Time to pop an anti-ageing pill

It’s no longer snake oil. Scientists have a pipeline full of promising anti-ageing compounds just waiting for human trials. Elizabeth Finkel reports.

Could this be the next frontier in the human battle against old-age?
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"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.

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.

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Elizabeth Finkel is editor-in-chief of Cosmos.
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