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

Most antiaging factors or life span extenders are associated with calorie restriction (CR). Very few of these factors function independently of, or additively with, CR. In this study, we focused on tschimganine, a compound that was reported to extend chronological life span (CLS). Although tschimganine led to the extension of CLS, it also inhibited yeast cell growth. We acquired a Schizosaccharomyces pombe mutant with a tolerance for tschimganine due to the gene crml. The resulting Crml protein appears to export the stress-activated protein kinase Styl from the nucleus to the cytosol even under stressful conditions. Furthermore, we synthesized two derivative compounds of tschimganine, alpha-hibitakanine and beta-hibitakanine; these derivatives did not inhibit cell growth, as seen with tschimganine. alpha-hibitakanine extended the CLS, not only in S. pombe but also in Saccharomyces cerevisiae, 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 Styl pathway. Based on our results, we propose that tschimganine and its derivatives extend CLS by activating the Styl pathway in fission yeast, and CR extends CLS via two distinct pathways, one Styl-dependent and the other Styl-independent. These findings provide the potential for creating an additive life span extension effect when combined with CR, as well as a better understanding of the mechanism of CLS.