The Biology of Aging: Introducing Bio Eats World (ep 1)


Hi Everyone. Welcome today's six Z podcast I'm zonal editor-in-chief Andreessen Horowitz and what follows is the very first episode in our new show bio eats world a podcast all about how biology is technology. The show covers healthcare, which we've covered a lot on this show, and which, of course, it's top of mind right now given the Cova crisis but this show covers how will diagnose and manage all kinds of diseases, create new medicines and therapeutics and access and deliver healthcare. But also goes beyond healthcare because biology is an everything, it's in the products we use daily our food or manufacturing processes much more bio in other words is eating the world and says we. Believe. That biology is where information technology was fifty years ago on the precipice of changing everything. That's why the name of the show is bio eats world. It is part of our expanding basics and Z podcast network, which you can read more about it a six thousand seat dot com slash pot network, and it's led by Hannah anarchy whose voice you have heard on this podcast for over three years now and Lauren Richardson who you've heard on Journal Club, which will also be moving to this new show feet. So please be sure to subscribe to bio. It's world wherever you like to get your podcast and please feel free to rate it as well. Hi I'm Lauren and I'm Hannah and this is our first episode in the new podcast bio eats world where we talk all about how biology is breaking out of the lab and clinic and into our daily lives and really on the verge of revolutionizing our entire world in ways, we're only just beginning to imagine. So Hannah the title of this first episode is the biology of aging what aspects of aging are we going to be discussing? Today well, really we've been trying to dream up ways of slowing down aging for as long as we've been aging rate, but the field of studying aging as a science is pretty new. So in this episode, we look at the entire kind of biology of aging what we've learned, what's reality, and what is translating into actually increasing our health span and potentially one day possibly slow down aging what's health span, and how's that different from lifespan your. First thought when you think about studying aging might be how we might slow it down. But really the way a lot of people in the field think about it is increasing our health span, which is the amount of time that we live healthy. What's really interesting about this episode is it's about not just increasing health span and age span. But what we're learning about disease particularly chronic age related diseases that might help us be healthier today joining. Me For. This conversation is Laura Deming founder and partner of the Longevity Fund Kristen Fourteen e founder of bio age clinical stage company focused on finding drugs that extend health span using machine learning and Vj Ponte a sixteen z general partner on the Bio. Fund were there any insights from this episode that changed the way you think about aging yourself? Yeah. Well, I definitely enjoyed hearing about the drug already widely available that really might increase our lives. And I also loved hearing about what the difference between Benadryl and UNISOM is. So we start with a little bit of a history of the field talk about where it's come and where we are today. So where actually are we in the biology of aging today? There's been a big surge of talk even over the past few years about what the science of longevity is. It's developed but where are we actually today mortality is like this thing that philosophers pined for Millennia but yeah, the biology of aging new. New, insofar, as its new anything actually works I, guess, right. One of the earliest discoveries in research that goes back decades is that if you could severely restrict food intake an animal's calorie restriction, they would live substantially longer, but it's only been fairly recently the bill actually intervene and actually impact how long a mammal can live and one of the interventions. That was first shown to work in mammals, para BIOS exposing old mice to young blood, and that really was first discovered fifty years ago. The major acceleration came during the nineteen nineties, the two thousands, and it's mostly attributable to the first finding. Cynthia Kenyon Gary Rivkin Tom Hughes that you could delete a single gene and against double its lifespan everyone thought. Aging. So complicated, you know, how are we going to have a dramatic impact on aging when it's really all these different systems and processes that are going wrong simultaneously, and then you know, wow, wait a minute this one tweak, and then suddenly this massive difference in lifespan. So a lot of invertebrate geneticists went into the fields and and mapped out all. These on Jebediah genes that impact worms, flies and east, which is awesome. But now which of those translate to humans, those are the ones that matter for for translation going back to kind of the history, the field be kind of how these really sort of highly advanced intellectuals going to kind of losing a lot of their momentum forward. Practically Nobel laureates Elie. Claiming that gut bacteria can of control aging and maybe that's coming back around now in some areas of current biology at back then it's not as well supported. It's only recently they started to how the traction in the field specific discoveries that period of time was just. So critical to the fields birth Cynthia Kenyon when she was making these I was told you'll fall face of the earth. Literally if you pursue this research to do the study, and if you look at her first paper, she was the lead author because no Grad soon was willing in her lab to do the work. That was such a controversial first step to you know young principal investigator. That was how unexpected it was really thought that it would be the end of your career kind of go into this field niche. Kind of you know started a new they didn't even want to touch it. Yeah. Exactly worse than unexpected like bad science. So can we talk about what that traction actually is looking right now what does the most promising traction I think one thing that we feel really strongly is this critical decade patients are for the first time receiving drugs that were developed in the context of aging. And Fascinating to watch these first clinical trials occur companies are actually developing drugs, and when that first patient gets actual clinical benefit, we're going to see people actually affected by these kind of ideas that have percolated in the field for decades. One of the kind of examples of this. Sort of prominent in the field is a trial testing a drug called met foreman in the elderly, and so it's actually looking at all cause mortality, not just a specific disease as an end points four minutes off this drug, which retrospectively has been shown to be somewhat correlated to a decrease mortality in for example, diabetic patients, it was discovered by analyzing health records right so so That's a great way to find repurpose drugs living longer. Yeah. So it's of these drugs. Millions of people have been taken for decades. You can actually go back in time and ask the question you know are people who are on metformin living longer and they are and that's kind of amazing. So that's where the whole hypothesis for this compound came from. It's now being tested in the clinic, which is so exciting I gotta go get me up. Chris. Other, key approaches that we haven't touched on yet that we should be describing as this new field kind of evolves there's also restore bio which you know was testing a molecule that's similar to rep, and that was for tract infections in the elderly dot trump did not work when try Kennedy's three. But if that had replicated I would have been one of the more big examples. There are some sort of drugs and clinical sort of landscape today that are four metabolic disease things like national ideas or VCD which when you over express these proteins in mice, make the myself longer. So there's this key. Link between like things that we already are using to treatment bulk disease in the clinic and kind of what might actually impact lifespan. So that's the connection with Metformin. Let Foreman impacts, cancer deaths to. So again, it's like a broader ejaculated mechanism. Yeah. Okay. That's interesting. In one way that we try to classify these companies three generations one is focusing on traditional pathways. So things that might affect for example, insulin signaling in the body, and those are kind of known targets that people are doing with existing modalities. Second would be trying to screen for novel targets using platforms that are high throughput and kind of. Model organisms or kind of novel kind of in Vitro in Vivo screens the third would actually target damage directly. We're not saying evolve pathway that were knocking up or down you'd rather saying instead of damaged accumulated and that's we're kind of going off during a more engineered fashion. So you know, for example, targeting recalled snacks and sells. So soles that get older credit with age the idea of Zombie cells. They're scouring to built up in the license zome of each cell called like the few sin, and that is aging related type of damage which when targeted. Relevant these disorders that people kind of starting to work on three different small examples of clinical work being done. But for age related diseases and it's like three different frameworks. Well, the question right for the first generation of companies is, what's the low hanging fruit because something is very well conserved through invertebrates up to mammals probably it's in humans to right. So Am tour is very interesting target that said the genes that are the most important for invertebrates are probably not the most important ones for humans, right so I think a lot of those new pathways have yet to be discovered and we'll have much higher impact on longevity phenotype says well, and damage I. Guess also is sort of going directly to the major causes. Of Disease. So I think those all make sense as approaches I I mean it's so unexplored now therapeutically right even those drugs that have a very mild impact on longevity are thing could be incredibly meaningful really important consideration as well. Would you call like ten percent increase in? Yeah like a few percent increase in lifespan rapamycin is probably the most well validated drug for extending mouse lifespan right but you know the amount of compounds that were tested to that level of scientific rigor is about thirty pounds thirty drugs into my did thirty random experiments, right? And, one of them boosted lifespan by fourteen percent. So I think there's GonNa be tons of things that have much higher effect. The Napa my get back to thinking about just the biology of it. It's. Is there any other trend for the? Why now is it just finally but people like Cynthia Kenyon being brave enough serve help create the field are there any other sort of confluence of things coming in here mapping out every single molecule in a blood sample in human blood sample proteins, metabolites, whatever we can get our hands on and seen which of those predict living a long healthy lifespan and going after those that are causal. Even five years ago really technologies that we're using didn't exist kristen you really kind of changed my thinking here when we first you're talking about biomarkers for. Longevity and how important those were and to be able to test our hypothesis in human, and that's where it all counts and so kind of when you pointed out that this was the key problem i. think that was such a big watershed for the field of if we just make a fast easy cheap reliable biomarker for aging, that's really going to change the whole field in a way that is more than just getting one to work at the biomarker. Thing is actually very interesting because let's make an analogy cholesterol as a biomarker for heart disease and because they're such a causal. Between cholesterol and heart disease. You don't have to run a trial waiting for people to die of heart disease and that's huge and especially also you can measure it. You can see small changes go up and down you have something that's not binary dead or alive. You have something that has a lot of nuance to it and so having bar markers is both really useful but I think somewhat reflects just. Of the space to is there another approach where we're all aging differently and we need to understand things on an individual level in terms of what our aging type is that different systems age in different ways the same as with any biomarker with cancer you can personalize the hell of it and say, you've got these weird mutations and therefore you're part of this special. sub-type right and I kind of think that personalized medicine is where you go after you sort of exhausted the things that are going to work for a population I mean as we discussed earlier, there are already mechanisms of aging conserved across species you know from east to us. So certainly, there are also really potent mechanisms of aging that are conserved across humans were focused. On targeting those first looking at the commonalities I. But certainly, you know for certain individuals, there will be particularities to how the age that you could. Also you know treat differently in different people are changing paradigms is not just a scientific paradigm or even clinical paradigm but as a healthcare delivery carradine as well. Now, there's this opportunity to say given that knowledge what can. We do against existing therapeutic areas existing disease. We don't have to talk about founder of you. We're talking about learning new biology, learn new targets that can directly go into clinical trial for a new disease, and I suspect that could be a very interesting sort of initial area initial application. So it's like what can learn about aging actually do to make you healthier right now. Actually end or can can actually can help you cure a disease that you have How what is that connection? Can we just spell that out? and. There's a couple of variants of this one variant would be an aging related disease. Disease these diseases where you age rapidly that's kind of obvious one. But maybe what's less obvious is other diseases by could we be talking cancer be talking? What, what are the? All of those right I mean age is the single biggest risk factor for those diseases like twenty year olds do not get Alzheimer's and we cannot cure Alzheimer's Today and it's therapeutically it's been a disaster. Everything has failed in the clinic thus far, and part of that is probably because we're studying it in the wrong way I mean when we're testing. Drugs in animal models mice don't get Alzheimer's and young animals do not get Alzheimer's at all Alzheimer's Disease Cancer Heart Disease and stroke. We have to study these diseases in the context of aging and that I think is a new perspective. If you think about just the biology of Alzheimer's, it's not even clear what's going on like even which protein is a Beta is Tau is Alzheimer and a aggregation problem is that problem is the apathy like the even the fueled can't even agree on the biology even targeting a fiber targeting top with these it's not a traditional pocket that you get a small molecule to go into. If you have something, we're the current drug design methods don't work it seems like applying. The. Current design methods is not the right thing to do. This feels like the type of radical shift that could have an impact and still keep us in small molecule and when we think about this, then actually the translation part is pre straightforward because I think the beauty of what we're talking about here is the current healthcare system won't have to change. That basically, we have indications and as Christian mentioned like like not just any indications but the biggest killers. Deal need a huge amount need. Numbers were there's at least today no drug at all. I'm curious like you could have a patient with the early signs of Alzheimer's like with MCI mild cognitive inhibition. Could you reverse phenotype? Could you just delay type? It think that is the whole promise and the practical approach approaches. Well, right that really if you have a drug enhanced that treats aging fundamentally, it should treat several different diseases and and yes, we can work within the existing medical system with the one caveat I don't think an aging drug is going to be a great drug for metastatic cancer you know or. Probably too far. Yeah, and sort of how far is too far, and really these targets will probably have their most potential when they're using the preventative fashion that of course, that's not something that the existing system can deal with but I do think that early disease like MCI. You can at least halt progression which would be massive you know and potentially reverse it with some of these mechanisms the reversal. Gets everyone excited definitely. But even if you could just slow down, YEP, in Alzheimer's slowing down, could still be very, very valuable. Yeah. What's w disease modifying and there you could ever land pointed against that. So it's interesting. You're saying almost that like the biggest hurdle is getting the biology of aging in its approach of its own, and then once you can get the right targets. Then you can sort of slot into the existing system and keep moving I think there's so much about the science. The biology of aging that has been validated that now has opened the door to now treating these as targets. Actually you know the findings you could just identify that target toss it over the fence to your favorite Pharma, and it would slot into the same type of programs that they would be running right now it doesn't require a radicals or envisioning a farmer to make this happen moreover, I think if you look at the history of former, it goes through waves of new technologies and maybe it's interesting question win or if longevity becomes at hot new trend and I suspect that north rather to happen, you have to have one or two clinical trials that showed this works, and then it probably just catches fire. One amplified wanting kristen said that I think went by relatively quickly that is very, very important. Is that these compounds if they are truly going after the biology of aging will be useful in multiple indication at first sounds magical but they actually precedence for this for existing compounds. So that alone is interesting that already presence can you compare an example there I mean. So my favorite stupid one is actually Benadryl and UNISOM. So actually it's exact same drugs you go to the pharmacy often they just happened to be on opposite sides of the aisle and actually when sold as a sleeping pill, it costs a lot more than as A. It's the exact same compound executive dose, and if you've ever take Benadryl for allergies, you get very sleepy. So that's a simple example better examples in in diseases. For example is of the ones. That's a great example what five or six vacation. That's right. More. And like the world's most valuable drug as well. Yeah, but this is a little different. I think in that one you just happened. There existed. So the humor cases, similar diseases. In the Benadryl case, it happens to make you sleepy. It's almost like taking advantage of the side effect. This is something fundamentally different. This is something we're actually the sort of way to save all these diseases is to slow down aging and that, and that's why it has such broad impact. So is it oversimplifying say aging as kind of root. Cause of all these diseases or is that amplifier of the disease or causal driver? You know driver? Yeah. Well, look at Immune Jane Right I mean your immune system declines horribly with age. You don't respond as well to vaccines. You're you're more likely to get incredibly sick when you do get the flu or a cold and that affects everything in your whole body makes everything worse. Point of view, it is a causal driver, right? Just a mathematical statistical definition. and. Then that makes it a very natural philosophical think about it. One of the hypotheses about why we have pathways that control aging is that we've evolved those for a reason that there's a benefits to living longer enough to have kids different environment and it really wouldn't do well to live longer and be great. You want to have ways impact all your health that pushes back all diseases otherwise kind of us get your. Debt of a different thing earlier. So that's gonNA perhaps why it'd be plausible to believe that there'd be sort of all disease sort of efficacy for these kind of anti aging therapeutics actually in what is the evolutionary selection for for aging or lack of aging because you could see that I'm once you've given birth to children or maybe gotten them to grandchildren there's then you have no purpose right I mean you're you're i. Like from revolutionary point of view and you've, let's say diminish purpose from a purely sort of cold evolution point of view. But you're still taking resources if you have a certain fixed mortality rate year-over-year. Actually here than it's are developed society your probability of being dead at any one point in time in your life is actually pretty high, even independent of aging over time and so if there anything that benefit you when you're young might be harmful to older or just kind things that it came late randomly past the point at which you're likely to be died from other non aging causes might accumulate into now that we have actually the ability to live long enough to know potentially benefited from the number of years there's. been no selective pressure potentially to kind of live longer in that sort of period of life. One of the things that I'm always curious about is what don't we know now that we need to know because the problem with biology is is that it's just so complicated longevity ageing biology seems to be amongst the most complicated. That's the thing that I'm always wondering about is what is going to be the big surprise of the big curve ball and what can we learn from it? That's a really good point Reich I. Think. We're all waiting for the first clinical trial to be successful, and that's going to be so important for the field right for. Pharma. Companies that traditionally don't work in this area to really get confidence and excitement around it. But yeah it. There's so much risk associated with bringing these mechanisms forward and figuring out the indication path. I mean, you can even have a good mechanism, but have you know defining these indications for the first time of course, we're going to get it wrong. The first few times there's there's so much. To figure out because it's really such a new field. No. Okay. So we've talked about the explosion of the field of the study of the Science Balaji of aging, and then we've talked a little bit about what that brings us actually right now in terms of understanding biology and disease. But where do we meet resistance again where we try to get this into the the health that exists today as a kind of preventative medicine what does that look like in terms of the end goal being a healthier life a longer life? Health. Span I think that's a great question because you you got the therapy in hand. Do you think it's actually slowing down aging and yes, you can work with the existing healthcare system and layer on indications one at a time. But really you're not getting to the whole aging population as quickly as you can right and what could that path look like in the future? So biomarkers is one route, right? Maybe people are still pre disease, but they're frail this sort of functional and molecular biomarkers that predict they're going to be sick like statins statins exactly like statins will you know sort does handlebar marker? With the hope prophylactically to avoid disease people often say that people don't WanNa pay for prevention, but we do pay for Stanton, there's this old joke that up plumbers have saved more lives than doctors, and that's the point about sanitation is just been this fundamental sort of floor for just for human health and then I think the next level up in my mind is gingrich. No disrespect delay or? Or Minimizing Reno's. As much as I do like them that's what comes to mind I mean basically no one should have type two diabetes. I mean, that's another version of sanitation. It's now the question is, could you? Like. The with longevity gene hand where you have these biomarkers a no one should have these aging related diseases or maybe nobody should have disease before the age of blank and that blank goes from like sixty to seventy to eighty to ninety onward. That's right preps while we really just need is something to have this rock-solid biomarker that the clinicians are convinced is an issue and then you have buicks that can help you manage to that biomarker. At least there's a paradigm for that. Well, we'll exactly but any therapy that really delayed aging that really delay the onset of disease would save a tremendous amount. Of money and you know and you can put a number on that and you can justify a certain cost It shouldn't be that hard I think that's where it comes back to this is the decade because it's the first time that we're going to see trials actually can all cause mortality with therapies that are already on market today and we're going to see the impact of those readouts. It's never been something that's ever been done before that's that's truly different for any other time in history, and that's the proof we need to get the system to really start recognizing it that way one would hopefully. Well. So that's a great point. I'm wondering like what would be the analogy like are we at like I live tour kind of thing we're looking because then then there's been what four generations of statins since then before then actually that model didn't even exist. Responding, to like the first modern Mark Trough Shift in paradigm and that kind of occurring potentially as a result of views. But for the field to right I, mean the point several of these hypotheses are being tested clinically we're GONNA have to wait while we really get the human proof of concept for the idea, and then once data comes in I think that's going to be huge osteoporosis is a really. Good example to write, it didn't used to be considered a disease, but there's sort of markers of your bones get weaker as age, and that predisposes you to really severe outcomes events and now it's recognized as one, and now there are drugs and there's a way forward and payers were convinced right. So there are case studies I think that we can follow or it's kind of flipped the understanding it slipped. Exactly. The mentality towards. Yeah. So where where are we in the hype cycle? Would you say yeah, biotech generally like it's shifted in the last few years to be a lot more accessible with, I would say like low upfront capital, right. So first of all, the data sets that my company relies on, we were for the first couple years a data company like people with laptops vastly cheaper than biology even if we were doing biology now they're incubator spaces. Now, there are Sierras like worship that can do all your chemistry outsourced. So I think the barrier to entry for biotech has gotten a lot lower and really able a lot of these new and exciting. Ways to work on targets and therapies in two thousand eleven two, thousand thirteen, there were so few companies that like just having enough money to finance companies in this space was limiting thing. Now I think there is actually enough money just even from the past couple of years to fund the good ideas and the people, and so we're not turmeric comes to us and says, Hey, I want to make. This is a common thing. Make a lot of money and then put it back into biotech. It's like no no. If you're actually get entrepreneur please started company that's what we need more of start a company. If you want impact space, we lock people is. Just fascinated by you were one of the first to really go out there and do a couple of things. One was we need biomarkers for aging put but also just built an aging company at all I mean there are very few companies when you started what have been the sort of easier and harder things even count it as a result of that focus. I mean, it's new, right? So everyone I think understands that it's riskier. I guess than if you have another company for Nash Other Company for cancer, everybody knows exactly how that's GonNa go from discovery through validation through your clinical trial design through your reimbursements. There's a lot of uncertainties because the space is so new but related to that. There's also so much opportunity I would say that there's more awareness now that these drugs are in trials, there's more I would say also appetite for novel mechanisms now that. The usual approaches are not working. So I think it's it's landscape is changed a lot not just at the start up level, but in terms of like big biotech as well. Well, there's one just common question for any founder serve in the Bio Pharma side when you can do many things, would you do I? What? How do you pick a therapeutic area? That's probably one of the hardest questions an entrepreneur has to deal. With? Yes there is no clear well trodden path but that means that we also have the opportunity to to really optimize and build something new. We're trying to design our first clinical trials. So should it be for an age related disease? Should it be for something closer to edging again, uncertainty plus opportunity right and trading those two things off and making a bad right we're really focused right now on just getting more people to be founders. Early Twenty tens of capital. There's just no money in the space right now the big ball neck is founders and we've seen many amazing companies built by both crowd soon, strictly out of their kind of peachy. But also people coming from software engineering, managerial positions, and a lot of these people out of the position they say I can't start w company because I. Don't fit the profile of a brilliant scientist founder or traditional investment bankers but they make an incredible founders and there's just a huge population of folks out there who I think should be company. So just to double down on the idea that if you want a really impact longevity, start a company that is exactly what we need right now what are the other? Types of founders that you tend to see coming into the field you know in this new field, the founders in this space typically combine a couple things. They either are biologists who have embraced machine learning or other areas or even people that are coming from the tech side that are learning the biology. It's a really unusual time where you can actually learn both. Maybe Learn Brooklyn beginning but actually it's almost like it's never too late because you can pick up both sides but if you can capture both sides, I think you'll have a huge advantage, a nontraditional founder for us would be someone that is coming maybe from pure farm aside, and we haven't seen that yet but I suspect they're coming in Christians nodding your head. And I suspect other coming either to be founders or as. Does and that they may be comes employees for these companies that culture and the talent landscape changing to involving intelligent. Interesting. That's it for the biology of aging and thanks so much for joining us on bio swirled. If you'd like to hear more about all the ways biology is technology, please subscribe to the a sixteen bio newsletter at a sixteen Z dot com slash new letter, and of course, subscribe to Bio East world anywhere you listen to podcasts.

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