GO­ING TO TRIAL

Cosmos - - Feature -

THE BRAVE NEW WORLD of anti-age­ing medicine will be of­fi­cially launched when reg­u­la­tory au­thor­i­ties ap­prove a drug that won’t be pre­scribed for any par­tic­u­lar dis­ease; it will be taken to fore­stall the dis­eases of age­ing. Prob­lem is: that’s not the way the world’s most in­flu­en­tial drug reg­u­la­tor op­er­ates. The FDA’S time-hon­oured wis­dom is to ap­prove one drug for one dis­ease.

In the hope of breach­ing that bar­rier, the Amer­i­can Fed­er­a­tion of Anti-age­ing Re­search (AFAR) has found a Tro­jan horse – an old di­a­betes drug called met­formin. It has been used for 60 years to treat the early stages of di­a­betes, but in 2014 Bri­tish re­searchers re­ported a star­tling fringe ben­e­fit. Com­pared with peo­ple of sim­i­lar age in the gen­eral pop­u­la­tion who did not have di­a­betes, met­formin users – even though a lit­tle more portly – were less likely to die from a num­ber of dis­eases. On av­er­age, they lived about 15% longer.

How does met­formin work? Most re­searchers think the ini­tial strike is aimed at the cell’s en­gine, the mi­to­chon­dria – specif­i­cally at part of its ma­chin­ery called com­plex 1. The net ef­fect repli­cates the mi­lieu cre­ated by calo­rie re­stric­tion, rais­ing the ra­tio of a low-en­ergy mol­e­cule, AMP, rel­a­tive to its high-en­ergy coun­ter­part, ATP. That chang­ing ra­tio seems to be the sig­nal to a master-switch en­zyme called AMPK that re­sets many dif­fer­ent meta­bolic switches. The liver stops re­leas­ing glu­cose from its stores (the rea­son met­formin re­duces blood sugar in di­a­betes) while TOR is damped down in tis­sues, slow­ing protein syn­the­sis.

The safety and af­ford­abil­ity of Met­formin have made it the prime choice for the first trial of an an­ti­age­ing drug. To that end, for the past cou­ple of years Nir Barzi­lai, who is based at Al­bert Ein­stein Col­lege in New York, and col­leagues at AFAR have been de­sign­ing the TAME (tar­get­ing ag­ing with met­formin) trial. It pro­poses to en­rol 3,000 peo­ple aged 65-79 in 14 cen­tres across the US, fol­low them for five years, and see how the drug af­fects the in­ci­dence of heart at­tacks, cancer, de­men­tia and death. It will also look at the trade-off from side-ef­fects; known ones in­clude stom­ach com­plaints and lac­tic aci­do­sis, a po­ten­tially dan­ger­ous build-up of lac­tic acid in the blood­stream..

“If the trial ends up the way we ex­pect, that should be enough for the FDA to ac­cept age­ing per se as a “treat­able in­di­ca­tion,” Barzi­lai tells me.

The trial has been wait­ing to go for two years now. Here’s the rub: no drug com­pany will fund the $US70 mil­lion trial for a cheap off-patent drug. Phil­an­thropic funds through AFAR will cover half. Barzi­lai has been await­ing a de­ci­sion from the Na­tional In­sti­tutes of Health (NIH) to fund the re­main­der.

A sec­ond old di­a­betes drug, acar­bose, is also a can­di­date for test­ing as an anti-age­ing com­pound. Still com­monly used in China, acar­bose stops the spike in glu­cose lev­els af­ter a meal by slow­ing the break­down of starches. Low­er­ing blood glu­cose lev­els seems to be a way to trig­ger anti-age­ing mech­a­nisms. Ev­i­dence that it ex­tends life come from mice: males get most of the ben­e­fit, with a 22% ex­ten­sion of av­er­age life­span; fe­males get only 5%. Be­cause undi­gested starches get to the lower bowel, side-ef­fects in­clude flatulence and di­ar­rhoea. The NIH has funded a tiny trial look­ing at the ef­fects of acar­bose on the blood pro­files of 10 hu­man sub­jects.

Met­formin and acar­bose may be the eas­i­est to get through the reg­u­la­tory hoops. In terms of sci­en­tific prom­ise, though, the judges’ choice goes to ra­pamycin.

In 2009, ra­pamycin was the first po­ten­tial an­ti­age­ing com­pound to suc­cess­fully run the gaunt­let of the In­ter­ven­tions Test­ing Pro­gram run by the Na­tional In­sti­tute of Age­ing. It was tested on mul­ti­ple breeds of mice at three in­de­pen­dent labs. Ra­pamycin-fed 20-month-old mice – the equiv­a­lent of 60-year-old hu­mans – in­creased their av­er­age life­span by about 10%. This ex­tra­or­di­nary find­ing shat­tered es­tab­lished no­tions that age­ing dam­age was ir­re­versible and that any in­ter­ven­tion would have to be­gin in youth. Even with the rusted-on dam­age of late mid­dle age, it was ap­par­ently not too late to in­ter­vene.

Yet for all its win­ning qual­i­ties, ra­pamycin has an un­likely chance of blaz­ing the trail as the first drug to

go to trial for the in­di­ca­tion of slow­ing age­ing. This is be­cause of its side ef­fects, which in­clude sup­press­ing the im­mune sys­tem, rais­ing blood sugar lev­els and trig­ger­ing can­cers – all ef­fects that have been seen with the high doses used by trans­plant pa­tients.

How­ever, low doses ap­pear to have quite dif­fer­ent ef­fects. In 2014 No­var­tis tested for the ef­fects of low doses of ra­pamycin on el­derly peo­ple re­ceiv­ing a flu vac­cine. A six-week treat­ment boosted their im­mune re­sponse – a seem­ingly op­po­site ef­fect to the high doses given to trans­plant pa­tients. Wor­ry­ingly in mice, though, low doses have the ef­fect of shrink­ing tes­ti­cles.

Matt Kae­ber­lein at the Univer­sity of Wash­ing­ton has been test­ing the ef­fects of ra­pamycin on a di­verse group of pet dogs to get a bet­ter mea­sure of ben­e­fits ver­sus risks. Dogs are much more like hu­mans than mice. They live the same cushy life­styles we do and suf­fer the same age-re­lated dis­eases. Like us, their hearts grow weaker with age.

To fund the tri­als, Kae­ber­lein has had NIH sup­port and phi­lan­thropy.

His find­ings are en­cour­ag­ing. In a pa­per pub­lished in March 2017 in Gero­science, he and col­leagues showed that feed­ing a low dose of ra­pamycin to 24 mid­dle-aged dogs for 10 weeks im­proved the pump­ing power of their hearts com­pared to un­treated dogs. The dif­fi­culty, given the drug is off patent, is find­ing funds to carry out costly hu­man tri­als.

Met­formin: its safety and af­ford­abil­ity have made it a prime choice for the first trial of an anti-age­ing drug. 04

From yeast to hu­mans, the same ba­sic cir­cuit con­trols the age­ing process. The points where can­di­date treat­ments tweak the com­po­nents of the cir­cuit are in­di­cated.

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