Jewish World Review Jan. 9, 2002 / 25 Teves, 5762

Cancer & aging: Two sides of the same coin?

By Robert A. Wascher, M.D., F.A.C.S. -- SCIENTISTS have long conjectured about the relationship between aging and cancer. Now, a new study published in this week's issue of the journal Nature only adds to the controversy. We have long been aware of the increased incidence of cancer that comes with aging.

This association has been explained by various theories, including a gradual weakening of the immune system with advancing age and, more recently, with the discovery of an important part of our chromosomes, called telomeres, that deteriorate with age. Telomeres, it seems, are necessary for proper cell division. However, a tiny bit of this chromosomal structure is lost with each round of cell division. When the telomeres reach a critical degree of shortening, the cell then becomes senescent, and no longer divides. In many cancer cells, an enzyme that maintains the length and integrity of the telomeres is over-expressed. In this way, it is now thought, cancer cells become "immortalized," and ceaselessly divide.

The new study, from Baylor University, adds another wrinkle to the aging/cancer debate, and is based upon the study of a protein called p53. Much has been written about this enigmatic protein and, in particular, about its role in the development of cancer.

Indeed, p53 is generally considered to be the most important "tumor suppressor protein" (TSP) in the body. Each of us is born with 23 pairs of chromosomes in every cell of our body. This means that two copies of every gene exist, although each gene within a pair may differ slightly from the other (this is why, for example, eye color varies between individuals, even within a single family). It is thought that p53 protein, like other TSPs, functions to prevent damaged cells from becoming transformed into cancer cells.

If one copy of the p53 gene is lost and the second copy is normal, then the cell continues to manufacture this vital protein. If, however, one copy of the p53 gene is lost, or if it has a mutation that prevents the resulting protein from effectively doing its job, then a "second hit" can knockout the remaining functional gene. Over the course of our lives, our cells are exposed to environmental, dietary and age-related stresses that cause cumulative damage to the genes in our cells. Certain combinations of these genetic mutations are known to result in the development of cancerous cells. In the case of the p53, at least half of all cancers have mutations in the genes that code for this protein.

Although all of its functions have yet to be elucidated, p53 plays an absolutely critical role in facilitating-or stopping-a cell's progression through what is known as the "cell cycle." During the cell cycle, certain deliberate and complex biochemical events must occur, in sequence, for a cell to grow and divide. If the cell cycle stops, then cell growth and division are said to be "arrested." In this case, the cell may become quiescent until the cell cycle is reactivated.

Alternatively, the cell may undergo a death process known as "apoptosis." The normal p53 protein plays a role in both cell cycle arrest and apoptosis in the presence of damaged DNA in our cells. Thus, when inactive (i.e., mutated) forms of p53 are present instead of the normal protein, the cell cycle may be permitted to proceed despite the presence of major cancer-causing mutations in the cell's DNA.

With this background in mind, the Baylor study's researchers serendipitously discovered a link between p53 protein activity and cancer/aging. The Baylor scientists were attempting to inactivate the p53 gene in mice, which usually results in the loss of the gene's function. However, the "gene knockout" mice actually developed hyperactive p53 function instead. Thinking that they had failed in their scientific objectives with these mice, the animals were set aside.

Not surprisingly, these mice, with their enhanced p53 protein activity, rarely developed cancers (mice, like humans, become more susceptible to developing cancers as they age). To their great surprise, however, the researchers noted that these same mice were developing signs of advanced aging, even though the mice were barely in the middle of their typical lifespan! The mice lost muscle mass, developed brittle bones, and experienced poor wound healing-all hallmarks of aging. Finally, these mice died at an average age of 96 weeks, of age-related diseases, representing a 20% reduction in their lifespan.

The study's authors speculate that the hyperactive p53 protein not only eliminated the ability of cells with damaged DNA to divide, but that it also throttled back the ability of normal stem cells to grow and divide. These stem cells (the same stem cells that are in the news lately), which also gradually accumulate genetic mutations over time, serve as a source of replacement cells for the tissues in our bodies as our older cells become senescent and die. Thus, the authors hypothesize that p53 acts as a double-edged sword. Early in our lives, p53 protein goes about its work of eliminating cells with irreparable damage to their DNA, thereby preventing these cells from developing into a cancer.

However, as time passes, this same protein may exact a heavy price on us by also gradually eliminating the pool of regenerative stem cells that would otherwise replace our body's cells as they die.

This study is the first report to propose a linkage between p53 protein and aging, and will likely stimulate a great deal of further research in this area. It is almost certain that, just as with cancer, other genes (and the proteins that they code for) play important roles in aging.

But this newly discovered linkage between p53 protein and aging appears to be a highly significant finding. As always, such research raises tricky ethical issues regarding the manipulation of cellular machinery to turn back the clock of aging (such experimental work is already underway with telomeres, and with the proteins that are capable of maintaining their length). As has been shown in research involving telomeres, it may be the case that attempts to manipulate p53 levels in noncancerous cells will result in a much higher incidence of cancer.

At the same time, p53 genes and protein are being used, experimentally, to fight cancers known to have mutations of the p53 gene. It is currently unknown whether these "gene replacement" therapies, or even the more traditional chemotherapies (most of which exert their anti-cancer effect by damaging the DNA of tumor cells, while causing "collateral damage" to many normal cells as well), will accelerate aging via an increase in p53 protein activity. This provocative study provides a new and surprising glimpse into cellular function as it relates to cancer and aging. Like many other such studies, however, it raises many more intriguing questions than it answers.

JWR contributor Dr. Robert A. Wascher is a senior research fellow in molecular & surgical oncology at the John Wayne Cancer Institute in Santa Monica, CA. Comment by clicking here.


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© 2001, Dr. Robert A. Wascher