Longevity and Ageing

Tom Bunn: good morning everybody, and welcome to Deep Dive webinar series. My name is Tom Bunn, I’m an associate on the fund ventures team, and I’m excited to walk you through discussion with a number of exceptional researchers and entrepreneurs in their respective fields. So for those of you new to these webinars, I Select Fund is an early stage venture capital firm in St. Louis, Missouri. Focused primarily on early stage companies in food, agriculture, and health. iSelect invest at the forefront of innovation, seeing emerging problems, solutions, and technologies in their infancy. And we use these deep dive presentations not only as a way for us to better engage with and understand new science and technology, but also to engage with the experts and entrepreneurs who are driving change and innovation in their respective fields.

So one theme that we have been researching for a couple years now is the biology of aging and longevity. As many of you may know over the last few decades, major breakthroughs in our understanding and our ability to understand with platform technologies such as gene sequencing have allowed us to better understand aging and its implications for.

Poor disease. These, have emerged again over the last few decades and with these breakthroughs we’re on the verge of potentially increasing and extending our healthy years of life with fewer morbidities at the late stage of, someone’s life and, more life at the end of someone’s life.

So for these reasons and others, which we will cover in today’s webinar, aging and Longevity is of increasing interest. To I select where a lot of interesting technologies and, research is, happening all over the world. So if you process comments, we are not soliciting investment or giving investment advice in any way whatsoever.

This presentation is general industry research based on publicly available information. Secondly, we have invited you to this because you are technologists, thought leaders, entrepreneurs, industry experts, early adopters or sophisticated investors that are part of our network. We value your thoughts, questions, comments, and insights into this topic and would appreciate it if you engage during the presentation.

We will have some time for q and a at the end but if you feel moved to do please raise your hand or type in a question during, the call and we’ll get to as many as we can. So finally, this presentation is being recorded and be available for replay. So with that, I’m pleased to bring you this week’s deep dive on aging and longevity.

So just a couple notes on what, we’re gonna do today. I’ll give brief speaker introductions. I’ll give a brief background on aging. But I will really let the bulk of this conversation be driven by our phenomenal guest this morning. And hopefully there’ll be some cross pollination among them as well, and among our audience as well.

Finally, we will have some time for discussion. I have some further prompts, but of course, if there are questions that arise from the audience that’d be terrific. So a big thank you to our guests. We have quite the guest list here today. On the left, going in alphabetical order Dr.

Thomas Pearls. Dr. Pearls is among the international leaders in the field of human exceptional longevity. He’s founder and director of the New England Centenarian Study, the largest study of centenarians and their families in the world. He’s also a principal investigator of the N I A funded Long Life Family Study and a professor of Medicine and geriatrics at BU School of Medicine.

Dr. Pearls, thanks so much for joining us today. Secondly, we have Dr. Chris Rhodes. Chris is the c e O of Davis, California startup Innate Biology, which is developing fasting mimetics. We’ll dive into what, that means and the implications of fasting on longevity and health. Throughout the presentation, Chris earned his PhD in nutritional biochemistry from uc, Davis.

Finally, Dr. Brianna Stubbs. Brianna completed her PhD in metabolic biochemistry at Oxford University. She also became a world Champion rower as part of the Great Britain Rowing white women’s four-person crew and won three other world rowing championship medals. She has published, peer reviewed studies looking at ketones, metabolism ketones, Esther supplementation in athletes and effects of ketones on appetite.

She’s now lead trans translational scientists at the Buck Institute for Research on Aging, where she works with a lab whose focuses ketones in the elderly for healthy aging. The buck. Mission statement is quite apropo. It’s to extend the healthy years of life. Which I think we can all agree is a noble goal.

Getting into a little bit of background just to set the stage for our, participants and guests. Aging and longevity, a few key concepts. So geoscience and longevity’s research aims is really to prevent and delay age related diseases, as I’ve shown here with the acronym a r d, and to increase health span.

So if you look at the, right hand side, upper right hand side of this green, this is a, graphical representation. Of what that really means. So on the top is present day, normal aging. You have a decently long, healthy life. And then you reach a point where you have some sort of chronic age related disease, are in a period of morbidity for a fairly long amount of time and then you die.

The, goal of, again, this longevity research is to optimize the amount of time that one is healthy before, before dying, and also potentially optimizing or increasing the lifespan as well. So healthspan is, the healthy years of your life. Lifespan, obviously is the, years of your life. But the goal here is to improve the healthy years of your life.

Researchers are increasingly contending that the aging process itself is behind many, of these age related diseases. So think of the, most common ways people die, be they cancer, heart disease, Alzheimer’s Upstream of those disease indications. Researchers, again, are increasingly finding that the aging process itself is, really to blame there.

And that we can and should treat aging as a disease. At least many researchers feel that way. I’m sure there are many who don’t as well. So researchers, again, as I mentioned over the last few decades, they’re exploring many lifestyle and clinical inter interventions. That show great promise in extending health span and delaying age related diseases.

And you can see just a smattering of, them on the bottom right here. They, range from healthy lifestyle choices to more clinical derived interventions. So on the healthy lifestyle fronts caloric restriction and fasting, which we’ll get into down the road in this presentation.

Slight nuance, slight difference there. Between ch caloric restriction and fasting. Fasting more about the interval of time between calor intake as opposed to strict chloric reduction. And then high, intensity interval training from another lifestyle point of view as has shown great promise in, in terms of turning on some of the genetic markers and bolstering the defenses at a cellular and genetic level.

Then in the areas in the clinic, some some popular or some promising rather approaches that are being explored. One is in the, field of Sy Alytics. Sy Alytics is a field that is trying to clear senescent cells. Senescent cells are. What’s called, what are often called zombie cells that collect, they aren’t dividing, but they aren’t quite dead.

And they are responsible for a lot of inflammation. They hang around and cause problems. And many think they’re to blame and, many of the chronic diseases we face, particularly as people get older, repurpose drugs there’s very interesting research coming out about metformin for instance, which is being.

Trialed for delaying the onset of many age related diseases such as dementia, heart disease, and cancer. Has shown promise in in mouse models. But of course, metformin is only prescribed to people with diabetes at this point. And again, this gets back to the point that currently aging is not considered a disease.

And then of course, genetics. So genetics good jumping off point for Dr. Thomas Pearls. Is foundational to a lot of these, research areas. So I’ll hand it over to Dr. Pearls to discuss his work on the genetic components of.

Thomas Perfs: Very much. Yep. Thanks very much. Tom, it’s very nice to be with all of you. My aim here is to probably talk for about 15 minutes and leave five or 10 minutes for people to ask questions, please. I’m in the middle of a big steering committee meeting that’s lasting all day, so I just dropped out for a bit of time so that I can be with you all, and then I have to jump back to that meeting.

What’s special about centenarians? They’re very rare. They’re about one per 5,000 generally in the population. And for people who are around a hundred or 101, it is one per 5,000. But as you get to older ages, obviously they’re much rarer 105 year olds. To about 109. We are what we call semi supercentenarians, and they’re about one per 250,000 in the population.

And 110 plus year olds are what we call supercentenarians or one per 5 million. Next slide.

Oh, I’m sorry. Go back one, Tom. Thanks. There, just to show you our oldest subject ever interestingly was Sarah Canals, who we knew back in the late nineties. She was the was 119, the second oldest person ever. This is a picture of her with her great, grandson. Next, please.

So it’s important to know that you can’t just group the why people, why these in centenarians are interesting. Just to age a hundred plus. Turns out that People say, who are 105 and older, who as I said, are so much rarer are a very different phenotype than say people who are a hundred and they in turn are quite different than people who are 110.

And let me explain. So about 90% of centenarians are disability free up through their early nineties. And, they speak to this Idea of the older you get, the healthier you’ve been, as opposed to what people have said in the past or the older you get, the sicker you get, and 15% of these people living to a hundred are what we call escapers or those who have no really appreciable age related disease at the age of a hundred, no dementia, cancer, heart disease, stroke, diabetes, and so on.

Now, on the other hand, people are living to 110. 70% of those individuals were escapers at the age of a hundred, and they live independently up to about age 106. These are truly our creme de la creme folks. Next slide.

Living to a hundred is quite a heterogeneous phenotype. Phenotype meaning clinical characteristics. So that I would say about 45% or so of veterinarians are what we call survivors or people who have age-related diseases before the age of 85. Another 40, 45% are these delays or people who have delayed age-related disease beyond the age of 85.

And then we have those Escapers that I mentioned. Now. When you hear that 40 90% have had age-related diseases before the age of 85 might say what’s so good about that? Remember that over 90% of ’em are living independently up through their early nineties. So they’re really quite resilient.

Even if they may have age-related diseases, they’re quite resilient dealing with these diseases much better than others, and living with them rather than dying of them. On the other hand, we’ve got these folks living to 110 who are not only delaying age related diseases, they’re also delaying I’m sorry, delaying age related disability or aging related diseases the disability from those things.

But at, if you’re living to 110, you’re delaying not only disability, but also diseases. And they fit this idea of Jim Fries. A scientist who I think is was at uc Davis, Chris who came up with this notion of compression of morbidity. That as you approach a limits of lifespan, you also have to compress the time that you’re sick towards the end of your life, especially diseases associated with mortality.

And that’s what we’re seeing with 110 plus group. And as a result, they’re also very homogeneous. Unlike the earlier groups that are quite a heterogeneous group, this group is quite alike in terms of their clinical characteristics. And so one has to suppose that they must have some pretty special characteristics in common that enable that homogeneity.

And what we have found is that while 75% or so, Average aging is probably your behaviors. The difference between people, according their to their health related behaviors if you’re smoking and overweight and a couch potato, it makes sense that on average those individuals are gonna die in their late sixties, in their seventies.

If you’re doing everything right, like the seventh day, adventis with A diet conducive to a healthy weight, not smoking, not drinking, being vegetarian, managing your stress you’re gonna live on average like a seventh Day Adventist to about 86 if you’re a man, and 89 if you’re a woman. So the vast majority and I would say that’s very optimistic to say, and I think realistic that humans have what it takes to get to 90.

They just need to do everything right from a behavior point of view. So the vast majority of the variation of living to age 90 is gonna be your health behaviors. On the other hand, to get to 110, we’ve discovered genetic signatures that. Which are combinations of genes that explain about 75% of the variation living to 110.

So the tables are turned in terms of the role of genes at these most extreme ages. Because they’re so alike, we think that we don’t need such a big sample size to make these kind of discoveries of what they have in common. More along the line of 500 to a thousand individuals at these most extreme ages, as opposed to what we normally want to see in these kind of genetic studies of complex diseases, which requires tens of thousands of individuals.

The other important thing to note is that the ASIN areas have similar frequencies of disease associated genes as the general population. So what’s probably really making the difference is protective genes, which is also a very optimistic point of view. Thinking that we’re gonna discover genes that slow down aging and decrease your risk for aging related diseases.

And perhaps trans, if they’re protective, maybe we could translate that protection into some kind of medicine or or other strategies. Next slide please. Quick, question

Tom Bunn: here. Dr. Pearls on, the mor on the compressing of morbidity point you mentioned. Do you have quantifiable data on that front?

I’m interested in, that. I, was reading a report last night around the average time at onset for, excuse me, for an age related disease in the US is about 63. With that lifespan being 79, so roughly 13 years or 16 years of of morbidity prior to death. Have you what, is the ballpark range of that compression that you’re seeing for these folks?

Thomas Perfs: Yeah so, for centenarians the big deal for people living to about a hundred, 101, which is the vast, majority of veterinarians it’s not the compression of morbidity or diseases. As Jim Freeze indicated. It’s the compression of disability, I would say. If you have to have these diseases, being able to compress the time that you’re experiencing disability into the last five to seven years of your life, a very, long life is what most of us would want.

But then when you really do start approaching the true limits of human lifespan, as Jim freeze posited, then you are delaying both disability and disease into the last three or four years of your life. Living to 110. So it’s a really, small proportion of, one’s life at these most extreme ages.

Got it. Thank you. Okay, next slide. W where are we now? There is a space there between these three studies that we’ll get to in a moment to describe a really new, exciting grant that we have. But I’m the principal investigator of these three studies, the Integrative Longevity Omic Study a sent the centenarian project of a group of studies called the Longevity Consortium and the Long Life Family Study.

Go ahead and click the button there. Tom, we just got a grant hot off the press that starts in two days called Raco, which is resilience and resistance against Alzheimer’s disease and centenarians and offspring. Up to this point we’ve enrolled about 2,500 centenarians or siblings in their offspring.

These studies, all of them together will boost that up to about 4,500 subjects. In about a year or so we have a pretty large group of research assistants at this point. Both at Boston University, at Einstein College of Medicine. We were greatly delayed by Covid, but now we’re up and running again in terms of recruitment and enrollment.

For Radko, we’re really doing the creme de la creme. We’re going to study the veterinarians that have been enrolled in these other studies who have the cognitive function of people 30 years younger in their seventies. And doing a whole range of bloodborne biomark blood biomarkers for Alzheimer’s disease, doing MRIs, as well as doing post mortem brain autopsies to gauge the individuals who have resilience.

That is, they have evidence of Alzheimer’s disease by these markers, but they didn’t have any clinical evidence of it. And those who were resistant, those who have just no evidence. Of Alzheimer’s disease at these extreme ages. And and then down the road start doing some real wonderful basic biology led by Rudy Tanzi and his group at Mass General doing using inter induced PLU pluripotent stem cells.

And derived neurons, putting that in their Alzheimer’s disease in a dish model, and using these neurons basically from supercentenarians. And understanding in that model what the actual biological mechanisms that seem to be conferring resistance. Or even or, resilience to Alzheimer’s disease.

I put the cart before the horse there. I just want to, in terms of all the data and biological samples that we’re collecting, but is very detailed and careful cognitive function. We use an actograph watch to measure physical and sleep functional data. We do very careful and expanded family pedigree, pedigrees.

We get medical and dental history, dietary habits. And the brain MRIs for raco a across four different cities. And then biological samples include blood fecal samples. We’re very, interested in microbiome, particularly in the kids who are in their seventies and eighties and doing terrifically well.

We’re establishing these induced by pluripotent stem cell lines. We already have about 10 of the, from Supercentenarians actually. And we get brain donations so that we can do gene expression studies from particular areas of the brain that are led by Winston Hyde at Beth Israel Deaconess.

Medical center and of course doing the brain autopsies. And I think that’s it for our and my slides. Is that right, Tom? Oh, okay. So just I’ve already been through each of these. And so I think that’s it. Great.

Tom Bunn: Yeah I’m, happy You mentioned epigenetic studies that are on the precipice of, beginning one of my questions was around a lot of what.

Dr. Stubbs and Dr. Rose will be talking about is, the epigenetic switches that may turn on from lifestyle factors such as fasting, caloric restriction. Is there any way you can back into that to retrospectively examine some of those decisions these centenarians have made in, in, in in the lives or our,

Thomas Perfs: retro scope, which is actually prospective is looking at the kids.

Who have half the rates of heart disease, stroke, diabetes, and cancer, compared to other people born the same ti say around the same time. Now, a good bunch of that could be behavioral. That they don’t smoke, that they don’t drink. Maybe they’ve in, maybe they have some really good health related behaviors, which can be quite common in these families.

But again, we think that there’s a pretty strong genetic component as well. We can follow these people over time through the Longevity Omic study which we get quite a large amount of money from the N I A. To do a slew of omics, so that includes met omics. So we can start looking at the epigenetics as well as transcriptomics.

The other omics that we’re doing are proteomics and, also as I had mentioned before the, microbiome and through a collaboration with Regeneron actually. We’re also doing whole exome sequencing, and then soon through the N I H we’ll be doing whole genome sequencing. And I want to mention that all these data.

Are going to be freely available within nine months of their generation on a web portal called the Exceptional Longevity translation web portal called Elite that is sponsored by the National Institute on Aging. And the pluripotent stem cells and the derived lines, including the, cortical neurons will be available through our regenerative medicine institute at Boston Medical Center at Boston University.

So all of these things will be freely available to academia as well as industry.

Tom Bunn: Fantastic. Dr. Pearls, thanks so much for, taking the time. I know you’re tight on time. We really appreciate you joining us and hope to speak with you very soon. Yeah, I’m

Thomas Perfs: sorry I can’t stick around. I’d love to hear Chris and Brianna’s talks.

I have to run back to the, this big steering committee meeting and thanks

Tom Bunn: everybody. No problem. We’ll, send you a recording. Oh, good.

Thomas Perfs: Great. Okay, thanks. Take care.

Tom Bunn: Next we have Dr. Brianna Stubbs as a rejoinder to my introduction of, to, of her earlier. I just wanted to say that she’s also a advisor for I select company Readout which is doing the breath analysis of, ketones which is how we got connected.

Missed that upfront, but I just wanted, to highlight that. Dr. Stubbs, can you talk a little bit about what you’re doing? I know many people on the line are probably familiar with, ketones but perhaps start somewhat at the at the beginning and would love to hear your focus.

Brianna Stubbs: Good morning. Thank you all so much for being here. So I think it is helpful to provide a little bit of background and context cause a number of people I speak to have heard about ketones only in the con context of the ketogenic diet. And so one of the things that people think about first when they think about keto or keto is, weight loss.

So gonna. Backtrack all the way back to the, basic biology to unpack that so we can understand a little bit more about the full potential of keto biology that really extends beyond just weight loss. You can see on the bottom left those chemical structures, there are the three keto bodies that our body will make naturally.

Acetone is the one that is in the breast, and that is the one that the biosense readout analyzer is detecting. Aceto acetate and beta hydroxybutyrate are the two ketones that circulate in the blood. And you can see here they’re very, small, simple molecules. And they’re like a way that our body will take a complex fat molecule and break it down so that it’s more readily available to be a fuel for particularly in the brain.

Because fat’s not very easy for the brain to use as pure. The brain normally determine depends almost completely on glucose and other small molecules like lactating. The evolutionary purpose of ketones is that when we are not able to eat enough carbohydrate in our diet the brain starts to be a bit of a a worry in terms of providing enough fuel.

We all have. Quite limited carbohydrate stores in our body. It’s tracks a lot of water. It’s very inefficient to store, but we all have a lot of fat. It’s very efficient to store energy as fat. And so evolutionarily the conversion of fat into ketones serves the purpose of providing this small, easy to, break down energy for the brain in times of starvation.

And Ketones aren’t just used in the brain. The heart is an avid user of ketones. Bodies as well. Skeletal muscle as well. Really every tissue in the body can use ketones apart from the liver, which is where they’re made. So really up until the sixties we really focused on the roles of ketones of the fuel.

And it’s been in the last sort of 15 years or so that we’ve started to understand that more than just being an energy substrate to, to power our mitochondria, that ketones can actually bind directly with proteins more like a drug. And have these signaling effects that trigger a lot of helpful biological processes and intercept with a number of the hallmarks of aging.

So if you look now to the bottom this slide is giving you an overview that I’m sure we’ll hear about from our next speaker. That caloric restriction and fasting are very, reliable ways to extend lifespan in multiple model organisms from yeast mice. And then obviously famous studies with research monkeys.

Really we, our hypothesis is that keto embodies play a role in the production and metabolism that keto embodies, plays a role in this extension of lifespan and of healthspan that we see. Some work that came outta both the Buck and uc Davis. Two independent papers published in the same edition of cell metabolism, showed that ketogenic diets in mice.

We’re able to extend lifespan and health span. Improving cognitive function and physical function in these mice as well as extending their lifespan. And so a lot of my work now focuses on using supplemental ketones. So taking separating out ketogenic diet from just the presence of ketones to try and understand exactly how much of a contribution.

That the ketones themselves make these lifespan and healthspan effects that we see. Next slide. I.

The two most promising, in my view, applications for keto biology and aging. And, those were the area the research is most advanced here in the brain and the heart. So I thought I’d just give you a little bit of an overview of, that mechanisms for that and also where the research researchers to date.

As I was mentioning in the introduction a second ago, Keto. One of the main purposes of keto and body production is to provide fuel source for the brain. And one thing that we see in the aging brain especially in people who go on to develop neurodegenerative disorders, is that their brain’s ability to metabolize glucose is compromised.

And, interestingly, see this years and years before people display any symptoms of the disease. If you put them in a. Scanner and use FDG PET type imaging to look at glucose metabolism in the brain. So really we actually don’t know whether this decline in glucose metabolism is the chicken or the egg, because if the brain is energy starved, it’s more likely that more damage is gonna occur, and that’s probably gonna feed the progress of the disease.

So what we have found in animal models and now up through into human models is that these people’s brains still can metabolize ketones very efficiently. And if we are able to use supplemental ketones, just so for example, Ketogenic fat drinks, and now people are looking at keto esters and keto salt.

All of these are different levels of potency over keto supplement or keto food. So if we just give, all we have to change with people is give them these supplements and we can see there’s a rescue in their brain. Energy metabolism. Their brain is less energy starved. But also, interestingly, in a six month study of these ketogenic drinks, they were also able to detect.

Cognitive improvements and declining cognitive decline as it will, a reduction in cognitive decline in patients who have mild cognitive impairment. So this is an area that I’m watching very closely and excited to see more research coming out as big companies like Nestle and whatnot start to get involved making food products that are based on keto bodies.

Thank you. And another area which, we are actually actively looking into at the moment is how keto bodies can affect the failing heart and somewhat similar to the brain. The failing heart has very dysregulated energy metabolism, inability to switch between glucose and fat and, really That is one of the things that drives cardiac remodeling.

The heart gets less able to pump. Interestingly now we’re, seeing a recognition that one whole subset of heart failure patients, it’s really a metabolic disease that involves their skeletal muscle and many other tissues in the periphery. It’s not just the heart. So we’re starting to learn that heart failure is.

Is a whole body syndrome. And so actually again, being able to rescue these multiple metabolic contributors as well as provide energy to the heart is, a important and multi-layered approach, let’s just say, to treating these diseases. So not only are ketones able to provide energy to the heart, but through their signaling roles, they’re able to Change epigenetic expression of oxidated stress defenses.

Ketones also can regulate components of the innate immune system. And really the list goes on. This is very well researched in, oh, back one for me. Not quite finished yet. Just wanna give an overview where the research is. A number of studies using animals. That have shown that both the ketogenic diet and keto supplements are able to appro improve cardiac function.

So as you see, I’ve listed here mice, rat dogs, and then interestingly in humans as well, where at the stage the graph you can see on the right is patients who have heart failure being given an intravenous infusion of keto bodies. The box circle on the left is the cardiac output me measures. So we see acute.

Improvements of cardiac output in the order of about 20%, I believe, and then the box that’s going down that’s on the right, that’s systemic vascular resistance. So it seems that ketones can even very acutely change some of these markers of heart function in patients who have heart disease. Now we can go to the

Tom Bunn: next Dr.

Stub. Just a quick question there. So in, in a presentation I heard you give you, you stated that heart’s relative to other organs are metabolically omnivorous I think you use it. So is this relatively new, science here? The fact that some fuel sources are perhaps better or trying to connect the dots there.

Brianna Stubbs: Yeah, I mean I really, don’t like describing any fuel sources better cause people are often like trying to look to be like, oh ketones of this superior fuel. I think what we actually see is that in disease, the ability to use regular fuels is compromised. So being able to fuel organs through alternative pathways is the best alternative.

The, substrate selection, our heart isn’t sentient. It’s choosing, its fuel dependent on the amount of oxygen available, the amount of fuel available, and it, its output needs and It’s easier for us to conceptualize when we think about sial muscle when we’re sitting at rest or doing very low intensity exercise.

It’s great for us sele muscle to burn fat, but when we’re doing those all out sprints, then we have to burn carbohydrates. There’s, no one fuel that no one fuel to rule them all, as it were. But I think that the key breakthrough that’s been made with. Keto research in the heart is that firstly we discovered that it was upregulated and then we discovered that it was adaptive.

And if you knocked it out or, dampen the ability to do keto oxidation in these failing hearts, then the outcomes were worse. That’s within the progression. Up to this point because when that first discovery of, oh, a failing heart oxidizes more key terms, when fat was discovered, people didn’t know whether that was a good or a bad thing.

But what we have actually seen is that it, is adaptive in mo many of these animal models.

Christopher Rhodes: Great. Thank you.

Brianna Stubbs: Okay. So really just to wrap up I’m not gonna go through all of the detailed mechanisms that have identified that ketones back signal, but if you are interested in understanding how ketones go above and beyond just being a starvation metabolite and a really a signaling metabolite and really encourage you to go away and look at the work of my academic mentors at the Buck, John Newman and Eric Verden, they really pull together this review, which is like the bible.

But you can see on the right here, just to give you an overview, we have ketones interacting with the NLRP three inflammasome. So that’s the component of the innate immune system. We have ketones affecting epigenetic changes through both directly becoming bound to his stones themselves in a modification that’s called BH Vation, which is a novel mo modification only discovered in the last couple of years.

Histone. BHB affects his ation dation because their histone dase inhibitors, sorry, a bit of a double negative. I always get a bit tied up there, but that affects expression of longevity related genes. Recently also very interestingly discovered that ketones can have an effect on senescence.

But then ketones also have direct receptor binding effects as well on these surface receptors, H two and ffa. Three. And that affects a sympathetic parasympathetic balance, but also interestingly other, the availability of other fuels. Like s So really A fantastic time to be part of this field as all of this research has been coming out.

If we had drawn this figure I’m, I just turned 30, I’ve been researching these molecules now for about nine years, but if we had drawn this diagram when I started in the field, that has maybe only been like one or two elements on it. It’s quite exciting to be seeing every year, every few years, new binding partners for ketones being identified and, some of that work we are doing at the buck.

And we have some papers that’ll be coming out soon. They’ll hopefully add to this list. And what I do there is really working to develop these ketones supplements and understanding them in, animal and human models. So that really what we wanna do is take this science and understand the implications for the humans.

And I hope that my career will be able to see drugs that are based on this keto body biology.

Tom Bunn: Fantastic. Thank you Dr. Stubbs. We’ll, circle around for some questions that have come up at the end here, but I’d like to get to Dr. Rhodes here. I think it’s a great segue talking about fasting metabolites.

It, which is what innate biology is, studying. Doc, Dr. Rhodes, can you tell us a little bit about yourself and the, company you founded?

Christopher Rhodes: Yeah, absolutely. So thank you Brianna. She’s totally right. She and I have a lot of the same problem. People always consider fasting, especially now that has become so popular as like a weight loss intervention and like sometimes miss the nuances of all the great things that fasting can actually do for you.

So a little bit about me. I got my bachelor’s of Science in biochemistry from Louis La Marymount University. Got out, didn’t really know what I wanted to do, like a lot of undergrads. Did a two year stint at an immunology fellowship at Stanford where I really got into longevity research, anti-aging research.

And of course, when you’re in that realm, you eventually come across fasting because as we’ve talked about a little bit today, It’s one of the few mechanisms that we know of to reliably extend lifespan, but then also healthspan as well. So it has this profound effect on almost every major disease, whether it’s neurodegenerative diseases, cardiovascular diseases autoimmune diseases.

Fasting can help with all of these. Various like negative health outcomes. And what’s really interesting about it is that it does so without actually adding anything to the system, right? It’s not some magic elixir or some novel exotic plant extract, right? It’s just triggering your own body’s natural mechanisms for these regenerative and protective processes.

So that was really, interesting to me. I thought that was so cool. I wanted to try it out myself, and I did it using my immunology. I did some like alternate day fasting and started testing my own samples using my immunology background, and found that it was even in me, a young, healthy person.

This like profoundly anti-inflammatory. Intervention so it could re increase the anti-inflammatory effect of my blood. And then also modify my macrophage polarization around my t and b cell repertoires in a really sensitive timeframe. So that’s what kind of got me really into fasting.

I could see it actually working in myself, and that’s what I brought to uc Davis. I was really interested in studying not only fasting, but human fasting because that was something that was. Was missing in the field. There were a lot of mice studies, but not a lot of human studies. And what I set out to do basically, and what eventually spun out into innate biology was decoding this innate regenerative bio program of fasting and trying to figure out if there was a way that we could actually recreate it to get the benefits of fasting without all of the downsides of fasting, without having to actually do the thing, because that’s pretty hard to do, especially in the long term. So at Innate Biology, what we are doing is basically using human fasting as a roadmap for the development of these clinically derived longevity and healthspan molecules and developing this combination fasting mimetic.

And how we’re doing this is essentially by supplementing people with the same beneficial molecules that their body naturally produces during a prolonged 36 hour fast. We can recreate that physiological state of fasting and by doing that, get the same benefits of fasting without actually having to fast.

So what we have up here is basically how we discovered the platform. And this was basically my PhD work. So what we did was we took 20 healthy young men and women, 10 men and 10 women, to try and avoid a gender bias and get complete information. And we had them come in either a baseline state, a typical overnight fasted state.

Or a prolonged 36 hour fast. So mimicking the typical alternate day fasting cycle. And what we found was that in these people, 36 hours of fasting was able to like really functionally enhance their plasma. So their plasma when we expose them to human human cells, X vivo as a, model for.

That are homeostasis in the actual body. The plasma was able to affect these cells and induce anti-inflammatory effects, induce protective antioxidant effects, and then also produce these cardioprotective effects, increasing plasma cholesterol inflexibility, which is like the gold standard marker for cardiovascular disease risk.

And that’s really profound. So again, to be able to functionally enhance young, healthy people in such a sensitive timeframe, we were really fascinated by that and wanted to figure out what’s the difference between these two states of plasma that could be causing these these beneficial effects. So we did comprehensive metabol omics looking at over a thousand different metabolites between the baseline state and the fasting state.

And what we found was, of course fasting induces a very profound metabolic shift, we found that there are over 300 different, significantly different metabolites between the baseline state and the fasting state. Of course, ketones were in there as well. And that’s very like universal, these responses and not subtle at all.

And then when we’ve looked at these 300 different metabolites we combed through that list looking for those that had already been known to. Be bioactive. So some kind of literature result of either having an anti-inflammatory effect, the lifespan extension effect the ability to do induce autophagy.

Something that gave us a clue that like, yes, these might be these beneficial components of the plasma. And then we narrowed that list to around 30 potential targets and actually took those targets and then screened them on our own in vitro analysis to see if they could mimic these beneficial effects on their own in isolation.

And eventually what we found was that there were four of these metabolites that were the most potent that could replicate all of the beneficial effects that we were seeing from our analyses. And when we combine them together, could actually. Synergistically enhance each other’s functionalities. And that is basically what became the basis for our first product, which is the fasting mimetic.

And what we like what we did there, we found that it was working in vitro. The FDA considers all metabolites to be dietary ingredients, which is great, perfect for our supplement. So we knew that it worked in vitro, but really wanted to see that it also worked in actual humans. So over the past couple months since we’ve been in the Indie Bio Accelerator, we were able to perform a small and a five clinical study, basically looking at the effects of supplementation with these four fasting metabolites.

So what we did for this was we actually had five people come in and eat a standardized breakfast on its own. And then we looked at their plasma functional metrics like we were talking about, before, or we had those same five people come back in after a washout period. Eat that same standardized breakfast, but just with supplementation, with the fasting etic and assess their plasma functionalities again.

And what we found, we can go to the next slide, Tom, was basically that when the participants ate the standardized breakfast on their own, they had this. Loss of plasma functionality, and that’s really typical, especially in the nutrition world. This is called the postprandial response. So as your body is dealing with all of the fuel and food and foreign matter that’s coming into your body, it triggers these pro-inflammatory responses.

So that’s what we see is that. Without supplementation, with FM O one, you get this decrease in anti-inflammatory ability of the plasma. You don’t really get a change in antioxidant ability. And then you also get a reduction in plasma cholesterol, lux ability. But eating that same standardized meal just with supplementation with the FAS medic was able to not only prevent that loss, Of function but actually at a gain of function as well that was able to mimic those beneficial effects that we were seeing in actual 36 hour fasting.

And then we can go to the next slide too, Tom. So that was really great. We confirmed that this had an acute effect in humans that could mimic these beneficial effects of fasting and prevent those negative effects of eating. But we also wanted to figure out, okay, if people take this in the long term are there gonna be any potential negative side effects where the holistic benefits to taking this supplement?

So we combined the four metabolites together and ran a cele elegant study. In this study there were a hundred worms in each group. The control group was just under normal feeding conditions, no supplementation. And then the the Fasci medic group was also under normal feeding conditions, but also with lifelong supplementation, with the Fasci Mimetic combination.

And what we found was that we could increase the median lifespan of these worms by 96% even when they were normally eating, which is a really great lifespan extension in this model. And then when you actually take that and compare it back to literature results of the lifespan extension effects you can get from actual fasting, you can see that they’re like, not only comparable, but the fast supplementation actually gives you a greater lifespan extension than fasting on its own.

So really good validation that we’re capturing a lot of these beneficial lifespan extension effects. With these for uniquely upregulated fasting metabolites. So that’s where we are. We are taking these supplements that are like commercially available on the market already putting them together and giving them to the consumer so that they can basically get the benefits of fasting without necessarily having to fast or use it as an adjunct.

To the fasting that they’re already doing since this is meant to mimic a 36 hour fast or at least some of the components of a 36 hour fast. Many people do fasting right now as like the 16 eight style, so they’re not really maximizing the benefits of their fast because they’re not depleting their gluco in stores.

They’re not switching over to full fasting metabolism. So we really think that we can help people get these maximum cellular health benefits of fasting through this adjunct supplementation. Super

Tom Bunn: interesting, wondering what your thoughts are. So it seems stripe or slight cellular stress has these, this cascade of potentially beneficial metabolites.

One thing that comes to mind is I’ve read a lot about cold exposure and heat exposure. It’d be interesting to, to compare plasma levels that you’re seeing here with other types of stress-inducing activities. Is that something that’s on your roadmap or you, gonna stick

Christopher Rhodes: with?

I think that, like the whole biomimicry aspect. Is definitely where it’s at. I think that being able to look at any state of the body as it changes around and adapts to its environment is really, cool because then once decode that roadmap and recreate it, you can get these similar effects, right?

If you think of the body as a computer, right? And all of the metabolites molecules that are. Floating around in us. It’s like chemical code, right? Hypothetically, if you can recreate that code, you can recreate the, these bio programs for what your body is doing and shift it in ways where you want it to go towards more of these health and regenerations towards more stress resistance, like cold, response, these hormetic effects.

So I think that’s super cool. And I think that I would love to be able to study every single helpful regenerative state of the body exercise or figuring out how you can replicate the holistic satiety program so that you can help people actually do fasting more easier so they can naturally get the benefits without the, additional weight of hunger.

Sure.

Tom Bunn: Awesome. Question for both of you. Just curious kind of what’s next from a research point of view. Obviously Chris you’re going, to market soon, but just strictly from a research point of view both, Chris and Brianna, curious to get your thoughts on how to optimize next steps, what you think this field may look like in 1824 months and what’s, just beyond the horizon for your research.

Christopher Rhodes: Sure. I can go first if that’s okay with Brianna. Yeah. All right. Perfect. So for, any biology, like our, plan moving forward is basically to we have this great N of five study that’s our pilot proof of concept. We’re gonna be going into a larger scale clinical study to further vetted out and vet out the capabilities of the actual mimetic itself.

And then beyond that, We still have that great robust data set of these over 300 significantly different fasting metabolites that we can continue to comb through to find novel targets for like new products, new pathways, new indications and then like really start cranking out the hits as they say.

So that’s what an A biology will be doing with its science in the future. And then continuing on to again, like try and pioneer this new wave of biomimicry and this new wave of these clinically derived longevity and healthspan molecules. Great.

Brianna Stubbs: So I think for me, and this answers one of the questions that was in the chat.

We really need to define the. PK p d or the relationship between the level of ketones in the blood and the effects that we’re interested in because really at the moment we, don’t know how high ketones have to be to have an effect this kind of has relevant for, fasting and the ketogenic diet and really, anyone who’s looking to use ketones, whether it’s from a supplement or if it’s through like a lifestyle nutrition intervention.

Historically in the literature people have said that Ketosis is anything over no 0.5 millimoles of bhv. But we’re starting to see this really interesting class of drugs called SGL two inhibitors, which indu a very, mild ketosis that doesn’t go over that threshold, but patients who are on those drugs see improvements in cardiovascular risk.

And so it’s possible that these signaling effects of ketones occur at much lower levels than was thought previously. So I think that for me, one of the big questions that. In the near term that we’ll try and address is understanding the, relationship between circulating keto levels and, the physiological response.

Tom Bunn: Terrific. We have about two minutes left. Looks like a, question came in from Alexandria vso. They ask if someone were to do a 36 hour fast, how often should they do it?

Christopher Rhodes: That’s a fun question. So when I first got into fasting, I was doing alternate day fasting because that’s where all the literature results are, right?

If you’re looking at lifespan, extension and mice, it’s always a alternate day fasting regimen. So I actually did that for. Two years straight felt great. Didn’t really have any like problems with it from a physiological perspective, but it can be a bit mentally draining and there’s this element of social isolation that goes along with it.

So just from my own personal experience, you can do alternate day fasting. Seemingly indefinitely, but it might become like a mental drag. Obviously anytime you’re doing fasting, especially in the long term, the most important thing is to make sure that on your eating days, especially in an alternate day fasting context, you are getting the maximum amount of like micronutrients and macronutrients that you can to make sure that you’re not running into any kind of like weird deficiency as you progress through.

So that would be my advice, but hypothetically, you can do it indefinitely.

Tom Bunn: Great. Thank you for the question, Alexandra.

If there are no further questions I want to thank our panel, Dr. Rhodes, Dr. Stubbs and Dr. Pearls for joining us this morning. Really appreciate your time and your expertise. We for the audience, we host these, once a month will be diving into a topic and more on the food and agriculture side.

In October that David Yoakum will be leading. And I think there’s a lot of potential for more research, more deep dives in this particular area here. As I mentioned a lot going on in terms of the clinical side and the clinical development. We could spend any number of deep dives going into one of those.

So keep an eye out for more content. Related to longevity and aging. And in the meantime also keep an eye out for the webinar David Yoakum will be hosting next month. So thank you all again for joining and we will see you soon.

Christopher Rhodes: Okay, thanks.