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Third Public Conference: Cellular Aging
and Apoptosis A Link Between Silencing, Metabolism and Aging Speaker Although calorie restriction has repeatedly been shown to increase
the longevity of rats, mice, and various other animals, it is not clear
why the skinny animals outlive their husky peers. Working in simpler
models, including yeast and C. elegans, Dr. Guarente has uncovered
a highly conserved gene that may bridge the conceptual gap between energy
status and life span. He has carried out this work as a Professor of
Biology at the Massachusetts Institute of Technology in Cambridge, having
previously been on the Harvard University faculty. Dr. Guarente has
a long association with the two institutions, having earned his Ph.D.
at Harvard after completing undergraduate work at MIT. His awards and
lectureships include election to the American Academy of Microbiology
in 1998, and being named Novartis Professor of Biology in 2000. Dr.
Guarente is a member of several editorial boards, including Genes
and Development, Trends in Genetics, and Journal of Anti-Aging
Medicine. Topic Proposed molecular explanations for aging include genome instability, oxidative damage, and changes in chromatin structure. Of the three, Dr. Guarente's data indicate that chromatin structure is the most important mechanism governing aging in yeast. Much of his research focuses on SIR2, a key gene for determining whether genetic material is active or silent. SIR2 can repress formation of ribosomal DNA circles that accumulate and are associated with aging in yeast. Yeast cells typically divide 20 to 25 times before entering senescence; in Dr. Guarente's experiments, deleting SIR2 reduced this number by half, so that yeast cells aged twice as fast. When extra SIR2 was added to the cells, on the other hand, their life span increased. SIR2 encodes a NAD-dependent histone deacetylase, which apparently silences aging-related parts of the yeast genome through selective deacetylation. Knowing that life extension has often been linked with calorie restriction, Dr. Guarente and his colleagues decided to test this idea in their model. When they limited the glucose available to yeast cells, life span was extended only if both SIR2 and adequate levels of NAD were present. If NAD synthesis was disrupted or SIR2 deleted, the cells lived no longer than amply nourished yeast cells. Moving up the ladder to C. elegans, Dr. Guarente showed that
transgenic worms given extra copies of SIR2 outlived their less well-endowed
peers. Higher animals, unlike yeast, don't accumulate rDNA circles with
advancing age. In worms, Dr. Guarente proposes that SIR2 increases longevity
by maintaining chromatin organization and silencing unstable parts of
the genome that might otherwise be mutated or inappropriately expressed.
Taken together, these findings link genome silencing with metabolic
rate and may provide a mechanistic connection between calorie restriction
and life extension.
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