Spring Chicken Page 25

  There were maybe two or three people in the world who were not surprised that rapamycin extended lifespan, and one of them was a fascinating Russian émigré scientist named Mikhail Blagosklonny. Considered eccentric even by the standards of aging researchers, he is nevertheless respected as one of the more original thinkers in aging research.

  Born and educated in St. Petersburg, where he received both an MD and a PhD in cancer research, he now works at the Roswell Park Cancer Institute in Buffalo, New York, perhaps the closest thing to an American Siberia. From his remote outpost, Blagosklonny had been arguing for years that rapamycin could be the magic bullet that aging researchers had been looking for. In a small but prescient paper published in 2006, Blagosklonny had predicted that rapamycin would likely extend lifespan in mammals. Three years later, the RapaMice proved him right. This was huge, in his view: There was already a drug on the market, safety-tested and approved for use in people, that actually seemed to slow aging. Moreover, its molecular target happened to be the most potent lifespan-extending pathway ever discovered. “It is an extraordinary luck that such a drug exists,” he exulted.

  But the really interesting part was his reasoning, which pointed to a completely new, counterintuitive understanding of how aging actually works. Going back to the mid-1900s, most scientists believed that aging was the result of damage that accumulated over decades, eventually leading to cellular dysfunction, which then caused age-related disease. Basically, our cells got dinged up until they no longer worked properly. That was the reason there was a Hayflick limit. Aging happens due to loss of cellular function.

  But as Blagosklonny thought about cells in general, and cancer cells in particular, Blagosklonny began to realize that in fact, the reverse is true: Many of the bad things we associate with aging are in fact the product of excess cellular function. That is, our cells and our body systems work too well. Or too much. Cancer would be one obvious example: rather than dying out, cancer cells divide and grow ad infinitum—thanks to their hyperactivated TOR pathways. But it wasn’t just cancer. He and others began to see many other aspects of aging as resulting not from a loss of cellular function, but from runaway cellular function. At some point after we stop growing, the engine that had powered our growth becomes an engine powering aging.

  “We are programmed to function at a high level because it gives you a lot of advantages at the beginning of your life,” Blagosklonny said in an interview via Skype (he dislikes travel, and avoids face-to-face interactions for the most part). “But after development is finished, it’s like a car that is leaving the highway and going to the parking lot. If you run your car in a parking lot at seventy miles per hour, it will be damaged.”

  Valter Longo agrees, but with a slightly different twist: “The programs optimized for growth and development don’t fail,” he says, “they simply start contributing to the problem since there is no evolved purpose for them anymore.” So aging isn’t programmed, as August Weissmann had thought more than a century ago; it’s more like a program gone wrong, or one that has outlived its purpose.

  In the past, this did not matter much, because the vast majority of humans died before the age of fifty. Very few of us reached the “parking lot.” Now we do, and hyperfunction becomes a problem. Hyperfunction is why 25 percent of women over seventy are diagnosed with breast cancer, versus just two percent of women under forty. It’s why women in their fifties keep piling on fat to feed children they can no longer bear, and why the male prostate gland keeps growing through middle and older age, a leading cause of awkward TV ads about urination, and also of prostate cancer. Hyperfunction is also why we grow hair in our ears instead of on our heads where it belongs. And at the cellular level, the continuation of cell growth leads to cellular senescence, the toxification of our aged cells.

  So Blagosklonny was not at all surprised that rapamycin had slowed aging in the mice. He expected it. He was itching with impatience—it should be tried in people right away, he argued. “It’s not a question of should we do this, it’s a question how,” he said. Blagosklonny was so convinced by the mouse study that he had begun taking it himself, a move that would have made professor Brown-Séquard proud. “Immediately it worked—as a placebo,” he joked. “After five minutes, I felt so good!”

  Beyond that, his only evidence that it works is that his marathon times have actually improved in the five years since he began taking it. Yet he betrays no doubt.

  “Some people ask me, is it dangerous to take rapamycin?” he said. “I want to write article with title, ‘It’s more dangerous to not take rapamycin, than to overeat, smoke, and drink and drive without belt—taken together.’ ”

  The fact that you’ve read this far means, of course, that you are far too intelligent to take a powerful, possibly dangerous drug just because you read about it in a book written by an English major who has no business giving anyone medical advice. Also: While rapamycin has passed muster with the FDA, it is only approved for transplant patients who are, by any standard, already very sick. Whether or not it should be used by healthy people, as a preventive against aging, is another question entirely—one to which most experts answer in the negative. “I’d like to see fewer side effects of a drug like that before I’d start taking it,” says Randy Strong, the University of Texas at San Antonio pharmacologist who figured out how to feed rapamycin to mice.

  For one thing, there’s the fact that it is approved as a powerful immune suppressor. The RapaMice had lived in a sterile environment, where they were exposed to few if any pathogens. Actual human beings, out in the germ-infested real world, could be increasing their risk of an infection. The second reason that taking rapamycin long-term might be a bad idea is because it seems to increase insulin resistance, which is a step down the road to diabetes, obviously a bad thing if your goal is to live to be one hundred.

  There is some evidence that rapamycin might not be all that bad—in some circumstances, for example, it actually seems to improve immune function. But the evidence that it slows aging in people just is not there yet. And, finally, the big hurdle: For a drug to work against aging, it has to be completely safe for healthy people to take—with zero risk whatsoever. “It’s got to be safer than aspirin,” says Strong.

  Valter Longo wasn’t much interested in trying rapamycin in people, much less taking it himself; he felt that it worked on pathways that are too central for normal cellular function to be used safely. But his work with the yeast, and TOR, and then cancer patients had led him to think more about the role of growth factors in promoting aging. His lab has identified several drugs that block the growth-hormone receptor, and that might be suitable for human trials. “It’s the master switch,” he says.

  Still, whenever he gave a public talk, especially in Southern California, he would get asked the Growth Hormone Question—sometimes even by doctors who prescribed HGH injections to their patients. He was convinced it was a bad idea, but people weren’t getting the message, so in 2007, he got on a plane to Ecuador in search of definitive proof.

  He eventually found himself in a car heading south on winding, ever-scarier mountain roads leading deep into the Andes Mountains. His destination was the remote, dirt-road village of San Vicente del Rio, where he was going to study a very unusual group of people. He had long suspected that higher levels of growth factors led to a shorter lifespan, but until now he’d had precious little evidence to work with. Then he had found out about Dr. Jaime Guevara-Aguirre, an Ecuadorean endocrinologist who had been studying a population of about a hundred individuals who lived in the mountains of southern Ecuador.

  Called Laron little people, they possessed an extremely rare genetic mutation similar to that found in the dwarf mice (and in Chihuahuas, for that matter). Because of the mutation, their cells lacked growth-hormone receptors, meaning their bodies were essentially deaf to it, and as a result they only grew to be about four feet tall, or less. While the growth-hormone receptor mutation is only thought to affect about three hundred pe
ople worldwide, a cluster of more than one hundred of them lived in this remote part of Ecuador, scattered among several mountain villages. Locally, they were known as viejitos, “little old men,” because they tended to be small and wrinkled, but inside, they were anything but old.

  Guevara-Aguirre had been studying the Laron for more than twenty years; he was, in effect, their family physician. He had initially been curious about their small size, which was seen as a handicap. Indeed, perhaps as a result of their stature and their remote, rural environment, many of them drank heavily, and suffered from odd health problems as a result. They also seemed to get into a lot of fights, also likely due to their short stature. But despite this, another interesting pattern had emerged over time: None of them had ever died of cancer. And none had diabetes, despite the fact that one in five were obese, a far higher rate than average in Ecuador. Among the local population, 20 percent of their non-Laron relatives died of cancer, and at least 5 percent from diabetes.

  Longo suspected that it was their lack of growth-hormone receptors that rendered them immune to both cancer and diabetes. In the lab, he had seen similar patterns in mice, worms, and even yeast: Reduced growth “signaling” to an animal’s cells seemed to be strongly correlated with longer lifespans. The Laron did not necessarily live longer, as they tended to die from things like accidents and seizures (and drinking, and in fights), but what struck Longo was that for some reason few to none of them died of diseases of old age.

  “They eat whatever the hell they want, they smoke, and they drink, and they still live pretty long,” Longo told me. In fact, since his research began, they have begun to eat and drink even worse stuff than they used to, consuming fantastic quantities of soda and cake without guilt. “Now they think they are immune,” he sighed. “They’re getting cocky.”

  At least they were protected—unlike the Southern Californians who insisted on taking growth-hormone shots, flipping the “master switch” in the wrong direction. But so, too, was practically everyone else, because growth hormone and IGF can be triggered not only by expensive injections but by, say, a trip to McDonald’s.

  The millions of Americans who were gorging themselves on high-carb, fast-food diets weren’t shooting themselves up à la Suzanne Somers or Dr. Life, but they might as well have been. When we take a big hit of sugar, like by drinking a Coke, our bodies respond by producing a surge of insulin, to help transport all that sugar to our cells. Not only do many of those calories then end up in our fat cells, à la Phil Bruno, but the insulin response, in turn, triggers good old IGF-1—insulin-like growth factor—which goes streaking directly at TOR, telling it to turn those calories into proteins, cells, growth. This is a good thing when we’re young, but if we’re not young anymore, then it makes bad things happen.

  Longo’s idea dovetails with much emerging research on nutrition, which is beginning to confirm that sugar and carbohydrates are far worse dietary villains than fat ever was, and that the true cause of rampant obesity, heart disease, and diabetes can be found in the mountain of sugar that most of us eat every year.

  Longo even goes a step further, and suggests that high-protein diets may be just as bad as high-carb diets, and for the same reason: Excess protein intake also activates the growth hormone receptors, and TOR, the two main drivers of cellular aging. In an eighteen-year study published in March 2014 in the prestigious journal Cell Metabolism, Longo’s team showed that middle-aged people who had eaten a diet high in dairy and meat were much more likely to die eventually of cancer—and that very high meat consumption is as risky, mortality-wise, as smoking. People who ate 10 percent protein or less—versus the 30 percent recommended in “healthy” diets like the Zone—lived longer, on average. And they were one-fourth as likely to die of cancer as the meat lovers.

  Longo instead looks to different role models: the centenarians of Molochio, the village in Calabria in southern Italy where his parents happen to have been born. He has befriended one of them, a 109-year-old singer named Salvatore Caruso who still lives on his own—a pastoral version of Irving Kahn. Only he’d never touch a knish; he eats a far healthier diet, consisting of mostly green vegetables, some pasta, and a little bit of wine. Meat is an occasional luxury. Even Longo marvels at how little he consumes. The key to Caruso’s diet, according to Longo, is its low carbohydrate content and its low protein content—intentionally or not, he thinks, it keeps his growth factors and TOR in check, which effectively slows the rate of aging. He and his cohort were trained to eat less, in effect, by history—war, poverty, and periodic famine.

  “People his age, or eighty or ninety, they’ve been through bad periods and they understand,” Longo says. “But that’s what those bad periods did to them; they were fasting all the time.”

  One reason (voluntary) short-term fasting is so effective, Longo thinks, is because it can be uniquely tailored to each individual’s physiology, not to mention hunger tolerance. But most of the time, you still get to eat more or less normally. Longo started doing it himself about ten years ago, he says, about the same time as he started working with the Laron, but his motivation was more personal—a particularly scary doctor’s visit.

  “You think you’re pretty healthy, but then when you look more closely, you’re not,” says Longo. “My blood pressure already ten years ago was 140, my cholesterol was high; this is the story of half of the population of Europe, and maybe 80 percent of the U.S.: You find yourself in your thirties and forties, and you’re starting to be a candidate for Lipitor, a candidate for hypertension medication, a candidate for cardiovascular medication—and next thing you know, you’re a patient, you know! And what we’re looking at is that you don’t need to do any of these drugs. For 90 percent of the people, you can get rid of all of them, for life.”

  Longo models his own diet after the basics of Caruso’s diet, plus what he’s learned through his work. Most days he skips lunch completely, and at dinner he eats a low-protein, plant-based, vegan-ish diet designed to push down his IGF-1 levels (not just to keep himself rock-star thin at age forty-six). Once or twice a year, he’ll put himself through a bare-bones fast for up to four days, taking in a bare minimum of nutrition, in order to “reset” his system. He believes this is the best option, based on mouse and human studies, and also because it happens to work for him.

  Even his taste in automobiles reflects this on-off dichotomy: He drives to work in an ultra-efficient, all-electric Nissan Leaf, which entitles him to a primo parking space. But back home in Playa del Rey, there’s a Ferrari sitting in the garage.

  Chapter 14

  WHO MOVED MY KEYS?

  Let’s spend the night together, wake up and live forever.

  —Jamiroquai

  On a spring evening in 2013, I finished up some interviews in Berkeley, then got in my rental car and joined the sclerotic flow of the evening rush on the 880, headed down the east side of the Bay toward San Jose. I was late, and as traffic slowed, I could feel the stress of freeway driving subtly accelerating my own aging process (along with the particulate pollution I was inhaling by the lungful). Eventually it cleared, and I found my way to a small office complex in the town of Mountain View.

  I had come for the monthly meeting of something called the Health Extension Salon, a loose collection of Bay Area people with an interest in aging research. I had been to many aging talks and conferences by then, typically serious affairs attended by scientists and a handful of self-taught amateur gerontologists, most well over sixty, listening to talks that quickly devolved into the dense alphabet soup that is modern molecular biology. When I walked into this room, though, I saw something that stunned me: young people.

  The room was packed, with a standing-room crowd of about 150. The average age seemed to be well under forty; I could count the gray heads on the fingers of three hands. The wine was gone, my punishment for being late. This being the heart of Silicon Valley, the crowd had a definite tech start-up vibe: There were two guys in SpaceX jackets, and a quick saunter around
the place confirmed that the host company was somehow involved in robotics. Later, promised the tousle-haired organizer, Joe Betts-Lacroix, there would be “Twister racing,” an activity not normally pursued at aging-science meetings. But first, we were going to hear about stem cells and Siamese twins.

  The featured speaker on this February night was a researcher from UCSF named Saul Villeda, and he fit right in. Dark-haired and stocky, he too was far younger than the typical lead scientist. He spoke more like a Southern California surfer than a jargon-spewing academic, spiking his sentences with the occasional “like.” But he also proved to be a natural at explaining complex subjects to lay audiences, and when we met in his office a few days later, he revealed that he had honed this particular talent by discussing his work with his parents, who had emigrated from Guatemala with no education beyond the fifth grade.

  When Saul was born in 1981, the family lived in East Los Angeles, where his father worked as a janitor, and his mother as a nurse’s aide. They eventually saved enough money to realize the American dream and buy a house, but the closest place they could afford was way out in Lancaster, California, a small blue-collar town on the edge of the Mojave Desert. Saul did exceptionally well in school, with an aptitude for science, and he got into UCLA on a scholarship. Next was graduate school at Stanford, where he ended up in the lab of a professor of neurology named Tony Wyss-Coray.

  Along with another Stanford researcher named Thomas Rando, Wyss-Coray had helped to revive the old nineteenth-century technique of parabiosis—joining two animals together, so that they shared one circulatory system. Rando was interested in muscle, while Wyss-Coray had begun to look at the effect of old blood on mouse brains. Villeda stayed in his lab as long as he could.