- The timing is now right to work on longevity due to advancements in tooling and available technology.
- The speaker was motivated to work on longevity due to personal experiences with aging relatives and a desire to solve cancer.
- The lack of funding for aging therapeutics prompted the speaker to start a fund to support research and drug development in the field.
- Over the past few years, there has been a significant increase in investment and interest in longevity research and companies.
- The speaker does not have a clear recommendation for diet and supplements for longevity, but suggests low protein and sugar intake and intermittent fasting as potentially beneficial.
- There is a secret list of on-market drugs that the speaker's fund believes may have an impact on lifespan, but it is not publicly released.
- Studies have shown significant increases in lifespan in worms and mice through genetic manipulation and caloric restriction, but the effects may vary depending on genetics and other factors.

- The speaker's grandmother is in her mid-nineties and has lived a long life.
- The speaker recommends prioritizing sleep for good health.
- Feeling better doesn't necessarily mean something is good for you.
- There is limited data on aging in humans, but a trial is being conducted to test the effects of a diabetes drug on aging markers.
- The speaker is more interested in studying the animal kingdom to learn about longevity.
- The speaker believes that impacting lifespan by 3 months to 10 years is possible, but a larger impact will require advancements in tooling and technology.
- The speaker is unsure if there are currently any therapies that can result in unbounded longevity.
- The speaker believes that longevity research is important and should be pursued ethically.
- The speaker started the fund to cure diseases like cancer and Alzheimer's, and believes it makes sense to cure these diseases if possible.

- The speaker believes it is important to cure diseases and work on aging.
- They discuss two different perspectives on the world: one that sees limited resources and one that sees unlimited resources.
- The speaker leans towards the latter perspective and believes in exploring the cosmos for unlimited resources and energy.
- They discuss the potential impact of immortality on society, including decreased motivation and innovation.
- The speaker questions the assumption that fear of death is the core motivator for people and argues that there are other factors that drive motivation.
- They also discuss the idea of cognitive enhancement and its potential value in longevity.
- The speaker mentions the importance of individual choice in cognitive enhancement and expresses interest in the topic.
- They discuss the use of psychedelics for cognitive enhancement and mention the idea of stoicism and caloric restriction.
- The speaker talks about the challenges of maintaining energy for creatively demanding side projects.

- The speaker discusses the unpredictability of success and the importance of defining what winning looks like before starting a project.
- They mention their personal motivation hack of not spending time with people who annoy or stress them out.
- The speaker also talks about keeping expectations low and finding happiness in what they can control.
- They discuss their move from New York to California and the differences in culture and opportunities.
- The conversation shifts to the vilification of the tech industry and the concentration of wealth in a few individuals.
- The lack of founder-driven companies in biotech is highlighted, with the funding environment favoring venture capital over founders.
- The speaker mentions their own firm's focus on supporting founder-driven companies in the biotech industry.
- They discuss the parallels between the enabling technologies in software and biotech, such as AWS and the drop in cost of sequencing.
- The conversation ends with a discussion on the number of people in labs who want to start companies and the lack of available funding for new ventures.

- Lack of awareness and education about entrepreneurial opportunities is a major barrier for many people
- Pioneer.app is a project that aims to find talented individuals and provide them with support and resources to pursue their projects
- The project includes a tournament where participants work on their projects for 30 days and are voted on by the community
- Selected individuals receive a $5,000 grant and join the Pioneer community in San Francisco
- The podcast host discusses the importance of confidence and how systems like Pioneer and YC can provide that confidence to aspiring entrepreneurs
- The host also reflects on the authenticity of his podcast and the desire to make it more reflective of himself and natural conversations

- The speaker discusses the artistic nature of math and science, contrasting it with the perception of them as purely logical processes.
- They mention Newton's interest in alchemy and the Bible, highlighting the artistic and mystical aspects of scientific pursuits.
- The speaker raises questions about the next step in human lifespan and the importance of understanding what it means to be alive.
- They discuss the potential for extending fertility windows and the concept of menopause in relation to longevity.
- The percentage of longevity attributable to lifestyle choices versus genetics is estimated to be around 11%.
- The speaker discusses the practice of parabiosis (blood transfusion) and its potential impact on longevity, noting the lack of conclusive studies on its effectiveness.

- The speaker discusses the misconception that longevity is solely related to vampires and the focus on one drug, rapamycin, as a means to live longer.
- Rapamycin has multiple effects on the body, including its impact on the protein mTOR, but it also has side effects and is not recommended for continuous use.
- Some doctors suggest pulse rapamycin, taking it in large doses but on a schedule, as a potential option for longevity.
- There are companies working on developing safer versions of rapamycin that have the same benefits without the negative effects.
- Testosterone and growth hormone are also debated for their impact on longevity, with some suggesting they can improve healthspan but may not be beneficial for overall lifespan.
- The speaker mentions the correlation between being smaller and longevity, as seen in dwarf mice, but notes that there are other factors involved.
- The idea of replacing organs with new organic ones before they fail is discussed, but there are many factors and risks to consider.
- The speaker mentions a personal experiment with a cookie diet and the importance of understanding the effects of different foods on the body.
- The speaker concludes by discussing the difficulty of determining the optimal diet and the importance of considering historical knowledge for baseline health.

- Advancements in tooling and technology have created a favorable environment for longevity research.
- The speaker's personal experiences with aging relatives and a desire to solve cancer motivated them to work on longevity.
- Lack of funding for aging therapeutics led the speaker to start a fund to support research and drug development in the field.
- There has been a significant increase in investment and interest in longevity research and companies.
- The speaker suggests low protein and sugar intake, intermittent fasting, and prioritizing sleep for good health.
- The speaker's fund has a secret list of on-market drugs that may impact lifespan, but it is not publicly released.
- Genetic manipulation and caloric restriction have shown increases in lifespan in worms and mice, but results may vary.
- The speaker believes impacting lifespan by 3 months to 10 years is possible, but larger impacts require advancements in tooling and technology.
- Longevity research is important and should be pursued ethically, with a focus on curing diseases like cancer and Alzheimer's.
- The speaker discusses two perspectives on the world: limited resources and unlimited resources, leaning towards the latter.
- The potential impact of immortality on society, cognitive enhancement, and the challenges of maintaining energy for side projects are discussed.
- Lack of awareness and education about entrepreneurial opportunities is a barrier for many people.
- Pioneer.app aims to support talented individuals with resources and grants for their projects.
- Confidence is important for aspiring entrepreneurs, and systems like Pioneer and YC can provide that confidence.
- The artistic nature of math and science is highlighted, along with questions about the next step in human lifespan.
- Parabiosis, rapamycin, testosterone, growth hormone, and organ replacement are discussed in relation to longevity.
- The optimal diet is difficult to determine, and historical knowledge is important to consider for baseline health.

Laura Deming - https://twitter.com/LauraDeming - is a partner at The Longevity Fund. They invest in companies that will allow us to live longer and healthier lives.

You can learn more about them at https://longevity.vc/

The YC podcast is hosted by Craig Cannon - https://twitter.com/craigcannon

***

Topics

00:00 - Why focus on longevity now?

1:50 - How did Laura get started in longevity?

3:00 - Why raise a fund?

5:30 - What does Laura do personally for longevity?

8:45 - Worm and mouse studies

10:20 - Craig's personal habits

12:15 - Human studies

15:00 - Mica asks - Do you think immortality is going to be achieved by: 1. Curing all disease and stop aging so we could live with our own bodies forever 2. OR is going to be something like porting our brain, "mind" to a computer/robot?

17:15 - Most likely strategies to increase lifespan

19:25 - Ryan Hoover asks - Ask about the ethics of longevity. Jack J. Fernandes asks - Do people actually want to live longer?

21:20 - Mica asks - How would immortality change society? Wouldn't we become more complacent? Since we have "forever" to do things wouldn't that diminish our rate of innovation? And since less new individuals are being created we would have access to less new ideas. We would just stop creating new Newtons, Einsteins, Mozarts…

24:30 - Cognitive enhancement

25:30 - Daily habits

33:50 - Tech environment changes in the past 5-10 years

39:00 - What percentage of people in labs want to start companies?

41:15 - Pioneer

43:35 - Confidence

45:30 - Podcasting

48:50 - Choosing media to consume

51:55 - Sam Betesh asks - The last thing that led to a step function change in average life span was germ theory. What new areas of research might provide the next step function change?

54:45 - Extending fertility windows

57:00 - Jason Choi asks - What % of longevity is attributable to lifestyle choices vs genetics and the progress of technology in influencing both.

58:15 - Fatih asks - is blood transfusion a thing or just a hoax

1:00:20 - Rapamycin

1:02:05 - Testosterone

1:04:15 - Chris asks - Aubrey De Grey, IIRC, mentioned a number of times that we might, in the future, replace organs and tissues with new organic ones before they fail. Is this actually a reasonable idea, or is it more likely that we'll replace them with synthetic ones, if we replace them at all?

1:05:45 - Mica asks - Laura did a "cookie diet" for one month. Why did you do it? How did you feel? Doesn't it go against all the research on longevity? ;-)

1:07:45 - Is Laura actually not doing anything strange in her diet?

So, Laura, why now in terms of longevity?

What's happened to make you raise a fund and start investing in research and companies?

Yeah, so we think this is an insanely important part of the story because if you were Aristotle and you were like trying to start longevity fund, you would have a terrible time and feel like you're the worst idea.

Like why now, for the first time in like 2000, 3000 years is it the correct time to work on longevity.

To us, a lot of that comes back to tooling, and what's available for us to use.

Prior to the 1900s, if you wanted to impact biology, maybe you should have been a physicist.

You worked on optics, helped make the first microscope.

So, you know, there's so much that comes from physics and other disciplines into biology to push it forward.

But then I think in the 1900s, something kind of fascinating happens, which is that for the first time, there's kind of this acceleration of tooling, right?

X-rays, NMR, all these things, you know, the cathode ray tube discovered mass spectrometry, but, you know, by this guy trying to find the mass of the electron, which is so cool.

And so all these physics tools started coming online, but then also more biology-driven tools.

And so really, I think, and we can get into this more specifically maybe later time, but kind of what's excited us is just seeing the tools available to characterize life become available for the first time ever.

For all millennia, you had Darwin and Mendel talk about genetics.

And there was no knowledge of what was actually going on at the ground truth level.

And in 1953, for the first time, you have the link between molecular biology and what we're looking at with microscopes and genetics and this sort of concept of heredity, which is just super exciting.

Well, I mean, A, I think I was born in a very lucky time.

I think you always have to be cautious or, I guess, a little bit concerned if you believe that about yourself.

But then I think also, as a kid, A, just had a lot of relatives that were aging, and that was very striking.

And I remember talking to my dad about this, and I was like, oh, I want to solve cancer.

He was like, well, cancer is a subset of aging.

So if you want to solve cancer, you just solve aging and it takes care of all these other things as well.

And that coupled with hanging off my grandma, she was like, that just kind of made sense to me as a kid.

I was like, OK, well, I guess I'll go solve aging then.

Because cancer is not the number 1 cause of death in the US, right?

Well, you know, it's just like if you look at all the age-related diseases, you know, past the strain point are driving kind of like the majority of sort of natural deaths, so to speak.

So, you know, like once we got rid of infectious disease, like it really became the case like aging, which wasn't previously like necessarily the biggest issue, sort of rose to the forefront.

And so that kind of, I mean, it sort of just I think made sense to a small child that that was important.

And so why raise a fund rather than just go for curing cancer?

in a good way, like emperor has no clothes, extremely simplistic.

You have to understand, so I was at MIT, and I was a sophomore.

And I was also 16, and I had maybe $1,000 in my bank account.

And so knowledge about the financial industry, relatively low.

My dad had been a public investor, so I kind of knew a lot about the idea of investing in things like that.

And I'd worked in aging labs for maybe 4 years.

And I think the striking thing was just there was just no money to make drugs.

And it's kind of hard, you know, when you're in a lab, you just have no idea what's going on in the outside world.

And so I would ask venture capitalists, like I would call up a few in the phone book, and a few responded, and so I'd have these random conversations.

And I'd just be like, I'm just curious, I'm a student, can you tell me more about how this industry works?

And none of them had heard of aging therapeutics.

They were kind of like, Asian therapeutics?

And so that was just very striking that something that I personally believed on the technology, not just from a mission perspective, but on the technology side was super exciting, was generally not really looked at a lot by these folks who are supposedly the great translators of technology.

The first ever mutation found to really extend the lifespan was 1983.

And so really the field started about like 20, 30 years ago.

It's like, it made sense, like, if you think about like how long it takes for a field to get traction, like become known, like, okay, there may be like less than 100 good labs in this space.

Maybe like people just like haven't had enough time on like the venture or like investment side to understand that this is really cool and important.

Then it made sense that you might want to start a fund if that were the case, to help more drugs get started out of the space.

In other words, the big pharmaceutical companies are not investing in these pilot ideas.

You know, 7 years ago, there were like maybe like 3 companies have been started or so that had like the aging brand on them.

Like ArchVentures was 1 of the few that were like taking risks.

There's like maybe 10 million invested like that year in total into like the space, right?

And like in the past 4 years, we've had like 10 billion plus.

Like it's very, very striking to have watched it go from like 0 to like what it is today.

So you have not a million but many questions for you.

I think like on top of the list for me is what you do personally.

This is probably the most common question.

And I think all my friends will always say that I answer this terribly.

Because I'm kind of like, I come from a semi-scientific background.

And so we like to get to the ground truth of things.

If you start reading mouse studies on longevity, you will find mouse studies that say if you decrease...

They've done this really cool experiment where you take fat and sugar and protein and you decrease the level of each of them to keep the total calorie intake the same.

You can kind of test which component of diet is contributing to longevity.

And they did this, and they did a full matrix, and they did lifespan studies for each of the different proportions.

And what they found from that study in mice was that decreasing protein was the number 1 thing that increased longevity.

And so from that, you might infer that maybe less protein is good.

But at the same time, it doesn't seem like maybe if you work out a lot, that would be different.

And so I've come to the conclusion that I have some theses about what is good and what is not good.

But as a scientist, it's really hard to say that there's a good real hypothesis there.

Despite reading probably more papers on this than like most people in the world.

It, it really is something where, I, I don't see things that I think are extremely clear kind of like, movers for longevity, on like a diet level.

Obviously that like aren't confounded by other things.

I think right now it's just kind of like the sort of like bare minimal like try to eat low sugar.

I'm personally trying low protein just because I think that is somewhat supported by kind of like literature.

But low protein is like a gram per kilogram per day?

It's like what is the correct per person and also if you exercise.

I actually once tried to calculate out if you exercise, how much protein would be required to replenish all of your myosin and actin proteins.

I think that there might actually be up to a hundred fold increase in power, like in your muscles, where like, if they all fired at the same time, you get like, you know, sort of a lot of power.

But any, but I mean, I, you know, I just, I don't have any strong recommendations on diet.

Like, I really, like, I've read basically all the studies.

And I think maybe low protein, low sugar are both good.

Like intermittent fasting seems to be like somewhat supported.

I think it's kind of hard to maintain if you like, you know, have a graduating sleep cycle.

But Yeah, I wish I had better recommendations for that area.

And in terms of supplements, are you doing anything?

There's a variety of people who recommend everything from NAD+, all the way through to like metformin for the kind of more adventurous.

I think that, so we actually have a secret list at the fund of like on-market drugs and things that we think, based on our body of evidence, might be having an impact on lifespan, and we're monitoring them.

Some of them I personally think would be intriguing to take.

We don't release that list just because we were afraid that if we did, somebody acted on it and it didn't work out well for them, that's like a terrible thing to do to like them.

But we have a secret list of things that we think are like interesting.

And I think for the ND+, though, there's some evidence of like positive effect there, but we haven't seen great lifespan studies showing like a large increase in lifespan.

Because yeah, in the worm and mouse studies there have been like, you know, a hundred percent increase in lifespan, right?

So, worm studies, we've gotten up to tenfold reported, you know, possibly more.

That's by decreasing a gene product though.

So that's kind of like if you want to go and take a gene therapy or we had such a thing, from birth possibly like that would work, but probably the effect would be a lot smaller.

In mice we've got about up to a two-fold increase and that was a combination of a mutation and restricting the total cloric intake of the mouse.

On average, I think people will do CR to about 30% of normal cloric intake, but it really varies.

So if you take 40 different, And this is where it gets complicated.

You take 40 different, genetically different strains of mice and you change their diet in the same way, half will live shorter and half will live longer.

I think that there is, But I think it is a lot more sort of reliant on genetics and other things than we'd like to think.

So they've all lived, you know, about age 80 or above.

So, you know, hopefully, how about yourself?

What, what, what would you say the number 1 health hack that you'd recommend to your, your audience would be?

I mean, well, I mean, I've done a little bit of blood work, so everything's kind of anecdotal and based on feel.

And then I realized that I had developed this entire vocabulary around cheating.

So for example, if I was traveling, it was like cultural meat.

And then if I was over your house and you made chicken or something, I'd be like, whatever, I'll have it.

And at the point, it was like twice a month.

So then I started eating more protein, but really just more eggs.

I will say that actually 1 thing that's interesting on the health front, I think people have this like intuition that when they feel better, that's a metric for something that's good for them.

So if you look like a lot, to some extent, maybe you want to optimize robust, very cheerful lifespan, in which case, tautologically it is.

But most of the time, or a lot of the time, when you CR mice or you do other things, like make them live longer, so total number of years increases, they're not kind of like as happy on a day to day basis, like a little bit thinner, a little bit more lethargic in some cases.

So I think it's kind of like, you know, whenever someone says like, I really feel better because I'm doing X, I'm always like, oh, gosh, like, I wonder if that's like, the correct thing.

When people talk about healthspan, in my mind, it's very correlated to how I feel.

Like if I was going to do caloric restriction and every day would suck for 90 years I would opt out.

For instance like I know a lot of people who have experimented with like keto and other random diets and they're just caffeinated to the gills.

But 1 thing I've been curious about, like There seems to be relatively limited data on actual humans.

Is it even possible now or is everything so regulated?

Well, there is this fellow near Bars Light who's working on what's called the TAME trial and the point of that is to assay the effects of this drug, betformin, which is a very old diabetes drug, on sort of markers or biomarkers of aging that he has kind of like put forward.

And the cost for that will be about $60 million.

And if people do it, the idea would be, okay, well, here's a first pass at testing aging in humans.

The way that trial was sort of motivated was there was this kind of large finding that in hundreds of thousands of patients, or I think about actually 70,000 in that population, from kind of like a UK study, if you look retrospectively, people who had been taking metformin for decades, they had apparently a little bit better kind of health span.

The diabetics sit on this drug, even then their kind of non-diabetic counterparts who were not taking metformin.

And so I think that hard-studied studies have definitive evidence, but that kind of motivated all this sort of question asking of could we really nail down in humans at trial to test metformin in particular?

That said, I think that a lot of biologists will really kind of say, oh, it's very important to test things in humans.

If we could do that, we would be doing it all over the place.

But I think increasingly over the years, and maybe it's because I started out in worm biology, I'm more and more excited about the animal kingdom.

The animal Kingdom is just absolutely awesome.

We have 1 company in our current portfolio that's working on this, and they're amazing in fauna.

But there's such diversity of phenotypes, right?

And how can we learn from other animals as opposed to just our lowly selves?

Because for example, there's naked mole rats and rats.

Naked mole rats are pushing 30 on lifespan.

Their mortality rate at 30 is not going up.

So we're just watching these guys, waiting for them to start dying.

And then rats, which have very similar physiology, live maybe 3 to 4 years.

And so what on earth is different between these 2 animals, right?

I think it's also important because a lot of like your physician mathematicians and I used to be this way, we're always worried, what if there's like an inherent limitation on like the complexity level?

Or like what if given a certain complex system, a certain rate of metabolism, you have to die because there's some kind of theory about entropy increasing over time and that must strive, it's just too complex to really intervene.

But then these animals are basically the same size, have so many other similarities.

It would just be very hard to maintain like that theory and also accept this kind of like large differential longevity.

So someone asked a question that I thought was kind of funny.

So Micah asks, Basically, do you think immortality is going to be achieved by curing all diseases?

So in other words, like living forever, or like what's going to happen first?

That or are we going to just upload our consciousness to a computer and live forever that way?

I think that, so that is a question that I used to get very interested in.

Sort of like, well, you know, if you really care about this, like, you should be working on kind of like the biology.

I think so the way I kind of think about it, which is not a good answer, but it's kind of like a framework for thinking about this question is, I think about biology like a set of tools, right?

You can kind of see this in the kind of things that have become available recently for us to use to affect human health.

What I mean by that is prior to the 1900s, or even just the 1980s, or maybe the 1930s, the first time you really put this marker.

If you wanted to make a drug, it was a small molecule.

You got a plant, you found something from a plant that was useful, or you put some solvent in a wound, which we realized that's a bad idea.

There are always things that we would do.

But then in the 20th century, for the first time, we use proteins, insulin or antibodies created by our own bodies, or the bodies of the mice that we kind of clone them in, to treat disease.

And so we actually use something that came from life to treat a living organism.

We now, just in the past 3 years, have landmark approvals and viruses being used to blow up cancer.

Literally, these are called oncolytic viruses.

There's new drugs using genetically engineered cells.

You've probably heard of CAR-T and this whole immuno-oncology phenomenon, also stem cells being used.

And so I think the final frontier of all of that, like use of biology's own system to do cool stuff, is the brain understanding that system.

But I think to lead up to that, you kind of will do so many things that it may be the case that we kind of get there at the same time.

So, you know, that's like the final frontier and we solve it, but kind of like along the way, we've also kind of like done enough work on the other tooling kind of fronts that we get to kind of like to a kind of, you know, maybe we don't solve kind of like lifespan itself, but like longevity is definitely impacted by kind of like the work up to that time.

And do you sense that there's like a strong signal at this point as to what might be the way that we, you know, a bunch of people ask these questions, but like, you know, increasing lifespan like 20%?

had to put money on it, obviously you literally put money on it, what would be the most likely thing to take off in the next 50 years?

We have extremely strong confidence that it's possible to impact lifespan between, like, 3 months to maybe 10 years.

With what we have to infect, we're pretty certain that there are some things in the clinic already or on the market that with some probability are impacting lifespan.

Lifespan seems to be very malleable to a small degree.

I think the larger question is, well, A, how many of those can you put together to get kind of the maximal impact from that first wave?

And then B, our thesis is that none of those things will be sufficient on their own to result in an engineered lifespan.

So you have this first wave of things that kind of work, but they're kind of limited.

So then the question is, how can you go above that?

And we think that really all comes back to tooling.

And so that's where I don't know if we're Aristotle or we're Newton, or maybe in the best case scenario we're Einstein, or of someone today in the realm of physics in terms of going to the moon.

You've tried to go to the moon kind of like 1600s, it'll be a little bit hard.

More recently, maybe a little bit easier.

But like, I think that's where we have, we have some hope and optimism, but we're not as confident that there are things today that we'd point to to say, that's gonna result in kind of like unbounded engineered ability to kind of like impact longevity.

And that's why we also really care about tools when we think about investing in the space.

Not just the first wave of awesome therapies that will be available sooner, but maybe aren't as engineerable.

Right, so you're hedging if this is still a foundational stage.

1953, my argument for foundational stage would be this is the first time ever in history that we have the link between genetics and molecular biology.

Like, that happened in 1953, that's pretty landmark.

Maybe it's been 70 years, so you're like, well, what happened in 70 years?

Couldn't it just have happened right after 1953?

But I think that'd be the argument for like, that's why today makes sense from an engineering perspective.

And then ethically, Ryan Hoover asked about the ethics of longevity.

Another, Jack Fernandes, asked, do people actually want to live longer?

Do you have strong opinions on this or are you kind of stepping back?

And it was funny because when I started the fund, I never thought that people would ask those questions.

See all Y Combinator transcripts on Youtube

Increasing Healthy Human Lifespan, Laura Deming of The Longevity Fund