Recently, our lab has discovered a highly conserved transcription factor and co-regulator required and specific for dietary restriction in C. elegans. We believe that these proteins form a core-signaling pathway that responds to and integrates an organism's response to reduced caloric intake. In our initiation of this project, we will understand the molecular mechanism by which this pathway perceives and interprets the environmental signals that ultimately result in increased longevity. SMK-1 was originally characterized as a co-regulator of the FOXO3a orthologue, DAF- 16, required to mediate insulin/IGF-1 signaling (IIS). In worms, DR and IIS appear to independently modulate longevity. Therefore, we were very surprised to find that smk-1 is also required to mediate the response to dietary restriction, although daf-16 is not. Because IIS and DR appear to regulate longevity by two distinct transcription factors, DAF-16 and PHA-4, respectively, we aim to establish an informatics platform of DR regulation by pha-4 to discern the conservation and differences between these two longevity cues (Aim I). With the identification of a single forkhead (pha-4) specific for dietary restriction, we are well poised to address an important physiological question in biology: which tissues register and respond to dietary restriction (Aim II)? In this set of experiments, we will restore wild-type copies of pha-4 to animals normally mutant in this gene using tissue specific promoters to direct expression. Finally (Aim III), using a proteomics approach, we will identify proteins that interact with PHA-4 during adulthood under conditions of dietary restriction. The identity of proteins which comprise the PHA-4 complex required for the response to DR will provide the framework to understand the entire molecular pathway upon which the response to diet restriction is mediated. Public Health Relevance: The importance of our studies on human health are multifold. The mechanism by which dietary restriction (DR) results in an extended lifespan is unknown but appears to be conserved across phyla, affecting the lifespan of organisms ranging from yeast to mammals. Our goal is to understand the molecular underpinnings of this pathway to allow manipulation of the DR response resulting in increased healthy lifespan without harmful effects on metabolism, development or reproduction.
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