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Molecular Analysis of Aging

Leonard Guarente

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Department of Biology 68-280, Massachusetts Institute of Technology, Cambridge, MA 02139

Dr. Guarente and his colleagues are interested in discerning molecular causes of aging. Two approaches have led to the conclusion that specific changes in the rDNA of the nucleolus cause aging. In the first, a genetic study of aging was initiated in the budding yeast S. cerevisiae. In this organism, mother cells divide a fixed number of times and undergo phenotypic changes as they age. A key gene in this process is SIR4, which is involved in silencing at HML, HMR, and telomeres. An allele of SIR4, SIR4-42, extends life span by redirecting the SIR complex from telomeres to the rDNA. Strikingly, the redirection of the SIR complex occurs selectively in aging wild type cells to promote greater longevity. This study led to the model that deleterious changes in the nucleolus lead to aging and that a genetic response to stall these changes is the redirection of the SIR complex. In a second study, we have analyzed the yeast homolog of WRN, encoding a DNA helicase defective in the premature aging disease, WernerÕs Syndrome. Disruption of this yeast gene, SGS1, lead to premature aging in yeast mother cells. SGS1p is concentrated in the nucleolus in wild type cells. Strikingly, in old SGS1 mutant cells, as well as in old wild type cells, rDNA circles have popped out of genomic DNA and accumulated to high copy as extrachomosomal rDNA circles (ERCs). If the generation of ERCs is sped up or slowed down by genetic means, corresponding changes in the pace of aging are observed, demonstrating that ERCs are a cause of aging. The possible generality of WRN-DNA helicases and rDNA changes in mammalian aging is currently being assessed.

Kennedy et al. 1997. Cell 89: 381-391.

Sinclair et al. 1997. Science 277: 1313-1316.

Sinclair and Guarente. 1997. Cell 91: 1033-1042.

Dr. Guarente is Professor of Biology at Massachusetts Institute of Technology. He received his B.S. in biology from MIT and his Ph.D. in molecular genetics from Harvard University. He was the Jane Coffin Childs Postdoctoral Fellow at Harvard from 1978 to 1981, and was appointed Assistant Professor of Biology at MIT in 1981. He was named a full professor in 1991. The author of more than 120 publications, Dr. Guarente serves on the editorial boards of Genes and Development, Trends in Genetics, and the Journal of Anti-Aging Medicine. Since 1994, he has been serving on the NIH Molecular Biology Study Section.