EAGER: Antagonistic Pleiotropy in JNK signaling: mechanisms and implications for aging

University Of California-Berkeley, Berkeley CA

Investigators

Abstract

What causes aging is far from clear, but the theory of "antagonistic pleiotropy" postulates that aging is a consequence of the inverse correlation between age and selection pressure. Such a correlation allows positive selection of mechanisms with early-life beneficial effects, in spite of potential late-life detrimental effects. Understanding when and how such mechanisms become detrimental is crucial for understanding both the principles and constraints directing the evolution of aging, as well as the aging process itself. We recently identified a novel example of antagonistic pleiotropy. The current project will characterize this mechanism at the molecular level. In the nematode Caenorhabditis elegans the conserved protein KGB-1 provides protection during development against heavy metals and protein folding stress, but becomes detrimental during early adulthood by sensitizing animals to environmental stress and shortening their lifespan. Although little is known about KGB-1's targets and interactions, our recent work suggests that some of the age-dependent changes occurring following KGB-1 activation are mediated by age-dependent regulation of the longevity-associated transcription factor DAF-16. This project will: 1) characterize genetically age-dependent interactions between KGB-1 and DAF-16, as well as interactions between KGB-1 and proteins of the insulin signaling pathway, which regulates DAF-16; 2) identify, through genomic analysis, yet unknown targets of KGB-1 in developing larvae and in young adults, focusing on transcriptional targets and their regulators. Use of the genetically tractable C. elegans model organism allows pursuing the project's goals in the context of a whole animal, and provides an opportunity to flesh out a fundamental feature of the evolution of aging. Understanding aging is of increasing importance as biomedical advances increase human lifespan. The project will provide opportunities for training undergraduate and graduate students in scientific research, among them individuals from typically underrepresented groups, encouraging students to participate in scientific meetings and earning them, when appropriate, authorship on publications.