Dr. Nir Barzilai is one of the leading experts in geroscience, with more than 25 years of longevity research under his belt. He is the director of the Institute for Aging Research at the Albert Einstein College of Medicine and the author of the book Age Later.
He is also the leading researcher of TAME, the highly important human trial of metformin that is about to be launched. We interviewed Dr. Barzilai about his book, his multi-year work with centenarians, his views on the current state of geroscience, and, of course, TAME.
Last year, you published your book, which is short, accessible, and clearly aimed at a broad audience. Why is it important to educate the public about aging and the latest advances in geroscience?
That’s a great question. We have many constituencies to consider. We have people who are getting old and sick. We need the politicians to understand that there is a longevity dividend and that we should think of treating aging. We need the news media to say: “Are you kidding me? Aging can be targeted?” We need a lot of people to come and form this wave to ensure our success in influencing our healthcare system. The National Institute of Health is, in fact, the National Institute of Diseases. It consists of the National Institute of Diabetes and Digestive Diseases, National Institute of Cancer, etc. The only one that is really concerned with health is the NIA, the National Institute of Aging. Those silos are fighting us for resources though they all should be doing geroscience themselves. We have a war that we need to win by exercising all the power that we have.
This is why I thought that the book should be centered on my study of centenarians – because they are proof that people can live healthier for longer. If we are claiming that we as humans have the capacity to be healthy with a side effect of longevity, everyone should know about people who are still having fun at their advanced ages because they are not sick.
So, are you looking for allies in the audience to recruit the general public into this fight?
Absolutely. We have to explain that they don’t have to fear aging interventions, since we’re talking about healthspan and quality of life for longer; this is what “compression of morbidity” is all about. Some centenarians do not get sick. 30 percent of them die in their sleep, they just don’t wake up in the morning. People would like to know that, otherwise they think that longevity is when you have cancer for longer. You have to tell them the bottom line: that people can live healthier and die with fewer diseases.
You do devote a large part of the book to your study of centenarians. Could you explain to our readers the major takeaways from this research?
First, we found many longevity genes. These are not genes that do not exist in other people but mutations, variants that alter a biological function, and you can even measure that with a biomarker. These variants are associated with their hosts’ longevity.
The first longevity genes that we found were two lipid genes that haven’t been targeted before because they are responsible for good cholesterol, not bad cholesterol. One is called CETP and the other is called APOC3.
Based partially on our study, pharmaceutical companies have developed two different drugs. People sometimes ask whether this is gene therapy. No. You find the gene and then you can design drugs that mimic what this variant does. These are two specific examples of success.
What we didn’t find is the “master gene”, which means that you can probably get to be a centenarian in many ways. However, the genotype for another gene, APOE2, is the most common longevity gene across the world’s centenarians [APOE2 is a rare allele of the gene that produces apolipoprotein E, and it is thought to be protective against Alzheimer’s disease.] There are several genes that do something important that will allow you to get to 100 and beyond.
Some of the most common of these variants reside in the genes that are involved in the action of growth hormone IGF-1. Slower production of growth hormones accounts for almost 60 percent of the genotypes we see in centenarians. It’s a very important pathway to target.
So, centenarians sort of cheat the system? Their levels of growth hormones are generally lower, and this allows them to live healthier?
Correct, it’s like with animals. Small dogs live longer, ponies live longer, whenever animals are born dwarves as a result of a manipulation in the lab, they usually live longer. And we found that this is true for humans too.
You mean, like with dwarfism? Do we have population studies to support it?
Yes, we have some data that supports this. For instance, there is a type of dwarfism that’s called Laron syndrome [a rare growth hormone insensitivity] We don’t know if people who have it actually live longer, but they have less age-related diseases, like cancer and diabetes. But we also had centenarians with unusually low levels of growth hormones who were of normal height – probably because they experienced high levels of these hormones during puberty.
I understand that a healthy lifestyle is crucial for those of us who are not blessed with centenarians’ genes. But in centenarians themselves, lifestyle seems to make little difference. How do you explain that, and does it mean that soon we might have therapies that make healthy lifestyle obsolete?
Exactly. In the book, I tell the story of one of my centenarians, Helen Richter, who opened the door to me when she was 100, and she was smoking. So, I asked her: “Did nobody tell you to stop smoking?” This was her answer: “Four doctors did, but they are all dead.” It doesn’t mean that exercise and a healthy lifestyle could not have added more years to her life. If she stopped smoking, maybe she could have reached beyond her age of 110 at death. So, I’m not saying this can’t benefit a centenarian, but the thing is their genetics had slowed aging so much that they largely became protected from the effects of the environment. Suppose you have strong genetics for Alzheimer’s. Some women get Alzheimer’s by the age of 60 because of a certain genetic variant. But they don’t get the disease when they are 10, 20, or 30, right? Aging is needed for the genes to have an effect. We have centenarians with such Alzheimer’s variants, and they’re 100 and not demented.
So, what they experience could be called delayed aging?
Yes, this “delayed aging” is enough of a mechanism to protect them, to give them resilience against age-related diseases. When we did our first whole-genome sequencing in 44 centenarians, we found over 230 mutations that should have made them ill, around 5 for each one on average, but they didn’t have any of those diseases. It really shows you that whatever they have has slowed their aging enough to make them resilient to smoking and diseases.
Today you are the leading scientist behind the groundbreaking TAME trial. After working with centenarians’ genetics and epigenetics, with mitochondrial-derived peptides, and in other areas – why metformin?
The reason I’m doing this is not because I need proof that metformin has gerotherapeutic effects. It’s a tool for me to get the FDA to say that aging is preventable just as heart diseases and cancers are. This is the reason behind TAME. There were many reasons to choose metformin, and maybe the most important one is that we don’t want to kill anyone on the way to success, so we looked for the safest drug that is also a gerotherapeutic, and that’s metformin.
Rapamycin’s safety record, on the other hand, is abysmal. Although it’s used in different doses and circumstances, it didn’t make any sense to go with a drug for which we don’t even have preliminary data. Metformin has preliminary data. Clinical and observational studies showed that it can prevent diabetes, heart diseases, mild cognitive impairment, cancer and many other illnesses. It’s associated with decreased mortality. Diabetic people who take metformin die less than people without diabetes, so strong is its effect.
Yes, the effect of metformin on the lifespan of animals is about a third of that of rapamycin, but metformin is probably stronger when it comes to healthspan. In humans, the effect on mortality is stronger than in mice, and so may be the effect on healthspan.
The effect of metformin on healthspan is actually stronger in humans?
Right. Let me explain the comparison. There have been 20 or 30 studies that tested metformin in animal models, and the average extension of lifespan was about 7-10 percent. I’m comparing this percentage to the results we have in humans, where metformin lowers 5-year mortality by 17 percent. We didn’t see life extension in humans, because we didn’t test for it. It’s apples and pears. But it can be loosely compared.
Yet, rapamycin is also currently in human trials, and it’s a promising molecule. Do you envision a two-drug therapy with both rapamycin and metformin?
I think combination therapy is going to be a staple of anti-aging therapy. It is possible that some decisions will be made by personalized medicine. Maybe there will be groups that will be better off with either metformin or rapamycin. It is important to make sure first that the effect is additive or synergetic, and not antagonistic.
For example, we studied metformin and exercise. The hypothesis was that metformin and exercise will have additive effects in elderly, but it turns out that metformin prevents muscles from growing. So, there’s a trade-off. Interestingly, the strength of the muscle doesn’t change – it means that every gram of muscle tissue works better with metformin, that it gets healthier.
There also might be a timing issue. If I were you, I wouldn’t start senolytics now, because I don’t think you have that many senescent cells, right? But an 80-year-old should probably be on senolytics. Metformin? Maybe when you are 50, we have studies to support that. There’s time for every intervention, but the combination therapy is probably going to be an important factor.
We treat many diseases with drug cocktails, so it’s not unreasonable to expect that such a diverse phenomenon as aging would require a drug cocktail.
Yes, but when you combine many drinks together, it knocks you out. We will have to figure that out.
Could you explain the importance of TAME and its design? What will be measured? What are the endpoints?
Our first major obstacle was to convince the institutions that reviewed the grant proposal. Everybody was saying: “Aging can be targeted? And with one drug? You must be joking.” In the beginning, there was total disbelief.
The main feature of the design is that we are agnostic as to what diseases people have when they come to the study and which disease they are going to get. If your mother is diabetic, and you’re obese, you’ll get diabetes first, but for us it doesn’t matter because aging is the major issue that brings your next disease out. This concept is hard to explain. We don’t care what the disease is, but for every disease they develop, patients get points.
What we want to do is to move the time until you get the disease. Whatever it is, we want to show that you get it later. So, we cluster those diseases together- cardiovascular, cancer, cognitive – we want to delay all of them.
So, the time of onset is a major metric?
Yes, the time of onset – of any disease. We will not be getting significant results for any particular disease, in fact, we will try to avoid it. Why? Because if we are two years into the trial, and it becomes clear that we are preventing cardiovascular diseases, the FDA will stop the trial and say: “We cannot continue, not when there’s such a big benefit for CVD”. But our goal is to show the effect on all diseases. We’re carefully planning the statistics, so that the trial will not be stopped. Our endpoint is clusters of diseases, not one disease.
What you are saying is that if the study shows considerable benefits for a single disease, it can be stopped.
Yes, because if that’s the result, it’s not ethical towards people on placebo to allow the trial to continue, they will have to be given the choice to have the drug. We want to go the whole way. This is also the reason for not having too many people in the study – just 3000. You need 12 thousand if you want to show effect only on CVD. The ages too: between 65 and 80, because their chances to get any one of the diseases are higher.
So, the signal for any single disease might not be significant, but you are looking for the overall score for all the diseases?
Is it possible that metformin only has a considerable positive effect on people with existing metabolic problems?
No. Nine studies around the world showed that people on metformin have significantly less hospitalizations and mortality. The biggest relevant study to date was the diabetes prevention trial that gave people either exercise, metformin, or placebo to delay diabetes. Metformin delayed it by 30 percent, and these were non-diabetic people. Because of that, metformin is allowed for people who have pre-clinical diabetes. Many people who are not diabetic still get metformin. There are less studies about people who are totally normal – lean and healthy. But with this data about delayed mortality, you have to assume that metformin is doing what it is supposed to do. It’s not because you’re abnormal metabolically, it’s just that metformin targets aging.
You could argue that aging is what makes us metabolically abnormal.
Yes, to a great extent, this is one of the things that aging does.
In addition to exercise, which gets its share of praise in your book, another major thing people can do today to live longer is eating better. The problem is, as you note, that the data is often inconclusive. Do you think we have anything rock-solid – Mediterranean diet, eating less meat, intermittent fasting?
The data on Mediterranean diet is very convincing, except that the main research has been done in Spain, where they eat a lot of olive oil and nuts. The translation of the results to other populations has been a bit difficult, but there’s reasonable validation that this is probably the best thing for you to do.
But I want to concentrate on something I know about. In my lab, we often have animals subjected to caloric restriction as our positive control. If we seek a mechanism that targets aging, we have ad libitum fed animals, and caloric restricted. People usually interpret caloric restriction as eating less breakfast, lunch and dinner. But that’s not what we do. We give them food in the morning. They eat all the food in one go and fast for 23 more hours.
So, this is intermittent fasting?
Right. If we let them eat throughout the day, but less calories, they’re leaner but they don’t live longer. So, fasting is very important for the longevity of the animals. Has the same been proven in humans? Not yet.
Why don’t we have studies like that? It looks like an easy target.
First, it’s very hard to do longevity studies in humans. Do you want to run a study for 20 years and then to assess the effect? It would take ages. So, we need biomarkers that will show us it’s working. And I’m doing a study now at Einstein with some of our colleagues which does exactly that: we take young and old people, fast them for almost 24 hours, measure their biology, how the hallmarks are changing – insulin, ketones. We want to see what is the mechanism that upregulates their ability to deal with aging.
We will have to wait and see. But personally, since I started intermittent fasting, I have improved my exercise capacity, lost weight, I’m also maintaining my weight, and there are several other things that make me think it’s working well. But the truth is we don’t have the data. I don’t know how to get convincing data that it changes lifespan, but we can test the biology.
You tell the story of the very promising peptide humanin and of the familiar patent-related problems: the patent expired after the scientist who had owned it died, and now no pharmaceutical company would touch humanin because no profit can be made if there is no patent. Does it strike you as absurd? What can be done about that?
There is a new non-profit, Hevolution, coming out in August, that wants to target aging. I’m going to be on their scientific advisory board, but one of the things they are considering is investing in such drugs, so that pharmaceutical companies can still profit from selling the drug, just like a lot of people make money on metformin, despite it being very cheap. There is indeed a need for somebody to fund the most promising therapeutics that are now dead because of patent issues, and we must find a way to do it.
As someone who has been in this field for over 25 years, do you feel the tide turning in terms of policies, regulations, and funding?
I think it’s not symmetrical. In other words, we are definitely catching a wave, driven mainly by biotech and pharmaceutical companies. They are investing lots of money, and business is currently the main driver, probably. But I think after we do our study, the FDA will join the party.
Politicians are a different issue, it’s sometimes harder with them, and we are looking for ways to influence them. The previous administration was not interested in a lot of things. Things are different with this administration. After all, Biden wants to cure cancer.
I want to tell you a story. I was at an event in the Vatican a few years ago. The pope was there and also Biden as vice president. Biden gave his speech on the “cancer moonshot”. He explained how difficult and expensive it is because every cancer is different, and how the approach has to be personalized. Then the pope gets up and says: “I still hope that there will be just one pill that is very cheap and it will cure every cancer in the world.” Then I get up and say: “There is a pill that doesn’t cure cancer but it prevents cancer and all the other diseases too.”
There is the term “valley of death”, which means the period of disappointment in science that comes after the hype. Maybe governments can carry the science over this valley of death?
I don’t think geroscience has had a chance to fail yet. Currently, we’re just waving and saying “Hey, we have something important to do.”
What about senolytics? There have been failures on that front.
But in drug development, this is not an exception, this is the rule. 95 percent of the candidate drugs fail anyhow. That’s the statistics. The next one will be better.
Are private entrepreneurs ready for it? Won’t they lose interest when hard times come?
One of the things that startups in aging need is additional help because of the timeline. Since it’s aging we are talking about, we need a bit more breath to make the point, to deliver the results. I think that entrepreneurs must understand that the timeline can be a bit more extended, that they have to stick with us.
Many geroscientists cringe at the notion of extreme life extension. Did your work with centenarians make you wonder whether there is an upper limit to our lifespan that we will never be able to overcome? Do you think that resistance is futile?
There are two potential goals. One is living to our maximal potential lifespan as a species, which is about 115 years. Today, half of the people die before the age of 80. So, we have 35 years that we kind of need to take back, so we can use them. And that’s a lot. Metformin is not going to give us that. This is a big mission on its own.
The second question – is 115 really the top? And I don’t think it has to be. In fact, I think we have to do two things in parallel: to utilize to the fullest extent those drugs that we have, and also to start thinking about the fact that we don’t necessarily have to have limits.
So, you think it’s a legitimate thing to study, it’s not outrageous to even talk about extreme life extension?
Frankly, I don’t like the term. I don’t think it is helpful or that immortality is something we should be talking about now. I don’t think the society is ready to deal with it now, when healthcare is still so poor. But I’m not saying that the fact that there’s a limit on human life expectancy as a species mean that it cannot be broken. There’s a lot of flexibility for us. So, I don’t want to be a naysayer, but as of now, I’ve even started to use the word “longevity” less. I think “healthspan” is really a more important term.
I also do not think it’s helpful to call aging a disease. The elderly don’t want to be called sick. So, if we’re claiming that we want to help them, we will be undermining ourselves by calling them sick. But the good thing is I think it doesn’t matter. With the FDA, we are going to prevent a cluster of age-related diseases. Let them call it whatever they want. It’s not an obstacle, as far as I’m concerned.
Some people do think that it’s a major obstacle.
Well, I think they’re wrong. By calling aging a disease, you’re endangering your own funding base, your ability to succeed. If you told me that without aging being called a disease, there is no way to move forward, I would have changed my mind. But this is not true. We are still targeting the biology of aging.
In your book, you flag optimism as a potentially life-prolonging trait. Again, given your long career in geroscience, are you optimistic about it today? What have we achieved? How fast are we advancing? Are we on the verge of a breakthrough?
So, first of all, I was born an optimist. I’m the most optimistic person I know, so I have no doubt that we will succeed. I am astonished that TAME wasn’t funded five years ago. I am frustrated about that, but I haven’t lost my optimism. I’m very optimistic. Paraphrasing Bill Gates’ words, we tend to overestimate what will happen in the next few years and underestimate what will happen in 20 years. I think the next decade is going to be so different. There is just no way for it not to happen. The world might be stupid and crazy but we get things done.
There is no going back, we are going to make the world so much better. Aging research is not just about aging. It can also help people who have survived cancer, because radiation therapy accelerates aging immensely. So, these people need help, and they are going to get it from aging research.
Or the poor. Look: they don’t have money to buy good food. And they don’t exercise because they cannot buy a machine, they don’t live in a neighborhood where they can jog, they can’t go to a gym. Metformin might be a solution for them. It’s cheaper than everything else, right?
What about going to Mars? We’re not going to Mars before we solve aging, because by the time we get there, we’ll get cancer or something. So, no matter how you look at it, this is not just about aging, this is about how the world moves forward and how it deals with populations that need help.
Do you want to make a forecast? Where will breakthroughs occur? Will it be senolytics, or gene therapy, or metformin?
I’m not sure gene therapy will be the first to come, but it’s not far behind. I think there are other very good advances. I’ll give you one example – autophagy, the garbage disposal system in our bodies. It works less and less well as we age, the garbage clogs the cells, and they stop functioning. By the way, it’s green garbage disposal, because it takes all those things, like proteins, and recycles them.
There are several drugs in development that increase autophagy. I think they will be fantastic, very relevant for Parkinson or Alzheimer’s, because that’s what accumulates in those cells. In animal models, these molecules clear all that garbage from cells. It’s hard for me to predict what will be the next hit, because I know how difficult it is to do biotech, to do the right studies, to hang in there. But a lot will be coming soon from many directions, you just wait.
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