Long for This World

by Jonathan Weiner

  INTO THE NEST OF THE PHOENIX

  In ancient legend, the Phoenix was a solitary bird—beyond solitary: unique, one of a kind—that burned itself up in its nest and was reborn. In Egyptian hieroglyphics, the Phoenix represents the sun; in Christian symbolism, the Resurrection of Christ. In Jewish legends, the Phoenix represents the eternal rewards of humility. According to one Jewish legend, Eve offers the forbidden fruit not only to Adam but to every creature in the Garden—the cattle, the deer, the birds. All of them partake except the Phoenix. Only the Phoenix refuses the sin of pride, and that is why the Phoenix is the one creature on Earth that is still immortal. According to another Jewish legend, the Phoenix is made immortal not in Paradise but later, many years after the Fall, for good behavior on Noah’s Ark. Noah finds the bird sleeping in a corner with its head tucked beneath a wing. “Why didn’t you ask for food?” he cries. The Phoenix says, “I saw you were busy. I didn’t want to bother you.” And Noah blesses the bird. “Since you were so concerned about my troubles when I was feeding the lions, and when I was trying to figure out what to feed the chameleons, may it be God’s will that you never die.” From England to Russia and from Egypt to India and China, people told stories about the Phoenix, which lives a thousand years and then goes up in flames and is reborn to live another thousand, and so on and on forever.

  Each of us is that Phoenix. Each of us is one of a kind, and each of us is burned and consumed and constantly renewed and restored. Cells have never come together in the same way to build a body precisely the same as yours; nerves have never met to build a brain the same as yours; the memories that make you what you are have never formed anywhere on Earth or space, in any human skull but your own; and yet all those cells and tender filaments of nerve on nerve are forever falling apart and rebuilding and repairing themselves during every sleeping and waking moment of your life. It’s almost as if each instant is our last and first. We are always dying, and always reborn. And that is living. Our bodies are not finished products but works in progress, works continually being dismantled and repaired, rebuilt and restored, destroyed and healed at every moment in the act of living. Metabolism is both the building up and the tearing down of the body. Anabolism is the constructive part of metabolism; in the process of anabolism we build all of the molecular machinery that we call a living body. Flex a muscle and you encourage the body to build more muscle fibers at that spot. That’s anabolism, which can be encouraged artificially with anabolic steroids. Catabolism is the destructive part of metabolism, the tearing apart, from the Greek for “throwing down.” This throwing down and tearing apart is as much a part of life as the building up. If the Phoenix of the body never did anything but build, it would lose all shape and form; if it did nothing but tear down, it would soon reduce itself to ashes and dust.

  If we could only perform this supreme balancing act of death and restoration every day as well as we had done it the day before, tomorrow and tomorrow as well as last year and the year before, then we would be practically immortal. But, alas, with each passing year we perform the miraculous act of the Phoenix less and less well, until at last we die.

  The amount of action concealed in that simple word “living” is unimaginable. One single human body is a cooperative of one or two hundred trillion living cells. We have red blood cells that are built to catch oxygen, and white blood cells that are built to catch germs. Rod cells in the eye, built to catch light; hairlike cells in the ear, built to catch sound. Skin cells designed for the palms of our hands, and skin cells designed for the lining of our guts; and stem cells that lie buried in crypts just below each surface, designed to make more of each, each kind of cell patiently replaced, skin for the hands and skin for the guts. Every one of those cells contains thousands upon thousands of working parts: peroxisomes and ribosomes, centrosomes and centrioles, proteasomes and lysosomes, all of them wrapped in membranes within membranes within membranes, and all of them alive. And each of those working parts is made of enormous numbers of molecules, all of them in action like workers at a construction site, day and night.

  To understand what’s going on in aging, you have to be able to go deep—you have to look into the nest of the Phoenix and into the workings of the cells to see what’s going on in there as they build and destroy themselves from moment to moment. That’s part of the reason why the science of aging revived in the last years of the twentieth century. At last, decades after Crick and Watson put together their first scale model of the double helix, biologists had the tools to look inside living things at the finest possible level, the level at which all that machinery actually works.

  To power all of its molecular machinery, for instance, each cell contains anywhere from a few hundred to a few thousand mitochondria. And every one of those mitochondria contains a large collection of rotary motors. With every breath you take, you set off a long series of actions and chemical reactions that make those rotary motors spin around and around in every living cell of your body like zillions of turbines, windmill vanes, or airplane propellers. These rotary motors turn out a concentrated energy food, an energy-rich molecule called adenosine triphosphate, or ATP. And this ATP, more than any other molecule in the cellular inventory, makes all the rest of the machines go. This is the fuel of all our mortal engines. Without ATP it would be useless for us to breathe in air, to drink and eat. Without ATP, even the smallest piece of action in our bodies would slow down and stop.

  Because the mitochondria make ATP, ingredients for this energy food have to be shipped into them. They pass into each mitochondrion through tiny apertures in its membrane. Each of the apertures is equipped with a gate on molecular hinges. The raw materials are shipped in through the gate, and then the ATP is shipped out through the same gate, which swings open and shut day and night. Two Swedish molecular biologists, Susanna Törnroth-Horse-field and Richard Neutze, have spent years studying the mechanics of the hinges of this particular gate. It’s not unusual in biology to be that specialized. The living cell is so complicated that there are specialists at every gate. And Törnroth-Horsefield and Neutze can claim with justice that the precise mechanism of their gates’ action matters more than most. Their gates are to the life of the body as ports are to a nation. Through these tiny points on the map of each cell, vast quantities of supplies must funnel as they make their way to and from the interior. Most of our metabolites—the raw ingredients of metabolism, and the by-products of metabolism—have to pass through those gates. Although a camel cannot pass through the eye of a needle, write Törnroth-Horsefield and Neutze, it is amazing to think that every single day the camel’s weight in metabolites has to tunnel back and forth through a hole that is about a million times smaller in diameter than the camel itself.

  Take a breath. As you draw oxygen into your lungs, your red blood cells carry it, molecule by molecule, to every one of your hundred trillion or two hundred trillion cells; and each of those cells transports it down many paths and lanes and through many hundreds of gates and at last through that Camel’s Gate, and down into the tiny sealed factory of a single mitochondrion. There the mitochondrion uses the oxygen to produce your energy. Strangely enough, these hardworking mitochondria are the descendants of parasites. They began as bacteria. The bacteria invaded cells that were much bigger than they were, about a billion years ago. Either they invaded, or they got swallowed. Then they made themselves at home in those big cells, and never left. We descend from those big cells with the small bacteria inside them. We are like a people of mixed-race ancestry: animal and bacterial mixed inextricably together. Even now, a billion years later, the mitochondria in our cells still carry their own loops of DNA and they speak their own dialect of the genetic code. In a sense, the mitochondria are still strangers in a strange land, just as they were when they first got lost inside the distant ancestors of our cells. Their alien genes give them the necessary gift of using oxygen in the manufacture of ATP. Those alien genes also encode plans for the tiny rotary motors, which motors revolve at h
igh speeds and turn out the high-energy ATP that they export to the rest of the cell, day and night.

  In my first biology class, back in junior high school, I used to try to imagine the oxygen in my breath traveling down into the lungs and the alveoli in the lungs and from there through all the branching capillaries of the arteries until molecules of oxygen reach every single cell. There’s so much more to learn about those pathways now. Now molecular biologists have traced what Francis Bacon called “the secrecies of the passages” in almost infinitely finer detail, down through the membranes of the cell and into the mitochondria. In a way, it is sad how esoteric and arcane all this is, our anatomy at the finest level. John Donne when he lay on his sickbed was told by his doctors that he was sick because of vapors. He couldn’t see those vapors—he had to take them on faith. Maybe he would die because of vapors. “But what have I done, either to breed, or to breathe these vapors?” he asks, pathetically. As far as he knows, he’d never done anything to go toward a vapor or to draw a vapor toward him, “yet must suffer in it, die by it.” The classic lament of the patient whose life depends on doctors’ esoterica. Now our fates as mortals rest collectively on studies of molecules that are as alien to most of us as vapors. Francis Crick once said that a good scientist should be able to explain any laboratory result to a barmaid. That’s true. But there’s so much detail to understand about these molecular machines since Crick and Watson that scientists have trouble even explaining them to each other.

  We see so little of the action. We can feel our lungs expand when we breathe in. We can hear our stomachs growl when we’re hungry. We can feel our hearts beating. And a few other organs make themselves known to us. But each of these organs has organs. Every single cell is a city. And it is often on the scale of the cell that the real give-and-take of mortal life goes on. That is where the business is transacted. That’s where the wheels grind.

  The workmanship of all of these miniature machines is magnificent—but they are not quite perfect. Now and then, instead of getting shunted into the rotary motors and turned into useful ATP, a few oxygen molecules fly off like sparks. Almost instantly those oxygen molecules morph into what are called oxidants, or free radicals. Radicals in chemistry are molecules that can swiftly latch on to others; free radicals are loose and wandering and ready to bond wherever they strike. As they wander through the mitochondrion, oxidants damage its working parts in the same way that oxygen in the air will rust iron nails or bring a patina of green to bronze and copper. And this damage accumulates. Because we rust inside, some of our mitochondrial factories break down and stop. Free radical damage to our DNA can cause cancer. In our joints, it can cause arthritis. In the nerve cells of our brains, it may cause Alzheimer’s.

  So the paradox of mortality is there in every breath we take. We get energy by inhaling oxygen; and we lose energy, breath by breath, day by day, year by year, because of that same oxygen. This is one of the ironies of aging. Oxygen fuels us and oxygen burns us. It is oxygen that makes us go, and it is the very same oxygen that makes us come at last to a stop. Oxygen is double-edged, like the flaming sword that God’s angel brandished at Adam and Eve after their expulsion, the sword that turned each way, “to keep the way of the tree of life.”

  Gerontologists call this the free radical theory of aging. It is a universal theory in that it applies to the deterioration not only of our bodies but the bodies of worms, flies, and every other living thing. The theory was first proposed by a chemist, Denham Harman, in 1956. According to present theory, this is one of the main reasons that our bodies slow and break down with age. Oxidants are perpetually flying out of the molecular works. The machinery they damage most heavily is the gadgetry inside the factory, the mitochondrion itself. So the mitochondria wear out. Their life spans are much shorter than the rest of our bodies. Most of the mitochondria in our cells die and are replaced within less than a month, even the mitochondria inside the cells of the heart, and inside the neurons of the brain, which have to last a human lifetime.

  Sometimes oxidants fly into the DNA of the mitochondria. Then they damage its genes. The DNA of mitochondria suffers a much higher mutation rate than the DNA of the rest of the cell, which is ensconced far away from the factory, behind heavy fortress-like nuclear walls. The outer membranes of the mitochondria also get damaged and corrupted. There is much wear and tear at the camel’s gates, the gates through which all of those oxygen molecules go in and all of the ATP comes out.

  Mitochondria that have been damaged are not allowed to just sit there rusting away in the cell like an abandoned ironworks. Damaged mitochondria are swallowed by machines called autophagosomes, or self-eating bodies, which roam throughout the cell day and night and engulf whatever needs to be disposed of. These autophagosomes swallow so much that they swell like balloons—through the electron microscope their sides look as round and smooth as sausage casings. Then they haul their loads off to the scrap heap: they carry each damaged mitochondrion to some of the cell’s giant disposal centers, the lysosomes. A lysosome can dismantle a whole mitochondrion, tearing it to bits in that humble but vital process of autophagy, self-digestion. Lysosomes cut up the ruined mitochondria to be recycled for spare parts.

  Gradually our mitochondria wear down more and more, and the body has less and less energy. The rotary motors work less well, all of the machinery in the cell works less well, mistake piles on mistake, and finally we die; all because of free radicals flying like sparks through the mitochondria. Gerontologists call this the mitochondrial free radical theory of aging, or the oxidative stress hypothesis. It was proposed in 1977 by Denham Harman, the chemist, as a refinement of his original theory.

  Today most gerontologists agree that this process contributes to our bodies’ decline and fall. Every day, you burn through your body’s weight in ATP. And every day you manufacture your body’s weight in fresh ATP. This is an astonishing statistic. If your body weighs two hundred pounds, you will burn two hundred pounds of ATP today, and you will assemble another two hundred pounds of the stuff to burn tomorrow. A single-celled animal like Tokophrya will do the same thing on about one hundred trillionth the scale. So will a camel, and so will a blue whale. You are constantly and tirelessly tearing apart not only old mitochondria but every bit of the machinery in the body, all of those gates and hinges and windmills and sluices, every one of your gears and shafts and train tracks and repair robots. And you are rebuilding them just as constantly and tirelessly, night and day. And because you are making little mistakes now and then in tearing down and rebuilding the old factories—the mitochondria—the mitochondria are working a little less well at supplying you with energy, and you are beginning to feel a little tired.

  When he began studying aging, informally, in the libraries of Cambridge, Aubrey was fascinated by the invisible internal engineering of the mitochondrion. Thinking about it led him to his first original idea about aging. Very often what wrecks the cell is its failure to recycle its dead or failing mitochondria. Aubrey wondered why those roving disposal systems, the autophagosomes, don’t keep up their jobs and dispose of the rusting factories. Why does the cell start out so good at this recycling project and then get so bad at it? Why this slow decline? (The problem of aging in a nutshell.)

  It occurred to Aubrey that a roving autophagosome would be most likely to single out a mitochondrion for destruction if its outer membrane were damaged. In fact, damage by free radicals was probably the very thing that marked the aging factory for demolition. But what if a mitochondrion had suffered a mutation that prevented it from making ATP? Then its outer walls would no longer be rusting. A cell would not recognize such a mutant mitochondrion as part of its Rust Belt and cart it away for recycling. The mutant factory would look clean and new from the outside, and it would still be busy on the inside, but it would be useless.

  The death of a mitochondrion in a cell might be something like the death of an ant in an anthill. Being an engineer, not a lover of natural history, Aubrey didn’t put it
to himself this way. But the problem is one that would be familiar to an entomologist. If an ant dies, specialized ants that patrol the tunnels will pick up the corpse and dispose of it. They find the corpse by its odor. If a biologist paints that chemical odorant on the back of a living ant with the tip of a camel’s hair brush, then that unfortunate ant’s comrades will pick it up and carry it out and dispose of it, alive and kicking. But if the ants were ever to find an odorless corpse, they would ignore it and crawl right by.

  Inside a living cell, in Aubrey’s hypothesis, the autophagosomes play the part of those disposer ants. If any given mitochondrion accidentally stops the manufacturing process that should have stained it with the telltale mark of age, then that mitochondrion will be undisturbed and unmolested. The power plant really is broken, and it should be scrapped, but it is not scrapped. So that defective mitochondrion multiplies within the cell. Its descendants are also defective but they, too, lack the telltale mark of age. So they make more of themselves, too. Gradually the cell becomes contaminated by all these defective mitochondria, like an anthill filling up with dead and putrefying ants. The cell is sick and oozing with poisons.

  Aubrey laid out this argument, which had many twists and turns, in two technical papers in the late 1990s. It was an interesting but unpleasantly complicated hypothesis. It was ugly, as he himself was the first to admit. If true, it would resolve a few problems with the existing theory, and maybe introduce a few new ones. After publishing these papers, Aubrey wrote a technical book about the whole subject, The Mitochondrial Free Radical Theory of Aging. For this work the University of Cambridge awarded him a Ph.D. in biology in the year 2000. (The university gives Ph.D.s to its graduates if they do suitable work on their own.) Aubrey was now an authority on aging mitochondria.

  Along the way he met new heroes and kindred spirits.