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.

Drug­Baron was for­tu­nate to spend sev­eral days with Prof Rad­man and his team ear­lier this year, and hear about his re­search into pro­teome in­sta­bil­ity, and the in­sights that has given him 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 aging 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.

“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 aging.  “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 aging” 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 aging 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?

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 aging – re­veals a whole new ap­proach to treat­ing de­gen­er­a­tive dis­eases as­so­ci­ated with aging.

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 aging. An­other kind of im­mor­tal­ity.