Dec. 25, 1997 CAMBRIDGE, Mass.--MIT biologists have identified a mechanism of aging in yeast cells that suggests researchers may one day be able to intervene in, and possibly inhibit, the aging process in certain human cells.
The mechanism of aging, it turns out, is elegant in its simplicity. During a yeast cell's life, whenever a particular, coiled piece of DNA pinches off from one of its chromosomes, that extrachromosomal ribosomal DNA (ERC) replicates until the cell becomes overwhelmed and dies. Aging in yeast cells is started by the formation of that first ERC.
"The best part is, it's obvious it's a clock," said Leonard Guarente, Professor of Biology, referring to the ERCs' role in yeast cell mortality. "Set the clock early and the alarm rings early."
An article to be published in the December 26 Cell culminates a year's published work on this topic (articles appeared in Cell, Science and now Cell, again). The piece, co-authored by David A. Sinclair, a postdoctoral fellow in biology at MIT, and Professor Guarente, also communicates the researchers' enthusiasm for the work, with an overtone of wonder at its broad implications and precise beauty.
"It is remarkable that this mechanism of aging in mother yeast cells is so simple at a molecular level," the biologists wrote. "It is conceivable that inhibitors of this (aging) process can be found and if so, such strategies might eventually prove useful in forestalling aging in yeast and, perhaps, in higher organisms."
The discovery of the simple role of ERCs in cell aging and death has a profound appeal well beyond the laboratory. Indeed, William Shakespeare, a man of powerful intuition and observation, would be pleased to learn how closely Hamlet's phrase denoting mortality -- the "mortal coil" -- portrays an actual molecular drama. A drawing of ERCs in action shows that an aging yeast mother cell is full -- fatally full -- of little mortal coils.
PREVIOUS WORK: THE FOUNDATION
The MIT biologists' current research builds on two related discoveries published earlier this year in the magazines Cell and Science magazines.
The article published in Cell in May measured normal aging in yeast by determining the number of daughter cells a mother cell could produce before dying. Mother and daughter yeast cells are differentiated by their size: mother cells are bigger.
That article, by nine authors including Drs. Guarente, Sinclair and Mr. Kevin Mills, a graduate student in biology, also demonstrated that yeast genes SIR2, SIR3, SIR4, and UTH4 determine the life span in yeast. When these genes were deleted from a yeast strain, life span was shortened. When they were overexpressed, the life span of the yeast strain was extended.
The research also showed that the gene products encoded by SIR2, SIR3 and SIR4 promote cell longevity by moving from one cell structure to another (from the telomeres to the nucleolus). This action and the fragmentation of the nucleolus would form the basis of more groundbreaking discoveries.
A second article, published in Science magazine in August, reported further refinement in the MIT biologists' study of aging. This research, reported by Dr. Sinclair and Professor Guarente, identified the crucial role played by another yeast gene, SGS1, in determining the life span of yeast cells.
The gene SGS1 has a DNA code that corresponds structurally to the human gene, WRN. Mutations in WRN result in Werner's Syndrome, a disease whose symptoms resemble a fast-forward aging process. The MIT biologists demonstrated that experimental mutation of SGS1 -- the yeast homolog for WRN -- produced symptoms of aging in yeast cells.
Again, the biologists noted how aged SGS1 yeast cells displayed fragmentation of the nucleolus.
"Our findings indicate a particular cellular structure, the nucleolus, may be the Achilles' heel as cells get old. We think this fragmentation of the nucleolus is a cause of aging," Professor Guarente commented at the time.
The next phase of research would include "answering the question, can we find a way to slow down the fragmentation of the nucleolus as a way to slow down aging?" Professor Guarente said.
NEW RESEARCH: THAT MORTAL COIL
"Strikingly, the nucleolus of old SGS1 cells is enlarged and fragmented, and the following findings indicate that these changes may represent a cause of aging," wrote the authors in an introduction to the December 26th article in Cell. "We thus sought to identify the molecular events embodied by the enlarged and fragmented nucleoli of old cells."
First, the researchers tackled nucleolar enlargement. This, they discovered, was caused by ERCs -- the supercoiled circular form of DNA -- accumulating abundantly in old yeast cells. They named the supercoiled circular molecules "ERCs" -- extrachromosomal rDNA circles -- and showed that accumulation of ERCs is a general phenomenon that occurs as cells age.
Next, the researchers noted that the ERCs accumulated in yeast mother cells but not in daughter cells and that mother cells were subject to aging (i.e. sterility) due to this asymmetrical accumulation. Replicating ERCs were also presumed to cause enlargement and fragmentation of the nucleolus in mother cells.
But old age is not death, and the researchers still wondered, How do ERCs kill cells?
They suggest that the sheer abundance of ERCs could gum up components of the mother cells' replication machinery, leading to an inability to replicate the DNA necessary for life.
A WONDROUS PARADOX
Armed with data suggesting that the accumulation of ERCs may be the aging clock itself, the researchers wondered, what set the fatal accumulation in motion? What, as Professor Guarente inquired above, could "set the clock early (so) the alarm rings early"?
Their experimental results suggest a paradox. The formation of ERCs may be a result of damage to rDNA; that is, ERCs may be the cell's attempt to repair itself. Yet, the very mechanism which saves the cell becomes its "mortal coil" as ERCs "accumulate exponentially in mother cells resulting in fragmented nucleoli, cessation of cell division, and cellular senescence," the authors wrote.
Intriguingly, a yeast cell need not itself be damaged to set the mortal clock in motion. ERCs, the researchers note, can be inherited, with the same effect.
Near the concluding section of the Cell article, the authors wrote, "Once an ERC is formed or inherited, the period of time until a lethal number of ERCs has accumulated ... may be the clock that determines the life span of the cell."
The implications of the MIT research include possibilities of inhibiting the process of ERC-formation in mother yeast cells and in cells of higher organisms where cell division is asymmetrical. These latter cells -- known as stem or progenitor cells in mammals -- are found in organs such as the skin, kidney, liver and blood.
The authors suggest, too, that yeast mother cells may be analogous to mammalian stem or progenitor cells, just as SGS1 was homologous to the human WRN gene. Thus, the next phases of aging research have been defined by the MIT biologists' groundbreaking work.
Next, "it will be important to determine whether ERCs or other circular DNAs accumulate in stem cells of aging mice and humans," the authors wrote.
David Sinclair is supported by the Helen Hay Whitney Foundation. The Guarente lab is supported by a National Institutes of Health grant.
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