From Bench to Bedside: Translating Longevity Pathways to Glaucoma Supplements

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IntroductionGlaucoma is a leading cause of irreversible blindness, marked by progressive death of retinal ganglion cells (RGCs) and damage to the optic nerve. It often involves elevated intraocular pressure (IOP) due to dysfunction in the trabecular meshwork (TM) outflow system, as well as age‐related neurodegeneration of RGC axons. Age is the strongest risk factor: aging causes oxidative stress, mitochondrial decline, accumulation of damaged proteins and cells, and chronic inflammation – all of which contribute to glaucoma pathophysiology () (). Biologists studying aging (“longevity pathways”) have identified key regulators – AMPK, mTOR, sirtuins, autophagy, and cellular senescence – that govern metabolic health and tissue maintenance. These pathways overlap with mechanisms in glaucoma: for example, autophagy dysfunction and inflammation are linked to both neuronal loss and TM failure () (). Translational research now asks whether nutrition or supplements that modulate these pathways can protect the aging optic nerve and TM. This article maps each core pathway to glaucoma biology, highlights supplements that influence them, and suggests biomarkers (like NAD⁺ levels, cytokines, and OCT imaging) to measure effects. We also discuss critical gaps – notably, the lack of controlled trials comparing these supplements to standard IOP‐lowering care – that must be addressed to move from bench to bedside.Longevity Pathways in Glaucoma PathophysiologyEnergy Sensing: AMPK and mTORAMPK (adenosine monophosphate–activated protein kinase) and mTOR (mechanistic Target of Rapamycin) are nutrient/energy sensors that regulate cell survival and growth. AMPK is activated by low energy (high AMP/ADP) and promotes catabolism and autophagy, whereas mTOR is active with abundant nutrients and encourages growth and protein synthesis. In aging tissues, AMPK signaling tends to decline while mTOR signaling is relatively enhanced (), suppressing autophagy and stress resistance. In glaucoma, dysregulated AMPK/mTOR contributes to disease: for example, increased mTOR activity can drive fibrotic scarring in the optic nerve head and TM extracellular matrix, worsening IOP elevation and axonal injury () (). Conversely, activating AMPK (e.g. with drugs like metformin) has anti–fibrotic and neuroprotective effects. Notably, large observational studies have found that diabetic patients on metformin had a significantly lower risk of developing glaucoma than those on other medications (), implicating AMPK-mediated metabolism in optic nerve vulnerability. Reported mechanisms include AMPK’s promotion of autophagy and antioxidant defenses in stressed RGCs and TM cells. Nutraceutical modulators of this pathway include berberine and alpha-lipoic acid, which activate AMPK in metabolic tissues, though direct glaucoma data are limited. (Rapamycin inhibits mTOR and can induce autophagy in neurons, but as a potent immunosuppressant drug it is not a dietary supplement.) In summary, rebalancing energy sensing toward AMPK activation and mTOR inhibition may protect the aging TM and optic nerve by enhancing autophagy and reducing fibrosis ().Sirtuins and NAD⁺ MetabolismSirtuins are NAD⁠⁺-dependent deacetylases that regulate stress resistance and mitochondrial function. For example, SIRT1 deacetylates transcription factors to boost antioxidant genes, and SIRT6 in RGCs maintains chromatin stability and metabolism. Glaucoma studies show that sirtuins decline with age: deletion of Sirt6 in