Translating Aging

Gene therapy screening to discover aging targets (Martin Borch Jensen -  Gordian Biotechnology)Gordian Biotechnology is a San Francisco Bay Area biotech company that has created the first in vivo therapeutic screening platform aimed at drug development for complex diseases of aging. Co-founder and Chief Science Officer, Dr. Martin Borch Jensen joins the show today to discuss Gordian’s unique in vivo pooled screening in animals, as well as which indications they are targeting, their strategy to bring drugs to market, and how Gordian is currently tackling the challenges inherent to animal models. Martin also speaks about his passion from an early age to help fight age-related disease, and making the transition from academia to entrepreneurship, giving up a K99 fellowship at the Buck Institute for Research on Aging to make the jump into biotech.You’ll also hear about Martin’s involvement in multiple efforts to promote longevity science and bring new people into the field, including his apprenticeship program, the newly announced Longevity Impetus Grants program, and recording his “Science of Aging” seminar. Next, Martin shares what’s next for Gordian as they get ready to scale to the next level, which areas of longevity science he is most interested in but not currently working on, and how he predicts the field will evolve over the next five to ten years. For more information on Martin’s apprenticeship program and Impetus Grants application process, please visit MartinBorchJensen.com or follow him on Twitter.Episode Highlights:Dr. Martin Borch Jensen is the co-founder and CSO of Gordian BiotechnologyGordian Biotechnology created the first in vivo therapeutic screening platform to radically improve drug development for complex diseases of agingMartin is also involved with an apprenticeship program and a newly announced grant program to catalyze rapid progress in aging researchHow Gordian’s unique in vivo pooled screening in animals worksThey’re focused on removing the diseases of aging, beginning with their three lead indications, NASH (nonalcoholic steatohepatitis or fatty liver), osteoarthritis and idiopathic pulmonary fibrosisHow Gordian compiles their gene librariesWhile other companies start with in vitro models and then figure out ways to test them in living animals, Gordian starts with the second step They deliver hundreds of gene therapies at once to a single animalThe drugs that they ultimately develop won't necessarily be gene therapy, but instead whatever is most appropriate to pursue the indication once they know the target (small molecule drugs, antibodies)What a cell needs depends on what a cell isGene therapy has plenty of advantages, but the cost is very highHow Gordian is overcoming challenges that are inherent to animal modelsOlder mice are much more expensive and are rarely used in aging researchAnimal models can actually be useful if the animal has progressively developed a disease in the same way humans do, and has similar biologyExample of studying osteoarthritis in horses, because the load-bearing structure of their joints is much more similar to humans, as is their cartilage thicknessGordian’s strategy to bring drugs to marketMartin’s transition from academic to entrepreneur and what inspired him make the jump to biotechHe gave up a K99 fellowship at the Buck Institute for Research on AgingHe realized as a teenager that he wanted to try to fix agingMartin is good friends with Dr. Kristen Fortney, co-founder and CEO of BIOAGE; her journey showed him that it was possible to start his own companyMartin is also involved in multiple efforts to promote longevity science, and to bring people into the fieldHis apprenticeship program was developed as a way to bring people in, and train them to be able to work on direct projectsLongevity Impetus Grants is a $21 million (update: $26 million as of the release of the podcast) program that provides funding for scientists to start working on what they consider the most important problems in aging biology without delayThis was inspired by COVID-19 “Fast Grants,” created by Tyler Cowen, Patrick Collison, and Patrick HsuTheir goal is to take big bets on projects that could move the field forward, and recipients will be able to publish their findings regardless of what their results areImpetus Grants applications open on Monday, September 13, 2021Martin also recorded a comprehensive seminar about the science of agingWhat’s next for Gordian as they get ready to scale to the next levelMartin predicts that in 5-10 years, we will have ways of measuring biomarkers for aging in humansQuotes:“It's phenotypic screening, but also because it's gene therapies we're putting in, we know the target immediately. So I call it ‘pheno-target screening,’ combining the best of both discovery modalities that are used.”“At Gordian, we're focused on removing the diseases of aging. Right now we're doing that with three lead indications, and that number will grow, which are NASH and osteoarthritis and idiopathic pulmonary fibrosis.”“We've created the platform in order to be able to do somewhat unbiased screens or entirely unbiased screens, and just explore a lot more of the biology of these diseases than has ever been explored in vivo so far, because we have this higher throughput.”“The logistics of the other method simply don't allow you to test a wide range of things in the in vivo context.”“I'm very excited about gene therapy in the long run to treat aging, diseases of aging, and just the physiological processes of aging. Because it turns out that what a cell needs depends on what a cell is. And so you probably don't want the same treatment in every type of cell in your body.”“You need a targeted way to go in and give each type of cell and each tissue what it needs, if we're going to really exercise control over the aging process.”“Maybe animal models aren't so bad for many diseases, if you find an animal that has continuously developed, progressively, a disease in the same way that humans develop this disease, and has biology that resembles human biology and the relevant organ.”“We are a drug development company. We've developed this in vivo full screening platform in order to use it ourselves and discover the best drugs for each of the indications that we go into.”“We are in conversations with a whole bunch of pharma companies about partnering at the clinical stage around the assets that we are discovering with our platform.”“As a teenager, I came to the realization that I wanted to try to fix aging… The idea that everyone is going to get sick and be in pain, and then die, just seemed really bad.”“I wanted, with Gordian, not only to have the successful outcome of treating age-related diseases, but I also wanted to feel for myself that I was doing absolutely everything that I could towards the goal that I had decided.”“It's going to be really hard. There's going to be doubts and challenges… And so if you're doing it for reasons that won't compel you to push through all of that, it's probably not going to work out.”“[This apprenticeship program] is needed, because there are more things that should happen, and apparently could happen, than I could possibly ever go and do myself.”“The apprentices end up doing most of the legwork by far. And I'm kind of steering it.”“This is the real test of success for this apprenticeship - if the people in it end up running important projects within the longevity field overall, then it's a success.”“If there is something there, if the project does work out, that would actually be a really big push forward for the field, then we should try to fund those things. And many of them won't work out and that's okay. We can learn from that.”“Any nonprofit can apply from anywhere in the world. Or any researcher at a nonprofit.”“What you really have to explain to us is, How is what you're doing going to move the field forward, if it works, and why is the way that you're doing it, a good, robust, well thought-out experimental plan for doing it? Those are the main things that we look for.”“In five to 10 years, I think we will have drawn studies for biomarkers of human aging. So I think that in five to 10 years -hopefully more like five - we will have ways of measuring in humans, something that we choose to call aging.” Links:Email questions, comments and feedback to podcast@bioagelabs.comTranslating Aging on Twitter: @bioagepodcastBIOAGE Labs Website BIOAGELabs.comBIOAGE Labs Twitter @bioagelabsBIOAGE Labs LinkedInMartin Borch Jensen Website MartinBorchJensen.comMartin Borch Jensen on Twitter: @MartinBJensenLongevity Impetus Grants Website ImpetusGrants.orgGordian Biotechnology Website Gordian.bio

On today’s episode is Dr. Jennifer Garrison, Professor at the Buck Institute for Research on Aging, and the Faculty Director of the Global Consortium for Reproductive Longevity and Equality (GCRLE), which is devoted to supporting breakthrough research on reproductive aging and women in science through funding, training, infrastructure, and collaborative intellectual networks. Dr. Garrison explains that while there are plenty of scientists working on aging and plenty who are working on reproductive biology, there are precious few who are working at the interface of these two fields, which is what they are trying to build at the GCRLE. She shares her fascination with ovarian biology and how it fits into the broader context of longevity research, and details the issue of equality in terms of women having to plan their life choices around reproductive longevity in ways that men do not, as well as funding for women’s health being traditionally overlooked. Dr. Garrison answers questions about menopause across the animal kingdom, the link between reproductive span and lifespan in women, and the most important question we need to answer in order to truly understand ovarian aging. Dr. Garrison describes the key role played by the brain in reproductive success, the need for better animal model systems to understand menopause, and how hormone replacement therapy can help mitigate the negative health consequences around menopause. You’ll also hear about the profound economic and societal impact of menopause globally, as well as Dr. Garrison’s goals for the future and dream outcomes she envisions for the Consortium as they continue their cutting-edge research on the causes of ovarian aging. To learn more about their important work, visit BuckInstitute.org/gcrle/.Episode Highlights:The goal of the Global Consortium for Reproductive Longevity and Equality (CGRLE) is to extend the female reproductive spanThe Global Consortium began at the Buck Institute for Research on Aging through a generous donation from Nicole Shanahan and the Sergey Brin Family FoundationThere are plenty of scientists working on aging and others who are working on reproductive biology, but precious few who are working at the interface of those two fields - that’s what they are trying to buildThe GCRLE has three arms: Funding; providing resources to build out the field; and building a network communications platform to foster dialogue and collaboration among researchers working on female reproductive agingThey’ve also opened the world’s first ovarian biology core facility at the Buck InstituteOvaries are a very complex structure, and they age at a precocious rate - they’re considered geriatric by the time a woman is in her late 20s, early 30sNicole Shanahan’s became involved with starting the CGRLE to find out what causes ovaries to decline in function so earlyOvarian biology as it relates to reproductive longevity has been traditionally overlooked in terms of receiving fundingWomen’s health has been looked at as a subcategory of medicineEquality is a key piece to what they do - women need to plan their life choices around reproductive health in a way that men do notMenopause accelerates the aging processIt is relatively rare in the animal kingdom - humans are one of the only species that go through menopauseWomen who experience menopause later in life also tend to live longer and have an enhanced ability to repair their DNAThere is a clear link between reproductive span and lifespan in womenThe key question is, What is the cue that tells a woman’s ovaries to start declining in her 20s?The brain is a crucial player in reproductive successWe need better animal model systems to understand menopauseFemale reproductive health trajectory and how medical intervention fits inHormone replacement therapy is one of the best band aids we have to mitigate the negative health consequences of menopauseStudies show that there is a positive benefit to doing hormone replacement therapy on cognitive functionEconomic impact of menopause and related healthcare costsEmerging trend of reproductive aging in biotech industryDr. Garrison’s goals for the future and dream outcomes she envisions for the ConsortiumQuotes:“We started a few years ago, with a really generous gift from Nicole Shanahan and the Sergey Brin Family Foundation. We started a center at the Buck Institute to study female reproductive aging.”“When we started the center, we realized right away that if we really wanted to have an impact, and truly move the needle, that we were going to have to do something bigger. And that's where the consortium came in.”“What's different about the ovary, compared to every other organ in the human body, is that it ages precociously, meaning that it's actually the first organ by far to age in the human body, and it's aging at about two and a half times the rate of the rest of the tissues.”“I think research on women's health is underfunded in general.”“I think that as we make progress and advances in extending healthy longevity and health span, or the number of years that someone's healthy, if we don't address reproductive longevity, then I think gender inequality is going to get worse, not better.”“From the minute I went through puberty, whether I wanted to have biological children or not, every decision that I made was overshadowed by the fact that I was going to go through this reproductive decline in midlife - this biological clock, so to speak, that was ticking in the background. Decisions about overall health, my career, family planning. This is an issue of equity. Men don't have these concerns.”“Humans are really weird. We're very unusual as a species. There's almost no other species - there's very few species that go through menopause.”“Women who have later menopause tend to live longer. They also have an enhanced ability to repair their DNA.”“There's no question that the brain is a key player for reproductive success. It controls all aspects of female reproduction: Puberty, menstruation, fertility, conception, pregnancy, childbirth, childcare, and ultimately menopause.”“That's the goal is to give women more choice and control over their own bodies.”“By the time a woman actually might want to use her ovaries, she's left with approximately 2 to 3% of the number of eggs that she started with.”“The bottom line is that hormone replacement therapy is probably the best band aid we have to mitigate the negative health consequences of menopause.”“I think the basic science has to happen first. I can't emphasize that more strongly. Otherwise, like I said, everything we're doing is a band aid.”“I really want people to think about a scenario where women aren't constrained by an immutable biological clock, to think about a world where women aren't subject to the detrimental health effects of menopause. And just to consider for a moment, the implications for social, economic and personal empowerment, that that freedom of choice and freedom from health risks would give to half the population.”Links:Email questions, comments and feedback to podcast@bioagelabs.comTranslating Aging on Twitter: @bioagepodcastBIOAGE Labs Website BIOAGELabs.comBIOAGE Labs Twitter @bioagelabsBIOAGE Labs LinkedInGlobal Consortium for Reproductive Longevity and Equality Website buckinstitute.org/gcrle/Garrison Lab Website garrisonlab.com

Dr. Hanadie Yousef is a scientist, aging biology expert and the co-founder and CEO of Juvena Therapeutics, a Palo Alto-based biopharma startup developing protein-based therapeutics to promote tissue regeneration and increase healthspan to prevent, reverse, and cure degenerative diseases. Dr. Yousef joins host Dr. Chris Patil to discuss Juvena’s premise, their use of a machine learning platform to identify proteins that have therapeutic potential, and what most excites her about turning signaling proteins into therapeutics. She answers questions about handling potential challenges within Juvena’s approach, their strategy for bringing drugs to market, and the first aging indication that they are targeting - muscular rejuvenation. Dr. Yousef outlines Juvena’s plans for a clinical study in patients with Myotonic Dystrophy Type 1 by 2023, and shares what’s coming down the pipeline next for her team. You’ll also hear about Dr. Yousef’s transition from academic science to becoming an entrepreneur, her involvement with the On Deck initiative, which seeks to increase the number of scientists, researchers, and inventors in the healthspan and longevity field, and why it’s so worthwhile to invest in anti-aging science.The interview concludes with Dr. Yousef’s advice for potential new founders in the biotech industry. She also shares the areas of longevity science that she is most fascinated by, and offers her thoughts on how the field of aging pharma will evolve over the next five to ten years.Episode Highlights:Tissues deteriorate as we get older and our ability to heal slows down - this leads to a wide variety of age-related diseasesJuvena Therapeutics sets out to find regenerative cures for those diseasesDuring the aging process, critical regenerative protein signaling pathways that are important for instructing cells and tissues within our bodies start to changeThey start becoming over-expressed or under-expressedThere is a change and loss of healthy crosstalk between pathways that can instruct cellsThis leads to a loss of tissue homeostasisBy understanding what is changing within us, we can use that information to target protein signaling pathways that are important for stem cell function, immune cell function, etc. in order to rejuvenate tissues and reverse the aging processJuvena uses a machine learning platform by combining several data modalitiesTheir premise is to develop protein-based therapies that can target critical regenerative signaling pathways in our bodies to promote better regenerationThey do this by mining secretome of the most po-regenerative source of cells, which are human embryonic, or pluripotent, stem cellsAging models that they use are cells derived from people who are themselves aged or who have an age-related diseaseThere are challenges with every therapeutic intervention targeting the biology of aging Juvena’s strategy for bringing drugs to market and the first aging indication they are targetingThey are looking to promote tissue-specific rejuvenation, for example, better muscle differentiation, reduced atrophy and improved strength and functionThey are hoping to have FDA approval as an investigative new drug within the next year and a half - this would lead to a Phase One/Two clinical study for patients with Myotonic Dystrophy Type 1 by 2023Dr. Yousef’s academic background and transitioning to starting her own companyShe has a passion for both drug discovery and taking those inventions to build companiesThe inspiration and motivation behind starting Juvena Therapeutics with co-founder Dr. Jeremy O'Connell, as well as the process of pitching and acquiring fundingDr. Yousef was torn between an academic career and entrepreneurship, and she ultimately decided to embrace her role as CEO and focus on building the companyHow investors react to Juvena Therapeutics’ aging focus and how Dr. Yousef puts their minds at ease with regards to the expense of biotech and therapeutic investmentIt’s worth the risk - with a looming healthcare crisis of an aging population around the corner, the company that succeeds in anti-aging science could be one of the most lucrative and successful companies in the worldDr. Yousef’s involvement in the On Deck initiative - a fellowship program that seeks to increase the number of scientists, researchers, and inventors in the healthspan and longevity fieldAdvice she would give new entrepreneurs in this fieldShe is fascinated by the study of human centenarians, reproductive aging, and plant agingHer predictions for the field of aging pharma in the next 5-10 yearsQuotes:“As we all know, tissues deteriorate as we get older, and our ability to heal slows down, which leads to a wide range of age-related diseases. So Juvena Therapeutics sets out to find regenerative cures for these disorders.”“Through years of dedicated research, we discovered that the cures had been within us all along.”“By understanding what is changing within us, we can actually use that understanding to target those protein signaling pathways that are so important in regulating stem cell function, immune cell function, tissue regeneration and repair, in order to rejuvenate tissues, and to actually reverse the aging process and to bring our bodies back internally to a more healthy state.”“Ultimately, our premise at Juvena is to develop protein-based therapies that can target these critical regenerative signaling pathways in our bodies to promote better regeneration.”“What we're doing with our machine learning enhanced platform is really building a map of regenerative protein biology with a compounding database that's enabled by an array of in-house machinery and computational tools that we establish using these data modalities, to really identify the proteins that have therapeutic potential.”“What excites us about actually turning signaling proteins into therapeutics is their ability to really interact in more of a systems biology level with multiple pathways.”“Of course, ultimately, the goal is to calibrate homeostatic levels of signaling to more youthful levels, and not try to over induce any one particular pathway. And so by really recalibrating, and being careful about dosing, we'll be able to avoid things like oncogenic transformation.”“We are, right now, really interested in bringing our muscle regeneration protein therapeutic to market for a rare neuromuscular, muscle wasting disease, known as Myotonic Dystrophy Type 1.”“Our hope is that by 2023, we will be conducting what would be a combined Phase One/Two clinical study for patients with Myotonic Dystrophy Type 1 to test if our regenerative therapeutic can, in fact, do what it's doing in all the models and all the preclinical data to date.”“What's really coming is our ultimate goal of enhancing and promoting health span, and reversing multiple age-related and chronic diseases by developing a pipeline of protein therapies that act by rejuvenating your own body endogenous stem and precursor cell function to enhance regeneration and improve and rejuvenate your life.”“I am a neurobiologist, stem cell biologist and aging biologist by training.”“What came first for me was really a passion in general and biomedical research, and in the startup environment and in building companies.”“I really fell in love with the concept that actually understanding the mechanisms driving the aging process, and specifically, the changes in signaling that occur that lead to loss of stem cell function with age, we can actually use that understanding to reverse the process, to rejuvenate stem cell function to revitalize the body, and to then really reverse aging. And so that got me so excited. And I just fell in love with that and knew that that is what I want to dedicate the rest of my life to doing.”“It was this battle for me of, I love my research, I can really envision myself leading an academic lab and a faculty position to move this forward, really focus on brain aging. But then there was this also entrepreneurial opportunity to start my company and to instead really focus more on translational work, and really building the platform that enables a pipeline of protein therapeutics.”“The other things investors fear is just the expense associated with some of these indications.”“In the next decade, the largest demographic of people will be those over the age of 60. I think it's really in investors that just realize, it's worth the risk. Because the company that succeeds will be potentially one of the most lucrative, successful, and sought-after companies in the world.”“Some advice I wish I had going into this is really looking at what the target product profile of a drug you want to develop is, and as early as possible, creating a plan to really get to that preclinical stage in that translational stage where you need significantly more investment.” “I think in five to ten years, we'll get increasing acceptance of aging as a risk factor to diseases and more of an acceptance of therapeutics that can target the aging process.”Links:Email questions, comments and feedback to podcast@bioagelabs.comTranslating Aging on Twitter: @bioagepodcastBIOAGE Labs Website BIOAGELabs.comBIOAGE Labs Twitter @bioagelabsBIOAGE Labs LinkedInJuvena Therapeutics website

The Dog Aging Project is an innovative initiative that brings together a community of dogs, owners, veterinarians, researchers, and volunteers to carry out the most ambitious canine health study in the world. The goal of the Dog Aging Project is to understand how genes, lifestyle, and environment influence aging, and to use that information to help pets and people increase their healthspan, the period of life spent free from disease. Co-directors Dr. Daniel Promislow and Dr. Matt Kaeberlein join the show to discuss the origins of the Dog Aging Project, the overall goals for their initiative, and why dogs are a particularly good model for human aging. They talk about their funding through the National Institutes of Health, the extensive scale of the Dog Aging Project, and its “Community Scientist” component, with canine participants still living at home with their owners. Professors Promislow and Kaeberlein explain their use of molecular biology measures to predict health outcomes for dogs, their commitment to making their data available to the scientific community as a whole, and the difference between how small dogs versus large dogs age, as well as what diseases or conditions different breeds age and die from.Today’s fascinating conversation also touches on the impact of living in a rural versus urban areas on aging, how veterinarians feel about participating in the Dog Aging Project, the test of rapamycin in aging dogs (TRIAD), and the intrinsic value of being able to increase the lifespan and healthspan of our pets. Professors Promislow and Kaeberlein share what drew them to the field of aging, and review the importance of putting safety first in their work with dogs. Finally, you’ll hear their exciting predictions for what we can expect to see in aging research over the coming decades.For more information on the Dog Aging Project, visit DogAgingProject.org. Thank you for listening.Episode Highlights:Professors Daniel Promislow and Matt Kaeberlein are co-directors of the Dog Aging Project at the University of Washington in SeattleDog Aging Project started in 2007 to investigate whether IGF-1 was associated with aging for dogsChief Veterinary Officer is Kate E. CreevyOverall goals are to understand how genes, environment, and lifestyle shape healthy aging in dogs and the mechanisms by which they do so, and to determine whether we can intervene and improve healthy aging in dogsDogs are a very good model for human aging due to their similar environment (water quality, air quality, home setting)Dogs age seven to 10 times more rapidly than humans do, which means we have better success carrying out longitudinal studies with themThey also get the same types of diseases that we doThe Dog Aging Project is funded through the National Institutes of Health, and in particular, the National Institute on AgingThe scale of this project is notable, as well as the fact that the dogs are not in laboratories, but are living at home with their ownersIt’s a “Citizen Scientist” or “Community Science Project” effortThey now have upwards of 32,000 owners and dogs participating, and are still enrolling at DogAgingProject.orgThey collect information about the dogs’ health, disease, activity, diet every year, over the course of their entire livesThese molecular biology measures will allow them to predict what might happen in the future for dogs, and to improve diagnosis and prognosisThe samples are also stored in a biobank at Cornell, with the hopes that can be useful in studying overall aging as time goes on and new technologies become availableThe Dog Aging Project has always been an open science project, with data being made available to the scientific community on an annual basisThe rate of aging for dogs varies depending on size and breedBiological aging is faster in dogs than in humans, but the relationship is not necessarily linearWhat different breeds die of is very differentLarge dogs frequently die of Osteosarcoma, which is rare in smaller breeds and humansCertain organs may age faster than othersThe Dog Aging Project is able to control for different breeds using their genetic dataDogs who live in rural areas spend more time outside and engage in more physical activity - soon we will be able to tell how this affects the aging processVeterinarians are very enthusiastic about participating in this studyTest of rapamycin in aging dogs (TRIAD) clinical study looks at whether or not the drug Rapamycin can slow aging and increase healthy lifespan in dogsTranslating this to humans and bridging this to human trialIf they find success in increasing the healthspan of people’s pets, this could really change the way the field is perceived by the general publicChallenges of collecting and curating massive amounts of dataDogs who were administered rapamycin became more active afterwardHow Professors Promislow and Kaeberlein became interested in the field of agingDogs are becoming increasingly important models for understanding human healthSafety is always first priority for the animalsProfessors Promislow and Kaeberlein share their predictions for aging breakthroughs and challenges in the coming yearsWe will see advances in biomarkers or “precision geroscience” in the next decadeIt’s important to have realistic expectations and use consistent language when discussing aging - to use the term “curing aging” or “defeating aging” is misleading Quotes:“Dogs experience pretty much every aspect of the human environment.”“Dogs have the advantage, from the perspective of trying to understand aging, that they age about seven to 10 times more rapidly than people do. So that means that we can actually carry out longitudinal studies to understand the most important genetic and environmental risk factors in a few years, whereas in people it would take a few decades.”“A lot of what we know about human health and disease, we’ve learned from really simple organisms, like yeast, and nematode worms, and fruit flies.”“There is no upper limit. We hope to continue this project for many generations of dogs.”“The first, most important level is just to collect the information about health, disease, activity, diet from all the dogs. That's done through surveys, and all participants will be asked to contribute survey updates every year, so we follow the dogs throughout the course of their lives.”“Our scientists will also analyze what we call the Systems Biology Components - the epigenome, the microbiome, the metabolome. We're also looking at a panel of inflammatory markers, measuring frailty. So these are the sorts of things that we will track throughout the course of the life of these dogs. The hope is that these molecular biology measures that we collect will allow us to predict what might happen in the future for dogs and to improve diagnosis, and prognosis as well.”“Our expectation is that the samples that are collected and stored in the biobank will be useful to the field for exploring those other types of molecular markers that may be particularly predictive for overall aging, or certain age-related disease processes.”“The Dog Aging Project, from its inception, has been envisioned as an open science project. And so all of the data that we collect is being made available on an annual basis to the scientific community.”“The other thing about dogs is that a decade from now, when new technologies may be available, that's about the equivalent of 70 years of biological aging in people. So it's almost as if any human longitudinal study you had biobank samples for seven decades, we can get that sort of biological age resolution in a single decade of dogs.”“A Great Dane would be considered geriatric at seven years, whereas a Chihuahua might be considered geriatric at 12 or 14, and could very well live 18 or 19 years.”“The Dog Aging Project will eventually be able to tell us what the relationship is between the epigenetic age clock and actual aging of pathophysiological processes.”“There's just a lot to learn about how quickly different breeds age and what they age and die from.”“We shipped a kit to an owner to take to their veterinarian. And these kits are filled with, as I mentioned earlier, blood samples, hair, fecal samples, urine, and then they need to be delivered via FedEx, to our diagnostic lab. This was a rural veterinarian, and there wasn't a FedEx Office or drop-off point in that community. So the veterinarian, not the owner, but the veterinarian after work, drove 40 minutes to the next town over where there was a FedEx drop-off, so that they could deliver the kit. That's the kind of enthusiasm that we see from participating veterinarians.”“TRIAD is the Test of Rapamycin in Aging Dogs. That’s the only clinical trial the Dog Aging Project is carrying out right now. And the goal of that trial is really to test whether or not the drug Rapamycin can slow aging and increase healthy lifespan in dogs.”“Everybody on the Dog Aging Project team agrees that this isn't only about what we'll learn about human aging. There's intrinsic value in being able to increase the lifespan and healthspan of our pets. There's value to the pets and there's value to the owner.”“I think if we're successful in showing that it is possible to increase healthspan in people's pets, that will really be a watershed moment in the field in the way that we are perceived by the general public.”“There are lots of wearable devices on the market for dogs. And they're very much like the devices that humans were, typically though they go on the collar of the dog. And we will be putting those devices on the Precision dogs and the TRIAD dogs to measure their activity, how it changes with age.”“There are several companies now that are trying to develop therapies to treat aging or age-related indications with companion animals, at least as the first path to the market. Me personally, I think that's fantastic. Certainly, we view the Dog Aging Project as something that hopefully other people in the field will build off of.”“We would just want to encourage all of the companies that are considering moving forward in the companion animal space to keep that in mind, and make sure that whatever you are planning to bring to the market, that you do it in the context of safety. Because the last thing that any of us want to do is harm somebody's pet.”“We're excited to try and recruit these diverse populations to the Dog Aging Project, and maybe even to use that as a model for getting all communities excited about participating in this term that we'd like to use of ‘community science.’”“I fully expect that within the next decade, we will see the first geroscience intervention approved to treat an age-related indication.”Links:Email questions, comments and feedback to podcast@bioagelabs.comTranslating Aging on Twitter: @bioagepodcastBIOAGE Labs Website BIOAGELabs.comBIOAGE Labs Twitter @bioagelabsBIOAGE Labs LinkedInDog Aging Project Website DogAgingProject.org

Loyal is a San Francisco-based startup that is seeking to treat the underlying causes of aging in dogs. Loyal has raised $11 million in seed funding so far, and is planning to start clinical trials of medications in 2022 and 2023. In this episode, BioAge VP-Media Chris Patil talks with Celine Halioua, CEO and founder of Loyal.Celine beginswith by describing the striking difference in lifespan among the dog species, with smaller breeds like the Chihuahua living twice as long as larger breeds like the Great Dane. She explains how historical inbreeding to create larger dogs actually caused them to age faster, and her plan to develop a drug that compensates for this accidental genetic disorder. Celine tells us about The Healthspan Study, which tracks aging markers in dogs, as well as what inspired her to start Loyal, and how their research complements the goals of the University of Washington Dog Aging Project. Celine breaks down the role of caloric restriction in anti-aging across species, why dogs are one of the best models for human aging as a disease, her background in neuroscience and longevity, and her passion for developing drugs for healthspan and lifespan extension. Celine also offers her perspective about encountering skepticism in the biotech industry, the unique challenges faced by young women founders, and overcoming sexist assumptions following the controversial story of Elizabeth Holmes. Finally, Celine shares what’s next for Loyal and her dream to build a consumer-focused pharmaceutical company that people love.To learn more about Loyal and their dedication to aging health for dogs, visit LoyalForDogs.com. Episode Highlights:Loyal is seeking to determine why, on average, the larger a dog breed is, the shorter their lifespanWe do not see a 2X lifespan differential among varieties of other animalsLoyal also looks at ways to pharmacologically improve metabolic resiliency and fitness in aged animals to give them a longer, healthier lifespanHistorical inbreeding to create larger dogs led them to age faster once they were fully grownLoyal is developing a drug that plans to compensate for this accidental genetic disorderThese drugs will enter clinical trials in 2022 to 2023Loyal is also running “The Healthspan Study,” which tracks aging markers in dogs (register your dog here)Dogs are like family to their owners, and Celine noticed how heartbroken owners were about their larger dogs aging and dying so earlyThis inspired her to start LoyalDistinction between healthspan versus simply adding years to lifeThesis of Dr. Matt Kaeberlein of the University of Washington’s Dog Aging Project Most breeds have some sort of predisposition for some sort of diseaseLOY-001 specifically targets a cellular mechanism that is hypothesized to cause large and giant breed dogs to age faster and have shorter lifespans than their small-breed companionsThey are also developing a second drug that is explicitly for dogs of any size, who have already shown signs of agingCaloric restriction is one of the most fundamental agents of fighting aging - Loyal aims to replicate that effect with a drug, since most humans and dogs do not want to calorically restrict themselvesVeterinary drugs need to be approved by the Veterinary FDA (Center for Veterinary Medicine or CVM)Dogs are one of the best models of human aging as a disease because they’ve largely evolved in the same environment as humansBecause dogs have a shorter lifespan than we do, we can see whether longevity-based drugs have an impact on lifespan more rapidly than in an animal with an 80-year lifespan (like humans)Loyal has raised $11 million in seed funding - the largest amount for a woman solo founderHer goal is to show that pharmacological interventions to extend lifespan and healthspan are incredibly valuable and worthy of investmentShe has encountered skepticism in terms of both operational and societal barriersGoing against the current helps her company stand apart in startup culture, which has been beneficial for recruiting an amazing team, 70% of which is female; but she also has to go above and beyond to prove her competenceWhat’s next for Loyal and building a consumer-focused pharmaceutical companyIf they can succeed in developing a dog aging drug, it can help humans as wellFalse fail riskThe aging industry has a communal feel, rather than competitive, as we’re all pioneers in the field and individual successes are everyone’s successQuotes:“Fundamentally, we're developing various drug products that are targeting various concerned mechanisms by which dogs age to try to give them healthier years.”“Specifically, our first two products are looking at one of the underlying reasons as hypothesized why smallest dogs like a Chihuahua can live 18 or more years, while Great Danes on average will live seven to eight years.”“The larger a dog is, on average, the shorter that breed’s median lifespan, and that's abnormal. We don't see a 2x lifespan differential in humans, for example, or really any other species.”“It's actually a consequence of historical inbreeding of dogs, that was selecting for certain phenotypes like size, that basically looks to have created almost a genetic disorder for aging in these dogs.”“The drug that we're developing is hoping to compensate for the accidental genetic disease that we gave these dogs that causes them to become larger...and causes them to age faster after they're fully grown.”“We are basically doing a cross-sectional, observational - that means no drug, no intervention - study, looking at large and small, old and young dogs. And the idea of this study is basically to correlate various aging biomarkers of interest for our drug programs, and also just out of interest in general, to various dog sizes, breeds and conditions.”“There are different flavors of dog owners. But in general, people love their dogs. They see their dogs as family. They see their dogs as their furry children in some ways.” “Our first drug, LOY-001, is specifically indicated for large and giant breed dogs and extending their lifespan and healthspan and intervening while the dog is healthy.”“Caloric restriction is one of the most fundamental agent interventions there is. So the question is more, How do you emulate that with a drug? Because obviously, people don't really want to calorically restrict themselves or calorically restrict their dog.”“It's commonly accepted in the field that dogs are one of the best models, if not potentially the best model of human aging as a disease.”“Because dogs have a shorter lifespan than we do, if longevity-based drugs are efficacious in dogs, we could see whether they have an effect on lifespan much more rapidly in an animal with a 15-year lifespan than in an animal with an 80-year lifespan.”“Really my thing from, basically when I was 18, was how to develop better medicines for the worst diseases. And the worst diseases that I have always focused on, and been most interested in, were age-delayed diseases.”“I felt very strongly that my goal was to explicitly develop a drug for healthspan extension and lifespan extension.”“It's really fundamentally what I'm trying to do is prove a point to the broader population, to the medical community, to the development community, that yes, pharmacological interventions to extend lifespan and healthspan are incredibly valuable, and worthy of investment.”“I think when I walk into a room, there’s not necessarily an assumption of competency. And I've definitely also felt a requirement of almost like perfection.”“I'm very careful with how I word things because it's very easy, especially as a female founder, to get labeled as cocky or overconfident. So I'm much more conservative in my language than I might naturally be.”“Basically, people don't have very positive emotions or feelings towards pharmaceutical companies, which is understandable on some variables, but also disappointing because I think we want people to be excited about spending time...and working on developing new medicines. It's, in my opinion, one of the most important things to spend your life on because health is fundamental.”“I'm really interested in the opportunity of building a pharma company that people love.”“Actually if you think about it, aging encompasses probably the majority of cancers, plus nerve center disorders plus sarcopenia, arthritis, all these other diseases.”“Honestly, every company that's legitimate, that works on aging is only more helpful. It makes my life a little bit easier to prove that it's a valid thing to work on.”“We all win if we develop better medicines, and that's kind of where it's supposed to go.”“I feel like my only job is to help develop better medicines. So it means everything to me because I think it's the most important problem to work on.”Links:Email questions, comments and feedback to podcast@bioagelabs.comTranslating Aging on Twitter: @bioagepodcastBIOAGE Labs Website BIOAGELabs.comBIOAGE Labs Twitter @bioagelabsBIOAGE Labs LinkedInLoyal website LoyalForDogs.com

Dr. Ashley Zehnder is the co-founder and CEO of Fauna Bio, a San Francisco, Bay Area-based company founded in 2018. Fauna Bio has adopted a fascinating strategy for drug development, studying animal genomics to cure human diseases. They use unique and varied proprietary data sources to identify novel drug targets across a range of clinical applications, beginning with cardiovascular protection. Dr. Zehnder is a veterinarian-scientist at the intersection of animal biology and human health. Today she joins the show to discuss her background in Cancer Biology, her specialty training in exotic/non-traditional species, and the experience of launching Fauna Bio with co-founders, Dr. Linda Goodman and Dr. Katie Grabek in 2018.Dr. Zehnder explains how genomes from non-model systems and animals can inform our thinking about human disease, why her background in veterinary medicine gives her an advantage in studying comparative physiology, and what her team has learned about neurodegeneration from the hibernation process of the thirteen-lined ground squirrel. She talks about studying highly conserved disease traits across species and whether we can reactivate certain genetic pathways to reverse those diseases. You’ll hear about Fauna Bio’s work with RNA Seq. data, their focus on cardiovascular research and other indications they are now expanding into, as well as the company’s relationship with Novo Nordisk as they explore the connection between hibernation, metabolic changes, and obesity. Dr. Zehnder offers her perspective on the University of Washington’s Dog Aging Project, and talks about the current drug discovery pipeline at Fauna Bio. She addresses how Fauna Bio fits in with other aging research and concludes with her thoughts on how the field of comparative genomics will evolve over the next five to ten years.Episode Highlights:Dr. Ashley Zehnder is a veterinarian with a background in companion exotics (birds, mammals, reptiles)She completed a Ph.D. in Oncology and Cancer Biology at Stanford UniversityCo-founded Fauna Bio with Dr. Linda Goodman and Dr. Katie Grabek in 2018Her background in studying the molecular basis that drives cancer across all different speciesStudying human genetics alone became difficult and frustrating in trying to determine what drives human diseaseTurning to comparative genetics was a way to solve that problemOrigins of Fauna Bio as a company - decided academia was not the way to take full advantage of new, richer data sets; wanted to make them usable for drug discovery and drug development as quickly as possibleTraditional model systems organisms versus non-model systems and animalsModel organisms do not fit the bill in trying to do therapeutics discovery for more complex disordersInstead of trying to mimic human diseases in model organisms, Dr. Zehnder focuses on finding similar situations that already exist and have been solved in nature, and learning from those solutions directlyHer medical training as a veterinarian gives her an incomparable advantage in studying comparative physiologyScientists who focus only on humans have a blind spot to the fact that the same disease syndromes can be seen across the animal worldResearch on the thirteen-lined ground squirrel and neurodegenerationCertain adaptations that help animals end up causing diseases in humans; animals have a way of reversing these while humans do not200 Mammals Project looks at which animals, including humans, can go into torporLargely study mammalian species due to the similarities with humansThey work with RNA-Seq dataStudies on traumatic cardiovascular events (heart attacks) for hibernating species show that they may be resistant to damage caused by reperfusion injury Fauna Bio initially focused on cardiovascular health, and is now expanding into other organs of the body, such as the brain hypothalamus, liver, kidney, muscle and skeletal tissueTheir relationship with pharmaceutical company Novo Nordisk and studying how certain animals change their metabolismBrown fat versus white fatUniversity of Washington’s Dog Aging ProjectFauna Bio’s current drug discovery pipelineBranching out into more chronic diseases such as fibrosis30 to 50% increase in life expansion for species that are able to hibernate as compared to similarly sized counterparts who do not hibernateWhat they’re learning from animals is how to repair damage in a way that reduces diseaseHow the field of comparative genetics will evolve over the next five to ten yearsQuotes:“I'm a veterinarian. My background is in companion exotics. So I was clinically trained to treat birds, mammals, reptiles, all sorts of strange species. I ended up doing a Cancer Biology Ph.D. at Stanford, focused on the intersection of animal and human health.”“Looking at cancer traits across different species, why some species get cancers, why some species don't, and understanding the molecular basis that drives all those cancers, which turns out to be the same across all these species.”“We really have spent a lot of time trying to understand what drives human disease from a genetic level, and really became quite frustrated with the difficulty of trying to figure it out just by studying human genetics.”“We realized that there was this huge untapped opportunity in the emerging genomic data sets for hundreds of different species that are - the genomes are coming out in higher quality RNA Seq, and Proteomics has become exponentially cheaper. So there's much richer data sets available out there for animals that have naturally evolved disease resistance.”“It was very much aThree musketeers sort of moment, because we really needed all three of our skill sets to make what Fauna does work.”“That's really one of the key failure points in biological development and drug development, is that transition back from animal models into humans.”“Model organisms have a role. And if you need to knock out a gene and know what it does, I think that that's helpful. But in terms of trying to do therapeutics discovery for more complex disorders, they just don't fit the bill.”“We do use a significant amount of human genetic data on our platform to help enrich the gene sets that we work with.”“Let's stop trying to make these animal models mimic a human disease. And let's instead look for the reverse. Let's look for situations in nature, where there's been a solution to this problem already. And let's learn from that directly.”“There's a complete blind spot to the fact that we see all these same disease syndromes across the animal world.”“We're looking at disease traits and traits across species that are highly conserved. And I think that's why we've seen such success in the compounds in the genes that we've been looking at.”“Thirteen-lined ground squirrels - they increase their metabolism by 235-fold over a matter of one or two hours. And there's just not many other models in the world that can do that repeatedly, week after week for months at a time.”“Dogs are not necessarily a species with disease resistance, which is where we tend to focus, but a species that in many ways can age very similarly to humans - they get that same kind of cognitive disorders, they get some of the same metabolic syndromes, they can get some of the same types of muscle wasting and whatnot. But on a shorter timescale - they don't live as long. So you can do aging studies in a shorter timescale.”“We now have seven genetic targets that we validated in human cardiac fibroblasts that can reduce collagen formation up to 60%.”“If you look at similarly sized species - ones that hibernate and ones that don't, there is around a 30 to sometimes up to 50% lifespan extension for species that are able to hibernate.”“That's really what we're learning from these animals is how do you repair damage in a way that reduces disease.”“How do animals repair damage? How does that relate to lifespan extension? And how do they keep their tissues healthy even as they age? And I think that's something that we can learn from, from hibernators, and other species as well.”“I want to be able to show that we can create drugs or help others create drugs that are going to work better than drugs that are found by traditional means.”Links:Email questions, comments and feedback to podcast@bioagelabs.comTranslating Aging on Twitter: @bioagepodcastBIOAGE Labs Website BIOAGELabs.comBIOAGE Labs Twitter @bioagelabsBIOAGE Labs LinkedInFauna Bio Website FaunaBio.com

Joining host Dr. Robert Hughes today on this inaugural episode of Translating Aging is our distinguished guest, Dr. Eric Verdin. Dr. Verdin is the president and CEO of the Buck Institute for Research on Aging, where his research primarily focuses on the relationship between aging and the immune system, and how immune aging is regulated by nutrition. He is also a Professor of Medicine at UCSF.Dr. Verdin begins by sharing his medical background, including his early research on HIV transcription and what drew him to the field of aging. He discusses NAD Metabolism, its connection to the regulation of sirtuins, and his research on why NAD levels decrease during aging, which has a deleterious effect on a variety of organs. Dr. Verdin answers questions about whether NAD supplementation could be helpful in fighting aging and disease, the emergence of startup companies in the Bay Area that are attempting to address aging directly, and the challenges of conducting research on aging when it is not yet defined as a disease. He talks about establishing the world’s first Center for Female Reproductive Longevity and Equality after being approached by Nicole Shanahan (wife of Sergey Brin) about the connection between early infertility and the aging process. In addition, Dr. Verdin explains why the link between health span and life span may be more connected than we think, whether we can ever reach a life expectancy of 115 years or more in humans, and why he believes this period in time will later be viewed as the birth of a whole new age of biology and health.To learn more about Dr. Eric Verdin, the Buck Institute, and their cutting-edge research to help people live better longer, visit BuckInstitute.org.Episode Highlights:Dr. Eric Verdin’s professional background, medical education and experienceBackground in virology and evolution to field of agingHis work studying HIV transcription led to research on biology of agingMost compelling questions facing aging research Molecular study of aging as a field is less than 30 years oldNumber of hallmarks of aging seem to be happening independently of each other and we do not yet have a sense of the hierarchy of these hallmarksChronic inflammation is a key aspect of the aging process, but was not listed in that collection of hallmarksDeveloping a better understanding of the different manifestations of aging and how they are relatedWorking on one aspect of aging influences the otherNAD Metabolism and its connection to the regulation of sirtuins Decrease in NAD levels with age has deleterious consequences on a variety of organsSalvage pathway, CD38 Molecule, and PARP1 may play a roleDiseases that involve chronic DNA damage and NAD depletion offer insightNAD supplementation to help fight against aging and diseaseNAD precursors nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) have been shown to alleviate some of the complications associated with aging in animal models Questions about whether these supplements will be truly and rigorously tested to ensure efficacyEmergence of other startups that are focusing on aging research has created a number of amazing opportunities for translation - studying the process in humans and molecular pathways in particularDr. Verdin has helped launch startup companies Napa Therapeutics and BHB TherapeuticsChallenge that aging itself is not recognized as disease and how this impacts the ability to conduct clinical research on itExample of Unity Biotechnology, which targets cellular senescenceAlternative idea is to identify a series of novel indications that are clearly linked to aging, such as Frailty and SarcopeniaNovartis demonstrated that pretreatment with rapamycin increased response to influenza vaccinesReproductive senescence, and link between early infertility and agingNicole Shanahan has funded the Center for Female Reproductive Longevity and Equality at the Buck Institute for the first five yearsGoal is to increase female reproductive longevityHealth span versus life spanCentenarians not only live longer than most of us, but they spend less time being sick over their lifetime as well (5% versus 15%)Compressed morbidity and whether average life expectancy will ever reach 115 years or moreExciting collaborations and innovative research on the horizon for the Buck InstituteQuotes:“I think one of the great privileges of being a basic scientist is that you can essentially study whatever you want. And I have a lot of interests and a lot of curiosity.”“I just found it an irresistible topic to study.”“One of the things that really drew me to the field is this realization that this is a field where fundamental questions still remain to be answered.”“One of the things that fascinates me is really the idea of establishing clearer links between these hallmarks of aging and hopefully somewhat of a more unified theory of aging.”“No one really believes there is a single cause of aging.”“What is happening during aging is that NAD levels decrease, and that has been documented in a variety of organs.”“Given the fact that NAD levels are decreasing, there’s been an interest in trying to restore these NAD levels. And one way to do this is two potential precursors to NAD: One called nicotinamide riboside (NR) and the other one called nicotinamide mononucleotide (NMN). Both of these have been explored in the literature and in humans, and both of those actually restore NAD levels to some degree.”“These companies are just two examples of a whole ecosystem that is rapidly developing in the Bay Area.”“The way that most companies have decided to tackle the problem is to actually use the knowledge of aging and its pathways to target really unique indications.”“The hope is that once you have identified a drug that targets senescence, for example, in the knee, is that the same molecule could be used for further indications where senescence is also prevalent.”“As a physician, there is a part of me that resists the idea of calling aging a disease, but clearly aging itself is a risk factor for a whole series of diseases.”“It turns out, at least in many of the animal model systems in which we can increase life span, we also increase health span.”“Our life span is going to continue to increase, and I think our major goal is really to make sure that these gained years actually are quality years, spent with people who are fully in command of their mental and physical abilities.”“I’m incredibly optimistic of what we’re going to be doing in the future, but also I think we should be realistic about the difficulties that lie on this path.”“I think it’s an incredible time to be in this field, and I suspect that when we look back 20 or 30 years from now, we will really look at his period as the birth of a whole new age of biology and health.”Links:Email questions, comments and feedback to podcast@bioagelabs.comBIOAGE Labs Website BIOAGELabs.comBIOAGE Labs Twitter @bioagelabsBIOAGE Labs LinkedIn

Description:On Translating Aging, we talk with the worldwide community of researchers, entrepreneurs, and investors who are moving longevity science from the lab to the clinic. We bring you a commanding view of the entire field, in the words of the people and companies who are moving it forward today. The podcast is sponsored by BioAge labs, a clinical-stage biotechnology company developing therapies to extend human healthspan by targeting the molecular causes of aging.