Drug Baron

The Man Who Cured Ageing?


When Disraeli supposedly said “The only two certainties in life are death and taxes” he could not have imagined that little over a century later, such rock-solid logic could be under threat.  If a team of Croatian scientists, led by Professor Miroslav Radman, are correct, death need be no certainty.

DrugBaron was fortunate to spend several days with Prof Radman and his team earlier this year, and hear about their research into proteome instability, and the insights that has given them into the mechanism of aging.  Most intriguingly, these insights have the potential to underpin a whole pipeline of novel therapeutics for a wide range of degenerative diseases, and perhaps, ultimately, for ageing itself.

Swimming in the sea along the beautiful Adriatic coast around Split, home to the Mediterranean Institute of Life Sciences, you can find a tiny marine creature, a medusa, that potentially carries the secret to eternal life.

“For humans, death seems inevitable” says Professor Radman, “but that’s not true for all creatures.  The medusa Turritopsis seemingly lives for ever.”

Its easy to imagine living forever in the temperate blue waters of the Adriatic, but other creatures take this indestructability to whole new levels: an unassuming small pink bacterium, called Deinococcus, can survive doses of radioactivity ten times higher than those used to sterilize food and medical instruments, while the caterpillar-like tardigrades can survive two weeks on the outside of spacecraft at -270ºC in a vacuum.

Screen Shot 2013-08-14 at 08.51.59“Studying these indestructible species promises to teach us why humans degenerate and die” smiles Prof Radman, “and maybe show us how to stop that process” he continues with a gleam in his eye.  Is the fabled Elixir of Life about to become a reality in the Mediterranean sunshine?

Asked why we age, most scientists will tell you that the DNA, which carries the blueprint for making every protein in the body, accumulates mutations during your lifetime, causing cells to make faulty protein building blocks.  Eventually, enough damage accumulates to make the plans unreadable, or the building blocks so shaky that everything falls apart.

“Our studies of radiation-resistant bacteria tells us that is completely the wrong way round”, explains Anita Krisko, who together with Prof Radman is compiling an entirely different explanation for ageing.  “Even a low dose of radiation shatters the DNA, both in normal bacteria and the radiation-resistant ones.  The difference is that the resistant ones can repair the DNA and so avoid death.”

We have known for forty years how special proteins can repair DNA damage – thanks again to Prof Radman who discovered the SOS Repair pathway in bacteria in 1975, for which he has received numerous international prizes.  “It’s the loss of these repair proteins that triggers death – the radiation damages the proteins as well as the DNA, but as long as the proteins still function to repair DNA the organism survives.”

The key difference between the radiation-resistant bacteria and normal, every-day bacteria, then, has nothing to do with DNA – the proteins in the resistant bacteria are somehow protected from damage.

In fact, it is not the proteins themselves that are inherently more resistant to damage.  Instead, the radiation-resistant bacteria produce high levels of a protector molecule that chaperone its proteins.  And Prof Radman and his team have identified this ‘protein guardian’.  “If we give normal bacteria this factor, we give them the indestructible properties” he finishes.

So if we can make ‘immortal’ bacteria, can we pull off the same trick in humans?

“There is clear evidence that the same processes drive human ageing” continues Dr Krisko.  “If we look in cells from older people, there is much more protein damage.” But the strongest evidence comes from the rare disease, progeria, where young children age so rapidly that by their teenage years they appear as old as a pensioner.  In progeria, protein damage accumulates much faster than in healthy people.

This new understanding offers a real opportunity to treat progeria, and the milder premature ageing disease called Werner’s Syndrome.  The ‘protein guardian’ Radman’s team identified in the radiation-resistant bacteria can protect human proteins too.  “If we can find a way to deliver it as a drug we can give these people real hope of a cure” says the Professor, clearly excited by the prospect of putting his science to good use.

And what about the rest of us, who age more slowly, but age nonetheless? Can this same factor halt the aging process in all of us?

Professor Radman

Professor Radman

The gleam in Professor Radman’s eye is back: “Probably not.  Healthy people most likely already have plenty of their own ‘proteome protector’ molecules, made by their own metabolism.  But the same insight – that accumulation of protein modifications rather than DNA mutations underpins ageing – reveals a whole new approach to treating degenerative diseases associated with ageing.

These degenerative diseases, like Alzheimer’s Disease or Parkinson’s Disease,  are caused by damage to particular proteins (rather than accelerated damage to all proteins that we see in progeria).  Evolution has optimized long-lived proteins not just for function but for resistance to damage, such as oxidation, as well.  As a result, any change in the sequence (due to single nucleotide polymorphism, for example) makes the protein less robust.  For each of us, therefore, depending on our unique genomic sequence, there is a particular protein that is more vulnerable than the rest – and the function of the protein that’s lost determines the particular disease you develop.”

And its not just a hypothesis.  Prof Radman and his team are accumulating new evidence, showing the damage that occurs when the sequence is altered. This understanding of how protein damage occurs allows us to design specific ‘protein guardians’ for these vulnerable proteins – a whole pipeline of high-value drug product candidates invisible to conventional discovery approaches.

For Professor Radman, whose youthful twinkle belies his sixty years, it will almost certainly take too long to turn these ideas into drugs to secure his own immortality – but if he is right, he will surely secure a place in science history alongside Europe’s other geniuses such as Newton, Einstein and Pasteur, as the man who cured ageing. Another kind of immortality.

  • Cassidy

    The message here feels a bit befuddled. You say that protein modification is driving aging, not DNA mutations… I assume you mean post-translational modifications (PTMs)? If so, more explanation is needed. Still, you mention SNPs as a mechanism generating aberrant proteins? Which is it? If it is NOT PTMs, then it indeed goes back to DNA mutations.

    Also, when you discuss DNA repair proteins you leave out any discussion of the fact that repair proteins themselves are encoded by genes which are equally subject to mutations caused by oxidation, radiation, etc – in my understanding, it is the gradual degradation of these proteins (ie, mutation of these genes), as well as other housekeeping genes/proteins that primarily drives aging. My view remains that DNA mutation, coupled with molecular paradoxes like the end-replication problem, are the forces that control molecular senescence.

    • davidgrainger

      Thanks for the comment. Such a short overview necessarily compresses some of the details.

      Yes, Prof Radman’s work suggests its protein modifications driving ageing – all kinds of PTMs such as oxidation (carbonylation), glycation and so forth. The link with the DNA is that SNPs (ie. germline differences in sequences between individuals, as opposed to mutations acquired during life) make proteins more susceptible to oxidation (because the evolution optimised the structure to be compact and oxidation-resistant, so changes away from this optimum make them slightly less optimised and so more susceptible to oxidation). Thus different people (with different genomes) have different long-lived proteins that are more susceptible to damage. Thats why different people get different age-related degenerative diseases.

      At the same time it explains why many of these diseases of middle and old age are clearly heritable (from twin studies) but do not show linkage to specific SNPs even in very large GWAS studies – thats because many many SNPs that are silent in terms of their effect on the protein’s normal function interact to yield increased susceptibility to oxidative damage,

      Indeed, the DNA repair complexes are critical in this story – because when they are damaged by radiation, oxidation etc then the consequence is increased mutation rates in the DNA. In other words, instability of the PROTEINS leads to instability of the genome.

      This is precisely what Prof Radman’s key experiments in Deinococcus show: the DNA damage can be repaired as long as the DNA repair PROTEINS are in tact. As soon as the DNA repair proteins are damaged, then (and only then) does the DNA damage become fatal.

      Such observations are not at all consistent with DNA damage driving ageing and death (since in Deinococcus, and indeed in E Coli, it is PROTEIN damage that correlates with death, while DNA damage does not). Further, transferring the proteome protector from Deinococcus to E Coli transfers the protein protection and confers resistance to radiation-induced death. By going beyond correlation, these experiments prove that – for these bacteria at least – it is not DNA mutation but accumulated protein damage that controls molecular senescence.

  • Matthew Clark

    You need to get Prof Radman together with Aubrey de Grey here in Cambridge. That’s a start-up I’d invest in!

  • http://www.hollyip.com/ Suleman Ali

    This is a very thought provoking article. I would just add that mechanisms at the DNA/protein level are only part of the ageing story. Ageing, at least in humans, is a very multi-level process. Our molecules degrade, our cells degrade, our organs and bones degrade. Essentially there has been no evolutionary selection to preserve us much beyond the age of bringing up children. So the products of DNA coding themselves are flawed. For example vesicles in cells are going to get filled up with things the cell wants to get rid of, and there’s no way of avoiding that. Given that so many different things go wrong in ageing it’s going to be difficult to delay it substantially or cure it.

  • Jim Luterman

    Interesting article — and also interesting to note the synergy with this recent story (http://www.medicaldaily.com/biological-immortality-gabby-williams-genetic-condition-prevents-8-year-old-aging-252081)… hopefully some synergistic research findings from both approaches can benefit patients!

  • Amarshall

    This all seems a bit starry eyed and also rather upstream and preliminary for Drug Baron. Other than being a pioneer in DNA repair, its unclear why Miroslav Radman deserves special attention now. The post does prompt the question of where aging research should be prioritized: aging itself or diseases associated with aging. That might sound like splitting hairs and there clearly is overlap, but one might find ways of prolonging lifespan and cosmetic appearance without having much effect on diseases that manifest in old age. Given the rudimentary state of our understanding of aging research and the numerous small effect risk factors that likely contribute to accelerated aging over a lifetime, it would seem a better use of resources at this stage to focus on lifestyle and diet for prolonging healthspan (rather than hawking some elixir to consumers over a lifetime) and instead focus on traditional drug development for specific diseases that manifest as we age.

    • davidgrainger

      The central insight from Prof Radman – that proteome instability leads to genomic instability rather than the other way round – is, at least in the opinion of DrugBaron, of central importance to understanding the biology of ageing. The door that it opens can potentially allow us to discover drugs to treat the diseases of ageing that have, thus far, proved almost entirely intractable – due principally to the fundamental misunderstanding of the principal cause of ageing itself. For that insight, it seems entirely appropriate (and not at all premature) to focus on the work of Prof Radman today.

      Once you recognise that damage to specific proteins is key, the technology exists to identify which proteins are becoming damaged in which diseases. Such studies, rather than massive GWAS studies, have the potential at last to discover the real cause of diseases such as Alzheimer’s Disease.

      Once discovered, molecules that alter the conformation of the damaged proteins so they resemble the native conformation can be developed. Such targets (and hence drugs) could never be discovered by conventional approaches. They are ‘invisible’ to current approaches.

      No-one is suggesting “hawking some elixir” to consumers – but instead to use these groundbreaking insights to open fertile new pastures for drug discovery for diseases that current approaches, built round the existing paradigm of the biology of ageing, have completely failed to address.

      That is neither upstream nor starry-eyed – though in the sense that the opportunities these new discoveries highlight are only just beginning to be explored I certainly concede that we are in the earliest stages of this new field.

      • Amarshall

        I still struggle to see how much different this is from other work on protein misfolding and diseases of aging. And in terms of aging it seems likely that a network of misfolded proteins rather than a single protein target (with the possible exception of DNA repair enzymes or P53) would need to be drugged. That said, it is an interesting area. Perhaps some of the data out of centenarian genomes (100 over 100 Archon X prize) will provide us with hotspots/positions important on proteins involved in processes that lead to longer life.

  • http://www.hollyip.com/ Suleman Ali

    This Burrill Report article is interesting in highlighting how complicated it will be to cure ageing: