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How do you disrupt the ageing process? Companies like Nuchido based in north east England are taking cutting edge science and turning it into products that aim to slow down, stop or even reverse the ageing process to increase our healthy lifespan.

When people talk about ageing they often speak about a process of gradual but inevitable decline. If we are healthy and lucky enough we experience fewer long and debilitating periods of illness in our later years. Yet a growing number of scientists believe that by targeting the ageing process itself, we can use medicine to boost the body’s mechanisms to stay youthful and healthy for longer.

By reframing ageing as a disease process that can be delayed, stopped and even reversed, with the right medicines, they hope to increase our healthy lifespan – or healthspan – change the way we think about ageing, and revolutionise healthcare. Scientists like Nichola Conlon, chief executive of Nuchido, are among those who see the ageing process itself as the prime target for therapies.

Right now we invest a lot of money in cures for diseases like cancer, diabetes or heart disease, but what if ageing is the key to our susceptibility, asks Conlon. “If you want people to live healthier lives then we should address the root cause. If you get rid of three big diseases by tackling ageing there will be a much bigger impact than targeting an individual disease.

“The real focus is to increase healthspan. That’s what all of the science we’re doing is designed to improve. People won’t necessarily live longer but they will be in better health. That’s better than spending 20 years in a care home in a poor state with multiple diseases.”

Biology Pioneers

Nuchido was co-founded by molecular biologist Conlon after she received her PhD in physiology from Newcastle University – home to the largest institute for ageing research in Europe – and then specialised at network pharmacology pioneers e-Therapeutics in early stage drug discovery.

She works alongside world-leading scientists Tom Kirkwood and Thomas von Zglinicki to translate research breakthroughs into anti-ageing interventions. One of the company’s first objectives is to capitalise on medical research into a molecule in the body called nicotinamide adenine dinucleotide (NAD).

NAD is in all our cells but as we grow older its quantity falls dramatically. By itself NAD has no beneficial effect. Instead it acts like a sensor for cellular damage and activates other healing processes in the body.

Drugs designed to boost NAD can positively affect important proteins like sirtuin. Sirtuin (especially SIRT1) influences cell ageing and inflammation. NAD also maintains repair genes like PARP1, which track along the body’s DNA strands to make sure there is no damage.

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Photo by Guille Álvarez

Our cells degrade over time and the mitochondria – the power houses of human cells – become contributors to the ageing process. “When your mitochondria get old their energy production becomes less efficient, and you get a lot of free radicals which damage the cell,” says Conlon.

NAD boosts the mitochondria’s metabolism and promotes better function. “NAD slows down the rate at which cells age,” she says. “It decreases inflammation, aids cellular repair, helps to recycle proteins and repair DNA.”

Time Capsule

Nuchido is launching a supplement called Time Capsule in May 2019 aimed at increasing NAD and keeping its production high. It is not alone. American companies Elysium and ChromaDex already sell NAD-boosting supplements and that has created space for newcomers.

Conlon says the potential market for NAD pills and skin care products is huge. The forecasts for the worldwide anti-ageing market back that up. Statista estimated the size of the global market for anti-ageing products in 2015 to be $140 billion (roughly £107 billion today).

By 2021 it says the market will have grown to £217 billion (or £165 billion) – other estimates pitch it higher – for remedies including anti-wrinkle products, natural supplements and other intrusive therapies such as cosmetic surgery.

What effect a pill that turns back the clock on ageing processes will have on demand for skin creams and cosmetic surgery is hard to say. What is easier to predict is its effect on pharmaceutical companies. Conlon says that many of the big medical corporations are waiting for positive results from drug trials targeting the ageing process before they take the plunge and start making commercial anti-ageing drugs for the masses.

Ageing from AFAR

The Taming Aging with Metformin (TAME) trial run by the American Federation for Aging Research (AFAR) is being watched carefully by big pharma. It is the first large-scale study to target ageing using a drug therapy.

AFAR has recruited 3,000 elderly people to see if the type-2 diabetes drug Metformin can delay the development or progression of age-related disease such as cancer, heart disease and dementia. A positive outcome could make healthy longevity a reality for many people and save billions in healthcare.

The federation’s research group is led by the director of the Institute of Aging Research at Albert Einstein College of Medicine in The Bronx, Nir Barzilai. Speaking to the New York Times he said: “If metformin turns out not to work, there are several other substances in the pipeline that could be tried. Under the auspices of the National Institute on Aging, three research centres have tested 16 substances in different animal models and got incredible results with four of them.”

He added: “Our goal is to establish the principle of using a drug, or two in combination, to extend health span. The best we can expect from metformin is two or three additional years of healthy aging. But the next generation of drugs will be much more potent.”

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Taming Ageing

If TAME eventually establishes drug therapies that can improve healthspan it throws the doors wide open, says Conlon. “Right now some pharmaceutical companies are investing, but others are just sitting on the fence. If TAME can prove it works we will see big pharma developing drugs to tackle ageing.”

Pharmaceutical companies are naturally cautious because of the investment costs in developing new drugs. The average time it takes for a new human drug to come to market is 13 years. The cost in development and clinical safety trials is measured in hundreds of millions.

Because ageing is not currently defined as a disease by either the Food and Drug Administration in the US, or the Medical and Healthcare products Regulatory Agency in the UK, nobody can license a specific anti-ageing drug.

Illness related to old age is still seen as separate to the ageing process. “It’s almost like it’s not there,” says Conlon. “They look at ageing as ‘we have all these diseases and we’re going to treat them individually’. Actually, if we slow down ageing then it has a major impact on all related diseases.”

Disruptive Innovators

So how does a small start-up like Nuchido fund its activities in a market stymied by stalled investment? Simple, it picks the low hanging fruit of nutritional supplements and skin care products using established science. “These are massive markets that are crying out for active molecules that actually work,” says Conlon.

The way Nuchido approached the anti-ageing market was to look critically at traditional funding pathways. Biotech start-ups are customarily pumped with successive rounds of investment, then forced to wait until a larger pharmaceutical company buys them out to take their product to market.

“We didn’t want to go with that model,” says Conlon. “We’ve got an opportunity to generate revenue ourselves by doing exactly the same science that we would for drug discovery.
“We select the molecules that are safe to go in topical creams and supplements and actually put them to market. Firstly so we can make some money to keep funding the science, and secondly, because people want to take advantage of anti-ageing research now.”

Nuchido separates its research compounds into two groups: drug candidates and candidates for skin care and supplements. It takes forward safe products for its supplements, holds back the drug candidates as interesting science projects and looks for pharmaceutical patents it can sell at a later stage. “Although it might come across that we are doing skin care and beauty products, it is hard science,” explains Conlon.

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Networking the Problem

Traditional drug discovery identifies a particular target gene or protein in the disease process and develops a drug to affect that target. Instead Nuchido uses network analysis to identify and connect every gene, protein and pathway implicated in the disease process.

“Biology is incredibly complex,” says Conlon. “Even if one entity has a big role in the disease, biology displays redundancy. If you knock one node out, there are five or 10 other pathways that will simply rewire around it and the disease will work in a different way.”

You could end up with a diverse network of 100 different genes or proteins. The aim then is to find out how they communicate with each other and their neighbouring genes or proteins. Network maps can be huge and messy-looking, so using computer algorithms allows Nuchido to crunch the numbers on the best way to disrupt each disease.

“You might randomly remove five points from the network and have no impact, but if you target five points that have a high level of ‘between-ness’ – points at critical junctions – then you get a much higher rate of disruption,” says Conlon.

Promiscuous Drugs

Another thing to be aware of is that drugs are promiscuous molecules, she says. They stick to and affect lots of different things in the body. “You find either that the drugs don’t work or they have negative side effects. We decided to use that promiscuous nature to our advantage, to see if any drugs we already know about have a footprint that sticks to our targets.”

When Nuchido did drug discovery this way it saw its hit rate for finding candidate molecules increase massively – it was 200 times more efficient than traditional methods. “We couldn’t just do one thing and that is exactly what was happening in discovery,” says Conlon. “All of the leading ageing scientists were saying that if we wanted to make an impact we needed a multi-pronged approach.”

Waiting for the Shift

But until the large clinical trials such as TAME provide concrete data on the effects of anti-ageing therapies, companies like Nuchido must keep their big discoveries under wraps. Luckily opinion is shifting and Conlon says there has been an upturn in the thinking and execution of anti-ageing research in the past two years.

“Ten years ago you couldn’t talk about it because you might be laughed at,” she says. “You would not say that you were trying to research healthspan on a grant form. You would have named an individual disease such as heart disease or cancer, but never the ageing process.”

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Photo by Rod Long

In general medicine the big pharma corporations have too often called the tune on where to invest the billions needed to impact disease: one minute demanding dementia drugs, the next immunotherapy. Recent advances in pharmaceutical research, such as network discovery, have arrived in the nick of time to address what Conlon calls ‘the lottery of biotech’.

“People have spent millions on their products and then the pharmaceutical companies don’t want it any more,” she says. “All of that money is wasted. Unless you get an outstanding win on your data, it is lost.”

Question of Ethics

The ethical problems of discovery are also persistent. Big companies often only develop compounds that they can protect with a patent or make money from. If they find something that works, but another company owns the patent they simply ignore the data and no-one benefits, says Conlon.

Or the companies find a drug that is already known, can be repurposed and made cheaply, but it is off-patent and they will never make money on it however well it works. “It could cure cancer but if they are not going to make money out of it they will not even test it,” says Conlon. “They will look for a drug that does not work as well where they can get full ownership.”

Targeting ageing in itself may still prove to be problematic, she says, because if it is effective then companies will not be able to make as much money from treating diseases separately. It reads like conspiracy theory, but feels like cold hard economics. If you cannot protect your investment then why invest at all? It is an antithetical position for anyone who assumes that healthcare and medical companies should only do good.

To turn the market dynamic on its head Nuchido envisions tapping into the supplement or skin care markets and opening up the advantages of NAD-boosting products. It is a way to exploit benefits now without waiting 13 years for drug companies to develop a product. “Some supplements will be ignored by big pharma, but we want to look at them in more detail,” says Conlon.

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Photo by Christian Trick from Pixabay

Aged Cocktail

Nuchido’s cocktail, as Conlon calls it (the more prosaic label is ‘NCD201’), acts on the networks that increase NAD to make the whole cellular process more efficient. And to test its effectiveness the company is doing a placebo controlled trial at Northumbria University.

In fact, it’s overkill. “You don’t need a shred of evidence to put a supplement on the market,” she says. “We know how many hoops you have to jump through to get a drug to market, so we wanted to bring an element of the efficacy testing from drug development into this industry.”

She cites retinol as an example of the way skin care companies use beneficial compounds without succumbing to heavy FDA or MHRA medical regulations. “Retinol is in a lot of creams. It is converted into retinoic acid in the skin, which activates receptors that change the gene expression and increase collagen synthesis.

“Everybody knows that is how it works, including the regulators, but as long as you never say ‘we increase collagen’ it is fine,” she adds.

Hard Strategy

It is a topsy-turvy way of working, Conlon admits, but as long as the ingredients in Nuchido’s products comply with safety guidelines they can press on. It means the company can use profit from supplement sales to fund science and drug discovery, and avoid spreading itself too thinly through over-investment.

The next stage of the company’s research programme is to fund experiments into senescent cell products. Nuchido is investigating a new class of drugs (widely called senolytics) designed to clear or rejuvenate senescent cellsold cells that have stopped dividing – from the body.

In America there is abundant research investment into senescence and senescent cells, says Conlon. Experiments have shown that clearing out damaged cells might actually extend lifespan. Nuchido is now investigating what it considers to be strong links between NAD and senescence.

The optimistic vision of an end to ageing, or at least a longer and healthier life through medicine, does not sound far-fetched any more, says Conlon. What the industry must avoid now is hype. “Hype can be a double-edged sword,” she says. “Expectations can be too grand, then when it’s not as good as promised it seems like a failure.”

Actually, the exposure anti-ageing medicine is now receiving should really be seen in a positive light, she says. Sooner rather than later NAD and senescent cell therapies will be within the reach of ordinary people thanks to startups like Nuchido. “It is not a magical story any more,” concludes Conlon. “It is real.”

 

Extra Reading

1. An article from The Guardian in 2010 detailing how Harvard scientists observed a dramatic reversal of ageing in mice using senescent cell therapy.
https://www.theguardian.com/science/2010/nov/28/scientists-reverse-ageing-mice-humans

2. NAD supplement rundown that gives a grounding on what the enzyme does and whether it can restore youth.

Can NAD+ (Nicotinamide Adenine Dinucleotide) Restore Youth?

3. ‘Is Basis by Elysium a Hoax?’ asks this article, giving a critique of a popular NAD supplement.
https://alivebynature.com/basis-niagen-by-elysium-health-2/

4. Biotech startups don’t always live up to their promise – the cautionary tale of blood testing company Theranos and market fraud.
https://www.forbes.com/sites/matthewherper/2018/03/14/sec-elizabeth-holmes-theranos-fraud/