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.
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.
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