Longevity Science is Alive and Well

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Longevity Science is Alive and Well

Longevity comes of age

This week was “Longevity Week” with numerous events organised in the UK on what we now call “geroscience” – as term my spellchecker doesn’t like, though it permits “gerontology”.

Geroscience is predicated not only on the idea that human lifespan can be extended well beyond the biblical standard of three score years and ten, but also that we can avoid the degenerative diseases of old age which afflict so many seniors. So “healthspan” – the length of time that we can live without chronic and debilitating conditions such as diabetes, osteoarthritis, rheumatoid arthritis, macular degeneration, Parkinson’s or dementia – is just as important in this discussion as lifespan. That is an important starting point since, although life expectancy has increased significantly across the world within my own lifetime (from about 50 to 70), for many people those additional years are marred by ill health.

On Wednesday (17 November), a Master Investor event in central London brought together some of the leading scientists and entrepreneurs in this rapidly growing field. “Investing in the Age of Longevity” was the third event of this kind organised by Master Investor, inspired by our chairman Jim Mellon’s passionate advocacy for geroscience. Indeed, it all started about five years ago when Jim took a road trip across the USA in a Honda Odyssey with the aim of meeting all the key players – academic scientists, biotech entrepreneurs and visionary thinkers – who were formulating a body of ideas around the theme of longevity. The upshot of that road trip was Jim’s book Juvenescence: Investing in the Age of Longevity, written with Al Chalabi, which is still considered a brilliant introduction to the subject for non-scientists. It is also, unlike much of the literature, eminently readable.

There is, as ever, a demographic and economic backdrop to these nascent medical technologies. In terms of the raw demographics, for the first time in the history of humanity there will be more old people (that’s over-65s) than youngsters (under-16s) on the planet by 2050 – just 28 years away. The dependency ratio – that’s the ratio of the number of people in work and paying tax to the number of people who are retired and receiving pensions – is in free fall in the developed world and is beginning to decline too in developing countries on account of declining fertility rates. These over-65s, to the extent that they get sick, are proving to be an increasing burden on state-funded and insurance-backed healthcare systems. The USA spends just over 17 percent of its GDP on healthcare today; but by 2040, based on current trends, the healthcare burden will double to 34 percent of GDP.

It’s a similar story in the UK which, in contrast, spends only about 11 percent of its GDP on healthcare – overwhelmingly via the voracious National Health Service (NHS). Funding for the NHS now accounts for 40 percent of all state spending – up from around 27 percent 20 years ago. There is a joke doing the rounds that the UK is a healthcare system with a state attached. Yet, as anyone who lives in the UK knows, even given increased resources, the NHS is under incredible strain and is struggling to satisfy demand. And this situation is likely to get worse in the short-term.

Unless we find ways to improve the health of the growing cohort of over-65, the NHS – and other state healthcare systems – are going to collapse. Already in the UK, strokes cost the NHS £11 billion a year, cancer costs £15.8 billion, dementia costs £19 billion and diabetes weighs in at £23.7 billion. Even marginal increases in healthspan could reduce these numbers.

Just as the focus of medical science in the 19th and much of the 20th century was on the need to improve infant mortality and to cure the diseases of childhood, so the primary focus of medical science in the 21st century will be to prevent and cure the diseases of old age. Three leading healthcare economists have calculated that increasing the healthspan of humanity by just one year would be worth $38 trillion a year to the global economyi. By increasing healthspans, lifespans will lengthen too. That will have all kinds of social and economic consequences which I shall consider elsewhere. (Spoiler alert: we shall all have to work longer – in fact we can forget the concept of “retirement”).

I’m not going to offer an account here of what was revealed in each speaker presentation on Wednesday. Some of the talks were of a highly technical nature which, in any case, I am not qualified to evaluate. Rather, I just want to draw together some of the major themes that impressed me most as a non-scientist and as a finance man. These are: ageing science, prospective therapies, drugs in development and Juvenescence Ltd.’s unique approach to investing in this emerging sector.

Ageing science

In recent years we have learnt a great deal about the physiology of ageing. Medical scientists have mapped out processes involving mitochondrial dysfunction, telomere attritionii, cellular senescence – and so much more. Medical interventions have been shown to extend lifespan in many animal models (that’s generally poor old mice and rats). There have been some exploratory human trials, though it is still early days.

One of the keys to understanding ageing is to figure out why the immune system declines with age. A universal feature of physiological ageing is an increase in circulating levels of cytokines which cause inflammation. The thymus, which generates T-cells, the front-line soldiers of the adaptive immune system, atrophies with age with the result that more senescent T-cells circulate in the bloodstream.

Scientists are now close to a “unitary theory of fundamental ageing mechanisms”. These mechanisms include inflammation, fibrosis, macromolecular dysfunction, stem cell dysfunction and cellular senescence. Collectively, they lead to declining mobility, chronic diseases and a weakened immune system.

We know that as we age the risks of succumbing to the diseases associated with old age rise exponentially. Therefore, if we can slow down the ageing process, we can increase healthspans.

Therapeutics

As Phil Newman, CEO of Longevity Technology, pointed out there are four aspects to longevity therapeutics: prevention, diagnostics, treatments and rejuvenation.

One of the most promising therapeutics involves the removal of senescent cells – a process now called “senolytics” (another word my spellchecker doesn’t like). Senescent cells are like some cancer cells that do not divide (reproduce) but just hang around in the organism indefinitely. Senolytics might take the form of therapies e.g., blood transfusions or might be accomplished using new medications. Some treatments have already been shown to reduce the number of senescent cells in mice. One in-human trial of senolytics agents for patients with idiopathic pulmonary fibrosis has been carried out and more are planned. The two active senolytic agents in use to date are “D+Q” and “fisetin”.

Dr Michael Hufford, Co-Founder and CEO of LyGenesis Inc., explained how a new approach could revolutionise organ transplants. Currently, an organ transplant in the USA costs about $800,000 and there is a high rate of wastage of healthy donated organs because recipients are not matched within the required timeframe. (The number of organs discarded in the UK is lower because the country is more densely populated, and distances travelled are shorter – but this is still an issue here).

The technique developed by LyGenesis is more cost effective and results is less organ wastage. A patient with acute liver disease such as cirrhosis can now be treated in the following way. Cells from a donor liver are implanted endoscopically (that is, via a tube down the throat) into a major lymph node. Simultaneously, donor liver cells are engrafted on the recipient’s diseased liver to create a functioning ectopic organ. Such recipients in animal models have been shown to exhibit much improved liver function within three months thanks to organ regeneration.

A conventional organ transplant entails that one donated organ goes to one recipient patient. Using this technique, up to 75 patients could be treated from one donated organ. Even given the company’s fee of about $200,000 per procedure, the cost of organ transplant is likely to be more than halved. This approach could be equally applied to other organs including the thymus, pancreas and kidney. It is also possible that the technique could be used to treat genetic disorders such as MSUD.

“Autophagy” is the process by which cells clean up debris in the bloodstream. This also looks promising.

Drugs

Professor James Kirkland of the Mayo Clinic, Minnesota, explained that we need to move away from the traditional model of one malady, one drug, one target. In future, geroscience will involve drug combinations administered in different doses intermittently in a “hit and run” manner. Artificial intelligence applied to data analysis will optimise these combinations. So there probably won’t be a single one-hit wonder drug.

As Dr Daniel Ives, Founder and CEO of Shift Bioscience, said, ultimately only machine learning will enable us to untangle cellular rejuvenation pathways. (DeepMind (owned by Google) has made a start on this with its pioneering work on AlphaFold). Shift Bioscience’s USP is likely to be in terms of mRNA-based drugs which can rejuvenate targeted genes.

It turns out that some of the drugs that will be used to slow down the ageing process are already with us. Metformin, derived from the plant galegine, has been around since the early 20th century. It was shown to lower blood glucose as far back as 1918. In more recent years it has become a standard medication for diabetes. But over time it has been shown to reduce “all-cause mortality”. That is to say that it benefits not just the symptoms of diabetes but may decrease mortality even in non-diabetics.

Consequently, a human trial is about to be launched in the USA called TAME which will determine whether this might turn out to be one of the wonder drugs that can arrest the ageing process and extend healthspan. TAME will cost $10 million a year for about six years – but those behind it believe that it is easily financeable since the savings in healthcare costs if Metformin proves effective will be massive. The US Food and Drug Administration (FDA) has already indicated that it will look dispassionately at the data from the TAME trials.

It is not unusual in the history of medical science for drugs developed for a particular malady to go on to have a more universal application. Statins were developed in the 1970s as a lipid lowering (anti-cholesterol) medication. They are now part of every general practitioner’s arsenal – most adults over 65 years old in the UK are now on statins. Because they are so effective in reducing the incidence of cardiovascular disease and strokes, they are now being prescribed to people who have normal or low cholesterol levels. The University of Birmingham is trialling the use of Simvastatin in older patients with pneumonia to modify neutrophil function. (Neutrophils are the most basic cells of the innate immune system which combat bacteria).

Again, anti-hypertensive medication such as ACE-inhibitors have proved so successful that there is a body of medical opinion that they should be prescribed to people who do not have high blood pressure.

In future, many medical interventions will be preventative in nature. As Dr James Peyer, Founder and CEO of Cambrian Biopharma argues, “Waiting for people to get sick and ONLY THEN trying to cure them has not worked for age-related diseases”. With 14 compounds currently in development, James foresees that Cambrian’s first medicines to expand healthspan will be licensed in the early 2030s. These will vary in nature. Some will target specific genes; others will treat pathways and processes that deteriorate with age.

Juvenescence Ltd.

Juvenescence Ltd. styles itself as “a new kind of biotech company focussed on health and prevention”. It was founded in 2017 by Jim Mellon, Dr Greg Bailey (who is CEO) and Dr Dec Doogan (Chief Medical Officer). It has access to a world-class team of scientists who have a track record of developing top-selling supplements and medicines.

The company’s strategy is three-pronged. JuvLife focusses on consumer products to prolong healthspan and delay ageing. Some of these will compete with currently available health and fitness supplements. About 32 million people in the UK – that’s 61 percent of the adult population buy health and fitness supplements regularly. JuvTherapeutics will develop prescription medicines to treat and prevent age-related diseases. It is investing in other geroscience companies including LyGenesis. JuvRegen aims to develop regenerative medicines that could reverse the ageing process. In partnership with AgeX Therapeutics, JuvRegen is working on the use of stem cells to regenerate human tissue. This division is also working on the development of small molecules to combat inflammation and immune system decline.

Another division, JuvPet, will develop products for the animal health market. JuvYou, launching in 2022-23, will provide an array of diagnostic tools which will help ordinary people to track and improve their health metrics.

Juvenescence has had several successful funding rounds to date, but its stock market floatation has been delayed by the coronavirus pandemic. A man who knows about these things tells me it could happen in the second half of next year – whereupon it will be open to retail investors.

The year ahead

This year to date, about $2 billion has been raised by start-ups in the longevity/ geroscience sector. About $12 billion has been raised by the roughly 150 new players in this space over the last 15 years or so. That geroscience has become mainstream rather than an esoteric branch of biotech is reflected in the foundation of the Longevity Biotechnology Association (LBA). This new professional body will begin to educate the public and investors in 2022 and will formulate industry standards for clinical trials.

Despite all the problems we face right now, there is good reason to be optimistic about 2022 and beyond. And not just because there will be lots of space news. I suspect that we shall hear of medical breakthroughs too.

***

Last Saturday, in the company of one of my oldest friends and two geriatric pooches, I found myself back in Greenwich Park after a long absence. As one stands aloft beside the mortar-pocked statue of General James Wolfe, the view of the brash towers of Canary Wharf and of the City of London to the west is unlike any other in London.

The day before I had been treated to lunch at one of those venerable City institutions – the kind where one sips one’s pre-lunch G&T in a squeaky ancient red leather armchair while surveyed by portraits of long-dead plutocrats.

The City of London is no longer the premier financial market of the European Union. But it doesn’t seem to be too worried. According to the E&Y Financial Services Brexit Tracker, 7,600 jobs have been re-located to Europe since Brexit out of a sector that employs around one million people. That is far less than predicted. Yes, trade in European equities has largely migrated to Amsterdam. But the upside potential of Indian equities and developing market bonds is beguiling.

And, as I was reminded on Wednesday, we have advanced biosciences too. Scientific heft plus big finance is a strong combination. Don’t knock it. This is still a great country in which to live and prosper.

i Andrew J Scott (London Business School), David Sinclair (Harvard Medical School), Martin Ellison (University of Oxford).

ii Telomeres are the tips at the ends of each chromosome. “Rather like the caps on a shoelace” – so I read in Jim’s book.


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