From cities in the sky to robot butlers, futuristic visions fill the history of PopSci. In the Are we there yet? column we check in on progress towards our most ambitious promises. Read more from the series here.
In 1923, Popular Science reported that people were drinking radium-infused water in an attempt to stay young. How far have we come to a real (and non-radioactive) ‘cure’ for aging?
From the time Marie Curie and her husband Pierre discovered radium in 1898, it was quickly understood that the new element was no ordinary metal. When the Curies finally isolated pure radium from pitchblende (a mineral ore) in 1902, they determined that the substance was a million times more radioactive than uranium. At the time, uranium was already being used in medicine to X-ray bones and even treat cancer tumors, a procedure first attempted in 1899 by Tage Sjogren, a Swedish doctor. Coupled with radium’s extraordinary radioactivity and unnatural blue glow, the mineral was soon touted as a cure for everything including cancer, blindness, and baldness, even though radioactivity had only been used to treat malignant tumors. As Popular Science reported in June 1923, it was even believed that a daily glassful of radium-infused water would restore youth and extend life, making it the latest in a long line of miraculous elixirs.
By May 1925 The New York Times was among the first to report cancer cases linked to radium. Two years later, five terminally ill women, who became known as the Radium Girls, sued the United States Radium Corporation where they had worked, hand-painting various objects with the company’s poisonous pigment. As more evidence emerged of radium’s carcinogenic effects, its cure-all reputation quickly faded, although it would take another half-century before the last of the luminous-paint processing plants was shut down. Radium is still used today in nuclear medicine to treat cancer patients, and in industrial radiography to X-ray building materials for structural defects—but its baseless status as a life-extending elixir was short-lived.
And yet, radium’s downfall did not end the true quest for immortality: Our yearning for eternal youth continues to inspire a staggering range of scientifically dubious products and services.
Since the early days of civilization, when Sumerians etched one of the first accounts of a mortal longing for eternal life in the Epic of Gilgamesh on cuneiform tablets, humans have sought a miracle cure to defy aging and defer death. Five thousand years ago in ancient Egypt, priests practiced corpse preservation so a person’s spirit could live on in its mummified host. Fortunately, anti-aging biotech has advanced from mummification and medieval quests for the fountain of youth, philosopher’s stone, and holy grail, as well as the perverse practices of sipping metal-based elixirs, bathing in the blood of virgins, and even downing Radium-infused water in the early 20th century. But what hasn’t changed is that the pursuit of eternal youth has largely been sponsored by humankind’s wealthiest citizens, from Chinese emperors to Silicon Valley entrepreneurs.
“We’ve all long recognized that aging is the greatest risk factor for the overwhelming majority of chronic diseases, whether it be Alzheimer’s disease, cancer, osteoporosis, cardiovascular diseases, or diabetes,” says Nathan LeBrasseur, co-director of The Paul F. Glenn Center for Biology of Aging Research at the Mayo Clinic in Minnesota. “But we’ve really kind of said, well, there’s nothing we can do about senescence [cellular aging], so let’s move on to more prevalent risk factors that we think we can modify, like blood pressure or high lipids.” In the last few decades, however, remarkable breakthroughs in aging research have kindled interest and opened the funding spigots. Fortunately, the latest efforts have been grounded in more established science—and scientific methods—than was available in radium’s heyday.
In the late 19th century, just as scientists began zeroing in on germs with microscopes, evolutionary biologist August Weismann delivered a lecture on cellular aging, or senescence. “The Duration of Life” (1881) detailed his theory that cells had replication limits, which explained why the ability to heal diminished with age. It would take 80 years to confirm Weismann’s theory. In 1961, biologists Leonard Hayflick and Paul Moorhead observed and documented the finite lifespan of human cells. Another three decades later, in 1993, Cynthia Kenyon, a geneticist and biochemistry professor at the University of California, San Francisco, discovered how a specific genetic mutation in worms could double their lifespans. Kenyon’s discovery gave new direction and hope to the search for eternal youth, and wealthy tech entrepreneurs were eager to fund the latest quest: figuring out how to halt aging at the cellular level. (Kenyon is now vice president of Calico Research Labs, an Alphabet subsidiary.)
“We’ve made such remarkable progress in understanding the fundamental biology of aging,” says LeBrasseur. “We’re at a new era in science and medicine, of not just asking the question, ‘what is it about aging that makes us at risk for all these conditions?’ But also ‘is there something we can do about it? Can we intervene?’”
In modern aging research labs, like LeBrasseur’s, the focus is to tease apart the molecular mechanisms of senescence and develop tools and techniques to identify and measure changes in cells. The ultimate goal is to discover how to halt or reverse the changes at a cellular level.
But the focus on the molecular mechanisms of aging is not new. In his 1940 book, Organisers and Genes, theoretical biologist Conrad Waddington offered a metaphor for a cell’s life cycle—how it grows from an embryonic state to something specific. In Waddington’s epigenetic landscape, a cell starts out in its unformed state at the top of a mountain with the potential to roll downhill in any direction. After encountering a series of forks, the cell lands in a valley, which represents the tissue it becomes, like a skin cell or a neuron. According to Waddington, epigenetics are the external mechanisms of inheritance—above and beyond standard genetics, such as chemical or environmental factors—that lead the cell to roll one way or another when it encounters a fork. Also according to Waddington, who first proposed the theory of epigenetics, once the cell lands in its valley, it will remain there until it dies—so, once a skin cell, always a skin cell. Waddington viewed cellular aging as a one-way journey, which turns out to be not so accurate.
“We know now that even cells of different types keep changing as they age,” says Morgan Levine, who until recently led her own aging lab at the Yale School of Medicine, but is now a founding principal investigator at Altos Labs, a lavishly funded startup. “The [Waddington] landscape keeps going. And the new exciting thing is reprogramming, which shows us that you can push the ball back the other way.”
Researchers like Levine continue to discover new epigenetic mechanisms that can be used to not only determine a cell’s age (epigenetic or biological clock) but also challenge Waddington’s premise that a cell’s life is one way. Cellular reprogramming is an idea first attempted in the 1980s and later advanced by Nobel Prize recipient Shinya Yamanaka, who discovered how to revert mature, specialized cells back to their embryonic, or pluripotent, state, enabling them to start fresh and regrow, for instance, into new tissue like liver cells or teeth.
“I like to think of the epigenome as the operating system of a cell,” Levine explains. “So more or less all the cells in your body have the same DNA or genome. But what makes the skin cell different from a brain cell is the epigenome. It tells a cell which part of the DNA it should use that’s specific to it.” In sum, all cells start out as embryonic or stem cells, but what determines a cell’s end state is the epigenome.
“There’s been a ton of work done with cells in a dish,” Levine adds, including taking skin cells from patients with Alzheimer’s disease, converting them back to stem cells, and then into neurons. For some cells, “you don’t always have to go back to the embryonic stem cell, you can just convert directly to a different cell type,” Levine says. But she also notes that what works in a dish is vastly different from what works in living specimens. While scientists have experimented with reprogramming cells in vivo in lab animals with limited success, the ramifications are not well understood. “The problem is when you push the cells back too far [in their life cycle], they don’t know what they’re supposed to be,” says Levine. “And then they turn into all sorts of nasty things like teratoma tumors.” Still, she’s hopeful that many of the problems with reprogramming may be sorted out in the next decade. Levine doesn’t envision people drinking cellular-reprogramming cocktails to stave off aging—at least not in the foreseeable future—but she does see early-adopter applications for high-risk patients who, let’s say, can regrow their organs instead of requiring transplants.
While the quest for immortality is still funded largely by the richest of humans, it has morphed from the pursuit of mythical objects, miraculous elements, and mystical rituals to big business, raising billions to fund exploratory research. Besides Calico and Altos Labs (funded by Russian-born billionaire Yuri Milner and others), there’s Life Biosciences, AgeX Therapeutics, Turn Biotechnologies, Unity Biotechnology, BioAge Labs, and many more, all founded in the last decade. While there’s considerable hype for these experimental technologies, any actual products and services will have to be approved by regulatory agencies like the Food and Drug Administration, which did not exist when radium was being promoted as a cure-all in the US.
While we’re working on landing long-term moon shots like editing genomes with CRISPR and reprogramming epigenomes to halt or reverse aging, LeBrasseur sees near-term possibilities in repurposing existing drugs to prop up senescent cells. When a cell gets old and damaged, it has one of three choices: to succumb, in which case it gets flushed from the system; to repair itself because the damage is not so bad; or to stop replicating and hang around as a zombie cell. “Not only do [zombie cells] not function properly,” explains LeBrasseur, “but they secrete a host of very toxic molecules” known as senescence associated secretory phenotype, or SASP. Those toxic molecules trigger inflammation, the precursor to many diseases.
It turns out there are drugs, originally targeted at other diseases, that are already in anti-aging trials because they’ve shown potential to impact cell biology at a fundamental level, effectively staving off senescence. Although rapamycin was originally designed to suppress the immune system in organ transplant patients, and metformin to assist diabetes patients, both have shown anti-aging promise. “When you start looking at data from an epidemiological lens, you recognize that these individuals [like diabetes patients taking metformin] often have less cardiovascular disease,” notes LeBrasseur. “They also have lower incidence of cancer, and there’s some evidence that they may even have lower incidence of Alzheimer’s disease.” Even statins (for cardiovascular disease) and SGL2 inhibitors (another diabetes drug) are being explored for a possible role in anti-aging. Of course, senescence is not all bad. It plays an important role, for example, as a protective mechanism against the development of malignant tumors—so tampering with it could have its downsides. “Biology is so smart that we’ve got to stay humble, right?” says LeBrasseur.
Among other things, the Radium Girls taught us to avoid the hype and promise of new and unproven technologies before the pros and cons are well understood. We’ve already waited millennia for a miracle elixir, making some horrific choices along the way, including drinking radioactive water as recently as a century ago. The 21st century offers its own share of anti-aging quackery, including unregulated cosmetics, questionable surgical procedures, and unproven dietary supplements. While we may be closer than we’ve ever been in human history to real solutions for the downsides of aging, there are still significant hurdles to overcome before we can reliably restore youth. It will take years or possibly decades of research, followed by extensive clinical trials, before today’s anti-aging research pays dividends—and even then it’s not likely to come in the form of a cure-all cocktail capable of bestowing immortality. In the meantime, LeBrasseur’s advice is simple for those who can afford it: “You don’t have to wait for a miracle cure. Lifestyle choices like physical activity, nutritional habits, and sleep play a powerful role on our trajectories of aging. You can be very proactive today about how well you age.” Unfortunately, not everyone has the means to follow LeBrasseur’s medical wisdom. But the wealthiest among us—including those funding immortality’s quest—most definitely do.
