Hormetic Effects of Curcumin in RPE Cells: SIRT1 and Caspase-3 Inactivation with Implications for AMD

Retinal Pigment Epithelium (RPE), a component of the blood-retinal barrier, plays a pivotal role in maintaining retinal homeostasis and visual function. Dysfunction of the RPE is an early event that triggers photoreceptor death, in Age-related Macular Degeneration (AMD), a multifactorial disorder primarily caused by an imbalance between endogenous antioxidant defenses and reactive oxygen species production. Our in vitro study investigated the hormetic effects of curcumin in human RPE cells (ARPE-19), focusing on its capability to modulate two enzymes related to the onset of AMD: Sirtuin 1 (SIRT1), a NAD+-dependent deacetylase enzyme involved in cellular metabolism, aging, and stress response, and caspase-3, a crucial enzyme in programmed cell death. Curcumin exhibited classic hormetic doseresponses, with low concentrations (5-10 μM) providing cytoprotection while at high doses (≥20 μM) inducing toxicity. Under moderate oxidative stress, acetylated p53 was significantly reduced, indicating SIRT1 activation; curcumin 10 μM restored basal SIRT1 activity, while 5 µM did not. Both concentrations significantly decreased cleaved caspase-3 levels, demonstrating the anti-apoptotic effects of curcumin. Our results reveal curcumin's hormetic mechanisms of RPE protection and emphasize the critical importance of dose optimization within the hormetic window for AMD therapeutic development.