Aged Nrf2-Null Mice Develop All Major Types of Age-Related Cataracts. Rowan Sheldon,Jiang Shuhong,Francisco Sarah G,Pomatto Laura C D,Ma Zhiwei,Jiao Xiaodong,Campos Maria M,Aryal Sandeep,Patel Shaili D,Mahaling Binapani,Riazuddin S Amer,Duh Elia J,Lachke Salil A,Hejtmancik J Fielding,de Cabo Rafael,FitzGerald Paul G,Taylor Allen Investigative ophthalmology & visual science Purpose:Age-related cataracts affect the majority of older adults and are a leading cause of blindness worldwide. Treatments that delay cataract onset or severity have the potential to delay cataract surgery, but require relevant animal models that recapitulate the major types of cataracts for their development. Unfortunately, few such models are available. Here, we report the lens phenotypes of aged mice lacking the critical antioxidant transcription factor Nfe2l2 (designated as Nrf2 -/-). Methods:Three independent cohorts of Nrf2 -/- and wild-type C57BL/6J mice were evaluated for cataracts using combinations of slit lamp imaging, photography of freshly dissected lenses, and histology. Mice were fed high glycemic diets, low glycemic diets, regular chow ad libitum, or regular chow with 30% caloric restriction. Results:Nrf2 -/- mice developed significant opacities between 11 and 15 months and developed advanced cortical, posterior subcapsular, anterior subcapsular, and nuclear cataracts. Cataracts occurred similarly in male mice fed high or low glycemic diets, and were also observed in 21-month male and female Nrf2 -/- mice fed ad libitum or 30% caloric restriction. Histological observation of 18-month cataractous lenses revealed significant disruption to fiber cell architecture and the retention of nuclei throughout the cortical region of the lens. However, fiber cell denucleation and initiation of lens differentiation was normal at birth, with the first abnormalities observed at 3 months. Conclusions:Nrf2 -/- mice offer a tool to understand how defective antioxidant signaling causes multiple forms of cataract and may be useful for screening drugs to prevent or delay cataractogenesis in susceptible adults. 10.1167/iovs.62.15.10

Proposed Role for Internal Lens Pressure as an Initiator of Age-Related Lens Protein Aggregation Diseases. Clinical ophthalmology (Auckland, N.Z.) The process that initiates lens stiffness evident in age-related lens protein aggregation diseases is thought to be mainly the result of oxidation. While oxidation is a major contributor, the exposure of lens proteins to physical stress over time increases susceptibility of lens proteins to oxidative damage, and this is believed to play a significant role in initiating these diseases. Accordingly, an overview of key physical stressors and molecular factors known to be implicated in the development of age-related lens protein aggregation diseases is presented, paying particular attention to the consequence of persistent increase in internal lens pressure. 10.2147/OPTH.S369676