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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.

Inhibition of Sarco-Endoplasmic Reticulum Ca2+ ATPase Extends the Lifespan in C. elegans Worms