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Supplementation with nicotinamide riboside (NR), a form of vitamin B3 and a precursor of nicotinamide adenine dinucleotide (NAD+) extends lifespan in the nematode C. elegans and delays aging-related pathologies in mammals. During aging, levels of NAD+ decline causing metabolic dysfunction and oxidative damage. Studies in C. elegans found that when NR was administered during larval development it induced the mitochondrial unfolded protein response (UPRmt), which is frequently associated with lifespan extension. Both calorie restriction (CR) and ketogenic diets (KD) have been shown to extend lifespan, in part through increasing NAD+ and through increasing levels of the pro-longevity ketone body beta-hydroxybutyrate (BHB). In a previous study from my lab, NR increased C. elegans lifespan to a much larger extent when administered starting at the L1 larval stage as compared to when started at the L4 larval stage. Conversely, a high dose of BHB greatly increased lifespan when administered starting at the L4 stage. But this same dose decreased lifespan when it was first administered at the L1 stage. I further found that NR greatly extended lifespan when only administered during larval development and that the combination of both individual pro-longevity NR and BHB treatments significantly decreased lifespan. These chemical epistasis experiments suggest that NR and BHB function in parallel pathways to extend C. elegans lifespan through a common downstream target with hormesis playing a role. Therefore, human subjects who supplement with both NAD+ precursors and ketone esters should be aware of possible negative interactions when high doses of both are administered.