In one way or another, the superrich have always been trying to extend their lives. Ancient Egyptians crammed their tombs with everything they’d need to live on in an afterlife not unlike their own world, just filled with more fun. In the modern era, the ultra-wealthy have attempted to live on through their legacies: sponsoring museums and galleries to immortalize their names.
Today’s elite take life-extension a lot more literally. Skipping neatly over the matter of Bryan Johnson’s nightly penis rejuvenation regime, billionaires like Jeff Bezos and Peter Thiel are sinking big money into the prospect of therapies to extend our mortal lives.
But how would one do that exactly? In his new book, Why We Die, Nobel Prize–winning biologist Venki Ramakrishnan breaks down the biology of aging to examine what potential humankind really has for life extension. Ahead of speaking at WIRED Health this month, Ramakrishan sat down with WIRED to talk about the scientists and charlatans of longevity, and where he thinks the most promising interventions are when it comes to extending lifespan. This interview has been edited for length and clarity.
WIRED: As a biologist, your work focuses on how proteins are made. In 2009 your work on ribosomes, the site of protein synthesis, won you the Nobel Prize in Chemistry. But you don’t work directly on aging—how did you come to write a book that takes aging as its main subject?
Venki Ramakrishnan: Protein synthesis is one of the central drivers of aging. Although I don’t work specifically on aging, my overall field of protein synthesis is very central to aging. You can think of me as an aging-adjacent researcher. I’m looking at what’s going on in my neighbor’s back garden, if you like.
Why write the book now?
There are two reasons. One is that the tools of molecular biology are becoming more and more powerful every year. That’s leading to big advances in understanding processes, but it’s also giving us tools for tackling some of these problems. For a long time we actually had no idea what was involved in aging. Now we’re finding all sorts of the underlying causes for aging, and we’re in a position, perhaps, to do something about it.
There’s a huge amount of effort on what to do with an aging population. And of course there are people who would like to postpone the inevitable. All of this is leading to a huge amount of money, both from government and charities, but also a huge amount of private money, going into aging. This is creating a lot of very good work, but it’s also creating a lot of bad stuff. Shoddy or dubious work or even dubious promotion of things. There’s an excessive hype in the field.
I felt that somebody who is close to molecular biology but is not actually part of that community, without an agenda, could try and look and ask: What is known? What is unclear? What is promising? What is dubious?
Some of these longevity startups have Nobel Prize winners as advisors or directors, and they’ve attracted huge amounts of money. It’s not always clear how strong their science is, however. Does this distract from money going to the right places in aging research?
I certainly think it distorts priorities. Private equity is there to make a return on investment and so they want quick results, high market take-up. Science doesn’t often work that way; aging is complicated, it’s multifactorial, it needs careful long-term studies, it needs a clear consensus on how you even define aging.
And of course there are other priorities: infectious disease, pandemic control, global health, prevention of childhood diseases. If you ask Bill Gates, he’d have a whole different set of priorities. You could argue that those would actually improve average longevity far more than anti-ageing research, by reducing infant mortality and infectious disease and so on.
Right, a lot of the historic increase in average lifespan has been down to better nutrition, sanitation, neonatal care, vaccines, and so on. Today, we don’t think of cancer or heart disease treatments as ways to extend average lifespan, but in a basic sense isn’t that exactly what they are?
The thinking of the aging community goes like this: You take all the non-communicable chronic diseases that we get now: heart disease, cancer, dementia, diabetes. All of those diseases are highly correlated with age. Age is the biggest single risk factor for those diseases.
So their view is that we can tackle these diseases one at a time. Or the other way would be to say that the underlying cause is aging, and so you should tackle aging as a whole and that will have multiple effects.
That’s the theory. In practice, if you want to have a therapeutic intervention approved, you have got to have a disease. The US Food and Drug Administration is not calling aging a disease, nor is the World Health Organization, so what are you going to do clinical trials on? So typically clinical trials will be on some aspect of aging, like osteoarthritis or dementia.
Your book starts really small, right down to the molecular level, and then you go from here to build a whole theory of aging.
I think of aging as an accumulation of chemical damage to our bodies. It has to necessarily mean that initially the damage occurs to our molecules, starting with our genome and then to the proteins that the genes specify and make, and then to our organelles and the cell’s ability to get rid of defective products. That’s a big factor.
And then what that does to the cell itself, is that when the cell senses a certain amount of damage, it goes into this state called senescence. As you age, if the buildup of senescent cells is too large it causes real problems, you get inflammation, damage of tissue, and so on. And if stem cells, which are responsible for regenerating tissues, become senescent or die, you get a depletion of stem cells, and you have problems regenerating tissue—you have problems just maintaining the organism.
You have to view it as different levels of complexity, but at each level there are hallmarks of aging: Things that happen as we age, and they themselves accelerate further aging.
You also have this metaphor of organisms—or our bodies—being cities or societies. Each individual element isn’t enough to bring things grinding to a halt, but they can start a cascade where things go awry.
In our bodies cells are dying all the time and being replaced. We don’t even notice it, we certainly don’t think of it as death, even though millions of cells are dying all the time. So what do we mean by death?
Well, when we die the contrary is true. When we die most of our cells are alive, entire organs are alive—you can donate them to a transplant recipient. But you have a critical system failure, you have specific collections of cells that stop working, and that stops the whole organism working as a unit.
For us it’s the brain. We used to think of it as the heart, but really when the heart stops working, your brain and other organs stop working. So, aging is the accumulation of small defects until some critical system fails.
The city has lots of parts that have to work together. They function semi-autonomously—transport networks, postal system, restaurants, garbage disposal, they all work in a coordinated way. If that coordination fails the city will die, but if an individual thing fails then of course the city can repair it.
Let’s talk about epigenetics. You have this fascinating passage where you write about honey bees living for a year or two while worker bees in the same colony only live for six weeks. And yet these two creatures have almost identical genomes—it’s just that each has different genes turned on.
Normally as cells develop they’re turning on and off different sets of genes. Not all of it is epigenetics, a lot of it isn’t. But epigenetics is a way of preserving that state of gene expression in a more permanent way. It’s done by changing the patterns of modifications on our DNA, so some genes are silenced and others are allowed to remain active.
In some cases, as with histone modifications, you maintain some genes in an active state while other genes are inactive. You’re mapping a pattern of activity on your genes that can actually be inherited when the cell divides.
What does this have to do with aging?
The question is, what’s the purpose of these epigenetic modifications? One is to turn off all those genes that you don’t need, and that’s useful in development, because you want to specialize your cells. But with age you also accumulate epigenetic marks, and perhaps this was a mechanism to silence genes that might otherwise have a predisposition to cancer, for example.
These things might be useful early, but the consequence may be that as we get older we’re not functioning as efficiently as we could because of these epigenetic marks. That’s a theory anyway, it’s not been completely rigorously established, but there’s a lot of evidence for it.
There’s this dynamic where things that help the cell survive when it’s younger become a problem as it gets older. On that theme, you also write about these proteins called Yamanaka factors, which can in some ways return cells to a “younger” state. But they’re also associated with tumor growth. There’s this really fine line between rejuvenation and these cellular processes going awry. Why is that?
It’s a very good question. You may have noticed that aging and cancers have a real interplay. Many things that cause us to age later in life may have evolved because they prevent us from getting cancer early in life. For example the DNA damage response that sends cells into a senescent state.
That’s a good thing in early life because if you have DNA damage such that a cell could recombine its DNA in a way that causes it to become cancerous, that could kill the entire organism. Better to make that cell senescent or even induce it to commit suicide. But later in life you accumulate senescent cells and that causes you to age.
With the Yamanaka factors, a couple of them are oncogenic—they have the potential to cause cancer. The question is, can you give the Yamanaka factors transiently and maybe remove the most dangerous ones, so that they move cellular age back just a little bit, so the cells can then regenerate tissues, but not go all the way back to a pluripotent state where they can develop into all kinds of things including tumors.
That’s what the community is trying to do. They’ve done it in mice with some astonishing results, I would not have believed them if I hadn’t looked at the papers. But the safety and efficacy is something that really needs to be worked out.
After exploring the boundaries of molecular biology, you conclude that diet, exercise, and sleep are the best interventions we have right now for longevity. It’s a modest set of solutions, given all the options scientists are exploring.
We want to go beyond that, just as we have done for hypertension with statins and blood pressure medicines. I tried to control my blood pressure by weight and exercise and eventually it was a losing battle and it’s of course related to age. The hope is that if these medical interventions actually go one step beyond and do better. We’re not there yet.
In the book you worry that future longevity interventions won’t be equally distributed, and that’s also true of something even as basic as diet and sleep.
The inequality thing is very interesting. The top 10 percent in both the UK and the US live over a decade more than the bottom 10 percent. It’s not even that they live more, they live more healthy lives.
Why is that? Well the poor often don’t have the chance to exercise, their diets are often poor, and they work multiple jobs and have problems with sleep. All these things we think we can do, they’re harder if you’re poor and have to juggle jobs, child care, et cetera.
One worry I have is that if we discover sophisticated interventions—like turning on stem cells and so on, or having to give transcription factors to people intravenously—depending on the sophistication of the intervention only the rich might be able to afford them. That would make the disparity even worse. Not only are the rich living longer, they’re going to live even longer and healthier.
Hear Venki Ramakrishnan speak at the 10th anniversary of WIRED Health on March 19 at Kings Place, London. Get tickets at health.wired.com.
