Vision changes are an inevitable part of aging, but why are some more susceptible to age-related eye diseases and why do some individuals experience more severe decline than others? New research from The Jackson Laboratory (JAX) reveals that genetics play a key role in how the eye ages, with different genetic backgrounds influencing retinal aging in distinct ways.
The study, published in Molecular Neurodegeneration , examined age-related changes in genes and proteins of the retinas of nine strains of mice, mimicking the genetic variability found in humans. While all mice exhibited expected signs of aging, the severity and nature of these changes varied significantly between the nine strains.
A more accurate approach to model eye aging
Traditionally, studies of retinal aging and disease have relied on a single strain of genetically identical mice, limiting researchers' ability to understand the role of genetic variation. "The challenge in studying age-related eye diseases is that aging is heterogeneous," said Gareth Howell , professor and Diana Davis Spencer Foundation Chair for Glaucoma Research at JAX, who led the research. "Observing how aging occurs in one strain of mice might not be relevant to all mice – or humans. To overcome the limitations of previous studies, we wanted to know how genetic context drives aging of the retina."
In his work, Howell and his team leveraged nine strains of mice with different genetic backgrounds designed to better reflect human variability, generating data on age-related genetic and molecular changes in young and old mice. With their dataset now publicly available , Howell and his team hope their findings will help other scientists studying aging and vision loss – work that may also improve the utility of the eye as a window to the brain to predict neurological decline.
Genetic and protein analyses predict eye diseases
One of the most significant discoveries in the study was the identification of two mouse strains that closely resemble human retinal diseases. By performing eye exams – like what a human would undergo at a routine optometrist appointment, the researchers found that the Watkins Star Line B (WSB) strain developed characteristics of age-related macular degeneration and retinitis pigmentosa, a rare inherited form of blindness, while the New Zealand Obese (NZO) strain, known for its severe obesity and diabetes, developed diabetic retinopathy. Furthermore, gene and protein analysis in both strains of mice predicted that they would develop common age-related eye diseases.
"It was promising to see that the molecular data we generated predicted specific retinal cell abnormalities in these two strains" said Olivia Marola, a JAX postdoctoral associate and co-first author of the new paper. "When we saw unique changes in NZO's retinal ganglion cells at the molecular level, sure enough, we saw drastic functional changes in those cells."
These models will allow researchers to study how these diseases progress and explore potential treatments, explained Michael MacLean, a postdoctoral associate and co-first author of the work.
It could also help other scientists choose which mouse models to use in their own aging-related work or carry out further studies to pinpoint individual genes that are associated with accelerated eye aging and eye disease such as cataracts, glaucoma, macular degeneration, and diabetic retinopathy.
Retina as biomarker for Alzheimer's
Beyond vision research, this study could have broader implications for neurodegenerative diseases. Since the retina is a direct extension of the brain, understanding how it ages could provide clues about conditions like Alzheimer's and other forms of dementia.
"The eye is a crucial organ, and this research fills an important gap in our understanding of aging," said Howell. "But beyond that, the eye is a window into the brain. By understanding how the healthy eye ages, we may be able to work toward new ways of using the eyes to determine people's risk of developing diseases like Alzheimer's."
