The Hallmarks of Ageing is a seminal work. The 2013 paper was published in the highly regarded journal, Cell.
In it, Carlos López-Otín and his collaborators, Maria Blasco, Linda Partridge, Manuel Serrano and Guido Kroemer provided a coherent insight into why humans age and eventually die.
Not the most uplifting of topics you’d have thought – until you realise that the ‘hallmarks’ (there are nine in all) also potentially provide a roadmap to prolonging the natural human lifespan.
Genflow’s focus is on the Sirtuin 6 gene, which is seen as the ‘master regulator of healthy ageing’
In a sense, Lopez-Otin et al have also constructed the intellectual framework and underpinnings for a fledgling industry focused on longevity, spawning R&D-based companies such as Unity Biotechnology, Samumed, Bioage and Frequency Therapeutics.
But as Eric Leire, chief executive of newly-listed Genflow Biosciences, points out, the current crop of longevity companies tend to focus on just a single point of ageing rather than taking a holistic approach.
‘You’ve only solved one-ninth of the problem with this approach,’ he observes.
Genflow’s solution sets out to target four out of the nine hallmarks directly, and two others indirectly (we’ve listed them at the foot of the article).
Unlike its American contemporaries, the drug developer has opted for the path less trodden, not by just by basing itself predominantly in Europe (it is headquartered in the UK and carries out R&D in Belgium though does have a presence in the US).
Genflow has listed on the London Stock Exchange, rather than taking the show to the Nasdaq exchange that has bred the generations of big biotechs.
This is a quite deliberate strategy, says Leire: ‘It was very important to me to capture the open field in Europe.
‘We get a very generous grant, non-diluting grants, so that’s always very attractive and better than the US. We chose the London Stock Exchange standard list because it’s a senior market.
‘London’s history of investment in biotech is not matched by Euronext [the rival mainland Europe exchange]; neither is there the same [investor] expertise.’
Genflow’s focus is on the Sirtuin 6 gene, or SIRT6 for short, which is seen as the ‘master regulator of healthy ageing’.
The company’s R&D effort leans very heavily into the research carried out by Dr Vera Gorbunova at the University of Rochester in the US, who is also on the company’s scientific advisory board.
As Leire pointed out, tackling just one of the ageing hallmarks is unlikely to solve the puzzle.
The beauty of using SIRT6 is it focuses on four factors simultaneously. They are telomere attrition; genomic instability; epigenetic alterations; and loss of proteostasis (see the appendix at the end of this article).
‘There are perhaps two or more indirect effects,’ adds Leire. ‘The one we don’t have an effect on is mitochondrial dysfunction.’
SIRT6 overexpression has been shown to extend the healthy lifespan of mice. In humans, the aim is to find an ethical, safe and efficient delivery system SIRT6 gene variant found in centenarians.
Genflow will study a cluster population with Werner Syndrome in Sardinia, Italy (pictured)
Genflow’s work in the veterinary field with dogs is interesting with possibly lower costs associated with it than a fully human drug.
However, the two traditional human clinical programmes (GF-1002 and GF-3001) really catch the eye.
Both are in early-stage (phase I/II) clinical studies for the treatment of Werner Syndrome, a hereditary condition associated with premature ageing and an increased risk of heart disease and cancer.
The difference between the two programmes is the delivery mechanism for SIRT6: one will be intravenous, the other via dermal fibroblast (cells within the dermal layer of the skin).
Leire believes that some of the companies in the ageing arena have ‘set the bar too high’ targeting complex diseases such as Parkinson’s or osteoarthritis.
Not only are these prohibitively expensive and crowded fields, but proof of efficacy can also be difficult to ascertain.
The decision to focus on Werner Syndrome was a very deliberate one, Leire explains.
It has two very well defined but small cluster populations – one in Japan, the other in Sardinia. So, this makes the clinical trial process simpler and easier. Genflow will work with the Italian cohort.
The disease, because of its rarity, also carries with it orphan drug designation which largely protects the company’s intellectual property but can also lead to an accelerated timeline to market.
If the treatment can show efficacy in Werner Syndrome ‘it will allow us to shift the mindset of the regulators’, says Leire.
He adds: ‘We will be in the best position to say, “okay, you see we have data on accelerated ageing”. We can also show we can improve ageing.’
The onward development of the business will be aided by the London IPO that brought in £3.7million of additional funding and sees the shares trading currently at 12.4p.
This seems a modest sum for such an ambitious undertaking. However, the group does receive very generous grants from the Belgian region of Wallonia, home of its research base.
‘If a pound is invested by us in R&D, then Wallonia will invest another three,’ Leire explains.
Its collaborations here in the UK with Oxford University may also open up opportunities for grants, the Genflow CEO adds.
One would imagine that longevity companies will, as they start to emerge with viable products, begin to provoke a moral and ethical debate.
The issue to date has been theoretical, or the subject of fiction.
Films such as Forever Young and Benjamin Button have grappled with and largely failed to properly tackle (not to say trivialised) the thorny issue of turning back the biological clock.
Wider society, meanwhile, seems obsessed with the strain that the ‘boomer’ generation, for example, is exerting on the health service – the economics in other words.
Genflow’s argument doesn’t seem to be one about limping towards immortality (and all the philosophical issues this unearths).
It is about living a longer and better life in old age; one that’s devoid of the diseases that can make the last years of life debilitating and painful.
There is also an economic upside if the general elderly population is more sprightly in its golden years.
‘You look at the demographics; for the first time in the history of mankind, there are more people aged over 65 than people under five,’ says Leire.
‘Yes, the economic pressure will be unsustainable, but also the quality of life is a major issue if you are living your final years with Alzheimer’s or undergoing chemotherapy.’
In other words, it is not just about improving lifespan, it is about ‘health-span’, or how we can live a healthy old age.
The nine hallmarks of ageing
1. Telomere attrition, which is the gradual loss of the protective caps of our chromosomes
2. Genomic instability is the increased tendency for gene mutation, causing diseases such as cancer
3. Mitochondrial dysfunction, when our membrane-bound cell organelles don’t work as they are supposed
4. Cellular senescence is the cessation of cell division
5. Stem cell exhaustion, which is responsible for many of the physical problems associated with ageing, such as frailty and a weakened immune system
6. Loss of proteostasis, or in other words a failure of the protein-building machinery of the cell
7. Deregulated nutrient sensing is an alteration to the way the body takes on the correct nutrients in the right amounts
8. Epigenetic alterations are changes in the chemical structure of DNA
9. And altered intercellular communication: The change in signals between cells that can lead to some of the diseases and disabilities of ageing
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