More than 400 genes have been noted to modulate Caenorhabditis elegans longevity. Recent studies testing the role of proposed secreted insulin-binding proteins unexpectedly revealed a potent role for the EGF signaling pathway in promoting healthy aging and longevity in C. elegans. Activation of EGF receptor LET-23 is associated with increased mean and maximum lifespan, maintained pharyngeal pumping, extended locomotory function, and low lipofuscin and advanced glycation end product accumulation. Conversely, reducing the activity of the EGF pathway is associated with system-wide evidence of progeria. The EGF pathway appears to work in a manner largely independent of the insulin/IGF-like pathway, in that effects are additive with reduction of DAF-2/InsR activity and are not affected by DAF-16/FOXO transcription factor deficiency. Two novel regulators of EGF signaling, called HPA-1 and HPA-2 (for the high performance in advanced age locomotory phenotypes that their disruption confers), negatively regulate EGF action, possibly by binding and sequestering EGF. Interestingly, whereas HPA-1 appears to control aging of the animal overall, HPA-2 exerts an effect primarily on locomotory aging. As such, HPA-2 is an example of a protein with an effect on healthspan but not lifespan, a gene class that may have been missed in screens focused on longevity endpoint. To date, roles for EGF signaling in adult maintenance (particularly in non-dividing tissues) have not been addressed in other organisms-should EGF signaling exert a conserved impact on healthy aging, testing this hypothesis could hold implications for anti-aging therapies.
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