Long for This World: The Strange Science of Immortality - Jonathan Weiner (2010)
Part II. THE HYDRA
Chapter 8. THE METHUSELAH WARS
“Vermiculate questions,” Francis Bacon called them, “fierce with dark keeping.”
Controversies—niggly, bookwormy controversies—bedevil scholars in every age. Every field of study has battlegrounds that burn up scholars’ time and energy. To the casual bystander it’s all academic squabbling and logic-chopping. To the scholars themselves it is almost life-or-death. Aubrey’s work is contentious at least in part because it keeps him darting around in the no-man’s-land between battlefields. And yet if you take a long view of the Methuselah wars, you can see that they may be winding down, and you can see that Aubrey, or certain key positions of Aubrey’s, may just survive.
In the science of life today, the biggest battlefield lies between biologists who study life whole and those who analyze its working parts. They’re the “skin-out” people and the “skin-in” people. In the skin-out camp you have the naturalists, the ecologists, the field biologists, the evolutionary biologists. In the skin-in camp you have the cell biologists and the molecular biologists, experts on gadgets and widgets that are too small to see through a microscope.
Those who study nature whole and those who study it at the level of molecules rarely see eye to eye. Skin-out people look at the big picture and skin-in people look at the microscopic or submicroscopic picture. Skin-out people tend to think about the panorama of history, and skin-in people tend to think about the meshing of molecular gears. Francis Crick once scolded Stephen Jay Gould: “The trouble with you evolutionary biologists is that you are always asking ‘why’ before you understand ‘how.’” Meanwhile the evolutionary biologists blame the molecular biologists for asking how and never why.
The evolutionary biologists are tied to Darwin and nineteenth-century natural history. The molecular biologists are tied to Watson and Crick and twentieth-century physics and chemistry. Darwin was the greatest life scientist of the nineteenth century; Watson and Crick made the greatest breakthrough of the twentieth century, and from the beginning they’ve seen themselves as ringing out the old and ringing in the new. They see the skin-out biologists as describers, anecdotalists, stamp collectors. In universities, molecular biologists get most of the grant money, the new buildings, and the power. They’ve relegated the evolutionary biologists, ecologists, and naturalists to the corners of the old buildings and the natural history museums. The dustbins.
It has been an epic rift. The skin-in people tend to be excited about the engineering projects they can do. They study the body’s works and wonder how much of their new knowledge they can translate into how much power to improve or save human lives. The skin-out people, the evolutionary biologists and ecologists, tend to worry about what we’re doing to the rest of the planet, and what we can do to save the other ten or twenty million species that live on it.
In the early years of the molecular revolution, the skin-in people weren’t very interested in the problem of aging, because they didn’t think there was much they could do about it. One of the young revolutionaries, Leslie Orgel, a collaborator of Francis Crick’s, argued that aging is probably caused by damage to DNA. Our DNA is continually jostled and shaken by cosmic radiation from outer space, and by the agitation of the living molecules around it in our own bodies, and these collisions—along with a thousand and one other accidents—can cause mutations. If mutations occur in the egg and sperm cells, they can cause problems for the next generation. If the mutations occur in other cells, they can cause problems for our own bodies, because DNA contains information that is crucial for the cell in all of its manufacturing processes. When the wrong genes get the wrong mutations, you could say that a cell no longer knows how to live. Orgel argued that cells with mutations would make defective molecular machinery, and the defective machinery would then behave badly around the genes, and eventually the cell’s production lines would get hopelessly, viciously snarled. Errors would pile on errors. Orgel called this the Error Catastrophe.
Many skin-in biologists found this hypothesis intriguing. After all, DNA is precious. Genes can’t be repaired as simply as the rest of the cell’s apparatus. When genes are corrupted or destroyed, the cell has lost priceless information. It’s bad to lose a cake; it’s worse to lose the recipe. If mutations in cells can lead to cancer, maybe they also cause the many kinds of deterioration that we call aging. So the skin-in people were drawn to Orgel’s idea; but few of them worked on it. The Error Catastrophe is a difficult hypothesis to test. Each cell contains six feet of DNA, tightly spooled, with about three billion letters of genetic code on the spool. As the cell ages, it gets typos in unique, random places along those six feet of DNA, as well as typos in the elaborate machinery that reads the DNA. How would you keep track of all those typos and prove that they’re aging the cell? We all do have days when aging feels like an Error Catastrophe. But it is an ugly hypothesis to study. It would be very messy to prove; and even if you could prove it, what could you do about it?
By and large, then, the skin-in people left the problem to the skin-out people and their arguments about the evolution of aging. To skin-in people, those arguments were not really science at all. If you couldn’t understand a problem at the level of molecules, you weren’t a biologist; you were just a philosopher.
Then, in the 1980s and 1990s, both camps began to realize that aging might be malleable. Naturally, each camp assumed that the other side’s work had to be wrong. But each camp figured out how to make Methuselahs: creatures that live much longer than the rest of their kind.
The molecular work was started by a researcher named Michael R. Klass at the University of Houston. Klass reasoned that at least some of the sources of our longevity have to be in the genes. So he decided to go looking to see if he could find a longevity gene by making mutants in the laboratory and looking for Methuselahs. For his search he used the tiny round nematode worm Caenorhabditis elegans. He bred lots of mutant worms by feeding them a toxic compound called ethyl methanesulfonate. Then he grew them in petri dishes, where he let them graze like sheep or cows on lawns of bacteria. Every day he would collect the worms, put them on a nice fresh bacterial lawn, and see how many were still alive. Through the microscope he zoomed in on the worms’ throats, one by one, to see if they were still alive, still swallowing bacteria.
Klass created one thousand different strains of mutant worms. Out of that thousand he found just one strain that he considered to be Methuselah mutants. But he noticed that if he put those worms on a little lawn of bacteria in the center of a petri dish, they would wander off the lawn and try to graze on the bare glass. Apparently that strain seemed to have trouble smelling its food. So those worms were hungry. Probably those wandering worms weren’t getting enough food, he decided, and that was why they lived a long time. If they lived a long time because they were half-starved, that was not news—they’d be living longer because of calorie restriction. He was looking for a worm that lived longer purely because a mutation had extended its life span. He decided that he had failed. And after doing so much work, Klass concluded, reasonably enough, that aging genes must be very, very rare, if they exist at all. So Klass abandoned the experiment.
Not long afterward, a biologist named Tom Johnson asked Klass if he could look at that last mutant more closely. Johnson looked at the worms through the microscope. He thought they ate fine. Their calorie intake was not restricted. So after a great deal of work Johnson traced the gene that had mutated and made that mutant strain live so long. He named the gene age-1. Johnson found that when he raised age-1 worms in petri dishes at the warm, humid, Floridian temperature of 25 degrees C (77 degrees F), their maximum life span was more than doubled: it increased by 110 percent. A few strains did even better. Their average life spans increased by 120 percent.
At that time, most experts on the biology of aging mistrusted this work. They were evolutionary biologists. They thought it was impossible that a single gene could do very much for life span. According to the line of argument that ran from Darwin to Medawar to Williams to Kirkwood, when bodies age they just fall apart. The disintegration is not programmed. It is not written in our genes. So how could a single gene make so much difference? Something must be wrong with the experiments.
A few years later, a third molecular biologist, Cynthia Kenyon, decided to take up the search for longevity mutants. There was still so little interest in the subject of aging, and the study was thought to be such a backwater, that she had trouble finding a student she could persuade to work on it. When she did, at last, she found a mutant worm that she thought was perfectly beautiful. Under the microscope, ordinary old C. elegans worms look granular and ugly, as if they were made of cottage cheese. But these mutants stayed smooth and elegant almost to the end of their lives. Cynthia Kenyon published her first studies of Methuselah mutants in 1993, ten years after the first paper by Klass.
Kenyon’s mutants caused a sensation among molecular biologists. The science that grew out of Watson and Crick’s “secret of life” had now found the secret of the fountain of youth. If they could make a Methuselah worm, soon they’d be able to genetically engineer a human Methuselah. Whether or not that was true, the link between the gene and the long life of the worms was very clear, news of Kenyon’s mutants traveled fast, and here and there other molecular biologists began to enter the field of gerontology. I happened to be present one afternoon at the lab of a grand old man of molecular biology when a young scientist gave a seminar about longevity mutants. Seymour Benzer, one of the founders of the field with Watson and Crick, was fascinated. He seemed astonished to think that we really might be able to understand aging at the level of the genes. He began looking for longevity genes in fruit flies the way Klass, Johnson, and Kenyon had in worms. When he was eighty years old, Benzer discovered a Methuselah fly. He used to talk about that fly in an almost shady way, lowering his voice, making it thin and quiet, as if he and his listeners were convicts in neighboring cells, as if he had to drop his voice and turn it edgewise to slip a scribbled message between prison bars.
The evolutionary biologists remained skeptical about the molecular biologists’ Methuselah mutants. To the skin-outs it still seemed impossible that a single gene could matter that much to the life span. Disposable soma theory predicted that there should be many genes that go wrong with age. Aging was a Hydra with at least nine heads. You couldn’t kill it with just a single kick. According to disposable soma theory, the Methuselah mutants should not exist. I once talked about them with John Maynard Smith, a grand old man of British evolutionary biology, who worked out some of the mathematical theory that flows from present thinking about aging. He and I met on one of the upper floors of New York’s American Museum of Natural History. Maynard Smith was a brilliant scientist who had started out as an aeronautics engineer. He’d helped improve the fighters and bombers of World War Two, the planes that the young airmen of the RAF flew over London and Berlin after burning their initials into the ceiling of the Eagle. After the war, Maynard Smith had done both theoretical and experimental work on the science of longevity. Now he was nearing the end of his life. When I asked him about the biologists who thought it might be possible to engineer a human Methuselah, he shook his head. He said that something seemed to happen when serious people approached the problem of aging and death. They just seemed to go mad.
As a software engineer with a wide range of interests in biology, Aubrey de Grey is in the camp of the molecular types, the genetic engineers, and also in the camp the evolutionary biologists. Still, he’s a proud engineer at heart. When I told Aubrey what Maynard Smith had said, he smiled. “John Maynard Smith? I have the greatest respect for his intelligence. But he’s an evolutionary biologist. He finds it hard to think in an engineering-type way.”
That’s the way the two camps flame each other. They fire off those killing salvoes again and again. Once I was talking with a famous biologist—a molecular biologist—who had just joined Rockefeller University, and I asked him if he had ever heard of Maria Rudzinska. He looked blank. I described her work to him, how she had been trying to understand death and dying without looking at genes and molecules, just by watching aging cells through a microscope.
“There used to be a lot of deadwood around this place,” he said.
In the 1980s, while the skin-in people were making Methuselah mutants, the skin-out people made their own Methuselahs. They did it the old-fashioned way: not through genetic engineering but through Darwinian breeding experiments. At about the same time that Klass engineered the first Methuselah worm, a young evolutionary biologist named Michael Rose bred Methuselah flies. Typically fruit flies breed at the age of a week and a half. Rose watched carefully and selected only the flies that kept breeding in old age, and he bred those. It was work that could have been done in the nineteenth century just as well as in the twentieth. And it didn’t violate the disposable soma theory, because Rose assumed that many, many genes would be involved in making a Methuselah.
It was very hard work. Rose bred millions of fruit flies, and each experiment took between thirty and fifty fly generations. But he found that it was possible to play with a fly’s length of days. When he allowed only older flies to breed, generation after generation, they evolved longer life spans; when he allowed only the younger flies to breed, they evolved shorter life spans. Rose and his thesis adviser, Brian Charlesworth, announced the creation of the first of these evolutionary Methuselahs in 1983.
Again, unlike the Methuselahs of the molecular biologists, Rose’s were acceptable to the evolutionary biologists. These populations of fruit flies represented the same miracle that has happened again and again in the wild. See, for instance, the bats, the flying squirrels, the flying lemur of the Philippines, all of which are Methuselahs. Any population of living things that finds itself in conditions in which it is able to breed at later ages will begin to evolve longer life spans. Since Rose could replicate that miracle again and again quickly in the laboratory, he argued that adding years of vigorous healthy life must be comprehensible at the level of the genes. He didn’t know which genes had changed; evolutionary theory predicted that the change must have been produced by a constellation (or cluster or galaxy) of genes. Evolutionary biologists thought they understood the why of aging, and according to evolutionary theory the existence of a single powerful Methuselah gene was impossible. Even so, changes in life span could not happen so quickly and so repeatedly, both in the wild and at his laboratory bench, unless it was a relatively simple trick to bring off.
Rose championed the evolutionary Methuselahs and tended to brush aside the molecular Methuselahs. He dismissed those Methuselahs as Johnny-come-latelies. In his memoir, The Long Tomorrow, Rose writes, “It is always entertaining when molecular biologists rediscover findings from evolutionary biology. They have such an appealing naiveté, like the moment when my son Darius gleefully discovered at the age of one that gravity would help him knock over a glass of milk.”
To the outside world, of course, the battlefields of biologists weren’t very interesting. What was interesting was the creation of all these Methuselahs. Cynthia Kenyon, who put the Methuselah worms on the map for molecular biologists in the 1990s, was not only a gifted scientist but young, photogenic, buoyant, and articulate on camera. She was invited on dozens of television shows and news shows to talk about them. When people asked her, Wouldn’t it be weird to have adult grandchildren? she would shoot back a snappy answer to the interviewer’s questions. “I think every grandparent wants to live to see the grandchildren grow up.” She made the study of mutant worms sound sexy. “They are like eighty-year-olds who look forty.” And, “I can make your dog live forever!”
Michael Rose also got a lot of press. A generation before, at mid-century, Peter Medawar had dared to imagine that the total span of human life might be lengthened by “stretching out the whole life span symmetrically, as if the seven ages of man were marked out on a piece of rubber and then stretched.” Rose declared that ambition too modest. What if we could stretch out the time we spend young without stretching the time we spend withered and decrepit? If we learn to control the genes that govern life span, we could do that. Who knows? We could make youth last threescore and ten years, and age last only one or two years. Certainly we could prolong youth without prolonging age. We could open that door with a few twists of the skeleton key.
These twin victories on either side of the trenches in the Methuselah wars helped revive the field of gerontology. The skin-ins and the skin-outs still don’t get along. Skin-out biologists still doubt that you can kill aging with a single gene. Skin-in biologists are still playing with single genes to make more Methuselahs. (“My rule of thumb is to ignore the evolutionary biologists—they’re constantly telling you what you can’t think,” Gary Ruvkun of the Massachusetts General Hospital told a reporter from the New York Times not long ago.) Even so, more people on both sides are entering the field, and a resolution of the paradox is beginning to emerge. This battle is beginning to die down.
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 promote 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.
God 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.”