Leonard Guarente

Leonard P. Guarente, PhD, MIT - Leonard Guarente formerly studied gene regulation in eukaryotes.  In these early studies, his lab first purified the TATA-binding protein TBP and cloned the gene, discovered UASs, identified the first heteromeric transcription factor (HAP2/3/4/5), and provided the first evidence for coactivators.  He then turned his studies to the mechanism of aging and its regulation using yeast and subsequently higher organisms.  His lab identified SIR2 as the key gene regulating life span in yeast and C. elegans – an extra copy of SIR2 significantly increases the life span of both organisms.  Notably, his lab first discovered the novel biochemical activity of the SIR2 gene product – NAD-dependent deacetylase.  This activity suggested that SIR2 might be involved in linking diet to the regulation of aging, addressing the longstanding question of how calorie restriction (CR) might slow aging.  His lab established a system of studying CR in yeast and showed that CR extended the life span in yeast mother cells by activating SIR2.  This activation requires up-regulation of electron transport, which increases the NAD/NADH ratio and activates Sir2p.  More recently, his lab has made several findings regarding the mammalian ortholog of SIR2, Sirt1.  This protein is also an NAD-dependent deacetylase.  Importantly, it controls several physiological processes impacted by CR.  First, Sirt1 renders cells stress resistant by inhibiting pro-apoptotic transcription factors p53 and forkhead.  Second, Sirt1 also promotes the mobilization of fat from white adipocytes upon food limitation.  It does this by inhibiting the factor PPARg, which is important promoting fat storage in white adipocytes.  Dr. Guarente’s findings show that the life and health extension by CR are not passive events, but result from the activation of Sirt1, which then impacts on cellular and organismal processes to deliver the benefits. 

Dr. Guarente received his B. S. from MIT and his Ph. D. at Harvard, under the supervision of Jon Beckwith.  He trained as a postdoctoral fellow at Harvard with Mark Ptashne and has been on the faculty of MIT since 1981, where he is the Novartis Professor of Biology.  His book Ageless Quest (Cold Spring Harbor Press, 2003) describes the pathway of discovery of SIR2 as a key regulator of life span in response to diet.   Read more: http://web.mit.edu/biology/guarente/