We have uncovered a novel genetic pathway that determines adult lifespan in the nematode Caenorhabditis elegans. This pathway encodes components of DNA damage/cell cycle checkpoints, which are 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 postmitotic state. Down-regulation of checkpoint functions in adult C. elegans renders them very stress resistant and extends their lifespan. Through a whole genome RNA interference screen, we determined that many novel genes encode checkpoint functions and influence lifespan. We now propose to determine the mechanism(s) by which these genes act during aging and survival, and whether their functions are conserved in mammals. We will determine the role of lifespan-modulating checkpoint proteins in the survival of nematode neurons, which are crucial regulators of nematode lifespan, mouse cortical neurons, and dopaminergic neurons derived from human embryonic stem cells. We will modulate checkpoint functions in these post-mitotic cells and determine their resistance genotoxic and cytotoxic insults. We will identify chemical compounds that modulate survival through checkpoints, with a view to developing novel interventions into aging and neurological disease. This interdisciplinary project requires expertise in invertebrate aging, mammalian neuroscience, high throughout screening, chemical biology, molecular genetics and stem cell biology.
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