#202 – The cutting edge of anti-ageing science (Venki Ramakrishnan on on The 80,000 Hours Podcast)

By 80000_Hours @ 2024-09-19T22:41 (+13)

We just published an interview: Venki Ramakrishnan on the cutting edge of anti-ageing science. Listen on Spotify, watch on Youtube, or click through for other audio options, the transcript, and related links. Below are the episode summary and some key excerpts.

Episode summary

In today’s episode, host Luisa Rodriguez speaks to Venki Ramakrishnan — molecular biologist and Nobel Prize winner — about his new book, Why We Die: The New Science of Aging and the Quest for Immortality.

They cover:

• What we can learn about extending human lifespan — if anything — from “immortal” aquatic animal species, cloned sheep, and the oldest people to have ever lived.
• Which areas of anti-ageing research seem most promising to Venki — including caloric restriction, removing senescent cells, cellular reprogramming, and Yamanaka factors — and which Venki thinks are overhyped.
• Why eliminating major age-related diseases might only extend average lifespan by 15 years.
• The social impacts of extending healthspan or lifespan in an ageing population — including the potential danger of massively increasing inequality if some people can access life-extension interventions while others can’t.
• And plenty more.

Producer: Keiran Harris
Audio engineering: Ben Cordell, Milo McGuire, Simon Monsour, and Dominic Armstrong
Content editing: Luisa Rodriguez, Katy Moore, and Keiran Harris
Transcriptions: Katy Moore

Highlights

Is death an inevitable consequence of evolution?

Luisa Rodriguez: Are there clear reasons why you wouldn’t get an animal evolving not to die? Including more complex ones like humans?

Venki Ramakrishnan: I think the main reason would be that there’s no selective pressure on evolution to extend our longevity. Rather, what evolution really optimises for is for “fitness” — which is the biologist’s term for the likelihood that you’ll successfully pass on your genes. So evolution is selecting for reproductive ability.

Now, in the course of an organism, there’s always a tradeoff: how much do you invest in growth and reproduction versus maintenance and repair which will make you live longer? And the equation is different for different species.

If you take a small animal like a mouse, it hasn’t been selected for longevity: a mouse only lives for two years. And the reason is that it’s not an advantage to select for lots of genes that are involved in maintenance and repair, because a mouse is going to be eaten by a predator long before it gets old. So there, the selection has been for rapid growth and maturation and reproduction — so that before it dies of other causes, like being eaten or starving or in a flood or something, it actually has a chance to mature and reproduce.

If you look at larger animals, they tend to live longer, because they are more resistant to predation. And there, it’s an advantage to have them live longer because they have a longer lifetime over which to reproduce. So there’s a rough relationship between size and longevity and lifespan in these animals.

And I’ll give you another curious example, which is a bat called Brandt’s bat. Now, this bat can live for 40 years, but it weighs about the same as a mouse. How come a mouse lives only two years? Well, it’s because the bats can fly, so they can escape predation. They can also forage over a much wider area, so they’re not likely to starve like a mouse is. So for all these reasons, it’s worth it for evolution to select for longevity in a bat where it wouldn’t be in a mouse.

So death is not programmed; it simply happens because we accumulate damage. But in some species, it’s not worth investing in repairing all that damage. In other species, it is.

How much additional healthspan will the next 20 to 30 years of ageing research buy us?

Luisa Rodriguez: I’m curious what kind of gains you think we will get from ageing research in the next, say, 20 to 30 years?

Venki Ramakrishnan: If I had to venture a guess, I would say that some of these nutrient-sensing pathways, possibly removing senescent cells, are all things that might help us with some of the symptoms as we age.

I don’t know how much they will actually buy in terms of lifespan. It may be that they simply keep us healthier for a bit longer, or even significantly longer, but that we all end up dying at about that same age. It could be that it pushes everything back a little bit, so we start living longer, but at the end we have the same decline that we have now with all of the morbidities and problems of old age, but that we’ve postponed it by these treatments.

So I wouldn’t be surprised if more people started living into their 90s, rather than, say, high 70s or low 80s today. Maybe more people start living into their 90s. That I think I wouldn’t be too surprised about.

Luisa Rodriguez: And do you put much weight on ever increasing lifespan super significantly? Doubling it, for example?

Venki Ramakrishnan: I think that would require really major breakthroughs in ageing. A number of gerontologists pushed back against all the hype in ageing, and one of the things they did point out is that the brain is a particularly hard organ in which to prevent ageing. What would you do about the brain? Because neurons don’t typically regenerate at the same rate. It’s a very low rate of neurogenesis. So what would you do about an ageing brain?

That’s a hard problem to tackle, and that today nobody seems to have a really good answer to. If we’re very lucky, we’ll be able to prevent diseases like Alzheimer’s. But I think really preventing ageing of the brain could be a big challenge, and that would have to be overcome before we can think of extending that lifespan significantly.

The social impacts of radical life extension

Venki Ramakrishnan: I think if people live longer, that means a larger fraction of society will consist of older people relative to younger people. So that ratio of young people to old people will change. It’s particularly true that fertility rates continue to drop. Most Western societies are well below replacement age — and countries like the US are only able to maintain population because of immigration, otherwise the US population would also start to decline.

This means that you absolutely need to keep older people healthy, otherwise they’re going to be an incredible burden on the rest of society. It’s also not going to be pleasant for them to keep living longer if they’re not going to be healthy. So there’s a lot of effort to keep them healthy.

It might involve things like work. I mean, what are all these people going to do? You can’t have a smaller and smaller fraction of the population supporting old people who are in retirement. So there’s the question of what’s going to happen to careers, and will you have to change retirement age? I know in the US there isn’t really a formal retirement age, but are you going to change expectations of how long people can work?

There are lots of issues with this. One is that we all face cognitive decline. Cognitive decline starts from when we’re very young; it doesn’t just happen when we’re old, although it’s more obvious when we’re older. But in the early part of our lives, we compensate for cognitive decline with knowledge and experience. So we’re often more productive: even if we have cognitive decline, we’ve compensated in other ways.

But there reaches a point where we’re not gaining much in terms of knowledge or experience; we already know a lot and we’ve experienced a lot and we’ve plateaued out there, but we’re undergoing cognitive decline. And then you do see real decline. So that’s one problem.

Another problem is older people hang on to their jobs, whether it’s a faculty job, or being a corporate executive, or being the chief executive of the United States. There’s a question of generational fairness, because you are actually preventing somebody younger and more able from filling that job. So I think this is going to create a number of issues in society — both in terms of making society more livable and accessible for older people, but also what to do about these things.

Luisa Rodriguez: Is it kind of naive to think that the economy will expand because there will be more overall workers, and that it’ll kind of figure out how to allocate that labour such that the economy grows, and that’s actually a good thing?

Venki Ramakrishnan: It is possible. I mean, we live twice as long as we did, on average, say, 150 years ago. And nobody would want to go backwards and say we all want to have a life expectancy of 40.

So I think it’s possible, but it’s an adjustment that needs to be made, and it needs to be thought about and it needs to be done in a way that’s fair across generations. And maybe the economy will expand, but if the population doesn’t expand, it’s not clear that the economy will continue to expand in the same way. Yes, you may get productivity gains by other methods — AI or automation, things like that — but there is a real question about what the effects will be.

Could increased longevity increase inequality?

Venki Ramakrishnan: I think almost every medical advance has benefited rich people before it’s benefited everybody else, and often rich countries before it has benefited poor countries. You can see that all the way from early measures like public health and sanitation, to fertilisers and food supply, to antibiotics to cures for cancer, heart disease, et cetera.

The result is that today, even in rich countries, the top 10% economically live almost 15 years more than the bottom 10%. My stepdaughter, who’s in public health in New York, pointed out that if you looked at New York City alone, people in the richest ZIP code live 35 years more on average than people in the poorest ZIP code.

Of course, this is not just due to ageing, because a lot of it is due to infant mortality, poor health, poor healthcare throughout their lives, crime, poor nutrition — so there are many factors that affect this. But longevity and ageing, I’m sure, is one of them — and many of the things that we can do to stay healthy in old age are not as easily available to poor people.

So there is this disparity. Now, imagine if you have treatments that are very sophisticated and only wealthy people can afford them, or people with good insurance: then you will dramatically increase this disparity in life expectancy or lifespan. And it’ll have knock-on effects, because the rich people will live longer, and the wealth you accumulate roughly depends on how long you live. They’ll keep accumulating wealth throughout their lives, and they will pass on greater wealth to their offspring, and then those people will also live longer.

So you can just see how you can get a divergence between rich and poor. And you might get two classes of citizens: rich people who live very long and have healthy lives, and poor people who have short and relatively unhealthy lives. I should point out that even today, not only do the rich live longer, but they live a larger fraction of their lives healthy: their healthy years are even more than the poor. So the poor not only live shorter lives, but they live unhealthier lives as well.

You can see how all of these things are going to potentially create big differences — unless we do things to combat that. For example, by having universally accessible healthcare and good environments, education, preventive health, public health, primary care. If we were able to distribute these evenly across the population, then that would be a big help.

Luisa Rodriguez: Yeah. So given those risks, do you have an all-things-considered view on whether extending human lifespan and healthspan is worth doing?

Venki Ramakrishnan: I think it’s not a question of what I think. If scientists find out ways to extend lifespan in a healthy way — I mean, nobody wants to extend lifespan and just be miserable for 30 years — but if they can extend the number of healthy years that we live, it’ll be impossible to stop. Because once the technology is there, who’s going to say, “I’m not going to use it”? If somebody came to you with a pill and said, “If you take this pill, you’re going to have 10 extra healthy years of life,” most people would take it. So I think it’s not really something you can… Once knowledge is out there, you can’t unknow things, and you can’t deliberately say, “I’m not going to use it” — because other people will use it, even if you don’t.

Does injecting an old body with young blood slow ageing?

Venki Ramakrishnan: Well, there’s no question that when they connected an older animal, like an older rat, to a young rat, the blood of the young animal benefited the older animal. But it’s also true that the blood of the older animal had a detrimental effect on the young animal. There was at least one study which said that the detrimental effect of the old blood was actually greater than the beneficial effect of the young blood. Which means that as we’re ageing, we are accumulating factors that are not good for us, that maybe were useful early in life — this goes back to evolutionary theories — but maybe later in life, they’re not so beneficial to us. They’re hanging around because we evolved that way.

So that has led to the idea that you could look for factors in blood that have beneficial effects. In that case, you could find out how they worked and maybe try to mimic the same effect. Or you could also find out what the bad actors were, the things that caused problems in old blood, and figure out ways to eliminate them.

So both are possible, and there’s a lot of work being done in the area. As with all these ageing findings, it’s not prevented people from jumping the gun. There are companies that sprung up that took blood from young donors and sold them to rich old men who wanted to live longer. You get these sort of bizarre things happening. And it just tells me that, of course, none of us wants to get old and die, but there are people there who are very rich, and they’ll do anything they can to stay young if possible, and preferably not age and certainly not die. And they’re not necessarily ready to wait for the evidence because they feel that by the time the evidence comes along, they might be too old and they might die, or might already be dead.

So I can understand their psychology, but it’s not a very healthy situation for the field.

Luisa Rodriguez: Out of just curiosity, given that they’ve already done it: for the individuals who have received blood from younger people, is there any reason to think that it’s helped them?

Venki Ramakrishnan: I think there’s absolutely no evidence yet that it has helped them in any way. The best case is Bryan Johnson, a tech billionaire, who spends $2 million a year on various anti-ageing measures — including trying all these things, and also measuring lots of data on himself. He’s a data freak, and he thinks of himself as doing a service to the research community by being a guinea pig for all these potential avenues.

There was a period when he actually received blood transfusions from his son, and I think also gave blood transfusions to his dad in a three-way exchange or intergenerational exchange. But what I read was that he didn’t notice any improvements in the markers that he was measuring, and eventually dropped the transfusions. Although I believe he said that in principle, the principle is still true — which I agree with. The principle is true in the sense that there are these experiments.

But again, you have to wonder how efficacious they are. Maybe young blood doesn’t really help you much. Maybe it’s the removal of the old blood that actually helped. So I think people need much more research to clarify what is going on.

Freezing cells, organs, and bodies

Venki Ramakrishnan: People have worked out procedures to freeze cells. For example, biologists routinely freeze all kinds of cells, including human cells, and then know how to thaw them and they’re still alive and can function. You can even do that with certain tissues. You can do that with embryos. People freeze embryos. Women will often freeze their eggs. They’ll freeze their eggs if they’re going through chemotherapy, so that they can still, after they’ve finished having chemotherapy, have children.

So there are all sorts of legitimate uses of cryogenics. Now, people are trying to figure out how to freeze larger and larger entities, biological entities like tissues or organs. It’d be great if you could freeze organs and store them for future use — but the reality is that people haven’t frozen even a small animal, like a mouse, and resuscitated it into a live mouse. And I think that’s a real problem. So how do you do that to an entire human being?

It hasn’t stopped companies from offering services where they’ll take your body and freeze it — or in some cases, they will freeze only your head, because there’s this extreme idea that, well, our consciousness is all in our brain; we don’t really care about the body. We just want to be existing as a conscious person. How would they even live without a body, even if you somehow thawed that brain? People say, “I’ll dump that brain into a computer, and then I’ll exist as a computer entity.” Well, what if you dumped it into two computers, then are there two of you? Which one is the real you? It creates all sorts of silly logical contradictions.

The reality is our existence and consciousness is very intimately tied to the rest of the body as well as the brain. The brain interacts with our body: it interacts through hormones and various other signals. It doesn’t exist in isolation.

Now, these companies don’t actually promise that you’re going to be able to successfully resuscitate the body. They simply say, “We will freeze your body using this protocol, and it’ll cost you x amount of dollars. And in return, we’ll keep it frozen for x number of years.” So these people who are into this are betting that eventually some technology will come along to thaw this and somehow fix it all.

Luisa Rodriguez: Do you have a sense of what’s being done to close that gap?

Venki Ramakrishnan: I don’t think it’s possible. There are people who, in the case of a mouse, one thing they have done is they’ve been able to freeze the connections: they’ve been able to preserve the connections between the neurons in a mouse. But the way they do that is by injecting antifreeze in the mouse while its heart is beating and it’s still alive, and this antifreeze then goes into the brain and kills it. So effectively, the procedure kills the mouse, and then they can freeze it. But even that simply preserves a connection; it’s not preserving the state of the neurons.

So there’s no guarantee. The idea that you could thaw this brain and it would work like a mouse brain, there’s absolutely no evidence for that. All you can say is if you want to look at the connections in the brain, you could do that with this procedure. It doesn’t mean that the state of the brain — which in some ways reflects its state at the moment of death — would exist. And the other thing is that people would do this when they’re old. You’d be pickling your old brain. This is not some youthful brain like when you’re 20 or 25.