Spring Chicken Page 26

  He had recently established his own lab in UCSF’s new Center of Regeneration Medicine and Stem Cell Research at the tender age of thirty-two, a fact that made him a bit of an outlier. Because of tight funding, most scientists nowadays consider themselves lucky to get their own lab before they turn forty or forty-five. A look at the history of science shows why this is a problem: Most major discoveries tend to be made by younger researchers, in their twenties and thirties, when they are still at the peak of creativity, still coming up with their good ideas. Einstein, for example, was just twenty-six when he wrote down his most famous equation, E = mc2.

  One reason for this is because, basically, younger scientists have younger brains: Their minds are plastic, creative, and rich with neurons that enable them to make the kinds of connections among observed and even obvious facts, and the intuitive leaps, that lead to great scientific discoveries. As we get older, even the smartest and most creative thinkers seem to stiffen and dry up, and run out of ideas.

  And this, in a way, would be the subject of Saul Villeda’s presentation.

  It isn’t pretty, what age does to our brains. The trouble stems from the unfortunate fact that, like heart muscle cells, neurons do not regenerate. (Not much, anyway.) So, just as a baseline, we typically lose about ten percent of our neurons over a lifetime. The problem is, we also lose more like one-quarter of our synapses, the connections between neurons that are crucial for every mental process. Not only that, but our neurons themselves become less connective, with fewer of the dendritic spines that let us form memories, thoughts, ideas.

  This erosion happens very, very slowly, at first, but a recent BMJ study found that significant cognitive decline is already evident in many people by the time they reach their forties. We are not the only animal whose brains decline with age. Even fruit flies lose their memories. Scientists test for this by exposing the flies to plums, and giving them a mild electric shock. When they are given cherries, they get no shock. Eventually they learn that cherries are good, plums bad. Then, just a couple of weeks later—late middle age, for a fruit fly—they forget which is which. In a related story, I haven’t been able to locate the remote control for my TiVo for months.

  Fruit-fly brains have something else in common with ours: Over time, some of them tend to build up “plaques” made of cellular waste products in between their neurons, which cramps their style in a major way and sometimes kills them. This is the same kind of gunk that Dr. Alois Alzheimer, a Bavarian physician who ran the Frankfurt Asylum, observed inside the brain of his most unusual patient, when she died in 1906 at the age of fifty-six.

  Her name was Auguste D., and she was the wife of a railway clerk who had become, literally, demented. She was confused and disoriented, had difficulty remembering things, and suffered from paranoia and hallucinations. She also accused her husband of having an affair with a neighbor, which may or may not have been the case. She knew it was the eleventh month of the year, but believed that the year was 1800, not 1901. “She sits on the bed with a helpless expression,” Alzheimer wrote in his intake notes. “At lunch she eats cauliflower and pork. Asked what she is eating, she answers spinach.”

  After she died, he figured out why. Her brain was a complete mess. Under the microscope, he could see that the space between her brain cells was filled with gummy plaques made of some mysterious substance. The neurons themselves were also disheveled, like tangled skeins of yarn. They were so striking that he sketched a few of them:

  Credit: Bernard Becker Medical Library, Washington University School of Medicine

  Alzheimer felt certain that these plaques and tangles had snarled Auguste D.’s thinking. A few years later, the syndrome was named Alzheimer’s disease in an influential textbook. But it took until the early 1970s before it was recognized as the primary cause of what until then had simply been called senility. Already, Alzheimer’s is listed by the CDC as the sixth-leading cause of death, but even that is misleading, because many patients actually end up dying from something else, such as an infection or heart failure. Something like 40 percent of Americans older than 84 are affected by Alzheimer’s. By 2050, according to the Alzheimer’s Association, the number of Americans living with the disease could more than triple, to sixteen million, and the costs to care for them will top $1 trillion.

  The strange substance in Auguste D.’s brain was called beta-amyloid, also known as A-beta, a protein whose origin and precise function are somewhat mysterious. Whatever its job, we produce more and more of it with age, and when it clumps together in plaques it also proves toxic to neurons and very pro-inflammatory—and very strongly associated with Alzheimer’s disease. Over the past decade or so, several major pharmaceutical companies developed drugs that proved very effective at clearing A-beta out of brain cells, in the lab dish and in mice. There was only one problem: In clinical trials in actual patients, they failed to work. One or two of them actually made patients’ scores get worse, on memory tests similar to the ones I’d been subjected to in The Blast (“squid, cilantro, hacksaw…”).

  Eli Lilly had two major candidates fail in Phase III trials—a setback for the company, but perhaps a step forward for science, as the fiasco is forcing a new look at a hundred-year-old disease. More scientists are questioning the whole amyloid-causes-Alzheimer’s theory itself; Businessweek magazine dubbed it a “drug graveyard.” Out of more than two hundred potential Alzheimer’s drugs that have been tested in clinical trials since 2002, only one has made it to market, and that one, called Aricept, is both insanely expensive and not all that effective (it delays the disease by about four months). Some researchers believe that another toxic protein called tau, which is also found in the brains of Alzheimer’s patients, may be the actual culprit. Others believe the disease may start somewhere else entirely—and require a whole new way of treatment—or better yet, prevention.

  What separates the Augustes of the world—the people who go into dementia in their fifties, for no obvious reason—from the Irving Kahns, who keep picking stock-market winners into their second century? How preventable is cognitive decline?

  One surprising answer came from a study of 678 elderly nuns. Researchers from the University of Kentucky went back through convent archives and found autobiographies that 180 of the nuns had written when they were young and just entering the order. They analyzed the women’s writing styles and found that the more nuanced and complex their sentences, and the richer their vocabulary, the less likely they were to have developed Alzheimer’s or other forms of dementia. The more sophisticated writers also lived an average of seven years longer than those the researchers dubbed Listers, because their life stories amounted to little more than lists of names, dates, and places. On autopsy, it was found that the better writers’ brains were also less gunked-up with amyloid than the Listers.

  Another interesting, related observation came from The Blast. Autopsies of study subjects found that the brains of many cognitively “intact” patients were in fact loaded with amyloid plaques and tangles; they looked worse than the brains of some people who had actually been diagnosed with dementia. A British study found similar puzzling results: A third of “non-demented” subjects had massive amounts of junk in their brains. Inside, their brains had all the hallmarks of clinical Alzheimer’s. Yet they had not developed any outward signs of the disease. Why?

  One theory is that people with more education and more sophisticated, well-trained brains appear to develop what’s called cognitive reserve, the way longtime athletes have built stronger, more stress-resistant cardiovascular systems. Education and learning develops more neuronal pathways and synaptic connections, so these people have in effect a buffer zone that protects them as degeneration begins to take place. It also gives them more tools with which to mask their cognitive impairment, consciously or not. Aging is hiding in their brains, just as it hides in our bodies. But it can’t hide forever. When these smarty-pants patients eventually do develop the disease, or whatever it is, they tend to decline mo
re quickly.

  Use It or Lose It applies to our brains, too. It’s similar to the old English farmer whom we met a few chapters ago, who retained his strong leg muscles well into his seventies, because he used them, every single day. A study of nearly two thousand elderly people published in June 2014 in JAMA Neurology found that those who had used their brains more from age forty onward were able to delay the onset of memory loss by more than ten years.

  More research has shown that patients who resisted Alzheimer’s often also resisted depression, which often goes hand in hand with brain aging. Those with a more “resilient” personality profile seemed better able to hold off cognitive decline, whether or not they had brain gunk. Similarly, the optimistic nuns also lived longer, by about seven years. By contrast, pessimists generally fared poorly, or at least their brains did. Depression eats away at our synaptic connections, truncating the size of the neural network, and eating into our cognitive reserve. Likewise, lack of sleep does much the same thing. Researchers are now realizing that sleep is absolutely crucial to brain health, especially in older adults; it gives brain cells a chance to clear out toxic or harmful metabolites, which would otherwise build up and further jam the network.

  No wonder you feel dumb the day after an all-nighter. Even jet lag causes major disruption: In one study at the University of Virginia, scientists took a group of aged rats and advanced their light-dark cycle by six hours for a week, then by another six hours. Within four weeks, half of the rats were dead. (A shocker: Jet lag ages you.)

  I don’t know if this is good news or bad, but there are more things you can do that might help prevent Alzheimer’s than there are drugs to treat it. A major 2011 study from UCSF found that if seven basic risk factors were addressed, including diabetes, midlife obesity (defined as waist size of thirty-nine inches or more for men, thirty-six for women), midlife hypertension, smoking, depression, low educational level, and physical inactivity, half of all Alzheimer’s cases could actually be prevented. Yet another recent long-term study found that people who had been fitter at age twenty-five had stayed more cognitively “intact” at age fifty.

  Mark Mattson of the NIH thinks there’s a good evolutionary reason for this: Exercise sharpens memory so that we can better remember that we passed important things like sources of food, water, and building materials while we were out hunting. If you happened to walk past a promising hunting spot, or a fallen tree, or a spring, it was important to be able to find it again. So there may be a connection between my dad’s maniacal bike riding—he cranked out twenty-five hundred miles between May and November 2013, more than I managed the entire year—and the fact that he’s still mentally on his game.

  Less-intense exercise also seems to have an effect: One well-done study found that merely walking twenty minutes a day was enough to slow or reverse the decline in cognition of patients who had already been diagnosed with Alzheimer’s—something few drugs have been able to achieve. There’s even an NIH-funded study going on to determine whether ballroom dancing has any helpful effect on brain function in seniors. It’s probably safe to try it, without waiting for the results of this particular bit of taxpayer-sponsored research.

  All of which suggests that, in part, the disease may have its origins in metabolism. Also, as Villeda points out, exercise itself also changes the “milieu”—that is, the chemical composition of our blood—in ways that seem to be favorable for the health of our neurons. When I would get stuck while writing this book, for example, I would stop working and go out for a one-hour bike ride; invariably, by the end of the ride the problem had been solved.

  The only problem is that it’s a temporary kind of effect. Still, a multitude of data is suggesting that the brain itself is far more plastic than we might have thought—and that even its aging may ultimately be reversible. So I may yet find that lost remote control.

  Saul Villeda wasn’t always convinced that old brain cells could be revived. In the lab with Tony Wyss-Coray, he had seen that the blood of Alzheimer’s patients was markedly different from that of healthy older people, so the next question was whether those chemical changes in blood were somehow causing or promoting cognitive aging. “We were really asking, in terms of cognition, A, there’s a blood-brain barrier, so does blood even have an influence on the brain? Number two, does old blood do something to the old brain?”

  The question could only be answered via parabiosis. They joined several dozen pairs of mice together, just as Frederick Ludwig had done: old with old, young with young, old with young. After the critters had gotten to know each other, and had been swapping blood for a while, they would look for any change in the younger mouse brains. Several months later, they had their answer, summed up in the title of the resulting Nature paper: “The Aging Systemic Milieu Negatively Regulates Neurogenesis and Cognitive Function.” In English, they found that young brains that were bathed in old blood (the “aging systemic milieu”) worked poorly, with less protection and renewal of neurons than they should have had. Which is depressing: Old blood hurts your brain. But then Villeda started wondering: What about the other way around? What would young blood do to old brains?

  The problem is that it’s a bit difficult to tell what’s going on in a mouse brain. For starters, you can’t really do cognitive testing on a mouse that’s sewed to another mouse. So Villeda tried another way: He would simply take blood plasma from young mice and inject it into old mice, and then run the old mice through a gauntlet of mental tests. Mice can’t exactly take the SAT, so instead he placed them in a radial-arm water maze, a kind of Habitrail filled with milky water. Hidden just under the surface of the opaque liquid, in one part of the maze, there was a little platform that they could climb up onto to get out of the water. “These animals hate to get wet,” he explained. “They’ll do anything to avoid it.”

  Before any plasma injections, the mice went through a period of training in which they learned to find the safety platform in the water maze. Then, after a week or so, they were plopped back into the maze. Young animals could find the platform again almost immediately, while old animals would blunder around hopelessly, making as many as thirty errors before finally finding the nice, dry island. “It was kind of sad,” Villeda said.

  Then Villeda discovered something amazing: After the older mice had been injected with the young blood for a few weeks, they were suddenly able to find the platform again, on the first or second try. “Something is happening with the aging blood that is detrimental,” he said. “There’s something in young blood that we’re losing.”

  After the mice were “sacrificed,” he looked at their brains, especially the neurons from the hippocampus, the region where memories are formed. Under an electron microscope, younger neurons appear “fuzzy,” because they have more dendritic spines, little branches sticking out from their neurons that help make connections with other neurons. In old animals, the dendrites had many fewer spines, as if they had been pruned off by a zealous gardener. This made the neurons less connective, less able to link memories with thoughts and actions. But in the old mice that had been injected with young plasma, the neurons had become fuzzy again—which, obviously, had helped them remember and negotiate the water maze. Young blood had restored their old brains.

  “We saw an actual reversal of aging-related decline,” Villeda told me, still sounding amazed. “I always thought of aging as a final blow—once you get there, there’s no coming back. I’m not sure that’s the case anymore.”

  Now the big question was, What was it in young blood that produced this effect?

  It wasn’t only in the brain, either. Other studies had found that younger animals’ blood also seemed to rejuvenate muscle and bone in older animals. And Villeda wasn’t the only one looking for the answer. Across the country, at Harvard, another Stanford alumnus was searching for the precise factor that was responsible for this amazing rejuvenation effect. The race was on.

  “It’s not like looking for a needle in a haystack,” said Amy Wagers,
when we met in her office in Boston. “It’s like looking for hay in a haystack. There are so many possible metabolites, or proteins, or factors, and any of them could be the one.”

  Her search had lasted ten years, since she had been part of the team that had helped revive the parabiosis technique in the early 2000s. As a postdoc, she had worked with Irving Weissman, the noted Stanford biologist who had first isolated human stem cells from blood; Weissman had collaborated with Tom Rando to see how aging blood affected muscle regeneration. In a groundbreaking 2005 paper published in Nature, they reported that young blood seemed to improve the ability of old mice to repair their injured muscles. Not only that, but their livers had also miraculously healed. Something in young blood was telling the old mice, on a cellular level, to act “young,” too, and to regenerate and heal as successfully as they once had.

  This meant that older cells still had the potential to thrive and regenerate, but the oldness of their blood was preventing this from happening. The implications of this were huge: It meant that we might retain the ability to regenerate various body tissues well into later life. The trick would be figuring out how to unlock that potential—by finding the factor, or factors, that might be responsible. The search would take a decade, and it isn’t over.

  Wagers decided to look for a possible rejuvenating factor: whatever it was in young blood that seemed to turn back the clock on older cells. She was joined by a veteran cardiologist and stem-cell researcher named Richard T. Lee, who was also an old cycling friend of hers (and whom we met in chapter 6). Lee was getting tired of seeing his patients’ hearts basically wear out with age as they lived into their eighties and beyond. Younger patients he could treat with statins and blood-pressure medication, and procedures such as stents and valves. But there seemed to be nothing he could do to solve these very old patients’ problems. More and more of them suffered from something called diastolic heart failure, where the heart muscle has thickened so much that the chamber fails to fill properly; so far, there is no known treatment.