In this study, we explored the effect of two arsenolipids with different molecular masses, AsHC 332 and AsHC 346, which are commonly found in seafood, on aging and lifespan-related indicators in the model organism Caenorhabditis elegans. The possible mechanism by which the arsenolipids promote aging was analyzed by measuring the expression of DAF-16 protein in the nematode, the longevity of aging mutants and stress-related genes. The results showed that AsHCs significantly reduced the body length, body width, brood size and head thrash frequency of C. elegans in a dose-dependent manner (P < 0.05). Moreover, the resistance to heat stress (P < 0.0001) and ultraviolet stress (P < 0.05) was significantly reduced by AsHCs. The lifespan of C. elegans was significantly shortened (P < 0.01). The accumulation of lipofuscin was increased (P < 0.001). The relative expression of the daf-16, sod-3, ctl-1, gst-4 and hsp-16.2 genes was up-regulated, while the nuclear localization of DAF-16 was not significantly promoted, and there was no effect on the lifespan of the daf-16(mu86) mutant. AsHC 332 and AsHC 346 had the same toxic effects on nematode aging, which may shorten the lifespan of C. elegans by regulating the transcription factor DAF-16.