Extending cell life yields clues to growth.

Extending cell life yields clues to growth

In Tom Robbins' novel, Jitterbug Perfume, characters search for the essence of life in an ancient perfume bottle. Muses the novel's narrator: "To physically overcome death -- is that not the goal? -- we must think unthinkable thoughts and ask unanswerable questions."

In the laboratory, researchers on a similar quest employ a different sort of vessel -- a petri dish packed with cultured cells -- to identify chemical factors that might either extend life or hasten its demise. And though the scientists may pose questions that have no immediate answers, the ultimate goal, notes molecular biologist Thomas Maciag, seems clear: to painstakingly amass clues about the regulation of cell survival and proliferation that might help elucidate the causes of cancer, atherosclerosis and other illnesses in which cell growth runs amok.

Using cultured endothelial cells derived from a human umbilical vein, Maciag and his colleagues at the American Red Cross in Rockville, Md., say they have now succeeded in prolonging in vitro cell survival, defined as the number of times a cell population doubles during its lifetime. Though endothelial cells in the petri dish normally stop dividing after 20 to 60 doublings, those treated with a new chemical agent retained their youthful appearance and lasted long enough to undergo as many as 140 population doublings, the researchers report in the Sept. 28 SCIENCE.

Maciag and his co-workers based this study on their previous work demonstrating that cultures of endothelial cells show signs of aging, including an inability to divide -- changes perhaps similar to those that cells undergo in the aging body. They also relied on reports from other researchers that the cellular protein interleukin-1 alpha (IL-1 alpha) appears to inhibit growth of these cells in vitro. In their current work, Maciag's team detected elevated levels of IL-1 alpha and its messenger RNA--the genetic material that normally directs production of the protein -- in cell cultures that had doubled their population many times, but not in younger cultures.

Injecting the older cultures with daily doses of a compound that blocked the messenger RNA from producing IL-1 alpha, the team prevented the onset of cellular senescence and extended the lifespan of the cells. Stopping the injections allowed the aging process to resume unimpeded, the scientists note.

Because continued exposure to the compound that halted production of IL-1 alpha cannot stave off cell aging and cell death indefinitely, Maciag suggests that the protein may be the first of a repertoire of chemicals that slow endothelial cell growth. "IL-1 alpha may be the 'switch' of choice in the repertoire, but other factors may [sequentially] kick in to inhibit growth," he notes.

Attempts to uncover this secret arsenal, he says, may help cancer biologists and cardiovascular researchers understand why some cells in the body -- such as breast-cancer cells and those that form plaque beneath the endothelial lining of blood-vessel walls -- proliferate out of control, while others do not. He adds that factors governing proliferation of endothelial cells in vitro are likely to differ from those regulating other cells, such as fibroblasts, which also undergo senescence but appear to recognize IL-1 alpha as a growth promoter. Maciag notes that similarities in structure between IL-1 alpha and fibroblast growth factor suggest a common evolutionary origin.

Besides its influence on growth, IL-1 alpha acts to differentiate endothelial cells, he observes, prompting those cells to mature into capillary-shaped cells that line blood vessels and the lymphatic system. Maciag speculates that IL-1 alpha might clamp down on cellular growth in order to stimulate maturation, since a limited amount of energy may prevent both processes from proceeding simultaneously.