Courtesy copyright GETTY

---

As CEOs of the expanding cadre of companies set up to tackle ageing and age-related diseases joined thought-leading scientists for the Longevity Leaders conference in London this week, the mood was much sunnier than the damp, grey February weather. There has never been more optimism that the holiest of grails, extending human lifespan (or at least “healthspan”, the period of good health most people can expect to enjoy) is finally within reach. 

Money is pouring into new ventures dedicated to understanding ageing (this week saw Sergey Young launch a $100m Longevity Vision fund, hot on the heels of Jim Mellon’s Juvenescence venture with its own $100m kitty) at a rate that proves that what was once seen as the preserve of crackpots is fast becoming mainstream.  No longer do serious scientists laugh at the idea that modern technology, from genomics to gene editing, might one day soon deliver not only insights but medicines to extend lifespan.  And an eager media jumps on each new study showing animals engineered to live longer, from worms to mice.

But is this optimism well-founded? Will the same approaches that brought us new drugs for diseases like cystic fibrosis, and gene therapies to cure inherited diseases, crack biology’s biggest secret?

The proponents, busily raising cash for a veritable fireworks display of moonshots, clearly think so.  And the title of the research science session at the Longevity Leaders conference reveals the dominant approach in 2019: “Cracking the code to treat ageing as a unitary disease”.  The assumption underlying all this exciting new activity is simple: ageing is a disease like any other, so we can beat it like we might beat blood cancers with immunotherapy.  All we have to do is understand what “goes wrong” with the body as it gets older, and “put it right”.  Maybe not exactly simple, but certainly tractable.

Yet there is a niggling logical flaw with this fundamental assumption that ageing is some kind of bug in the system: the problem is we ALL have it.  That's simply not true of diseases we can treat.  If you haven’t been diagnosed with Duchenne Muscular Dystrophy (DMD), cystic fibrosis or haemophilia by the time you reach 18, then you haven’t got it and you never will.  That's because these diseases really are caused by bugs in the system: a single faulty component, coded for by a single faulty gene, makes those individuals function less well than those without the bug.  Treating these diseases is the same as patching an operating system – putting right the malfunctioning component makes the system perform as well as the original design allowed.

But ageing isn’t like that. Of all the one hundred billion or so humans that have ever lived we can be pretty certain not a single one of them has lived beyond 125 years old.  Yet, there is no fundamental biological limit against living longer: tortoises and oak trees manage it.  Individuals of some tree species can live a thousand years or more.  So why do humans all degenerate and die at around the same age (unless, of course, something gets us earlier – such as an infection, a road accident or a bug in our genetics...)?  The simplest answer is because ageing is a feature – and NOT a bug.

Built-in obsolescence doesn't sound like a great feature for the prototype human.  So why might we all possess such a feature?  Studies of the humble yeast can throw some light on that question: some yeast, appropriately called “budding yeast”, reproduce by a daughter cell budding off from the mother.  A mother can spawn twenty or thirty such daughters before they stop reproducing and die.  Crucially, at each budding event the small daughter cell receives the best protein components, and the mother retains any damaged ones.  This ensures each new generation remains as “fit” as every previous generation – but at the same time results in the mother cell getting less fit – in other words, less competitive at harnessing the resources in the environment to grow.  She grows more and more slowly, and eventually fails to create a new daughter altogether.

In effect, ageing of the individual is the unavoidable price to pay for keeping each new generation as capable as the last one.  Ageing may not itself be the feature that's selected for, but is instead the inescapable by-product of some essential biology.  Worse still, as the ageing individual gets less fit she risks becoming a burden to the species – slow, inefficient and reproductively incapable.  Any food she consumes is, in effect, wasted.  So the species as a whole becomes more competitive in its niche if she dies.  Both these effects mean that evolution can select FOR ageing and death of the individual.
What experiments with yeast tell us is that there is an optimum lifespan for any organism, which depends on the ecological niche it finds itself in.  Some species compete through speed, others through robustness. But one thing is for certain: evolution has already optimised the essential physical trade-offs to give the species the optimum performance as a whole in that given niche.  If ageing were a bug, evolution would have quickly eliminated it.  Instead, ageing is a feature evolution chose for us.

We already know that the physical laws of the universe limit what is possible – grass and oak trees co-exist in balance in a field because they have evolved different but equally competitive solutions to the trade-off between speed and robustness.  Grass grows quickly, but dies as soon as resources become limited.  Oak trees take an age to establish but are virtually indestructible.  That physics prevents you doing both at the same time is obvious just by looking at the countryside: if evolution could generate oak trees that grow as fast as grass (or grass as robust as oak trees) then such a Gr-oak™ would have dominated the ecological niche.

Evolution, then, optimised the trade-off between speed and robustness in humans perfectly for their niche. Our excellent, but still limited, robustness – which manifests as ageing – is a feature because it is the necessary price to pay for the competitive excellence we enjoy in our youth.

Seen this way, ageing is not a “unitary disease” (in effect, a “bug” in the system) that can be patched, by putting right some supposed imperfections that evolution has somehow failed to remove.  It is an immutable feature of being human.

Does that put pay to the rising hopes of increasing lifespan, or even “healthspan”, that investors are backing today? Yes and no.  It certainly re-affirms the long-held belief that ageing is different and more complex than the diseases we typically can treat.  It means that hopes of identifying what “causes” ageing from, for example, genetics or genomics are likely to fail (in the same way you can work out why one smartphone doesn't work by comparing it to others that do and spotting the differences; but you cannot work out how it delivers its features by simply examining the isolated functions of its components).  And it sets a very high bar for interventions that increase lifespan – 21st century scientists will have to do something evolution has not yet managed.

And yet there is still hope. Evolution moves at a tectonic pace – almost infinitely powerful, but almost infinitely slow (particularly for species, like humans, that already have a long generation time).  Our lifespan, a key “feature” of us humans, was optimised for an ecological niche we now no longer occupy.  For early man, competing for resources with sabre-toothed tigers and woolly mammoths, a degree of speed and agility was needed – which had to be paid for with reduced robustness.

But for modern humans, almost complete dominance of our environment, thanks to our collective brains, is assured.  A modern human could shoot a sabre-toothed tiger without leaving his armchair.  This raises the possibility that mankind can re-engineer a different solution to the physical trade-offs that determine our lifespan.  Changing one feature (ageing) will, of course, have to be paid for in other ways – but maybe those costs that would have been significant (in terms of our survival) a million years ago are barely noticeable today.

If this analysis is correct, then we need to think very differently about approaches to preventing “ageing”.  It is not, as the Longevity Leaders conference will discuss, a case of patching a bug – but instead a case of engineering a whole new feature.  Materially increasing lifespan, then, will require us to create Human 2.0™.

Is Human 2.0™, who perhaps grows up more slowly, has slightly less athletic prowess, but lives to a grand old age of 200 years, a fantasy or a possibility?  Definitely the latter – but the ethics associated with the necessary interventions will be much more complex than simply patching a bug in Human 1.0.

Thinking of ageing as a feature, and not a bug, promises to take ageing research in an exciting, but wholly new, direction.

David Grainger is currently Chief Executive of Methuselah Health Inc, a privately held biopharmaceutical company discovery and developing treatments for age-related diseases.