Mitochondrial unfolded protein response (UPR), which is a mitochondrial proteostasis pathway, orchestrates an adaptive reprogramming for metabolism homeostasis and organismal longevity. Similar to other defense systems, compromised UPRis a feature of several age-related diseases. Here we report that dimercapto succinic acid (DMSA)-modified cobalt oxide nanoparticles (CoONPs), which have received wide-spread attention in biomedical fields, is a promising UPRactivator and, more importantly, provides a gate for extending healthy lifespan.UPRactivation by CoONPs was tested in transgenetic() specifically expressing UPRreporter Phsp-6::GFP, and the underlying mechanism was further validated by mitochondrial morphology, mtDNA/nDNA, metabolism-related genes' expression, mitonuclear protein imbalance, oyxgen assumption and ATP level in. Then therapeutic response aganist senescence was monitored by lifespan analysis, lipofusin contents, MDA contents, Fe accumulation, pharyngeal locomotion performance as well as athletic ability (head thrashes and body bends) at different developmental stages of. RNAi towardsorUPRpathway was applied to clarify the role of UPRin CoONPs -mediated anti-aging effects. Finally, the effect of CoONPs on mitochondrial homeostasis and D-galactose-induced cell viability decline in mammalian cells were studied.CoONPs was revealed as a bona fide activator of the UPRsignaling pathway, through fine-tuning mitochondrial dynamics and inducing a stoichiometric imbalance between OXPHOS subunits encoded by mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) at early life stage ofPhenotypically, CoONPs treatment protectfrom external stresses. More importantly, dietary low level of CoONPs effectively extend lifespan and alleviate aging-related physiological and functional decline of worms, demonstrating its potential roles in delaying aging. While the protective effect exerted by CoONPs was compromised in line withorRNAi treatment. Further studies verified the conservation of CoONPs in activating UPRand exerting protective effects in mammalian cells.The results reveal beneficial effects of CoONPs on mitochondrial metabolic control, thus presenting their potential efficacy in anti-aging care. mt mt mt mt mt mt mt mt mt3 4 3 4 3 4 3 4 3 4 3 4 3 4 3 4 3 4 3 4Methods: Results: Conclusions: Caenorhabditis elegans C. elegans C. elegans C. elegans ubl-5atfs-1 in C. elegans. C. elegans atfs-1ubl-5
