Good morning, and welcome to iSelect Industry overview Webinar Series.

Here at I Select, we are privileged to live at the forefront of innovation, seeing emerging problems, solutions, and macro trends well before they make their way to the wider culture and market.

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One such macro trend that we’re exploring is longevity, neuroscience and anti-aging. These topics aim to understand the relationship between aging and age related diseases in the prospects for biomedical intervention.

Molecular biology, neuroscience, chemistry, cell biology, genetics, Indocrinology and pharmacology all intersect with this field.

Before we get started, a few 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.

You’re all also on mute. You can use the chat window to ask a question. After the formal part of the presentation, we will open your phones so you can ask questions or offer advice.

Finally, this presentation is being recorded and will be available for replay.

And with that, I’m pleased to bring you this presentation on longevity.

So this is the longevity industry of deep death. Thank you again for joining us.

This morning, the topics covered will be What is the study of longevity in aging?

My colleagues just pointed out to me that I spelled aging the British way throughout the presentation. So if you’re offended by that, I apologize.

We’re gonna dive into why it is important.

We’re gonna touch on some of the demographic factors at work.

And then we’re going to touch on some of the areas of research being pursued. Each of which could be a deep dive in their own right.

We’re also going to touch on a few of the major companies in the funding they’ve received, who those investors are.

A little bit about who the movers and shakers are, who are the thought leaders in this field.

We’re also going to touch on some regulatory hurdles.

And finally, where I think we should focus as a fund.

So what is aging and longevity?

Aging is the leading risk factor for the chronic diseases that account for the bulk of morbidity, mortality and health costs.

The study of longevity in aging also known as Jira Science aims to identify the damages that accumulate with age identify how to reverse these damages and identify ways to increase human lifespan and health span.

Health span is an interesting word in this field that takes lifespan and basically amps it up to include not only the years in your life but the life in your years. It’s not just about the number. It’s about the number paired with health. Is there is there can I ask a question, please? Is there a common measure of what that is?

Is there a standard for health span?

I think health span is loosely defined as as just the number of years that you’re healthy before chronic morbidity hits. Okay.

So aging is a hodgepodge of metabolic processes, damages, and pathologies with multiple points of intervention.

It’s not one disease. There’s a big front right now, a big – not front, but a big push to make it in the eyes of regulatory agencies.

As a disease. But right now, it is not it’s certainly not one disease, and it’s not classified as as one disease by the regulatory agencies.

It’s also important to note that this field has only recently gained widespread respect.

In the early twentieth century, scientists found that caloric restriction increased lifespan of mice.

But other than that, it was more or less an academic backwater for about one hundred years.

Only in the last decade or so, have have scientists really climbed out of this backwater to make it a respectful field.

And since then, it’s been only gaining steam.

And a little bit on why this is important demographic aging is one of the greatest problems threatening economic prosperity and social stability.

And this is referred to as the the Silver tsunami tsunami, and that’s coming.

And we’ll get into that right now.

So what is the silver tsunami?

This is a term used to describe rapid population aging that is coming for nearly all countries.

All but eighteen of the world’s countries have an aging population.

And this is based on two factors, rising life expectancy and decreased fertility rates.

And one of the reasons why life expectancy has gone up is because we’ve already gotten pretty good at fighting disease. Infectious disease, for example, is not nearly as big of a problem as it once was.

If you get tuberculosis, you can solve it, you can cure it.

With some of the aging diseases, the diseases associated with aging, It’s not it’s not quite as simple.

The silver tsunami in in in popular culture is often associated with Japan is they have a very – they have one of the most predominantly aged populations. And this flood of problems associated with this demographic aging, we’ll probably hit them first.

So this slide talks a little bit about Medicare and Social Security and Medicaid as it relates to GDP.

You can see right about now in twenty eighteen, social security is still a higher percentage of GDP than Medicare. But you can see in just a few years Medicare will supersede Social Security as a much higher percentage of GDP.

And that’s because, again, the populations are aging.

This happens in about two thousand and thirty. When the Medicare costs outweigh social security.

An important number here is the dependence ratio.

This is the number of pendants between zero and fifteen and over sixty five to the number of people aged fifteen to sixty four.

So this number keeps going up and up as we have in and aging population.

Stan, Drunk and Miller of Duane Capital formerly of George Soros hedge fund He said, this is a pretty interesting quote. He said, I see a storm coming. Unfunded pension and medical liabilities are the least sustainable situation I’ve seen in my career.

So why is this happening?

Well, for one retirement now lasts nearly twenty years.

You can see that in nineteen fifty, the average time between retirement and life expectancy was only about eight years. Today, that number is about nineteen years. And by two thousand and fifty, it’s projected to be about twenty two years.

Current retirement age was established prior to the rapid rise in life expectancy that occurred in the second half of the twentieth century.

Which is now creating a whole host of problems in terms of liabilities for for pensions and and and Medicaid that that we’re about to face. So as I’ve alluded to, Americans are getting older.

In the U. S. There are eight thousand people turning sixty five every day.

By twenty fifteen, nineteen million Americans will be over eighty five and half will have Alzheimer’s.

You can see this graph.

We’re at about forty million people between sixty five and eighty five right now. That number will go to about ninety million by two thousand and fifty. What was the percentage that you said would have Alzheimer’s? Half. Half over eighty five. Of the over eighty five, half of that’s gonna have Alzheimer’s. Yeah.

Really wow.

So life expectancy is rising fast.

As you can see here, this is a chart that basically takes data points from nearly all countries from the 1800s to twenty twelve. And you can see a pretty systematic increase in life expectancy throughout that time period.

An interesting statistic is, at least in the US, life expectancy is increasing at six and a half hours per day.

And we can see that America has gained about ten years since nineteen fifty.

So this is the important part, I think. And that is that old age is the costliest time for healthcare.

You see that about twenty five thousand dollars per capita spend on the eighty five plus demographic.

That’s about ten thousand dollars higher per capita per year spent on the second highest demographic, the seventy five to eighty four year olds, and that’s about six thousand higher than sixty five to seventy four year olds.

This is a result of of chronic conditions associated with with aging that result in in, you know, morbidity and ultimately mortality.

So why focus on longevity?

The aim of Geroscience and longevity researches to prevent and delay age related disease.

As I just mentioned, an individual’s final years are the costliest to the healthcare system.

And I think this is the most important part of longevity research.

The goal of the U. S. National institutes on aging states it as the compression of morbidity.

So this goes back to the definition of health span that we’ve talked about earlier.

It’s about increasing the healthy years of your life, not just adding years to your life.

So you can see this graph on this on this page. When you increase health span, the time of morbidity goes down significantly.

So that ultimately reduces the cost.

I think that is – that’s the crux of the argument for pursuing longevity research and aging, anti aging research. So the only sustainable solution is to extend healthy lifespan or health span.

So now we’re going to get into an overview of the science.

This slide does a good job of explaining kind of the four rough areas of research. You have regenerative medicine, which My colleague David Yokom, Yokom touched on a few weeks ago.

We have gene therapy, which I believe he also touched on a few weeks ago.

P3 medicine is a combination of participatory, preventive and predictive medicine. That’s a common – commonly thrown around in this field.

That takes personal traits of the patient into consideration.

There’s a lot of big data components to it to allow predictive analytics to to to to work.

It relies heavily on genomics and bioinformatics.

But what we’re really gonna touch on today is Jiro Science. And that’s the relationship between aging and age related diseases and the prospects for biomedical intervention.

Some examples that we’ll touch on are senescence, parabiosis, and autophagy.

So one of the most commonly cited ways to increase lifespan is caloric restriction. And the premise here is that eating less can make you live longer.

This was first observed in mice in the 1930s.

But it’s important to know that the efficacy also depends on genes, the genes of the mice. For example, if you feed genetically distinct groups of mice same thing, sometimes fewer than twenty percent live longer.

And that is all to say that it’s not just caloric restriction.

That causes increased lifespan, but also the genes that play in the individual organism.

There’s been very little experiments in in humans. There’s been some in monkeys that have shown promise.

But again, very little data in humans.

And one of the reasons why they think caloric restriction works is because of a concept called sirtuins.

These are genes that are part of a regulatory network that control organisms’ health during times of adversity.

So, essentially, when when cells are starved of food and calories, these sirtuins come in and help protect the cell.

And as Davidson Sinclair of Harvard University is one of the foremost leaders in this field. His work touches on why why this happens and and attempts to translate the the idea of core restriction.

Into practical medical interventions.

So another concept is insulin and insulin growth factor.

This basically boils down to the fact that genetic pathways related to growth in insulin signaling are linked to aging.

For example, scientists have observed mutant genes that help worms live longer.

These these genes are similar to insulin like growth factor and insulin receptors in human So in mice with these mutations, lifespan can increase.

One of the longest living mouse mutants is a dwarf mouse deficient in growth hormone, prolactin and thyrot stimulating hormone.

And so in one study, people with similar dwarf mutations suffer less related disease.

Interesting component here is that many drugs developed for diabetes have turned out to be relevant for agents. Examples of this are metformin, which is the closest drug being approved for for any semblance of anti aging effect.

And the protein FGF twenty one. Metformin is actually in a clinical trial right now with three thousand patients that is targeted to be finished in about six years.

It’s called the targeting aging with metformin, the TAME trial. Again, it will follow three thousand seniors for six years, and it will track a single biomarker associated with aging.

So can I understand this a little bit better?

Are they seeing that that mice that have stronger insulin production and who are more effective at processing the sugars in their bloodstream have this anti aging effect? Yes. That’s it. Okay.

Yep.

This is also the drug that they’re – the diabetes drug that they’re testing for obesity or there’s a diabetes drug that’s in a weight related trial as well.

I believe it is. I remember in my research that metformin was associated with anti obesity effects.

I think this trial is just on this biomarker with aging, but I think you’re right about that. Did you see anything at all about the study that came out this week?

I mean, it’s very recent.

This shows that when you exercise, your body releases proteins that cause the cells across systems in your body to communicate and to change the way they process energy.

I did not see that, but it’s interesting in light of these studies, absolutely.

We have another company that’s doing an exercise on a fill.

Oh, yeah.

Uh-uh. That’s interesting.

So another area of research is called parabiosis. This is this is getting a lot of has gained a lot of steam in Silicon Valley.

Peter Teal is very invested in it.

For better or for worse, he’s he’s associated with with a a vampire often because shared biosis is, you know, linking old and young mice with with a single bloodstream or or transfusing, injecting young blood into old mice. I think just because of its its, you know, relationship with popular culture.

It’s gained a lot of steam. It’s often cited in publications that are that are elucidating anti aging efforts.

But the the genesis came from nineteen seventies paper, waking old and young mice with single bloodstream can increase lifespan. That’s continued into the two thousands where scientists at Stanford show that this procedure might help repair wounds in old muscle stem cells.

And continued on to twenty eleven when papers came out showing injecting young blood into old mice, made mice better at remembering things and improved heart and muscle function with age. As George Church said on parabiosis, it’s not just prolonging a very age state or going for longevity.

Actually reversing it.

So what’s causing this? Possibilities include proteins, small vesicles, or cells in the young mouse, cleaning the blood of the old mouse, But the big question from a commercialization standpoint is whether we can isolate a few key factors that are responsible for the parabiosis effect.

And how many of these longevity related phenotypes in mice will translate to improved human health. Another area of research is called senescence.

And this is basically that a fraction of cells get older than the others.

And so we should try to eliminate them. So as you get old, so do your cells, but some get worse than others.

Telomerase is a part of DNA that keeps the end of your DNA long enough so your cells can still divide. When one of your cells runs out of telomerase, it can’t make many more copies of itself.

So if the cells if the cell stays even when it stops working, and start secreting signals to the immune system, we call it a senescence cell.

That is a dead cell that doesn’t go away. And these dead cells have many inflammatory attributes that that cause a lot of the morbidities around aging.

There have been a number of papers recently, predominantly from the Mayo Clinic have shown that clearing out these senescent cells makes my makes my healthier. An old age and made them live a longer, healthy lifespan.

How do they how do they go about clearing out some ethanol in the mice? That’s kind of the crux, because targeting – or finding these senescent cells from my understanding, correct correct me if you know you know more.

The the the biggest crux of the issue is that’s in essence and sales are hard to identify.

So clearing them out, killing them is is kind of the fundamental scientific challenge.

My my present is slightly different. I think it’s actually killing them.

That’s hard because they go into this state of kind of suspended animation and stuff, we can break ourselves die and semesters just go there and stay and stop doing anything else.

And so they have difficulty killing them.

And so they did a researcher before we were talking to are using multimodas of action simultaneously to cause apoptosis in the cell and kill it off and kill off to clear it up.

Once it’s dead, it’ll clear, but it’s killing it.

So there and there are there are a variety of, I guess, known compounds that have some impact on sinescence, but not really effective. How strong is the research, how much research is there on the connection between the senesce themselves and inflammation.

I I don’t know the answer to that. I know I know they’ve been at it for quite a few years with a whole team of researchers at Mayo.

Yeah.

But they are kind of the go to resource.

Are they the leaders and the thought leaders on this issue? Certainly one of them.

Okay. It’s largely mayo on harder to know.

Yeah. Important to note also that that from an anticancer point of view, cellular senescence is critical.

So, basically, senescence happens, evolved to basically keep cancer at bay. But but what we found is that that this effect to a great degree also causes aging morbidities.

So autophagy. This is basically that the waste management unit of the cell worsens with h.

So, essentially, your cells need cleaning from the stuff they produce.

Research has found that increasing a protein In this case, ATG five helps clean this molecular waste that helps to clean this molecular waste can make mice live seventeen percent longer.

And so how this works is that cells recycle old proteins and other molecules into a big vesicle called a lysosome.

And these lysosomes contain many proteins and their job is to chop up old cell parts that they encounter.

So mutated genes basically don’t allow this lysosome to to work well.

And and they found that these genes are are associated with a lot of neuro degenerative disorders, including Parkinson’s.

So this this area of research is is is big for neuro neuroscientists.

Another area of research is the hypothalamus.

In a nutshell, it’s that a surprising number of things can increase lifespan when only changed in the brain tissue.

So changing something just in the brand can be enough to make a mouse live longer.

For example, if a hypothalamus thinks it is too warm, It can decrease the core body temperature of a mouse resulting in a slightly longer lifespan.

What we know to date is that the hypothalamus makes something called growth hormone releasing hormone, which is in charge of releasing growth hormone. And that this growth hormone appears to be closely tied to then.

So the hypothalamus is is a potentially an important area of research.

Reproductive system.

This is an area that doesn’t have too much commercial viability, but It’s interesting nonetheless that removing that is that removing the ability to reproduce can increase lifespan.

In research done in the last century show that if you take young worms and get rid of their gonads, they live sixty percent longer.

Interestingly enough, from court records of Korean units.

The units tend to live longer than their contemporaries by fourteen to nineteen years.

It’s not completely without hope, though, because some some research that tried to transplant young ovaries into old mice, not too dissimilar from parabiosis to see if that helps.

And there’s some indication that it does.

So mitochondria is another area of research.

Basically, that mitochondrial mutations can affect lifespan. No surprise there.

As we know, mitochondria are the powerhouse of the cell.

And we know that we can make a mouse live longer by increasing the level of proteins that are supposed to clean up mitochondria.

You can also mutate things that should be helping the mitochondria and end up increasing lifespan.

It is counterintuitive And and one hypothesis here is that a little bit of stress is good because it forces your cells to put up their defenses and ramp up production of molecules that neuter the reactive the reactive oxygen species. It’s kinda like the the George Carl joke where he says he he always eats off the floor because it he says it’s keeps his immune system in practice.

So some key players and VCs in the longevity space. Again, this is based on breaking it down into four distinct areas. You have regenerative medicine, P3 medicine, gene therapy, and and Jiro Science.

Most of the companies I’m gonna talk about today fall into the Jiro Science field.

So these are some notable companies.

They’ve raised quite a few dollars in venture funding. You see some regenerative medicine.

Some focused on metabolic and cardiovascular conditions.

A company called Ciliary, focusing on regenerative medicine as it pertains to up up found up foundry.

Are you say it?

A family.

Some regenerative medicine focused companies taking stem cells from placenta.

A company called Calico, which is a spinout from Alphabet, which is notoriously secretive as to what they do.

Basically, all they’ve said so far is that they’re trying to increase understand the biology of aging and and and how to understand how they can increase life span.

Human longevity is a genome sequencing company company at its core.

So it’s applying machine learning to genomic data in order to to basically get super predictive and precise in in in interventions.

They’ve raised a whopping five hundred million dollars Insilico is a Baltimore based company focusing on next generation AI and blockchain technologies for drug discovery.

Hovinescence is an AI focused company that’s developing drugs by AI.

Myto Bridge, small molecule therapeutics designed to enhance mitochondrial function.

Rapomicin Holdings their weed compound e RAPa fights prostate cancer.

And Unity Biotechnology isn’t is a senescent cell focused company that that targets it as themselves in in doing so prevents the downstream inflammatory effects.

As far as investors go, You have some well known investors.

Obviously, Alphabet, Calico is a spin out of Unity Biotechnology, Arch Venture Partners, Bezos, X additions as Jeff Bezos’s fund and male clinic ventures as well.

So as far as total VC investment over the past year and change, we see about eight ninety million dollars invested since the beginning of twenty seventeen.

In twenty sixteen, I believe it was about six fifty million dollars So increasing increasing slightly, you have some big winners here, cellularity, human longevity, adding to their round that they raised in twenty sixteen, raised two hundred million dollars in twenty seventeen.

And you see that the deal stages run the gamut from seed to some later stage stuff.

As far as M and A activity, there hasn’t been much at least in terms of pure gerolentology companies.

After Xantica is a bit of a stretch here, but they are focused on three of the the the main core functions of of gerontology gerontology, which is oncology, cardiovascular, and and renal and metabolic diseases. They’re required by Pfizer in December of twenty sixteen.

Mito Bridge is focusing on mito mitochondria enhancements.

Universal sells is a is a stem cell focused company that is producing pluripotent stem cells that have lower immunological rejection to further enable investigation of of this type of therapy.

So the top VCs in longevity.

You can see we’ve partnered with a few of them. We have F prime up there. Male clinic ventures.

We could be investing soon with OrbiMed in a blood based diagnostics company.

And longevity fund, which is founded by a twenty three year old woman who went to MIT at age sixteen, and he began working in a molecular biology lab at the age of twelve. So as far as other entities in the space, There’s a whole list of notable scientists who are known for being, you know, big personalities and and tons of YouTube videos.

This guy Aubrey de Gray is is very prolific on YouTube.

He’s notable for claiming that the person to live that a person alive today will live to a thousand years old.

David Sinclair is an Australian board scientists at Harvard Medical School has been influential influential in in sirtuins in the in the research around why caloric restriction seems to make some mice live longer.

George Church is considered the the father of synthetic biology.

And has been also relatively prolific in the longevity space. He wants to build synthetic DNA including a complete synthetic human genome, which he calls de novo synthesis.

And as far as foundations and organizations go, there’s one called Sen’s Research Foundation, which is focusing on strategies for engineered negligible The Buck Institute is also very prolific. They’re the nation’s first independent research institute focused solely on aging. And extending healthy health span.

They’re based in Nevada, California. And again, some venture funds you have, Peter Fields’s fund is very interested.

Google Ventures, obviously, is interested with their work with Calico.

The longevity fund, which actually we just got an intro to yesterday, which which is run by the twenty three year old woman.

And I would encourage all of you to look at all some of the other organizations and entities on this slide as they’re relatively interesting.

So as far as the labeling and reimbursement goes, Human longevity drugs may still face labeling and reimbursement challenges. As aging is not considered a disease, regulators and payers will take issue with labeling and paying for longevity drugs.

So from a payer perspective, the minimal cost of drugs like metformin and rapamycin repurposed as longevity agents will allow out of pocket payments.

And, you know, while the payers are unlikely to wanna get too involved, the long term survival data and long term interest in reducing health costs may push them to do so.

But important to note that the FEAs is not considering aging as a disease.

So a lot of these efforts facing uphill battle from a regulatory point of view.

So where we should and should invest, Well, in my opinion, we already are invested.

While it may not be a pure play Jiro Science investments.

In my opinion, anything that helps people live longer and improve morbid conditions or improved diagnosis to target those conditions can be considered longevity focused investments. So we have co factor genomics, which we invested in last year, that uses RNA sequencing and machine learning to to to more accurately diagnose diseases.

Two cancer focused drugs, ulysses, and immunophotonics.

In QA therapeutics, which is a exercise in the pill drug that allows people to feel full quicker.

And thus decrease the amount of calories that they consume.

So where should we focus?

As I mentioned, we’ve already been talking with senescent cell focused companies.

We’ve seen a promising company out of Mayo Clinic and Scripps Research Institute. We will need to compare thoroughly with Unity Biosciences, kind of the five hundred pound gorilla in the space.

They’ve raised a lot of money. I think over three hundred million dollars Another area I think that we may want to focus on is retargeting old drugs to do new tricks.

As metformin is currently doing with diabetes and now in aging, using FDA approved compounds that work in other targets, ideally with some patent life still on on on the compounds and then optimizing them for for senescence or longevity. Companies with compounds that can easily target known indication.

So this goes back to the regulatory hurdle I mentioned earlier.

That since the FDA is is not labeling aging as a disease, ideally, we need to go after companies that that have a very well defined indication they’re they’re going after with, hopefully, corollary longevity benefits.

Another area is machine learning innovations that help identify new longevity genes or bring personalized medicine to the clinic.

And finally, gene therapy solutions that advanced the the speed efficiency and afford affordability of gene therapy development regulatory approval. So in conclusion, this is a pretty scattered space that’s undergone significant advancements in the last twenty years, but there’s still a very many perspectives and entities that are trying to coalesce around one central idea of of anti aging.

There’s still a lot of work to be done.

But we think it’s an interesting field that that has a lot of potential.

Would welcome any questions now.

So something was really interesting to me about this.

There was a kind of a common thread that was running through a lot of these elements here.

If you look at caloric restriction in the way the cells respond to caloric restriction and how they process energy. And you look at the fact that mice that have stronger insulin production have greater longevity.

Too. Okay? And then you see that changes in the hypothalamus and little changes to the hypothalamus by themselves can change longevity.

And we know we know that sugar stimulates the hypothalamus and that hypothalamus then stimulates the body to want more food and to consider more food.

Okay.

So there’s really interesting line running through all of these things that impact longevity of how sugar is really a negative for your metabolic system here.

Okay?

And so what this tells me is that our investments in things like bodyamos and other alternative sugars are going to turn out later to be proven to be investments in longevity types of products.

Too. And perhaps ways to impact longevity on a bigger scale than just about anything that you’ve talked about here today. Absolutely. That really jumped off the page of me when I heard this presentation.

Did you see any specific research about how sugar itself and anything that impacts, like, diet sugar in your diet either on a macro or on a individualized study impact longevity?

I didn’t see a specific study. I’m sure they’re out there.

One common thread if you do a Wikipedia search on any of these, you know, thought leaders is that they’re they’re diet they’re they’re very They’re very vocal about their diets.

And almost unanimously, they don’t eat refined sugars that they don’t eat added sugars.

So while I’m sure research is out there, I did not find it. I think just based on the practice of these thought leaders, I think I think you’re onto something.

I said one other thing in terms of some of the companies we’ve talked to, it is important to make sure that they have an endpoint that is measurable that they can go after because aging is not an endpoint.

And if for any, you know, whatever reason you are targeting aging would also be a prolonged and extended trial that you’d end up having to go through versus you know, if you have a specific condition, a related condition that you can go after them and show improvement in your term. Then you’re gonna get approval for that condition, and then you just keep extending, right, the, you know, what the the uses are.

Wasn’t rent a sense targeting. Fralty is one of their endpoints? Fralty is one of their endpoints.

Yeah.

They had five or six different endpoints they were going that they had shown some progress against.

And the interesting end of the FDA had fast tracked them for a variety of things. And it’s hard to tell whether it was because of prior research, because of team because of the endpoints or because they were down on some level. Sometimes they were using compounds that head were known in the compounds.

It had already been through a variety of trials, but in other times, they were using novel. Agents as well. So I’m not sure where that stands or why they are getting the treatment there again.

It was very interesting. Thank you.

From the audience, we welcome any questions.

When you relisten to this, please share among your friends. We do these presentations once a week on Wednesday mornings.

So we look forward to Seeing you back here next week.

Thanks again. Thanks. Bye.