Going to trial: anti-ageing pills

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 for Aging 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.