Dr Nir Barzilai: Creating a template for all aging trials

There are few voices in Longevity research as distinctive as Dr Nir Barzilai’s.

Brimming with jokes and references, his sentences digress and then return to his point of focus like ever-tightening loops of a knot. Dr Barzilai isn’t satisfied until he has attacked an idea from as many angles as he can. Besides his already impressive natural ebullience, this makes sense when you consider what he has spent most of the last decade achieving.

After years of planning and building, he is leading the first human trials in a drug that will directly target aging. And he has finally received his last portion of funding.

After landing a position at the Albert Einstein College of Medicine in New York, Barzilai studied some of the longest-living centenarians in the US. It was in these individuals that he and his colleagues discovered the first identified ‘Longevity genes,’ a set of variants that contributed to the centenarians’ markedly longer and healthier lives.

For the past several years, Dr Barzilai and fellow aging researchers from AFAR (the American Federation for Aging Research) have been tirelessly fundraising and lobbying the US FDA for a completely new type of trial, one that uses the diabetes drug metformin to directly target aging as an indication. Called TAME (Targeting Aging with Metformin) Dr Barzilai’s groundbreaking trial has been stalled for many years, awaiting a hefty $40 million in funds, which many speculated might never arrive.

Now, with the money recently secured by private donation (“I can’t tell you who gave us it,” he said “but it will be a great story one day!”) he sat down with us to discuss metformin and how TAME, which is slated to begin in the November 2019, could change medicine forever.

Q: You began your career studying endocrinology. How early on was aging a subject of interest to you? Has it informed your whole life? Or was it something that only really became interesting after you began studying insulin, a hormone linked to the aging process?
A: You know what they say about children’s imaginations. I remember I was 13, and I was walking with my granddad, he was 68 years old. He was balding, white hair, walking very slowly, and he was telling me everything that he was doing when he was young [Dr Barzilai’s grandfather drained swamps in pre-state Israel].

And I just couldn’t believe him. You don’t see yourself as your grandparents, but that’s what you’re going to become! They’re not a different species; they weren’t born like that, they started exactly like you. He died that year, by the way. From then on aging was of great interest to me, all the way through medical school and my residency. It’s what I really wanted to understand.

I took endocrinology because there were no experts in aging, really. And there are lots of interesting endocrine changes that come along, as we grow older. I thought it was a great place to start.

Q: Your research into aging started in the 90s with the (still ongoing) Longevity Genes Project. You found, in your Ashkenazi centenarian cohort, two Longevity-boosting mutations: a gene variant that down-regulated IGF-1, and high levels of humanin-like peptides being produced by their cells. Now, aging is commonly believed to be in the evolutionary shadow, so – if that is the case – how did these mutations emerge in them and then go on to become conserved?
A: Well, you’re right, there’s no evolutionary pressure for greater longevity. My colleagues and I wrote a paper where we suggest that there is an inverse relationship between fertility and longevity in nature. We selected a cohort of Ashkenazi Jews living in the US, people who are really great to study because of their genetic homogeneity. We separated them into centenarians (people with really exceptionally long lifespans) and we had a control group (who had normal lifespans) and we asked both groups how many children their grandparents had.
Ashkenazi Jews
We found out that the centenarians tend to have fewer children than the control group. We found a clear trade-off, an antagonistic relationship, between reproductive fitness and length of life. You see this in a lot of populations, even from work in England looking at the royal family.

That means that if every generation of longer-living people follow this trend for having fewer children that means we’re losing Longevity genes as we go, right? So when you flip open the Old Testament and see that Abraham lived to be 175 and Moses 128… maybe it was right! But we lost those longevity genes on the way.

So this continuation and conservation of genes for longer life isn’t selected for by evolution. It enters and leaves family lines by chance. Not many people go on to live to 100 without medical intervention, but the people who do still happen to have a genetic variant that explains their longevity.

Q: You’re best known for your work with Metformin, a diabetes drug that many researchers believe could also prove to be beneficial for Longevity. In a nutshell, how does it regulate aging?
A: We haven’t fully understood and mapped out the mechanisms by which metformin acts upon aging, but here’s the best summary I can give. Metformin gets into the cell by a transporter called OCT-1 and it binds to complex 1 of the mitochondria, which are the energy generators of our cells. This binding causes two major changes in how the mitochondria work.

First there’s the metabolic part: you have a change in the energy sensing of the cell. It activates a hormone that senses for nutrient deprivation, called AMP Kinase, which normally goes up when you haven’t eaten for a while. When AMP Kinase goes up, it triggers a decrease in another signaling pathway called M-TOR. M-TOR is a major pathway of aging.

This is a very simplified explanation, but when it is reduced, cells conserve more energy, they don’t synthesise as much fat and cholesterol, and they focus on burning their reserves.

Secondly, metformin acts like very weak cyanide. This means it disrupts slightly (not totally, like cyanide does) the process by which we break down nutrients with oxygen for energy. With this, there’s less Reactive Oxygen Species being released, less inflammation, and less DNA damage.

It also has a number of non-mitochondrial effects, not all of which we understand in terms of how they may contribute to aging. But it improves loads of things, and pushes back the onset of age-related diseases.

Q: So take us into the aging trial, TAME, that you’re conducting with metformin. What is its structure? Why is it so different from other trials? And why did it need to be? 
A: Okay, so, basically put, our hypothesis is that aging drives disease.

How? Well, if your mother is diabetic and obese – you’ll probably get diabetes. If you have high cholesterol – you’re probably going to have heart disease. But none of this happens without age. High cholesterol creates a roughly three-fold increase in the risk of heart disease. Aging, on the other hand, increases it by 1000. Aging really is the major risk factor.

But how do you design a study to measure that? How do you design a study that is basically agnostic to disease? You create a study that says: ‘I don’t care what disease you have, and I don’t care what disease you’re going to get. Whatever it may be, if I can move it by two or three years, then I’m not targeting anything particular, I’m just targeting aging.’

So that’s what we did. In TAME (which stands for Targeting Aging with Metformin) we’ve clustered all of the major age-related diseases – cardiovascular disease, cancer, cognitive decline and mortality – and for every subject in our study we’re going to show that instead of contracting any one of them after, say, two years, you’re going to contract one in four.

Q: That’s an enormous shift from how clinicians are accustomed to conducting trials.
A: Right! This is something that is hard to understand for clinicians with a disease focus. “You’re looking at disease clusters in 3000 people?” They say, “You’re out of your mind! To show that you can prevent diabetes you’d need four times those numbers.” But actually, it’s the opposite! If the onset of any one disease is one event, then we need less people, because if somebody doesn’t get diabetes, they can get cardiovascular disease or cancer, or Alzheimer’s, or they can also just die! And I’ll end up getting many more events with less people.

Then they’re back at me saying, “But wait just a minute, you’re not going to end up finding significance for one disease. If you want to really to be significant, you’re going to have to be significant for allof those diseases, so, again, you’ll need around 50,000 people!” But we say no! We don’t care about – if anything we’re actually trying very hard to avoid – significance for any specific disease. We only want significance for the cluster, which is aging.

Q: And that’s what’s so interesting about what you’re doing. Metformin won’t solve any of these diseases, but a phrase I’ve seen you use before is ‘contraction of morbidity’. It will push back the time of their onset to the very end of their lives, extending healthspan.
A: Yes. We have a lot of preliminary data, and we know that metformin delays any one of those diseases by about 30%. We know that already. We just haven’t measured it on all the diseases together. Metformin is going to be cheap and available, it is non-patented, and it’s going to be the first treatment. Then in the future there are going to be better drugs and combinations of drugs. It’s going to get much better than metformin.

Q: A key point here is that, even though it will be helpful, metformin’s efficacy is a secondary consideration to you. What’s more important is TAME’s design itself. Why?
A: There’s so many new biotechs and new IPs beginning to target aging. We want to create a template that anybody doing aging trials can follow. Maybe metformin will fail. But instead of doing what we had to do – which was to come up with a really good committee to carefully craft a study design – the next generation of researchers can just take the template and do what they want with it. It’s public knowledge.

What we are really trying to do is drag the pharmaceuticals towards buying the biotechs and developing those drugs. The biotechs have money for proof of concept, but not the billion dollars you need to develop a drug.

Q: Why do the pharmaceuticals need to be dragged along?
A: Well, the pharmaceuticals are not going to jump without having a medical indication to follow. They need a business plan; they won’t develop a drug that healthcare providers don’t pay for.

Q: You’ve recently secured, from a private donor, the final $40 million needed for TAME to go ahead. Why has it been so difficult to secure funding for the trial? I can understand why Pharma companies wouldn’t have wanted to buy into it because they’re not going to make any money from metformin, but I would have expected an organisation like the NIH to want to. 
A: We wanted the NIH to be partners in this, but their process was difficult. First of all, nearly everyone involved in aging is also involved in TAME, so for the review process they had to get someone from outside the field. And they were saying things to us like, “We didn’t know aging could be targeted and we’d only need one drug to do it. That’s ridiculous!”  Or, another one was, “What if it doesn’t work?”

Well, if we knew it worked, we wouldn’t do the study! Unfortunately, we wasted valuable time negotiating over things like this, when really we weren’t going to break past their conservative approach. As for why others might not have been as forthcoming with funds, there are a lot of young people who are very much into solving aging right now. Some of them are even immortalists. And they are ready to do something, but they’ll invest their money in biotechs, and not a trial that won’t generate any profit. The people that did donate to us were looking more at a legacy. They invest money not to make money, but to fund an idea that will make all of us able to develop better drugs faster. But that’s difficult to sell.

Q: With so many people engaging with this problem, have we been able to shift that paranoia you find amongst aging researchers when talking about anti-aging pills? Or are they still frightened of being taken for quacks?
A: Anti-aging is something we try to distinguish ourselves from. A lot of anti-aging is still filled with charlatans who will sell things with a promise even when there’s no hope. “Take this drug and you’ll live forever!” But if they’re lying and it doesn’t work, you’re too dead to sue them! So they’re really our enemy. Immortalists also don’t play very well with the public; they see them as highly selfish individuals.

You even find that if you tell people you’re an ‘aging researcher’ that you’re going to depress a lot of people, because aging sounds like such a bad idea. I looked instead at exceptional Longevity, which again draws a response from people accusing me of wanting to extend everyone’s lives so far that they’ll be sick and frail yet never die [Barzilai echoes the myth of Tithonus here, whom Zeus made immortal but not eternally young]. But Longevity and health go together. What we want to do is extend healthspan and make people healthier for much longer. If, as a side effect, the drug that does so also has you living longer, we apologise, you might not have budgeted for that!

Q: Maybe we can budget for it, though. There’s an argument floating out there that it could improve the economy rather than weaken it, right? If fewer people are sick, and able to contribute for longer.
A: Right, the Longevity Dividend. Not only will we stay healthier for longer, but also we’ll see a ‘contraction of morbidity.’ You mentioned this earlier. Only at the very ends of our lives will we experience a decline in health. The cost of the last two years of life of a centenarian is a third of that of someone who dies at 70. Multiply that difference by every person, and the Longevity Dividend is really huge. It will be an enormous thing for the economy and our healthcare systems if we can harness that.

Q: Do you feel optimistic that we’ll be getting there soon? We’re at a very exciting moment in translational research, but will enough treatments make it across the gap between mouse and human trials?
A: I feel extremely optimistic. The maximum lifespan of humans is about 115 years. In aging we argue about that a lot, but it’s around there. And we die now, on average, before the age of 80. That’s 35 years that we need to win back from death first. And I think it could be relatively simply done with metformin, with rapamycin and others. That doesn’t then mean that we can’t go on to do even better in the future.

How much better? Well think of the first age-reversing magic trick, which has been being performed by nature for hundreds of millions of years. Let’s say you take a sperm cell from a man who is 70 years old, and you take an egg from a woman who is 50. For the setup the magician (nature) gives us (the audience) all kinds of signs and ways to determine that these sex cells are actually the biological ages of 70 and 50 years old. Then the lights dim, nature fertilises the egg with the sperm, and when the embryo is formed, guess how old it says it is? It says it’s new! Applause please! The embryo doesn’t remember the ages of its parents. It starts at zero again. If we can do that in our own bodies, we can surely find a way to do it in another context. That’s why I’m optimistic we’ll be able to do better than metformin and some other low-hanging fruit.

Q: How close to achieving that are we? I know you work closely with Life Biosciences, who are doing some cellular reprogramming development at the moment. 
A: Cellular reprogramming is a little premature right now.  There are brilliant researchers in the field, but not a lot of them know how to develop drugs. They’re using viruses and other things as other methods, but it’s all very difficult, and risky to boot. I’m sure it will happen one day. But part of the motivation behind the metformin story is how well-known on a clinical level the drug is. And we really don’t want to kill anyone trying to get this stuff off the ground. I’m optimistic, but the timeline may be a little different to what some hope.

Q: What timeline are we talking about here? Where do you see the field in five, ten or even twenty years’ time?
A: You know, I’ve been asked this question from the beginning of my career, and I’ve been saying the same answer and I’m always wrong. Do you know of Yogi Berra? Well, Yogi Berra said, “It’s tough to make predictions, especially about the future.” So I’ve always said that we’re five to ten years away my whole life. And that’s it, I’m sticking to it. This time I’ll be right.