Long for This World

by Jonathan Weiner

  Evolutionary biologists can see why tinkering with genes might extend the lives of worms, or flies, or mice. It’s true that Darwinian evolution does not design bodies to be long-lived. And yet, there are conditions in nature that permit a population of animals to grow up relatively slowly and reproduce at later ages, just as the flies do in Michael Rose’s laboratory breeding experiments. Suppose a pair of mice drift out to sea on a log and arrive on an island where there are no cats, hawks, or owls. Suddenly they are safer. Generation after generation, their descendants can flourish if they invest in slow, careful growth, in the kind of cellular quality controls that biologists call “longevity assurance systems.” The mice on that island will live long and prosper. Their descendants will inherit their good genes and live longer yet. So aging is in some ways under the control of the genes, even though aging itself is not designed by evolution.

  If you look at populations of animals on islands, as Darwin did, you see again and again that when birds or lizards or tortoises get marooned on an island where they are suddenly without predators, they begin to live longer and longer lives. Their descendants are Methuselahs.

  This is likewise true of animals that evolve some other kind of protection from their enemies: the shells of tortoises, the wings of birds and bats. All these creatures have evolved adaptations by which they can lift themselves out of the usual rut of danger. With those adaptations they can escape from a thousand ancestral enemies as surely as if they had drifted onto islands. And they too tend to live much longer than sibling species that failed to evolve such a route to safety.

  If evolutionary theory is correct about the origin of aging, then life span should tend to lengthen whenever a species escapes a danger that had weighed on it for a long time. Bats make a test case. It turns out that many species of bats are Methuselahs. There are more than a thousand species of bats in the world. They live on every continent but Antarctica and they range in size from the bumblebee bat of Burma, which has a body not much more than an inch long, to the Giant Golden-Crowned Flying Fox of Maitum, Sarangani, in the Philippines, which has a wingspan of five feet. They fit the pattern that present thinking about aging would predict. A greater horseshoe bat weighs about as much as a white-footed mouse, but the mouse lives at most eight years, and the bat lives more than thirty. A big brown bat weighs less than a house mouse, but the house mouse lives at best four years and the bat, nineteen. An Egyptian fruit bat weighs less than half as much as a Norway rat. The rat lives at most five years, while one Egyptian fruit bat is known to have attained the ripe old age of almost twenty-three. The little brown bat, which is the most common bat in the United States, is the size of a little brown mouse; the mouse can live three or four years and the bat as long as thirty-four.

  Because they soar so high above their enemies, and can live such a long time, it makes perfect sense in evolutionary terms for bats to invest in expensive maintenance plans—unlike the house mouse or the brown rat, which sprout and die like weeds. It is the same with flying squirrels, flying opossums, and the flying lemur of the Philippines. Strictly speaking, they glide rather than fly, but as gliders they’ve evolved much longer life spans than mammals of about the same size that can’t take to the air. The same principle holds again and again. Naked mole rats are safer than rats and mice because they spend their lives in burrows and tunnels. They can live almost thirty years. There are even parasitic worms that have found their niche in the safety of long-lived human guts. They live a hundred times longer than their cousins in the soil.

  Presumably those Methuselahs evolved their long life spans gradually, over many generations. There are also conditions in nature that can induce an individual animal to slow down, grow carefully, and postpone reproduction during its own lifetime. Take calorie restriction. In principle, evolutionary biologists can understand why calorie restriction might lead animals in the lab to slow their rate of aging. It would be adaptive to be able to do that in the wild. During a famine, you don’t want to breed; you don’t want to bring a new litter of pups into the world to starve. You’d rather slow or suspend your growth, enter something almost like hibernation. You’d want to conserve fuel and energy, riding out the bad times, waiting for better times when it will make sense to reproduce. Calorie restriction probably triggers an adaptation that evolved over many millions of years to help animals cope with drought, famine, and deprivation in the natural world.

  Now molecular biologists are finding and exploring some of the mechanisms by which our bodies respond to calorie restriction. In the laboratory, they are studying the genes and cellular tricks that come into play. Many of these genes turn out to be the very same ones that were transformed in the Methuselah mutants.

  The quest to find Methuselah mutants has led to a whole bestiary of genes and their products. There is Sir2 (Silent Information Regulator 2), which was discovered in a yeast Methuselah. There is Indy (I’m Not Dead Yet), which was discovered in a fruit fly Methuselah. And on and on: chico, InR, daf-2, fos. Although the field is still tangled and confused, virtually all of these genes seem to be involved in the workings of calorie restriction and the regulation of metabolism. In other words, they connect the work of the skin-outs and the skin-ins; they link the evolutionary theory of aging with the calorie-restriction research of the last sixty years or so.

  So far the study of Sir2 has been the most exciting. Sir2 was discovered by the molecular biologist Leonard P. Guarente, at MIT. Building on that discovery, Guarente and his students and former students began exploring a whole class of proteins called sirtuins (named for Sir2), which are found everywhere in the tree of life, from yeast to mice to people. Work on sirtuins led them to the discovery of resveratrol, which is found in the skins of grapes. Resveratrol switches on sirtuins and prolongs the lives of laboratory mice.

  One of Guarente’s former students, David Sinclair, now at Harvard Medical School, has helped found a company called Sirtris to exploit the possibilities of resveratrol and find its active ingredients. Sinclair suspects that Sir2 may turn out to have two roles in the cell. First, it works hard to keep the genome stable, to prevent mutations from taking place—a kind of preventive medicine. Second, when DNA does get damaged, it makes repairs: surgical medicine. As our bodies age and we accumulate more and more DNA damage, Sir2 may get so busy doing emergency surgery that it can no longer keep up with its normal, calmer role of preventive medicine. Sinclair thinks that may be the origin of the Error Catastrophe. Although these are still very early days, Sirtris is now testing sirtuin activators in four clinical trials; and Sinclair himself has begun taking daily doses of resveratrol. As he is the first to admit, it is still too soon to say if he is young for his age.

  In 2009, a paper published in Nature announced another promising drug that slows aging in mammals. This work began with a good idea at the U.S. National Institute on Aging (NIA). The NIH set up the program to allow investigators to test compounds that might intervene in the aging process and extend healthy life span. Scientists anywhere are encouraged to nominate compounds if they can make a case based on our current state of knowledge that they have a chance of making a difference. A series of compounds have now been tested. The first two did not do much for the mice, but the results of the third compound are remarkable.

  That compound is rapamycin, an antibiotic that was discovered in microbes found in soil samples from Easter Island. The compound’s name is derived from Rapa Nui, which is what Pacific islanders called the place. It targets a piece of cellular machinery that is known simply as TOR (Target of Rapamycin). TOR became a target of interest to gerontologists when work in the laboratory of the molecular biologist Seymour Benzer, at Caltech, linked it to both longevity and caloric restriction. TOR not only helps to shape the life span in flies, worms, and yeast; it is also influential in what is known as the “insulin-like signaling pathway” by which a cell learns if there are nutrients around it.

  TOR, like the sirtuins, plays a central role in metabolism. It helps pr
omote the manufacture of proteins; it also inhibits the self-devouring behavior of autophagy. There, TOR seems to be part of an ingenious feedback loop. It enhances autophagy when the cell needs it, and then cranks it down when the housekeeping work is done. When the cell floor gets dusty, it helps draw the broom out of the closet and gets it sweeping. When most of the dust is gone, the broom goes back in the closet. In other words, TOR plays a role in both faces of metabolism: in the creative side, anabolism, and the destructive side, catabolism.

  So it made sense to test rapamycin on mammals—on mice.

  Testing began simultaneously in three laboratories: the Jackson Laboratory in Bar Harbor, Maine; the University of Michigan; and the University of Texas Health Science Center. Giving the mice the drug proved to be more complicated than the experimenters expected, and that turned out to be a lucky thing. Near the start of the experiment, when researchers added rapamycin to the mouse pellets, they found that the mice digested it quickly, so that the drug didn’t build up to high levels in their bloodstreams. (Human patients have the same problem with rapamycin. They digest most of it in their guts and not much of it gets into circulation. A recent study suggests that taking the drug with grapefruit juice can help.) The researchers were forced to develop a special feed that delivered the antibiotic in capsules for timed release. Developing that special feed took them more than a year. By the time they had it ready the mice in the first cohort of the experiment were already six hundred days old. That put the mice in late middle age. A mouse of six hundred days is about as old as a man of sixty years.

  The researchers decided to proceed anyway and the results were more interesting for the delay. Of the female mice in that first cohort, those that did not get the rapamycin had a maximum life span of about 1,100 days. The female mice that got the drug had a maximum life span of about 1,250 days. The maximum life span of male mice was also increased, from about 1,080 days to 1,180 days. If you look at the life expectancy of those middle-aged mice at the time they began to get the drug, the females’ life expectancy was raised by 38 percent and the males by 28 percent. (Maximum life span is defined here as the average life span of the longest-lived 10 percent of the cohort. This is a more informative index of maximum life span than the age of the single very oldest mouse in the cohort. In fact, when the researchers analyzed the data, on the first of February 2009, 2 percent of the mice—38 out of 1,901—were still alive.)

  We seem to be reaching a kind of hub here. Both the work on calorie restriction and the work on autophagy lead to TOR. And it makes sense that these two lines of research should intersect, because one of the adaptive responses of the body during a famine is to increase the rate of recycling of its own proteins. We start to tear ourselves down faster than we build ourselves up. We get thinner.

  Molecular biologists are now studying rapamycin closely and trying to figure out how the experiment worked and why. They want to know why these middle-aged mice did not get thinner on their rapamycin diets. They also want to know whether rapamycin will help to postpone a wide array of late-onset diseases, from cardiovascular and neurological problems to diabetes to cancer. Since rapamycin has serious side effects, they will look for more benign and sophisticated drugs that target TOR, just as they are looking for ever more sophisticated drugs to target sirtuins.

  It’s intriguing that these new drugs play important roles in pathways that influence so many diseases. With sirtuins, the list includes diabetes, osteoporosis, and cancer, as well as neurodegenerative, cardiovascular, inflammatory, and mitochondrial diseases. With rapamycin, the list is also long, and one particularly promising line of research involves Huntington’s disease.

  With Huntington’s the junk forms because one gene has a sort of stutter in its genetic code. It repeats the letters CAG more than thirty-five times. That unfortunate string of extra letters of code means that the protein is defective; the cell manufactures it with an extra piece or flange sticking out of it and that extra piece seems to make it clump inside the cell.

  Recently a team led by David C. Rubinsztein, a biochemist at the University of Cambridge, tried treating these cells in a petri dish by giving them rapamycin, on the theory that boosting the body’s ability to take out the garbage in this way might help. It did. Rubinsztein’s team also tried rapamycin on a strain of mice that had been engineered as models of Huntington’s disease. To test its grip, they let a mouse hold a metal grid with its forelimbs, lifted it by the tail so that its hind limbs were off the grid, and gently pulled backward by the tail until the mouse finally let go. The antibiotic helped sick mice do better on this grip test, and it reduced their tremors.

  Most people don’t show symptoms of Huntington’s until they are at least forty years old, and in almost every case they know the disease runs in the family. These days the mutation is easy to test for. Someday it might be possible to postpone the onset of symptoms and give people more healthy years. In the best scenario, you could delay the onset of Huntington’s so long that they would never get the disease because something else would get them first.

  The same kind of strategy might work with Parkinson’s and other neurodegenerative diseases in which garbage piles up in or around our nerve cells. It may be the same kind of story will be found with the molecular trash known as Lewy bodies, which accumulate in the nerve cells of people who develop Parkinson’s, as well as with the trash that piles up in the nerve cells of people with amyotrophic lateral sclerosis (ALS) and other diseases that are rarer and less well known but just as deadly. Typically the damage starts to pile up at least five or ten years before the first symptoms. If the problem could be diagnosed and treated that early, for instance with a drug like rapamycin, which hastened the cells’ own brooms, then we might postpone some of the worst diseases of old age, in the best case indefinitely. Two neurologists at Harvard Medical School, Peter T. Lansbury and Hilal Lashuel, note in a review of the problem that this approach has a few strong medical advantages. You don’t have to know exactly why the crud is building up and you don’t have to know exactly what harm it is doing. All you have to do is encourage the cells’ brooms to sweep it up. This is exactly the point that Aubrey de Grey has been making in his arguments about the Seven Deadly Things.

  Because most of these nerve cells have to last us our entire lives, they are particularly vulnerable to junk piling up. They can’t dilute it by dividing and dividing, like cells in the bone marrow or the gut or the skin. But it is possible that this basic problem of garbage piling up in cells will turn out to be the cause of many diseases of the human body; and early treatment, as here, may turn out to be a way of helping the body stay healthy for longer and longer amounts of time.

  Again, the point is that evolution has already given us the broom. Evolution gave us the tools we need for keeping house; evolution gave us the whole house. But evolution did not give us the means to keep house for as long as we would like. Now that we live longer and longer, we wear out the brooms.

  The cell’s brooms include not only autophagy and lysosomes, but a parallel system involving a molecule called ubiquitin, which tags misfolded proteins in the part of the cell where they are manufactured, the endoplasmic reticulum. Proteins that are misfolded as they come out of the endoplasmic reticulum are carried right back into the body of the cell, into the fluid called the cytosol, where they are dumped into barrel-shaped garbage-disposal units called proteasomes. This particular garbage-disposal process is known as endoplasmic reticulum-associated degradation, which has the acronym ERAD. Here we’re getting drawn into the cellular machinery at a very fine and grungy level. The garbage barrel known as the proteasome has a narrow mouth. That limits the size of the junk that can pass into it and the recycled bits that can pass out of it. The autophagosomes that carry trash to the lysosomes are often much smaller than the piles of Huntington’s trash they are trying to dispose of. They’re like boa constrictors trying to swallow elephants. They may or may not be able to do the job on their own.

  Go
d speed the broom. Again, rapamycin has unpleasant side effects when taken long-term. But there may be other drugs that can help the brooms and enhance autophagy. Rubinsztein reported recently that lithium, valproate, and carbamazepine seem to help induce autophagy, too. Combinations of those drugs may do as well as rapamycin with fewer side effects. Of course, as he notes, keeping the housekeeping crews cranked up this way may cause problems of its own. The sorcerers’ apprentices may do damage we can’t imagine with each extra whisk of the brooms. Or not. Even if autophagy speeds up so much that a brain cell throws out many of its mitochondria, Rubinsztein thinks the cell will still manufacture enough of its energy compounds, its ATP, to function. So you might be able to get the brain cells to stay cleaner and run cleaner with fewer factories and less energy; and the result might be less cellular pollution and longer life.

  Huntington’s is the disease that first led biologists to the evolutionary view of aging: the view that our bodies are powerless against declines that begin once we have passed the age of reproduction, because evolution is blind to them. That idea was first expressed by J.B.S. Haldane, one of the most brilliant and eccentric British biologists of the twentieth century. Aubrey de Grey likes to quote Haldane’s maxim about the acceptance of controversial scientific ideas. There are four stages of acceptance, said Haldane: “One: This is worthless nonsense. Two: This is an interesting, but perverse, point of view. Three: This is true, but quite unimportant. Four: I always said so.”

  Chapter 9

  THE WEAKEST LINK

  Toward the end of my summer in London, I went on a day trip with Aubrey. I wanted to visit the site of the very wildest of Aubrey’s eureka moments, the place where he had solved the hardest problem of all.