Person:

Stroustrup, Nicholas Edward

The measurement of lifespan pervades aging research. Because lifespan results from complex interactions between genetic, environmental and stochastic factors, it varies widely even among isogenic individuals. The action of molecular mechanisms on lifespan is therefore visible only through their statistical effects on populations. Survival assays in C. elegans provided critical insights into evolutionarily conserved determinants of aging. To enable the rapid acquisition of survival curves at arbitrary statistical resolution, we developed a scalable imaging and analysis platform to observe nematodes over multiple weeks across square meters of agar surface at 8 μm resolution. The method generates a permanent visual record of individual deaths from which survival curves are constructed and validated, producing data consistent with the manual method for several mutants in both standard and stressful environments. Our approach allows rapid, detailed reverse-genetic and chemical screens for effects on survival and enables quantitative investigations into the statistical structure of aging.

Insulin-like peptides (ILPs) play highly conserved roles in development and physiology. Most animal genomes encode multiple ILPs. Here we identify mechanisms for how the forty Caenorhabditis elegans ILPs coordinate diverse processes, including development, reproduction, longevity and several specific stress responses. Our systematic studies identify an ILP-based combinatorial code for these phenotypes characterized by substantial functional specificity and diversity rather than global redundancy. Notably, we show that ILPs regulate each other transcriptionally, uncovering an ILP-to-ILP regulatory network that underlies the combinatorial phenotypic coding by the ILP family. Extensive analyses of genetic interactions among ILPs reveal how their signals are integrated. A combined analysis of these functional and regulatory ILP interactions identifies local genetic circuits that act in parallel and interact by crosstalk, feedback and compensation. This organization provides emergent mechanisms for phenotypic specificity and graded regulation for the combinatorial phenotypic coding we observe. Our findings also provide insights into how large hormonal networks regulate diverse traits.