DNA Rings of Death

Ordinarily when we think of aging, it's the outward signs that come to mind: wrinkles, graying hair, and withering muscles. But time may leave a much more telling mark in the nuclei of our cells. Scientists have found tiny circles of DNA that appear to clog up the nuclei of yeast cells and cause them to stop dividing, and ultimately to die. The findings, reported in the 26 December issue of Cell, suggest that yeast might provide a useful model for learning about aging in humans and for assessing ways to slow it down.

Lenny Guarente, a molecular biologist at the Massachusetts Institute of Technology (MIT), discovered the circle buildup while using the budding yeast, Saccharomyces cerevisiae, to study Werner's syndrome, a hereditary disease in which people age prematurely and often die before turning 50. No one knows how defects in the Werner's syndrome gene cause premature aging. But the human gene, discovered about a year and a half ago (Science, 12 April 1996, p. 193), has a yeast equivalent--SGS1--that makes yeast cells age prematurely. SGS1 mutants, Guarente's team found, stop budding and quickly become sterile. They also noted an intriguing change in the nucleolus, a small structure within the nucleus where RNAs that help make up the cell's protein factories, the ribosomes, are transcribed from the ribosomal DNA. Normally compact and crescent-shaped, the nucleoli of the mutant cells had become enlarged and fragmented.

As mother cells replicate their DNA prior to budding, they also copy ribosomal DNA. Guarente and MIT colleague David Sinclair found that this ribosomal DNA replication can go awry while creating DNA circles. The researchers suspect that the first such circle in each cell arises by accident, because of the highly repetitive nature of ribosomal DNA. The MIT pair also showed that circles almost always stay in the mother cell, indicating that their numbers continue to build with each cell division. The circles are seen in both normal cells and the SGS1 mutants, but they accumulate much faster in the mutant cells, suggesting that they may be linked to the rate of aging. Guarente suspects that certain proteins normally hold circle formation in check and thereby slow aging.

Experts are intrigued. "They've really come up with the clearest molecular mechanism for aging that anyone has come up with yet," says David Shore, a molecular geneticist at the University of Geneva in Switzerland. While yeast have very little repetitive DNA outside the ribosomal genes, humans have lots. That DNA might give rise to circles as it replicates, and the yeast work suggests that the circles of any kind of DNA that can replicate could have an aging effect. Although no one has yet found this aberrant DNA in mammalian cells, the idea, says Shore, "is screaming out to be tested in humans."