We previously showed that salmon milt nucleoprotein (NP) promotes thermotolerance in Caenorhabditis elegans; however, the active component and physiological mechanism of this effect has remained unclear. L-arginine (AR) is a major component of protamine and thus it has been proposed as the possible active component of NP. In this study, the viability of C. elegans treated with AR under heat stress was assessed and AR was shown to extend the survival term of the heat-stressed organisms. Additionally, AR was shown to restore the thrashing movement of the worms that is suppressed by heat stress. Treatment with AR was furthermore shown to promote thermotolerance in a DAF-16- and SIR-2.1-dependent manner, where DAF-16 and SIR-2.1 are homologs of FoxO and SirT1, respectively. Taken together, these data suggest that AR is one of the active components of NP and promotes thermotolerance via the activation of DAF-16 and SIR-21. (C) 2016 Elsevier Inc. All rights reserved.