Understanding and Slowing the Human Aging Clock: Paving a Path Via Protein Stability

Innovation That Matters

Dr. David Grainger, CEO of Methuselah Health based in Barbraham, Cambridge, U.K., is not shy about believing that contrary to past anti-aging research, protein stability, not DNA stability, is the key to understanding the clock of human aging. Methuselah Health is a drug discovery company focused on the role of proteome instability in a number of human diseases linked to aging. The aging process underlies development of many major diseases of middle and old age – diseases that are poorly treated by existing drugs, representing the biggest unmet medical need in the developed world, by far. Methuselah’s team has developed analytical platforms for the detection of post-translational modifications across many different proteins, for developing methods to identify novel candidate targets in the pathogenesis of ageing-related diseases. Methuselah Health is backed by leading life sciences venture capital firm Medicxi.

In addition to heading Methuselah, Grainger is a cofounder of Medicxi. He also co-founded XO1, which was acquired by Johnson & Johnson’s Janssen Pharmaceuticals in 2015; and created  Funxional Therapeutics.  Grainger has also led an internationally-recognized research group in Cambridge University’s Department of Medicine, where he published more than 80 first author papers in leading journals including Nature, Science and Nature Medicine. He has 150 patents and patent applications in his name, and is also the chair of the Translation Awards Committee of the British Heart Foundation. 

WuXi AppTec Communications, as part of a new industry series, recently interviewed Grainger about the clinical direction and goals of Methuselah as well as what the future holds for research into extending human life.

WuXi:  How do you define aging? Is it an illness itself? Is it a specific group of diseases?

David Grainger: At the simplest level, aging is the change in characteristics that occur with the passing of time. Much like a bottle of fine red wine, those changes can be positive or negative.  In some sense, childhood development is aging – the characteristics and capabilities of the individual are changing as they get older. But this kind of positive change is usually called “development,” while the term “aging,” at least for people, is reserved for the subsequent decline in functions.

Fortunately, there is much simpler scientific definition to fall back on: aging is the time-dependent change in the rate of mortality within a population, enshrined in the classical Gompertz equation. Quite simply, with every passing year your chance of dying increases, initially quite slowly but by the age of 90, in humans, that rate is rising exponentially. Exactly the same equation describes your likelihood of developing many age-related degenerative diseases, such as diabetes, osteoporosis or Alzheimer’s disease.

The simple question behind all of aging biology is, why should this be so? Why do our characteristics and capabilities remain pretty consistent for decades and then, quite precipitously, decline? Our DNA, which encodes our proteins, remains largely uncorrupted, so why do we die?

At Methuselah, we see age-related diseases and, eventually death, just as different facets of the same underlying process – the mysterious, and so far unexplained, biological process that results in the Gompertz curve. Our mission is to understand that fundamental biology so we can intervene to prevent age-related diseases and, eventually, extend lifespan.

WuXi:  What is your anti-aging technology and how are you applying it?

David Grainger: Our technology is based on a striking observation made by our scientific founder, professor Miroslav Radman, more than a decade ago. Radman was studying a radiation resistant bacterium called Deinococcus radiodurans, and comparing it with common E. Coli exposed to large doses of radiation.

Above 1Gy of gamma radiation, the DNA of E. Coli is shattered, its proteins oxidised by free radicals, and the bacteria die. Interestingly, the DNA of D. radiodurans is also shattered by 1Gy of radiation, but the bacteria manage to piece it back together and survive. And the reason they can do that is that their proteins are resistant to oxidising damage. This tells us that protein stability, and not DNA stability, is the fundamental clock of aging.

Methuselah Health was therefore founded to develop a platform capable of looking for damaged proteins with quantitative accuracy, so we could test the hypothesis that aging (and the classical Gompertz curve) have their origins in the accumulation of damaged protein variants.  If we can identify these damaged variants that accumulate, we have the opportunity to design treatments to prevent or remove them.

We are currently applying this platform, which has taken about four years to develop, to biological samples from individuals with various age-related diseases to identify causal pathways in diseases such as Alzheimer’s disease – causal pathways that would be invisible to conventional genetics approaches because protein damage is not encoded in the genome.

WuXi: What is the goal of your technology? Is it improving quality of life for more years or extending the average life span?

David Grainger:  Eventually, we hope that Methuselah Health can extend the average lifespan. We believe we understand, for the first time, why the risk of disease and death increases exponentially, and that we can intervene to slow that fundamental clock of aging.

Doing so will improve quality of life as well as average lifespan, because slowing the fundamental clock of ageing will extend the period before the risk of developing diseases become significant. This is in marked contrast to approaches that seek to prevent the symptoms of specific diseases – such approaches might increase lifespan but the months and years that were gained would still be plagued by age-related diseases.

Targeting the central clock of aging has been the dream of anti-aging science for decades – maybe even centuries.  But for the last five or six decades – arguably the only period in human history when we have had sufficient scientific capability to properly understand biology – the unfortunate focus on DNA as the central biological clock has held back progress.  At Methuselah Health, we have called this DNA-centricity.

By shifting that focus to the proteins, professor Radman has already dramatically advanced the field. And the Methuselah platform is, in effect, the telescope that allows us to shine a light on this new world of protein stability and its role in aging.

WuXi: What is DNA-Centricity and why is it such a central theme for you and Methuselah Health?

David Grainger:  We have written about the unfortunate focus on DNA as the central clock of aging on a number of occasions, such as here in Forbes. Genetics has been incredibly powerful in helping us understand a certain class of diseases – those that arise from miscued development of the organism, when the plans set out in the DNA are flawed by an inherited error. Some of these diseases can occur relatively late in life (beyond where we typically think of ‘development’) but they have in common the failure to set up the organism in the optimum way.

But these diseases never exhibit Gompertz kinetics in a population – they have a peak incidence in a given decade of life, and if you haven’t developed it by then you likely never will.  That is very different from age-related diseases, where the likelihood of developing them rises inexorably as time progresses.

Buoyed by the success of genetics in identifying the causal pathways in these “age-independent” diseases, the scientific community has assumed that the age-dependent diseases will have similar, if more complex, origins, and that ever larger genetic studies (culminating in the sequencing of the entire human genome) would somehow uncover the fundamental clock of aging.

Twenty years after the first genome sequence was published, we are no further forward in our understanding of biological aging and the mechanism behind age-related diseases.

To us, at Methuselah Health, this abject failure is entirely understandable. If you look in the wrong place, you can look forever without finding what you are looking for.  By shifting our focus to the protein stability domain, we believe we have found the central mechanism that underpins ageing and age-related diseases.

WuXiPlease briefly explain Methuselah’s theory that examining proteome instability can help unlock some of the mysteries of age-related degenerative diseases, and indeed some of the mechanisms of ageing itself. 

David Grainger:  Protein damage has, to a large extent, been ignored as a cause of aging because of the assumption that, as long as the DNA sequence is intact, new undamaged copies can easily be made. This is absolutely true in the vast majority of cases where the damaged protein is more unstable than the undamaged versions.  Very quickly the damaged ones will be cleared and replaced.

But just occasionally, a damaged protein has a longer half-life than the perfect copies. Now something undesirable happens: gradually, over time, the proportion of the damaged variant increases until it begins to affect the function of the tissue.  If the half-life is very long (perhaps because the damaged variant is being mis-trafficked into a compartment where its degradation pathway is missing) it can become the dominant species present even though the gene sequence remains unaltered. Realizing how easily this can happen can be quite a shock to a DNA-centric scientist.

We believe the accumulation of these long-lived damaged proteins (which we call Hyper-Stable Danger Variants or HSDVs) underpins the development of age-related diseases. By applying the Methuselah platform, we can see the HSDVs and so understand which pathways we need to target to prevent these diseases.

Perhaps most excitingly, the HSDVs could also explain the Gompertz curve.  While HSDVs would be expected to accumulate only to an equilibrium level (assuming a constant rate of generation and half-life), which would yield time-independent disease incidence (like diseases caused by DNA mutations), if HSDVs accumulate in the protein translational machinery, this can set up a feedback loop.  As damaged proteins accumulate in the ribosome, this will reduce the fidelity of translation creating more damaged proteins.  Eventually, the population of ribosomes will reach the point where they make only poor quality proteins.

Methuselah Health has tantalizing evidence that the central clock of biological aging is the fidelity of translation.  Once you understand that fundamental biological mechanism, you have a chance to intervene.

WuXi: Do you need a different business model than a traditional biotech or pharma company? If so, what are the differences?

David Grainger: Absolutely not. Understanding aging is no different from understanding any other biological process. And developing interventions to prevent age-related diseases, or even slowing the fundamental biological clock of ageing, is no different from conventional approaches. The only differentiation is where we are looking for our targets for intervention.

Our biggest issue is the sheer importance of the central mechanisms we are uncovering. There is absolutely no reason why the insights coming out of the Methuselah platform could not provide targets to prevent many of the most prevalent diseases known to medicine, from atherosclerosis to osteoarthritis; from diabetes to autoimmunity; from neurodegeneration to ageing itself. That many targets would overwhelm the capacity of a global pharmaceutical company, let alone a small biotech company.  So our business model is built around disease-specific partnerships with pharmaceutical companies with the capacity to help us exploit all the new biology we are uncovering.

WuXi: What kinds of global partnerships do you have or plan to pursue?

David Grainger: Methuselah Health is very fortunate to have been founded by Medicxi – a leading, and well-financed European venture capital house, with Johnson & Johnson, GSK, Novartis and Google’s Verily healthcare arm as investors in their fund, and members of their scientific advisory board. These connections, and access to capital, have supported the development of our platform, and allowed us to translate Professor Radman’s original insight in bacteria into a unified model to explain biological ageing in man.

Going forward, we are currently in discussion with a number of the world’s leading pharmaceutical companies to form strategic collaborations to pursue preventative drugs for major diseases, and we expect to announce those alliances later this year.

WuXi: How soon will an anti-aging medicine be available?

David Grainger:  Without an understanding of the fundamental clock of biological aging and the cause of Gompertz kinetics for disease and death, which – until Methuselah began to look at protein stability – seemed out of reach, there was no imminent prospect of drugs to prevent age-related degenerative diseases let alone extending lifespan.

Even with the insights the Methuselah platform has provided, we have to be realistic about the time it will take to deliver drugs that prevent diseases like Alzheimer’s disease. With new targets being discovered as we speak, we might expect it to take a decade to see the first approved drugs based on our current findings.  Unfortunately (from a drug development perspective) age-related diseases still occur slowly, making clinical trials large and long – and while understanding the biology better has the potential to identify biomarkers that could simplify development, there is a limit to how quickly new medicines can be brought to patients.

The biggest prize, and the biggest challenge, will be to use these insights to design an intervention that safely modulates the central clock of biological aging.  Such a drug would delay the risk of all the age-related diseases, giving patients years of extra disease-free lifespan. But the clinical development pathway there will be even more challenging. Methuselah Health may, for the first time in human history, understand the biology of aging sufficiently to design quite literally an elixir of life, but even then, it’s hard to imagine such an agent being available to patients in the next 20 years.

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