Aging and its myriad insults and injuries form a burden shared by all of humanity, but not one that is equally distributed.
Nir Barzilai, MD, director of the Institute for Aging Research at the Albert Einstein College of Medicine in Bronx, New York, has spent more than a decade studying a population of healthy centenarians who defy known trends, attempting to identify the genetic signature that may explain how they avoid the seemingly inevitable destructive forces of aging-related disease. In doing so, he and his colleagues have laid the groundwork for promising new therapeutic targets that may extend these benefits to the general population.
Medscape spoke with Barzilai about his work with centenarians, the possibility of future clinical applications, and getting the medical establishment to care about aging as a verifiable indication.
The Wonders of Aging
Medscape: Most people take an interest in aging when it begins to personally affect them, but I know your interest began a bit earlier.
Barzilai: It started when I was a child of 13. I walked with my grandfather every Saturday, and he would tell me about his life. He was about 67 years old, slow, with white hair and a big tummy. I would think, I don't know if I believe his stories, because how can a man like this have done these things he's telling me?
They say that children have imagination, but we really don't understand that our grandparents are who we're going to look like when we're their age. It was the most fascinating thing for me ever, this process of aging and how transformative it is.
During my residency, I had an attending who always asked when a patient presented whether they looked younger or older than their age. You started understanding that there's biological age and chronological age. How is it possible that for two people who are 61, one looks 40 and another looks 80? Things like this kept my interest in this problem of aging.
Medscape: What was the state of biological and genetic aging research when you began?
Barzilai: It was really very incredible. Several studies showed that if you took very primitive organisms, such as nematodes, and changed one gene, they could live three times longer. This proved that aging can be modulated. That's what gave us hope.
It was a great field to be in, because there were not many people in it at that time. You felt like a total pioneer. We all brought our knowledge from other fields, and we transformed it from hope to promise.
Medscape: Were there clinical populations of interest being studied at this time?
Barzilai: When genetics started to reveal that aging could be targeted, people were also looking at the variety of diseases we describe as "progeria," where aging is premature. The thought was that if you understand what this disease is about, you'll also understand aging.
But I thought, this is the opposite of what these genetic studies have shown. There are many [factors that shorten the lifespan], but what is the mechanism by which you're resilient and live longer?
Why Some of Us Can Live a Healthy Century of Life
Medscape: Is this how you came to start working with centenarians?
Barzilai: Yes. It became obvious that the one place I should be looking was in centenarians and finding out why they're living longer, healthier lives, and whether their genetics were similar in any way to what we were seeing in these model organisms.
Maximum lifespan is considered to be about 115 years. I work with around 700 people who are 100 years or older who have been healthy for a long time.
Medscape: You've noted that some these centenarians' lifestyles and diets are quite average, sometimes even what we'd consider poor. What seems to set them apart?
Barzilai: They are not only living longer, they are healthier for 20-30 years longer than others. They also have contraction of morbidity; in other words, they're spending their years being healthy until they die, pretty much.
And we found that this is not attributed to healthier lifestyles. Some of them smoked for decades; some are not eating particularly well. Maybe if they did these things, they'd get to 120 years, but they don't need it.
Medscape: It's when you get to the genetic level that the differences appear.
Barzilai: They have some overlap with the animal models that predict longevity if you genetically alter their insulin and growth hormone signaling. Those are exactly the kind of genes we find in centenarians: those associated with insulin and insulin-like growth factor 1 (IGF-1).
We have shown in 700 centenarians and their families that the women with the lowest IGF-1 level survive the longest. They actually survived twice as long as females with the highest IGF-1 levels.
Dwarfs in nature live longer. The little dog lives longer than the large dogs, ponies longer than thoroughbreds. It's all around nature that less growth hormone in any species is better. Now we're showing it with drugs that were developed to do that, where we can stop this growth hormone in action at a certain age and we get terrific benefits with health span and life extension in animal models.
Then there's the cholesteryl ester transfer protein (CETP) gene, which does not exist in those model organisms or in rodents. But people who have a mutation in CETP have longevity and healthy lifespans, less Alzheimer disease and cognitive decline—things like that. So what we found in nematodes and other model organisms was a good story, but not the whole story.
Interventions to Come
Medscape: What would you say are the most promising areas of research for applying this clinically?
Barzilai: The National Institute on Aging has the Intervention Testing Program, where people suggest drugs that they think work on the biology of aging. Those drugs will be tested in animals at three centers around the United States to see whether they have an effect on targeting aging. There have been six drugs that have been really successful. They extended the health span and delayed aging.
Also, TAME (Targeting Aging with Metformin) is a national study I'm leading. Metformin, of course, is a drug that's been around for 60 years and is used for type 2 diabetes. It has peculiar side effects in that if you give it to people without diabetes, they don't develop diabetes, and if you give it to people with diabetes, they don't get cardiovascular disease, Alzheimer disease, or cancer; they live longer with diabetes on metformin than if they didn't have diabetes. When we give animals metformin, they live longer.
But of course, metformin is not just the best drug in animals. It has the advantage of having been tested as a generic in humans, which has generated so much data that we can use to break the barrier and have the US Food and Drug Administration (FDA) make an indication that will target aging. If there won't be indication to target aging, then biotech and pharmaceutical companies are not going to develop drugs to target aging.
Medscape: In 2015, you prominently participated in an episode of the National Geographic documentary series Breakthrough, called "The Age of Ageing." It begins with you and your other colleagues approaching Congress to plead for taking aging seriously as an indication. Can you explain the necessity of that process?
Barzilai: A bunch of my colleagues and I decided to go to the FDA and to write a study [on behalf of] the National Institutes of Health and to the American Federation of Aging Research actually testing metformin with an indication to target aging, which was the TAME study.
The burden is that there has to be a mechanism that you can show in more than one preclinical animal model. Metformin will delay aging in worms, and also in rats. So it is key to show that a drug targets aging in multiple models, and metformin is such a drug.
If we don't have an indication, the healthcare providers are not going to pay for the drugs for their insurers. If the healthcare providers don't pay for this medicine, then the pharmaceutical companies are not going to develop them, because they need an economic plan.
Part of the reason the FDA supported this effort is that they have trouble with nutraceuticals and all of the charlatans in this field. It's important for them to show that studies can be done in which you're really targeting aging. So it's part of the FDA's mission too.
Medscape: The future certainly seems bright, but it remains out of reach for the moment. For patients and practitioners eager to delay aging at the present time, what do you recommend? Is the best advice still minding your diet and exercising?
Barzilai: We have to remember we're talking about health span, rather than just lifespan. In that area, first of all, they should know that help is on the way. Living longer and healthier is something that is possible and will be possible soon, when can target these things with drugs.
In the meantime, interaction with the environment is important. In general, one half of the people die around the age of 80 years. If you exercise and diet, you're more likely to get over the age of 80.
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Cite this: Is an Antiaging Drug Around the Corner? - Medscape - Sep 14, 2018.