Concentrations of sirtuin 1, 3, and nestin in aqueous humour and tears of primary open-angle glaucoma patients: a pilot study

Abstract Introduction: Primary open-angle glaucoma (POAG) is a chronic neurodegenerative disease in which stress-response and mitochondrial homeostasis pathways are dysregulated. Sirtuins, NAD⁺-dependent deacetylases, govern oxidative stress control, bioenergetics, and neuronal survival. Nestin, an intermediate filament protein classically expressed in neural progenitors and upregulated in reactive glia, is a putative marker of cellular remodelling and injury. We investigated whether SIRT1, SIRT3, and nestin in ocular biofluids are altered in POAG and whether these signals relate to disease severity. The aim of the present study was to identify novel potential biomarkers and elucidate possible pathways for the development of innovative therapeutic interventions based on the modulation of the redox mechanisms. Methods: In the present cross-sectional pilot study, we recruited patients affected by POAG that were planned for cataract or glaucoma surgery. The control group was formed by patients affected by simple senile cataract. POAG patients were classified based on the progression of the visual field in the past year in progressors and non-progressors. Clinical and demographic characteristics were recorded. Aqueous humour (AH) and tears samples were collected. Analytes concentrations were measured via ELISA assay. Results: We recruited 87 participants: 57 POAG (30 non-progressors, 27 progressors) and 30 cataract controls. Aqueous SIRT1 concentrations were lower in POAG than in controls (28.22±35.34 ng/mL vs 54.97±47.02 ng/mL p=0.026). Within POAG, SIRT1 followed a non-linear, stage-dependent pattern—lowest in early disease and relatively higher in advanced stages—consistent with early depletion followed by compensatory up-regulation rather than a monotonic damage index. SIRT3 concentrations were not different among the groups (17.78±19.63 vs 8.42±9.75 p=0.298). Nestin signals were frequently at or near the lower limit of detection in both groups, limiting interpretability despite biological plausibility as a gliotic marker (0.37± 1.0 vs 0.10 ± 0.34 p=0.328). Tear SIRT1 did not separate diagnostic groups but showed a modest positive correspondence with aqueous SIRT1, sustaining the prospect of a non-invasive surrogate. Conclusions: Aqueous SIRT1 emerges as a potential candidate biomarker and a pathway signal with therapeutic relevance in POAG. Tear-based SIRT1 remains promising as a surrogate marker. Nestin is currently constrained by sensitivity. Prospective, adequately powered longitudinal cohorts with conversion/progression endpoints are warranted. Mechanistic studies should investigate SIRT1/SIRT3 axes as therapeutic targets, including NAD⁺-augmenting strategies, direct sirtuin modulators, and mitochondrial-supportive interventions, to transform molecular insights into clinical neuroprotection.