Selenium (Se) is an essential trace element because of its presence in selenoproteins in the form of selenocysteine residue. Both Se deficiency, which compromises selenoprotein functions, and excess Se, which is toxic, have been associated with altered redox homeostasis and adverse health conditions. Surprisingly, we found that, although Se deficiency led to a drastic decline in selenoprotein expression, mice subjected to this dietary regimen for their entire life had normal lifespans. To understand the molecular mechanisms involved, we performed systemic analyses at the level of metabolome, transcriptome, and microRNA profiling. These analyses revealed that Se deficiency reduced amino acid levels, elevated mononucleotides, altered metabolism, and activated signaling pathways linked to longevity-related nutrient sensing. The data show that the metabolic control associated with nutrient sensing coordinately responds to suppressed selenoprotein functions, resulting in normal lifespan under Se deficiency. Display omitted •Se deficiency reduces selenoprotein expression but does not affect lifespan of mice•Se deficiency reduces amino acid levels and elevates mononucleotides•Se deficiency activates pathways linked to nutrient sensing•Se deficiency is associated with pro-longevity mechanisms Yim et al. report that selenium deficiency in mice is associated with pro-longevity mechanisms because of reduced amino acid levels and altered nutrient signaling.