Inhibition of Sarco-Endoplasmic Reticulum Ca(2+) ATPase Extends the Lifespan in C. elegans Worms

The sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) refills the endoplasmic reticulum (ER) with Ca(2+) up to the millimolar range and is therefore the main controller of the ER [Ca(2+)] level ([Ca(2+)](ER)), which has a key role in the modulation of cytosolic Ca(2+) signaling and ER-mitochondria Ca(2+) transfer. Given that both cytosolic and mitochondrial Ca(2+) dynamics strongly interplay with energy metabolism and nutrient-sensitive pathways, both of them involved in the aging process, we have studied the effect of SERCA inhibitors on lifespan in C. elegans. We have used thapsigargin and 2,5-Di-tert-butylhydroquinone (2,5-BHQ) as SERCA inhibitors, and the inactive analog 2,6-Di-tert-butylhydroquinone (2,6-BHQ) as a control for 2,5-BHQ. Every drug was administered to the worms either directly in the agar or via an inclusion compound with γ-cyclodextrin. The results show that 2,6-BHQ produced a small but significant increase in survival, perhaps because of its antioxidant properties. However, 2,5-BHQ produced in all the conditions a much higher increase in lifespan, and the potent and specific SERCA inhibitor thapsigargin also extended the lifespan. The effects of 2,5-BHQ and thapsigargin had a bell-shaped concentration dependence, with a maximum effect at a certain dose and smaller or even toxic effects at higher concentrations. Our data show therefore that submaximal inhibition of SERCA pumps has a pro-longevity effect, suggesting that Ca(2+) signaling plays an important role in the aging process and that it could be a promising novel target pathway to act on aging.