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

Wenwen Liu,Keting Bao,Huiling Lin,Lanxin Zhang,Zhifan Mao,Bei Jiang,Zelan Hu,Jian Li,Conglong Xia,Wenjun Li

doi:10.18632/aging.102951

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 verapamil-induced 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.

Highlights

Aging essentially involves physiological decline that leads to impaired function and promotes mortality [1]
We found that verapamil (400 μM)-treated group exhibited significant improvement in worms’ survival; treatment with 100 μM verapamil did not lead to any positive effect (Figure 1G)
Since verapamil inhibits the activity of calcineurin and facilitates autophagy, we evaluated whether autophagy is linked with calcineurin activity in verapamil-mediated lifespan extension

Summary

Introduction

Aging essentially involves physiological decline that leads to impaired function and promotes mortality [1]. Several studies have revealed the hallmarks of aging (e.g., loss of proteostasis, mitochondrial dysfunction, and telomere attrition) and the associated signaling pathways (e.g., insulin/IGF-1, mTOR, AMPK, and germline signaling pathways) [4,5,6,7,8,9,10] Based on these findings, novel antiaging agents have been developed to target multiple signaling pathways by either activating or inhibiting certain intermediate proteins [11]. Novel antiaging agents have been developed to target multiple signaling pathways by either activating or inhibiting certain intermediate proteins [11] These candidate agents include senolytic drugs (dasatinib and quercetin), mTOR inhibitors (rapamycin), AMPK activators (metformin), sirtuin activators (resveratrol), and so on [12,13,14,15]. Some of these drugs have shown promising potential in promoting longevity and have entered the clinical trial stage [16]

Methods

Results

Conclusion