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 #
3R01AG025941-05S1
Application #
8461371
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Guo, Max
Project Start
2007-05-01
Project End
2013-02-28
Budget Start
2012-05-01
Budget End
2013-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$94,200
Indirect Cost
$34,200
Name
Stanford University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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
Zimmerman, Stephanie M; Hinkson, Izumi V; Elias, Joshua E et al. (2015) Reproductive Aging Drives Protein Accumulation in the Uterus and Limits Lifespan in C. elegans. PLoS Genet 11:e1005725
Goodlin, Gabrielle T; Roos, Thomas R; Roos, Andrew K et al. (2015) The dawning age of genetic testing for sports injuries. Clin J Sport Med 25:1-5
Gierman, Hinco J; Fortney, Kristen; Roach, Jared C et al. (2014) Whole-genome sequencing of the world's oldest people. PLoS One 9:e112430
Zimmerman, Stephanie M; Kim, Stuart K (2014) The GATA transcription factor/MTA-1 homolog egr-1 promotes longevity and stress resistance in Caenorhabditis elegans. Aging Cell 13:329-39
Goodlin, Gabrielle T; Roos, Andrew K; Roos, Thomas R et al. (2014) Applying personal genetic data to injury risk assessment in athletes. PLoS One 10:e0122676
Zhang, Xiaoling; Gierman, Hinco J; Levy, Daniel et al. (2014) Synthesis of 53 tissue and cell line expression QTL datasets reveals master eQTLs. BMC Genomics 15:532
Aerni, Sarah J; Liu, Xiao; Do, Chuong B et al. (2013) Automated cellular annotation for high-resolution images of adult Caenorhabditis elegans. Bioinformatics 29:i18-26
Van Nostrand, Eric L; Sánchez-Blanco, Adolfo; Wu, Beijing et al. (2013) Roles of the developmental regulator unc-62/Homothorax in limiting longevity in Caenorhabditis elegans. PLoS Genet 9:e1003325
Cho, Ukrae; Zimmerman, Stephanie M; Chen, Ling-chun et al. (2013) Rapid and tunable control of protein stability in Caenorhabditis elegans using a small molecule. PLoS One 8:e72393

Showing the most recent 10 out of 23 publications