We have uncovered a novel genetic pathway that determines adult lifespan in the nematodeCaenorhabditis elegans. This pathway encodes components of DNA damage/cell cycle checkpoints, whichare known to prevent inappropriate cell division. However, because non-dividing cells comprise the C.elegans adult soma, it appears that these checkpoint proteins also control the survival of cells in a postmitoticstate. Down-regulation of checkpoint functions in adult C. elegans renders them very stress resistantand extends their lifespan. Through a whole genome RNA interference screen, we determined that manynovel genes encode checkpoint functions and influence lifespan. We now propose to determine themechanism(s) by which these genes act during aging and survival, and whether their functions areconserved in mammals. We will determine the role of lifespan-modulating checkpoint proteins in the survivalof nematode neurons, which are crucial regulators of nematode lifespan, mouse cortical neurons, anddopaminergic neurons derived from human embryonic stem cells. We will modulate checkpoint functions inthese post-mitotic cells and determine their resistance genotoxic and cytotoxic insults. We will identifychemical compounds that modulate survival through checkpoints, with a view to developing novelinterventions into aging and neurological disease. This interdisciplinary project requires expertise ininvertebrate aging, mammalian neuroscience, high throughout screening, chemical biology, moleculargenetics and stem cell biology.
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