tools possible so you can get the serendipity moments and things like that. That's where the breakfast

No, I'm just wondering, are we looking at things that hang around for microseconds? Are we thinking of things that hang around for years? Are we looking at proteins? We're looking at short lived metabolites? What would your platform be able to assess? And,

and it looked at live tissues or the tissues dead when they get taken apart by this apparatus?

And this question is being directed at me regarding maldi? imaging? Yes. So a typical industry application from all the imaging, and that's, you know, full disclosure, I'm at Vir biotechnology. Now, that's where I landed. I haven't made any public announcements of that, because complicated reasons. But a typical industry use for something like maldi imaging, is to take a section of say, a rat brain that's been treated with some drug, and then image that brain and see what parts of the brain that drug actually penetrated into so pharmacologically, it's a really useful procedure for determining drug penetrants and absorption in different endpoint organs. But for something like aging biomarkers, I think it would be a really useful application for determining whether or not certain metabolites pool up in aging organisms, whether or not there's effectively like a metabolic backlog for some mitochondrial metabolites, for example, or in the case of protein accumulation, you could use it to assess whether or not certain proteins are accumulating in certain organs like the brain, which, as we know, is a hotspot for protein accumulation in aging humans.

Now, just add a comment to the point that I think it was Lynn made. So this this whole discussion around hallmarks of aging, following these papers in 2013 2014, I'm not an expert, but on those specific papers, but if I'm not mistaken, there was no real discussion of the quantitative levels of change only the approximate rough like qualitative change in each. And I was doing some literature review around telomere measurement, for example. And apparently, according to at least some of the telomere researchers, I found, this is still an open problem in the telomere research space, how to measure telomeres, and harmonize the measurements. So another basic thing that might be useful to the field would be just a standard set of measurements for each of the homeworks. And then are the hallmarks actually totally comprehensive, or are they just convenient, a convenient mental box of the various things that are going on? Just a thought?

And now I hope the conversation Allison, can I come back on that one? Um, I completely agree with you. We lacked quantification in anything. And but the problem is, everything depends on your cell type, your organism, the inducer of the aging process. So not just chronological age, but the biological age from the tissue you took it from. So what are you actually measuring when you're saying can we measure hallmark of senescence Yes, we can measure how much reactive oxygen species species there are in the mitochondria in a particular point in time. And we can say that that comes from a senescence cell. But is that reflective of a senescence cell in you versus me versus my tissue culture dishes? I don't know. So we can quantify for the condition that we have, but we can't quantify and make it a universal. And so I don't know if that answers your question at all. But if the quantification is so dependent on what you're looking at, that I could give you a number of quantities for I've done quantitative proteomics on senescence, I could tell you for a particular skin fibroblasts grown in a dish for a particular condition, how many of a certain type of protein molecules there are, but I don't know if that tells us anything about the aging process, or what happens in in a real complex system. So Rob, how would you do it? What are you actually specifically asking for?

I don't know, the answer is I'm simply pointing out that it's just it's a little funny that at this day and age, something like telomeres, you know, 3040 years of research, and there's still no standard approach amongst the researchers in the field themselves, that they can agree upon. I saw paper, like in 2016, where it was clearly stated, there was no standard, agreed upon method of quantitation. So it just seems like one of the necessary and, and immediate steps to to make progress in the field, just, you know, just start with this basic stuff. It's not easy to do, or, or, I mean, it's tedious. And it's, it's annoying, maybe, but it doesn't necessarily lead to exciting headlines. But it's, it's just an obvious step to do. So, like the hallmarks of 2013 paper, and quite sure, there was no quantitative description of the changes there. So maybe there's an update that I'm not aware of. And I'm not an instrumentation expert, I'm very interested in that area and thinking of trying to study it a little bit in the years ahead, but just feel like it's very important. It's all this stuff about measurement instrumentation. quantitation. And to your point about how it depends what you're looking at, well, that just says it's very complex. So measure as much as you can, until you can properly character, you can properly identify what it is that you're measuring. And you'll have the measurement problem, right? Like,

there's, there's finite resources. And part of the problem is that nobody, you know, there's not enough money, especially money from government or wherever, just for this basic research to sort of take a systematic view and try to say, we're going to develop good quantification of every hallmark, that would be a huge process. So instead, people in the field run around to what they think is important, there's not been a lot of fixing, you know, coming up with the final answer for telomeres, because for a lot, lots of people think telomeres aren't that important, right? And until you know, and part of that's because the easier thing to measure was the average telomere length. And then as people figured out that it's actually the critically short telomeres that matter. Well, now some more people are actually thinking, Okay, now maybe telomeres are worth looking at. But it's only when you count the short ones, which is harder to do. But so in the meantime, people were running around together hot areas. And so you know, senescence cells are obviously have gotten a lot of attention. So there is more work now trying to quantify those, but it's not easy necessarily to quantify those in different tissues. But that's, you know, but clearly, because of the obvious prominence and importance of senescence cells in recent years, there's actually a lot more work in that area. So I think you kind of get the profile of the, you know, the quantification work gets more and more improved in whichever areas seem most promising.

What other areas apart from telomeres? You know, you could say, okay,

hmm, all the hallmarks? What are you know, I'm not an expert in this. So I'm just saying like, what are the best, so best available current methods for for quantifying them? This is not mentioned in the hallmarks paper

accelerator.

You know, quantifying is much harder than just identifying, right, so it will follow, but it takes a while. And, you know, the sense areas to the extent to which they're different, slightly different from the hallmarks of the same problem. So, you know, it's not easy to measure, what is your total glucose of pain, age, you know, ag crosslink, burden and tissue. But you know, those things will come? Well, maybe they won't you know, that some people will say that fixing it is actually easier than quantifying it.

A job and you're still on the call, aren't you? If I recall correctly, two years ago, you were leading an effort to put together a standardized database of these various essays for these various hallmarks.

Yeah, well, it turns

out A very Hallmark Hallmark thing, you know, like one of these hallmarks is a whole area of biology unto itself. So it's not something that you can just kind of do by saying, okay, we're gonna quantify these, it's like, oh, you have to become a specialist in cell to cell communication, but also very vague. They're like giant categories. So you can't just like quantify salt, intracellular communication, intercellular communication, and then have a single scalar variable that tells you like how good it is or not, you know, that there's like, a million different protein variants circulating in a mammal that are going back and forth between cells. And that's, you know, then there's interactions between them. So now you have a billion and say, you know, like, your, if you're working on some very specific part of the biology of intercellular communication, specifically how, you know, some muscle satellite cell is talking to some nearby progenitor cell or something. And a specific part of their communication between them. That's the area you're focused on. And great, you could probably find the particular signal that they're passing back and forth. And that's the thing you could measure for that particular thing. But in a way, it's kind of an ill formed spec, to say, let's just quantify all these

on that subject. Is there any sort of like, you know, reliable level of correlation for say, you know, age linking, right, you know, is it the same? Is it fair to say that the progression in skin is the same for internal organs? Then could you use skin measurements, you know, wrinkles, and such as a proxy for an overall measure? Or is it, there's no guarantee that it maps uniformly in any way?

Well, I hate to be boring here, but it's like, What are you trying to measure? Are you trying to guess someone's chronological age? Are you trying to figure out how long it is, before they're going to die? If

nothing, specifically, was, is there a way to put a number on how progressed age linking is, so I'm just

I mean, you know, Keith, as an example, here, you know, you can look at skin aging on different parts of the body. And, you know, look at the huge difference in aging of the skin of the parts that are exposed to the sun all day, like in the face versus in the parts that aren't. And there's a pretty big difference. So

aren't there particular systems, at least for many people that tend to? How can I say this age more quickly? And what I mean by that is they cause trouble, like, like the, like the vascular endothelium? You know, this is the thing, which gets a G's piled up on it, and loses its flexibility and eventually gets all inflamed. And then, you know, you have a heart attack? I mean, can't we just look into particular tissues? Which are, you know, the kind of weak points of most people's bodies?

Who's the task force for this kind of topic? Like, is there someone in this network that is working specifically on on this kind of instrumentation stuff? Or

are people narrow it down to something that's measurable like Steve Horvath, and you get the methylation clock and you've got tissue specific methylation clocks, and you've got global methylation clocks, and you've got Grimm age. So he's the most quantitative person there is, but he's not going by the hallmarks, these just go by does this tell you how long you're going to live for,

is working on some methylome clocks that are going to be tuned to the different hallmarks. But you know, she's in order to train that she has to have assays that do that, evaluate the hallmarks to begin with, so but but in general, the instrumentation problem is, is going to come from people outside this community, right. The people who are who are diehard working on aging, first and foremost are, you know, are plugging at the individual things that need to be, you know, that will make progress and, you know, the toy truck The trick is, how do we look around at the things the wider world and figure out which new, you know, new or almost ready advances in instrumentation can be pulled in and used right away?

Yeah.

I could go around in our other groups, because even you know, as I mentioned, the molecular machines, we often have similar types of requests. And then you know, I can see whether we can crowdsource it from the community like I think because oftentimes when we do technical competitions, many folks that are working on implementation, they don't really know what's needed. So that seems to be real. We communicate gap between those that are needing the tools, but they don't really know who are making them. And then those who are making them, but they don't necessarily really know who exactly would like to use them. So if it was a concrete shopping list, I could try to try to look around and see if there's someone either already working on it or at least interested in working. And one more thing, we have Steve Howard, and joining our group on June 20 22nd, in case you have specific question in that area,

one way to measure or look at h crosslinking. In the cardiovascular system is rather simple. And that is to take the blood pressure, the systolic minus the diastolic, that that pulse pressure difference gives a good idea of the stiffness of the large arteries. And you can also do some imaging of the heart to see if the left ventricle is thickening, indicating more resistance from the peripheral blood circulatory system. And you cannot do that thing with with looking at, like the sound wave or the echoes from the heartbeat coming bouncing off the arteries. And not getting it exactly right. But there's a there's a new test relatively new that that just uses like a standard cuff, but has a higher frequency capture and it actually sees the vibration or stiffness of the arteries kind of a generalization of what you said about systolic over diastolic minus guys. Yeah, yeah. And also, and also, you could look at the Horvath age, and you're not gonna see what they're not the extracellular matrix, it's possibly that's sort of separate and more back paging. I can age doesn't that get it all? antibodies? I'm not sure.

Yeah, on the spirit of this, I think an important tactic that's, that's kind of emerging from this conversation is, and I'm noticing traction in certain large private companies here, the more that we can correlate some internal matter, like if you can get that same measure, you know, either it's imaging your heart, or if there is some more easily collectible, physiological telltale of it something in your voice, something in your eyes, etc, the more that we can set up correlations between those things, more, I think we can, you know, use those proxies to, to to leverage, like massive data collection initiatives that would do something useful. And that's personally where I'm finding real buy in on massive private companies. So I think I think there should be some intellectual power to making these correlations where we can build to link some sort of external measure to some sort of internal measure as best as we can. And I think that will open the floodgates to attraction here.

Is the wasn't that MIT group, you mentioned doing audio based, diagnostic or other examples?

That's that's the one clear example I can't get into specifics. But I could say that things have gone well there and something massive is underway with upgrades of that. So. Okay,

any other questions or comments? I would say that, and if not, I'm going to open up the gathering riches, you know, usually at what we did, after the normal meeting, we always moved into breakout rooms. Now we have the gathering space, but which you can just sit at tables talk to each other, and a much more decentralized way. And so I think it'll

be fine.

I know that you're very, very busy. I really appreciate that you took the time. And I see all of you again, for the next problem meeting soon, I'll be following up with bids. But those who are interested, I'll meet you and together room out to sit at tables and and chat. And All right. Well, it was really, really, really good to see all of you. And I'm hoping that you'll apply to the accelerator or and shared with other projects. It's a little bit of a different type of accelerator in the sense that Yeah, they come with no strings attached. So we're not, we're not taking any shares, right up front or anything. It's really just trying to see whether those people that are already on these calls could actually help products along in a more systematic way, rather than what we're doing on the call. So take advantage of that if you want to and and yet, I see many of you and the other. I buy