Two scientists at the Massachusetts Institute of Technology believe they have discovered a "senescence factor" that builds up in dividing cells and can indicate signs of aging.
The cause of aging, they say in a study published yesterday, may lie in a simple mistake in cell division that causes circular bits of redundant DNA to accumulate within the nuclei of cells. This "junk" builds up to levels equaling needed DNA, clogging normal cellular machinery.
The evidence so far comes only from brewer's yeast cells, but David A. Sinclair and Leonard Guarente believe that the same process probably occurs in mammals, including humans.
"At the moment this is our best candidate for what goes wrong in aging," Guarente said. He and his colleagues are searching for the phenomenon in diverse species, but Guarente warned that finding proof in human tissues "may be a long process."
The finding, published in the journal Cell, stems from work on a rare human disorder of premature aging called Werner's syndrome. Because of a gene mutation, affected individuals appear normal until their teen years, then develop signs of accelerated aging and die in their 30s.
Guarente and Sinclair have been deciphering the mechanisms behind an analogous gene defect in yeast that causes the single-celled organism to become infertile, show signs of aging, and die after a life span half that of normal yeast cells.
The MIT scientists noticed yeast with the Werner's syndrome-like gene defect had abnormalities in a structure within their nucleus called the nucleolus. Inside the nucleolus, tiny factories called ribosomes assemble proteins to sustain the cell's life and carry out its mission.
Human cells contain thousands of ribosomes in their nucleoli, while yeast cells have about 140. This makes them susceptible to errors in the replication of the ribosomes' DNA. "Because ribosomal DNA is the most-repeated DNA sequence in the cell, the cell has a challenge in keeping these repeated DNA sequences stable," Guarente said. "These repeats could be the Achilles' heel of the cell."
Occasionally, a circular chain of ribosomal DNA "pops out," he said. Whenever the cell divides, these useless circles multiply, too, eventually becoming so numerous that the ribosomes that contain them burst -- accounting for the abnormalities the MIT scientists first observed in yeast cells with the premature-aging gene.
The researchers have discovered the aberrant circles in old yeast cells without the premature-aging defect. In a key experiment, they tricked yeast cells into creating DNA circles to see if their presence would lead to signs of aging.
"It did," Guarente said. Yeast cells containing such created DNA circles had 40 percent shorter life spans than normal.
Pub Date: 12/27/97