Coburn, CK; (2012) The biology of death in Caenorhabditis elegans. Doctoral thesis , UCL (University College London).

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Abstract

The model organism Caenorhabditis elegans has been extensively studied in biogerontology. A putative mechanism of ageing is oxidative damage, but this has been challenged in recent studies. One piece of supporting evidence for the role of molecular damage in C. elegans ageing is the presence of blue fluorescent material within intestinal lysosome related organelles, believed to be lipofuscin. This heterogenous, cross-linked aggregate of oxidatively damaged lipids and proteins that accumulates in an age-dependent fashion in post-mitotic mammalian cells. Lipofuscin can be identified by its fluorescent properties, fluorescing blue under UV light. C. elegans intestinal fluorescence has been equated with lipofuscin based on its similar spectral properties, and its increase in ageing populations. This investigation initially set out to verify this assumption. Individual animals were followed in situ on agar pads and their in vivo fluorescence measured from early adulthood until after death. Intestinal blue fluorescence proved to increase not with age, but instead in a striking burst at death. Such death fluorescence also appeared in young worms when killed, irrespective of age or cause of death. Using NMR-based comparative metabolomics the blue fluorophore was identified as anthranilic acid, derived from tryptophan by kynurenine pathway activity. Death fluorescence is generated within intestinal cells, typically in an anterior to posterior wave, by action of the conserved calpain-cathepsin necrotic cell death pathway, a type of cell death previously only observed during neurodegeneration. Using mutational analysis and in vivo fluorescent reporters, we demonstrate that this wave is propagated by calcium influx. Strikingly, inhibition of systemic necrosis delays stress-induced mortality, demonstrating its role as a driver of organismal death. This first description of the biology of death in C. elegans implies that the passage from life to death entails a regulated, programmed transition that is amenable to analysis.

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