The search for immortality is the oldest tale in the world. Literally: the oldest written story known to historians is The Epic of Gilgamesh, first written down in Sumerian cuneiform on clay tablets, about 4,000 years ago in what is now Iraq. In it, King Gilgamesh seeks a plant which grants eternal life. (He finds it, but a snake steals it before he can use it.)
The Fountain of Youth, the Philosopher’s Stone, every civilisation has its own version. Human life is short. Ageing and death come too soon, and we dream of ways of staving them off.
Now, though, for the first time in human history, we seem to understand some of the real underlying processes of ageing. And, more astonishingly, we have some idea of how to slow them down, and perhaps even turn them off. The idea of something a bit like Gilgamesh’s plant – of longer life, if not actual immortality – could be within our grasp.
In the coming decades – in the lifetimes of people alive today – we could find ways to allow people to live to see their 150th birthday, or even beyond: to make old age no more dangerous or disease-ridden than youth.
Almost all the diseases that afflict us, from cancer to dementia to heart disease, even many infectious diseases like Covid or influenza, are strongly linked to our age: a serious way to reduce ageing would reduce a huge amount of suffering.
“You’d be a fool to bet against it working in the next 50 years,” says Andrew Steele, a computational biologist and author of Ageless: The New Science of Getting Older Without Getting Old.
And people are betting heavily on it working, perhaps sooner than that. Jeff Bezos, the founder of Amazon, has invested very large sums of money in the biotech company Altos, focused on “cellular rejuvenation”.
Recently, a paper came out in the journal Nature Ageing which found that by turning certain genes off in mice, a key biological sign of ageing could be delayed – and, remarkably, without any damaging side-effects. Another, in Ageing Cell, found something similar. Other studies in recent years have extended lifespan in various species of animal, from roundworms to fruit flies to mice.
There are two main parts to what the researchers did. The first is telling the cells to revert to an earlier form. The cells in our body, apart from our sperm and eggs, all have the same genome. The DNA in your kidney cells is the same DNA as in your brain cells or your skin cells. But each of them do different things: they have specialised, “differentiated”. That’s because each cell only “turns on” a particular set of genes.
But all of the cells in our body originally come from just two cells, the sperm and egg that made us. To make all those hundreds of different types of cell, early in our development our bodies had lots of non-specialised cells which had the potential to become anything: part of a kidney or a brain or your skin. These “pluripotent stem cells” are how our body makes its various specialised parts.
About 15 years ago, scientists discovered that they could instruct a particular set of four genes in any cell to turn on, and it could induce that cell to revert to becoming a stem cell. The genes are known as “Yamanaka factors”, after their discoverer, the Nobel-winning Japanese biologist Shinya Yamanaka.
Experiments looking at what happens if you turn on the Yamanaka factors are not new. But unfortunately, what happens if you turn them on all the time – by genetically engineering the mice so all their cells produce them constantly – is disastrous: “The mice die in a variety of horrible ways,” says Steele. They’d get awful teratomas, tumours made of hair and teeth. “Cancers, organ failures, because the organs’ cells don’t do what they’re meant to do.”
What turning on the Yamanaka factors all the time did was reset the cells’ clocks to zero. That’s not a metaphor. Another recent discovery is that cells have a very accurate biological clock within them.
DNA is made of a long chain of smaller molecules known as nucleotides. There are four of them, C (cytosine), A (adenine), G (guanine) and T (thymine): all the complexity of life comes from arranging them in different orders.
As we get older, the Cs change slightly: a little chemical marker gets attached, called a methyl group. It turns out that reading the number of Cs in your genome that have become methylated tells someone’s age to within three years. In a mouse’s, it’s to within about three weeks.
Wolf Reik, a researcher at Cambridge’s Babraham Institute, told me a few years ago that this is the most accurate biomarker of ageing that we know of. And turning on the Yamanaka factors in a cell for a long time resets the methylation clock to zero.
What’s not clear, at least not yet, is whether methylation represents the cause of ageing, or just a readout of it. But either way, it is useful.
What researchers on the Nature Aging paper did was genetically engineer mice so that the Yamanaka factors would turn on only in the presence of a particular drug, the antibiotic doxycycline. Then they tried giving the mice doxycycline at various regimens. What they found was that mice who were given the drug sporadically – perhaps for two days out of every seven – their DNA methylation clock went backwards: on this very reliable measure of biological “age”, they had got younger.
That’s only a proxy measure: we don’t actually care about whether mouse DNA loses some markers, we care about whether the mice (and by extension humans) get healthier and live longer. “It’s frustrating that none of the things they measure are functional,” says Steele, things like how long the mice run on a treadmill or, of course, how long they live. But what’s exciting, he says, is that they seemed fine. “You might think that periodically activating these really powerful genes would have some awful effects, but it didn’t. To translate it to humans, you don’t want something that’ll make us grow a third arm or die or whatever.”
Of course “translating it to humans” is the eventual dream. There are obstacles: for one thing, the mice that these studies were carried out on were genetically modified. “Genetic engineering is ethically very difficult in humans,” says Prof Jürg Bähler, a geneticist at University College London’s Institute of Healthy Ageing. And even if it were allowed, editing embryo DNA wouldn’t be of any use for people who are alive now.
But it’s not an insurmountable challenge. In recent years, the rise of “gene therapy” has given hope to sufferers of genetic diseases by modifying the genetic code in the cells of an actual, existing human. It is much harder – it requires editing the DNA in not one or two cells but millions or billions, using a virus to insert the new code into the cells. But it is working. People have been treated for sickle cell anaemia, congenital blindness, and other awful diseases. “We’re already using gene therapy in humans,” says Steele. “It’s in its infancy, but it’s existing technology. It feels like decades, rather than centuries, before we’re really good at it.
“We’ve got the platform working in humans, and the concept working in mice. I don’t think it’d be totally mad to see some reprogramming by rejuvenation in the next 10, 15, 20 years.”
Of course, what’s interesting is what we mean by “reprogramming”. It could mean that we simply slow down the onset of the various diseases that ageing causes – or it could mean that we stop ageing altogether, allowing us to live as long as we choose.
In the near term, at least, the former is more likely. “Some people, including myself, would say there’s a natural ceiling for human life, about 150, and you can’t go beyond that,” says Bähler. “It’s controversial; it depends on who you ask. But [ageing] is such a complex, multifactorial process.”
Even just slowing the ageing process would be a huge deal, of course. “There’s been a huge increase in lifespan in the last 200 years, from 30 or 40 years to something like 80 now,” says Bähler. “But what happens is people live longer and stay sick longer. They still get cancers at the same age, there are all these different morbidities. And even if you cure one of them, say cancer, which would be a huge challenge, it wouldn’t have a big impact on [average] lifespan – maybe one or two years, because of all the other diseases.” But if you changed the underlying process, you’d help people stay healthy for longer.
Steele is more bullish. “What kills you is being ill,” he says. “If you can defer those diseases by ending the ageing processes that cause them, what would we die of?” He says that what we should be aiming for is “negligible senescence”. “A risk of death that doesn’t depend on how long ago you were born.”
“I think that’s the ultimate thing it’ll be like to be a human,” he says. “I’d be absolutely shocked to come back in the year 2500 and find that’s not what life looks like.” The question is whether it’ll come sooner than that: whether we’ll get lucky and see it in our lifetimes.
People invariably raise two concerns, whenever anti-ageing research is mentioned. One is overpopulation: what will happen if people stop dying? Steele thinks this concern is overblown. “I ran some calculations,” he says. “The UN thinks the world population will be 9.8 billion by 2050. If we literally cured ageing by 2025, which is a ridiculous assumption, that number would be 11.5 billion. It’s not nothing, it’s 16 per cent bigger. It’ll make fighting climate change harder. But I’d happily work a bit harder to stop all those people dying of cancer and dementia.
“Besides, that’s not what will happen: we’ll face a much slower change than that.”
The other concern is that the only people who will see the benefits of this technology will be the very rich. But that’s unlikely as well. For one thing, every technology starts out expensive and becomes cheaper: the computing power on your smartphone would have required a multi-billion-dollar supercomputer 30 years ago.
But for another, says Steele, “If you’re Jeff Bezos, you don’t want to be taking the very first pill that Altos Labs makes.” Instead, you want it to have been rigorously tested in a big randomised controlled trial. “If you want a big trial, you need to scale down the costs so it’s not £100 billion a dose. It’s not like a supercar or a yacht. You can’t have a custom-built biological treatment, you need the big trials.”
So what the billionaires who want life-extension treatment want, and need, “is a functioning industry that works at huge scale,” says Steele. “They want to be the 100,001st person to take the drug.”
He also points out that any breakthrough in ageing treatments would save health systems hundreds of billions, perhaps trillions, a year by preventing dementia and cancer and other diseases of old age: the treatments could be very expensive and still save lots of money.
We’re not at the very threshold yet. The Yamanaka-factors-and-methylation approach probably isn’t the whole story: “There are 10 main hallmarks of ageing, on various scales,” says Steele. “Think about proteins like collagen – it’s the most abundant protein in your body, and as you get older it changes function. It’s outside your cells so rejuvenating your cells doesn’t sound likely to change it.”
But there are other approaches being taken, as well. Bähler mentions rapamycin and metformin, two drugs that have shown promise: “There’ll shortly be a trial, the first trial of a drug for anti-ageing,” he says. “There are side effects, but there may be ways around them. It’s definitely happening.”
For 4,000 years, humanity has dreamed of, and looked for, a way to end ageing. We’ve never managed it, and it still kills about 100,000 people every day. We have come to terms with it, and even rationalised it as a good thing, even as it ravages us. But we – or our children – may be the first generation to see an end to it. Gilgamesh would be envious.