Treatments to extend a healthy lifespan are already being trialled, according to a respected biologist with an Oxford PhD and an important new book. by Nicky Pellegrino.
The quest for eternal youth is the stuff of sci-fi and legend. For thousands of years, people have been seeking ways to stave off death. China's first emperor, Qin Shi Huang, was famously obsessed with finding an elixir to prolong his life but died in 210BC at age 49, ironically, it appears, after consuming a would-be immortality potion that turned out to be toxic.
Today, the average life expectancy in New Zealand is 81.86 years. Live that long and no matter how healthy your habits, your body will have deteriorated. Many of your cells will have exhausted their ability to divide and will have become senescent. Those that survive will be too worn out to do their job properly.
You will lose muscle mass and strength. Your immune system will start failing to protect you from infection and instead fuel chronic inflammation. Proteins will start to misfold and clump, forming the amyloids associated with Alzheimer's. Your microbiome will change. Your DNA will be damaged.
Blame evolution, which is only interested in keeping us strong and healthy during our reproductive years and has engineered a lot of biological trade-offs to ensure that happens.
According to Andrew Steele, we are on the cusp of all that changing. He believes most of us will live long enough to benefit from some sort of treatment that will extend our "healthspan" as well as our lifespan.
Steele is a computational biologist with a PhD from Oxford University who used machine learning to decode human DNA. For the past three years, he has been working on a new book, Ageless: The new science of getting older without getting old, looking at the cutting-edge research happening around the world with the bold aim of curing ageing.
"The ideas for treating ageing aren't pie-in-the-sky theoretical biology – they're being tested in labs and hospitals today," says Steele. "In 2011, the removal of 'senescent' cells in mice was shown to defer multiple diseases and extend lifespan. By 2018, drugs that destroy these cells were undergoing trials in people."
Not everyone approves of this, he concedes, speaking from his home in Slough, England. "It's really surprising the reaction you get when you tell people that you're working on ageing biology; sometimes it can be hostile. But once you break it down and explain that this isn't kooky sci-fi madness – it's just about treating cancer, treating dementia and heart disease and not just treating these things but preventing them before they happen – it's quite an easy sell."
The ambitious work that biogerontologists are doing is pitting them against evolution, which may not seem such a bright idea when you think what a stellar job it has done so far at ensuring the survival of our species. But as Steele points out, we long ago stopped leading the kinds of lives evolution has optimised us for.
"Evolution creates organisms that do really, really well in their natural environment. For humans, that meant living in small hunter-gatherer societies and particular climates.
"The environment we've made for ourselves today is so different from what we evolved for.
Human beings in the modern world live in a kind of lab environment of our own devising. So, I think we've got scope to tweak our biology in ways that will optimise it for the here and now."
Leader of the pack
Steele has identified 10 hallmarks of ageing and traced the science progressing towards eliminating them. Out in the lead, he believes, is the field of senolytics: treatments to slow down the cellular ageing of the body.
The problem with senescent cells accumulating in the body is they pump out molecules that fuel inflammation and can turn nearby cells senescent, too, or even cancerous. There is some evidence that getting rid of them may be helpful.
"It just so happens that we've stumbled across the drugs that are going to enable us to do this quite quickly," says Steele, who is excited about breakthroughs so far.
The first came from scientists at the Mayo Clinic who were working with mice that have a genetic defect that makes them age more rapidly. They gave some of those mice a second gene, which caused any senescent cells to commit suicide when given a particular drug. Although the mice didn't live any longer, they were healthier.
"The really exciting stuff came five years later," says Steele. "The same group started using two drugs – one that is used in chemotherapy called dasatinib and a flavonol called quercetin, which is found in fruit and vegetables. The idea is these drugs kill the senescent cells but leave the rest of the cells in the body intact.
"The mice in that study got biologically younger. They also lived a bit longer and, crucially, had a longer healthspan – less cancer, fewer heart problems, fewer cataracts, they could run further and faster on a treadmill, they even had better fur.
"When you read about these mouse experiments, that's one of the key things that always gets reported," says Steele. "It's probably just so obvious. You see these gorgeous mice with lovely thick fur and plump skin and then these ragged skin-and-bones counterparts who haven't got whatever treatment is being investigated."
Steele's hope is that within years, senolytics will be being used, initially to treat particular conditions such as osteoarthritis but gradually, if they prove safe, for those in the early stages of a range of diseases and eventually for healthy people as a preventative. Since the book went to press, however, there has been a setback. The company Steele identifies as leading the race to develop a drug, Unity Biotechnology, reported last year that a trial targeted at relieving osteoarthritis in knees had failed.
This news hasn't discouraged Steele. "I don't think it's a big deal. There are good explanations for why that trial went wrong. They injected the senolytic drug, UBX0101, into the knee. The knee is effectively a little sac of fluid, so when you put a drug in there, it's localised to some degree, which means any side effects will be minimised. However, what a lot of the senescent-cell community think is wrong with this approach is these cells affect all of the body, so it's quite likely that removing the handful that are in your knee isn't going to be enough to reduce the symptoms."
Vying with senolytics to be the first anti-ageing treatment off the blocks is a class of drugs that mimic the beneficial effects of dietary restriction (DR).
DR has been shown to extend healthspan and lifespan in a menagerie of animals.
"Everything from single-cell yeast through to worms, spiders, mice, rats, guppies, trout, pond creatures and dogs," says Steele.
Eating fewer calories is believed to boost a process called autophagy, which is the way cells get rid of broken proteins and mangled molecules, recycling their ingredients to make new versions. The failure of autophagy in old age is associated with conditions such as Alzheimer's, arthritis and heart problems.
In humans, the science around DR is tricky to prove, because we have considerably longer lifespans than mice and single-cell yeast. In the shorter term, people do seem to get healthier with lower cholesterol and fewer blood markers of inflammation, but there are issues with bone density and anaemia, plus it reduces immune function and lowers sex drive.
"And it's important to emphasise this isn't just eating a bit less," says Steele. "This is eating 40 per cent less all the time, every single day, and the participants report that the hunger doesn't go away."
Fortunately, it appears starvation may not be necessary. Metformin, a medication long used to treat type 2 diabetes, seems to mimic the effects of DR and so slow the ageing process. A US trial with healthy older volunteers was due to start, but unfortunately it's been delayed by the pandemic.
"If it works, then easily within the next five years that is going to benefit a lot of people," says Steele.
Gene, stem-cell therapies
Other treatments, such as gene therapies and stem-cell therapies, may seem more futuristic. "But I feel like a lot of the groundwork is being laid now," says Steele. "There are gene therapies being used for particular diseases where a single gene goes wrong.
"Beta thalassemia is a blood disorder that's just had a gene therapy approved. Those patients have a really awful prognosis, so doctors are willing to take a bit of a risk to improve their quality and length of life. Once we prove it's safe and start to understand a bit more about the mechanisms, there are lots of areas where intervening in a single gene can slow down ageing. It's hard to give exact timelines for this, but it's not inconceivable that it's 10 or 20 years away. Even if you're in your fifties now, it's not crazy to think that you might benefit from some of those therapies in your old age."
Any new therapy carries risks, particularly treatments that tinker with the cells, where researchers are walking a tightrope between curing ageing and causing cancer.
One well-established area of anti-ageing research is telomeres. These are protective caps on our chromosomes, often compared to the plastic tips on our shoelaces. Telomeres shorten each time a cell divides until they become critically short and send out a signal to stop the cell dividing any more; then either it dies or becomes senescent.
People with shorter telomeres die sooner than those with longer ones, so a lot of effort has gone into the science of lengthening them, in the hope that by doing so we can reverse ageing. An enzyme that does the job – telomerase – has been identified by two Nobel Prize-winning scientists, Elizabeth Blackburn and Carol Greider, but cancer is getting in the way of this being an immortality enzyme for cells. Because most cancers activate telomerase, cells can divide over and over again and so form a tumour.
Scientists are working to get around this problem of increased cancer risk. In one trial, mice were given telomerase plus extra DNA-defending genes that encouraged cells to die if they had pre-cancerous mutations. Those mice lived 40% longer than the unmodified mice.
Rich v poor
Drugs such as metformin may be cheap, but flashy gene and cell therapies, when they do emerge, are going to be expensive. So, will the rich live longer while the poor are destined to die young? Steele isn't convinced that health inequity will necessarily be a problem. He argues that the cost of these radical new anti-ageing treatments will be offset against what is currently spent on cancer, heart disease, failing eyes, creaky joints, failing brains and the other diseases of old age that won't be a problem any more, particularly as the decades pass and the newer anti-ageing drugs come off patent, allowing cheaper generic versions to be manufactured.
Steele is also primed to respond to the question of whether dramatically extending life – and thus presumably growing the global population – is such a great idea when the planet is already environmentally burdened by about 7.8 billion of us.
"What really matters isn't how many people there are – it's the amount of resources we use," Steele says. "Before I moved into ageing biology, I was a physicist and was thinking seriously of becoming a climate scientist, so this is something I'm very concerned about.
"Take climate change – the richest billion or so people in the world emit something like half the greenhouse gases. What that means is there are six or seven billion people right now who are emitting the other half. If we want to bring all those people up to a wealthy, modern standard of living, we're going to have to find a way to do that with a much smaller footprint on the planet. And that's not just in terms of carbon dioxide but also land and resource use.
"So, characterising the environmental problem as being about people is the wrong way to look at it, because it's quite a small subset of wealthy people who are driving it and that means this is a problem we're going to have to solve anyway, irrespective of anything to do with birth or death rates."
If anti-ageing therapies do work, Steele believes they will bring about the eradication of the single largest cause of human suffering. And he would happily work harder to cut down his carbon emissions to get such an enormous bio-medical benefit.
Steele is in his thirties now, so how long exactly does he want to live? What is the limit? He doesn't have such a snappy answer to those questions.
"I don't think there's a hard limit. But I'm having fun being alive right now, and I'd like to see what the future holds, what science and technology bring to us in the future. If you asked me 'would you like to get dementia next year?' or 'would you like to get cancer next year?', my answer is definitely no. Even if I was 80 or 100 or 150, I can't see a point where I would like to degenerate."
The global pandemic we are navigating right now does seem a powerful motivator to press on with anti-ageing science. The elderly have been the most vulnerable to Covid-19, more likely to die from it or suffer long-lasting effects.
"The reason for that is the ageing process: the decline in the efficiency of the immune system, the decline in what doctors generally call reserves, the ability of the body to withstand stresses. One of the strongest things we could do to try to prepare for the next pandemic is decrease the biological age of the population's immune systems, which means that we're all a little bit more resilient."
Words of warning
Perhaps unsurprisingly, it is the wealthy and privileged titans of Silicon Valley who are leading the way in the quest to live forever – or at least dramatically longer. Many millions are being spent by a number of biotech companies as they try to hack the code of lasting health and longevity.
Google has established a company called Calico to tackle the problem of ageing. And Amazon's Jeff Bezos is a backer of Unity Biotechnology, the lab that had the disappointing results last year with a trial targeting senescent cells in the knee.
The noisiest proponent of anti-ageing science is probably Aubrey de Grey, co-founder of Sens Research Foundation, which aims to transform how age-related disease is researched and treated. He is given to bold statements that the first person who will live to be a thousand years old has already been born. Among his backers is PayPal co-founder – and New Zealand citizen – Peter Thiel.
Based on the patchy science that has happened so far, a number of anti-ageing treatments are already available, but unlike that misguided Chinese emperor, we may need to be careful what we swallow or inject. Some therapies don't work while others may be counterproductive or even dangerous.
Google the word "senolytics" and you will find a lot of herbal life-extender supplements on the market, often with the antioxidant quercetin as an ingredient. Steele isn't buying any of them.
"I'm not necessarily saying they're completely useless, but without understanding the doses that are required and a bit more clinical data, I would say it's premature. In five years' time we'll know the answer – probably."
Stem-cell therapy is offered in some clinics, including in New Zealand, as a solution for joint pain, but Steele isn't booking in for it. "I'm really confident that we're going to see progress in stem-cell therapy. There are some cool results in mice that show you can give particular kinds of stem cells that will improve lifespan and healthspan. But there's nothing solid enough yet that I would consider doing."
He is also dismissive of human growth-hormone injections as a path to enduring youth, pointing out that Laron mice, which are genetically bred to have an absence of growth-hormone receptors, live substantially longer than normal mice.
"Adding growth hormone may make you stronger and more muscular in the short run, but quite likely it is accelerating your ageing."
In the US, you can pay thousands of dollars to have a transfusion of plasma from a teenager or young adult. This treatment is based on macabre-sounding heterochronic parabiosis science. Two animals, usually rodents, have the skin on one side of their bodies peeled back and then are stitched together. As they heal, the artificially conjoined twins start to share a blood supply. The older rodent benefits from this with cellular rejuvenation, but the younger one suffers as a result.
Armed with that information, you may think that injecting a few vials of youthful plasma would give your ageing cells a giddy-up. Except, as Steele points out, there's a bit more going on. For a start, the older rodent has the benefit not only of more youthful blood but also of younger organs to filter toxins, deliver oxygen and influence the immune system.
"Also I spoke to Irina and Michael Conboy, the two scientists who have pioneered these experiments in recent times," says Steele. "They said they've noticed young mice tend to be more energetic and they drag the old mouse around the cage, basically subjecting it to an enforced exercise programme, and we all know how great exercise is for our health."
In the meantime …
Lives nowadays are twice as long on average as they were in the early 1800s, and the trend is set to continue. Steele would like to see vastly increased funding for biogerontology. He believes that treating ageing as a disease will bring greater gains than trying to pick off the various preventable conditions one by one.
"If we entirely cured cancer, we'd probably add only two or three years to life expectancy. That's because if you're 80 and you get cancer and we zap you with whatever magic bullet the scientists have invented, you're still frail, you're still old, you've probably got some sort of heart problem simmering away in the background, a bit of diabetes, you may be suffering from the early stages of dementia, and one of those things is waiting in the wings to come and finish you off."
Steele is convinced anti-ageing therapies are on their way. In the meantime, his advice is that we can help ourselves by obeying the usual rules of living well – don't smoke, eat a balanced diet and not too much, take exercise, get enough sleep, look after your teeth, be vaccinated, wash your hands and wear sunscreen.
Aside from that, says Steele, "we can sit back and let the science happen".
Ageless: The new science of getting older without getting old, by Andrew Steele (Bloomsbury, $31.99)