Long For This World_ The Strange Science Of Immortality Part 2

I was sitting there by the cafeteria door, scribbling notes in the back of my book, when an elderly voice called my name. I looked up and saw Maria Rudzinska. Her hair was gray, pulled back in a tight bun, her gla.s.ses thick and mended with tape. Behind the goggle lenses, her eyes looked huge and watery. She stooped. Her cardigan hung loosely from her shoulders, as if she had been wearing it ever since the age when it had fit. Around her neck she wore a medallion so big that I had to force myself not to stare at it, a big bronze sun. She was so stooped and the chain was so long that the sun hung down almost to her belt.

"Look, he is always writing!" she exclaimed, speaking not to me or to anyone standing nearby but to an invisible audience. I recognized that voice and that audience. They both belonged to the Old World, where people loved writers who were always writing, because they themselves were always reading.

Rudzinska led me into the cafeteria. Over lunch she told me her story. During the war, she said, she and her husband, Aleksander Witold Rudzinski, had fought in the Resistance in Warsaw. Aleksander had been wounded. At the same time, working under great difficulties, without supplies, sometimes without much food, she had managed to carry on her research. I've long since lost my notes, but as I remember the story now, she told me that she'd sc.r.a.ped gunk from the side of an aquarium tank in a half-abandoned laboratory and studied what she found through the microscope. It was unusual for a woman to become a scientist in those days; much less while half-starving in the war. But she'd been entranced by the lives of single-celled animals ever since her first scientific paper in Cracow in 1928: "The Influence of Alcohol on the Division Rate in Paramecium caudatum Paramecium caudatum."

Somewhere in the gunk on the wall of the tank she found a rare, single-celled pond creature called Tokophrya Tokophrya, and she fell in love with it. The adult Tokophrya Tokophrya looks like a miniature hydra. It's another stick figure of life. Its body is a stalk. At the base it has a sort of suction cup called a holdfast. At the top it has sixty or seventy tentacles. The tentacles stand out from it in long straight lines like rays around a child's drawing of the sun, waving in the water. If a paramecium swims too close, it gets stuck and impaled. Then looks like a miniature hydra. It's another stick figure of life. Its body is a stalk. At the base it has a sort of suction cup called a holdfast. At the top it has sixty or seventy tentacles. The tentacles stand out from it in long straight lines like rays around a child's drawing of the sun, waving in the water. If a paramecium swims too close, it gets stuck and impaled. Then Tokophrya Tokophrya sucks its victim's innards through the tentacles, as if it were drinking its prey (still alive and struggling) through a dozen straws. sucks its victim's innards through the tentacles, as if it were drinking its prey (still alive and struggling) through a dozen straws.

In all that, it is like the hydra. But the way Tokophrya Tokophrya gives birth is more like us. A tiny bud, a baby, grows in the cell inside a miniature womb called a brood pouch. When the baby is ready to be born, it whirls and struggles in the pouch for ten or twenty minutes, and then bursts out. The parent looks pretty tired. But it recovers quickly and gives birth again in a couple of hours. A healthy gives birth is more like us. A tiny bud, a baby, grows in the cell inside a miniature womb called a brood pouch. When the baby is ready to be born, it whirls and struggles in the pouch for ten or twenty minutes, and then bursts out. The parent looks pretty tired. But it recovers quickly and gives birth again in a couple of hours. A healthy Tokophrya Tokophrya can perform this miracle as many as twelve times in twenty-four hours. Its name means, in Greek, "the well of birth." can perform this miracle as many as twelve times in twenty-four hours. Its name means, in Greek, "the well of birth."

Each newborn Tokophrya Tokophrya swims away. Within a few hours it metamorphoses into a young adult, growing a st.u.r.dy holdfast, with which it grips the floor of the test tube or the petri dish. It stays put in that one spot for the rest of its life, giving birth to more swims away. Within a few hours it metamorphoses into a young adult, growing a st.u.r.dy holdfast, with which it grips the floor of the test tube or the petri dish. It stays put in that one spot for the rest of its life, giving birth to more Tokophrya. Tokophrya.

This vaguely mammalian style of labor and delivery fascinated Rudzinska. When a paramecium or an amoeba is ready to reproduce, it just splits in two. After each of the halves is full-grown, those split also. Biologists thought of cells like that as virtually immortal. There is never a moment when you can say that one has died. It just goes on and on.

By contrast, Tokophrya Tokophrya endures the labor of birth, like us. And day by day, while standing on its holdfast and trawling with its tentacles for food, endures the labor of birth, like us. And day by day, while standing on its holdfast and trawling with its tentacles for food, Tokophrya Tokophrya grows old-just like us. So grows old-just like us. So Tokophrya Tokophrya makes a good subject for a study of mortality, and because of its holdfast, it is a convenient one; unlike the amoeba or the paramecium, or the yeast cells that swirl around in a pint of beer, each makes a good subject for a study of mortality, and because of its holdfast, it is a convenient one; unlike the amoeba or the paramecium, or the yeast cells that swirl around in a pint of beer, each Tokophrya Tokophrya stays put. Each mortal poses for the camera all its life. Through the microscope, Rudzinska could watch a single cell on its ride from birth to old age and death and try to figure out what goes wrong inside the cell. It was as if she had the whole problem of life and death on the head of a pin. stays put. Each mortal poses for the camera all its life. Through the microscope, Rudzinska could watch a single cell on its ride from birth to old age and death and try to figure out what goes wrong inside the cell. It was as if she had the whole problem of life and death on the head of a pin.

When Rudzinska came to New York as an emigre after the war, she worked on other things, including the longevity of the amoeba. She was one of the first biologists to use the new high-powered electron microscope to study the intricate machinery inside cells, those tiny bubbles that keep themselves alive and intact so much longer than a mere bubble of water drifting on a pond. Her microscope back in Poland could make things look one hundred, two hundred, five hundred times larger than life. The electron microscope made them more than fifty thousand times larger than life.

That was useful research, she told me, but as a scientist her heart still belonged to Tokophrya Tokophrya and the way it seemed to diagram the mystery of aging. She was convinced that and the way it seemed to diagram the mystery of aging. She was convinced that Tokophrya Tokophrya would be ideal for the study of length of days. Only a few people in the world were working with would be ideal for the study of length of days. Only a few people in the world were working with Tokophrya Tokophrya. She'd lost her own stocks of the creature as an exile and emigre the stocks that a biologist in Brooklyn shared with her were not ideal for her purposes. She must have told me why, but I've forgotten. What I remember is the tale of her search. She looked everywhere, in ponds, lakes, ditches, and puddles in several states, but she could not find Tokophrya Tokophrya, and she could not quite find her way back into the thrill and romance of scientific research that she had felt in Poland during the war. Eventually she fell sick with a high fever, and spent weeks lying in a bed in Rockefeller's research hospital. She thought, Can this be where my story ends? Can this be where my story ends?

Then, one day in the hospital, while looking out her window, she thought of the fountain pool near her laboratory in Theobald Smith Hall. The pool was not far from York Avenue, but like the rest of the Rockefeller campus it seemed a world apart. It was surrounded by slate walks and marble love seats and ivy-covered sycamores.

From her hospital bed, she asked one of her young laboratory a.s.sistants to go down to the pool and collect some water there. She told her a.s.sistant to take the water and put a drop under the microscope. And there at last, just as she had hoped, was Tokophrya Tokophrya.

That was how Maria Rudzinska recovered her life's work.

After our lunch, she led me to her laboratory. When successful scientists are in the prime of their careers they can command whole floors of prime research s.p.a.ce, as Alex Carrel did in his heyday in Founder's Hall. But when they are old and retired, they have to make room for the next generation, Rudzinska explained, ruefully. She worked in the bas.e.m.e.nt of Theobald Smith Hall. Rockefeller's buildings are linked by a system of underground tunnels, and because it was a cold winter day, she led me from the cafeteria through a few of these twisting tunnels until we came to her small, windowless laboratory. She walked slowly and it took us a while to get there.

In her recent experiment, she'd been a.s.sisted by two younger scientists, although she usually preferred to work and publish alone. She'd invited both of them to be there when I arrived. They were older than I was, but they looked very young when they stood next to her. They each wore an extra-bright, extra-wide smile that was somewhere between the beaming of reverence for the old master and the beaming of indulgence for the ancient.

Rudzinska explained her latest experiment. With the help of her two young collaborators, she'd collected a few more jars of water from the fountain pool. In her laboratory, they had grown-or, in the jargon of cell biologists, they had isolated and cultured-more Tokophrya infusionum Tokophrya infusionum in screw-capped tubes. Through the microscope they could see a field of in screw-capped tubes. Through the microscope they could see a field of Tokophrya Tokophrya waving their tentacles in the water, each one standing on its holdfast. The researchers would search for a single healthy specimen. Using a very fine platinum wire with a tiny loop at the end, like a shepherd's crook, they'd pick out that specimen. They transferred it to a gla.s.s slide that had a little shallow depression, called a well. The well was filled with sterilized water. waving their tentacles in the water, each one standing on its holdfast. The researchers would search for a single healthy specimen. Using a very fine platinum wire with a tiny loop at the end, like a shepherd's crook, they'd pick out that specimen. They transferred it to a gla.s.s slide that had a little shallow depression, called a well. The well was filled with sterilized water.

At the end of each day of the experiment, Rudzinska had inspected the Tokophrya Tokophrya in the well through a microscope. It gave birth again and again. She counted the new arrivals, removed the parent with the shepherd's crook, and put it in a fresh drop of water. On Monday, Tuesday, and Wednesday the cell gave birth all day long. But it was growing older: only one birth on Thursday and one on Friday. None on Sat.u.r.day. in the well through a microscope. It gave birth again and again. She counted the new arrivals, removed the parent with the shepherd's crook, and put it in a fresh drop of water. On Monday, Tuesday, and Wednesday the cell gave birth all day long. But it was growing older: only one birth on Thursday and one on Friday. None on Sat.u.r.day.

The aging cell's tentacles weakened, too. Rudzinska was feeding the cell with Tetrahymena Tetrahymena, which is another protozoan that lives in pond sc.u.m. (Through the microscope, it looks something like a hairy mango.) She made sure her Tokophrya Tokophrya specimen got just enough specimen got just enough Tetrahymena Tetrahymena every day, not too many and not too few, by directing a stream of them with a fine pipette right at the every day, not too many and not too few, by directing a stream of them with a fine pipette right at the Tokophrya Tokophrya. When it had caught enough food, she would remove the Tokophrya Tokophrya, with its prey still in its arms, and transfer it to a fresh well, filled with two drops of sterile pool water.

The healthy cell's cytoplasm was bright and clear. The old cell was dark and shabby, full of dirt and age spots. One of the most famous researchers at Rockefeller, Christian de Duve, had won the n.o.bel Prize in 1974 for his discovery of a key way the cell cleans up its garbage. He spotted a sort of floating garbage disposal inside the cell, which he called the lysosome, from the Greek: literally "splitting body." Lysosomes swallow cellular trash and digest it. That is one of the cell's great secrets of rejuvenation. The process by which the cell consumes itself in the lysosome is known as autophagy, which means, literally, "self-eating." It is as vital to the life of the cell as eating; but in Rudzinska's aging Tokophrya Tokophrya cell, the garbage-disposal system seemed to be failing, too. Everything was failing. When cell, the garbage-disposal system seemed to be failing, too. Everything was failing. When Tetrahymena Tetrahymena brushed against the elderly cell, they just pulled away and swam on. The cell got darker and weaker, and on Sunday it died. brushed against the elderly cell, they just pulled away and swam on. The cell got darker and weaker, and on Sunday it died.

Rudzinska was looking at a relatively simple life through the transparent walls of its body using one of the most powerful microscopes in the world, and she still could not figure out what was going wrong inside it. The cell died and she did not know why. There were so many possible explanations. At about that time a biologist tried to list them all and counted three hundred theories of aging: genetic theories, evolutionary theories, mathematical and physicomathematical models of aging. Which one was right? This is what Rudzinska was trying to understand, quietly and patiently. Where was the fatal damage? Was it in the clear jelly of the cytoplasm or inside the dark coiled ball of the nucleus? And why did it happen? Did it have to happen at all?

In retrospect, I was lucky to have met a gerontologist in 1984. I was just in time to catch a glimpse of the slightly depressive backwater that the field had been for generations. "Research on aging, like its subject matter, does not move very fast," as the British immunologist Peter Medawar put it in 1981, when that science was still in the doldrums. "In almost any other important biological field than that of senescence," wrote Alex Comfort, another British gerontologist, in 1979, "it is possible to present the main theories historically and to show a steady progression from a large number of speculative ideas to one or two highly probable, main hypotheses. In the case of senescence this cannot be profitably done."

Comfort was a familiar name to me. Yes, Rudzinska said, Alex Comfort was not only a gerontologist; he was also the author of the worldwide bestseller The Joy of s.e.x The Joy of s.e.x.

"We were so angry with him for writing that," she added.

Such a hard and unappetizing problem, aging. The aging of a living thing is not like the aging of a fine cheese or a fine wine. There the chemistry alters, the molecules change around, and the cheese and wine improve. Nor is aging like the deterioration of a car or a can-opener or any other manmade machine. When gadgets break down they can't fix themselves, and neither can they make more of themselves-whereas a living body, even a microscopic bubble of life like Tokophrya Tokophrya, can accomplish both those miracles as long as it lives. Even when Tokophrya Tokophrya is ancient, too frail to reproduce, it is still repairing and remaking its own working parts, which is also a kind of reproduction, in a sense; the cell performs the hard work of pa.s.sing its own body along from one moment to the next, creative work that never stops till death. is ancient, too frail to reproduce, it is still repairing and remaking its own working parts, which is also a kind of reproduction, in a sense; the cell performs the hard work of pa.s.sing its own body along from one moment to the next, creative work that never stops till death.

So what is aging? Why does the cell stop repairing itself? This is the question that Bacon was asking at the start of the scientific adventure. He knew nothing about single cells but he understood this question. Again, we are so very good at growing and staying in shape when we are young. The mortal body of that single coddled Tokophrya Tokophrya would have a chance to last and last if it could only keep up the repairs on Friday the way it did on Monday, when it was young. would have a chance to last and last if it could only keep up the repairs on Friday the way it did on Monday, when it was young.

Through the microscope, Rudzinska could see so many signs of trouble. Tokophrya Tokophrya wears a few coats, or membranes, one on top of the other. Its outermost membrane, called the pellicle, is made of two separate layers that are linked by fine mortise-and-tenon joints. Those joints were popping loose, and the layers were separating. The cell was literally coming apart at the seams. wears a few coats, or membranes, one on top of the other. Its outermost membrane, called the pellicle, is made of two separate layers that are linked by fine mortise-and-tenon joints. Those joints were popping loose, and the layers were separating. The cell was literally coming apart at the seams.

Of the many studies of aging that she had on her mind in 1984, the most interesting was already fifty years old. In 1934, a biologist at Cornell University named Clive McCay had reported a remarkable breakthrough with laboratory rats. McCay found that if he fed the rats all the nutrients they needed but cut their daily allowance of calories in half, the rats would live about twice as long. Since that time, McCay's discovery had survived test after test. Back when I visited Rudzinska, experimenters were still raising thousands of rats and mice on calorie-restriction diets. The rats and mice got thin and scrawny, but they did live a long time. n.o.body knew why.

So Rudzinska investigated the clue of caloric restriction with her Tokophrya Tokophrya. Was there something about the reduction of calories that slowed down the metabolic rates of the cells of those mice? Did slowing down their metabolisms make them live longer? She found that when she kept the cells chilly and half-starved, they did live longer.

Rudzinska tried that experiment again and again. She put a single Tokophrya Tokophrya in a hanging drop of water on the gla.s.s lid of a chamber. Then she fed it, say, three in a hanging drop of water on the gla.s.s lid of a chamber. Then she fed it, say, three Tetrahymena Tetrahymena. The next day when she checked on it, it was still healthy and it had produced about that same number of babies. But if she gave a Tokophrya Tokophrya forty forty Tetrahymena Tetrahymena, it would produce only one baby. If she gave it a hundred Tetrahymena Tetrahymena, swamped it with fish food, the Tokophrya Tokophrya just ate and ate, gorged without stopping. It ballooned out into a giant-dark, opaque, with short, stunted tentacles. It stopped giving birth. It lost its tentacles. And after a few hours, the cell fell apart-cut short in its prime. On the other hand, if she kept a just ate and ate, gorged without stopping. It ballooned out into a giant-dark, opaque, with short, stunted tentacles. It stopped giving birth. It lost its tentacles. And after a few hours, the cell fell apart-cut short in its prime. On the other hand, if she kept a Tokophrya Tokophrya on a restricted diet, half-starved for on a restricted diet, half-starved for Tetrahymena Tetrahymena, fed them only one day every two weeks, her Tokophrya Tokophrya would live about twice as long. would live about twice as long.

So calorie restriction worked for species as far apart on the tree of life as mice and Tokophrya Tokophrya, which seemed to argue that it might also work for us.

Rereading her papers now, I can see that for all her pains she was a bit isolated, cut off from the news. Most of the names she cites in her papers were already half-forgotten then, biologists who had studied aging in the paramecium and in the amoeba when she was a young scientist in Poland. All around her, biologists at Rockefeller were helping to establish molecular reality; but she did not work with genes and molecules. What you can see inside a cell at 500 or even 100,000 times life size is still coa.r.s.e compared to what you can see if you get down to the molecular level. The brave new world of molecules was pa.s.sing her by. And of course she could not begin to explain why multicellular animals like us age, and why unicellular animals seem to escape from aging, or why some multicellular animals do not seem to age at all, like the hydra; while some unicellular animals do age, like Tokophrya Tokophrya, even though these two creatures have such a strong family resemblance in body plan and lifestyle that each is like a crude sketch of the other. This kind of confusion is discouraging to scientists, to people who like to figure things out.

Down in the bas.e.m.e.nt of Theobald Smith Hall, Rudzinska and her two young a.s.sistants had set up a little demonstration for me. I looked through a microscope on the laboratory bench and saw a whole field of Tokophrya Tokophrya standing close together, swaying gently on their holdfasts like a field of alien corn. I turned the k.n.o.b of the microscope slowly and surveyed the field. There were hundreds and hundreds of cells. It was something to see them, after hearing so much about them, and I looked up to thank the old biologist. Then I put my eye back to the lens. Just when I was about to take my eye away for the last time, I spotted a cell that was shaking back and forth on its holdfast. There was a baby trembling inside it. After a moment, the baby popped out and swam away. standing close together, swaying gently on their holdfasts like a field of alien corn. I turned the k.n.o.b of the microscope slowly and surveyed the field. There were hundreds and hundreds of cells. It was something to see them, after hearing so much about them, and I looked up to thank the old biologist. Then I put my eye back to the lens. Just when I was about to take my eye away for the last time, I spotted a cell that was shaking back and forth on its holdfast. There was a baby trembling inside it. After a moment, the baby popped out and swam away.

I left the bas.e.m.e.nt laboratory and swung out of Theobald Smith Hall into the pale winter day. Before I walked down the main path to the stone gate on York Avenue, I made a detour through the campus and found Rudzinska's fountain. It had been drained for the winter. A few wet dark leaves from the ivy and the sycamores, the last of the wreckage of the year before, lay plastered to the concrete basin like tea leaves in the bottom of a cup. Somewhere in there, Tokophrya Tokophrya lay dormant and encysted, waiting out the winter. lay dormant and encysted, waiting out the winter.

At the time, I found it romantic that science could not answer these elemental and universal questions, questions that must have struck every thoughtful mortal again and again from more or less the beginning of their lives and from more or less the beginning of time. How did we come to be mortal? Do we have to be mortal? What can the science of life do about our mortality? What is is aging? The image of that microscopic birth in the laboratory still floated before my eyes. I felt as if I had just been granted a glimpse into the fundamentals of birth and death-as if I'd seen as much as anybody could see, looked down to the bottom of the well. No one understood the problem of mortality. aging? The image of that microscopic birth in the laboratory still floated before my eyes. I felt as if I had just been granted a glimpse into the fundamentals of birth and death-as if I'd seen as much as anybody could see, looked down to the bottom of the well. No one understood the problem of mortality.

It was clear that Maria Rudzinska loved her work. She loved the questions. She used to sign her letters Doctor Tokophrya Doctor Tokophrya. But it was also clear to me that she would not be the one to find the answers. And I found that beautiful. I loved the mystery-or else I'd persuaded myself to love it. Everyone knows that we have to grow old and die, just as surely as everyone hopes for long life. If you drink your cup to the bottom, you reach dregs. If you blunder, if you mess up, if you fumble as you reach for the cup, it spills and it shatters. That is our portion on this planet. The lines of an inscription in Osmington Church, Dorset, carved in 1609, take the shape of the cup:

Man is a Glas: Life is a water that's weakly walled about: sinne bring es death: death breakes the Gla.s.s: so runnes the water out finis.

Finis! End of all mortal explanations-whether you think of the problem as spiritual or physical, sacred or secular. We are gla.s.s, and we break. We are water, and we spill. We are dust, and to dust we shall return.

That was the problem of mortality as I'd grown up with it. That was the problem of aging with which my generation came of age. Rockets might take us to Mars someday, or out beyond the asteroid belt, but wherever we baby boomers went we would go on bearing the same mortal weight. Rockets might take us to the stars, but only myths could take us to Mount Olympus. We were mortals-and yet the Eagle Eagle had landed on the Moon. had landed on the Moon.

So we believed in limits, and we didn't-just like the readers of Mandeville's travels when he described a wonderful bird the size of an eagle in the Egyptian city of Heliopolis, the City of the Sun. The bird is called the Phoenix. "And he hath a crest of feathers upon his head more great than the peac.o.c.k hath," and his neck is iridescent like "a stone well s.h.i.+ning." And the Phoenix lives forever.

Chapter 4.

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 G.o.d'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 s.p.a.ce, 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 Metabolism is both the building up and the tearing down of the body. is both the building up and the tearing down of the body. Anabolism 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. 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 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. 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 pa.s.sing 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 s.h.i.+pped into them. They pa.s.s 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 s.h.i.+pped in through the gate, and then the ATP is s.h.i.+pped out through the same gate, which swings open and shut day and night. Two Swedish molecular biologists, Susanna Tornroth-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 Tornroth-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 quant.i.ties 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 pa.s.s through those gates. Although a camel cannot pa.s.s through the eye of a needle, write Tornroth-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 high speeds and turn out the high-energy ATP that they export to the rest of the cell, day and night.

In my first biology cla.s.s, 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 pa.s.sages" 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 cla.s.sic 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 workmans.h.i.+p 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 acc.u.mulates. 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 G.o.d'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 sc.r.a.p 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 astonis.h.i.+ng statistic. If your body weighs two hundred pounds, you will burn two hundred pounds of ATP today, and you will a.s.semble another two hundred pounds of the stuff to burn tomorrow. A single-celled animal like Tokophrya 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. 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 nutsh.e.l.l.) 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 sc.r.a.pped, but it is not sc.r.a.pped. 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 publis.h.i.+ng these papers, Aubrey wrote a technical book about the whole subject, The Mitochondrial Free Radical Theory of Aging 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.

One of them was Denham Harman, born in 1916 and still at work when Aubrey entered the field of gerontology toward the end of the century. (Harman is still going strong as I write, in the fall of 2009, at the age of ninety-three.) For decades, Harman had been trying to persuade more scientists to explore the causes of aging. In 1970 he founded a new a.s.sociation, the American Aging a.s.sociation, which goes by the acronym AGE. It is a society of scientists who focus on the study of aging and its cure, and publish the peer-reviewed journal Age Age. Aubrey felt stirred and inspired when he listened to Harman, or to Richard Miller, another leader of the field, who opened one international gerontological conference with the simple words, "Aging is bad for you." Optimists like Harman and Miller surveyed the spectacle of the body's almost endless self-consumption and renewal and felt hopeful. Aubrey read Harman's studies of the potential of antioxidants: natural or artificial compounds that can soak up the free radicals in the body and prevent their doing so much damage. He read Miller's studies of calorie restriction. Somehow the two were clearly connected. If we eat less we burn less; the metabolic fires slow down and there are fewer free radicals shooting around in the cells like sparks.

After all, we are looking at a body that is constantly and creatively and minutely maintaining itself as long as the body is alive. Even our skeletons are alive. Every one of our 206 bones is constantly being torn down, restored and remodeled like every other part of our living machinery. Cells called osteoclasts carve away the old bone, and cells called osteoblasts build up the new. As at most construction sites, the demolition goes faster than the rebuilding. Three weeks per site for demolition; three months for reconstruction. Even in our bones, a careful balance of creation and destruction, day and night. Too much destruction and we develop diseases like periodont.i.tis, rheumatoid arthritis, osteoporosis. Too much creation and we suffer, too, as in the rare condition osteopetrosis, literally bones of stone, in which the osteoclasts fail to do their jobs and the osteoblasts make the skeleton increasingly dense, heavy, and brittle; or another rare condition, fibrodysplasia ossificans progressiva, in which even muscles, tendons, and ligaments turn to bone.

Our very skeletons are full of youth, and fight all the way down to the dust. Like the Phoenix, we destroy ourselves and restore ourselves-burn ourselves down and build ourselves up-not every thousand years but daily and hourly-all the way down to the bone. Life seen this close up looks like a kind of bonfire, like the flames of the Phoenix when it self-immolates in its nest. But the Phoenix of legend is immortal and we are not. Why did life evolve this way, so that the miracle of the resurrection succeeds brilliantly in our youth and then fails? Why not perfect renewal of the body forever?

Life is a kind of sacrifice, a sacrifice we have made from the beginning, and make every day of our lives. Each mortal body is a story of sacrifice and renewal that slowly fails. It is a very old story for which we all, at least at one time or other, would love to change the ending.

PART II.

THE HYDRA.

They are ill discoverers that think there is no land, when they can see nothing but sea.

-FRANCIS BACON, THE ADVANCEMENT OF LEARNING.

Chapter 5.

THE EVOLUTION OF AGING.

Not long ago I was talking about the problem of mortality with a physicist and he told me, with a smile, that it's in the nature of everything to fall apart. That is what the law of entropy tells us about inanimate objects like planes, trains, and automobiles. That's also what common sense tells us about animate objects like our own warm, breathing bodies. But we don't fall apart between the years of, say, six and twelve. We grow bigger and stronger in those years. If we can do that much when we are growing, then why can't we at least hold steady, hold our ground, from the ages of twenty to a hundred and twenty? We don't, but that doesn't mean our failure to do so is mandated by the laws of physics. If that's breaking the laws of physics and common sense, then we've already broken them. Every human body breaks those laws in the womb from the moment sperm meets egg. Those two microscopic cells meet in the dark and nine months later, after a miraculous construction project, a baby is born with a body made of trillions upon trillions of cells, from the brain cells inside the still-soft skull to the skin cells in the ten fingers and ten toes. And the history of the development of life on Earth is at least as spectacular as the development of each life in the womb. Life on Earth, from small beginnings, has attained extraordinary profusion. Three billion years ago, life was all microscopic single cells. And now there are millions of species of living things, from shrimp to whales, from mites to elephants. The development of life on Earth is like the development of a life in the womb: it defies common sense, and the intuitions of physicists, like a ball that rolls uphill.

If life can do so much in the first half, why does it fail in the second? Why can't it keep the ball rolling? Bacon makes this point in the first pages of his History of Life and Death History of Life and Death. He chastises the physicians and philosophers of his time for missing it. Conventional wisdom in Bacon's day held that there is something in the body that can't be repaired, some "radical moisture" that can never be replenished. Our bodies lose that moisture and dry out and that's why we get old. But that idea is "both ignorant and vain," Bacon writes; "for all things in living creatures are in their youth repaired entirely; nay, they are for a time increased in quant.i.ty, bettered in quality." So much so that "the matter of reparation might be eternal, if the manner of reparation did not fail."

We grow up, and then we seem to hold steady for years. A woman between the end of p.u.b.erty and the onset of menopause balances the building up and the tearing down of her bones so perfectly that they grow neither too heavy nor too light. Her whole body-flesh, blood, bone, and sinew-is a kind of fountain in which the new continually replaces the old and the form stands as if it would stand forever. Then, after menopause, the balance fails, and bone ma.s.s declines, and osteoporosis sets in. But why does the balance have to fail? Why did this failure evolve? Which is to ask the most fundamental question of the science of mortality: How did old age and death come into the world?

The answer that has now emerged in the science of mortality gives hope to the field's optimists.