Aged Nrf2-null mice develop all major types of age-related cataracts

Authors: ROWAN, SHELDON - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; JIANG, SHUHONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; FRANCISCO, SARAH - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; POMATTO, LAURA - National Institutes Of Health (NIH); MA, ZHIWEI - National Institutes Of Health (NIH); JIAO, XIAODONG - National Institutes Of Health (NIH); CAMPOS, MARIA - National Institutes Of Health (NIH); ARYAL, SANDEEP - University Of Delaware; PATEL, SHAILI - University Of Delaware; MAHALING, BINAPANI - Johns Hopkins University School Of Medicine; RIAZUDDIN, S. - Johns Hopkins University School Of Medicine; DUH, ELIA - Johns Hopkins University School Of Medicine; LACHKE, SALIL - University Of Delaware; HEJTMANCIK, J - National Institutes Of Health (NIH); DE CABO, RAFAEL - National Institutes Of Health (NIH); FITZGERALD, PAUL - University Of California, Davis; TAYLOR, ALLEN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Investigative Ophthalmology and Visual Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/19/2021
Publication Date: 12/9/2021
Citation: Rowan, S., Jiang, S., Francisco, S., Pomatto, L., Ma, Z., Jiao, X., Campos, M., Aryal, S., Patel, S., Mahaling, B., Riazuddin, S.A., Duh, E., Lachke, S., Hejtmancik, J.F., De Cabo, R., Fitzgerald, P., Taylor, A. 2021. Aged Nrf2-null mice develop all major types of age-related cataracts. Investigative Ophthalmology and Visual Science. 62(15):10. https://doi.org/10.1167/iovs.62.15.10.
DOI: https://doi.org/10.1167/iovs.62.15.10

Interpretive Summary: A cataract is a condition when the lens of the eye is no longer transparent and it results in visual impairment. Most cataracts occur during aging, which we refer to as age-related cataracts, and these constitute a leading cause of vision problems and blindness worldwide. Treatments that can delay cataract formation or progression would have enormous medical and economic benefits, but developing these treatments requires accurate animal models of age-related cataracts. These animal models have remained elusive. In this study, we characterized mice that are lacking a regulatory gene called Nrf2. Nrf2-deficient mice developed age-related cataracts that mirror the development of age-related cataracts in humans. We tested whether two different beneficial dietary treatments, a low glycemic index diet or a low-calorie diet, could reduce the incidence of cataracts. Neither treatment significantly altered the rate of cataracts in this small study. Nrf2 appears important in human cataract prevention and developing new treatments that prevent cataracts in Nrf2-deficient mice may lead to future treatments for age-related cataracts in humans.

Technical Abstract: 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 11-15 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 -/- 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.