Establishment and application of a zebrafish model of Werner syndrome identifies sapanisertib as a potential antiaging drug

Abstract

Aging is a complex process that affects multiple organs, and the discovery of a pharmacological approach to ameliorate aging is considered the Holy Grail of medicine. Here, we performed an N-ethyl-N-nitrosourea forward genetic screening in zebrafish and identified an accelerated aging mutant named meteor ( met ), harboring a mutation in the Werner syndrome RecQ - like helicase ( wrn ) gene. Loss of wrn leads to a short lifespan and age-related characteristics in the intestine of zebrafish embryos, such as cellular senescence, genomic instability, and epigenetic alteration. Therefore, we conducted a screening of antiaging drugs using the met mutant and revealed that sapanisertib effectively ameliorated most of the aging phenotypes of the mutant. Mechanistically, the geroprotective effects of sapanisertib may be attributed to inhibition of mTORC1/2. Furthermore, sapanisertib also attenuated chronological aging in wild-type aged zebrafish and replicative-senescence in human foreskin fibroblasts. Taken together, our study introduces a unique and efficient model for large-scale antiaging drug screening in vertebrates and suggests sapanisertib as a potential therapeutic option for treating premature aging and promoting healthy aging.