Novel Rapamycin Derivative With Lower Immunosuppressive Activity and Cytotoxicity Extends Lifespan of Caenorhabditis elegans.

Abstract

Rapamycin is a multifunctional drug derived from Streptomyces hydroscopicus with several biological activities, such as anti-fungal, anti-tumor, anti-proliferation, and immunosuppressive activities. In recent years, rapamycin and its derivatives have attracted widespread attention in the field of lifespan extension or anti-aging. In view of the strong immunosuppressive activity and certain cytotoxicity of rapamycin itself, it may cause some potential adverse reactions for long-term use. In this study, a rapamycin derivative with lower immunosuppressive activity and cytotoxicity was selected for further study. Based on the analysis of lifespan extension, the rapamycin thiazole-derivative FIM-X8 showed a strong effect on extending the lifespan of Caenorhabditis elegans. The influences on the survival of nematodes under high temperature or oxidation conditions were also analyzed. Further studies on the longevity-associated genes showed that lifespan extension induced by rapalogs was comprehensively regulated by multiple metabolic pathways, and it was closely related to the key role of mTOR in the regulation of growth and metabolism. Genes rsks-1 and daf-12 mutant nematode strains were selected to elucidate the mechanism of lifespan extension, and we found that great importance was attached to gene rsks-1 when FIM-X8 extended the lifespan of C. elegans.