The Buck Institute for Research on Aging is just off US-101, about 30 miles north of San Francisco. The modernist, I.M. Pei–designed campus borders the Olompali State Historic Park in the foothills of Marin County’s Mount Burdell; groups of deer often graze near its parking lots. When it opened in 1999, the Buck was the first biomedical research institution dedicated solely to aging; today, it is the best funded and most prestigious independent aging research facility in the world. If major advances are made in the fight against aging, it’s likely the Buck will have a hand in them.
In early December 2018, just a few months after RAADfest, I visited the Buck Institute for a daylong symposium titled “Live Better Longer: A Celebration of 30 Years of Research on Aging.” That wasn’t an arbitrary demarcation: Aging is one of the rare areas of modern science with a specific launch date. In this case, it was January 1988, when Tom Johnson, a behavioral geneticist at the University of California, Irvine, published a paper that linked a genetic mutation he named “age-1” to longer lifespans in a transparent, microscopic, mostly hermaphroditic roundworm known in scientific circles as C. elegans.
Prior to Johnson’s discovery, aging had not received a lot of attention from researchers. In the 1820s, Benjamin Gompertz, a self-trained mathematician, concluded that humans don’t start to break down at some magic age but are constantly declining and losing the ability to repair themselves, a concept now referred to as the Gompertz law of mortality. The first hint that there might be a cellular mechanism underlying the aging process came more than a century later, in the 1930s, when two Cornell scientists discovered that rats kept on calorically restricted diets lived significantly longer than their more satiated brethren.
But overall, the field was mostly known as being a haven for charlatans and quacks peddling immortality elixirs and other magical cures — a reputation that continued even after Johnson’s work was published. “In the early 1990s, this was viewed as crazy science,” Valter Longo, director of the University of Southern California’s Longevity Institute, told me. “When people asked, we used to say we worked on something else. We were almost ashamed to say, ‘I work on aging.’”
But over the course of the next decade, the tools of molecular biology began to reveal the inner workings of how lifespan is regulated. In 1993, Cynthia Kenyon, an assistant professor at the University of California, San Francisco, discovered that mutations on a different gene, called daf-2, caused C. elegansto live twice as long as expected. Several years later, Gary Ruvkun, a researcher at Harvard Medical School, showed that these so-called worm-aging genes were closely related to genes in the insulin-signaling system of humans. Around the same time, MIT’s Guarente and some of his colleagues discovered the first of several genes in yeast — which are also present in humans — linked to dramatically extended lifespan.
Johnson, Kenyon, Guarente, and Ruvkun were all part of the opening panel at the Buck symposium, and it was impossible to ignore how much the field had changed. Kenyon, who in 2014 was hired away from her job at UCSF by Calico — the Google-backed biotech company dedicated to combating aging — described her inability to find collaborators, or even grad students, when she was starting out. Guarente recounted the reaction of his department chair when Guarente shared one of his discoveries: “Just what the world needs — long-lived worms.” A few years later, however, one of Guarente’s former postdoctoral researchers sold a pharmaceutical company named Sirtris Pharmaceuticals, which made products based on some of those long-lived worms, to GlaxoSmithKline (GSK) for $720 million.
Ultimately, the Sitris research didn’t pan out, and GSK closed the company, but today, more and more aging-related products are available for consumers. Longo founded a company that sells a five-day fasting-mimicking diet meal kit called Prolon, short for pro-longevity, which his research has linked to changes in biomarkers associated with aging, like inflammation. Guarente told the audience about Elysium Health, a company he helped launch that sells a supplement called Basis, which appears to raise NAD+ levels by up to 40 percent. (The salutary effects of NAD+ were one of the things that Faloon, the Church of Perpetual Life founder, enthused over at RAADfest.) Later on, the president of Unity Biotechnology described his company’s development of senolytics, the class of potentially age-extending drugs that also had everyone at RAADfest buzzing, to treat osteoarthritis, macular degeneration, and pulmonary fibrosis.
Whereas in the past scientists hoped to discover one all-important “aging factor” to target, these days the consensus is that paradigm-changing gains in longevity will come from an all-hands-on-deck approach.
“I think the big success of geroscience drugs will be in their combined action against multiple age-related diseases,” Jan Vijg, a molecular geneticist at the Albert Einstein College of Medicine, told me at Buck. “I think it’s reasonable to predict that maybe three to five years from now, we’ll have a number of drugs based on these little worms that we once thought, well, it’s just an interesting phenomenon.”
Hermaphroditic roundworms aren’t the only unusual animals investigated at Buck for their anti-aging insights. After the day’s second panel, I ducked out of the auditorium to meet up with Rochelle Buffenstein, a native Zimbabwean biologist with strawberry-blond hair, glasses, and a wry sense of humor. While we were having lunch, she told me that her love of food has kept her from adhering to a calorically restricted diet in the hopes of extending lifespan. “I once spoke at a caloric-restriction society meeting and must have looked like the most unlikely person to be there,” she said. “I don’t know if not eating would make me live 20 percent longer, but I’d definitely feel like I was living 50 percent longer.”
Buffenstein has worked as a comparative physiologist in the United States since the late 1990s. After stops at the City College of New York and University of Texas at San Antonio, she was hired by Calico in 2015. When she came out west, Buffenstein brought with her the world’s largest collection of one of the weirdest and most fascinating creatures in existence: the naked mole rat.
Buffenstein keeps her collection of more than 3,500 of the hairless, blind rodents in a series of basement labs at the Buck. Naked mole rats have two massive buck teeth, small holes where their ears should be, and wrinkled, semitranslucent, grayish-pink skin. I’ve been obsessed with them ever since I saw a full-page picture of one as a child, but when I’d visited Buffenstein a year earlier, I hadn’t gotten a chance to visit her animals. (She gave me a naked mole rat plushie as a sort of consolation prize.) Now, after scrubbing my arms up to my elbows and putting on disposable shoe covers and a snood cap, I followed Buffenstein into a tropical walk-in-closet-sized vivarium that housed a colony of several hundred naked mole rats in a series of tubes and clear polycarbonate enclosures that looked like a massive hamster Habitrail.
“Evolution moves by tiny steps, and I think it’s unlikely we’re going to find an intervention that will recapitulate what evolution does,”
Naked mole rats are one of just two eusocial mammal species: Each colony has a single breeding female and a small handful of breeding males. “Lysistrata,” the name of this colony’s breeding female, was written in black ink on a notecard taped to one of the first enclosures in the room. In the wild, naked mole rats live underground, in burrows, and as a result have almost completely lost the ability to regulate their internal temperature, which meant these rooms were kept around 85 degrees Fahrenheit with high humidity.
As soon as we walked in, the animals began chirping. “They have 19 different vocalizations I can recognize,” Buffenstein said before pointing out how the colony designated some of the small, dead-ended enclosures as bathrooms. “They also sometimes eat others’ poop, but only while it is being voided,” she said. (It’s crucial to maintaining a healthy bacteria balance in their gut.) “They really are the most incredible creatures. Do you know they can live for up to 18 minutes without oxygen?”
As amazing as all of that is, the most remarkable thing about naked mole rats — and the reason they are housed at the Buck — is that they seem to have overturned Gompertz’s law of mortality, which is to say their likelihood of dying doesn’t increase as they get older. That doesn’t mean they’re immortal, although a few of Buffenstein’s animals have lived for more than 30 years, roughly 10 times as long as mice and other similarly sized rodents. But naked mole rats, along with Galapagos giant tortoises, rougheye rockfish, ocean quahog clams, and Greenland sharks, are one of a motley crew of creatures that remain active and capable of reproducing right up until they die.
“They maintain heart function, hormone levels — every molecule we’ve looked at in terms of pathways,” Buffenstein said. Put another way: Somehow, even as they get older, naked mole rats don’t seem to age. If Buffenstein can determine exactly how they’re able to do that, the hope is that will help us understand how we might be able to mimic that ability in humans.