Walter Isaacson: As a young scientist, Leonard Hayflick didn’t set out to study aging and he certainly didn’t intend to risk his reputation to become one of its most disruptive trailblazers, but that’s what happened. The year was 1961, Hayflick was a 30 something biologist at the Wistar Institute in Philadelphia. His job was to grow and feed tiny communities of cells in test tubes for other more senior scientists to study.
Walter Isaacson: The scientific consensus was that cells grown in perfect laboratory conditions would continue dividing and replicating indefinitely. It was long assumed that if cells could replicate indefinitely in a lab, aging must have nothing to do with biology. It was inevitable. At that time, nobody was even studying aging. Then one day, Hayflick walked into his incubator room and his world was turned upside down.
Walter Isaacson: One of his cell cultures had done the impossible. The cells had stopped dividing, then died but rather they had entered a state of inactivity like a clock that stopped ticking. In biological terms, the cells had become senescent. Hayflick assumed he’d made a mistake, but he kept getting the same results. Little did he know that those tiny seemingly insignificant cells would shatter the current scientific consensus, but even more incredible than that, those cells contain the answer to one of the greatest mysteries of human history, why do our bodies age?
Walter Isaacson: And if we know what causes aging, can we do anything to slow it down? I’m Walter Isaacson and you’re listening to Trailblazers, an original podcast from Dell Technologies.
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Walter Isaacson: Leonard Hayflick may not have set out to study the mystery of aging, but that doesn’t mean he wasn’t intrigued by what he found. After all, the desire to understand why we age is almost as old as history itself. Sue Armstrong is the author of Borrowed Time: The Science of How and Why We Age.
Sue Armstrong: There’s always been a fascination with aging and dying because I think uniquely among species, we can anticipate the future and anticipate are dying and it’s a pretty fearful prospect and so there’s always been a fascination with a search for a fountain of youth or something like that.
Walter Isaacson: More than 2000 years ago, the Greek philosopher, Aristotle believed that aging was due to an internal flame inside of us slowly burning out. As mystical as that sounds, it’s a belief that persisted for centuries. One of his students was Alexander The Great and that famous conqueror was obsessed with finding a so-called river of paradise that supposedly healed the ravages of time.
Walter Isaacson: If that story sounds familiar, it’s probably because of the tale of Ponce de Leon, the Spanish explorer, who first landed in Florida in 1513. He was obsessed with finding a fountain of youth, a river whose waters turned old men into boys. Since the dawn of the scientific revolution, legends like these have transformed into theories about how and why the body ages. In the 17th century, doctors thought that blood was what made a person old or young.
Walter Isaacson: They hypothesized that overcoming old age was as simple as a blood transfusion. The fountain of youth, they believed was inside us all along. But science wasn’t getting much closer to the answer of why our bodies age until Leonard Hayflick’s startling discovery. Senescent, or cells that have entered a coma like state, hold the key to understanding what happens to us as time marches on. Sue Armstrong.
Sue Armstrong: I think what Leonard Hayflick did was really changed the whole paradigm. It was an extraordinary thing suddenly to find that you had these senescent cells. But one of the interesting things is that we look back across history now and we see that senescent cells are an important part of the story of aging in an organism. But at the time they weren’t seen as that at all. Nobody quite understood what the relevance of cells simply hitting a limit, a number of divisions that they couldn’t go on any further from.
Walter Isaacson: So what exactly did Hayflick discover? Deep down at the cellular level, there is something like a ticking clock keeping track of the number of times our cells divide and replicate themselves. At a certain point, after about 50 population doublings, those cells stop dividing and become inactive. Or as scientists say, senescence. Today we call that point the Hayflick Limit.
Walter Isaacson: Just like us, ourselves get old and they can’t function like they used to. Senescence is aging. These senescent cells are part of our lives from beginning to end, and over time they build up inside almost every part of our body. When we’re young, our immune systems are able to sweep away senescent cells and dispose of them. But as we get older, that ability declines and so those cells accumulate in our bodies, inflaming our tissue, causing us pain.
Walter Isaacson: And this is significant. The buildup of senescent cells is now linked to diseases like osteoarthritis, glaucoma, heart disease, strokes, and degenerative diseases of the liver, kidney, and brain. In other words, some of the worst conditions associated with old age. If we want to live longer, healthier lives to increase what scientists call our health span or the portion of our lives when we feel young and vigorous than knowing how and why senescence occurs is the first step.
Walter Isaacson: In the 1960s this was a radical proposition. Leonard Hayflick was sure he was right about cellular senescence, but at first nobody believed him.
Leonard Hayflick: At first, my work was ridiculed. In fact, my paper describing this work was sent to one of the best, most well known journals in the field at that time and it was rejected.
Walter Isaacson: That rejection from the Journal of Experimental Medicine was written by Peyton Rouse, one of the most famous biologists of that era, would later win the Nobel prize in medicine. In his letter to Hayflick, Rouse wrote, as anyone who works with cell cultures will know, cells will replicate indefinitely the suggestion that aging is the interpretation is notably rash. He was essentially telling Leonard, Hayflick, you’re wrong, but Hayflick persisted.
Leonard Hayflick: I could not turn away from the very convincing experimental results that I obtained and argue that I was wrong. The evidence that I had was overwhelming. In my judgment, it took 10 years for other people to realize that the judgment was accurate.
Walter Isaacson: Hayflick submitted his study to another journal called Experimental Cell Research and they accepted it. His work would revolutionize the field of aging. Hayflick went on to become a professor of anatomy at the university of California in San Francisco, president of the Gerontological Society of America and co-founded the National Institute On Aging. Today at age 92 he’s still pondering the questions of human aging, but Hayflick’s groundbreaking discovery of cellular senescence, was just the beginning.
Walter Isaacson: Scientists now understood that to figure out what causes us to decline with age, they had to look deep inside our cells and the obvious questions were, how do our cells know when they’ve reached the Hayflick Limit? What causes them to stop dividing? It would take another 20 years to answer.
Walter Isaacson: Since even before the time of Leonard Hayflick, geneticists had inferred the existence of a mysterious part of our chromosomes called a telomere. Chromosomes are the tiny threads of our DNA that live inside our cells and they get copied every time our cells divide and make new cells. The nature of telomeres remained a mystery until after Hayflick’s discovery of senescence. When a few scientists began to wonder if telomeres were related to the natural lifespan of cells.
Walter Isaacson: One such trailblazer was a Tasmanian molecular biologist named Elizabeth Blackburn working at the university of California at Berkeley. In the late 1970s Blackburn theorized that telomeres are actually the reason that our cells are able to divide as long as they do. Sue Armstrong.
Sue Armstrong: Every time a cell divides, a bit of that telomere is lopped off, but the telomeres aren’t replenished at the same time, they don’t divide with the rest of the DNA. As they get shorter and shorter and shorter, it gets to a point where they can no longer maintain the integrity of the chromosome, and that’s the point at which the cell realizes that it must no longer divide and it becomes a senescent cell.
Walter Isaacson: In other words, telomeres play a protective role in our cells, warding off the effects of aging. Imagine for a moment that a string of chromosomes is like your shoelace. Now think of a telomere as that plastic tip on the end of the shoelace called an aglet, which protects the shoelace from becoming frayed. The longer you wear your shoes, tying and untying those shoelaces, the more wear and tear occurs on the aglet.
Walter Isaacson: After a while, that little plastic aglet just falls off altogether and the shoelace unravels. If our shoelaces break down too fast, we can just buy new ones, but our chromosomes contain our precious DNA. If they degrade too fast, we wouldn’t live very long and we certainly wouldn’t be healthy.
Walter Isaacson: But after a few years of experimentation on microscopic organisms, Blackburn confirmed her theory that telomeres protect cells against premature aging, but then something very peculiar happened. One day she observed that some of the telomeres on these tiny creatures were growing, that they were getting longer. If some telomeres were getting longer, that means they were literally turning back the clock of aging.
Walter Isaacson: The shoelace tips will repair themselves. How is this possible? In 1984 Carol Greider was one of Elizabeth Blackburn’s graduate students at Berkeley.
Carol Greider: I’m Carol Greider, a professor of molecular biology and genetics.
Walter Isaacson: Together, they devised a hypothesis that there must be some substance inside our cells responsible for rejuvenating telomeres, a kind of telomere fountain of youth. In what would become a legendary experiment, Blackburn and Greider started by gathering some ponds con.
Carol Greider: We decided to turn to an organism called Tetrahymena, which is a single cell pond animal closely related to paramecium. If you went out to a pond nearby and scooped up some cells … some water, you would see these little single celled animals swimming around.
Walter Isaacson: Blackburn and Greider put fragments of pond scum in a test tube with tiny broken bits of telomeres. The goal was to see if the mysterious substance, an enzyme would reveal itself by using the DNA to repair the telomeres.
Carol Greider: We were basically just doing trial and error experiments, trying to devise a new way to look at something that was unknown. So there were multiple different things that we didn’t know. We didn’t know if the enzyme existed in the first place. There were predictions that there were other ways to overcome the telomere shortening other than an enzyme, and we didn’t know exactly how to look for it. We just used our best guesses.
Walter Isaacson: For nearly a year they repeated their experiment, tweaking parameters, looking for clues. Finally, on Christmas day, 1984 Greider made the discovery that would come to revolutionize the science of aging.
Carol Greider: So after playing around for about nine months, working in the cold room using biochemical techniques, I changed one particular parameter in the experiments and amazingly I found exactly what we thought we were looking for. And so that was the first real aha moment.
Walter Isaacson: Staring at her x-ray image Greider saw that the telomeres of the microscopic pond water creatures had been repaired. She burst out dancing with joy. They had proved the existence of a natural enzyme in our cells that allows telomeres to function as long as possible. She and Blackburn named the new substance telomerase. It’s what creates and maintains our telomeres, which are responsible for keeping us healthy as we age.
Walter Isaacson: In 2009 Blackburn and Greider received the Nobel prize in medicine for their incredible achievement. Soon after this discovery, scientists began to hypothesize that if we’re more likely to develop osteoarthritis or heart disease because our telomeres are becoming too short, then perhaps we can artificially engineer telomerase to assist the rejuvenation. After all our health spans or how long we can live without the ravages of old age diseases, depends on the health of our telomeres and the work of telomerase. Can technology now step in and take over that work?
Walter Isaacson: Mark Twain famously said, “Life would be infinitely happier if we can only be born at the age of 80 and gradually approach 18.” Twain was lamenting the inevitable slide from vigorous youth to decrepit old age. Why, he wondered, does the end of our lives have to be defined by disease and infirmity? Wouldn’t it be great if we could stay young while we grow old?
Walter Isaacson: Following the discovery of telomerase, many gerontologists and biologists began to realize that they were on the cusp of making Mark Twain’s dream come true. Not that we could actually grow younger, but that we could turn back the clock of aging by replicating the work of telomerase inside our chromosomes and repairing the damage caused by the buildup of senescent cells.
Walter Isaacson: But research into these solutions proceeded slowly for two reasons. One, because scientists are naturally cautious and their experiments have to endure many trials and peer reviews before they see the light of day and two because like many great endeavors, the science of aging needs funding. Enter Laura Deming.
Laura Deming: My name is Laura Deming. I’m founder and managing director of Longevity Fund.
Walter Isaacson: Deming is a venture capitalist who funds a significant amount of age related research in Silicon Valley. When Deming was just a seven year old girl, she decided she was going to find a cure for aging.
Laura Deming: My grandma had come to visit us and that was the first time that I had really seen the impact of some of these aging related symptoms and diseases on somebody that I really love. Now, at the time, aging wasn’t seen as something that you could treat, so my first thought was, well, let me just go cure cancer. That should take care of most of the problems. But then my dad, who’s very smart, pointed out that aging is actually a core determinant of many of the diseases that we see arise in prevalence with age, and if we could just target that one factor, we might be able to treat all diseases.
Walter Isaacson: At the age of 14 Deming went to MIT to study physics and at 17 she dropped out and moved to Silicon Valley. There she decided to dedicate the next phase of her career to becoming a venture capitalist in order to invest in biotechnology to cure aging related diseases. What Deming had realized was that finding solutions to rejuvenate human bodies and increase our health spans required a massive effort and an important component of that effort was raising capital to invest in the development of science and medicine.
Walter Isaacson: A new generation of trailblazers needed support. The next Leonard Hayflick might be around the corner.
Nathaniel David: I’m Nathaniel David. I’m a biochemist. I’m co-founder and president of Unity Biotechnology.
Walter Isaacson: In a laboratory overlooking the Bay just South of San Francisco, Nathaniel David is thinking about your knees. More specifically, he’s thinking about painful soreness and inflammation that occurs in the knees, hips, and other joints as they age. A disease known as osteoarthritis, which affects more than 14 million Americans.
Nathaniel David: We all began life at conception as a single cell and over the arc of say 50 cell divisions, we, the single cell, encounter some form of unresolvable stress. We’ll pull an emergency brake and stop dividing forever. When cells pull this emergency brake, they begin to produce hundreds of factors into their surrounding environment, poisoning that environment, distorting that environment, essentially making tissues functionally old and in some cases diseased.
Walter Isaacson: Recall that osteoarthritis like other aging related diseases is linked to the buildup of senescent cells in our body as we get old. Like dirt and grit building up in the engine oil of your car, senescent cells can accumulate to the point where critical parts of our body stop functioning like they used to and for almost a decade, David has been focused on finding a way to reverse the trend of this buildup ever since he had what he calls a yorica moment.
Nathaniel David: I was sitting around at an airport in Calgary, Canada eating French fries. I remember this quite vividly and five different people sent me the same PDF with subject lines of, oh my God. Or various colorful metaphors in all caps and exclamation points, things like you have to read this paper.
Walter Isaacson: What David read was a report by a scientist, Jan van Deursen, who would eventually become his collaborator at Unity Biotechnology. Van Deursen had just published a study that demonstrated a method for eliminating senescent cells in mice, effectively turning old decrepit rodents into vigorous healthy ones. When David got home, he started making a list of questions he needed to answer. Did senescent cells contribute to aging? Was there a molecule that could eliminate senescent cells from living human tissue? And was there a way to do it all safely?
Walter Isaacson: Recognizing that the answers to these questions were within reach, David pulled together several collaborators and founded Unity Biotechnology, and the first thing they did was examine arthritic knees.
Nathaniel David: We did a clinical study looking at this, that if you go into patients with arthritis of the knee and we can … we clipped out a bit of tissue from their knee and we counted senescent cells, we saw that the more senescent cells you had, the more the arthritis had damaged the bone of your knee, the more that the knee was inflamed, but most interestingly, the more senescent cells we could count in a patient, the more pain they were in.
Walter Isaacson: This was a startling discovery. Not only are senescent cells causing osteoarthritis, they are also directly linked to the pain that we suffer. Suddenly the need for radical innovation became apparent to David and his colleagues.
Nathaniel David: We make what are known as senolytic medicines. These are molecules that we can introduce into tissue which will cause the selective elimination of senescent cells from that tissue.
Walter Isaacson: And that groundbreaking medicine is an experimental drug which David and his colleagues at Unity Biotechnology are now testing. If successful, it will inject molecules into the tissue of arthritic joints that can purge senescent cells. In a sense, it will mimic what our younger bodies can do naturally that our older bodies struggle to do. Laura Deming’s Longevity Fund was one of the earliest investors in Unity Biotechnology, which also raised over $200 million in startup capital from Silicon Valley Titans like Peter Teal and Jeff Bezos.
Laura Deming: In the history of Longevity, we’ve never tested longevity drugs in patients in comprehensive clinical trials. For the first time this year, drugs including Unity’s are getting their time in the limelight to see an effect in patients. It’s the first real scientific test of longevity therapeutics in humans that will kind of spark the first wave of results in the field. And that’s why it’s so exciting.
Walter Isaacson: What Nathaniel, David, and others are doing, is not just turning back the clock on all day age, they are disrupting the clock itself.
Nathaniel David: Think of eras before antibiotics or eras before widespread use of vaccination, what it was like for children just to get to adulthood. That’s been redefined by those innovations and it’s my belief that medicines that target fundamental mechanisms of aging will similarly redefine what it means to be old. I believe it will allow us to live far more vibrant, rich lives in the latter chapters of our life than our parents or grandparents could, and that is a world I look forward to living in and it’s a world worth leaving to our children or our grandchildren.
Walter Isaacson: Aristotle wasn’t totally wrong. There is a sort of flame of human liveliness that seems to burn down as we age. Even today as trailblazers like Nathaniel David, Carol Greider and others, investigate senescent cells. Other scientists are investigating the role that our blood plays in keeping us youthful and still more scientists are looking at aging from a genetic perspective.
Walter Isaacson: They are identifying genes associated with longevity and genetic switches that can be manipulated to increase our health span. Leonard Hayflick likes to point out that even if we cure osteoarthritis, heart disease, Alzheimer’s, and all the diseases associated with shortened telomeres and senescent cells, our bodies are still going to get older. One way or another, the clock is always going to keep ticking. So when we talk about the science of aging, the goal is not immortality so much as the elimination of all the things that make us afraid of living as long as we do, but you don’t have to wait for technology to catch up and sweep away all your senescent cells.
Walter Isaacson: We already know that shortened telomeres are associated with things like stress, depression, extreme fatigue and poor diet. If we take care of our mental health, stimulate our minds, exercise, eat healthy, and get a good night’s sleep our telomeres are more likely to stay long and luxurious as we age.
Walter Isaacson: There is a fountain of youth inside us after all. I’m Walter Isaacson, and you’ve been listening to Trailblazers, an original podcast from Dell Technologies. For more information on any of our guests, go to our website, delltechnologies.com/trailblazers. Thanks for listening.