Leonard P. Guarente

Prof. Leonard P. Guarente is an American biologist best known for his research on life span extension in the budding yeast Saccharomyces cerevisiae, round worms Caenorhabditis elegans, and mice. He is currently a Novartis Professor of Biology at the Massachusetts Institute of Technology. (http://web.mit.edu/biology/guarente/)

Prof. Leonard Guarente of Biology Department, Massachusetts Institute of Technology

Based on the discovery that SIR2 is a key regulator of longevity in both yeast and worms, he is interested in determining whether this highly-conserved gene also governs longevity in other organisms, including mammals.

Science [edit]

Sir2 is the founding member of the Sirtuin family of enzymes. Prof. Guarente is recognized as the leading proponent of the hypothesis that caloric restriction slows aging by activation of Sirtuins.

Initial discovery that happened in 1995 identified gene SIR4 (Silent information regulator 4) as a longevity regulator. When SIRT4 was mutated in a single cell organism Saccharomyces cerevisiae [1 longevity was extended. It was later determined that the complex of SIR2 and SIR4 are responsible for longevity phenotype [2, and that over-expression of SIR2 alone was sufficient to extend lifespan. Moreover, scientists in Guarente laboratory determined that SIR2 is necessary for longevity extension by Calorie Restriction [3.

Imai Shin, a postdoctoral fellow in the laboratory of Leonard Guarente determined that SIR2 was an enzyme. It was NAD+-dependent protein de-acetylase [4. This NAD dependence explained how SIR2 could connect diet to physiology and suggested the mechanism, by which Calorie Restriction (CR) could extend lifespan.

The involvement of SIR2 in the metabolism and lifespan determination appeared to be conserved in other organisms. In round worm, Caenorhabditis elegans, expression of SIR2 (sir2.1) is sufficient to extend longevity [5. In fruit fly, Drosophila melanogaster, overexpression of sir2 also extended lifespan [6. Overexpression of SIRT1 (mammalian sir2 homolog) in mice improved their health and retarded numerous age-associated diseases [7.

Leonard Guarente has written an autobiography titled "Ageless Quest: One Scientist's Search for Genes That Prolong Youth". The book was published in 2003 by Cold Spring Harbor Press.

Over the last decade, it was unambiguously shown that sirtuins regulate aging processes and play an important role in diseases of aging in mammals in general and in humans in particular. Some of the peer-reviewed publications on this subject are collected here (http://web.mit.edu/biology/guarente/publications/).

References [edit]

1. Kennedy, B.K., et al., Mutation in the silencing gene SIR4 can delay aging in S. cerevisiae. Cell, 1995. 80(3): p. 485-96.

2. Kaeberlein, M., M. McVey, and L. Guarente, The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev, 1999. 13(19): p. 2570-80.

3. Lin, S.J., P.A. Defossez, and L. Guarente, Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science, 2000. 289(5487): p. 2126-8.

4. Imai, S., et al., Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature, 2000. 403(6771): p. 795-800.

5. Tissenbaum, H.A. and L. Guarente, Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature, 2001. 410(6825): p. 227-30.

6. Rogina, B. and S.L. Helfand, Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci U S A, 2004. 101(45): p. 15998-6003.

7. Bordone, L., et al., SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell, 2007. 6(6): p. 759-67.