The focus of this proposal is to extend and deepen our understanding of the mechanisms underlying the increased life expectancy of long-lived (Age) mutants in the nematode Caenorhabditis elegans. These mutants have revealed the intimate relationship between increased longevity and an increased ability to respond to stress. The best understood class of these Age mutants are those which also affect dauer development and adult survival, resulting in two-fold or more increases in life expectancy. Mutants in this pathway, such as age-1/daf 23 (phosphatidyl inositol 3' kinase or PI3K) and daf-2 are clearly involved in signal transduction. We hypothesize that a normal function of this pathway is to produce a signal cascade in response to exogenous stress. When altered (such as occurs in age-1 or daf-2 mutants), there is a disruption of an intracellular kinase cascade which leads to altered activity of a variety of downstream effector molecules that result in an increased response to stress and increased longevity. Consistent with this expectation, using candidate-gene approaches, we have identified a novel gene (tkr-1) that extends life when over expressed. tkr-1 differs from the previously identified """"""""gerontogenes"""""""" in that 1) it was not identified by mutation and (2) over expression leads to extended longevity.
The Aims of this grant are focused on testing and extending the hypothesis that tkr-1 and other gerontogenes (age-1, daf-2, and others) function in the same or interlocking signal-transduction pathways that determine the ability of these worms to respond to stress and that a major mechanism of life extension is through increased resistance to stress. To accomplish these Aims, we will combine genetic, molecular and candidate-gene approaches, taking advantage both of the powerful genetics, as well as the almost completed genomic sequence, of C. elegans. We propose complementary sets of approaches to achieve these objectives: Molecular characterization of tkr-1 and genetic and molecular characterization of downstream targets of tkr-1.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Molecular Cytology Study Section (CTY)
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Mccormick, Anna M
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University of Colorado at Boulder
Other Domestic Higher Education
United States
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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

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