Nir Barzilai, credited with identifying the first human longevity gene, wants to set the record straight when it comes to discussing his life’s work exploring the biology of aging: It’s not “anti-aging” research and he’s not trying to increase “life span.”
With those linguistic ground rules in place, Barzilai says he has five approaches for targeting aging and improving people’s health span. They range from scientific investigations as the founding director of the Institute for Aging Research at the Albert Einstein College of Medicine to entrepreneurial endeavors, which include co-founding CohBar Inc., a start-up developing mitochondria-based therapeutics to treat a wide range of age-related diseases.
In the short-term, however, Barzilai’s most significant project may be a clinical trial getting underway this year. The study, called TAME (Targeting Aging with Metformin),will attempt to show that metformin, a diabetes drug, can slow the rate of aging by delaying the time to occurrence of a composite of age-related diseases, including cardiovascular disease, cancer, and cognitive decline.
“The idea is we are agnostic to the diseases because the thing that’s common to all those diseases is aging,” Barzilai says. “That’s the major risk factor; so when you age, you are at risk of getting anyone of those diseases. We are going to shift the time until you get the diseases by giving metformin. That will be our endpoint.”
The study will take five-to-six years, but if successful, Barzilai says, it will establish aging as a FDA regulated indication, creating a market for medicines that treat aging, not just specific age-related diseases.
“We took care of many diseases,” Barzilai says, “and now we have aging and it’s miserable. We need a new approach and the new approach is targeting aging.”
In addition to leading the Einstein College of Medicine’s Aging Research Institute, Barzilai is a professor in the Departments of Medicine and Genetics. He is also director of the Paul F. Glenn Center for the Biology of Human Aging Research and of the National Institutes of Health’s Nathan Shock Centers of Excellence in the Basic Biology of Aging. Barzilai received his medical degree from The Ruth and Bruce Rappaport Faculty of Medicine at the Technion-Israel Institute of Technology in Haifa.
WuXi AppTec Communications’ interview with Barzilai is part of an exclusive series spotlighting the inside perspectives of thought leaders on topics shaping the future of new medicines.
WuXi: How would you describe the history of anti-aging strategies?
Nir Barzilai: The word anti-aging is the enemy of the biologists of aging. Anti-aging and organizations that are anti-aging are people usually who are selling snake oil to the public. It’s people who are doing things without any controlled studies. They’re selling things like growth hormone. It’s a billion-dollar-a-year industry and that’s probably the most harmful thing out there. Thankfully most of the other products that are anti-aging don’t contain what they’re supposed to contain. So it’s helping the economy, but not causing much damage. It’s at least not dangerous and some products might be good, but we have no idea.
We’re trying in our labs to target aging. We’re not anti-aging. For us anti-aging is the enemy. It gives us a bad name.
Now that I have defined that I am not part of anti-aging, but part of targeting aging, what happened to us in the last decade is we went from hope to promise. While we knew there was a biology of aging, we didn’t know if it can be targeted. But we have been targeting it, all over in many labs with many methods and we have shown in preclinical studies that aging can be targeted. This is the short history.
WuXi: What is your approach to targeting aging and what is the goal?
Nir Barzilai: I have five approaches. The first two approaches are scientific in the sense that in an aging center we have 50 labs and cores. We are the biggest in the world. They are all trying to target pathways that are in the biology of aging. So, for example, I’m doing it in rodent models. I have rodent models where I’m targeting a pathway and getting animals to live longer.
The second part in my research, which is increasingly important, is human study. Because one of the problems with studying animals is we know a lot of the biology but we couldn’t predict what it means for human aging. On the other hand, if you are thinking there are seven billion people in the world then all the genetic experiments have already been done.
So what Regeneron Pharmaceuticals is doing, for example, is they don’t look at mice, they go to humans and find genetic alterations, and relate them to clinical records to see if those things are accelerating diseases or protecting against diseases.
What I have is a study of families of centenarians. In centenarians we find what we call longevity genes that protect them against age related diseases. So this is very important information and there are two drugs that have already been developed based on some of our findings.
My third approach is that the problem now is if you have a disease, you identify the biology of the disease. You pick something and develop drugs and the FDA approves those drugs if they are safe and effective, and the health care provider will pay for the patients to use these drugs. You think of hypertension, high cholesterol or things like that.
The problem with aging is that FDA doesn’t approve of aging as a targeted condition. And so I’m leading a study that is called TAME, which means Targeting Aging with Metformin.
Metformin is one of those drugs that affects aging. It’s a cheap generic drug that has been in use for 60 years. It’s very safe. We – meaning a bunch of scientists –went to FDA and talked with them about a study, at the end of which we will have an indication that is similar to aging.
We are not in favor – that is, most of the scientists, the FDA and Congress –of declaring aging as a disease; first of all, because not everybody who ages is sick and because we do not want to have ageism. We don’t want to look at people and say we are going to send you to a concentration camp or something; and so we found a way to call it aging. The way we do it is our outcome in the TAME study, the primary outcome, is the time to new occurrence of a composite of diseases that includes cardiovascular disease, cancer, and cognitive decline.
The idea is we are agnostic to the diseases because the thing that’s common to all those diseases is aging. That’s the major risk factor, so when you age you are at risk of getting anyone of those diseases. Which one you’ll get depends on your genetics and environment. If your parents have diabetes and you are obese you probably will get diabetes first. We are going to shift the time until you get the disease by giving metformin. That will be our endpoint. It’s a composite of age related diseases. So for the National Institutes of Health, the improvement of aging is the delaying of the composite of age related diseases.
My fourth approach to targeting aging is that I have my own biotech company. It’s called CohBar. It’s doing well. CohBar Inc., of Menlo Park, Calif., is developing mitochondria based therapeutics (MBTs) to treat a wide range of diseases associated with aging and metabolic dysfunction.
The fifth approach is working with David Sinclair (director of the Paul F. Glenn Center for the Biological Mechanisms of Aging at Harvard University) to raise venture capital funding for companies targeting aging. We are doing well with that. We already have six companies.
WuXi: Why did you choose metformin for the TAME clinical trial?
Nir Barzilai: First of all, if you give metformin to a variety of animals, from worms to rats, they will live longer and healthier. Also, studies have been done individually in each one of the diseases that I told you that show, for example, metformin prevents diabetes in non-diabetics. In people with diabetes, it prevents cardiovascular disease. People on metformin have less cancers, less Alzheimer’s disease and people on metformin die less than even non-diabetic people. The clinical trial will last five or six years.
WuXi: What are the major challenges you face in bringing to market drugs that slow the aging process?
Nir Barzilai: The major challenges are what I told you before: that the health care provider doesn’t have a (disease) indication and is not going to pay for that. So the first thing is regulation. I’m dealing with that. I’m at the FDA, I’m at the Congress. I think we have a path forward. But we have to do the TAME study first.
The second thing is that the investment in developing drugs for aging is more of a long term (challenge) until the regulation falls in place and until we know how we are going on with it. For each company that we are forming we need to find something – a disease related to aging. We need to find some disease indication to target sooner and then it will become aging later. So we’re trying to find something that is sooner rather than later in all of our companies. We’re looking now at a company that actually has another kind of metformin. This drug is a super metformin and our indication is actually a therapy for cancer. With cancer we can get to the market much faster.
WuXi: What are the societal implications of extending life span?
Nir Barzilai: First of all, I want to correct you. Life span is a side effect. I’m really looking at health span. What happens in my centenarians, they live healthier, 20 and 30 years longer and sometimes they’re not sick. They just don’t wake up one day. The end of their life is short. We call it the compression of morbidity.
The second thing is that from a societal perspective, there is a longevity dividend. It’s estimated that by 2050, if we will extend health span by two or three years, we will save $7 trillion in medical bills. So there is almost no way to pass over this opportunity. We’re going to delay not one disease, but all diseases.
Then the implications that we will need societal changes are really age of retirement and things associated with Social Security. It will all have to be adjusted, but you know we are already there. We expect that 65 is really too early to retire. People will have capacity to work five years more initially. There are implications of Social Security and individual implications. You know when I talk about those drugs that we’ll develop and there is a commercial on the television, it will say, ‘this drug will extend your health; you won’t be sick, but the side effect, we are sorry, is that you might live longer. So I don’t know if you’re prepared for that. I don’t know if you have enough Social Security; if you have enough retirement and things like that.’ So this will have to come too.
WuXi: Are there any ethical considerations in extending health span?
Nir Barzilai: I’m perplexed by the question. When you treat patients now for pneumonia or for diabetes, do you have any ethical considerations that are different from what we’re saying? What’s not ethical about extending health span to people? Is this not ethical? I’m an M.D. It’s what I’ve been doing my whole life.
If I’m telling you that the future is, it will take you 80 years to become what’s now 60, is this a problem? We’re extending health span. There are people who want immortality. So if we can be immortal, it’s a totally different consideration. Who can be immortal and is immortality going to be for everyone, and if you’re immortal what about reproduction? There are lots of issues, but the maximum life span of humans is considered to be around 115. We argue, is it 113 or 122? But it’s around 115, and we die at age 80 from diseases, so we have the capacity as a species of 35 more years. Let’s work on that. There’s nothing ethical about it. We took care of many diseases, and now we have aging and it’s miserable. We have one disease with treatment and then a second disease with treatment, and a third disease, and the treatments have side effects. This is not working for us anymore. We need a new approach and the new approach is targeting aging.
WuXi: What kind of reception are you getting from the investment community? Is this the next wave in venture capital investment?
Nir Barzilai: We have no problem getting investors. The interesting thing about the investors is that they are relatively young. I think that old people don’t believe that something can be done for them. But young people see old people and look at the world differently from how we were raised and they are excited. We don’t have any trouble getting money to support a big venture.
Big pharma is interested, but they are not there yet because all this progress hasn’t been formalized yet. I think what will turn things around is when TAME is underway and TAME is finished, then pharmaceutical companies will understand they are not going to get stuck. Their medications are actually going to make it.