Forever young: The science of disrupting death and growing old gracefully

Heart disease, strokes, cancer and dementia are the four horsemen of our apocalypse. But instead of fighting them off individually, a burgeoning biotech sector is waging war on the scheming general that sends them all into battle – old age itself.

Not content with transforming the way we live, tech billionaires are planning to disrupt death by stalling the rate at which we age. By teaming up with Yuri Milner and investing in cellular rejuvenation research at Altos Labs, Jeff Bezos has recently rejoined the crowded field of silicon valley giants who are trying to hack our biology.

Paypal co-founder Peter Thiel and Oracle’s Larry Ellison are already there while Google was a characteristically “early adopter” – establishing its anti-ageing subsidiary, Calico, back in 2013.

Given that a major anti-ageing breakthrough is anticipated in the next decade, the new field of Geroscience biotech is attracting a fresh wave of venture capitalists sensing an imminent return on their investment.

But what are the social and ethical implications of a brave new world that could allow Jeff Bezos to extend his prime, while the rest of us wither on the vine?

Computational biologist, Andrew Steele explains why that’s a common misconception: longevity might be a by-product of anti-ageing research but the real objective is extending healthy lifespans and the years we are free of debilitating disease: “Cancers, heart diseases and strokes are proxy wars and usually the precursor to all of that is getting old,” he says.

As a seasoned campaigner for more transparent government funding for medical research, Steele is convinced that the current model has its priorities all wrong: “We’ve found that government funding for cancer research works out at just £2.80 per citizen per year – for a disease that affects one in three of us! But if you try to find out how much we spend on anti-ageing research, nobody knows. Ageing is just not seen as a distinctive sphere of medicine but it underpins everything. Even biologists don’t know about ageing. You can do an entire biochemistry degree without ever having a lecture on the subject. I wanted to raise the awareness of this field – the world’s biggest humanitarian challenge – that even doctors don’t understand. I’m 36 now so I have a one in a hundred chance of dying in the next year. By 90 it will come down to the roll of a dice because I’ll have a one in six chance of death. Our chances of dying double every eight years. But what is so universal about our remarkably consistent, synchronised increase in risk until we descend into frailty and death?”

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It’s the question that drove Steele to pivot from his physics PhD at Oxford to a new career as a computational biologist looking for the patterns in big data that might unlock the secrets of ageing.

In his lauded 2021 book Ageless: The Science of Getting Older without Getting Old, Steele sets out a compelling thesis: rather than developing treatments for more than 200 types of cancer, research should instead focus on the DNA damage that underpins them all, the chronic age-related inflammation that emboldens them and the increasingly frail and failing immune defences that allow them to take root.

There are nine recognised hallmarks of ageing of which stem cell exhaustion, mitochondrial dysfunction, senescence and telomere attrition are perhaps the best known.

When I ask Dr Steele which area is likely to see the biggest breakthrough in the next decade, he is unequivocal. “It’s definitely senescence. When ageing cells stop dividing they become senescent creating a toxic cocktail of molecules that spreads around the body. Young people have strong immune systems that are very good at clearing these toxins away. But in older people, the toxic molecules accumulate in tissues causing damaging inflammation.”

Steele enthuses about a new generation of Senolytic drugs that have been shown to slow inflammation and ageing in mice trials. “The mice become biologically younger, plumper and less frail; they become better runners on treadmills and improve cognitively. And they actually look fantastic!”

There are up to 30 Geroscience companies developing senolytic drugs around the world. They hope to establish proof of concept by establishing effective treatments for diseases like lung fibrosis and osteoarthritis as a precursor to licensing a universal anti-ageing drug.

Meanwhile, in the absence of a senolytic drug, how can we help the body rid itself of those inflammatory by-products? Fasting or dietary restriction has been shown to significantly extend life expectancy in fish, mice, and rats by inducing a state of autophagy in cellular tissue.

Literally translated as self-eating, autophagy is the “tidying up” process that occurs when “hungry” cells are denied fresh supplies of glucose and instead recycle and feed off cellular material, reducing the build-up of those inflammatory toxins produced by senescence.

Dietary restriction has several influential advocates in the longevity community. David Sinclair, a professor of biology and genetics at Harvard, maintains that it’s not what you eat that matters, but when. By taking on the bulk of his calories in the early evening and then skipping breakfast and sometimes lunch too, Sinclair is practising what he preaches to maintain low blood sugars. Sinclair does indeed look unnervingly young; although he is in fact 53, at first glimpse he could easily pass for a thirty-something.

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But it’s a controversial approach not least because experts can’t agree on the length of time, larger mammals like human beings would need to fast in order to induce an effective state of autophagy.

Steele stops short of recommending full-blown dietary restriction: “Participants in human trials have had to withdraw because of anaemia and there’s some evidence of a thinning effect on bone density. Subjects have complained of feeling permanently cold and of course, there’s a constant hunger that some people don’t ever get used to,” he says.

If only there was a drug that could safely mimic fasting, by lowering blood sugar and inducing autophagy with all of its anti-ageing benefits. Well, there might be!

Metformin had been used to treat type 2 diabetes for decades. It first attracted attention when scientists noticed that patients who took it to control the chronic condition actually outlived non-diabetics.

Metformin works by reducing blood sugar by limiting the amount of glucose that is dumped into the bloodstream, and by blocking the absorption of carbohydrates in the intestine. It also inhibits the liver’s production of new glucose.

If it wasn’t for Covid the TAME trial – short for Targeting Ageing with Metformin – would already be underway. In a randomised double-blind placebo-controlled trial set to last six years, we will soon discover if 1,500 patients on metformin contract age-related diseases like cancer, heart disease and dementia later than those in a parallel control group.

Confusingly, whenever a drug has so many good things going for it, that it’s not always easy to tell which factor causing successful outcomes, trial clinicians refer to it as a “dirty drug”. That's a good thing!

In anti-ageing terms, Steele thinks that metformin could be “an absolutely filthy drug”.

Metformin is believed to not only enhance autophagy and so reduce the effects of senescence but also to delay stem cell ageing, and protect against DNA damage by stopping the ends of chromosomes (telomeres) from fraying with age. It’s also believed to boost NAD levels – the molecule that governs energy release at a cellular and whole organism level.

But even if the benefits of taking metformin are shown to be modest with longevity gains likely to be measured in months rather than years – Steele explains why the TAME trial could still revolutionise medicine.

“Metformin could change not just the mindset but also the regulatory environment. At the moment you can’t get a drug approved to treat ageing because the FDA don’t recognise it as a medical condition. But the TAME trial has worked with the FDA to establish protocols which would allow it to become the first drug to be licensed for anti-ageing which would establish a model for the future approval of anti-ageing drugs.”

The new wave of senolytic drugs are likely to be among the first beneficiaries of the new precedent.

Because it’s been around for so long that it’s now out of patent, generic versions of metformin could be cheaply produced on a massive scale. Another older out-of-patent drug, rapamycin, has also attracted a lot of interest. Although it’s a potentially harmful immunosuppressant used to prevent the rejection of kidney transplants, safer, low doses of rapamycin have also been shown to extend lifespans in animal trials.

Steele explains that anti-ageing research used to be prohibitively expensive and impractical – because to put it crudely – scientists had to wait for participants to die before meaningful data could be generated. This has been hugely problematic given that humans live so much longer than mice.

But the recent development of an epigenetic clock – accurate biochemical ageing of DNA – means that we can now discover the impact of a drug on the rate of ageing during the trial itself, without waiting for the demise of a patient.

Epigenetic clocks will accelerate anti-ageing research with senolytic drugs again likely to benefit.

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Steele believes that unless you’re at death’s door, everybody is likely to benefit from anti-ageing research in the coming decades but warns in his book that those gains be incremental: “The cure for ageing will be a jigsaw of treatments which evolves with time, a succession of technologies which gradually improve life expectancy to the point that people will notice that they’ve stopped ageing – not a miraculous magic bullet discovered in a flash of insight by a lone genius.”

Meanwhile, Steele sets out his best anti-ageing advice in a chapter called “How to live enough to live even longer”: don’t smoke; follow a plant-based, low carbohydrate diet, stay lean and sleep well. But it’s exercise that may well matter most. Steele repeats the advice that has become such a mantra of medical science in recent years: “If exercise were a drug it would be the most valuable pharmaceutical ever developed.”

And in terms of its anti-ageing benefits exercise may well be the “filthiest” drug of them all. Exercise is believed to not only reduce senescence and inflammation in muscle cells but could also boost telomere length, stem cells, and mitochondria.

In addition to the efforts of the Silicon Valley billionaires, anti-ageing has also become a cottage industry with an army of so-called biohackers following the latest developments closely and experimenting with cocktails of metformin, rapamycin and other supplements as well as running the full gamut of dietary and lifestyle hacks to slow the ageing process.

Ever the computational biologist, Steele rues the lost opportunities for big data collection and wishes it were possible to regulate the biohackers’ efforts safely within the structure of a controlled trial.

Although he is not experimenting with any anti-ageing drugs (yet), Steele can understand why people in advanced middle age would want to try anything to delay the onset of age-related illnesses. When he’s 65 he thinks he’s likely to do the same because, at that point, you have far more to gain than to lose.

Given what’s coming down the track and that, on average, senior citizens rack up five separate comorbidity diagnoses by the age of 80, the final decade of indignity and dependence is not something you’d wish on your worst enemy let alone the people you love.

At the moment Steele is grateful for the way venture capital is driving the research but he believes at some point, the government have to step up and assume responsibility by funding a “medical moonshot” into anti-ageing.

“It might sound mundane but the single greatest piece of advice I could give people would probably be to write to your MP and spread the word about anti-ageing research. It’s the single most significant thing you can do to improve the health and happiness of the people you love.”

@seansmithwrites