Mechanism of the lifespan extension induced by submaximal SERCA inhibition in C. elegans

Abstract

We have reported recently that submaximal inhibition of the Sarco Endoplasmic Reticulum Ca²⁺ ATPase (SERCA) produces an increase in the lifespan of C. elegans worms. We have explored here the mechanism of this increased survival by studying the effect of SERCA inhibition in several mutants of signaling pathways related to longevity. Our data show that the mechanism of the effect is unrelated with the insulin signaling pathway or the sirtuin activity, because SERCA inhibitors increased lifespan similarly in mutants of these pathways. However, the effect required functional mitochondria and both the AMP kinase and TOR pathways, as the SERCA inhibitors were ineffective in the corresponding mutants. The same effects were obtained after reducing SERCA expression with submaximal RNAi treatment. The SERCA inhibitors did not induce ER-stress at the concentrations used, and their effect was not modified by inactivation of the OP50 bacterial food. Altogether, our data suggest that the effect may be due to a reduced ER-mitochondria Ca²⁺ transfer acting via AMPK activation and mTOR inhibition to promote survival.

Keywords: AMP kinase; C. elegans; Endoplasmic reticulum; Lifespan; Mitochondria; SERCA; TOR; Thapsigargin.