Anti-aging Effects Of Verapamil And Its Study On The Mechanism

Aging is a physiological process mediated by a variety of regulatory pathways and transcription factors,which is primarily manifested in functional decline of organism and increased risk of chronic diseases.Aging is an inevitable process,but the pace of aging can be regulated to a certain extent.Strategies to delay aging and prolong lifespan via developing anti-aging drugs have attracted much attention.Here,verapamil,an L-type calcium channel blocker,screened from 1386 approved drugs,was found to extend the lifespan of Caenorhabditis elegans(C.elegans)as well as delay senescence and improve cell viability in human fetal lung fibroblasts MRC-5.Also,verapamil showed a tendency to extend the lifespan of male Drosophila melanogaster.Verapamil treatment led to a significant improvement in healthspan of C.elegans by affecting age-related physiological parameters,including crawling speed,body bends,osmotic stress resistance and age-associated vulval integrity defects(Avid).Further study on mechanism revealed that verapamil acted on the ?1 subunit of L-type calcium channel and extended lifespan by inhibiting calcineurin in C.elegans.Moreover,verapamil significantly promoted autophagy as reflected by increased protein expression of LGG-1/LC3 and elevated mRNA levels of autophagy-related genes.Furthermore,autophagy gene bec-1 was required for verapamil to extend the lifespan in C.elegans.In addition,verapamil could not further induce autophagy in C.elegans when calcineurin was knockdown,indicating that verapamil-induced lifespan extension was mediated via promoting autophagy processes downstream of calcineurin.To sum up,anti-aging effects of verapamil and its underlying mechanisms in C.elegans have been studied in this thesis,which may lay a foundation for further research and anti-aging application of verapamil in the future.