Interview: How far have we come, and where are we going?
Eric Verdin, Chief Executive Officer, Buck Institute for Research on Ageing
Interviewed by Angela Tyrrell, SVP, Longevity Leaders
ANGELA: Tell me a little bit about The Buck Institute and your mission in ageing science.
ERIC: The Buck Institute was started in 1999 on the heel of some key discoveries showing that ageing could be studied biologically using the modern tools of genetics. Our mission today is to take what we have learned about ageing during the last 20 years and to start translating these discoveries for improving human healthspan and lifespan.
ANGELA: What were those key discoveries?
ERIC: The initial discoveries by several groups between 1985 and 1995 suggested that there are genes that can mitigate the ageing process. If these genes are mutated to either gain or lose function, one can dramatically impact healthspan and lifespan. These observations were made in a number of models like C.Elegans (or worms), Dresophlla fruit flies and eventually mice. The goal of the Institute for the past twenty years has been to build on these initial discoveries and try to provide a fuller understanding of what ageing is.
We’ve learned a number of key lessons. Firstly, we’ve learned that there are genetic pathways that interact together and appear to control ageing. Secondly, these pathways seem to be conserved across different species. So, we find the same pathways in yeast, in worms and in humans. Thirdly, we can speak to these pathways via small molecule drugs to have the same effect as mutating the gene, and subsequently impacting the ageing process. Finally, these genes that control ageing don’t just control lifespan, they also control healthspan. The animal models we studied did not only live longer, but they appeared to be healthier for longer.
When you start to look at humans a whole new level of complexity arises, but I think we really need to start examining the relevance of this research in humans. This is something that we are determined and poised to do.
ANGELA: That leads us to the development of a therapeutic field based on this science. When do therapeutics start to come into the picture, and how do you see that field progressing?
ERIC: We are very much in the middle of this and it’s not without its ups and downs. The Buck Institute was associated with launching one of the first ageing therapeutics companies along with the Mayo Clinic, a company called Unity. They have been targeting senescence, trying to eliminate senescent cells. Now it is a public company with a market capitalization of close to a half a billion dollars. It’s considered one of the early successes of the ageing field. There were others before, but they almost uniformly ended in failure.
ANGELA: Are there any technologies or pathways that you see emerging beyond cell senescence that you think could prove to be particularly interesting or significant?
ERIC: I tend to look separately at how to target an identified pathway, and at the types of intervention. A lot of people are focussed on developing drugs that control ageing, and this is fine. But I don’t think it is where the most important work lies today, because these drugs are going to take years to develop and many are going to fail.
We need to focus on what we have today. Some of the key areas that we really have to address to increase our longevity are things like nutrition, exercise, sleep and stress. Unfortunately, a lot of the knowledge in these fields is fragmented. For example, how exactly does exercise impact longevity? We know it does, but we don’t know what forms of exercise are effective – endurance vs high intensity interval training? 10,000 steps vs 4,000 steps? We need a molecular-level data to increase our knowledge.
ANGELA: That leads perfectly to my next question: where do you see major gaps in our knowledge and in which areas would you like to see ANGELA: That is a very admirable mission, and I more research emerging?
ERIC: At a basic biology level we have identified what are commonly called The Hallmarks of Ageing. This is a series of problems that we see emerging during ageing and include things like mitochondrial dysfunction, stem cell dysfunction and so on. We have eight or nine of those. The problem is that we don’t really understand how they are related. As a result, our understanding of ageing is still as a process caused by multiple factors. I remain convinced that there has to be a unifying theory, and this is something we’re interested in at the Buck.
One of the oldest questions in ageing science is why do different species have different life expectancies? Why do we live to eighty years while a mouse only three? There’s an inherent diversity across species. If we understood why certain other species live so long, we might be able to replicate this in humans.
We can also go back to the question of exercise – we know that exercise increases lifespan, but we don’t really understand how it works. The same goes for nutrition. There’s a clear link between over-eating and a shortened lifespan, or decreased nutrition (such as calorie restriction) and increased lifespan. But we don’t fully understand the best recommendations to make to people. There’s a lot of work right now on fasting which seems to have a beneficial effect, but we don’t know how, and we don’t know what forms of fasting. We don’t really know what we should be eating – carbohydrates or proteins or fats – or in what proportion. We can raise the same sort of questions for sleep or stress.
There is a lot of conflicting information in the public domain right now. Some studies generate a high degree of publicity that they potentially should not receive. Other very strong studies may not receive any attention from press. Part of the mission of the Buck is to publicise validated and curated information to help people make the best lifestyle decisions to maximise their healthspan.
ANGELA: That is a very admirable mission, and I look forward to seeing more of your work.
How do you see this field evolving in the next five years?
ERIC: In the next five years there’s a critical need to be able to measure the validity of interventions without waiting for our whole lifespan. Right now, if we make an intervention that we think will increase lifespan we need to study it for twenty or thirty or forty years for an answer. We cannot run clinical trials this way. One solution is to develop biomarkers of ageing. That is, we need to be able to assess whether a given person is ageing well or ageing poorly at a biological level.
A comparative field would be statins, a class of medicines to lower cholesterol levels. We know that by measuring cholesterol we can predict a person’s risk of a heart attack. So the pharmaceutical industry developed medicines that lowers cholesterol as a preventative measure. We measure the effectiveness of statins by measuring cholesterol. We need a similar paradigm for ageing.
There is a lot of interest in the field to identify markers that predict a person’s rate of ageing, because we know all of us are ageing at a different quality, a different rate. Some of us are going to live to 90 or 100. And some of us are going to live to 70. The question is, can you look at a 40-year-old and predict their trajectory? Imagine the potential if we can deploy anti-ageing intervention to those at risk of early death or declining health. So, for me, the priority for the next five years is the development of biomarkers of ageing.
We are also in the early stage of testing some anti-ageing interventions, which I think will progress over the next five years. There are clinical trials ongoing for senolytics, for metformin and for rapamycin. I hope that in the next five to ten years we will see the first ageing drugs available.
ANGELA: Do you see a change in how industry - and I’m thinking particularly of Big Pharma - are approaching or starting to approach this field?
ERIC: They have been sideline players to date. Ageing interventions are intensely disruptive to Big Pharma’s business model, which is traditionally organised into therapeutic areas around things like heart disease or infectious disease. It’s the way that medicine as a whole tends to be organised. If you have a heart problem, you see a cardiologist. If you have a lung problem, you see a pulmonologist.
Ageing biology presents a different way of organising medicine and of treating disease. Ageing affects every single organ, so if your intervention targets an ageing pathway, you will affect the development of diseases in different organs. That doesn’t fit in the traditional field of medicine. So, one of the biggest challenges we face – not just with industry, but with physicians and funding agencies as well – is convincing people that we should be studying disease in the context of pathways that are universal across different organs. We need to change the way that we practice medicine to aim for a preventative approach. I think a lot of people will be reluctant to accept the new model, but this is ultimately what we should be working towards.
ANGELA: Agreed! And to finish off Eric, what would you do with five extra years of healthy life for yourself?
ERIC: I love life! I would keep doing exactly what I what I’m doing now, working to try and change the world. In the old days when labour was physically intensive, the whole idea of retiring, of drawing a pension, was the norm. I envision a future where people remain physically and mentally healthy for longer. So, for me, I have no intention of retiring because this is what I love to do.
This article is an extract from the Longevity Trends 2020 report.
The report captures Longevity Leaders' extensive research into this space, including the most important longevity trends of 2020 that businesses, policy makers, scientists and the general population need to be aware of.
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