Spring Chicken Read online

  Perhaps the strongest evidence that cellular senescence hastens the aging process came from cancer survivors, who had been subjected to powerful chemotherapy drugs that left them riddled with senescent cells, thanks to rampant DNA damage that basically stopped their cells from dividing. In follow-up studies, researchers began noticing that these long-term cancer patients were developing other age-related diseases much earlier than normal. “Twenty years down the line, they are showing up in the clinics with multiple age-related pathologies, including secondary cancers that are unrelated to their primary cancer,” Campisi says.

  A similar phenomenon was observed in patients who had been treated for HIV with powerful antiretroviral drugs—which also left their bodies, and primarily their immune systems, junked up with senescent cells. Many of those former HIV patients have also been found to suffer from conditions such as atherosclerosis, which is fostered by high levels of inflammation. Because of all their senescent cells, these former cancer and HIV patients are basically bathing in inflammation, which may cause them to age more quickly. So what happens if you make senescent cells go away?

  At the Mayo Clinic in Rochester, Minnesota, two thousand miles away from the Buck, a team of researchers staged an elaborate experiment designed to see what would happen if we could somehow flush the senescent cells out of an animal. It was anything but simple: For starters, lead scientist Darren Baker and his team had to create an enormously complicated genetically engineered mouse. They began with a specially designed mouse that lacked the gene for a key protein, and thus aged prematurely due to a pileup of senescent and dysfunctional cells. They then crossed that mouse with another one that they had created, whose senescent cells could be cleared using a special senescent-cell-zapping drug. (Told you it was complicated.)

  The new, hybrid mouse was not only one of the most exotic and expensive rodents ever to walk the earth, but also one of the most unhealthy. They aged extremely rapidly (because of all those senescent cells), forming cataracts at an early age, and losing muscle and fat tissue like very old people who are basically wasting away. In short, they suffered from something like frailty, and they were only in mouse middle age. Plus, they got all shriveled and wrinkly. But when Baker’s team used another special drug to clear away their senescent cells, their condition improved drastically: They became much stronger, and lasted longer on treadmill tests, the cataracts cleared up, and even their wrinkles went away. They were rejuvenated, in short—all without taking any mouse growth-hormone shots.

  “Someday, you might go in and get your senescent cells removed, like changing the oil in your car,” study coauthor James Kirkland told me. First, though, we’ll have to figure out how to identify them, and then remove them without damaging their neighbors—no easy task, since senescent cells make up only a small percentage of cells overall, and are scattered all over the place. “It’s still science fiction,” Kirkland warns.

  The job gets easier, though, if you can figure out where senescent cells tend to hang out—remember, they are relatively scarce. Kirkland, like Campisi, has been studying cellular senescence for years—and he believes that these cells are driving much of what we recognize as aging. The big mystery—one of the mysteries—was where, exactly, they could be found, as they are extremely difficult to tag and locate (except in million-dollar exotic engineered mice, that is). Kirkland concluded that the most powerful and malign pockets of senescent cells are found in one particular kind of human tissue, one that most of us find a bit too abundant: fat.

  Chapter 9

  PHIL VS. FAT

  There is no love sincerer than the love of food.

  —George Bernard Shaw

  Phil Bruno was SuperSizing again. It was just past 5:30 p.m. on a February evening in 2004, and he was driving home from work. A few miles from his house, he pulled into a White Castle, one of the many fast-food outlets lining the Manchester Road in the suburbs of St. Louis. Sure, he was only a quick drive from his own kitchen, where his wife, Susan, was cooking their usual big Italian dinner, but he was hungry now. He’d been doing it so long, it was almost automatic.

  Ten minutes later, with a bag of hot burgers on the seat beside him, he pulled into another drive-through—this time McDonald’s. There, he ordered another meal, a Double Quarter Pounder with Cheese combo, plus an apple pie for dessert. Oh, and a chocolate shake to wash it all down. “The reason I did this is because I would be embarrassed to order too much from one drive-through,” he explained to me in a matter-of-fact email. “I didn’t want the person at the window to look at me funny.”

  Because when a man who weighs nearly a quarter-ton pulls up and orders multiple Value Meals, that’s the kind of thing fast-food workers tend to talk about. Particularly if the person has been doing it every single day, as Phil Bruno was, at that point in his life. And it didn’t end at the drive-through: Some nights he would fix himself a quick sandwich while waiting for dinner.

  Phil had always loved food; it was part of the fabric of his tight-knit Sicilian family. Grandma and her lasagna were right down the street. In college he had played basketball, carrying 215 pounds on his big-boned, six-three frame. But then he’d gotten married, and had two children, then three. Suddenly, his weekends and evenings became all about the kids: homework, dinner, baseball and soccer practices. He stopped exercising. He didn’t mind; everything was about family. But the weight piled on, pound by pound, year by year, without stopping. He didn’t fight it. He even embraced it. Phil Bruno does everything with gusto, and what he did, at that point in his life, was eat. “I had to work hard to get this big,” he says now.

  He didn’t have to work that hard. In part, Phil Bruno was a victim of his own middle-aged biology. As we grow older, and growth hormone and testosterone decline (along with other chemical changes), the calories we consume are far more likely to end up as fat. Beginning around age thirty-five, our total body fat percentage increases by as much as 1 point per year, even if our overall weight stays the same. More important, the distribution of that fat changes, from “subcutaneous” fat—the fat under the skin that makes young people look ripe and smooth—to abdominal or “visceral” fat, also known as a gut or a belly, or that stupid little pooch that you just can’t get rid of. Waist circumference also expands, seemingly unstoppably, increasing about an inch and a half every nine years, according to one long-term study of middle-aged women. These changes are almost universal: If you compare an older person and a younger person of the same weight, says Luigi Ferrucci, the older person will almost always have more visceral fat on them. We’ll be able to survive longer when the Apocalypse comes, but we won’t be particularly good looking. As an older but athletic friend of mine recently put it, “Sometime in your mid-fifties, everything just changes shape.”

  This I knew all too well, thanks to The Blast. A couple of months after my stay at Harbor Hospital, a manila envelope arrived in the mail containing my results. They were mostly unremarkable, except for one thing: my body-fat percentage was a lifetime-high 24.3 percent. My body was nearly one-quarter fat, which put me on the very high end of “normal”—and right up against the threshold for obesity, which is 25 percent body fat and above. For fit males, normal is more like 17 to 20 percent; for athletes, which is what I used to consider myself, it’s lower, like from 13 percent down to 6 where things start to get body-builder freakish.

  Women tend to run a few points higher than men, because their bodies are built to pack on fat for nurturing babies, so normal is more like 25 percent—and obesity starts at 32 percent body fat. Which means that some very obese women can be nearly one-half fat tissue. On the other hand, this means that women are more likely to survive a famine than men, which is probably the point.

  Even though I was still within the realm of “average” (barely), I did not handle this news very well. I emailed the Blast staff straightaway, informing them that their machine was miscalibrated. Curtly, they informed me that it was not: It was a dual-energy X-ray absorptiometry, or DEX
A, scan machine, far more accurate than the old-school method of measuring fat with pinchy calipers and a creepy guy with a clipboard. Unfortunately, their results also agreed with my $100 bathroom body-fat scale, which had recently shown a jump from a still-acceptable 18 percent to my current, porcine 24 percent. The nice lady informed me, helpfully, that according to the body scan, most of the fat was found in my midsection. “Welcome to middle age,” she wrote. So that was that.

  Phil was on another level altogether. My body-mass index, or BMI, was a shade over twenty-five, on the low end of the overweight range. Anything above thirty is considered obese. Phil’s BMI was an off-the-charts forty-five, but more importantly, his waist circumference was pretty close to his height; studies have shown that one’s waist size should be less than half of one’s height. And it was more than just a number. All his eating had turned him into a “physical and emotional wreck,” as he describes himself. His joints ached whenever he had to go up and down the stairs in their two-story home; his legs “felt like they were filled with sand.” His heart hammered away inside his chest, all the time, and he was possessed by a strange, burning thirst that no amount of ice water could quench; all it did was send him staggering into the bathroom every half hour, all night long. “I was forty-seven years old,” he says, “but I felt like I was eighty.”

  As it turned out, though, middle-aged biology was no match for Phil Bruno.

  Prodded by a friend, he finally went to see his longtime family physician, whose name was Dr. Ron Livingston, on June 6, 2004. He’ll always remember the date, because the results were so sobering. For starters, he couldn’t even be weighed on the office scale, which maxed out at 350 pounds. He had to go to a nearby grocery store, and step on the scale used to weigh pallets of food off the delivery trucks. It said he weighed 475 pounds. Phil’s blood pressure was at a fire-hose-like 250 over 160, putting huge strain on his arteries and his heart. His blood sugar was also off the charts at 600, or six times higher than what is considered normal; and his A1C, an important blood marker for diabetes, which should have been under 5.8, was a sky-high 16.

  He had full-blown diabetes, obviously, but that was just one of his problems. He walked out of the doctor’s office with prescriptions for no less than twelve different medications and supplements, from fish oil to blood-pressure medicine to Lipitor for his cholesterol to Glucophage for his diabetes. And he never forgot what Dr. Livingston had said, when he finished checking him out: “Bruno, I’m surprised you’re even still alive. I’m expecting you to drop dead right here in my office.”

  Everyone “knows” that being fat is bad for you, but most people would be at a loss to explain exactly why. Some reasons, of course, are obvious: More weight means more stress on your joints and, more seriously, on your heart. And it tends to go hand in hand with diabetes, which is what Dr. Livingston had diagnosed Bruno with that day. Although not all heavy people are diabetic, most people with diabetes are overweight or obese.

  Diabetes itself is now thought to speed up the aging process enormously. The body becomes unable to process the sugar that we eat, which ends up rollicking around in our bloodstream, inflicting massive amounts of cellular damage in every tissue that it touches. Excess blood sugar even makes you look older: One study showed that people with higher blood sugar actually did appear older than they were, perhaps because this damage is visible in their very skin. The older we get, the less efficiently we process sugar, and the more prone to diabetes we become. Centenarians, on the other hand, seem to be able to handle sugar with no problem—like my grandmother, who scarfed down a breakfast pastry every morning for her entire life with complete impunity. Glucose is her bitch.

  But diabetes is only part of the reason why excess fat has also been associated with serious health problems including cancers of the kidneys, colon, and liver. A massive 2003 study published in the New England Journal of Medicine found that the high rate of obesity in the United States—one-third of the population—is responsible for 14 percent of cancer deaths in men, and 20 percent in women. New evidence points to the possibility that fat itself may be causing all these problems.

  Until fairly recently, fat tissue was thought to be inert, mere energy storage for the body—as passive as a passbook savings account. You “deposit” calories by eating, and “withdraw” them by exercising. If you burn thirty-five hundred calories by jogging (for about five hours), then you will lose one pound, or at least not gain it. Otherwise, the fat is sitting there, not doing much of anything, or so it was thought.

  In the 1990s, scientists began realizing that our blubber might do lots more than just jiggle. Over the last decade, they have come to recognize that fat is in fact a huge endocrine gland, and it wields powerful influence over the rest of the body. “For a typical North American, their fat tissue is their biggest organ,” says James Kirkland, who helped pioneer the study of fat’s endocrine effects. Kirkland believes that when it comes to aging, fat could also be the body’s most important organ.

  It’s remarkably easy to gain weight—as both Phil and I learned—even huge amounts of weight, without really trying. Conditioned by millennia of feast-and-famine cycles, the human body has evolved into a remarkably efficient fat-storage machine, whose mission is to squirrel away any precious excess calories. Evolution has not yet caught up to the fact that food is now relatively abundant and cheap for most of us. Our genes still think we are hunter-gatherers, and to them, fat equals survival. A massive study in the Lancet estimated that taking in just ten more calories than you burn every day can lead to a significant weight gain of twenty pounds over twenty years. Go from 10 extra calories to, say, 138—the 12-ounce can of Coke I used to drink every afternoon—or a 200-calorie candy bar, and those extra twenty pounds can pretty quickly turn into fifty or one hundred.

  But not all fat is bad. Subcutaneous fat helps protect the body from injury, like padding, and it also secretes immune factors that help fight infection and heal wounds; that’s where those wound-healing senescent cells come from. Fat in general is highly resistant to infection, and some scientists think it is crucial to the functioning of the immune system as a whole. It also keeps us warm in cold weather, keeps us afloat in water, and it can look nice, if properly placed. Without it, there would be no Kardashians.

  “SubQ” fat also produces a hormone called adiponectin, which appears to help control metabolism and to protect against certain cancers, notably breast cancer—plus other good things that have not yet been identified. It is no accident that Nir Barzilai’s Jewish centenarians tend to have higher-than-normal levels of adiponectin.

  So much for the good news. The bad news is that, as we age, we gradually lose this good fat, which is one reason why our hands get more bony looking and “interesting.” Instead, we pile plump, juicy fat onto our midsections, forcing us to buy ever-larger pants. This “visceral” fat is not the same stuff as the nice, wound-healing, adiponectin-secreting subcutaneous fat. For example, subQ fat also produces leptin, another important hormone that tells the brain, Hello, you have plenty of stored energy, so you can stop eating now.

  Visceral fat produces very little leptin, so the satiety center of the brain never gets that message. This might be because visceral fat served a different evolutionary purpose, as short-term energy storage designed for quick access to produce short bursts of energy, like during an intense hunting session (which may be why men have more visceral fat, and women more of the “nurturing” subQ stuff). The stress hormone cortisol, activated during fight-or-flight situations, tells the body to sock away still more visceral fat—which, if your stress comes from a sedentary desk job, you never really get to burn off. Instead, the visceral fat just sits there, in between your liver and other vital organs, while you’re stuck at your desk shopping online for new pants.

  The pants aren’t the problem. The fat is the problem. Over the last decade or so, and especially since Phil Bruno was diagnosed in 2004, Kirkland and other scientists have discovered that this abdomin
al or visceral fat infiltrates our vital organs, bathing them in a nasty chemical stew that wreaks havoc throughout the body. Visceral fat produces an array of inflammatory cytokines including not only IL-6, the king of chronic inflammation, but another one called TNF-alpha, for “tumor necrosis factor,” which is every bit as bad as that sounds. (Yes, it’s linked to cancer, but it also contributes to cellular insulin resistance.)

  No wonder Phil Bruno felt so much older than his forty-seven years. His fat was, in effect, a giant toxic tumor that was poisoning the rest of his body. As his doctor warned him, he was at extreme risk for dying of diseases that normally afflict much older people, chiefly diabetes and cardiac arrest, but also stroke, cancer, and dementia. “Obesity has a lot of things in common with an accelerated-aging kind of situation,” says Kirkland.

  So aging makes us fat, and then our fat makes us age. And just as butter and lard get rancid with time, old fat causes us to age even more quickly. Kirkland believes that senescent cells buried in fat tissue may be the major culprits in the systemic inflammation that accompanies aging—and the older we get, the more senescent cells are lurking in our fat deposits. Another, equal problem is that our fat cells themselves become dysfunctional, and less able to do their job of, well, storing more fat. This leaves free fatty acids circulating around in our bloodstream, a dangerous situation called lipotoxicity—or, if you prefer, fat poisoning. Not good. And no wonder obesity has been linked to telomere shortening (which, in turn, creates more senescent cells).

  This negative feedback loop only accelerates with age. Problem fat, though, overwhelmingly affects the middle-aged to older crowd, which is why the “metabolic syndrome”—a combination of obesity, insulin resistance, high blood pressure, and poor cholesterol—afflicts just 7 percent of people in their twenties, but nearly half of those in their sixties. Phil Bruno had the metabolic syndrome, and probably so does every heavy person you see at the mall. Another scary statistic: More than two-thirds of Baby Boomers are overweight or obese.