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Nathan Cheng on Longevity Startups at EARD2021

The industry has grown substantially over the last 20 years.

Nathan Cheng at EARD2021Nathan Cheng at EARD2021
 

In his talk at Ending Age-Related Diseases 2021, Nathan Cheng of On Deck outlined the history of the longevity industry and offered ways of moving forward.

Script

Today, I’ll be giving a talk about longevity startups, past, present and future. Oliver already introduced me, but I’ll quickly go over some of the projects and companies I’m affiliated with. Right now, my full-time preoccupation is dealing with organising the On Deck Longevity Biotech Fellowship. I’m the program director there.

I also am the founder of Longevity Market Cap, Longevity List, Healthspan Capital, and the host of the Longevity Biotech Show. It’s a podcast. Basically, if we just quickly look at some conflicts of interest, if you’re interested in that, just get that out of the way.

The title of the talk, Longevity Startups: Past, Present, and Future. Why talk about this, or why am I talking about this? There’s two parts to that question, the first part being why me in particular, and then why this topic?

Let’s just talk about the first part: why me? I got really interested in longevity because Laura Deming had a YouTube video a while back talking about how there needed to be more founders in this space. Naturally, and naively, I thought to myself, maybe I could be a founder in the space.

Obviously, my background is physics, so I did a lot of intensive self study to figure out what was going on in this space and, obviously, taking biology courses. One of the things that I did was start a newsletter, the Longevity Market Cap newsletter, which was basically my attempt to figure out what was going on in this space of aging, biotech, longevity biotech, and just see what was going on, what was being worked on, what wasn’t for my own personal reasons, and that started to take off.

I also started a website, Longevity List, which is a database of companies, but then also a jobs board, because I noticed there was a lot of companies posting jobs. I figured a lot of people would be interesting in joining these companies if they have this intense passion for the aging movement and longevity in general.

Throughout the time writing this newsletter, it took off. At some point, once the leadership got to a certain point, I realized maybe the way that I could help move this space forward was not by starting my own longevity biotech company but perhaps helping 100 people start their longevity biotech companies. This is my personal mission. The Longevity Biotech Show is interviews with founders in this space, just trying to get tips from them, to potentially help other people get into this space.

Finally, the thing that I’ve been involved with the most is the On Deck program, where we’re building a community for more people to get involved in the longevity biotech startup ecosystem. That could be founders, aspiring founders, investors, people looking to join startups. We just announced that about two months ago, and we’re really excited to be launching that on September 12. More on that later.

Let’s just go over a quick overview. In terms of longevity startups, I’ve been really obsessed about learning about the entire landscape. Sometimes, it’s good to look at what happened in the past to get the context of how we got to the present state of the longevity industry and what lessons were learned.

I’ll also go over the state of longevity, some facts and outstanding trends and themes that are going on today. Finally, we’ll talk about the future, obviously a little bit speculative; there are some things on the near-term horizon that I think are very, very salient, and also talk about outstanding challenges to the development of the longevity biotech startup ecosystem.

Longevity startup history: Basically, I’ve laid out a very rough inflection point timeline, not exactly everything fits into this point. We have five areas.

We’re looking at the prehistory. That’s the science that laid the foundation for the first companies. In the 2000s, we had our first wave of longevity startups, and they crashed. In 2013, we started to get a growing sense of legitimacy, other bigger players, well-known people getting into the space. 2016, there was more of an explosion of different approaches to anti-aging biotechs. That continued to our present day, which I’ll talk about, including the future.

Let’s talk about the prehistory first. These were the scientific findings that laid the foundations for the first longevity startup. The science of aging wasn’t so well-known prior to the 80s and 90s. Obviously, there was experiments in rats with caloric restriction.

That was known, but the molecular genetics of aging wasn’t really well known. It didn’t even exist until experiments by Tom Johnson and Cynthia Kenyon in the 80s, 90s. That was one set of experiments that set this field in motion, but then obviously David Sinclair and Leonard Guarente looking at sirtuins and also the work going on with telomerase with Carol Greider and Elizabeth Blackburn, and different developments in stem cells, like embryonic stem cells. Those set the stage for the first companies.

In the 2000s, a set of three companies, Geron, Elixir, and Sirtris, were either founded or rose to prominence in this time. They were really based on those scientific discoveries in the 80s and 90s. Those were telomeres in stem cells and the discovery of certain longevity genes, which we’ll discuss in a second.

First of all, we had Mike West at Geron, which was co-founded in 1990, and they were really interested in activating telomerase and also looking at stem cell therapies derived from human embryonic stem cells.

Cynthia Kenyon, she was the co-founder of Elixir Pharmaceuticals along with Leonard Guarente, and they were looking at trying to find ways to drug the daf-2 IGF-1 axis. Those were the longevity genes that were discovered; they found a mutant in C. elegans that allowed them to live twice as long in that daf-2 mutation. Cynthia Kenyon co-founded Elixir Pharmaceuticals in 1999. It’s also backed by Robert Nelson at ARCH Ventures, who’s also a very big proponent of the anti-aging biotech space and still active today.

Of course, David Sinclair, Sirtris Pharmaceuticals. He discovered sirtuins and their relation to lifespan extension in yeast. He co-founded Sirtris in 2004, and they were developing resveratrol and other drugs to activate sirtuins to potentially extend lifespan.

During this time in the 2000s, there was a lot of hype, especially around Sirtris, because resveratrol was a molecule found in red wine, obviously, and this got all over the mainstream news. Eventually, GlaxoSmithKline acquired Sirtris Pharmaceuticals for $720 million, which was a very big deal at the time, but unfortunately the first wave of longevity startups eventually ended.

Geron is actually still here. It’s still the company traded on the NASDAQ, but they eventually pivoted away from from doing anything with aging. They had telomerase inhibitors, but they didn’t develop those any further. They stopped their stem cell trial because of financial trouble. Eventually, Mike West ended up at Ajax Therapeutics, working on basically some of the assets that eventually made their way to Ajax Therapeutics from Geron.

Elixir Pharmaceuticals, same thing, the company pivoted away from aging. They looked more into diabetes and obesity with ghrelin antagonists. They had a potential deal with Novartis, but that fell through. By 2010, the company was wound down. Eventually, in 2013, as we’ll see later, Cynthia Kenyon joined Google’s anti-aging play, Calico.

And then David Sinclair. Okay, so we talked about the acquisition of Sirtris by GSK in 2008. There were issues with clinical trials of some of the drugs that they were developing, and ther were controversies about the science of sirtuins and resveratrol and that domain, and eventually GSK shut down Sirtris in 2013. Of course, David Sinclair is still part of this community, doing great work at Life Biosciences, he was a co-founder there in 2017.

That was the first wave, what were the lessons learned? Number one, choose your investors wisely. It seems like a lot of these companies started off in aging, but then they ended up pivoting away, whether it’s because of management where their lead investors tried to try to move them towards more lucrative short-term goals.

Number two, the science doesn’t always work on the first try. That’s a common theme in a lot of biotech in general. Just things to be aware of, sometimes you have to be patient.

Let’s talk about growing legitimacy. In 2013, Google actually joined in as well as another company that started called Human Longevity, Inc. These were headed by two very prominent people in biotech.

The first wave of startups were founded by people that we all know very well and we think they’re super ballers. At the time, they were first-time biotech scientists, founders. When Google came into the field of anti-aging with Calico in 2013, that was co-founded and helmed by Art Levinson, who was an ex-CEO of Genentech, which was basically the company that started the entire industry of biotech. Cynthia Kenyon still is there as VP of aging.

The other company was Human Longevity, Inc, founded also in 2013 by Craig Venter and Peter Diamandis. Google getting into the game with an extremely well-known and prominent leader from biotech, that just helps give legitimacy to the field.

Eventually, in 2014, Calico partnered up with AbbVie, which further cemented this idea that anti-aging could be a real thing, it’s not just some fringe idea. Now, Calico has a clinical trial currently running, and they’ve invested over three and a half billion into this joint venture.

Human Longevity, Inc. was started by Craig Venter, who is well known from the Human Genome Project. Their whole idea was to do really high-end diagnostics, like full-body MRIs, genome sequencing, and the company, at one point, had a $1.6 billion valuation in 2017. These were great, getting people who are well-known in biotech into the field.

Then in 2016, we started to get a bunch of new approaches in anti-aging biotech. Just quickly, because we’re going to be a little short on time, we have the senolytics explosion, cellular reprogramming, parabiosis or approaches inspired by parabiosis, we have targeting mTOR and also the rise of AI, ML drug discovery.

Let’s take a look quickly. The senolytics explosion, the first company in the space was Unity Biotechnology, started by Nat David, Judy Campisi, and Jan van Deursen. It was backed by ARCH Venture, which also backed Elixir.

There was another company in 2014, Oisin Biotechnologies,and they’re still here and doing great stuff, but then what really set this subfield in motion was in 2016. They published at the Mayo Clinic a seminal paper where they showed when you removed p16-positive cells in a transgenic mouse model, p16 is a biomarker for senescent cells, they found that you could extend median lifespan by 27%.

There was a very distinct difference between the aging phenotype of the treated mice and the non-treated mice, as you can see over here. After that paper, in the four or five years afterwards, there were 17 new biotech startups in senolytics. That was a really great moment for that specific approach.

Cellular reprogramming traces its roots back to induced pluripotency, obviously, by Shinya Yamanaka and the Yamanaka factors, and then in 2016, Ocampo and Belmonte showed that you could do partial epigenetic reprogramming, which extended the lifespan of progeric mice and also ameliorated some aging phenotypes in wild-type mice.

A bunch of reprogramming startups started to spring up from there. Ajax Therapeutics does stem cells, but they also have something in this space, Turn Bio, Retro Biosciences, Iduna Therapeutics, which is at Life Biosciences, and Shift Biosciences. Which is Daniel Ives, originally in mitochondrial but now doing the stuff in cellular reprogramming.

Also, there is parabiosis. Some of these experiments done by the Conboys and Tom Rando, by joining an old mouse to an young mouse found that the blood of the young mouse could rejuvenate tissues of the older mouse. Of course, Grifols did some clinical trials in there, which were really promising for Alzheimer’s disease.

Alkahest in 2014 was founded, and they have a proteomics platform where they can see how the blood proteome changes as people age, and they’re developing plasma fractions and antagonists for certain blood factors. They were eventually acquired by Grifols in 2020. And a bunch of other parabiosis startups, or inspired by parabiosis startups, were formed in the preceding years.

Obviously, there was also mTOR. I don’t want to go into too much detail there, but in 2016, the big news there was resTORbio spinning out from Novartis and held by Joan Mannick. They were looking at using a mTOR inhibitor to see if you can reduce respiratory infections in elderly patients. That’s obviously super relevant to today, but it failed in phase three for reasons that you can look up in Joan Mannick’s paper in the Lancet that was just published a month ago. There’s other companies working in this space as well.

Generally, AI drug discovery was really hot coming up to 2016, 2018. Many companies in longevity also have this angle where they use AI and machine learning heavily. Insilico Medicine, Alex Zhavoronkov; BioAge, Kristin Fortney; and Spring Discovery, Ben Kamens. In general, AI and ML is becoming a tool in biotech, so we’ll see more of that.

Honorable mentions. Some other approaches that haven’t fit in my timeline, just looking at mitochondrial therapeutics, autophagy is also really big. Another domain is trying to target aging and dogs as a stepping stone for translating therapies to humans. Obviously, great companies in that space.

Another theme that’s emerging is founder-led biotech startups. This idea of a West Coast model where the founder is the key person leading the company throughout the entire process. Platform companies also, there’s a huge overlap there, and things like TechBio. Also, tissue engineering, that’s been developing all the wild things like 3D bioprinting, all the other things like Jean Hebert’s work at Albert Einstein College of Medicine, definitely check him out.

Let’s just quickly look at the current landscape. Today, in 2021, we have clinical trials, we have more VC firms, we have a new kind of structure, discovery companies, which are umbrella companies. We also have more infrastructure developing for longevity startups, like accelerators and so forth, so let’s just go over that quickly.

Quick stats, there’s about 120 longevity biotech companies active, depending how you count it. On my website, Longevity List, I’m only looking at diagnostics. If you look at Karl Pfleger’s website, agingbiotech.info, it’s maybe close to 170. How much funding has there been, today, it’s about $9 billion over 120 companies.

There’s 40-plus longevity clinical trials by these companies, and there’s about 12 more longevity-focused VC firms, and four mega-companies called discovery companies, or companies that have many smaller companies in their portfolio. We’ll get to that in a second.

Just a graph of what’s going on over time. Obviously, there’s been tremendous growth in active longevity startups over the past few decades. Geography wise, it’s still very much dominated by the U.S. and the West Coast, obviously on the East Coast as well, Boston and San Francisco, San Diego, those areas. Switzerland has a couple, which is great, and obviously, the UK. anti-aging clinical trials.

This Gantt chart was taken from my website, longevitymarketcap.com, I have a clinical trial tracker there. We have about 40 or so clinical trials, most in Phase 2, no approvals yet by the FDA, we’re still really waiting for that first zero to one in aging therapeutics. Once we get there, I think that field will really open up after that point. Of course, you should check out lifespan.io’s Rejuvenation Roadmap, which is also a really great resource.

I’ll just quickly skip over this because it’s just looking at longevity venture capital. There’s just a bunch of new funds, they’re getting bigger. In 2011, there was only one fund, Laura Deming’s longevity fund. Now, there’s 12, and funds are getting much bigger; you can definitely check that out and new funding methods like crowdfunding or DAOs like with VitaDAO.

Discovery companies. There’s four big discovery companies that operate in a hub-and-spoke model, there’s Juvenescence, Life Biosciences, Cambrian Biopharma, and Rejuveron, and it’s a new model; they can invest on longer timescales and centralize their resources, which is great.

Accelerators and infrastructure. We have accelerators: Longevity fund has AGE1, Foresight Institute has their Healthspan Extension Accelerator. We have apprenticeships, Martin Borch Jensen at Gordian Biotechnology has a bunch of young longevity padawans that he’s training. There’s internships at Loyal, which seems really great.

Community ecosystem, so the stuff that we’re building at On Deck with our On Deck Longevity Biotech Fellowship, trying to connect people who are just really passionate about this space, whether they’re founders, investors, or early hires. These are all things that are up and coming, and we’re super optimistic about that.

Let’s talk about the future of longevity. Why not? Let’s speculate. Some things that are pretty obvious: there’s been a lot of rumors about seismic funding, about two to three really big initiatives will be announced, potentially this year. I hear in the fall, that’s when the first one is going to be announced, that it’s going to be on the scale of billions of dollars per year, so that’s really great. More money will just accelerate things in this area.

More mature assets, eventually getting to the clinic. I think that’s happening. Definitely some of the more mature senolytic companies are going to get to trial. The TAME trial, obviously everybody’s waiting for that. There’s going to be a couple of clinical trial readouts from Unity and BioAge in the coming months and year.

Then, hopefully, we can get our first approval. That would be just incredible and would completely changed the paradigm. I think, in general, just different modalities, like cell and gene therapies playing a bigger role, I think that’s just something happening in biotech in general. Just more awareness in general.

Just to pause for summary, how we got here. We just took a look at the historical context from the science, the first wave of startups to growing legitimacy. The lessons learned about investors pivoting people away from longevity. Science being early, and sometimes it takes a while for these things to be worked out. We looked at the current landscape and where we’re going in the future.

Roadblocks to progress. Let’s just take a look here, what do we need in longevity? I could say biomarkers, but everybody knows that. What I want to really focus on is that we need more longevity startups. If you think about just how many longevity startups there are, we have 120.

Compare that to oncology: we have 3,200 startups active in cancer. Just the sheer scale of the problem of aging and how it is a risk factor for cancer and Alzheimer’s disease and cardiovascular disease. It’s just obvious that we need more startups, maybe like an order of magnitude more, in longevity.

How do we create more longevity startups? Number one, we can go really high up in the pipeline and increase awareness about longevity, because not that many people even know that there are companies developing therapies to target aging. That’s number one. Write about it, tweet about it, volunteer at lifespan.io, make podcasts, make YouTube videos, TikToks, whatever, but that all helps.

Number two, maybe we can make it easier for people to get involved in longevity startups. That’s what I’ve been really focused on. With the On Deck Longevity Biotech Fellowship that we’re launching, we’re really just focused on community, going to find the people who are really passionate about doing something about aging.

That could be a founder, it could be aspiring founders, it could be operators, people looking to join a longevity biotech startup, or it could be investors who want to get deeper into this startup ecosystem. We’re just bringing them all together in this community.

We’ll have really awesome, great programming throughout the year. It’s remote-first about two to three hours of programming a week, a lot of social and networking things. We’ll also have some in-person events, pending COVID.

We’re taking applications for people who are interested in longevity biotech startups. Our deadline is August 31. We have scholarships available. If you want to check us out, go to beondeck.com/longevity-biotech.

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