In my view, we can probably eliminate aging as a cause of death this century—and possibly within just a few decades, soon enough to benefit most people currently alive.
What could that achieve, in humanitarian terms? I’ll start with some numbers. Around 150,000 people die each day worldwide—that’s nearly two per second—and of those, about two-thirds die of aging. That’s right: 100,000 people. That’s about 30 World Trade Centers, 60 Katrinas, every single day. In the industrialized world, the proportion of deaths that are attributable to aging is around 90 percent—yes, that means that for every person who dies of any cause other than aging, be it homicide, road accidents, AIDS, whatever, somewhere around 10 people die of aging.
Many people, when thinking about the idea of adding years to life, commit the “Tithonus error”—the presumption that, when we talk about combating aging, we’re only talking about stretching out the grim years of debilitation and disease with which most people’s lives currently end. In fact, the opposite is true. The defeat of aging will entail the elimination of that period, by postponing it to indefinitely greater ages so that people never reach it. There will, quite simply, cease to be a portion of the population that is frail and infirm as a result of age. It’s not just extending lives that I’m advocating; it’s the elimination of the almost incalculable amount of suffering—experienced not only by the elderly themselves, of course, but by their loved ones and caregivers—that aging currently visits upon us. Oh, and there’s the minor detail of the financial savings that the elimination of aging would deliver to society: It’s well established that the average person in the industrialized world consumes more health care resources in his or her last year of life than in an entire life up to that point, irrespective of age at death, so we’re talking about trillions of dollars per year.
I consider that if funding is sufficient we have a 50/50 chance of developing technology within about 25 to 30 years from now that will, under reasonable assumptions about the rate of subsequent improvements in that technology, allow us to stop people from dying of aging at any age—equivalent to the effect of today’s antiretrovirals against HIV. There are a few big caveats to that statement, though. The first is that it’s only a 50 percent chance. Any technological prediction as far in the future as 25 to 30 years is necessarily very speculative, and if you asked me how soon I thought we would have a 90 percent chance of defeating aging, I wouldn’t even be willing to bet on 100 years. But I think a 50 percent chance is well worth shooting for—don’t you? The second caveat is that aging won’t be totally defeated by the initial versions of this technology. We’ll have to carry on improving it at a reasonable rate in order to keep aging permanently at bay.
Cancer is a deal breaker for building an ageless organism. If we fail to make a breakthrough against this one disease, we can still expect to be dead in our mid-eighties. Diabetes and hypertension can be held at a safe, manageable level precisely because they are essentially stable diseases. By contrast, what makes cancer so fearsome a foe is that it’s a constantly evolving disease, a hive of genetic inventiveness that continuously finds new and better ways to outwit our attempts to control it. Within a single tumor exists such an astonishingly varied population of cells, each with its own combination of normal and abnormal genes, that at least some cells nearly always have a way to survive any particular attack. It ultimately just doesn’t matter if a given therapy kills 99 percent of the cells in a tumor.
We have a 50/50 chance of developing technology within about 25 to 30 years that will allow us to stop people from dying of aging.
To defeat cancer, we need a therapy that does not depend on anything that a cancer could escape through a mutation-driven change in gene expression. So any solution would have to have three key characteristics to be viable. First, it would necessarily involve denying cancerous cells access to some tool that is absolutely indispensable to their survival, so that they couldn’t just make up for its loss by tweaking some other gene expression pathway through mutating its other genes. Second, we would have to take away that tool in such a way that no mutation could restore it, either. And third, this tool would have to be one that our normal, noncancer tissues could do without.
As I considered this problem, I quickly saw the tool that I wanted to lock up: telomerase. Our DNA comes equipped with a stretch of nonsense or “noise” DNA called the telomere. Telomeres are to our genes as the brief, silent stretch of leader tape at the beginning of a music cassette is to the songs on the tape: They give the “cassette player” (the DNA-replicating machinery) something to hold on to and advance over, so that it won’t skip over the essential information at the beginning of the very first “song” (gene) on the tape.
One key difference between telomeres and cassette leaders is that leaders stay intact as long as the tape does, whereas telomeres become ever-so-slightly shorter every time the cell replicates itself or is hit by damaging agents like free radicals. If it weren’t for telomerase, this gradual shortening would eventually lead to the complete loss of the telomeres in cells that replicate frequently during a life span, and thus the gradual erosion of the genes themselves. Telomerase periodically relengthens the telomere before it becomes critically short.
As with all of our other genes, the DNA that encodes the telomerase enzyme is present in all of our cells—but because it’s needed only after quite a few cell divisions have occurred, it’s not needed in most cells for most or all of the time, so it’s turned off. This widespread lack of the need for telomerase is used by evolution as a key component of our defense against cancer, because having a limit to the size and renewal of telomeres prevents our cells from replicating themselves indefinitely—the crucial hallmark of cancer.
To become a full-blown cancer (as opposed to a cell with a single, potentially threatening mutation—a genetic risk factor for becoming a cancer) requires the accumulation of five to ten mutations, and statistically that requires multiple rounds of cell division and selection. The arithmetic is complex, but the consensus is that, to pose a health threat, cancers have to replicate at least 200 to 300 times, even though a clinically relevant tumor contains “only” a million million cells, which could be achieved by “only” 40 or so divisions if the originating cell had all the necessary mutations from the outset. And to be genuinely malignant (that is, to be the founder of a colony of cancer cells that spreads its way throughout the body, as opposed to a localized tumor that could be simply removed with surgery and forgotten about), cancers must then be able to keep up the feverish pace of their replication even longer.
The frenzied reproduction of cancer cells is also a key part of their ability to evade our assaults, because it is essential to their capacity to evolve new solutions to the challenges that we throw up against them.
If we could snatch this one tool out of the hands of cancers, we would cause any and all the aspiring cancers we developed to fizzle out before they became life-threatening—indeed, before many of them even became actual cancers, because they wouldn’t get the opportunity to undergo the full spectrum of mutational events needed to give rise to the kind of renegade cell that can truly pose a threat to the body.
Of course, I am hardly the first to think the problem this far through. Several biotech companies—most prominently Geron, which first made a name for itself in telomere research—are working to develop anticancer drugs that would work by deactivating telomerase. But these pharmaceuticals suffer the same problem as all other approaches based on drugs that affect gene expression: They act as a force of natural selection against a disease with evolution at its disposal. A telomerase inhibitor would kill off those cancer cells in which it effectively turned off the enzyme, but it would leave behind any cells that harbored mutations, allowing them to keep on renewing their telomeres in the face of it. Different cancer cells might bear any number of variations that let them escape the drug’s effects. Some would simply crank their telomerase activity up even further; some would enhance the activity of drug-metabolizing enzymes that degrade the inhibitor; still others would change their cell surface proteins in ways that would make it harder for the drug to penetrate into the cell. Whatever the mechanism, if even one cancer cell can evade the effects of such a drug, it can act as the seed for the tumor’s renewed blossoming in a dark spring.
So, again, there is no sense in doing the job only halfway. If we’re going to snatch telomerase out of the hands of cancer cells, we must really take it away. And there is only one way that I can think of to do that reliably: by deleting the gene that encodes it.
Removing telomerase from every cell in our body would preempt cancer before it had a chance to get started. But you can surely see why no one else has explored this option. Deleting telomere elongation capacity throughout the body would also be life-threatening, because it would mean that our regular proliferating cells (like those in the skin or the lining of the gut) would suddenly have iron limits on their ability to reproduce themselves and thus replenish tissue.
From the moment that we denuded our cells of telomerase, a clock would be ticking. With each division the telomere would shorten by a notch from whatever it had been when we took telomerase out. We would be under the specter of a rather horrible death, as our stem cells went off-line one by one. With each failure of a stem cell responsible for supplying key functions, the tissue would fail to be renewed and would slowly degenerate.
So, the effect of telomerase deletion on frequently dividing cells would be very serious indeed—fatal, in fact. I calculate death would arrive around a decade from the point when telomerase was deleted.
But hang on, I immediately thought; we already have a proposed solution to “normal,” age-related cell loss: stem cells. So we might just be able to deal with cell loss if we had a sufficiently sophisticated program of stem cell replenishment—using cells engineered to lack the one linchpin function for cancer, namely telomere elongation.
Of course, these stem cells would eventually peter out too, as their telomeres were worn down—but this is just the same situation that we face with all aging damage. If we introduced stem cells with nice, long telomeres in the first place, we could let them wind down and eventually be lost to apoptosis, senescence, or other sources of damage—and just top our tissues up with more stem cells before enough of those cells were lost to begin to impair tissue function. Neglect your medicine and you will eventually suffer the consequences; keep up with your schedule and you will stay young and healthy into a boundless future.
In this case, the same “damage” that might eventually kill us (the running down of our telomeres) is simultaneously the very thing that we need to ensure does happen, or else we will be killed by another means (the unchecked cell division at the heart of cancer). Putting an expiry date on all of our cells, but ensuring that they are regularly replenished with new ones, erases both problems at once.
At that point we’d have cancer licked. No cancer could reach a clinically significant stage. At worst we would end up with a few little pebble tumors, small balls of abnormal cells that had exhausted their ability to grow, no more life-threatening than a mole or a small cyst. And our normal tissues would be preserved intact, provided that we underwent regular rounds of replacement of stem cells.
From Ending Aging by Aubrey de Grey. Copyright © 2007 by the author and reprinted by permission of St. Martin’s Press, LLC. Aubrey de Grey is chairman and chief science officer of the Methuselah Foundation.
