Significance Age-related bioenergetic insufficiency increases the vulnerability of retinal ganglion cells to intraocular pressure during glaucoma pathogenesis. This paper addresses these relationships and provides a deeper understanding of this common neurodegeneration. We demonstrate an intraocular pressure-dependent decline in retinal pyruvate levels coupled to dysregulated glucose metabolism, and detected mTOR activation at the mechanistic nexus of neurodegeneration and metabolism. Supporting this, oral supplementation of pyruvate or mTOR inhibition by rapamycin strongly protects from neurodegeneration. Bioenergetic enhancement thus provides a readily clinically translatable strategy for neurodegenerative disease. This study provides important avenues for neuroprotection against glaucoma by targeting key metabolic pathways that may be mirrored in other neurodegenerative diseases in which metabolic dysregulation may play a key role.