Resveratrol and Sirtuin Pathways: From Trabecular Meshwork to Longevity

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Resveratrol’s Promise in Glaucoma: Ocular Cells and Systemic AgingResveratrol is a polyphenolic compound often touted as a “caloric restriction mimetic” and SIRT1 activator with antioxidant and anti-inflammatory effects. Early studies showed resveratrol can boost stress resistance and extend lifespan in organisms from yeast to mammals (). In cells and animal models, resveratrol activates SIRT1 – a deacetylase linked to longevity – which in turn induces autophagy (cellular cleanup) required for its healthspan benefits (). These same pathways – reduced oxidative stress, enhanced cellular renewal – underlie interest in resveratrol for age-related eye diseases. In glaucoma, where trabecular meshwork (TM) cells and retinal ganglion cells (RGCs) suffer chronic stress and senescence, resveratrol’s anti-aging mechanisms are being explored.Trabecular Meshwork: Fighting Senescence and StressThe TM tissue acts as the eye’s drainage filter and becomes less cellular and more dysfunctional in glaucoma. Chronic oxidative stress and inflammation in TM cells trigger senescence (marked by SA-β-gal, lipofuscin) and cytokine release (IL-1α, IL-6, IL-8, ELAM-1). In cultured TM cells subjected to high oxygen stress, chronic resveratrol (25 µM) virtually abolished the rise in reactive oxygen species (ROS) and inflammatory markers, and sharply reduced senescence markers (). In one study, resveratrol-treated TM cells had much lower SA-β-gal activity and protein carbonylation despite oxidative challenge (). This suggests resveratrol may preserve TM cell health by blocking stress-induced aging. Resveratrol also influences Nitric Oxide (NO) pathways in TM cells. In glaucomatous human TM cells, resveratrol increased endothelial NO synthase (eNOS) expression and boosted NO levels, while lowering inducible NOS (iNOS) at higher doses (). Since NO promotes blood flow and may reduce outflow resistance, increased NO could improve ocular perfusion and outflow facility. Likewise, lowering iNOS (which drives damaging oxidative stress) underscores resveratrol’s antioxidant role (). These effects align with its anti-inflammatory action: resveratrol downregulates pro-inflammatory IL-1α and related cytokines in TM cells ().Resveratrol’s benefits may also extend to autophagy in TM cells. Although specific ocular data are scarce, resveratrol is known to promote autophagy via SIRT1 in many cell types (). Autophagy is the process that clears damaged proteins and organelles, and it typically declines with age. Inducing autophagy could help TM cells dispose of stress-damaged components and maintain outflow function. In summary, preclinical TM data indicate resveratrol buffers TM cells against chronic stress and aging () ().Retinal Ganglion Cells: Neuroprotection and SIRT1Glaucomatous loss of RGCs leads to vision loss, and protecting these neurons is a key goal. In multiple rodent and cell studies, resveratrol has consistently shown neuroprotective effects on RGCs. It promotes RGC survival under stress by antioxidant and anti-apoptotic mechanisms (). For example, in cultured RGCs exposed to hydrogen peroxide (H₂O₂), resveratrol stimulated cell survival and growth, reduced apoptotic signaling, and lowered ROS levels (). It also blocked hypoxia-induced RGC death by suppressing pro-death pathways (e.g. diminishing ErbB2 protein) (). These actions are mediated in part via SIRT1: resveratrol prevents phosphorylation of stress kinases (c-Jun N-terminal kinase) in RGCs through SIRT1-depende