Spring Chicken Read online

  While the vaccines produced with WI-38 have saved countless lives, they also propelled Hayflick to the center of the abortion controversy, with religious hardliners (including the Vatican) objecting to the fact that the cell line had originated in the tissue of an aborted fetus. But their complaints were nothing compared to the wrath of a far larger, more powerful foe: the federal government, which accused him of basically absconding with federal property to create WI-38, and then using it for personal gain. Hayflick says he used about $100 worth of grant-funded supplies to help start his cell line, but insists that he never profited personally from WI-38, even as pharmaceutical companies made billions from the vaccines they manufactured with it.

  The controversy cost him the NIA job and his faculty post at Stanford, which fired him unceremoniously. He “absconded” (his word) with a liquid-nitrogen tank containing his precious WI-38 cells, strapped into the backseat of the family station wagon, beside his kids, and drove across the Bay to Oakland, where for a while he supported his wife and five children on $104 a week in unemployment benefits. He ultimately ended up taking a far less prestigious faculty post in Florida. Hayflick battled the government for years before the case was eventually settled in 1982—shortly after Congress passed a law that permitted researchers and institutions to patent and profit from inventions created with government funding, as a result of which we now have what is known as the biotechnology industry.

  Today, at eighty-five, Hayflick sits in his living room overlooking the Pacific, still as healthy and pugnacious as a prizefighter in his prime. The infamous nitrogen tank containing the original WI-38 cells resided in his garage until a few months ago, when he donated it for research. Those frozen cells are now more than fifty years old—even older than Carrel’s fake chicken-heart cells were purported to be. Hayflick himself is also doing well for his age: He is sharp, lively, combative. “I have no pathologies,” he says, a fact he attributes to genes from his mother, who passed away a few months earlier at the age of 106. Even in his eighties, he remains a battler, penning frequent letters to the editors of scientific journals, as well as longer opinion pieces attacking the anti-aging industry and the research establishment. “I broke my ass for twenty years trying to get people to accept my ideas,” he says. “It was not easy, I assure you.”

  His chance observation, that cells don’t live forever, is now enshrined as the Hayflick limit, as universally accepted as Carrel’s immortal-cell dogma was in its day. Hayflick’s two papers, originally published in obscure journals, are now among the most-cited biology papers of the last fifty years. More important, though, was the implication of the Hayflick limit, which shaped the entire field of aging research.

  He thinks Carrel had perpetrated something close to fraud with his “immortal” chicken cells for it later turned out that his assistants had been replenishing them, inadvertently or not. But Carrel’s wrongheaded ideas also had influenced the study of aging. To be blunt, Carrel didn’t believe that aging was real. Rather, he wrote in 1911, it was a “contingent phenomenon.” Given the right conditions, he asserted, he could keep a human head alive forever, just as easily as he had kept the chicken-heart cells growing.

  “Senility and death of tissues are not a necessary phenomenon,” he wrote; aging results from accidents and causes outside the cell, he insisted. And for decades, many scientists believed this, even after Hayflick published his two papers. During the 1950s, it was thought that aging was caused primarily by radiation from the sun and from nuclear activity (this was the Cold War, after all).

  Hayflick’s work showed that the aging process itself had to originate somewhere inside the cell itself. The implications for aging biology were huge. Our cells themselves grow old, are mortal. “I think of Hayflick’s work as a huge turning point, because it focused attention on the possibility of studying aging at the cellular level,” says Steven Austad.

  It was indeed a defining moment in human biology, but it was also the point at which Hayflick parted ways with many of his colleagues. To Hayflick, his limit was essentially proof that nothing could be done to slow or stop the process of aging—that it was a natural, inevitable consequence of the fact that our cells also aged and died. “Interfering with the aging process?” he scoffs, toward the end of my visit. “That’s the worst thing you could do. Have you ever thought that through? How long do you want Hitler to live?”

  Fortunately, not everyone saw things his way.

  Hayflick’s papers had left two important questions unanswered: Why is there a Hayflick limit? And what, exactly, is its relationship to aging?

  He himself remained deeply puzzled by one odd observation: His cells seemed to know how old they were. If he froze a batch of WI-38 cells at, say, their thirtieth division, and then unfroze them a few weeks or months or even years later, they would resume dividing—but only for another twenty times. “They remember,” he told me, still sounding faintly amazed.

  There had to be some sort of counting mechanism, he finally decided. And it was clearly independent of clock time, as his experiments with freezing and thawing the cells had shown. A cell’s biological age, therefore, had almost nothing to do with its chronological age. The only thing that seemed to matter was how many times it had divided. He and his students would spend the next decade looking for this counter, which he called the “replicometer,” with no luck. It took another quarter century for the answer to emerge, and it came from an unlikely source: pond scum.

  In the late 1970s, a young Berkeley scientist named Elizabeth Blackburn was looking at a simple but unique protozoan called Tetrahymena, often found in stagnant water (which is why she likes to call it pond scum). Blackburn noticed that Tetrahymena had lots and lots of repeating DNA sequences on the ends of its chromosomes. The sequences first appeared to be “junk” DNA, without any function, just two thymines and four guanines—TTGGGG—repeated many times.

  These telomeres, as they were called, cap the ends of chromosomes, protecting them in a way that’s often compared to the plastic tips on the ends of shoelaces. Telomeres contain no meaningful genetic information, just a repeating series of amino acids (in humans, the sequence is TTAGGG, slightly different from pond scum telomeres). But they are far from useless: They serve as a sort of sacrificial barrier, protecting the more important, information-carrying DNA as it is copied. With each successive cell division, the telomere “caps” are chipped away slightly. When they are gone, the “laces” themselves—the important DNA—begin to fray, and when the damage gets bad enough, the cell may stop dividing.

  But as usual in science, one discovery merely led to more questions. If our telomeres eroded like this, then why were we still here? Our cells had to have some way to repair their own telomeres and keep their DNA intact.

  A decade later, still working on the pond scum, Blackburn and her graduate student Carol Greider discovered the answer: an enzyme called telomerase, whose job was basically to repair the ends of chromosomes, tacking on more TTAGGGs even as they were chewed up with each successive cell division. Telomerase helped maintain the “caps” of our DNA, keeping the shoelaces from coming unraveled.

  It wasn’t hard to find correlations between telomere length and health. One major study conducted over a period of seventeen years found a strong association between telomere length and overall mortality. Not to be alarmist, but the shorter your telomeres, the shorter your life, the study found. In another, more revealing study, a UCSF colleague of Blackburn’s named Elissa Epel studied a group of mothers who had cared for a chronically ill child for a period of several years—in other words, as stressed a group of people as you’re likely to find. She found that the longer a woman had been in the caregiver role, the shorter her telomeres tended to be—the equivalent of between nine and seventeen years of additional cellular aging. Caring for aged parents would also tend to have the same effect—proving yet again that aging fuels itself.

  Other studies found links between shorter telomeres in white blood cells and
many common diseases of aging, or risk factors for them, including vascular dementia, cardiovascular disease, cancer, arthritis, diabetes, insulin resistance, obesity, and on and on. Endurance athletes, on the other hand, seemed to have rather long telomeres, relative to the average person. And some long-lived seabirds have telomeres that actually grow longer with time.

  So, pretty clearly, people with shortened telomeres are messed up. But the studies left a major question unanswered: Are short telomeres a cause of aging—or are they merely a symptom of some underlying biological stress, from a psychological situation or a chronic disease? More recently, another large study of more than 4,500 people found that, if you control for unhealthy behaviors like smoking and alcohol abuse, there is no link between shorter telomeres and mortality.

  Blackburn, Greider, and another researcher named Jack Szostak would eventually share the 2009 Nobel Prize for their discovery of telomerase. But it remains far from clear whether telomerase is a magic bullet for aging. Some evidence hints that it might be: In a widely publicized study published in Nature in 2010, researcher Ronald DePinho took mice that had their telomerase gene knocked out, and were in horrible health as a result, and gave them a telomerase activator. Their health was magically restored—which was a big deal because DePinho, now head of the MD Anderson Cancer Center in Houston, had previously been known as a telomere skeptic. In humans, studies found that people with low levels of telomerase had higher levels of six major cardiovascular risk factors. But critics pointed out that all the study had really shown is that it’s really bad to have no telomerase.

  The notion that our cells have a built-in “clock” that can be reset, with a simple enzyme, is immensely appealing because it’s so simple. Why not simply add (or turn on) telomerase, and keep those cells dividing? Anti-aging doctors like Jeffry Life offer telomere-length blood tests, costing from $200 to nearly $1,000, that purport to measure one’s cellular age. Those same anti-aging doctors also sell a purported “telomerase activator” called TA-65—based on “Nobel Prize Technology,” according to its marketing materials—so long as you’re willing to pay $600 for a month’s supply. Not an issue for the likes of Suzanne Somers, who takes it, but the rest of us need to know that its active ingredient is derived from the Chinese herb astragalus, which is available from the Vitamin Shoppe for about $15 a bottle.

  There’s another problem, too: Activating telomerase might cause cancer. One thing that cancer cells all have in common is amped-up telomerase. To repeat: Telomerase is activated in 100 percent of tumor cells. Cancer cells have long telomeres, too, obviously (which is why they keep dividing), and in fact one focus of recent cancer research has been to find ways to inhibit telomerase in cancer cells. A mouse study of TA-65, sponsored by the manufacturer itself, found that it not only failed to increase their lifespan, but the mice who were taking the stuff actually developed slightly more liver tumors than the control mice.

  “[Telomerase] is the single most distinguishing characteristic between cancer cells and normal cells,” Hayflick scoffs. “So that should be a red flag. Would you let yourself be inoculated with telomerase?”

  Hmm, not if you put it that way.

  More questions about the whole telomere/telomerase theory of aging are raised by the fact that some animals with very long telomeres and lots of telomerase actually live a very short time—such as laboratory mice.

  At best, then, the jury is out as to whether short telomeres are truly the cause of aging—or, rather, a symptom of age-related diseases. What may be more important, anyway, is the fate of our cells, and what happens when they stop dividing.

  One of the most important tests I was subjected to in The Blast was a simple blood analysis that can predict, perhaps more than any other single marker, the state of a person’s health. It’s also a test that your doctor will probably never give you. Certainly, Blast staff never talked about it with me or shared my results; I didn’t even know it existed until weeks later, when I talked with Luigi Ferrucci.

  The test detects something called interleukin-6, or IL-6, which is a kind of “cytokine,” a chemical messenger produced by our cells. Normally, IL-6 is supposed to help fight off infections and heal wounds, which it does as part of the body’s inflammatory response. But in older people, IL-6 and other inflammatory cytokines seem to be hanging around all the time, in ever-higher levels, for no apparent reason. It’s one of the biggest mysteries in aging: The older we get, the more inflammation we carry around in our bodies, and nobody quite knows why. Where does it come from?

  IL-6 is like the Lance Armstrong of the inflammatory cytokines, the leader of a dirty bunch. It is responsible for most fevers (one of its functions is to raise body temperature), but it also appears to control the release of dozens of other inflammatory agents, the way Lance once led the Tour de France pack. Oh, and it’s deadly—or at least, it correlates directly with mortality rates. According to the twenty-five-year-long Rancho Bernardo study of older Californians, the higher your levels of IL-6, the earlier your checkout time from Hotel Earth.

  It’s also one of the markers to which Luigi Ferrucci pays closest attention in The Blast. Subjects with higher levels of IL-6 are more likely to have more things wrong with them—multiple diseases of aging, or other risk factors for death. “While we can’t say there is a causal mechanism, this is one of the strongest biomarkers that we have,” he told me.

  In particular, chronic inflammation seems to greatly raise the risk of death from cardiovascular disease, cancer, and liver disease. Which makes sense: Inflammation helps to form arterial plaques, and constant exposure to IL-6 makes cells more likely to turn cancerous. Inflammation has even been implicated as a contributor to depression. As we get older, it becomes so common that one of Ferrucci’s Italian colleagues coined the term inflammaging to describe the conjuction of the two. But nobody could come up with a satisfactory explanation why so many older people seem to suffer from this kind of low-grade inflammation, until relatively recently. And one possible answer, it turned out, goes back to Hayflick and his limit.

  Hayflick recognized two possible fates for our cells when they stop dividing: Either they become cancer, that is to say immortal; or they enter a state he termed replicative senescence. But what did the senescent cells do?

  In the late 1990s, a cancer researcher at the Lawrence Berkeley National Laboratory named Judith Campisi began to look at that question. It had been thought that senescent cells were basically benign, sitting there quietly like nice old retirees at the local McDonald’s. Campisi wasn’t so sure. She also wasn’t convinced that the Hayflick limit really “caused” aging, in any meaningful way. “You can go into a ninety-year-old person, and take a biopsy, and you get a lot of cells that are still dividing,” she says. “So the idea that you got old and died because your cells ran out of cell division just didn’t cut it for me.”

  She began to take a closer look at the so-called senescent cells, and found that they were far from the benign cellular retirees Hayflick and everyone else had believed them to be. Rather than just sitting there harmlessly, she found, the senescent cells oozed a brew of inflammatory cytokines. “The big aha came when we realized that when a cell becomes senescent, it starts to secrete molecules that cause chronic inflammation,” she says. “And inflammation causes or is a major contributor to virtually every major age-related disease that we know of.”

  Senescent cells make very bad neighbors, less like those nice, McLatte-sipping retired folk and more like a Clint Eastwood character gone bad, sitting on his porch with a Budweiser, a lit cigarette, and a shotgun. Their toxic secretions help poison the cells around them, in turn making them more likely to become diseased or cancerous—or to go senescent themselves; senescence seems to be contagious. The good news is that in living tissues, senescent cells are not all that common—the highest percentage ever observed is 15 percent (in the skin of very old baboons). But like Neighbor Clint, it doesn’t take many of them to make the neighborhood an unpleasant pla
ce.

  Born in Queens and still very much a New Yorker, with her penumbra of frizzy brown hair, Campisi seems a bit out of place in her own office, in the sleek, I. M. Pei–designed headquarters of the Buck Institute for Research on Aging, a stunning postmodern marble palace nestled against a Marin County hillside. In 2005, Campisi and her colleagues found that most types of senescent cells had a typical “signature” of cytokines that they secreted, with IL-6 usually at the front of the pack. She dubbed this the senescence-associated secretory phenotype, or SASP, which is scientist-speak for a polluted cellular environment. (Scientists love acronyms, as you may have noticed.) Curiously, though, it was the same bunch of cytokines that are responsible for the basic low-grade inflammation that afflicts older people—which made Campisi and others wonder if senescent cells and SASP were helping to promote the aging process itself.

  “[Senescence] evolved to suppress cancer, but we think what it also does is drive these degenerative diseases later in life—and it even will drive, we think, secondary cancer, late-life cancers, the cancers you get after the age of fifty,” she says. “It drives cancer, it drives neurodegeneration, it drives sarcopenia [loss of muscle]. That’s what senescent cells do: They create this chronic inflammation.”

  It’s the catch-22 of aging: Cells go senescent instead of turning cancerous, but senescent cells, in turn, create inflammation that helps cause other cells to become cancerous. Yet senescent cells do perform one very important function: They help with healing. If you jab a mouse with a scalpel (or yourself, for that matter), some cells around the wound will immediately go senescent and start SASPing all over the place. That in turn helps heal the injury and protect from infection. So in the short term, senescent cells are essential to keeping body and soul together; but in the long run, they might kill you.