During the past decade, it has become clear that the rate of aging, like many other processes in biology, is subject to regulation. In many animals, including mammals, longevity is regulated by a conserved insulin- and IGF-l-like signaling pathway. This longevity system was discovered in the genetically-tractable organism C. elegans, and a great deal about it has been learned by studying this animal. In C. elegans, DAF-2, an insulin/IGF-l-like receptor, activates a conserved signal transduction pathway that inhibits longevity, at least in part, by inhibiting the activity of the transcription factor DAF-16. In mutants defective in this signaling pathway, DAF-16 accumulates in the nucleus and coordinates expression of a battery of diverse downstream genes that together produce dramatic extensions of lifespan. This study addresses key, unsolved questions about this signaling pathway. Sensory neurons regulate the DAF-2 pathway, possibly in response to environmental cues, and this study tests the hypothesis that sensory neurons influence lifespan by controlling the production or release of specific insulin-like peptides. The C. elegans heat-shock transcription factor, HSF-1, which regulates the highly-conserved heat-shock response, acts with DAF-16 to regulate the expression of genes required for youthfulness and longevity. This study will determine how HSF-1 activity is regulated and how it functions in this system. Finally, a large number of genes with unknown functions act in this system to influence longevity. This study will better define the biochemical roles that these genes play in the aging process. Together these studies may ultimately define new therapeutic strategies for combating age-related disease and increasing the quality of old age.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG011816-20
Application #
8433362
Study Section
Special Emphasis Panel (NSS)
Program Officer
Guo, Max
Project Start
1994-04-01
Project End
2014-03-31
Budget Start
2013-05-15
Budget End
2014-03-31
Support Year
20
Fiscal Year
2013
Total Cost
$353,219
Indirect Cost
$124,598
Name
University of California San Francisco
Department
Biochemistry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Zhang, Peichuan; Judy, Meredith; Lee, Seung-Jae et al. (2013) Direct and indirect gene regulation by a life-extending FOXO protein in C. elegans: roles for GATA factors and lipid gene regulators. Cell Metab 17:85-100
Safra, Modi; Ben-Hamo, Shani; Kenyon, Cynthia et al. (2013) The ire-1 ER stress-response pathway is required for normal secretory-protein metabolism in C. elegans. J Cell Sci 126:4136-46
Tank, Elizabeth M H; Rodgers, Kasey E; Kenyon, Cynthia (2011) Spontaneous age-related neurite branching in Caenorhabditis elegans. J Neurosci 31:9279-88
Kao, Aimee W; Eisenhut, Robin J; Martens, Lauren Herl et al. (2011) A neurodegenerative disease mutation that accelerates the clearance of apoptotic cells. Proc Natl Acad Sci U S A 108:4441-6
Henis-Korenblit, Sivan; Zhang, Peichuan; Hansen, Malene et al. (2010) Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity. Proc Natl Acad Sci U S A 107:9730-5
Lee, Seung-Jae; Kenyon, Cynthia (2009) Regulation of the longevity response to temperature by thermosensory neurons in Caenorhabditis elegans. Curr Biol 19:715-22
Lee, Seung-Jae; Murphy, Coleen T; Kenyon, Cynthia (2009) Glucose shortens the life span of C. elegans by downregulating DAF-16/FOXO activity and aquaporin gene expression. Cell Metab 10:379-91
Gaglia, Marta Maria; Kenyon, Cynthia (2009) Stimulation of movement in a quiescent, hibernation-like form of Caenorhabditis elegans by dopamine signaling. J Neurosci 29:7302-14
Alcedo, Joy; Kenyon, Cynthia (2004) Regulation of C. elegans longevity by specific gustatory and olfactory neurons. Neuron 41:45-55
Libina, Nataliya; Berman, Jennifer R; Kenyon, Cynthia (2003) Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan. Cell 115:489-502

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