Aging: Transcript
News Anchor 1: Anyway, well here’s one way in which people can live longer. Maybe you can stick around a few years…
News Anchor 2: People are living radically longer and healthier lives. Stay tuned for the latest updates in longevity news.
News Anchor 3: These are regions of the planet where people seem to live longer
News Anchor 4: Kinda gray the one on the right. He’s kind of balding a little bit. And, so, he was not treated with this genetic engineering. But they did treat the one on the left.
News Anchor 5: Do you want to stay young forever?
[Narration]
Caleb: We have always been obsessed with cheating death. For thousands of years humans have sought the panacea for dying and getting old. In past eras we dedicated entire fields of study to developing a successful strategy to prevent and even reverse aging. In many ways, we still do.
What is our current understanding of the aging process, and how did we get to where we are today? How feasible is it to actually “cure” aging? Is immortality within our grasp, and if so, should we reach for it? And if so, should we reach for it?
My name is Caleb, and hopefully I can answer some of these questions, and more.
Let’s start in the Middle Ages, 500 to 1500 AD. We are in Europe.
During the Middle Ages, dogma and tradition dominated every aspect of life. The age of science was still a few hundred years in the future, so medical knowledge varied greatly depending on who you asked.
At this time, the Catholic Church held an enormous amount of power in the intellectual community. Christians believed that any disease or misfortune was either punishment for a sin, demonic possession, or the result of meddling with dangerous magic. As such, the Christian-approved cure for most ailments was penitence, prayer, or help from specific saints. The belief that care for the soul was more important than medical care was so dominant in Middle Ages Europe that most monks were forbidden to practice medicine.
Let's go back to that magic thing for a moment. At this time, magic was rampant throughout Europe. The Catholic Church viewed magic as being in direct opposition to themselves, since most of it was related to rituals upheld by Paganism, a religion the church was trying to snuff out. In actuality there were two leading branches of magic at the time. The first, so-called demonic magic, usually involved asking the favor of some Pagan deity. The second, natural magic, was kind of like the precursor to modern science, only with magic. It included astrology and alchemy, as well as disciplines of natural science such as chemistry and astronomy. Pliny the Elder compiled hundreds of examples of natural magic in his 27 volume “Natural History”. For example, he includes this cure to the wrinkling associated with old age: steep some leaves in the urine of a boy not yet adolescent. Mix that with potassium nitrate and apply to the abdomen.
How most people believed this stuff is a mystery to say the least.
Alchemy, by the way, was very popular and often considered a legitimate science. One of the goals of alchemy was to create the Elixir of life, which cured all diseases and granted eternal youth. The idea of the Elixir of life appears to even predate alchemy, and references to it exist as far back as the epic of Gilgamesh, over four thousand years ago.
The prevailing medical theory was the humors theory established by the Ancient Greek philosopher Hippocrates. According to this theory, all human discomfort was caused by an imbalance in the four bodily humors: blood, yellow bile, black bile, and phlegm. Black bile and phlegm were said to be in excess at old age, which corresponded with lethargy and depression. The contemporary cures for this included therapy, flattery, wearing brightly colored clothes, playing games, and listening to music.
Maimonides, a well-known physician of the period, felt that the eldery could maintain their health by avoiding excess, keeping clean, and drinking a lot of wine. Roger Bacon, who is famously accredited with inventing the scientific method, believed that aging and death are the consequences of the original sin of Adam and Eve in the garden of Eden. Bacon argued that aging was pathological and that medicine could help prevent aging but never cure it. To cope with it, he suggested a balanced diet, exercise, moderation, decent hygiene, and inhaling the breath of a young virgin. Whatever that means.
This isn’t to say that things weren’t on the verge of change. During the medieval period, the Islamic empire, at the height of its power, placed a new emphasis on education. The first hospitals were invented, and thousands of Greco-Roman texts were translated and adapted. Charlemagne took to revitalizing monastic schools and eventually invented the liberal arts. All of this led to the founding of the first medieval universities.
Flash forward to the Renaissance. Universities had grown into powerful intellectual centers, and there was a new focus of human matters over divine ordeals. Medical schools had begun to pop up across Europe, and as life expectancy went up, concerns about aging did too.
For the first time, aging was being considered worthy of its own entire field of study. Gabriele Zerbi, an Italian physician, wrote the first book about geriatrics, the care of the elderly. He felt that only a careful study of aging could help reverse its effects. Luigi Cornaro was a Venetian nobleman who found himself unhealthy and unhappy after 35 years of drinking and partying. He subjected himself to a strict diet of 11 ounces of food and 14 ounces of wine day in an effort to prolong his life. He wrote about his findings at the age of 83. Paracelsus, the legendary physician, had a unique perspective. He compared the aging process to rust forming on metal, and believed that it could be slowed by proper nutrition and by ingesting mystical substances. He also believed that extending one’s life this way was unchristian.
The industrial revolution brought about a paradigm shift in scientific and medical thinking. Advances in chemistry, anatomy, and physiology meant that there was more demand than ever for empirical research to back up medical claims.
Sir John Floyer, an English physician, wrote the first English book on geriatrics, which was still considered to be the first modern text on geriatrics a century after its publication. Floyer also advocated for hot or cold baths to help deal with the effects of aging. His hometown happened to have several famous hot and cold water spas. Erasmus Darwin, the grandfather of Charles Darwin, suggested that aging was a consequence of decreased irritability and response to the sensations of tissues. Benjamin Rush, a signer of the Declaration of Independence, believed that aging was caused by other diseases and that aging itself was not a disease. Christoph Hufeland proposed that it was possible to profoundly prolong the human life through external conditions and exposures. This prolongation was not limitless, however, as Hufeland believed that the aging body accumulated some damage that could not be prevented or reversed.
Then, in 1859, everything changed when Charles Darwin wrote his seminal work “On the Origin of Species.” Now aging was no longer a mysterious fate but a simple side effect of natural selection. The possibility of a cure seemed more realistic than ever.
Over the next century, scientific understanding as a whole would increase at an exponential rate. Profound advances in physics, chemistry, and technology paved the way for modern theories of molecular biology. We’ve been able to examine the aging process at a fundamental, molecular level. So why, then, do we age?
It’s hard to say. Despite our incredible medical advances, for now all we have are theories. The theories of aging can be split into two categories: programmed theories and damage or error theories.
According to the damage error theory, aging is just an accumulation of irreversible damage to our cells. DNA is constantly being damaged by environmental factors and errors during cell division. Sometimes, when a cell suffers too much DNA damage, it stops dividing and undergoes apoptosis, programmed cell death. In one study, researchers found that the ratio of the percentage of DNA lost each year in dogs versus humans, was the same as the ratio of their maximum lifespans. Other culprits include damage by free radicals and declining mitochondrial function due to free radicals.
According to the programmed theory, aging is dictated by a biological clock, similar to the one that determines how we grow and develop as children. Proponents of this theory will argue that lifespan, like other phenotypes, is the result of natural selection. Researchers have shown that by altering or suppressing specific genes, they can drastically increase the lifespan of certain lab animals. Some of these genes have homologues across species, which could be an indication that there is a single genetic cause for aging in all organisms. The discovery of telomeres in the 1970s only strengthened this theory.
A telomere is a region on the ends of chromosomes that protects them from damage during cell division. During chromosome replication, duplication all the way to the end of the chromosome is impossible, so after each division, that cell’s telomeres become shorter. In some organisms, this phenomenon has been attributed to cellular senescence. When a cell’s telomeres are too short, it senesces, or stops dividing. Telomere length is therefore analogous to a biological clock that determines how fast we age.
The telomere theory doesn’t work for all organisms, but it is exciting, because there are some animals that possess the ability to replenish their telomeres. These animals appear to possess biological immortality, also known as negligible senescence. Animals like the hydra, lobster, and fish like the sturgeon and rockfish, and some tortoises and jellyfish, don’t seem to experience any sort of aging at all, and can only die from accidents or predators.
Progress to cure aging is so rampant that researchers have already seen mild success in the lab. Two groups in 2017 and 2018 were able to increase the lifespans of mice by up to 36 percent by reprogramming epigenetic markers. A more recent study on humans used a mixture of drugs to reset the epigenetic markers used to measure a person’s biological age. Participants showed indications of a renewed immune system.
Some entrepreneurs are already proposing clinical trials of anti-aging gene therapies. In 2015, the CEO of a longevity company called BioViva injected herself with a protein that lengthens telomeres. The company claims the trial was a success, although no results were ever published.
In 2019, the gene therapeutics company Libella said it was conducting a trial on humans of a gene therapy that it claimed could reverse aging by up to 20 years. To participate, you had to pay Libella 1 million dollars. It is not known whether the trial was successful or even took place.
If complete reversal of aging becomes possible in the near future, whether it costs a million dollars or some other amount, there are questions we need to ask ourselves about if what we’re doing is really worth it. Now I’ll introduce Luke, who will attempt to answer these questions.
Luke: But with all of this talk about how we slow down aging, it raises the question, should we? Before he became pope, Pope Benedict XVI wrote, “disposing of death is in reality the most radical way of disposing of life.” Once he became pope, talking about the indefinite postponement of death, he preached, “humanity would become extraordinarily old, [and] there would be no more room for youth. Capacity for innovation would die, and endless life would be no paradise.”
One thing to note about the pope’s viewpoint, is that he’s saying that death gives life some amount of meaning. But the state of anti-aging research is by no means targeting “endless life.” Instead, the research community is trying to heal a variety of ailments that are believed to be linked to whatever causes us to age. So, the pope’s perspective points out that, ethically speaking, it’s important to consider the meaning of death in our lives, and that meaning very well could change if life could be extended. But, with the way research looks right now, death is definitely not off the table.
And the state of anti-aging research has changed quite a bit since the former pope made these statements over ten years ago, so this perspective makes sense: using life extension to combat illness has a very different ring to it than the alchemists of olden times concocting a potion to live forever. Perhaps developing these therapies, provided that it’s done so in an ethical way, might even be an obligation. Fr. Austriaco, a priest and ethicist at Providence College, writes that “Catholics are called upon to alleviate suffering and illness.”
I was intrigued by how the ethical perspective of anti-aging work could change based on the perceived state of life extension therapy, even among two people within the same institution. I brought in Jeffrey Behrends, ethics professor at Harvard, to help us look at the key ethical issues.
[Interview]
Luke: You could still die in, say, a car accident, but you’re not going to die by the normal processes of aging.
Prof. Behrends: Yeah. You’re like an elf in Middle Earth.
Luke: *laughs*. Exactly
Prof. Behrends: Yeah, okay, so then I think it’s quite complicated, right? So that makes the treatment rather unlike other means at our disposal of preventing illness or injury. Most of our means of preventing illness don’t radically alter our expectations for how long we might live. And this would be, I think, quite complicated to work out.
[Narration]
Luke: Professor Behrends brought up the point that, if we are to look at life-extension therapy simply from the perspective of treating illness, we must be careful to not over-simplify this process. This potential cure looks unlike any other treatment that we’ve seen before. If the therapy only extends life by a moderate amount, though, then this consideration is less relevant.
And then, of course, we must be careful to not evaluate ethics in a vacuum. Imagine a world where we can take it as a given that any life-extension treatment were morally permissible. We would still have the issue of access. Caleb mentioned people paying millions of dollars to participate in anti-aging trials. Studies have shown a 10.1 year difference in lifespan in women in the United States between the top and bottom 1% by income, with that difference increasing to 14.8 years for men. We don’t want to make death favor the poor anymore than it already does. And this was one one of Professor Behrends’ primary concerns when discussing this issue.
[Interview]
Prof. Behrends: And I think this is something that’s important to have our sights on anytime we’re talking about some sort of new emerging technology, but I guess especially in cases in which it would have some relatively profound effect on human flourishing. So imagine that, you know, we think through this and we decide that it’s all morally above board and also it would be really good for the subjects. Then there’s this kind of pressing question: okay, well, who has access to this? And there’s a kind of concern that it could be impermissible for people to opt in to this, even if it would otherwise be okay for them, because it could exacerbate existing unjust inequalities.
[Narration]
Luke: On top of all of this, in addition to the ethical concerns that we’ve discussed, Professor Behrends brought up the idea that it’s also just difficult to conceive of this strange alternative reality with such a different relationship between death and life.
[Interview]
Prof. Behrends: The counterfactual is so unlike the way that we normally relate to our existence that I actually just find it really hard to think about.
[Narration]
Luke: Elongated life is so unlike anything we currently know. As anti-aging research progresses, we will have to grapple with these issues more and more. So, where does the current state of life-extension stand? First, we need to be familiar with two things: Steve Horvath and DNA methylation. We’ll start with the latter: DNA methylation is a process where DNA molecules are manipulated, changing the behavior of the DNA without changing its sequence. Steve Horvath, on the other hand, is a professor of human genetics and biostatistics at UCLA. Here, he describes the moment when he discovered a connection between methylation and aging. This comes from a TEDx talk that he did at UC Berkeley
[Presentation]
Prof. Horvath: But when I correlated the methylation data with age, I almost fell off my chair because the signal was so strong. And I immediately decided that I will drop everything else in my lab and will focus on using methylation data to build aging clocks.
[Narration]
Luke: Okay, so Steve Horvath discovered a way to create an epigenetic clock, essentially a way to find your true age. For example, a 50 year old in poor health might actually have a true age of 80. This measurement tool has enormous impacts on our ability to treat aging.
[Presentation]
Prof. Horvath: For example, we can apply certain drugs or compounds to cells growing in a dish and just evaluate whether these drugs reversed or at least slowed the aging of the cells.
[Narration]
Luke: So this aging clock is important because it allows us to measure the impacts of various treatments on someone’s true age. But the question still remains about which treatments might be able to reverse or slow aging. Very recently, we’ve found a promising lead here. In May of 2020, Dr. Harold Katcher, professor at the University of Maryland, along with Horvath and other researchers, released a pre-print of a paper for a method that might have a significant impact. While pre-prints rarely merit any discussion, this paper is a major exception: it took the anti-aging community by storm. But first, you need to know one word: parabiosis.
[TV Show]
Gavin: Are you really not familiar with parabiosis?
Richard: I can’t say that I am.
[Narration]
Luke: In the popular show Silicon Valley, Richard, an entrepreneur, is pitching an idea to tech billionaire Gavin Belson. In the middle of his presentation, a tall, athletic man named Bryce walks in, attaching an IV to his arm as Gavin does the same. With Richard confused as to what is going on, Gavin explains:
[TV Show]
Gavin: Well the science is actually pretty fascinating. Regular transfusions of the blood of a younger, physically-fit doner can significantly retard the aging process. And Bryce is a picture of health!
[Narration]
Luke: Interestingly enough, this scenario gets at the idea of what Katcher and his team did. In their study, they took the blood of young mice and injected it into the blood system of older mice. Compared to a group of old mice injected with a saline solution, these infused older mice, showed an age reversal of 75% in the liver, 66% in the blood, 57% in the heart, and 19% in the hypothalamus.
All of these were measured using the epigenetic clock methods pioneered by Steve Horvath. These treated mice also performed better in memory tasks than the untreated ones. To put it simply, Harvard Medical School professor David Sinclair said, “This is astounding.” But what about humans? Well, also measured with Horvath’s clock, in a different study, scientists were able to reverse-age some people by two years, but we’re still in the early days.
Professor Sinclair certainly seemed hopeful about the success of the blood experiment with the mice. He tweeted, “If this finding holds up, rejuvenation of the body may become commonplace within our lifetimes, able to [systematically] reduce the risk of the onset of several diseases in the first place or provide resilience to a wide variety of infections.” Katcher and his team are currently working on beginning human trials.
The images of billionaire Gavin Belson and his blood boy rightfully raise some red flags for a treatment like this. There’s also the additional problem that, in its human form, it might rely on the blood of the young. Fortunately, for this latter point, Dr. Katcher believes that a commercialized product based on this study would not require the extraction of blood from living people. It’s better to think of this study as a stepping stone to future advances: we have shown what is possible, not let’s make it practical. Professor Sinclair seems optimistic about the accessibility of anti-aging treatments.
[Interview]
Prof. Sinclair: The big breakthrough will be not if but when somebody figures out how to recapitulate these changes with a pill.
[Narration]
Luke: As treatments like this advance, they will likely become more and more accessible, but we still must be vigilant. If the right precautions are taken, we might be able to open up these treatments to everyone.
Throughout the centuries, humanity has been obsessed with aging. We have also grappled with questions about the morality of life extension: who gets access to these treatments, does the extension of life alter its meaning? Very soon, our obsession may come to a culmination; it is very possible that we may see successful anti-aging treatments for humans in the next 15 years.
If, and likely when, that does happen, these crazy, futuristic fantasies will become reality. Similarly, these difficult ethical questions will soon leave the domain of interesting thought exercises. As advances continue, society may soon answer these questions with its actions. At the same time, these treatments may greatly alleviate much of the age-related suffering facing humanity. This is truly an area where excitement and reservation meet.