Numerous mutations that increase the life span of the nematode Caenorhabditis elegans have been identified. Many of these are evolutionarily conserved. There is a compelling case that increased stress resistance is involved in increased longevity; however, the specific molecular mechanisms underlying this stress resistance are mostly unknown. Also unknown are what type(s) of stress resistance (resistance to oxidative damage, mutations in DNA, refolding of denatured proteins, etc.) are most crucial to increased longevity. It is also unclear to what extent differential tissue-specificity of stress resistance is important for enhanced longevity. The nematode is an efficient system for exploring tissue-specificity during aging because it is short-lived but multicellular, allowing the study of important aspects of metazoan response to stress that cannot be explored in single-celled organisms. We intend to identify necessary effectors, as well as those that are sufficient for mounting a stress response. We propose an integrated set of methods for addressing these issues. Our general hypothesis is that the ability to resist stress is a necessary part of the life-extension mechanism(s) in C. elegans. (We already know that stress-resistance is not sufficient.) We have previously isolated mutants showing altered response to the intracellular superoxide-generating quinone: juglone, and demonstrated that some O2-stress resistant mutants have increased mean and maximal life spans. We will extend these studies both by selecting more stress-resist mutants and by identifying mutants using novel high-throughput strategies. These studies will also address whether these changes are dependent on known regulatory proteins like DAF-16 and will utilize microarray-based studies to complement the mutational and RNAi approaches, as they can identify critical genes and gene products that might be missed by transcription-based analyses (e.g., heat shock factor). ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG016219-05
Application #
6822108
Study Section
Special Emphasis Panel (ZRG1-BDA-D (02))
Program Officer
Mccormick, Anna M
Project Start
1999-08-01
Project End
2009-07-31
Budget Start
2004-09-15
Budget End
2005-07-31
Support Year
5
Fiscal Year
2004
Total Cost
$387,979
Indirect Cost
Name
University of Colorado at Boulder
Department
Genetics
Type
Other Domestic Higher Education
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
Johnson, Thomas E (2013) 25 years after age-1: genes, interventions and the revolution in aging research. Exp Gerontol 48:640-3
Cypser, James R; Wu, Deqing; Park, Sang-Kyu et al. (2013) Predicting longevity in C. elegans: fertility, mobility and gene expression. Mech Ageing Dev 134:291-7
Wu, Deqing; Tedesco, Patricia M; Phillips, Patrick C et al. (2012) Fertility/longevity trade-offs under limiting-male conditions in mating populations of Caenorhabditis elegans. Exp Gerontol 47:759-63
Park, Sang-Kyu; Link, Christopher D; Johnson, Thomas E (2010) Life-span extension by dietary restriction is mediated by NLP-7 signaling and coelomocyte endocytosis in C. elegans. FASEB J 24:383-92
Ventura, Natascia; Rea, Shane L; Schiavi, Alfonso et al. (2009) p53/CEP-1 increases or decreases lifespan, depending on level of mitochondrial bioenergetic stress. Aging Cell 8:380-93
Park, Sang-Kyu; Tedesco, Patricia M; Johnson, Thomas E (2009) Oxidative stress and longevity in Caenorhabditis elegans as mediated by SKN-1. Aging Cell 8:258-69
Wu, Deqing; Cypser, James R; Yashin, Anatoli I et al. (2009) Multiple mild heat-shocks decrease the Gompertz component of mortality in Caenorhabditis elegans. Exp Gerontol 44:607-12
Wu, Deqing; Rea, Shane L; Cypser, James R et al. (2009) Mortality shifts in Caenorhabditis elegans: remembrance of conditions past. Aging Cell 8:666-75
Budovskaya, Yelena V; Wu, Kendall; Southworth, Lucinda K et al. (2008) An elt-3/elt-5/elt-6 GATA transcription circuit guides aging in C. elegans. Cell 134:291-303
Johnson, Thomas E (2008) Caenorhabditis elegans 2007: the premier model for the study of aging. Exp Gerontol 43:1-4

Showing the most recent 10 out of 29 publications