MICHAEL WEST got talking to a guy next to him on an aeroplane. “The man asked what I did and I told him,” says West. The man seemed impressed and West continued, thinking he had a friendly audience. “But after a while he said: ‘You’re lying to me. I read everything and I’ve never heard any of this. This is so amazing and so revolutionary that if it was true, I would know about it already’.”
The unbelievable story that West told his neighbour was about the science of ageing. An account of how biologists had finally figured out what causes us to grow old and die, and how biotechnologists like him – he founded biotech firm Geron in 1990 – were closing in on a cure. A cure for ageing.
West realised his life’s work had an image problem. “Rejuvenation, age reversal – I completely believe it is possible,” he says. But “the gap between what scientists know and what even the educated public knows is huge.”
Make no mistake: you are going to want to know about this. In a few weeks, an anti-ageing pill will be launched. In a few years, the first scientifically validated anti-ageing drugs could be on the market. Biotech companies are springing up to commercialise discoveries, and investors are betting serious money on what many predict will become the biggest industry of all time. As somebody who is approaching 50, I want to know about it too. The wrinkling, sagging and greying that are the outward manifestations of my inner decay are already upon me, and it is downhill from here.
Before we go any further, let’s address the bugbear that haunts this field. History is filled with charlatans and hype-mongers who claimed ageing would be cured in their lifetimes or that immortality was within reach. This time it really is different. “In the past decade, we have made a major discovery,” says Richard Miller, a gerontologist at the University of Michigan. “We have proven that you can slow the ageing process using drugs. Ten years ago, people would have said, ‘That’s science fiction, there’s no reason to suspect that can ever be done’,” he says. “Those people have been proven wrong. It’s doable.” This isn’t just slowing ageing in worms, flies or even mice, it is in humans too.
“It’s completely different to the old stuff, which was a bunch of cowboys, really awful,” agrees David Gems at University College London. Unlike many other biogerontologists, he has no commercial interests in anti-ageing medicines. “These are proper scientists working to normal standards. At the moment, it looks great.”
One important way in which it is completely different is that the goalposts have moved. Anti-ageing research used to shoot for life extension. Not any more. “I don’t think anyone here wants anyone to live to 200,” Janet Lord at the University of Birmingham, UK, told me at a recent scientific conference. “What we do want is to stop the last years of life being lived in ill health.”
Yes, that’s right: longevity research is no longer about living longer. “The aim is to keep people healthier before they die,” says Linda Partridge, a director at the Max Planck Institute for Biology of Ageing in Germany. “It is sometimes called compressing morbidity.”
To put it another way, it is about extending “healthspan”, the number of disease-free years towards the end of life. That means keeping life expectancy the same, which for children born in 2019 in developed countries is 85, but being healthy for 84 years rather than decrepit for the final 10.
Of course, giving people drugs that slow the ageing process may well lead to them living longer. But that would merely be a happy by-product: the treatment would be considered a failure if those additional years weren’t lived in good health. “When I tell people that I work on ageing, they often say I’m a bad person, I should stop, that we don’t want the world to fill up with a lot of sick, old people,” says Miller. “That is an incorrect, old fashioned, but very, very popular view of what anti-ageing drugs do. But it is not the aim. If these drugs work, it won’t happen.”
Extending healthspan – or “quality-of-life span” – would be an achievement on a par with the doubling in life expectancy that has happened worldwide over the past 150 years. That is a fantastic achievement, but healthspan has lagged behind. Between 2000 and 2015, global life expectancy at birth rose by five years to about 85, but the number of healthy years rose only by 4.6 years. An average of 20 per cent of life is now spent in a state called “late life morbidity”, which is a jargony way of describing a daily battle against an ever-growing burden of chronic diseases. That is terrible for individuals, but also for society. “Eighty per cent of healthcare costs in the US are associated with degenerative diseases,” says West. “The cumulative cost is tens of trillions of dollars.”
That is another way in which the new quest for anti-ageing medicine is different. It is less about baby boomers raging against the dying of the light than about defusing an economic time bomb in healthcare. “The greying of the population is a major challenge,” says João Pedro de Magalhães at the Institute of Ageing and Chronic Disease at the University of Liverpool, UK. “We need to develop interventions and therapeutics that at least retard the process of ageing.”
At this juncture, there is every reason to believe that healthspan can be extended. “Ageing is due to our biology, and this biology can be targeted with medicines,” says Joan Mannick, chief medical officer of resTORbio. One of the leading companies in the field, resTORbio has trials of anti-ageing drugs that are about to enter the final stage before they can be signed off for human use.
From a biological point of view, ageing is essentially the progressive loss of the body’s ability to repair itself, which is an unfortunate product of evolution. When we are young, wear and tear to cells and organs decreases our ability to pass our genes to our children and grandchildren, so has been selected against. But the rapid rise in longevity has left evolution for dust. “We’re living way, way beyond the ages at which we died in our evolutionary past,” says Partridge. “So natural selection has not had a chance to modulate the later parts of our lifespan.”
“Longevity research is no longer about living longer. It is about keeping people healthier before they die”
As our repair processes fail, damage proliferates. Organs and tissues clog up with clumps of protein and other detritus. Genetic mutations accumulate. Chromosomes start to unravel. Some cells become cancerous, others turn into zombies. Immune defences weaken. The powerhouses of our cells, mitochondria, fall into disrepair. Low-level inflammation, called inflammaging, creeps through the body.
These are the sorts of things I can already feel. But soon enough they will progress to age-related afflictions ranging from heart disease to cataracts. And the older I get, the faster they will hit me. “The incidence of almost every chronic disease suddenly increases exponentially around the age of 60,” says Mannick.
Thank science, then, that we now know enough about those repair processes to reboot them with drugs. And if things go to plan, they will be available before I enter my seventh decade.
But let’s not jump the gun. Many in the field are extremely wary of making predictions about exactly when anti-ageing drugs will appear, and with good reason: they remember the last time.
That time was 2013, when pharmaceutical giant GlaxoSmithKline scuttled an anti-ageing company it had bought just five years earlier for $720 million. Sirtris Pharmaceuticals was developing drugs based on a natural molecule called resveratrol. In experiments on yeast, it extended lifespan by up to 50 per cent. Sirtris founder David Sinclair of Harvard Medical School once told Science that resveratrol was “as close to a miraculous molecule as you can find”. It wasn’t.
“The smart money is on senolytics: drugs that destroy worn-out cells”
“The science was not ready,” says James Peyer of Apollo Ventures, a biotech incubator that searches out promising longevity research and turns it into companies. “That really killed off the field.”
Which brings us to another thing that is now different. Sirtris essentially had the field to itself. Its claims were perhaps overhyped, but they weren’t baseless. It simply fell victim to the harsh facts of drug development, where promising results in animal models rarely survive contact with the human body. According to Miller, about 90 per cent of experimental drugs that work in mice fail in people. Even those that do work rarely make it all the way to market: de Magalhães says the success rate of drug candidates is about one in 5000. There is no reason to think that anti-ageing drugs will have a higher strike rate.
Sirtris also had all its eggs in one basket in the form of resveratrol and some closely related compounds. Today, about 50 firms are exploring dozens of different compounds and biological pathways. Human trials are under way. Everyone accepts that most of these companies’ efforts will fail. But they also believe that at least one will succeed, with potentially world-changing consequences. “If just one company becomes successful, given that slowing down ageing would impact so much in medicine and society, that would be transformative,” says de Magalhães.
A lot of the smart money is on a class of drugs called senolytics, which seek out and destroy worn-out cells that build up as we age. These cells have suffered some sort of irreversible damage and entered a state called senescence where they hit the emergency stop, hunker down and await destruction.
This process probably evolved to stop cells from becoming cancerous. But it eventually backfires. “Senescent cells are normally cleared out, but that goes wrong during ageing and they accumulate and cause tissue damage,” says Partridge. The cells are like zombies: beyond repair, yet undead and causing havoc. They pump out a range of inflammatory proteins that are a major cause of inflammaging. “Senescent calls are very bad for you,” says Lynne Cox, a biochemist at the University of Oxford. “They destroy the tissues around them.”
The cells are now known to cause many age-related diseases, says Darren Baker, who is based at one of the hotbeds of this research, the Mayo Clinic in Minnesota. The list includes the diseases we are familiar with: cancer, atherosclerosis, type 2 diabetes, osteoarthritis, Parkinson’s, Alzheimer’s and cataracts. Tellingly, if you take senescent cells from an old mouse and transplant them into a young one, it ages prematurely and acquires the diseases of old age.
The opposite is also true. “If you remove senescent cells from old mice, they get better, they rejuvenate,” says Cox. And it appears to never be too late to do so. Recently, Baker’s lab tested senolytics on a cage full of very old mice. They didn’t miraculously rejuvenate, but their decrepitude eased. For this reason, Cox sees senescent cells as “the most interesting therapeutic target” in the anti-ageing portfolio.
Other researchers agree that the science holds great promise. “Senotherapy has exploded,” says Gems. “There are a number of very good signs about it. It gives a proper account of how multiple diseases of ageing are being generated from a single underlying cause. It could really change things.”
Clear out the trash
One great advantage of senolytic drugs is that people could take an occasional dose, perhaps once every six or 12 months, to clear out the cellular trash. Most other anti-ageing drugs would probably have to be taken much more regularly, which raises safety concerns.
If you are wondering when these drugs might be available, the answer is soon. Maybe. The usual caveats about the vagaries of drug development apply, but from where we are now, they could be in the clinic in as little as six years, says Peyer. You can even get them now, but that is a risky business (see “DIY anti-ageing”).
Peyer’s optimism is buoyed by news from the first human experiments of senolytics. In January, a team led by Mayo Clinic researchers reported results from a pilot trial targeting a lung disease called idiopathic pulmonary fibrosis. This condition has an unknown cause, but is characterised by a build-up of senescent cells. In the trial, 14 people were given doses of two drugs – a leukaemia treatment called dasatinib and a plant pigment called quercetin – over three weeks. They tolerated the drugs well and showed some improvements in symptoms.
That is miles away from being proof they cure anything. But also in January, Unity Biotechnology, a firm seen as one of the companies most likely to succeed, announced promising results from an early clinical trial of a senolytic for osteoarthritis. Approval in a clinical trial for a specific condition is a necessary first step for any anti-ageing drug (see “Ageing isn’t an illness…”).
If you worked on anti-ageing drugs that you believed were safe and effective, would you be tempted to dabble? Many scientists and biotech execs are. “We know biohacking happens all the time,” says Lynne Cox, a biochemist at the University of Oxford. “There’s a lot of DIY.”
One of the most popular hacks is the diabetes drug metformin, which has a good safety record and extends life and the duration of health in some animal models, although it recently failed a major test in mice. Other hot favourites are spermidine, a nutritional supplement that restores mitochondrial function in older mice, and nicotinamide mononucleotide, another compound shown to extend longevity in mice.
At the more extreme end of the spectrum are people who occasionally take the chemotherapy drug dasatinib and plant extract quercetin, a combo being investigated as a senolytic, a drug that targets worn-out cells. They are “very cheap, readily available, easily used”, one user told me. At least one biohacker has used human growth hormone to try to regenerate his thymus, a key organ of the immune system that degenerates with age.
None of these has been tested in human trials and so people using them are clearly taking a risk – and not just with their health. “I’m deeply concerned about biohackers, because if somebody dies taking a senolytic, it is going to damage the field for quite some time,” says Cox.
The good news is that safe interventions that increase longevity are available to all. Intermittent fasting has been shown to work, and exercise appears to be a senolytic. Spermidine is found in many foods, especially the fermented Japanese soya-bean dish called natto. These may be less tempting than a pill, but they are definitely safe.
If these front-line attempts fail, there are plenty more. Two other companies, Cleara Biotech and Senolytic Therapeutics, have drugs in development. Another approach is “senomodifiers”, which don’t kill senescent cells, but coax them to start dividing again. Intriguingly, the most promising senomodifiers are based on resveratrol, the compound that flamed out so spectacularly last time around.
Further over the horizon are molecules that can rejuvenate white blood cells and restore their prowess at clearing senescent cells. “Companies are popping up everywhere. Everyone understands senolytics is a gold mine,” says the CEO of a company called Repair Biotechnologies, a man who goes by the name of Reason.
Another hot area is a new take on an old anti-ageing strategy: caloric restriction. If you were playing buzzword bingo at a conference on ageing, “senolytics” would be top of your list. But a close second would be “mTOR”. This is a protein complex inside cells that plays a critical role in ageing, and which gerontologists have long believed could be targeted to slow the process down.
mTOR is an acronym for “mechanistic target of rapamycin”, which tells you more about how biochemical knowledge advances than what mTOR actually does. The keyword is rapamycin, a drug developed as an immunosuppressant for transplant patients that later turned out to extend lifespan in worms, flies and mice. Biochemists discovered it was interacting with a protein complex in the cell. They named this mTOR and set about working out what it did.
What they discovered made biological sense. One of the most reliable ways to make an animal live longer is to starve it. Caloric restriction and periodic fasting have been shown to extend both lifespan and healthspan in every animal they have been foisted on, probably because they activate some of the protective pathways that are progressively blunted by ageing.
The mTOR complex turned out to be a crucial hub in this system. “It evolved for surviving starvation,” says Mannick, whose firm resTORbio is developing drugs based on rapamycin. “Its key function is nutrient sensing. If you eat, it is activated and tells the cell to grow and divide. If you don’t eat, it switches off, which upregulates protective pathways.”
These pathways include autophagy, the process by which cells scavenge dysfunctional organelles and molecules for energy. “It’s sort of like a garbage disposal system for cells,” says Mannick. This reduces the accumulation of the gubbins that would otherwise build up in tissues, and hence slows or even reverses the ageing process. Intriguingly, mTOR seems to become progressively stuck in the “on” position as animals age.
Actual starvation isn’t necessary: rapamycin is just one of many drugs known to inhibit mTOR in mice even when they are first given it only late in life. And just as with senolytics, the science is now being turned into therapies for humans.
The regeneration game
Last year, resTORbio published the results of a clinical trial to see whether mTOR inhibitors can reverse immune system ageing. In it, 264 people over 65 were given two drugs – not rapamycin itself, but newer compounds that work in a similar way – followed by a flu shot. Older people often fail to respond to the injection and influenza is a major cause of hospitalisation and death among this group. But those given mTOR inhibitors responded much more powerfully to the shot and caught fewer respiratory infections. A bigger clinical trial has since confirmed the effect. This year, resTORbio hopes to move into the final stage of clinical trials, before filing for regulatory approval in 2021.
If either of the drugs succeed, it would be a medical landmark: the first of a new generation of medicines specifically designed to target ageing. “It’s a game changer,” says Mannick. “This shows what we might be able to do if we start targeting ageing pathways. It could really change healthcare.”
The chances are that resTORbio’s drug will fail, but there is no shortage of others that hit mTOR or targets up or downstream of it. The pathway has long been implicated in cancer, heart disease and neurodegeneration, says Partridge, so has been “hammered by the pharma industry”. Many existing drugs for all sorts of diseases target it.
Plenty of these drugs have now been tested for their anti-ageing properties in a programme Miller runs on behalf of the US National Institute on Aging. It puts promising compounds through their paces in mouse experiments at three facilities. It has validated six compounds, as well as eliminating some promising ones, including the diabetes drug metformin. Most of the winners inhibit the mTOR pathway, but some work in mysterious ways, suggesting that there are still things we don’t know about the basic biology of ageing and hence new avenues to explore.
Other approaches are in the pipeline too (See “The lure of young blood”). West – who we met on the plane at the start – has a new company, AgeX Therapeutics, which is working on using stem cells to replace worn out cells. Other start-ups are developing ways to regenerate a gland known as the thymus and restore mitochondria.
It is still early days. “The path between these initial discoveries and something that I personally would give to a lot of people has many steps,” says Miller. “We have good reason to think there is such a pathway, but we’re only at the beginning.” Nonetheless, there is a decent chance that, by the time I get to 60, I won’t face a descent into decrepitude, but a long and productive third age.
“A new biotech company is about to launch an anti-ageing pill on the US market”
These hopes might still be scuppered. “The biology of ageing moves so quickly,” warns Gems. “Things look incredibly plausible, then a couple of years later they disappear.” It is possible that no drugs will emerge from the pipeline. Another risk is that they will emerge too soon, before they are properly verified. For some in the industry, waiting five years for a drug to get through trials is five years too many.
In a few weeks, a new company spearheaded by a successful biotech investor and a renowned academic will launch an anti-ageing pill on the US market. The details are under wraps, but it will be an mTOR inhibitor that hasn’t been through clinical trials. It has barely even been tested in humans. But based on mouse studies, the company claims it can add eight years to lifespan and fulfil the goal of extending healthspan.
The medicine is a cocktail of existing compounds that are “generally recognised as safe” by the US Food and Drug Administration. As such, it doesn’t need to be tested in clinical trials, but can be sold as a nutritional supplement. That means the company cannot make explicit health claims, although the name of the product drops heavy hints and the promotional materials, if approved, will say something like: “modulates pathways associated with normal ageing and promotes improved healthspan”. Would I take it? I would give it a try, if I could afford it.
After the company announced its plans at a recent scientific conference, the mood in the room became testy. Many scientists expressed disapproval or anger, fearing yet another round of hype and disappointment that could damage the whole field and send investors running to the hills. “Some of us are uncomfortable about companies coming in and leaping ahead without first getting evidence in humans,” says Lord. “There could be reputational damage. The last thing we want is for the whole field to be marred.” Mannick echoes this: “We can do so much good, but we have to do it right,” she says.
So maybe this is an unbelievable story that you have heard before. But for all of our futures, I sincerely hope not.
Ageing isn’t an illness…
Leading anti-ageing firm Unity Biotechnology is having success with a drug designed to treat osteoarthritis. But, of course, osteoarthritis isn’t ageing, just a consequence of it. Even if Unity’s drug clears all the hurdles it faces, it won’t enter the market as an all-purpose, anti-ageing medicine, but as a drug for osteoarthritis.
That would be progress, but far from mission accomplished. “The goal for this industry is to create a medicine that can extend healthy human lifespan by preventing multiple diseases,” says James Peyer at Apollo Ventures, which invests in biotech start-ups. “But you can’t do a clinical trial for that.”
Herein lies what may be the biggest obstacle to this entire enterprise: you can’t treat ageing as a disease, because it isn’t one.
To get any drug through clinical trials, you need an “indication”, a single illness that you can demonstrate your drug works against. But ageing isn’t an indication, or at least not one that is much use to biotech companies. The US Food and Drug Administration (FDA) has recognised it as such only once, in a small-scale trial of the diabetes drug metformin, for many years the great hope of anti-ageing medicine. But the biotech world dismisses this as a way forward because of the time it would take to finish the trial. “The obvious test for a drug is to give it to an awful lot of 20 to 40-year-olds and come back in 50 years, but that’s impractical, no one will ever do that,” says Richard Miller at the University of Michigan.
It may be possible to find a proxy indication, but that would require major scientific progress. Despite many candidates, there is as yet no widely accepted method to measure somebody’s biological age, and hence no way to tell if an anti-ageing medicine is doing what you want it to do.
The route through the morass, says Peyer, is to carefully select one age-related disease and establish that your drug works for it. You can then fan out to other diseases. This is the strategy that many of the leading companies are pursuing.
In time, the authorities may conclude that a drug works across a range of age-related diseases and give it blanket approval, says Peyer. There is precedent for this in the form of cancer drugs called PD-1 inhibitors, he says. These first worked in melanoma, and were then tested on a series of other cancers. “After success, success, success, the FDA said, ‘We get it. You don’t need to do another clinical trial, just go ahead and use the drug in all solid tumours’,” says Peyer. “A longevity drug is going to follow the same rubric.”
The lure of young blood
An enduring hope in anti-ageing circles is a modern take on an old discovery. In the 1970s, biologists began experimenting with a gruesome procedure called parabiosis, where the circulatory systems of two animals are plumbed together, sometimes for weeks on end, so they share blood. Parabiosis was developed to help in the study of conjoined twins, but it also hinted at some intriguing effects on longevity. Old mice joined to young ones were rejuvenated, while the young mice aged prematurely.
More recent experiments carried out at Stanford University in California confirmed the effect. “They found incredible things,” says Mark Allen, CEO of a company called Elevian. “Old animals exposed to young blood had, by many measures, a reversal of biological ageing in the heart, brain, lungs, bone, many organs. The opposite happened in young animals.” Even just injecting blood plasma from young people – or plasma from human umbilical cords – rejuvenates old mice.
This is the basis of the “young blood” craze that has made headlines around the world and which recently prompted the US Food and Drug Administration to warn about unregulated plasma transfusion therapies.
The two leading companies in the field – Elevian and Alkahests – aren’t in the transfusion business. Regular transfusions are impractical, so they are looking to see what it is in blood that might cause the effect. Elevian is focusing on a protein called GRF11, which it says declines with age and has broad rejuvenating effects on mice. Alkahest has a drug that blocks the action of a blood protein that rises with age and is associated with a number of diseases. It recently announced positive results from a trial on its initial target, an eye condition.
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