The Art of Aging

by Sherwin B Nuland

  The message would prove to be vintage de Grey, including its hint of immodesty. And in a similar vintage was his response when I expressed hesitation about punting, based on some friends’ tale of falling into the Cam on a chilly autumn day: “Evidently, your friends did it without expert guidance.” As I would learn, de Grey is a man who will not allow himself to be less than expert at anything to which he decides to devote those prodigious energies so enthusiastically trumpeted in the e-mail, nor will he allow himself to hide his expertness under a bushel.

  Of course, to conceive of being the herald and instrument of such a transformation as his theories promise requires a supreme self-confidence, and de Grey is the most unabashedly self-confident of men. Soon after we met, this unexampled man to whom self-deprecation is not known told me without a breath of irony that “one must have a somewhat inflated opinion of oneself,” if success is to crown such great endeavors. “I have that!” he added emphatically. By the time he and I said our goodbyes after our total of ten hours together over a period of two days, I was certain that there are those de Grey watchers who would with good reason question if the high regard in which he holds himself is at all inflated, rather than simply being realistic. Whether one chooses to believe that he is a brilliant and prophetic architect of futuristic biology or merely a misguided and quite nutty theorist, there can be no doubt about the astonishing magnitude of his intellect.

  De Grey calls his program Strategies for Engineered Negligible Senescence, which allows him to say that it makes SENS to embark upon it. Here, in no particular order, follow his seven horsemen of death and the formulations for the breaking of each animal and its rider. An attempt has been made to present them in a form comprehensible to the general reader, but those seeking further and more detailed information might wish to consult his website (http://www.gen.cam.ac.uk/sens/index.html), where such is provided. The website also has references to the vast volume of literature he has produced.

  1. Loss and atrophy, or degeneration, of cells. This element of aging is particularly important in tissues containing cells that have been thought unable to replace themselves as they die, such as heart and brain (see chapter 2). De Grey would treat it primarily by the introduction of growth factors to stimulate cell division and also by periodic transfusion of stem cells specifically engineered to replace the types that have been lost.

  2. Accumulation of cells that are not wanted. These are (a) fat cells—which tend to proliferate and not only replace muscle but also lead to diabetes by diminishing the body’s ability to respond to the pancreatic hormone, insulin, and (b) cells that have become senescent—which accumulate in the cartilage of our joints. Receptors on the surface of such cells are susceptible to immune bodies that de Grey believes scientists will in time learn to generate, or to other compounds that may make the unwanted cells destroy themselves without affecting others that do not have those distinctive receptors.

  3. Mutations in chromosomes. The most damaging consequence of mutations is the development of cancer. The immortality of cancer cells is related to the behavior of the telomere and the role of telomerase in maintaining its length. If we could eliminate the gene that makes telomerase, the cancer cell would die. De Grey’s solution for this problem is to periodically (the suggested period is ten years, for certain theoretically based reasons) replace all the stem cells from which our tissues are repopulated, with ones that have been engineered not to have that gene.

  4. Mutations in mitochondria. Mitochondria are the micromachines that produce energy for the cell’s activities. They contain small amounts of DNA, which are particularly susceptible to mutations since they are not protected by being housed in the chromosomes of the nucleus. De Grey proposes copying the genes (of which there are thirteen) from the mitochondrial DNA and then putting those copies into the DNA of the nucleus, where they will be far safer from mutation-causing influences.

  5. The accumulation of “junk” within the cell. The junk in question is a collection of complex material that results from the cell’s breakdown of large molecules. Intracellular structures called lysosomes being the primary microchambers for such breakdown, the junk tends to collect in them and cause problems in the function of certain types of cells. Atherosclerosis, or hardening of the arteries, is the biggest manifestation of these complications. To solve this difficulty, de Grey proposes to provide the lysosomes of the involved cells with genes to produce the extra enzymes required to digest the unwelcome material. The source of these genes is to be certain soil bacteria, an innovation based on the observation that animal flesh does not show accumulation of degraded junk when it is buried in the ground.

  6. The accumulation of “junk” outside the cell. The liquid in which all cells are bathed—called extracellular fluid—may come to contain aggregates of protein material incapable of breaking down. The result is the formation of a substance called amyloid, which is the material found in the brains of people with Alzheimer’s disease. To counter this, de Grey proposes vaccination with an as-yet-undeveloped substance that might stimulate the immune system to produce cells to engulf and eat the offending material.

  7. Cross-links in proteins outside the cell. The extracellular fluid contains many flexible protein molecules that exist unchanged for long periods of time, whose function is to give certain tissues such qualities as elasticity, transparency, or high tensile strength. Over the period of a lifetime, occasional chemical reactions gradually affect these molecules in ways that change their physical and/or chemical qualities. Among these changes is the development of chemical bonds called cross-links between molecules that had previously been able to slide along one another quite easily. The result is a loss of elasticity or a thickening of the involved tissue. If the tissue is the wall of an artery, for example, the loss of distensibility may lead to high blood pressure. De Grey’s solution to this problem is to attempt to identify chemicals or enzymes capable of breaking cross-links without injuring anything else.

  Even condensed and simplified as they are in the foregoing paragraphs, it must be obvious that these are enormously complex biological problems and even more complex proposed solutions. At least some of the former may prove impossible to overcome, and all or a few of the latter may prove impossible to implement. Moreover, de Grey’s descriptions are sprinkled with such vague notions as “growth factors” and “stimulating the immune system,” which might very well prove to be little more than slogans in this context, as perhaps is the invoking of still-unknown “chemicals or enzymes capable of breaking cross-links without injuring anything else.” In addition, it must be emphasized that not a single one of the seven problems has yet come close to being solved. In the case of several, such as the extracellular cross-links, promising results are being obtained by researchers—so much so that a company called Alteon, in Parsippany, New Jersey, has been engaged in clinical trials. In others, such as the prevention of telomere lengthening or the transfer of mitochondrial DNA to the nucleus, it is fair to say that molecular biologists can only speculate about the day, if ever, when these attempts will come to fruition. But de Grey is fazed by none of this incompleteness. It is his thesis that time is being lost, and nothing is accomplished by pessimism about possibilities. The “pie in the sky” that his formulations were called by one of the biogerontologists I later consulted is a tasty delicacy whose promise already nourishes de Grey’s soul.

  But the thought of possibilities was not the reason why I had traveled to Cambridge to meet Aubrey de Grey. It is for others to challenge his science and even the completeness of his understanding of the biological world to which he is such a latecomer. My purpose was something else entirely. In addition to taking his measure, my purpose was to see what sort of man it is who would devote the labors of an incandescently brilliant mind and a seemingly indefatigable constitution to such a project. Not only does the science seem more than a little speculative, but even more speculative is the assumption on which the entire undertaking is based, namely, that i
t is a good thing for the men and women now populating the earth to be provided the means to live indefinitely.

  I arrived at the Eagle a few minutes early on the appointed day, which gave me time to record some of the words engraved on a memorial plaque near the entryway, reading “An inn has existed at this site since 1667, called ‘Eagle and Child.’…During their research in the early 1950s, Watson and Crick used the Eagle as a place to relax and discuss their theories whilst refreshing themselves with ale.”

  Thus properly steeped in history and atmosphere, I entered the pub just in time to see de Grey through the window, parking his secondhand twenty-five-year-old bicycle across the narrow street. Narrow, in fact, is precisely the right adjective for the man himself, who at a bit under six feet one inch weighs 147 pounds, his spareness accentuated by a mountain-man chestnut beard extending down to midthorax that seems never to have seen a comb or brush. He was dressed like an unkempt graduate student, uncaring of tailoring considerations of any sort, wearing a hip-length black mackinaw-type coat that appeared to be borderline shabby. Adorning his head was a woolen hat of a half dozen striped transverse colors, which I would be told had been knitted by his wife fourteen years ago. As if to prove its age, the frazzled headgear (which was knitted with straplike extensions that tied under the chin) was not without a few holes. When it was removed, its owner’s long straight hair revealed itself to be held in a ponytail by a circular band of bright red wool. But in spite of the visual gestalt, de Grey cannot disguise the fact that he is a boyishly handsome man. As for the sound of him, being the product of a private grammar school followed by Harrow and then Cambridge, it hardly needs to be described. To an American, he is of rare fauna, and his distinctiveness was catch-your-eye apparent even there among his Cambridge colleagues.

  Having seen a photo of de Grey on his website, I was prepared for my subject’s appearance of spareness and even his laissez-faire attitude toward externals. But I was most definitely not prepared for the pallor that accompanied them, nor for the intensity of those keen blue-gray eyes and the face in which they are so gleamingly set, the whole making for an expression of concentrated zeal, or even evangelism, that never let up during our subsequent six hours of nonstop conversation across the narrow pub table that separated us on that first day.

  The website photo shows eyes so gently warm that I had commented on them in one of my e-mails. But I would see none of that during the total of ten hours we spent together, though it reappeared during the fifteen minutes during which we chatted with Adelaide de Grey in a courtyard between laboratory buildings after our Monday session at the Eagle.

  Adelaide Carpenter de Grey is a highly accomplished American geneticist and an expert electron microscopist who is nineteen years older than her husband. They met early in 1990, midway through her Cambridge sabbatical from a faculty position at the University of California, San Diego, and were married in April 1991. Neither of them has ever wanted to have children. “There are already lots of people who are very good at that,” explained Aubrey when the subject came up. “It’s either that or do a lot of stuff you wouldn’t do if you had children, because you wouldn’t have the time.” At the age of eight or nine, and being raised as the only child of an artistic and somewhat eccentric single mother, he determined to do something with his life “that would make a difference,” something that he and perhaps no one else was equipped to accomplish. Why fritter away resources in directions that others might pursue just as well or better? With that in mind no less now than as a child, de Grey has trimmed away from his days and thoughts any activity he deems superfluous or distracting from the goals he sets for himself. He and Adelaide are two highly focused—some would say driven—people of such apparent similarity of motivation and goals that their work, hers in genetics and his in life-extension, is the overwhelming catalytic force of their lives.

  And yet, each member of this uncommon pair is touchingly tender with the other. Even our brief fifteen minutes was sufficient to observe the softness that comes into de Grey’s otherwise determined visage when Adelaide is near, and her similar response. I suspect that his website photo was taken while he was either looking at her or thinking of her.

  Adelaide, though at five feet two inches much shorter than her husband, looks his perfect sartorial partner, dressed in a similar way and apparently just as uncaring about her appearance or grooming. One can easily imagine them on one of their dates as described by Aubrey. They have walked from the small flat where they have been living since he took it over from his roommates when the two of them married almost fourteen years ago, and are now in the local laundromat talking science as the machines beat up on their well-worn clothes for yet another time. They are hardly bon vivants, nor would they want to be; they quite obviously like things just as they are. They appear to care not at all for the usual getting and spending—and even some of the normative emotional—rewards of living in our world, at a time when the name of Aubrey de Grey has become associated with changing that world in as-yet-unimaginable ways.

  But six uninterrupted hours of compelling talk (most of it pouring out of him in floods of volubility, let loose by intermittent questions or comments from me) and the consumption of numerous pints of Abbot Ale still awaited us before I would meet Adelaide and be taken to the laboratory where de Grey performs the duties of his “day job.” Very soon after we began speaking, an hour before noon on that first day, I asked him, rather preliminarily, why it is that the hackles of so many gerontologists and others who might be expected to be familiar with the science of his proposals are raised by the very mention of these formulations—even by the mention of his name, in fact. And right there at the very outset of our discussions, he replied with the dismissive impatience that would reappear whenever I brought up one or another of the many objections that either a specialist or the common man in the street might have to the notion of extending life for millennia. “Pretty much invariably,” he curtly told me, their objections “are based on simple ignorance.” Among the bands of dazzling light that de Grey will not confine to a bushel is his certainty that his is one of the few minds capable of comprehending the biology of his formulations, the scientific and societal logic upon which they are based, and the vastness of their potential benefits to our species.

  The burden of much of my challenge to de Grey was that he should justify his conviction that living for thousands of years is a good thing. For certainly, if one can accept such a viewpoint as his, everything else follows from it: the push to do the research beyond just elucidating the biological process of aging; the gigantic investment of research talent and money to accomplish and apply it; the transformation of a culture based on the expectation of a finite and relatively short lifetime to one without limits to its horizons; the perception—because rejuvenation inevitably occurs as a result of de Grey’s proposals—that all human beings are physiologically much the same age; the changed status of all relationships within the family, which is, after all, the primary group in which personality is formed—it goes on and on.

  De Grey’s response to such a challenge comes in the perfectly formed and articulated sentences of which all his writings consist. For he does have the gift of expressing himself both verbally and in print with such clarity, completeness, and consecutive sequence of explanation—even if without conciseness—that a listener finds himself entranced by the flow of seemingly logical statements that follow one after the other. As is true in his own directed life, de Grey never rambles in conversation. Everything he says is pertinent to his argument, and so well constructed that one becomes fascinated with the edifice being formed before one’s eyes and ears. So much is this true that I could not but fix my full attention on him as he spoke. Though many possible distractions arose during the hours in which we confronted each other across that pub table as people came and went, ate and drank, talked and laughed, smoked and coughed, I never once found myself looking anywhere but directly at him, except when going to fetch food—a meal fo
r me and only chips for him—or another pint. It is only when reflecting upon the assumptions on which all of his thesis is based, that a listener discovers that he must insert the word “seemingly” before “logical” in the second sentence of this paragraph. Here follows an example of de Grey’s thinking:

  The reason we have an imperative, we have a duty, to develop these therapies as soon as possible is to give future generations the choice. People are entitled, have a human right, to live as long as they can; people have a duty to give people the opportunity to live as long as they want to. I think it’s just a straightforward extension of the duty-of-care concept. People are entitled to expect to be treated as they would treat themselves.

  It follows directly and irrevocably as an extension of the golden rule. If we hesitate and vacillate in developing life-extension therapy, there will be some cohort whom we will deny the option to live much longer than we do. We have a duty not to deny people that option.

  When I raised the question of ethical or moral objections to the extreme extension of life, the reply was similarly seemingly logical and to the point:

  If there were such objections, they would certainly count in this argument. What does count is that the right to live as long as you choose is the world’s most fundamental right. And this is not something I’m ordaining. This seems to be something that all moral codes, religious or secular, seem to agree on: that the right to life is the most important right.