Verapamil extends lifespan in Caenorhabditis elegans by inhibiting calcineurin activity and promoting autophagy

Abstract

Previous evidence has revealed that increase in intracellular levels of calcium promotes cellular senescence. However, whether calcium channel blockers (CCBs) can slow aging and extend lifespan is still unknown. In this study, we showed that verapamil, an L-type calcium channel blocker, extended the Caenorhabditis elegans (C. elegans) lifespan and delayed senescence in human lung fibroblasts. Verapamil treatment also improved healthspan in C. elegans as reflected by several age-related physiological parameters, including locomotion, thrashing, age-associated vulval integrity, and osmotic stress resistance. We also found that verapamil acted on the α1 subunit of an L-type calcium channel in C. elegans. Moreover, verapamil extended worm lifespan by inhibiting calcineurin activity. Furthermore, verapamil significantly promoted autophagy as reflected by the expression levels of LGG-1/LC3 and the mRNA levels of autophagy-related genes. In addition, verapamil could not further induce autophagy when tax-6, calcineurin gene, was knocked down, indicating that verapamilinduced lifespan extension is mediated via promoting autophagy processes downstream of calcineurin. In summary, our study provided mechanistic insights into the anti-aging effect of verapamil in C. elegans.

Host–commensal interaction promotes health and lifespan in Caenorhabditis elegans through the activation of HLH-30/TFEB-mediated autophagy

“…Our results pointed to autophagy as a key pathway responsible for the longevity program initiated in C. elegans upon feeding with BGHV110. These findings are completely comparable with the upregulation of autophagy and prolonged lifespan in C. elegans induced by the anti-aging drug verapamil [ 35 ]. Given the crucial role of nutrient deprivation in the induction of autophagy and lifespan determination [ 36 ], it was important to distinguish between the upregulation of autophagy due to possible lower intake of BGHV110 and the autophagy promoted by bacterial biomolecules.…”

Targeting Autophagy Induction as A possible Protective Mechanism by Verapamil Compared to Rapamycin (Sirolimus) Against Gentamicin -Induced Ototoxicity in Guinea Pigs

“…It was also found to increase fusion between autophagosome and lysosome in liver, so it was tried for autophagic flux restoration and treatment of obesity [41] . It was also reported to have cytoprotective effect via induction of autophagy [42] , in addition to recent study that suggested that verapamil extends lifespan by promoting autophagy [43] . As far as we know there is no definitive dose for verapamil to induce autophagy in guinea pigs, so we depended on human equivalent dose (FDA label dose is 240: 480 mg.…”

Crotamiton derivative JM03 extends lifespan and improves oxidative and hypertonic stress resistance in Caenorhabditis elegans via inhibiting OSM-9

“…Finally, 10 drugs which showed up to 10% increase in mean lifespan extension were chosen for the third screening with 60 worms per concentration (400 μM, 100 μM and 25 μM), respectively (Figure 1-source data 2). Apart from recently reported verapamil hydrochloride 21 and chlorpropamide 22 listed in our screening results, crotamiton was finally selected as one hit compound with significant effect on C. elegans lifespan extension in this study ( P < 0.01) (Fig. 1a).…”