Could the reduction of telomeres and of proliferative capacity over time be a cause of human aging? It is probably not the main cause. After all, cells can usually divide more times than is required in a human life span. Nevertheless, the functioning of the older body may at times be compromised by the senescence of a subset of cells. For instance, local wound healing could be impaired by a reduction in the number of cells available to build new skin at a site of injury, and a reduction in the number of certain white blood cells could contribute to age-related declines in immunity. Further, it is known that atherosclerosis typically develops where blood vessel walls have been damaged. It is conceivable that cells at repeatedly injured sites could finally "use up" their replicative capacity, so that the vessels ultimately fail to replace lost cells. Then damage would persist, and atherosclerosis would set in.
Some investigators suspect that the loss of proliferative capacity observed in human cells lacking telomerase may have evolved not to make us decrepit but to help us avoid cancer. Cancers arise when a cell acquires multiple genetic mutations that together cause the cell to escape from normal controls on replication and migration. As the cell and its offspring multiply uncontrollably, they can invade and damage nearby tissue. Some may also break away and travel to parts of the body where they do not belong, establishing new malignancies (metastases) at distant sites. In theory, a lack of telomerase would retard the growth of tumors by causing continually dividing cells to lose their telomeres and to succumb before they did much damage. If cancer cells made telomerase, they would retain their telomeres and would potentially survive indefinitely.
The notion that telomerase might be important to the maintenance of human cancers was discussed as early as 1990. But the evidence did not become compelling until recently. In 1994 Christopher M. Counter, Silvia Bacchetti, Harley and their colleagues at McMaster showed that telomerase was active not only in cancer-cell lines maintained in the laboratory but in ovarian tumors in the human body. Later that year groups led by Harley, who had moved to Geron Corporation in Menlo Park, Calif., and by Jerry W. Shay of the University of Texas Southwestern Medical Center at Dallas detected telomerase in 90 of 101 human tumor samples (representing 12 tumor types) and in none of 50 samples of normal somatic tissue (representing four tissue types).
Even before such evidence was obtained, however, researchers had begun exploring some of the details of how telomerase might contribute to cancer. That work suggests telomerase probably becomes active after a cell has already lost its brakes on proliferation.
The first clue was an initially mystifying discovery made independently by Titia de Lange, now at the Rockefeller University, and by Hastie's group. In 1990 these investigators reported that telomeres in human tumors were shorter than telomeres in the normal surrounding tissue—sometimes dramatically so.
Studies by Greider's, Bacchetti's and Harley's laboratories explained why the telomeres were so small. The teams had induced normal cells from humans to make a viral protein causing cells to ignore the alarm signals that usually warn them to stop dividing. The treated cells continued to proliferate long after they would normally enter senescence. In most of the cells, telomeres shortened drastically, and no telomerase was detected; eventually death ensued. Some cells, however, persisted after their siblings died and became immortal. In these immortal survivors, telomeres were maintained at a strikingly short length, and telomerase was present.
These outcomes imply that telomeres in cancer cells are small because cells synthesize telomerase only after they have already begun to replicate uncontrollably; by then, the cells have presumably lost a substantial number of telomeric subunits. When the enzyme is finally activated, it stabilizes the severely clipped telomeres, allowing overly prolific cells to become immortal.