Concepts familiar from grade-school algebra have broad ramifications in computer science.
Researchers in the Department of Biology may not have discovered the fountain of youth, but they have recently demonstrated that a yeast gene, SGS1, plays a crucial role in determining the life span of yeast cells.
The biologists' research, reported in the August 29 issue of Science, suggests scientists may be able to identify -- and perhaps, one day, to control -- a universal aging mechanism.
The potential for discovering such a mechanism, at least among humans, arises from the fact that the SGS1 yeast gene has a DNA code that corresponds structurally to the human WRN gene. Yeast is an attractive organism for aging research because of the potential for researchers to isolate mutant cells with altered life spans.
Mutations in WRN result in Werner's Syndrome, a disease with symptoms resembling a fast-forward aging process. The researchers predicted that experimental mutation of SGS1 genes would produce symptoms of aging in yeast cells.
"We wished to determine the role, if any, of SGS1 in yeast longevity," wrote the authors, Professor Leonard Guarente, postdoctoral fellow David A. Sinclair and graduate student Kevin Mills. Their groundbreaking work developed from research on aging processes in both yeast and human cells. What is common to both is a finite life span, and similar characteristics of aging found in old cells of each type.
People suffering from Werner's Syndrome offer a scientifically compelling illustration of human aging, since mutations in the WRN gene have already been shown to cause premature aging. Their symptoms, which begin in early adulthood, include graying and loss of hair, osteoporosis, cataracts, atherosclerosis, loss of skin elasticity, type II diabetes, and a propensity for certain cancers.
Side-by-side photographs displayed by Professor Guarente vividly illustrate the condition. One shows a girl of 15; the other, the same person at 40, her hair straggly and gray, her skin wizened and her eyes drooping unevenly.
Werner's Syndrome sufferers appear to be twice their real age. Aged yeast cells, too, appear to be twice as old as they are in chronological time. What's more, they show up microscopically as enlarged cells with reduced capacities such as sterility.
Earlier research, published in Cell in May, measured yeast aging by determining the number of daughter cells that a mother cell can produce before dying. Mother and daughter yeast cells are differentiated microscopically on the basis of size.
As mother cells grow older, they undergo a number of changes: an increase in cell size and slowing of the cell cycle, loss of mating potential, and a decrease in the ability of old mother cells to produce small daughter cells with full life span potential.
The Cell article, by nine authors including Drs. Guarente and Sinclair and Mr. Mills, demonstrated that genes SIR2, SIR3, SIR4 and UTH4 determine life span in yeast. When these genes were deleted from a yeast strain, life span was significantly shortened. When they were overexpressed, the life span of mutant yeast extended well beyond that of the wild-type (i.e., unmutated) strain.
The research described in Cell showed that the gene products encoded by SIR2, SIR3 and SIR4 "move from the telomeres to the nucleolus, thereby promoting longevity," said Professor Guarente.
The article in Science reports further developments in the biologists' study of aging. The discovery of the action of SGS1, with its homologue in WRN, the rapid-aging gene, suggests we may one day discover what triggers and what slows the aging process itself.
In a summary, the MIT biologists wrote, "our data show that deletion of SGS1 causes premature aging in yeast on the basis of three phenotypes: (i) the average life span of SGS1 cells is about 40 percent of wild type, (ii) SGS1 cells prematurely assume the aging-associated sterility, while mutations in other yeast genes do not result in a shorter life span, or do not exhibit the age-specific phenotype of sterility, and (iii) the Sir protein silencing complex redistributes from telomeres to the nucleolus in old SGS1 cells, as observed in old wild-type cells."
The last part of their summary "harks back to the earlier paper. We also found that the effects of mutating SGS1 caused normal aging to occur at an accelerated pace," said Professor Guarente.
"The finding raises the possibility of locating a general aging mechanism. That would be important because we can study the aging process in a simple organism like yeast in order to learn general principles of aging," Professor Guarente said.
In fact, the authors found that old SGS1 cells, mutant or old wild-type, display a novel change: fragmentation of the nucleolus.
"Our findings indicate a particular cellular structure, the nucleolus, may be the Achilles' heel as cells get old," Professor Guarante said. "The nucleolus contains highly repeated copies of the ribosomal DNA (rDNA). This repeated nature of the rDNA may render it less stable than the rest of the genome and thereby make it vulnerable to the fragmentation that we see in old cells. We think this fragmentation of the nucleolus is a cause of aging."
The research described in Science opens the way for future study of the aging process. The next phase of investigation, said Professor Guarente, will include "one, establishing how general this mechanism of aging is in higher organisms such as humans, and two, answering the question, can we find a way to slow down the fragmentation of the nucleolus as a way to slow down aging?"
Dr. Sinclair is supported by the Helen Hay Whitney Foundation and Mr. Mills by a National Institutes of Health (NIH) predoctoral training grant. The Guarente lab is also supported by an NIH grant.
A version of this article appeared in MIT Tech Talk on September 10, 1998.