And of course the body has other kinds of work to do besides maintenance. The body invests enormous time and energy into building gonads and attracting a mate to pass on those gametes. And then we put much of our life’s energy into feeding and raising the young and helping them grow until they are big enough to go off on their own and maintain themselves.
According to present thinking, it behooves the body to strike the right balance between investing in its own maintenance and in the creation of new young bodies to go out into the world and multiply when it is gone. Because mice rarely live more than a year in the wild but human beings could live for twenty years or more in the wild it made evolutionary sense for the tissues of the two mammals to invest differently. Lymphocytes in the lymph nodes slowly accumulate mutations, for instance, because DNA repair isn’t perfect not in mice or men. In the course of the life spans of both mice and men, these mutations accumulate about tenfold. But they do so in the space of about three years in a mouse, and eighty years in a man. Apparently the mouse doesn’t put as much energy into keeping itself up. The mouse lets itself go, as we say, because it is bound to go soon anyway. It makes babies and disappears.
So exactly what would it take to make the human body do even better than eighty years? What would it take to make the human animal immortal? We’d have to be able to regenerate every single one of our working parts, like the hydra, says Holliday. We’d need to be able to rebuild the heart and the blood vessels—without ever shutting it down for repairs. We’d have to repair, regenerate, and rebuild the brain—without losing the memories that make us what we are. We haven’t done that because at no stage in human evolution was it ever better and more profitable for a human body to invest its resources that way than to build quickly and pass on its genes.
What we have done instead is to adjust—and fine-tune, generation after generation—the life span of each of our working parts so that they all tend to age at about the same rate. That’s why we can look around us and guess the ages of the people around us, according to the disposable soma theory. Our bodies have invested just enough to maintain most of our working parts for the same period, so that they decline and fall at about the same time.
Holliday is one of many gerontologists who believe this theory solves the problem that Medawar first posed more than half a century ago. To Holliday it means that we are never going to be able to live much longer than we do now, because there are too many different kinds of things that go wrong with us that we will never be able to fix them all. So aging is irreversible. Antiaging medicine is a crock. At the end of his review, Holliday quotes Ronald Klatz, who writes in his book Advances in Anti-Aging Medicine, “Within the next fifty years or so, assuming an individual can avoid becoming the victim of major trauma or homicide, it is entirely possible that he or she will be able to live virtually forever.”
Holliday concludes, with the gloomy air of QED, “This is biological nonsense.”
In essence, in the view of the disposable soma, you could say that we come up against a modern form of the legend of the Hydra. Killing the Hydra was one of the twelve labors of Hercules. The monster had nine heads, and she helped guard the way to the Underworld. Hercules couldn’t kill her by cutting off her heads with his sword, or his scythe, because each time he lopped off one head, two grew back. He had to lop off every one and cauterize each stump with a torch. Even then he wasn’t done, because one of her heads was immortal. He had to bury that hideous head under a rock. And even then, long after he had slain the Hydra, venom from the monster’s blood poisoned Hercules, and took the great hero down, wrapped in an intolerable cloak of pain. It was the Hydra that killed him in the end.
Aging is many-headed, like the Hydra. If you are a pessimist, or perhaps a realist, you conclude that you can never kill it. If you are other-minded, you begin to plan your attack.
The disposable soma theory makes some specific predictions. It predicts, first of all, that aging is caused by the accumulated damage of mistakes in building and repairing the body. The mistakes begin even as the construction begins. We are declining in a sense from the moment we are born. Even from before we are born. From the first moments of the union of the sperm and the egg, we are making mistakes in the hurry to get the building up and get around to the union of more eggs and sperm. As Aristotle said, the smallest error in the laying of foundations can someday bring down a house.
Not long ago I went to visit Janet Sparrow, a medical researcher at Columbia University. She is the Anthony Donn Professor of Ophthalmic Science in the Department of Ophthalmology, with a joint appointment in the Department of Pathology and Cell Biology. In her laboratory, Sparrow is trying to find ways to prevent one of the common vision problems of old age, macular degeneration. It is a simple case of the simplest aging problem, the problem of clearing away debris as we get older.
Macular degeneration is a medical condition that usually begins to develop around the age of fifty. It’s a disease of the retina, which is one of those minutely engineered places in the body where you do not want debris to build up. The retina sends the messages to the brain that translate into vision. Our eyesight depends on the health of our retinas, which are extremely thin films of nerve cells at the back of each eyeball.
When a ray of light falls on the rod cells and cone cells in the retina, a certain chemical inside those cells, a chemical derived from vitamin A, has to switch very quickly from one chemical shape to another. The chemical has one shape in the dark and one shape in the light. This switching from the dark form to the light form triggers events that tickle the optical nerve, which sends a message to the brain that a ray of light has arrived. Your whole life, whenever your eyes are open, innumerable molecules of this compound are switching from the dark form (which is known as 11-cis-retinal) to the light form (all-trans-retinal), and back again.
Unfortunately, as it flashes back and forth between its two forms, which is a complicated procedure, one of these molecules sometimes brushes up against one of the molecules around it, and every once in a while the two of them get stuck together. No man is an island, no organ is an island, and no molecule is an island. All of our working parts are working next to hundreds of other working parts. If the wrong molecules happen to brush against each other and stick together, they can begin to clump. In the retina, this molecular accident often ends up as a clump of useless trash, a clunker of a molecule called A2E. The rod and cone cells try to clear away this trash by sweeping it into the lysosomes of cells nearby. But the lysosomes can’t break it down. So the A2E sits there inside the lysosomes. After seventy or eighty years of this kind of slow failure, the cells in vital parts of some human retinas are often as much as 20 percent junk: that is, 20 percent A2E by volume. They are almost as bad as cameras that are one-fifth full of dust. This is one of the common problems of old age.
A2E is an ugly and pervasive kind of biological trash called lipofuscin. It’s an age pigment. You really don’t want lipofuscin in your retinas. When light strikes lipofuscin, it glows, and it goes on glowing for a while even in the dark.
On my visit to Sparrow’s lab, I asked her if I could see some lipofuscin. “I’ll get a vial and I’ll come right back,” she said.
The little glass vial she handed me was full of brown muck. She explained that since I was over fifty, my own retinas already contained quite a lot of it. The stuff looked like the kind of crud you get on steel wool when you scour a frying pan.
Meanwhile, of course, all kinds of other material changes are taking place in our eyes as we get older, Sparrow told me. “Have you begun to notice trouble differentiating navy blue and black socks?” she asked.
“Yes, as a matter of fact.”
That’s a completely different material deterioration, Sparrow said. The lenses of our eyes turn yellow with age. The yellowing is caused by the chemical changes in the lens, and diminishes our ability to see the color blue, because yellow filters out blue light. So as we get older, we see blue less brightly. Often
, people who undergo cataract surgery to have a cloudy, yellowed lens removed and replaced by a clear new artificial lens can suddenly see all the blue light they experienced sixty or seventy years before. “Patients say, ‘Oh, blues are so bright. The sky is so blue! I haven’t seen that blue since I was a child!’”
The yellowing of the lens has nothing to do with lipofuscin. Neither does still another kind of junk, called drusen, which eye doctors can see glittering in the back of an aging eyeball through an ophthalmoscope. Drusen looks through the scope like tiny, shiny crystalline dots, whitish and yellowish. The term comes from the German word for a geode: drusen resembles the cup of semiprecious crystals you find when you split open a geode. Eye specialists have known about drusen for more than a century without being able to figure out where the crystals come from or whether they’re early-warning signs of macular degeneration. Drusen crystals also start showing up around the age of fifty.
That’s the way it is throughout the body. You get rare, semiprecious, specialized kinds of junk like drusen crystals in the eyeball, or crystals of calcium oxalate in the kidneys, which are called kidney stones. Other kinds of junk are found throughout aging bodies and can turn up almost anywhere, like lost sheets of newspaper, cigarette butts in gutters, plastic bags in trees, crumpled tissues in wastebaskets. Lipofuscin piles up in cells in many parts of the aging body, but seems to accumulate most in cells that do not divide. Skin cells and the cells that line our guts are always dividing and being sloughed off. Not much trash builds up in them before they die and are replaced. But heart cells and nerve cells have to last us our whole lives. About 10 percent of the mass of the heart of a centenarian is lipofuscin.
After making his study of aging mitochondria, Aubrey de Grey was fascinated by this problem of the accumulation of junk, rust, and scrap in the body. If that’s all aging really is, the slow accumulation of damage, then it’s reasonable to argue that there are three ways to fix it. You can try to repair our metabolism so that it does not generate so much trash; you can try to clean up the trash itself; or you can try to deal with the harm the trash does to the body. That’s when the problem passes into the domain of surgeons and geriatricians and home health aides. They help elderly patients with their weakening muscles, weakening eyes, cloudy lenses, stiffening joints, wrinkling skin, thinning hair, rusting memories, and on and on, the whole lugubrious list of symptoms that we all know from the inside out, and have always assumed that every generation that follows ours will have to endure as we do.
Aubrey decided that the easiest place to attack the problem is in the middle, in the cleaning up of the trash. The beginnings are too complicated. Metabolism consists of too many interconnected networks for anyone to safely intervene. It’s almost beyond imagination how complicated and delicate the action is in the retina when light strikes. And when you eat a piece of food, and some of those nutrients reach a cell in your skin, all of the networks of genes in your cell that have to work together to turn that bit of nutrient into a bit of you are unimaginably complicated, too. In the immortal verse of Walter de la Mare,
It’s a very odd thing—
As odd as odd can be—
That whatever Miss T. eats
Turns into Miss T.
Metabolism is a terribly complicated thing as well as odd, and to try to intervene in all of those invisible molecular pathways would make trouble for Miss T.
The pathologies of old age are also complicated, and—as anyone knows who is in the middle of them, or has watched a loved one endure them—they are interconnected. If macular degeneration is allowed to progress untreated it causes incurable blindness. In the Western world, it is now the most common cause of incurable blindness. Before you reach fifty, it’s rare, but by the time you pass eighty, the incidence is one in ten. Once Miss T.’s retinas are damaged, she is more likely to fall; once her bones have grown frail because of osteoporosis, she is more likely to break her pelvis when she falls. She is often dizzy anyway, and she has lost some of the redundant systems of nerves that used to help her keep her balance. Meanwhile, because of the osteoporosis, the vertebrae in her lower back are painfully compressed. When she breaks her pelvis, her surgeon finds it hard to operate on the vertebrae; and on and on. Meanwhile more damage keeps piling up.
But the dirt itself, the little piles of dust and lipofuscin and miscellaneous debris that accumulate in the corners and crannies of the cells, and cause the damage—that is comparatively simple to deal with, in Aubrey’s view. Cleaning it up may be hard, of course. But it should be easier to clean up the dirt than to overhaul the entire industrial landscape of the body, which produces the pollution; or to repair the body as it falls apart at last and Miss T. breaks down and dies.
Aubrey began seeking out researchers who study the pollution and ways to clean it up. On trips to Boston, Aubrey visited Ana Maria Cuervo, who was then in training at Tufts University and now runs a gerontology laboratory at the Albert Einstein College of Medicine, in the Bronx.
Cuervo studies the action of lysosomes throughout the body. The lysosome is the organ of self-sacrifice, within the cell. With its lysosomes the body does unto itself what it does unto others. Chomp, chomp, chomp. Producing nutrients to digest and recycle, along with a kind of microscopic excrement, indigestible trash.
Cuervo has done as much as anyone to show that the body gets weaker and weaker at taking out garbage as we get older. She has been working on garbage and lysosomes ever since she started out working toward a Ph.D. in the early 1990s. The lysosomes have fascinated her all her working life. (“Such a little fellow, and so much to offer.”) Cuervo wants to understand the ways the body carries out its continuous acts of self-immolation, in which not only old mitochondria are carted off to be scrapped but virtually every bit of the cell is perpetually dismantled and recycled for spare parts and reassembled.
Ana Maria Cuervo and Aubrey de Grey are friends—an odd pair of friends. He lives on beer and she lives on Diet Coke. She keeps a shelf of Diet Coke cans from all over the world above her desk and she’s always pouring another plastic cup of Diet Coke for herself and her guests. She is one of the few people I’ve ever met who talks faster than Aubrey. She agrees with him that the key to the problem of aging may well lie in a kind of sophisticated detoxification of our cells. She’s an experimentalist who hopes we can make cells live a long, long time by giving them extra genes for taking out the garbage. She writes papers with titles like “Keeping That Old Broom Working” and “The Ultimate Cleansing Diet.” In their campaign to figure out how to detoxify the body, to take out the garbage, she and Aubrey are comrades in arms. But when he talks about immortality, she just laughs. Immortality has absolutely no appeal for her. English is not her first language (she comes from Barcelona) and for some reason she always calls him Audrey.
“Audrey,” she says, “if I have to be here five thousand years, take me now!”
In her laboratory, Cuervo is trying to understand the molecular action in the cell’s chop shop. The lysosome is constantly devouring the rest of the cell and cutting it up into recyclable pieces and exporting those pieces to be reassembled in its daily acts of renewal.
Until recently, few people were interested in aging lysosomes. Aubrey was ahead of the curve in focusing on them and befriending Cuervo. She and her handful of fellow researchers worked in obscurity. Science has fashions, and elderly lysosomes were unfashionable. The genes that control the pathways by which the cell sweeps and carts bits of itself into the lysosome are known as “housekeeping” genes, and almost nobody was excited about housekeeping genes. Two biologists at the NIH, Shiwei Song and Toren Finkel, began a paper on housekeeping genes with a complaint about their low status. “In most schools, students tend to stratify into groups like the cool kids and the nerds,” Song and Finkel wrote. In the genome, too, some genes seem to get all the attention, and “life is a lot less glamorous for everybody else.” At the bottom of the “uncool” list were housekeeping genes.
If l
ysosomes were called the nest of the Phoenix, instead of the trash can, they might have more glamour. Of course, the whole field of gerontology suffers from the same image problem. It is seen as the science of aging, and most scientists in their prime find the thought of aging as unattractive as the thought of housekeeping.
But housekeeping is an inadequate description of the magical act of self-renewal on which life depends day by day; and aging is an inadequate description of the mysterious way in which this act of renewal slips and declines, very gradually, day by day. And this is not a corner of our existence; this is what we are. When we talk about eating, and taking out the trash, we are talking about fantastically complicated acts of creation and destruction. We are talking about the ways our bodies, some of the most complicated things in the known universe, destroy and rebuild themselves daily and hourly.
Humble housekeeping genes help cells divide and develop. They help cells fight off invading bacteria and viruses; they help the immune system. When something goes wrong with all this housekeeping we can develop cancer; or neurodegenerative diseases like Alzheimer’s and Parkinson’s. One of the secrets of success, we say, is just showing up; and one of the secrets of staying alive is just housekeeping.
Cuervo set out to learn if the decline in housekeeping is a major cause, or even the major cause, of aging. Clearly the decline makes the cell less efficient, which means that the cell produces more trash and cleans up less. If this failure of housekeeping leads to our mortality, then in effect we die from a pileup of junk.
The level of fine detail with which Cuervo and others can watch all this mortal housekeeping is amazing. Maria Rudzinska could only stare at a cell with a microscope as it grew old and filled with strange dark particles and died. She could no more see molecules than a tourist at the top of a skyscraper can see pebbles. Now Cuervo has the benefit of the half a century of tools that have been invented since Watson and Crick opened up the exploration of molecular reality. The tools with which Cuervo’s generation watches the action include not only light microscopes and electron microscopes but also special stains that make the working parts of molecular machines light up and glow in living cells as if they were followed by Broadway spotlights; along with all kinds of tricks that she and others have developed, including centrifugation of cell corpses through dense cushions, and the use of fluorescent dyes that stain certain streams of the autophagic traffic red and blue. Tricks of genetic dissection and X-ray crystallography allow them to open up molecular machines and count the teeth on each gear.
Long for This World Page 11