The Antagonistic Pleiotropy theory for the evolution of aging proposes that a gene may have pleiotropic effects at different life stages, and these effects could be under varying, and in fact opposite, evolutionary pressures. Because the strength of natural selection declines with age, deleterious effects of genes late in life may be outweighed by early-life beneficial qualities. This would culminate in positive selection of gene variants that are beneficial early in life, for development or reproduction, in spite of their detrimental contributions late in life, i.e. to aging and to lifespan. Despite the elegance and simplicity of the theory, a mechanistic understanding of how this principle manifests is still lacking. Here we investigate antagonistic pleiotropy as manifested in the function of the Caenorhabditis elegans JNK homolog KGB-1, which provides stress protection in developing larvae, but sensitizes adults to stress and shortens their lifespan. Previously we had shown that KGB-1's antagonistic contributions depended on age-dependent and opposing regulation of the stress transcription factor DAF-16 (Twumasi-Boateng et al., 2012) and that contributions were mostly cell-nonautonmous (Liu et al., 2018), but the underlying mechanism remains unknown. Here, we describe a role for the microRNA
mir-71in mediating the effects of KGB-1 on DAF-16 and its downstream antagonistic phenotypes. Fluorescent imaging along with genetic and survival analyses revealed age-dependent regulation of
mir-71 expression by KGB-1 - upregulation in larvae, but downregulation in adults. Furthermore,
mir-71 was required both for early life effects of KGB-1 - resistance to cadmium - as well as for KGB-1-dependent infection sensitivity late in life and shortened lifespan. In addition, KGB-1 activation in long-lived
mir-71 over-expressors reduced their lifespan to the same level as in wildtype animals, suggesting that KGB-1 gauged the effects of
mir-71. Not all of the effects of KGB-1 depended on
mir-71. KGB-1 activation increases larval resistance to protein folding stress, but
mir-71 disruption had no effect on that. At the same time, disruption of the argonaute gene
alg-1, a central component of the microRNA machinery, did. These results suggest that microRNAs play a role in mediating age-dependent antagonistic contributions of KGB-1 to survival.
mir-71 plays a central role, but additional microRNAs likely contribute redundantly.