Time to pop an anti-ageing pill

He’s not alone. Leonard Guarente, a professor
at Massachusetts Institute of Technology, has been
taking NAD+ boosters for years; and in 2015 started a
company, Elysium, to market them. There are likely
thousands of users by now. Even NASA has been
seduced. It hopes to use NAD+ to repair the DNA of
astronauts bombarded by cosmic rays during the yearlong
tip to Mars. DNA damage is one of the factors
linked to ageing.

Something has changed in the anti-ageing field.
Eccentrics and gullible-types have always availed
themselves of anti-ageing remedies. Dubious
supplements from gingko to hormones feed a
mushrooming $30 billion industry. But when evidence-clamouring
scientists start popping a pill, you sit up
and take notice. Like the soon-to-be-50 Australian
professor, most aren’t aiming to extend their lifespan;
they are aiming to extend their “health span” – the
period of time before the diseases of ageing catch up
with them: heart disease, arthritis, cancers, kidney
disease and dementia.

This seal of approval from scientifically literate
customers reflects a revolution in the science of ageing.
Thirty years ago, there was none. Most scientific
thinking held that ageing was not amenable to
tweaking. No more than preventing wear and tear on
your car. Yet animals do age at different rates – a lab rat
lives for three years, but a mole rat for 40. Rather than
a random process of degradation, this surely suggests
some underlying program, one that might be hacked.

In the late 1980s, scientists proved that was
indeed the case – at least in yeast and roundworms.
They tinkered with the genes of these creatures and
extended their lifespans and healthspans. In the case
of roundworms, lifespan could be doubled by altering a
single gene!

Suddenly science had some levers to push – and in
a compelling demonstration of how the fundamentals
are conserved through evolution, the same genetic
levers were identified in mice and humans. But altering
the genes of humans is not on the cards. So for more
than a decade now, researchers have searched for drugs
to tweak those same genes.

NAD+ boosters have now become the party
favourite. In part because they’re not drugs; they are
natural products that restore body chemistry to a more
youthful state. By age 50, NAD+ levels are half what
they were at 20. Top up NAD+ levels in elderly mice and
their muscles becomes like those of youngsters, their
stem cells get more oomph and they live longer.

So have scientists finally found the fountain of
youth? And if it’s good enough for scientists, should the
rest of start taking NAD+ supplements?

I feel a bit like the character Morpheus in the movie
The Matrix, in the scene where he offers Neo either
the blue pill or the red pill: “You take the blue pill –
the story ends, you wake up in your bed and believe
whatever you want to believe. You take the red pill …
and I show you how deep the rabbit hole goes.”

I had a similar experience researching this story.
Some researchers I interviewed were in the blue-pill
camp: they felt that we probably know enough about
ageing to intervene. Others were red-pill types. The
rabbit hole was too deep, they didn’t think we knew
enough to start intervening.

So I’ll give you the Morpheus choice here.

Blue pill: tapping the fountain of youth

The reason some serious scientists are taking NAD+
supplements is because of a series of epiphanies, which
have erected a glittering scientific edifice on what just
three decades ago was just a swampy backwater.

Just about every university now has a department
for ageing research; and it’s not just academic
institutes. Google entered this space in 2015 with its
secretive subsidiary Calico, which is bringing big data
to bear on the problem. Craig Venter, who pioneered
the reading of the human genome, started the company
Human Longevity to decode the genes for long life.

California-based Alkahest is mining the regenerative
factors in youthful blood, and there are plenty more
variations on theme from start-ups such as Progenics
and Unity.

But roll back 30 years and studying ageing was
career suicide for any serious scientist. Meanwhile at
the other end of the biological spectrum, the science
of embryo development was booming. Just how
the mush of an egg turned into an embryo had long
been biology’s greatest mystery. By the late 1980s,
researchers had uncovered a genetic program that ran
the process in everything from roundworms to human
beings. These lessons from embryos would help propel
the study of ageing into the mainstream.

Lesson number one was that the fundamentals of
biology are preserved across the species. In the late
1980s Cynthia Kenyon was compelled by this lesson.
She was a 30-something slim blonde, possessed of
exceptionally youthful features and an infectious
enthusiasm for science. Her model organism was the
one-millimetre-long, 959-cell-strong roundworm,
Caenorhabditis elegans. Kenyon was struck by its
very obvious ageing. In two weeks it went from agile
slitherer to a decrepit creature barely able to drag itself
across the culture dish.

She felt sorry for the worms. She was also
intrigued. Perhaps, like development, ageing was
also a process under some sort of control. She set out
to see if tweaking genes, by bombarding the worms
with mutagenic chemicals, might affect their lifespan.
Her hunch was rewarded by a remarkable mutant. At
four weeks of age it was still slithering like a teenager.
Tweaking a single gene more than doubled its lifespan.

In 1993 Kenyon published a paper in Nature
revealing the identity of that gene as “daf-2”, which
may not mean all that much to you; but there was a
revelation lurking behind the name.

One of the big lessons of the 1980s was that genes
don’t change all that much during evolution. They
acquire some code changes and get repurposed, but
it’s still possible to recognise them. Sort of like the way
words change in language – you can still pick out the
ancient Greek roots.

So it wasn’t surprising that mammals turned out to
have two genes that resembled daf-2. The surprise lay
with their job description. In humans, the counterparts
of the worm’s life-extension gene are the insulin
receptor gene and its close relative, the insulin-like
growth factor 1 receptor gene (IGF1R).

To understand why this was such a revelation, you
need to know a couple of things.

Insulin’s job is to mobilise the body to respond to
food intake. Like a warehouse overseer receiving a
stock delivery, the hormone is released into the blood
to ensure many systems are quickly mobilised. The
insulin ‘receptor’ conveys these signals to the body
tissues so nutrients are used as needed or stored as fat.

Roundworms showed that signals about food
availability also had a link to ageing. But even before
the worm discovery we knew that.

Back in the Great Depression of the 1930s, many
people went hungry. Wondering about the effect on
growth and long-term health, Cornell University
nutritionist Clive McKay set up rat experiments to
mimic calorie restriction. To his surprise the rats, so
long as they received adequate nutrients, actually lived longer. The experiment has been repeated in yeast,
worms, flies, mice and primates.

The rough rule of
thumb is: restrict calorie intake by 30% and see up to a
30% increase in lifespan. The effects are smaller in mice
and even smaller in primates.
Not many people have the willpower to adhere to
a lifelong diet, though occasional “fasting mimicking
diets” developed by Walter Longo at the University
of Southern California seem to have beneficial effects.
Nevertheless the holy grail has been to find a drug that
could mimic fasting.

Kenyon’s identification of the daf-2 gene provided
an entry point into the circuit linking food intake with
life extension. In the following years, she and others
teased out more key components. Research showed
the same components played a role in the ageing of
different species. Long-lived dogs and long-lived
people showed evidence of tweaks to their IGF1-R
gene. Another genetic tweak that doubled a worm’s
lifespan, daf-16, turned up in long-lived men. They
were more likely to carry a particular variation in a
gene called FOX0-3A, which harboured within it the
recognisable code of daf-16.

Another entry point into the ageing circuitry
came from the yeast Saccaromyces cerevisiae. It might
seem absurd to go looking for the secrets of ageing
in a single-celled yeast, but this cell resembles one of
our own in that it has multiple chromosomes housed
in a nucleus. Remarkably the yeast also possesses
many recognisable features of ageing. A single yeast
cell will eventually age and die after a couple of days.
If coaxed to bud off daughters, it will undergo a kind
of menopause; spawning so many daughter cells and
no more. It also demonstrates the universal feature of
ageing: deprive yeast of calories and it lives longer.

Just as with roundworms, the search for mutants
delivered. In 2000, Leonard Guarente’s lab at MIT
found yeast mutants that continued to spawn for about
about 30% longer than normal. The gene responsible
was named Sirtuin 2 (Sir 2). It was a completely
different component of the ageing circuit to anything
unearthed in the worm. It made parts of the DNA
code inaccessible or “silent” – the prefix Sir stands for
“silent information regulator”.

Sirtuins work by increasing the stickiness of the
histone proteins that wrap up DNA. Worms, flies, mice
and humans all have them – and experiments with
worms, flies and mice indicates that increasing sirtuin
activity modestly extends lifespan.

Yeast studies also delivered another windfall. Like
other organisms, yeast lifespan increases when calories
are restricted. As yeast doesn’t have insulin or IGF1
receptors, some other genetic components must be
responsible for sensing calories. In 2005 researchers
found that role was played by a curious gene known
as the “target of rapamycin” or TOR (in mammals the
gene is called mTOR). When the TOR gene senses
low levels of calories, it responds by slowing down
protein synthesis. It also stimulates recycling of a cell’s
components, a process known as autophagy.

It seemed to make sense. Calorie restriction flips
a metabolic switch from “abundance” to “austerity”.
Like when you get a big salary cut, you don’t go
adding extensions to the house; you hunker down, live
modestly, recycle your old things and delay your plans
to have babies. Somehow responding to this stress also
lengthens lifespan.

These days researchers think autophagy plays a big
part in the lengthening. For instance, Walter Longo’s
recent studies on mice and humans shows that fasting
accelerates the refurbishing of tissues, clearing away
damaged “senescent cells” while turning on renewing
stem cells.

The name “target of rapamycin” is an accident of
history. Rapamycin was discovered in a bacterium that
grows in the soils of Rapa Nui, better known as Easter
Island. Rapamycin’s ability to flip the TOR lever makes
it a drug with profound effects. Until now, its major
medical use has been to stop the rejection of foreign
tissues in transplant patients by toning down their
immune systems. But it was destined for greater things.

By the early 2000s, the science of ageing was
buzzing. Worms and yeast had provided threads that
researchers followed to reveal an entire circuitry of
ageing. In lab animals these components could be
tweaked to increase lifespan. But that involved altering
genes – not possible for humans. Could chemicals
achieve the same hack?

Enter Sydney-born David Sinclair. He had long
been compelled by the lessons of ageing learnt from
yeast. In 1997at Lenny Guarente’s lab he had found a
mutant yeast that aged faster. The faulty gene, SGS1,
was related to one causing Werner syndrome. Just like
yeast, affected people age faster.
But it was yeast’s Sir 2 gene that captivated him.
It appeared to be a lever that flipped during calorie
restriction. Perhaps chemicals could do the same thing.
In 2003 he hit pay dirt with a plant-derived compound
called resveratrol. To everyone’s delight, it was found
in red wine – though you’d have to imbibe litres to get
an active dose. Soon after, he spun off the company
Sirtris to commercialise compounds like resveratrol; it
was bought by GlaxoSmithKline in 2008.

Sinclair, who now heads labs both at the University
of NSW and Harvard Medical School, says GSK has a whole stable of sirtuin-activating compounds in testing,
some of which are 1,000 times stronger than resveratrol.

His attention, in any event, has shifted to NAD+.
The chemical had been hiding in plain sight since
2000, when sirtuins were identified as an anti-ageing
lever in yeast. It was clear NAD+ acted like a grease
for the sirtuin mechanism. Since its discovery some
100 years earlier as a yeast co-factor that stimulated
fermentation, NAD+ had been found to grease a
multitude of metabolic reactions – but few thought
of it offered a potential treatment. It was, as Sinclair
put it, “the most boring molecule in biochemistry”.
How could raising the levels of such a commonplace
substance have any effect?

Furthermore, it was also not clear how to raise its
levels: NAD+ itself is very unstable, and can’t actually
get inside cells where it is needed.

Two things changed the game. One was that
researchers discovered NAD+ levels decline with age
but are raised by calorie restriction and exercise. The
other was identifying several natural precursors of
NAD+ – nicotinamide mononucleotide (NMN) and
nicotinamide riboside (NR) – that were much more
stable, could enter cells and raised NAD+ levels when
given to animals.

Johan Auwerx’s laboratory at the Swiss Federal
Institute of Technology in Lausanne showed in 2016
that NR boosted the multiplication of skin, brain and
muscle stem cells, and slightly increased the longevity
of mice, even when given in middle age.

Sinclair’s lab showed in 2013 that mice treated
with NMN boosters had improved muscle strength,
and earlier this year that mice treated with NMN had
superior ability to repair their DNA – the reason NASA
is now engaged in talks with Sinclair’s lab.

As well as astronauts, children who have undergone
radiation therapy for cancer might also benefit from
this treatment. Sinclair is planning clinical trials using
NMN or a closely related compound.
What’s missing is a proper long-term controlled trial to see
if NAD boosters will actually do anything to forestall
human ageing. Getting a trial off the ground for any
anti-ageing compound turns out to be extremely
difficult. (See Going to trial: anti-ageing pills)

Which brings us back to NAD+ boosters. The
excitement is that NAD+ boosters are not drugs. So you
needn’t wait; there are companies willing to oblige by
providing NR supplements, such as Guarente’s startup,
Elysium. It has some cred – no less than five Nobel
prize winners on its advisory board. There are small, short term trials in the works. So far, Elysium has conducted a trial of 120 people aged 60–80 to look at how effectively its supplement raised NAD+ levels over 8 weeks. They also looked at whether there are any acute toxicity concerns by checking the effects on blood profiles, blood pressure, physical strength, and sleep.

The results suggested that the supplements do indeed raise NAD+ levels, and there don’t appear to be any acute toxic effects. The effects on other blood markers and strength are yet to be reported.

So what do you do? Just because something is a
natural compound doesn’t guarantee that boosting
its levels in middle age is a safe thing to do. As Sinclair
reported at a recent conference in Sydney, NMN
not only helped aged mice develop stronger muscles
but also triggered the growth of tiny blood vessels.
That might flag a risk, since cancer cells rely on newly
formed blood vessels to spread.

On the other hand, it’s pretty clear what the effects
of ageing are – a dramatically increased likelihood of
developing all sorts of diseases.

Depends if you’re the punting type.

The red pill: a never-ending rabbit hole

You might think with all the epiphanies of the past 30
years, surely we know enough about ageing to go full
speed ahead with interventions? All the candidate
compounds, so far, seem to hack into the same pathway
triggered by calorie restriction.

Well, yes – but this rabbit hole goes very deep.
Take calorie restriction, the supposedly iron-clad
way to trigger lifespan extension. In fact, studies in
mice show very different effects, depending on their
breed, gender and even what they are fed. Rafael
da Cabo, who runs the long-term calorie restriction
study on rhesus monkeys at the US National Institute
of Ageing, told me some breeds of mice actually live
shorter lifespans when calorie-restricted; and females
may respond better than males or vice versa. Nor is it
just about calories: sorry paleo dieters but high-protein
diets shorten lifespan in mice. So go figure where you
as an individual, endowed with a specific gender and a
unique set of genes, fit into all this.

And while it’s all very well to conceptualise the
biology of ageing as a circuit, circuits end up controlling
something. So what exactly does this circuit control?

Over the years, one compelling theory has been that
it controls the integrity of mitochondria, the engines of
our cells which clearly degenerate as we age. According
to the theory, the corrosive by-products of cellular
combustion – free radicals – cause ongoing damage as
an inevitable consequence of being alive. But numerous
recent experiments show that slowing the generation
of free radicals in mice or flies, doesn’t actually slow the
ageing process. In fact, it seems to have the opposite
effect. Nowadays the paradigm shift is that stress
signals like those from free radicals, fasting or exercise
trigger an adaptive anti-ageing response.

It doesn’t mean past theories are entirely wrong. As
da Cabo says: “Nothing has been disproven.” It’s just that there is a lot of other stuff going on in ageing as
well. At least nine targets appear to be controlled by the
ageing circuitry, ranging from the fraying of telomeres
on the tips of chromosome to ‘epigenetic’ disturbances
that change how the DNA code is read.

Kenyon’s epiphanies with worms suggested for
a while that tweaking the controls for ageing might
be simple. Indeed these days it’s possible to extend
the lifespan of worms ten-fold. But mammals are
complex. Da Cabo offers the metaphor of a Model T
Ford compared to a modern Tesla. Back in the 1920s
you could tune the engine with a few tweaks from a
spanner. Good luck trying that with a Tesla!

Luckily, just like today’s car mechanics, researchers
now have mind-boggling tools to deal with mindboggling
complexity – they can monitor the activity
of every gene and the output of metabolism –with socalled
‘omics technologies’ – and leave it to machinelearning
algorithms to figure out what’s going on.
This is the sort of big data approach that Google’s
subsidiary Calico is applying to the biology of ageing.

The company’s chief scientific officer: Cynthia Kenyon.
None of this means the era of anti-ageing medicine
has to wait for us to explore every blind alley of the
rabbit hole. Indeed, most of the researchers I spoke
with passionately believe they are more than ready to
start testing the plethora of promising new compounds
in their pipelines.

What’s needed is the faucet at the end – the
regulatory framework that will incorporate “ageing”
as a medical indication. So that people who need to last
longer don’t have to be punters.