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Alexey Obolensky, Victoria Peshti, Yariv Kanfi, Haim Cohen, Eyal Banin; Age-Dependent Ocular Changes in Sirt6 Knockout Mice. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6078.
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© ARVO (1962-2015); The Authors (2016-present)
Sirtuins (Silent Information Regulator Two, Sirt)) are a family of proteins with histone deacetylase and/or mono-ribosyltransferase activity. Overexpression of sirtuins in many organisms promotes longevity, while their absence may cause early senescence. The purpose of the present study was to assess the role of Sirt6 in retinal aging.
Retinal function and structure were compared over the span of 10 months between three groups of mice: homozygous Sirt6-/- knockouts, heterozygous Sirt6+/- (hz), and normal wild type (wt) mice. At 1, 6 and 10 months of age, retinal function was evaluated by electroretinography (ERG) and quantitative histologic techniques were used to assess retinal structure.
Sirt6-/- mice demonstrated a high rate of early postnatal lethality and were characterized by developmental retardation, low body weight and a short lifespan. By 5-6 months of age, severe corneal injury was often observed in Sirt6-/- mice including corneal scarring, vascularization, signs of stromal edema and inflammation. At 1 month of age Sirt6-/- mice demonstrated a trend toward lower dark-adapted b-wave amplitudes as compared with wt animals. At this time, no changes in outer nuclear layer (ONL) thickness were found between wt and Sirt6-/- mice. However, at 6 months, dark adapted ERG responses were significantly (by 45% at highest stimulus intensity) reduced in Sirt6-/- animals compared with wt control. Cone function was also markedly affected, being 2.5-3-fold lower in Sirt6-/- mice. ONL thickness was significantly reduced in the central retina of Sirt6-/- mice (p<0.02) at this time point. At 10 months of age severe impairment of retinal function was observed in Sirt6-/- mice, with dark-adapted b-wave amplitudes reduced by 39% and cone-flicker ERG amplitudes reduced by 75% as compared with wt. Further thinning of the ONL not only in the central but also in the mid-peripheral and peripheral retina was evident, accompanied by thinning of other retinal layers. No significant differences were found in ERG amplitudes between wt and hz mice up to the age of 10 months.
Sirt6-/- mice demonstrate age-dependent corneal injury and impairment of retinal function accompanied by thinning of the ONL. The results may suggest a role for Sirt6 in maintaining survival and function of retinal cells over time.
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