This proposal is about intrinsic mechanisms of aging, which are inherent and always occur during the normal aging process. Intrinsic mechanisms involve an internal clock that specifies lifespan during normal aging. Besides damage accumulation, another mechanism for intrinsic aging has recently been found in C. elegans termed developmental drift. Developmental pathways are established in the young adult to guide the formation of different tissues. Key regulators of these developmental pathways become aberrantly expressed in old age, leading to a cascade of changes in expression of downstream genes that has detrimental effects on tissue function and that limits lifespan. Developmental drift is conceptually novel because it proposes that that old worms are not the same as young worms with damage accumulation. Rather, old worms have inherent, programmed differences that make them more susceptible to degeneration and death. This proposal uses C. elegans as a model system because of its short two week lifespan and powerful genetic tools. DNA microarray experiments have been used to define a molecular signature for aging that includes 1254 genes that differ in expression between young and old worms. Seven transcription factors have previously been identified as candidates that may be responsible for these age-related changes. All seven transcription factors are key regulators of development in diverse tissues, such as the intestine and the skin. This proposal will use ChIP SEQ experiments to determine whether these transcription factors are directly responsible for causing expression of their downstream genes to change with age. Expression experiments using an automatic cell lineage analyzer to digitize images of GFP-expressing worms will be used to extract precise expression data from individual cells. These data will show how expression of the seven transcription factors changes with age. Transgenic worms will be engineered to convert old worms into young worms;specifically, expression of the seven aging regulators in old worms will be altered to resemble expression found in young worms, and then lifespan experiments will be used to test whether converting worms to their younger state is beneficial. A key prediction of the developmental drift hypothesis is that changes in old age should resemble changes that occur during development. This will be tested by finding out if the network of genes directly downstream of a transcription factor during aging are the same as its downstream network during development.

Public Health Relevance

This proposal is about a new mechanism for aging called Developmental Drift, which explains how animals change as they grow older and how this makes them more susceptible to disease. Developmental drift will be studied in C. elegans, which has the shortest lifespan of any model organism and provides the most powerful system to study aging. The basic principles for normal aging uncovered in this proposal are likely to be relevant to humans and is of the utmost concern as the US population continues to age.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG025941-07
Application #
8634006
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Guo, Max
Project Start
2005-04-01
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
7
Fiscal Year
2014
Total Cost
$321,850
Indirect Cost
$116,850
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; Kleimeyer, John P; Ahmed, Marwa A et al. (2017) Two genetic loci associated with ankle injury. PLoS One 12:e0185355
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
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
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
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
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
Locke, Adam E (see original citation for additional authors) (2015) Genetic studies of body mass index yield new insights for obesity biology. Nature 518:197-206
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

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