GOING TO TRIAL
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.