Abstract
Purpose :
Aging is a leading risk factor for retinal degenerative disease. A better understanding of the mechanisms of aging could lead to treatments for age-related retinal disease. When DNA methylation patterns are observed genome wide over the course of an individual’s lifetime, these marks change in a predictable way, and can be used to generate a DNA methyl-aging clock (DNAmA Clock) in humans and mice. Trisomy of the 21st chromosome (T21) causes premature aging and early onset of age-related retinal diseases including cataracts, macular degeneration and glaucoma. Adults with T21 have also been shown to have an accelerated DNAmA Clock. We show that age acceleration of T21 tissues already occurs in the fetal retina. If we can better understand the molecular mechanisms of accelerated aging in T21 individuals, we may be able to better understand mechanisms of age-related retinal diseases in both T21 and normal individuals.
Methods :
To identify the DNA-methyl age, we extract genomic DNA and profile the CpG methylated regions using the Infinium MethylationEPIC Kit for human samples or the mammalian methylation array developed by Arneson et al., 2021 for mouse samples. We then calculate the DNA-methyl age based on comparison to the Horvath Pan-Tissue clock. We apply this assay to normal and T21 human retina, and normal and T21 mouse retina and other tissues. We use the mouse model of T21 called Ts65Dn.
Results :
We observe a robust DNA-methyl age acceleration in T21 fetal human retinal samples when compared to age matched controls. To further understand the region of the 21st chromosome that is important for age acceleration, we perform similar analysis of the retina from the Tn65Dn mouse model of T21, and also observe robust age acceleration in Tn65Dn mice compared to controls. Other tissues in Tn65Dn mice at various ages also show an accelerated aging profile in the Horvath Pan-Tissue clock.
Conclusions :
We show that the DNAmA Clock is accelerated in the fetal retina of humans with T21. Additionally, mice with a homologous region of the human 21st chromosome have an accelerated DNAmA Clock. These results indicate that the age-acceleration that occurs in T21 humans is also present in mice and will allow future studies to better understand the molecular basis of age acceleration and potentially develop new approaches to age-related disorders, such as macular degeneration.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.