Anti-Aging Molecule Sirt6 in Neuroprotection in Diabetic Retina SUMMARY Diabetic retinopathy (DR) is the most frequent cause of blindness in working age adults in the US today. It was traditionally characterized as microvascular complications due to its clinical manifestation of a period of vascular leakage and degeneration followed by neovascularization. However, recent studies in animal models and patients have shown that retinal neuron injury, in particular retinal ganglion cell (RGC) dysfunction and loss, occurs at early stage of DR and contributes to vision loss. Moreover, though less studies, dysfunction and degeneration of axons of RGC is also evident in diabetes. Current therapies for DR targets clinically significant vascular leakage or neovascularization, which happens much later, and do not protect retinal neurons. This project is to delineate the mechanisms of RGC injury and axonal degeneration during DR in order to identify novel strategies to limit injury and preserve vision. Increasing evidence indicates that stress-induced premature senescence (SIPS) plays a key role in many diseases. There are a few studies reporting SIPS in DR but they are exclusively focused on endothelial cells and have not linked SIPS to DR pathology. There is a significant knowledge gap on how Db induce SIPS in the retina and how to regulate such mechanisms for DR treatment. Sirt6 is a key anti-aging molecule belonging to the sirtuin family that is evolutionarily conserved nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases and shares homolog with yeast Sir2 protein, a critical regulator of the lifespan of yeast. We now propose to test a hypothesis that Sirt6 suppresses chronic activation of the DNA damage response (DDR)-ATM (ataxia-telangiectasia mutated) pathway to prevent dysfunction/degeneration of RGCs and their axons in DR, partly by inhibiting RGC senescence and mitochondrial dysfunction. We will use our newly developed Sirt6 global and conditional knockout (KO)/overexpression mice, AAV2-mediated gene knockdown, clinic-relevant non-invasive imaging and functional tests, immunohistochemistry, biochemistry and morphometric analyses to test this hypothesis. This study will identify novel roles of Sirt6 and DDR-ATM pathway in RGC and axonal degeneration in DR and establish a link between these them. It will also provide proof-of-concept that boosting anti-aging mechanisms may be utilized to treat DR.