Assessing the Impact of Age, Sex, and Menopause on Scleral Biomechanics and Gene Expression

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Glaucoma is the leading cause of irreversible blindness worldwide and is projected to affect 112 million people by 2040. Aging is a major risk factor for developing glaucoma. Yet, evidence suggests that the age of menopause modulates a woman’s risk of developing glaucoma. Overall, women represent 59% of the glaucoma population highlighting the need to understand the impact of menopause on ocular tissues. Glaucoma is multifactorial but elevated intraocular pressure (IOP) remains a major risk factor. Elevated IOP increases optic nerve head (ONH) deformation contributing to the loss of retinal ganglion cells and vision loss in glaucoma. The extent of ONH deformation is related to IOP and ocular biomechanical properties. Age and menopause modulate the stiffness of tissues throughout the body and are known to affect gene expression in the retina. Here, our hypothesis is that menopause will decrease scleral stiffness, exacerbating ONH deformation thus increasing the risk of developing glaucoma and that these effects are mediated by altered gene expression profiles in the sclera. This proposal addresses the hypothesis in a rat model using age and surgical menopause across two integrated Aims. Aim 1 measures the biphasic mechanical properties of the scleral and Aim 2 assesses gene expression of the sclera. This proposal achieves these Aims by examining young (3-4 months) and older adult (20-24 months) male and female Long-Evans rats. Young females are divided into pre- and post-menopausal groups. Menopause will occur by ovariectomy (young) of physiologically (older adults). In our integrated Aims, one eye is used to assess scleral mechanics while the opposite eye is used to assess gene expression. Age, sex, and menopause affect multiple gene networks; therefore, we will use RNAseq, an unbiased approach, to examine gene expression associated with extracellular matrix remodeling. Our preliminary data show that ovariectomy decreases scleral stiffness, supporting our hypothesis. We also show that age and ovariectomy modulate retinal gene expression. This proposal provides functional (e.g., scleral mechanics) and mechanistic (e.g., gene expression) insight into the association between age, sex, menopause, and glaucoma. This proposal will set up future applications to investigate pathways affected by age and menopause as potential treatments. These treatments can target mechanical properties or gene expression to decrease the susceptibility to developing glaucoma.