We are using the nematode, C. elegans, as a model system for aging because it has a short lifespan, a powerful genetic toolkit and many mutants are already known to lengthen lifespan. Our goal is to identify genes that are differentially expressed in old versus young animals, and then to use these genes as molecular markers to dissect apart mechanisms of aging. We used DMA microarray to perform genome-wide screens for genes that change expression in old worms, in the dauer state and in two insulin-like signaling mutants with altered lifespans. By combining the expression results from these DNA microarray experiments, we identified a core set of 733 genes that show consistent changes in expression across different aging experiments. Interestingly, we discovered that the age-regulated genes are regulated by a GATA transcriptional circuit involving the elt-3 and egr-1 GATA transcription factors. Elt-3(+) and egr-1 (+) both promote longevity since RNAi treatment of either gene suppresses the longevity phenotype of daf-2 mutants Furthermore, expression of both genes decrease during normal aging, and causes changes in downstream aging target genes. From the large set of aging-regulated genes, we have generated a set of GFP aging reporter genes that will allow us to examine the process of aging at the molecular level.
In specific aim 1, we will use expression levels of the GFP aging markers as molecular clocks for aging, allowing us to study aging mechanisms such as whether there is a similar effect of aging in different tissues, and whether the GFP aging markers can predict the remaining life spans of worms while they are still alive.
In specific aim 2, we will analyze the functions of the elt-3 and egr-1 GATA genes that control expression of the downstream aging markers. In particular, we will test whether we can either speed up or slow down the rate of aging by decreasing or increasing expression of these two aging regulators.
In specific aim 3, we will examine upstream control of the elt-3/egr-1 GATA transcriptional network, such as regulation by the insulin-like signaling pathway. In addition, we will determine whether age-related changes in this transcriptional network are due to extrinsic factors such as cellular damage or to an intrinsic genetic pathway that first regulates elt-3 during development and that might continue to regulate elt-3 during aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG025941-03
Application #
7602970
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Mccormick, Anna M
Project Start
2007-05-01
Project End
2012-04-30
Budget Start
2009-05-15
Budget End
2010-04-30
Support Year
3
Fiscal Year
2009
Total Cost
$283,215
Indirect Cost
Name
Stanford University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Kim, Stuart K (2018) Identification of 613 new loci associated with heel bone mineral density and a polygenic risk score for bone mineral density, osteoporosis and fracture. PLoS One 13:e0200785
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Mann, Frederick G; Van Nostrand, Eric L; Friedland, Ari E et al. (2016) Deactivation of the GATA Transcription Factor ELT-2 Is a Major Driver of Normal Aging in C. elegans. PLoS Genet 12:e1005956
Frøkjær-Jensen, Christian; Jain, Nimit; Hansen, Loren et al. (2016) An Abundant Class of Non-coding DNA Can Prevent Stochastic Gene Silencing in the C. elegans Germline. Cell 166:343-357
Zimmerman, Stephanie M; Kim, Stuart K (2016) New insights into old worm proteomes. Worm 5:e1184391
Sánchez-Blanco, Adolfo; Rodríguez-Matellán, Alberto; González-Paramás, Ana et al. (2016) Dietary and microbiome factors determine longevity in Caenorhabditis elegans. Aging (Albany NY) 8:1513-39
Ehret, Georg B (see original citation for additional authors) (2016) The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nat Genet 48:1171-1184
Shungin, Dmitry (see original citation for additional authors) (2015) New genetic loci link adipose and insulin biology to body fat distribution. Nature 518:187-196
Fortney, Kristen; Dobriban, Edgar; Garagnani, Paolo et al. (2015) Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity. PLoS Genet 11:e1005728
Dobriban, Edgar; Fortney, Kristen; Kim, Stuart K et al. (2015) Optimal multiple testing under a Gaussian prior on the effect sizes. Biometrika 102:753-766

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