Tschimganine and its derivatives extend the chronological life span of yeast via activation of the Sty1 pathway

<jats:title>Abstract</jats:title><jats:p>Most antiaging factors or life span extenders are associated with calorie restriction (<jats:styled-content style="fixed-case">CR</jats:styled-content>). Very few of these factors function independently of, or additively with, <jats:styled-content style="fixed-case">CR</jats:styled-content>. In this study, we focused on tschimganine, a compound that was reported to extend chronological life span (<jats:styled-content style="fixed-case">CLS</jats:styled-content>). Although tschimganine led to the extension of <jats:styled-content style="fixed-case">CLS</jats:styled-content>, it also inhibited yeast cell growth. We acquired a <jats:italic>Schizosaccharomyces pombe</jats:italic> mutant with a tolerance for tschimganine due to the gene <jats:italic>crm1</jats:italic>. The resulting Crm1 protein appears to export the stress‐activated protein kinase Sty1 from the nucleus to the cytosol even under stressful conditions. Furthermore, we synthesized two derivative compounds of tschimganine, α‐hibitakanine and β‐hibitakanine; these derivatives did not inhibit cell growth, as seen with tschimganine. α‐hibitakanine extended the <jats:styled-content style="fixed-case">CLS</jats:styled-content>, not only in <jats:italic>S. pombe</jats:italic> but also in <jats:italic>Saccharomyces cerevisiae</jats:italic>, indicating the possibility that life span regulation by tschimganine derivative may be conserved across various yeast species. We found that the longevity induced by tschimganine was dependent on the Sty1 pathway. Based on our results, we propose that tschimganine and its derivatives extend <jats:styled-content style="fixed-case">CLS</jats:styled-content> by activating the Sty1 pathway in fission yeast, and <jats:styled-content style="fixed-case">CR</jats:styled-content> extends <jats:styled-content style="fixed-case">CLS</jats:styled-content> via two distinct pathways, one Sty1‐dependent and the other Sty1‐independent. These findings provide the potential for creating an additive life span extension effect when combined with <jats:styled-content style="fixed-case">CR</jats:styled-content>, as well as a better understanding of the mechanism of <jats:styled-content style="fixed-case">CLS</jats:styled-content>.</jats:p>