Earlier in this book, we explored how extending the healthy human lifespan will have a significant impact on the rate of change in the world. The equation was fairly simple—longer lives means more time spent at our productive best which means more innovation. But what we didn’t cover in any detail was how this would happen. Here, on the back end of our exploration of the related field of healthcare, we want to turn our attention to this question of longevity, seeing how the forces of convergence are rewriting the rules in the race between technology and mortality.
And the place to start: mortality itself, the life clock known as aging. “Aging is not just a running down of the system,” explains longevity researcher and director of the National Institutes of Health, Francis Collins. “It is a programmed process. Evolution probably had an investment in having the lifespan of a particular species not go on forever. You’ve got to get the old folks out of the way so the young ones have a chance at the resources.”
To get the old folks out of the way, evolution devised a fail-safe: planned obsolescence, otherwise known as aging. It’s a redundant plan. Scientists now believe there are nine main “causes” of our decline, the nine horsemen of an internal apocalypse. We’re going to spend the rest of this chapter investigating the strategies being deployed to defeat this decline. Yet, before we do that, we first need to meet these horsemen, and explore the fundamental question they answer: What, exactly, is killing us?
And now that we know what’s killing us, let’s see what just might be saving us.
Want to win a Nobel Prize? Study worms. And don’t just study any worm. Study the roundworm, Caenorhabditis elegans, or, as her friends call her, C. elegans.
And this worm has a lot of friends.
Six scientists have already taken home Swedish gold for their work on the creature. As a result, C. elegans was the first organism to have its genes sequenced, its whole genome screened, and its connectome, the wiring diagram of the brain’s neurons, mapped. But despite this celebrated history, many feel the roundworm’s greatest contribution is still to come, as C. elegans is also the first animal to go head-to-head with death—and win.
In a petri dish, C. elegans lives about twenty days. Back in 2014, a group of NIH scientists at the Buck Institute for Research on Aging decided to try and increase that number. Previous research had shown there were two ways to have an impact. Knocking out a gene named rsks-1 increases lifespan by six days; knocking out daf-2, meanwhile, extended it by twenty days. But what happened, these researchers wanted to know, if they knocked out both genes at once?
“Taking an educated guess, [the researchers] estimated that such double-mutants might live about forty-five days,” wrote NIH director Francis Collins, who funded the work. “But, to their surprise, when they actually created such worms, some of the critters were still alive and squirming at a hundred days. That’s an amazing five-fold increase in worm lifespan—the equivalent of four-hundred-year-old humans.”
Applying this same process to human lifespan—that’s exactly what’s at the heart of the field of longevity. Genetics, of course, play a critical role. Building out on this earlier work on C. elegans, other researchers have since identified over fifty more genes that seem to trigger age-related decline. Five of these genes seem especially key, as removing any of them produces a 20 percent boost in lifespan.
But it’s not just genetics. Martine Rothblatt’s mission to produce an endless supply of human replacement parts is also crucial to longevity. As is the democratization of surgery being provided by robotics, and the drug discovery work being done by AIs and quantum computers. But the point isn’t this or that technique, it’s the combinatory power of all of these approaches that are leading us in a very new direction.
The old direction was our thirty-year lifespan, which held constant from the Paleolithic Age to the front end of the Industrial Revolution. During the twentieth century, marvels such as antibiotics, sanitation, and clean water extended our average age to forty-eight years by 1950, then to seventy-two years by 2014. But these days, Ray Kurzweil and longevity expert Aubrey de Grey have begun talking about “longevity escape velocity,” or the idea that soon, science will be able to extend our lives by a year for every year we live. In other words, once across this threshold, we’ll literally be staying one step ahead of death.
Kurzweil thinks this threshold is about twelve years away, while de Grey puts it thirty years out. Why should we believe them? One basic fact: You can’t take it with you. All the money in the world is useless in the grave. So how much would the wealthy pay for an extra healthy decade or two or three? A lot. This helps explain the increasing investments being made into anti-aging technologies, with Google’s Calico—an acronym standing for “California Life Company”—being perhaps the most visible example. More critical, while a longer life for the wealthy might not seem that worthwhile of a goal, as we’ve seen with every other accelerating technology, it isn’t long before the benefits become demonetized and democratized. And this means that possibly you, and definitely your children, will have the potential to tack decades onto your lives, simply because, as time passes, all of us will intercept a gaggle of anti-aging technologies along the way.
Let’s turn our attention to a few of the most promising ones.
Easter Island is remote. It’s exotic. It’s home to strange rumors and stone heads and sometimes strange rumors about stone heads. Some say the elders, with the right spells, can wake the heads from their slumber, controlling them like a giant stone army. Others say the heads themselves have the control—over your life force, with both the ability to steal it, bringing on an early death, or amplify it, conferring virility and strength on a chosen few. Then, in the mid-1960s, a small team of researchers discovered that this last bit, that conferring of strength and virility part, might be more than a rumor.
It started when the very small and very isolated community living on Easter Island decided they’d had enough. Enough smallness. Enough isolation. It was time, they decided, to build an airport.
Scientists freaked out. One of the most ecologically untainted regions of the world was about to lose its purity. In an emergency effort, an international team was rushed in to collect flora, fauna, and microbial samples, including—most critically for this story—dirt excavated from beneath one of the island’s mysterious heads.
The dirt ended up in the hands of a Canadian microbiologist named Suren Sehgal, who discovered it did, in fact, contain magical powers—of the antifungal variety. Sehgal purified the compound, naming it rapamycin after the island’s original name, Rapa Nui. Despite its potential, Sehgal’s research money ran out, and the compound was shelved until the late 1970s, when he got enough funding to take a second look. This is when he discovered there was more magic in that dirt. Rapamycin wasn’t just an antifungal, it also suppressed the immune system, giving it a lot of potential in organ transplant operations.
This potential became an industry. Rapamycin has since been used for everything from coating heart stents to ensuring that patients don’t reject their new kidney. And then researchers made an even more incredible discovery about this magic dirt: Rapamycin inhibits cancer growth.
The compound blocks a protein that facilitates cell division. Do this in worms, flies, and yeast and the result isn’t just cancer protection, it’s longevity. This raised the next question: Would the magic work in mammals?
In 2009, NIH scientists answered that one, showing that rapamycin extends the lives of mice by as much as 16 percent. In 2014, the combination of all of these findings led Novartis to decide to test it in humans, marking the first official trial of an anti-aging compound by a major drug company. But once scientists figured out that there really was magic in that dirt, the search for other anti-aging compounds was under way.
One place this search led was our medicine cabinet, where we found a drug called metformin. The world’s most common diabetes drug, metformin blocks sugar production and helps regulate insulin. But it also slows the “burn rate” of cells, defending against oxidative stress, fighting cancer, and—as we recently learned—significantly extending the lifespan of worms, mice, and rats. Does it work in humans? That remains an open question, but researchers are trying to find out.
While rapamycin and metformin protect against the ravages of old age, other scientists are looking for compounds that turn back the clock entirely. Known as senolytic therapies, these drugs destroy the inflammation-producing zombie cells believed to be one of the causes of aging. A half-dozen companies are now involved in this effort, producing about a dozen drugs that obliterate zombie cells, delaying or alleviating everything from frailty and osteoporosis to cardiological dysfunction and neurological disorder.
Backed by investments from Jeff Bezos, the late Paul Allen, and Peter Thiel, Unity Biotechnology is one of the most interesting of these. They’ve developed a way to identify, then kill senolytic cells, or at least they’ve developed a way that works in mice. But it really works. Periodic treatments from midlife forward both extend lifespan by 35 percent and keep the mouse healthier along the way. Everything from lower energy levels to the development of cataracts and kidney dysfunction—all common symptoms of aging—are either avoided entirely or their onset is significantly delayed. With nearly a dozen drugs under development for nearly all the maladies of decrepitude, including a few that have completed Phase I human trials and are still moving forward, Unity remains one to watch in the anti-aging space.
Finally, there’s Samumed, maybe the most watched of today’s longevity companies. Backed by a $12 billion valuation, this San Diego–based biotech is focusing on the Wnt signaling pathways, which, like the name sounds, are one way the body sends messages. In this case, those messages govern a group of genes that both aid the growth of a developing fetus and seem to play a heavy role in aging. Errors in Wnt signaling have been directly linked to twenty different diseases, including cancer. This is also why these pathways have been a longtime target of almost every major pharmaceutical company. Samumed, though, may have cracked the code.
They’ve focused their efforts on one particular Wnt pathway that regulates the behavior of adult stem cells. Via this methodology, Samumed has developed nine different so-called “regenerative medicines.” All are in the FDA’s pipeline, including everything from hair-loss drugs to Alzheimer’s drugs. Yet it’s their success against arthritis and cancer that has garnered the most attention.
We’ll start with arthritis, which afflicts 350 million people worldwide. We currently have no known treatment for the condition. But, in 2017, Samumed published the results of a small study on knee osteoarthritis. Sixty-one patients were in the trial, each receiving a single injection of a Wnt-rebalancing drug directly into their knee. All sixty-one saw improvement. When researchers measured the impact of the drug six months later, they found less pain and greater mobility, including an average of nearly two millimeters of new cartilage.
“The molecule stays [there] for about six months,” explains Samumed CEO Osman Kibar, “during which it [stimulates] stem cells to grow new cartilage. And that new cartilage is that of a teenager. The key is that progenitor stem cells are there even when you’re eighty years old, they just need to be properly signaled.”
Yet this may only be the beginning.
“An injection of the same molecule into the spine of rats whose intervertebral disc has been destroyed regenerates a whole new disc,” Kibar says. “If you look at the quality of the cells, the disc is younger and stronger.”
Getting this to work in humans is a different story. Very few drugs make the leap from mice to men (or women), but other Samumed molecules developed to repair both rotator cuff and Achilles tendon injuries have already made it through Phase I trials, and their knee arthritis drug is now entering Phase III. There’s still a lot more work to be done, but the upside could be a drug that provides decades of healthy mobility.
Arguably the more exciting arm of Samumed’s research is their work in cancer—which is essentially stem cells gone haywire. By silencing the signaling pathway that leads to this frenzy, Samumed’s drugs target—quite literally—every type of tumor. Most of these medicines are still in preclinical or Phase I safety and efficacy trials, yet, under compassionate use laws, Samumed has been able to give them to terminal patients. Here too the results have been remarkable.
In one small effort, a low-dose three-treatment protocol halted tumor growth in 80 percent of the study group. In another study involving pancreatic cancer, a longer protocol with this same compound managed to stave off this normally fatal disease. “All treatments had failed this woman,” explains Kibar, talking about one patient’s experience. “She weighed less than seventy pounds, and the doctors had sent her home [to die]. But now, after a year on our medicine, she’s back to normal. She’s traveling, dating, weighs one hundred and twenty pounds, just living her regular life. Of course, we’re still in the early days for this compound, but it’s a promising start to say the least.”
In the early 2000s, a group of Stanford researchers went looking for the fountain of youth in an unusual place: the Dracula myth. Legends going back to the ancient Greeks, recaptured in the Roman poetry of Ovid, and revived again in Gothic vampire tales, talk of the rejuvenating effects of young blood. These Stanford researchers decided to test the theory—on mice.
Updating the gruesome, ancient technique of parabiosis, they linked together the circulatory system of a young mouse to the circulatory system of an old mouse, then pumped the former’s blood through the latter’s system. Results were visible to the naked eye. The young blood revived the older animal.
Upon closer inspection, the benefits went far beyond the visible. A variety of the old mouse’s tissues and organs now had the characteristics of a far younger, healthier mouse. Follow-up studies both confirmed this finding and showed that the opposite was also true. Transfuse younger animals with blood from older ones and the clock spins forward, accelerating decrepitude, amplifying aging.
This work sparked a ton of interest. Within a decade, researchers had begun to tease apart why this youthful transformation was occurring. A team at Harvard got involved, discovering that young blood sparks the formation of new neurons in the brain and reverses age-related thickening of the walls of the heart. Finally, getting down to the root of the matter, the Harvard team also found one particular molecule, known as “growth differentiation factor 11,” or GDF11, that appeared responsible for all, or at least some, of these benefits.
In a 2014 paper published in Cell, a different team of researchers showed that simply injecting GDF11 into mice increased strength, memory, and blood flow to the brain. Additional studies have extended these benefits, demonstrating that GDF11 can reduce age-related cardiac issues, accelerate muscle repair, improve exercise capacity, and amplify brain function.
All of this work has sparked entrepreneurial interest. The Harvard spinout Elevian, for example, led by entrepreneur Dr. Mark Allen and a quartet of the school’s regenerative biology professors, is seeking longevity in GDF11 and similar age-retardant molecules. The Stanford spinout Alkahest, meanwhile, is searching for an optimized plasma cocktail as a treatment for Alzheimer’s.
Wired called these kinds of efforts a “needle in a haystack approach,” because blood plasma contains more than ten thousand different proteins. Really, it’s a needle in a gold-stack approach, because identifying which proteins produce the young blood effect has led to a biological gold rush. Startups are hot on the trail, not to mention major pharmaceutical companies. In 2017, the National Institute on Aging committed $2.35 million in funds for scientists interested in the work. So yes, here in the twenty-first century, not only are flying cars and personal robots both suddenly real, but, well, so is Dracula.
For thousands of years, we’ve been searching for the location of the fountain of youth. But what all this work makes clear is that what we’ve actually been hunting is less a place than a time. The fountain of youth is a specific period in history, the point at which technologies converge on mortality. So while “Will we be able to live forever?” remains an unanswered question, turning a hundred years old into the new sixty—that is, significantly extending human lifespan—has changed from a question of “if” to a matter of “when.”