Insulin signaling, dietary restriction and DNA damage : multiple roles for smk-1 in the mediation of C. elegans life span
- Author(s): Wolff, Suzanne Christine
- et al.
Insulin signaling, mitochondrial respiration, and dietary restriction share conserved roles not only in the regulation of C. elegans life span, but also in the timing and control of diverse functions such as reproduction, stress resistance and metabolism. These autonomous pathways differ in their dependence on known transcription factors and in their temporal requirements, but converge to manipulate the core set of physiological systems necessary for extended life span in worms. Recent publications from our lab have established a genetic requirement for the uncharacterized worm gene smk-1 in the regulation of IGF-1/insulin signaling (IIS) and life span. I found that loss of smk-1 attenuates the transcription of target DAF-16 (FOXO) genes and the capacity for IIS mutants to withstand specific severe stressors. Loss of smk-1 did not alter the developmental phenotypes caused by reduced IIS. Because the long life span of worms undergoing dietary restriction was independent of daf-16, I began a screen against other forkhead proteins in C. elegans, searching for genes required for dietary- restriction induced longevity. I discovered that one forkhead transcription factor, pha-4, suppressed the life span of a dietary restricted worm. The effects of this gene were specific to the long life span of DR worms and could be induced during adulthood. Multiple publications have begun to suggest that the primary function of smk-1 in cells may lie in the mediation of DNA damage, and the mechanism by which smk-1 affects the aging process may lie in its capacity to affect checkpoint responses. This finding suggested that there might be an overlap between the response to nutrient availability, the regulation of life span, and a control of DNA damage. I examined the effects of smk-1 and components of the checkpoint machinery on life span. I find that a loss of chk-1 or smk -1 can affect life span in mutants with only somatic lineages. Epistasis analysis suggests that smk-1 lies upstream of chk-1 and cdc-25.1 activation. The physiological consequence of checkpoint loss on life span suggests that alterations to checkpoints may attenuate the life span of specific long-lived mutants