September 2, 2020

It’s funny, what gets you thinking about mortality. Wait, no. It’s not funny, it’s exhausting. Literally everything gets me thinking about mortality. I could be eating a Dairy Milk and think something like “Gosh, I wonder if I’ve already eaten the majority of Dairy Milks I will eat in my lifetime.” Then I might try to work it out. I have a problem.

But this time, the thing that got me thinking about mortality was digging a series of dams and waterworks on a British beach with my children, and thinking about doing the same when I was their age; my father bringing the proper gardening shovel from the shed in the house we were staying in, so he could shift some serious tonnage. (I have started doing this. If you go to the beach with a metal spade, you are King Dad, and the other dads have to build you a throne of sand.)

Those summers seemed to go on forever and there seemed to be an infinite number of them. These ones slip by in a rush: the children are speechless gurgling babies one minute; lanky-limbed argumentative great monsters the next. And the gap between my being the child and my being the spade-wielding, sunhat-wearing dad seems much smaller than it ought.

Anyway, middle-aged dad freaking out about mortality: breaking news, more at 11. But I read something recently that made me stay with the topic.

John Nerst, the blogger behind Everything Studies, read my first book recently. The book is kind of about AI, and whether it will kill us all; but it’s also about some people who worry about it, known as the rationalists. The rationalists are many things, but a lot of them are transhumanists: people who think humanity can and should change its base form, to extend life and become more than we are. And one key thing they want to change is the inconvenient “death” business.

Nerst doesn’t want to live forever. Our psychology, he thinks, requires finite story arcs – he doesn’t trot out the simple “death brings life meaning” thing, but starts from there, and he finds that the idea of living forever doesn’t work. “I want to live a long and happy life,” he says, “but I think I do want to come to a point when I’m satisfied, a point when I feel like it’s a good time for the story to end.” I really recommend you read the whole thing, partly because everything Nerst writes is worth reading, and partly because I can’t do the whole thoughtful piece justice with a few excerpts. But in essence, he thinks we don’t want immortality.

I’ll come back to whether I agree with him, later on. But for now I thought it was worth noting that the idea of hugely extended human life isn’t crazy. It’s already happened, to some degree: if you’re blessed, as I am, to be living as a well-off person in the rich west in the 21st century, you can already expect several decades more than could 99% of humans who have ever lived. 

Transhumanists just want to do that more. They get held up as cranks and weirdos — partly because lots of them are into cryonics, which I think is unfair: surveys suggest they’re no more likely than the rest of us to think it will work; they just think the bet is a worthwhile one. And on the subject of ageing, I think they’re right that ending it, or at least hugely changing it, is a plausible goal.

I spoke recently to a couple of scientists who are looking at human life extension. One of them, Wolf Reik, works at the Babraham Institute, a life-sciences establishment outside Cambridge. He studies a process called DNA methylation.

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The DNA in our cells is made up of four “letters”: C, G, A, T, the nucleotides cytosine, guanine, adenine and thymine. Each is a tiny bundle of atoms; when strung together into long sequences they form the famous double helix shape.

Sometimes, the cytosines change a little, gaining another group of atoms called a methyl group. About five years ago, scientists at UCLA noticed something interesting. If you measured the percentage of the cytosines which had this methyl group, it told you — with remarkable accuracy — the age of the person you took it from.

“It’s the best biomarker for ageing that exists,” said Reik. “It is accurate to within 3.6 years.” And more than just predicting your chronological age, it also told you important things about your health. Reik found the same process happened in mice, accurate to within 3.3 weeks, which is very similar, proportional to the length of a mouse’s life, to the accuracy in humans.

There are two possible explanations for this. One is that this epigenetic “methylation” process is a sort of readout, tracking the real processes of biological ageing. That would be exciting in its own right — you could use it as an important health indicator, and, in the future, the patterns of DNA methylation could provide information on risks of specific cancers or other diseases.

But the second possibility is that this is the underlying process of ageing. And that would mean that, if you can change it, you would go some way to halting — or reversing — the ageing process itself.

At the moment it’s too early to say whether that’s the case. But Andrew Steele, a computational biologist whose book Ageless comes out next year, told me that there are a few interesting hints. First, this methylation process tracks ageing from fertilisation to death. At first it’s a rapid change, up until the age of about 20; then there is a slower, steady increase. “If this were just some random phenomenon,” he said, “you wouldn’t think you’d see the same changes from development to adult life, when you’re not developing. It’s suggestive, but not conclusive, that it’s something fundamental, something causal, about ageing.”

There have been some experiments that support the idea. If you turn an adult cell into an induced pluripotent stem cell, by inserting four genes called “Yamanaka factors” into its DNA, its methylation clock reverts to zero.

And in some experiments, scientists used the same process on mice, inserting the Yamanaka factors into their DNA. It was, said Steele, a catastrophe: the mice’s cells in their organs tried to turn into stem cells, meaning that they weren’t doing their jobs; the mice had systemic organ failures. And the stem cells also caused the mice to develop grotesque cancers called teratomas, horrible balls of teeth and hair and blood.

But when another group of scientists did the same, but this time with the Yamanaka factors switched off except in the presence of a particular drug, and then gave that drug at periodic intervals, they found that the mice aged more slowly than normal mice. It’s inconclusive – they observed proxy measures, rather than simply waiting to see how long the mice lived – but it’s tantalising. “There’s no guarantee it will work in humans,” says Steele, “but these processes are fundamental and appear to be conserved across biology, in mice and flies and rats and dogs, so there’s a strong possibility.”

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If methylation really is the driver of ageing, then the dream, of course, is to create some drug that will slow the process. The Yamanaka-factor mice were all genetically modified, so that precise model wouldn’t work on adult humans. But the Yamanaka factors are a “sledgehammer”, says Steele, forcing all the cells back to age zero. “Reprogramming like this resets the clock,” says Reik. But in theory we can find a more precise method. “We could say, instead of zero, I want to go back to 20. That’s quite an exciting prospect.”

The first step is still to make sure that this really is a driver. Reik and colleagues have plans for more research — manipulating the mouse genome, seeing how methylation interacts with gene expression. He plans to look at certain developmental disorders, such as kabuki syndrome, that affect ageing, and see if they work via the methylation system. His lab has made, he says, “exciting breakthroughs” in rejuvenation since we first spoke about it two years ago.

Methylation won’t be the whole story. There are other forms of cell damage that accumulate over a lifetime and that this won’t fix — Steele’s book looks at ten “hallmarks of ageing”, things that drive and aggravate the ageing process. But it seems centrally important, and understanding it could lead to breakthroughs. Besides, there are other hopeful avenues. “The most promising current research is probably senolytics,” says Steele: “drugs that kill senescent cells, and which have made mice live longer, helped with arthritis and other age-related conditions, and are currently in trials for the same in humans.

“I think that curing ageing is a totally legitimate medium-term medical goal, and maybe short-term if we get lucky.”

And lots of other animals (Steele mentions tortoises and some salamanders as especially good examples) don’t age as we do. It’s not some inevitable fact about life. It could well be that we find something which will dramatically change how humans age. Major life extension is not wild speculative madness.

So let’s get back to whether we’d want it. I entirely agree with Nerst on one thing: actual, you-cannot-die immortality is likely a curse, not a blessing. No one reads vampire stories or ghost stories – souls forced to wander the earth long after all their loved ones have died, unable to rest – and thinks “Yup, gotta get me some of that.” Immortality is the archetypal monkey’s-paw wish-that-goes-wrong. 

But on the other hand, ageing — look, I am sorry to say it, it feels like something you shouldn’t say — sucks.

Not getting older. I like getting older. Mainly, I like how little I care about what other people think about me, now. I wear practical, comfortable clothes and engage in pastimes I enjoy, rather than wearing and doing things I hope will make people think I’m cool. (They never did.) I feel I am much more myself than I was in my teens and twenties, as though for all those years I was building a personality, and now it’s ready to be taken out and used. There’s a lot of good stuff about getting older.

Ageing, though. Cancer is a “disease of ageing”, we’re repeatedly told, and it is. But almost all diseases are diseases of ageing, to some degree. All your organs start to go wrong. You get weaker, you get slower. Your senses lose acuity. Even your brain changes; there is real decline in your mental faculties which gathers pace as you reach the end of middle age. Then there’s dementia, which scares the shit out of me. Anything incapacitating does, really. 

I’m still too young to really notice any physical decline; if there is any, it’s likely being offset for the time being by the fact that I drink less and exercise more these days. But I see older friends and relatives getting cancers and heart disease and all these other things, and they’re not that much older. I can remember when they were my age, and it doesn’t feel very long ago. So it would be nice to sort the whole ageing thing out.

“It’s crazy that more biologists aren’t focusing on ageing,” said Steele. “The potential is there to reverse the greatest cause of disease and suffering in the modern world, and yet there is surprisingly little interest.” Living fit and healthy lives right to the end: that seems worthwhile.

But I’m kind of dodging the question. Nerst wasn’t talking about making everyone healthy. I think most people would want that. How about real transhumanism? How about living for hundreds of years? Thousands? 

Nerst suspects we wouldn’t want it. “My grandmother, who I spent a lot of time with as a child, passed away just about a year before turning 100,” he writes. “She remained present and independent until the end, but had for years casually commented that she was ready to go. I believe her. I think she felt her story was over.” And, he thinks, a lot of elderly people feel the same. I suspect he’s right.

I have three questions, though. First: how much of being tired of life is a product of being literally tired, just from living in a slowly failing body? Everything is harder work when you’re very old, and you can do fewer things, and learning new skills is harder. If we were capable of learning judo, or kite-surfing, or Go, at age 90 as easily as we are at age 15, would we still be so bored?

Second, how different would it be if all your friends and relatives didn’t have an unfortunate tendency to die? If we all could live on as long as we wanted, wouldn’t it be more appealing?

Third: maybe many people would still feel they have had enough after 80 or 90 years. Maybe most people would. Maybe almost all people would. But … what if I don’t? What if a few people get to their century, still healthy and fit, and think: actually this is still pretty good, I want to carry on for a few more years? What if they think the same after their second century? Their fifth?

I would like to have the option. I don’t know how I’ll feel when I’m ten thousand years old. Maybe I’ll still be bang up for another ten thousand. And I think everyone else should have the option too.

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Of course there are real practical difficulties. Our growing population right now is caused by people not dying quickly enough — birth rates are stable and will probably start declining soon, but the people who are already here are living longer, so the population is still going up. If people start living for millennia, we would struggle; it’d be like putting the plug in the bath but leaving the tap running. It’s not a coincidence that the rationalists, the transhumanists I write about in my book (all good bookshops!) are also keen proponents of getting humanity off Earth and to the stars. 

Also, if you want to choose when you go out, you need to be able to choose. You can’t have laws against assisted dying in the glorious transhumanist future.

But they are practical difficulties. Maybe they’re insurmountable, but maybe not. I agree with Steele that ageing is probably the greatest cause of suffering and disease in the world, and we ought to try to do something about it. I sincerely doubt it’ll happen in my lifetime, but it’s a nice thing to hope for my children, or theirs.

Maybe this is all just a nerd’s version of praying for the afterlife, although I think not. But I like life, and being healthy, and learning about the universe. I’d like all those things to carry on. So even if I don’t want actual immortality, I would like to be able to choose the time of my leaving, without having to feel my body and brain slowly lose the fight against entropy.

In case that doesn’t happen, though, I have ordered the lesser dads on this Kentish beach to build me a mighty pyramid, and store my mortal remains in there, ideally with twenty or thirty of them entombed with me to serve me in the afterlife. It’s a long shot, but I may as well take advantage of being King Dad while I can.

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  • September 4, 2020
    "As I grow older" ? That almost sounds like expectation that I'll live longer, which apparently we've already established is wrong, regardless of how statistically likely. And no, life is not made meaningful by knowledge of death. If indefinite life extension ever is possible then I shall embrace... Read more

  • September 3, 2020
    Well said. I also liked the post that noted that death is part of natural selection. To me it would be a nightmarish world and the right to have children would have to be severely limited. Think of a world without kids .... Or teenagers. Think of a world where women look permanently 25yrs old and... Read more

  • September 3, 2020
    A species that ages and dies soon after successful reproduction will quickly out evolve one whose natural selection is constantly polluted by ancients - But you have to build to perfection and then self destruct - So having achieved the process of always building to perfection it is probably very... Read more

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