One of the pleasing prospects that's ballyhooed as a future benefit of the Human Genome Project is increasing human longevity. The trouble with longevity is that if you go waltzing far enough down the path of long life you might find that you have merged with the highway of immortality without stopping at the weigh station of wisdom. Is that a perfectly good thing?
Can longevity extension go past combating diseases and address the very process of aging itself? If not, longevity will be less attractive. If, on the other hand, we can stay forever young, we may never want to leave the party. Should all of us be allowed to hang around as long as we want? Even creeps?
Research that may bear on the practical end of these matters is proceeding with startling speed.
Dr. Francis Collins, director of the National Human Genome Research Institute at the NIH, told the Washington Post that within 30 years we'll know all the genes involved in the human aging process.
He cited an experiment in which manipulating one gene in a mouse extended the mouse life span by 30 percent. "Without manipulation, it seems that the maximum human life span is about 100 years. It is possible that could be extended if we understand the pathways of aging better," he said. He added that there are many ethical questions "that would have to be addressed before applying this on a broad scale." (I know people who already wish to sign up for the narrow scale.)
The elderly mice in question are Italian, and were engineered to be deficient in p66shc, a protein that tells a cell to self-destruct when it has sustained too much damage from free radicals (molecules produced throughout the body in the process of oxygen metabolism). This is thought to be a defense against the possibility that the damaged cells will become cancerous. But without p66shc, the mice live 30 percent longer. (Being mice, whose lives are brief, this means a few extra months of mousy joys.)
Dr. Huber Warner, director of the biology of aging program at the National Institute on Aging (NIA) is also optimistic about the Human Genome Project and the outlook for living longer. "The fruit-fly genome has just been sequenced. Now, if you look at genes known to be involved in diseases, two-thirds of those genes are found in the fruit fly, including some very important genes that are tumor-suppressor genes."
NIA is investing millions in research to find genes in animals like fruit flies or mice "which when mutated or expressed differently will alter the life span of those species," says Warner. "Now if you can identify those genes in model organisms, then the sequence of the human genome will give you the information you need to begin to extrapolate. We will figure out ways to manipulate the genes in the model organism and it'll suggest how those genes can be manipulated in humans."
Organizations like the NIA and the American Federation for Aging Research emphasize that they are not interested in increasing life span so much as increasing "health span," the years people can live with vitality, dignity and comfort.
Another avenue age scientists are racing down is telomere research. Telomeres are tasteful strands of nonsense DNA that decorate ends of chromosomes. Each time a cell divides, a bit of the telomere is clipped off. Eventually, when the telomere is a mere buzz-cut stubble, the cell stops dividing. There's a way around telomere loss: an enzyme called telomerase, which adds on extra telomere each time it's snipped shorter, so that it stays the same length, and the cell is not signaled to stop dividing. Scientific American has said telomerase "may well be the elixir of youth."
Some human tissues that divide indefinitely, such as reproductive cells producing sperm and eggs, contain telomerase. So do cells in embryos, but the telomerase gene is inactivated in most cells after birth.
Reactivating telomerase could replenish lost cells. Warner mentions the possibility of restoring epithelial cells in the retinas to restore lost eyesight. Telomerase genes have been successfully reactivated in retinal epithelial cells grown in tissue culture, in work done at the University of Texas Southwestern Medical Center and the Geron Corporation. Geron has filed for patents on hTRT, the telomerase reverse transcriptase protein. Warner notes, "The problem with turning telomerase back on is that's one of the things that happens in cancer." Cancer cells are all about telomerase and unrestricted cell division.
Steven Austad is a zoologist who studies aging. In his lucid, engaging book "Why We Age," he describes his study of opossums on a Georgia barrier island -- Methuselah opossums who had smaller families, often bred two years in a row instead of one, and aged more slowly, living a whopping three years instead of two.
Austad notes that when we discover and examine genes in the human genome that can increase longevity, they may prove to come with trade-offs. "Of all these genes in these small animals [that extend longevity], none of them are ever found in nature. And they all have downsides. People have not been eager to investigate the nature of their downsides."
Cancer obviously could be a downside, as could altered fertility.
Austad says he's been snorted at by other scientists when he argues that we should study the cells of long-lived animals like whales and elephants instead of short-lived ones like mice and fruit flies if we want to understand how we might live longer. "Elephants contain about 40 times the numbers of cells we do, and whales as many as 600 times as many cells. Yet elephants and whales live, to a reasonable approximation, just as long as we do. Therefore, their cells must be 40 to 600 times more resistant to turning cancerous than our own. Could we perhaps learn something about cancer resistance from studying these cells?" he has written.
So far, Austad himself isn't working with elephants. Instead he's looking at parakeets. "They live up to 20-plus years," he says admiringly. "That's seven times as long as a mouse, and they're the same size. They have unbelievable resistance to oxidative damage ... if we could somehow mimic that in humans ..."
So, downside or no, Austad also thinks findings from the Human Genome project will help us increase human longevity. "We already know that there are some genes that are associated with longer life in animals. I think we'll find the [corresponding] genes in humans that have a small but measurable effect on how long we live. And it won't be too many years before we have gene therapy for all kinds of things. It hasn't worked too well yet, but that's just a technical problem."
Is there any theoretical limit that would keep increased longevity from becoming immortality? Warner says "There's no theoretical limit. There's a balance between constant damage and repair. It's like a car. Theoretically you should be able to keep a car going forever -- not yours, maybe, and not mine -- but if you keep replacing the parts the car could last forever. Maybe the individual could live forever."
"The only limit is that there is no such thing such as immortality because accidents still happen," says Austad. "The theoretical limit is human behavior, not human physiology. If teenagers didn't drive cars like crazy people, that would probably have more effect on life expectancy than curing cancer."
Dr. Leonard Hayflick takes a darker view of longevity research than many scientists do. Hayflick's view of significantly increased longevity is, basically, that it won't happen, it can't happen, and if it did happen it would be a bad thing.
Hayflick, a professor of anatomy at the University of California at San Francisco's school of medicine, is the author of "How and Why We Age," and has been thinking about longevity for 30 years, ever since he discovered what's now called the Hayflick Limit. Until his research, it was thought that animal cells growing in tissue culture were immortal and could divide forever. In a series of meticulous experiments, Hayflick showed that normal cells in culture have life spans: They flourish and divide for a while, but after a certain number of generations, divide no longer and eventually die. The cell lines that do go on forever are cancer cells.
People fail to distinguish between curing disease and ending aging, Hayflick says. If all the diseases currently written on death certificates in developed countries were resolved, you could add perhaps at the most 15 years to human life expectancy. "And that's it. Period."
Aging itself will not be affected. "Aging is an inexorable process that begins at about the age of 30 in humans and continues indefinitely. If you resolve disease you then expose or reveal the underlying real cause of that vulnerability, and hence death."
Hayflick doesn't believe that we will be able to go beyond resolving disease to slowing or stopping the process of aging. You can replace parts all you want he says, but what will you do when you have to replace your brain?
It's true that people object to aging as well as to death. Long life, while much admired, isn't sought after so much as long healthy life, or perhaps long youth. We want to be 100 years old and dewy fresh.
Dr. Pier Paolo Pandolfo, one of the scientists who studied the mice that live 30 percent longer, told the New York Times that a drug to block the self-destruct protein p66shc (the one the mice were engineered not to have) could be applied in the form of a cream to reverse wrinkling and blemishes on aging skin.
Can we have both long life and long youth? "I would say that there's no question about that," says Austad. "Most people would say that if you can't have better function there's no sense in keeping people alive."
It's increasingly easy to imagine replacing our parts, renewing our tissues, and rewriting our DNA. We would also need to fix our memories. They can hold a great deal, but never needed to hold an infinite amount of experience. Yet there are various ways we might deal with that, such as adding memory chips to our brains. Or perhaps we'll even figure out how to get rid of unneeded, unpleasant old memories and provide room for delightful new memories. It'll be doable, eventually.
Is this really possible? I believe it is, though I'm not fool enough to suggest a timetable. To those who say it'll never happen, I say: Don't confuse "a hell of a long time" with never. I think rather highly of human ingenuity and biological science. I see no reason why we won't eventually learn how to live forever and to live forever young.
I think less highly of collective human common sense. (As Kay tells Jay in that brilliant philosophical work, "Men in Black," "A person is smart. People are dumb ...) And so there's no reason to suppose we will handle this knowledge wisely.
Why aren't we immortal already? If it's so easy to turn on a gene here and turn off a gene there, why do we wear out and die? It's all about reproduction, of course. Once we've produced the next generation and gotten them on their feet, what happens to us is of no relevance to the future. People who have two children and live to be 100 are less successful from an evolutionary standpoint than people who have three children and keel over in their 50s.
So the impressive genes that allow people to reach 100 on a diet of bacon and beer are not favored by natural selection. (Although if the centenarians spend all their time calling up their great-grandchildren and asking when they're going to have babies and the great-grandchildren cave in and produce more children than they otherwise would have, that might favor those genes a bit.)
Still, it seems a little odd that there are no immortal species around. Quahogs live to be 200, but they probably feel that's not nearly long enough. Perhaps species of immortal animals would always be outcompeted by species of mortal animals, since mortal species evolve and acquire exciting new bells and whistles to repel insect pests, protect against disease and fool dinosaurs into thinking you wouldn't dream of eating their eggs.
If we stop dying will our species stop evolving? Not if we keep reproducing. Not everyone thinks we need to keep evolving. Many of us feel that we are already the pinnacle of perfection and that all our species needs to do is stay as sweet as we are. Others disagree.
My friend Cynthia Heimel says she does not feel we are nearly finished evolving, and she is eagerly looking forward to an era when we have progressed to having just four toes on each foot. She says it is because little toes are no use and catch on the bed corner, but I believe she just wants to wear pointier shoes.
In the choice between living long and having kids, natural selection has always favored having kids. Now that choice will be up to us. Obviously if we choose to do both, the world will fill up with people to such an extent that we'll have to look for new planets.
We will ourselves become natural selection -- unnatural selection if you prefer. Instead of allowing the ceaseless cherry-picking of the generations to get rid of our back problems, our impetuous driving habits and that pesky fifth toe, we will do it all at once with gene therapy.
Will everyone get to live forever, or will we make decisions about how long people get to live and when they have to stop?
This is one of the reasons Hayflick thinks increasing longevity is a dreadful idea. "I defy anyone to describe a scenario in which it would be a good thing," he says.
Hayflick told the Savannah Morning News, "If indeed we had a way of extending human longevity the probability is very high that therapy would be available to the rich and powerful. I don't know how you feel about the rich and powerful, but I can think of lots of them that I would not like to see live forever." For example, he notes, "I don't think that having Adolf Hitler around for the next 500 years makes much sense."
You know Fidel Castro isn't ready to die. And while I am under the impression that I have accepted my own mortality, I must admit that I don't accept the mortality of my loved ones. It's not that I want them to be immortal, it's just that I don't want them ever to die.
The fact that we spend such a huge proportion of our health budget in the last few months of our lives is testimony to this. (As my father remarks, "You can't tell what truly expensive way of living a little longer will be discovered.")
Spending money on gene therapy will undoubtedly be more popular than the feeble unappealing ways we have now of extending life span a little. You know, boring stuff like eating right, keeping fit, signalling your lane changes.
There are some things people won't do to live longer, after all. Yes, we'll slam down melatonin, DHEA and random antioxidants by the fistful just in case they slow aging. But almost nobody has leapt on the caloric restriction bandwagon (which holds that since rats on meager diets live longer, maybe we would too, so let's not eat anything at all every other day), because it's so unpleasant.
I have also heard men complain about how unfair it is that women live longer on the average. (Some of them will glare at a lady as if she'd been sprinkling free radicals on their salads.) Yet although it has long been known that castration can extend a man's life span by an average of 14 years, guys consistently pass on the chance to even the score.
Is it any more unnatural to use gene therapy to become more or less immortal, than it is to use prolong life in other ways? After all, during most of human history most children died as infants, women couldn't effectively limit how many children they gave birth to (and were far more apt to die in childbirth), and very few of them reached old age -- yet hardly anybody objects to medical care to fight these causes of death.
But what all these changes amount to for our species is simply a movement along the spectrum from the kinds of species that have brief risky lives in which they produce as many progeny as possible -- like mice -- to the kinds of species that have longer lives during which they have fewer progeny, in whom they invest more parental care -- like elephants. These life strategies are called r selection and K selection, and there's nothing so unusual about a species becoming more or less K-selected.
But among all the variously r- and K-selected creatures in the world, one thing seems constant: Everybody dies eventually. Immortality is something different.
Then there's the matter of addressing ethical conflicts before we proceed. The track record on this is not so great. Conferences are held and panels meet and people go right ahead and do what they want. And people really really want to live. "If it becomes possible, people will do it," says Steven Austad.
There are people worrying now about the way better health care is producing an unprecedentedly large population of older people, and the effects this has on medical spending, education spending, Social Security and the GNP. Oh, and the ballot box.
Well, they haven't seen anything yet. The world will fill up a lot faster if nobody dies.
Maybe we'll make people choose between living forever and having kids. If you're going to bring more people into the world, you'll have to be willing to leave it yourself on a reasonable schedule. Conversely, if you refuse to leave the party, you can't bring crashers. Of course, this would create an interesting two-tiered world full of crabby child-haters who think they know so much because they've seen it all and breeders speaking smugly about how they're being not only natural but also more evolved.
What about natural selection? It got us this far, didn't it? If immortality is a bad idea, won't nature take care of it? It might do just that, but not in way we'll enjoy. Since natural selection is mindless and purposeless, it has no objection to dead ends and short-term successes. Eventually some species could come along which has all our excellences, plus the advantages of mortality, and it will eliminate us. Not if we can stop them first, of course, but eventually (and this is a very long run indeed) we will be out-competed. Will the new Lords of the Earth then turn to making themselves immortal? Very likely, but it won't be our problem. Mother Nature doesn't care, ahistorical, short-sighted fool that she is.
Perhaps in the far reaches of time, as one mortal species after another crushes species that have succumbed to the temptation of eternal life, a species will arise that will remain mortal, and will allow itself to change. Perhaps they will never be overthrown by another species. Perhaps they'll have a zoo, and we'll be in it, and will learn the full reality of a life sentence.
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