Discovering How the Retina Ages With Dr. Akihiro Ikeda, DVM, PhD

Why do age-related diseases occur when people age? This sounds like a simple question – when else should they occur? But it is a key question which applies to retinal diseases including age-related macular degeneration (AMD), which affects roughly 11 million people in the U.S. and usually leads to loss of central vision. Aging is the largest risk factor for AMD; studies indicate that people over age 60 are at greater risk than those in younger age groups. Dr. Akihiro Ikeda (DVM and PhD), a professor in Medical Genetics and the Associate Director of the McPherson Eye Research Institute, studies the onset and the underlying mechanism of AMD. The Ikeda lab’s working hypothesis is that for age-dependent diseases to manifest themselves in an age-dependent manner, there must be tight association between the disease-causing mechanisms and cellular changes that occur with aging. Therefore, it is important to understand how the aging process is regulated at the molecular level, and how the aging process is associated with disease mechanisms.

Dr. Ikeda and his lab associates (Sakae Ikeda, DVM, Wei-hua Lee, PhD, Erica Macke, Sarah Lewis & Yuyun Zhu) study agedependent retinal diseases using a forward genetics approach in mice. This approach is phenotype-driven, starting from observable characteristics in the animal. The advantage of this approach is that it offers the potential of identifying previously unknown genes and molecular pathways affecting age-dependent retinal phenotypes. Specifically, the laboratory aims to identify gene mutations that lead to early onset of aging phenotypes in the mouse retina, as well as to identify genes that cause the difference in the severity of age-dependent retinal abnormalities observed between different mouse inbred strains. Identification of these genes will allow Dr. Ikeda to elucidate the molecular mechanisms causing the age-dependent retinal abnormalities, and therefore, should enhance understanding of age-dependent retinal diseases and aging of the retina.

Most recently, the Ikeda lab reported (in eLife, one of the top journals in life science) the discovery of a protein that links aging and age-dependent diseases. The molecule, called transmembrane protein 135 (Tmem135), regulates retinal aging; a mutation in the gene encoding this protein results in age-dependent disease. To discover this novel protein and its role in age-dependent retinal diseases, Ikeda and his team studied a mouse model that exhibits retinal abnormalities similar to those seen in normal aged mice, but with earlier onset and faster progression. Interestingly, this accelerated retinal aging in mutant mice is also accompanied by symptoms similar to those observed in human AMD patients. Genetic mapping and positional cloning revealed that a mutation in Tmem135 is the cause behind these retinal symptoms, demonstrating that aging and age-dependent diseases are closely associated with each other at the molecular level.

The team next discovered that the protein regulates the size of the mitochondria, an energy-producing organelle that is essential for various metabolic functions of the cell. The regulation of mitochondrial size by TMEM135 determines the sensitivity of cells to environmental stress and the pace of aging in the retina. Functional loss of TMEM135 results in higher sensitivity to such stress, leading to accelerated aging as well as age-dependent pathologies. The Ikeda lab now aims to determine the exact biochemical and molecular functions of TMEM135 in mitochondria as well as molecular pathways affected by defective TMEM135 in the retina, and to examine its roles in the aging process of other tissues and various age-dependent diseases.

Identification of new genes involved in retinal aging, such as Tmem135, could potentially lead to development of novel therapeutic approaches including previously-unknown drug therapies. Dr. Ikeda believes that his group’s unbiased genetic approach will identify multiple new entry points into the mechanisms controlling aging at the molecular level, providing more targets for therapeutic approaches against age-dependent retinal diseases. In addition to the Tmem135 project, the Ikeda lab is currently working on multiple studies to identify other genes associated with aging of the retina using mouse genetics; more genes equals more ideas for therapy. Their journey opens many exciting pathways forward.