February 2005

Do You Want to Live Forever?

Continued from page 2

By Sherwin Nuland

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De Grey calls his program Strategies for Engineered Negligible Senescence, which permits 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. (Those seeking more detailed information might wish to consult de Grey's website: www.gen.cam.ac.uk/sens/index.html.)

1. Loss and atrophy or degeneration of cells. This element of aging is particularly important in tissues where cells cannot replace themselves as they die, such as the heart and brain. De Grey would treat it primarily by the introduction of growth factors to stimulate cell division or 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 how to generate, or to other compounds that may make the cells destroy themselves without affecting others that do not have those distinctive receptors.

3. Mutations in chromosomes. The most damaging consequence of cell mutation is the development of cancer. The immortality of cancer cells is related to the behavior of the telomere, the caplike structure found on the end of every chromosome, which decreases in length each time the cell divides and therefore seems to be involved with the cell's mortality. If we could eliminate the gene that makes telomerase -- the enzyme that maintains and lengthens telomeres -- the cancer cell would die. De Grey's solution for this problem is to replace a person's stem cells every 10 or so years with ones engineered not to carry 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 housed in the chromosomes of the nucleus. De Grey proposes copying the genes (of which there are 13) 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 are the primary microchambers for such breakdown; the junk tends to collect in them, causing problems in the function of certain types of cells. Atherosclerosis, hardening of the arteries, is the biggest manifestation of these complications. To solve this difficulty, de Grey proposes to provide the lysosomes with genes to produce the extra enzymes required to digest the unwelcome material. The source of these genes will be certain soil bacteria, an innovation based on the observation that ground that contains buried animal flesh does not show accumulation of degraded junk.

6. The accumulation of "junk" outside the cell. The fluid in which all cells are bathed -- called extracellular fluid -- may come to contain aggregates of protein material that it is 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, transparence, or high tensile strength. Over 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 moved independently of one another. 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.

It must be obvious that, even condensed and simplified as they are here, these seven factors are enormously complex biological problems with even more complex proposed solutions. At least some of those solutions may prove inadequate, and others may be impossible to implement. Moreover, de Grey's descriptions are sprinkled with such vague phrases as "growth factors" and "stimulate the immune system," which might prove to be little more than slogans, as when he invokes yet-to-be-discovered "chemicals or enzymes capable of breaking cross-links without injuring anything else." In addition, it must be emphasized that researchers have not come close to solving a single one of the seven problems. In the case of several, there have been promising results. Indeed, research on extracellular cross-links has already yielded several drug candidates: a company called Alteon, in Parsippany, NY, has begun clinical trials of molecules that it says can reverse the effects of some conditions associated with age. In the cases of some of the other problems de Grey identifies, however -- 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 unfazed by this incompleteness. It is his thesis that time is being lost, and nothing is accomplished by pessimism about possibilities. For de Grey, "pie in the sky," as one biogerontologist I consulted called his formulations, is a tasty delicacy whose promise already nourishes his soul.

But others can challenge de Grey's science. My purpose was something else entirely. I found myself wondering what sort of man 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 it is a good thing for the men and women now populating the earth to have the means to live indefinitely.

Do You Want to Live Forever?

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