Aging has been shown to be under genetic control in model organisms. One of the genes that determines longevity in yeast and C. elegans (roundworms) is SIR2. The greater the activity of SIR2, the longer the life span in these organisms. The biochemical activity of Sir2 protein is that of an NAD-dependent histone deacetylase. A major challenge now is to determine how this activity might determine life span and whether the longevity dictated by SIR2 is subject to physiological regulation. One established physiological regimen that has been shown to extend life span is calorie restriction (CR). Limiting the calories in the diet extends the life spans of rodents, fruit flies, worms, and yeast. The mechanism by which CR extends life span is not clear. In yeast the extension induced by CR requires SIR2, implying that Sir2 protein and NAD are involved in the mechanism. In this proposal we will establish a petri plate-based replica of CR in worms and test the possible involvement of the sir-2 genes of this animal in the response to CR. Further, we will probe by genetic and molecular approaches how the sir-2.1 gene of C. elegans extends life span in this animal by regulating the known pathway of insulin signaling in worms. These studies ought to pinpoint the roles that the four sir genes play in the determination of life span in C. elegans. They also may shed light on a molecular mechanism of CR in an animal. These findings may have direct relevance to aging and the extension of life span by CR in mammals.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG021150-01
Application #
6508833
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Mccormick, Anna M
Project Start
2002-07-01
Project End
2007-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$316,392
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Ondracek, Caitlin R; Frappier, Vincent; Ringel, Alison E et al. (2017) Mutations that Allow SIR2 Orthologs to Function in a NAD+-Depleted Environment. Cell Rep 18:2310-2319
Chang, Hung-Chun; Guarente, Leonard (2014) SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab 25:138-45
Libert, Sergiy; Guarente, Leonard (2013) Metabolic and neuropsychiatric effects of calorie restriction and sirtuins. Annu Rev Physiol 75:669-84
Libert, Sergiy; Bonkowski, Michael S; Pointer, Kelli et al. (2012) Deviation of innate circadian period from 24 h reduces longevity in mice. Aging Cell 11:794-800
Chalkiadaki, Angeliki; Guarente, Leonard (2012) High-fat diet triggers inflammation-induced cleavage of SIRT1 in adipose tissue to promote metabolic dysfunction. Cell Metab 16:180-8
Blander, Gil; Olejnik, Jerzy; Krzymanska-Olejnik, Edyta et al. (2005) SIRT1 shows no substrate specificity in vitro. J Biol Chem 280:9780-5