Age-Related Changes in Vision
We focus much of our research on understanding aging in the eye for two reasons. First, most of the aged will confront age related vision problems with major compromises of quality of life and high health care costs and second the eye contains the slowest and fastest metabolizing tissues. Thus, we can test hypotheses in the most diverse metabolic conditions and seek unifying hypotheses.
Figure 1. Effects of cataracts (left) and age-related macular degeneration (right) on vision
Specifically, we determine the primary causes of eye lens cataract and degeneration of the macula (Fig 1), and apply this knowledge to extend the useful life of these organs. Current approaches involve defining roles for cellular proteolytic machines and determining adequate levels of nutrients during various life stages, which will result in delayed accumulation of damaged proteins in lens and retina, as well as delayed lens opacification and age-related maculopathy. The laboratory pursues this mission principally using clinical/epidemiological studies and laboratory tests in human cohorts, animal models, in cultured human and other mammalian lens or retina tissues, and lens and retina epithelial cells in culture. The major research questions seek to define and understand interrelationships between aging, regulation of lens protein metabolism, protease function and expression, and nutrition.
Ubiquitin Pathways and High Glycemic Index
A primary biochemical focus of our work is identifying ubiquitin-dependent processes and autophagic pathways that are involved in the removal of photooxidized proteins. High glycemic index diet causes enhanced oxidation and glycation-induced protein damage. When levels of damaged proteins are low, the ubiquitin-proteasome system and the lysosomal proteolytic system can degrade the damaged proteins and toxicity is averted (Fig 2, top). Such is the case in many tissues during youth.
Under chronic glycative stress, glycated proteins accumulate. These may include AGE's along with unmodified proteins, some including ubiquitin conjugates (Fig 2, box).
Some may oligomerize and cross-link forming the higher mass aggregates. Undegraded conjugates may also accumulate if there is insufficient proteasomal,
including deubiquitinating, activity. Accumulated oligomerized altered proteins may impair the proteolytic machinery, setting up a vicious cycle of stress, limited
proteolytic editing, and further damage to the proteome, resulting in some of the disease-related accumulation of AGEs and conjugates that is observed in vivo.
Figure 2. Schematic representation of the effects of high glycemic index diets of glycation-induced protein damage.
Dietary Modifications and Protein Degradation
Nutritional changes have the potential to alter the pathways affected by high glycemic index and oxidation. A possible mechanism by which these changes may occur is diagrammed in Fig 3. We are working to test the biochemical parameters that could validate this model.
Figure 3. Proposed Interaction Between Oxidants, Antioxidants and Proteases
Resulting in Prolonged Function or Dysfunction
The Laboratory for Nutrition and Vision Research also conducts epidemiological research focused on ocular diseases. research. We collaborate with the Nurses' Health Study at Harvard University, The Age-Related Eye Diseases Study of the National Eye Institute of NIH, The Melbourne Visual Impairment Project (VIP) and The Rotterdam study in the Netherlands.