“I need to last longer,” the professor tells me. He lets

my quizzical look hang for a moment, then quickly explains.

“I’m on my second marriage and my wife is expecting twins.”

Soon to be 50, the respected head of an Australian

medical institute is contemplating the latest offering

from the anti-ageing industry. It’s a product that tops

up the levels of nicotinamide adenine dinucleotide

(NAD+), a commonplace chemical made by our bodies

that is crucial for our metabolism.

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.

Less is more: restricting calorie intake has been shown to increase lifespan in every species studied. Cosmos Magazine

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.

{%recommended 4871%}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.

{%recommended 5339%}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.

ELSEVIER INC

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.

