Ryanodine receptor 2 (RyR2) mediated chronic calcium leak in the brain has been implicated in patients with late-onset Alzheimer’s disease (LOAD) and from aging macaques, but the direct downstream consequences of calcium leak remain unclear. Here, we present that RyR2 mediated chronic calcium leak leads to increased glyoxalase 1 (GLO1), a major scavenger of pro-oxidant, inflammatory dicarbonyl compounds, expression and activity. Our aging macaque model revealed significantly increased GLO1 expression in the prefrontal cortex (PFC) and entorhinal cortex with age, which correlated with increased calcium leak through RyR2. We characterized GLO1 cellular and ultrastructural localization in dendrites, axon terminals, and astrocytes in the aged macaque dorsolateral PFC. To test causation, we used a knockin mouse model which replaces the serine at 2808 with aspartic acid (S2808D-RyR2), causing calcium leak through RyR2. We report significantly increased GLO1 expression and activity in S2808D-RyR2 PFC and hippocampus, as early as 1-month-old and as late as 21-month-old. This increase was driven by several cell types. The publicly available proteomics data set generated from synaptosomes from S2808D-RyR2 illuminate the downstream effects of elevated calcium in vulnerable areas of the brain. These results further elucidate the role of GLO1 in neurodegeneration and the aging brain.