The eye as a model of ageing in translational research – Molecular, epigenetic and clinical aspects

Abstract

The eye and visual system are valuable in many areas of translational research such as stem cell therapy, transplantation research and gene therapy. Changes in many ocular tissues can be measured directly, easily and objectively in vivo (e.g. lens transparency; retinal blood vessel calibre; corneal endothelial cell counts) and so the eye may also be a uniquely useful site as a model of ageing. This review details cellular, molecular and epigenetic mechanisms related to ageing within the eye, and describes ocular parameters that can be directly measured clinically and which might be of value in ageing research as the translational “window to the rest of the body”. The eye is likely to provide a valuable model for validating biomarkers of ageing at molecular, epigenetic, cellular and clinical levels. A research agenda to definitively establish the relationship between biomarkers of ageing and ocular parameters is proposed.

Introduction

Ophthalmology is increasingly recognised as being at the forefront of translational research (Stahl and Smith, 2010). The unique access to and visibility of ocular tissues and range of visual functions permits investigation of a wide variety of physiological and pathological mechanisms. Stem cell biology, transplantation and gene therapy are all areas of research where the eye plays a prominent role in animal models as well as in clinical research. In this review we make the case that the eye can also play a key role in ageing research, with many ocular age-related changes having translational applications to other body systems. Further support for this argument comes from studies which show that visual impairment is a significant predictor of mortality (Lott et al., 2010). Cataract, glaucoma and age-related macular degeneration (AMD) are important causes of low vision in the elderly. Moreover, poor visual function is related to frailty (Klein et al., 2003, Kulmala et al., 2011), which is an age-related clinical concept of increased vulnerability to stressors due to impairment of multiple systems, resulting in increased risk of morbidity and mortality (Bergman et al., 2007, Fried et al., 2001, Fulop et al., 2010). AMD and low vision are also related to depression and increased morbidity (Brody et al., 2001, Huang et al., 2010, Mathew et al., 2011, Popescu et al., 2012).

Evolution, and behavioural studies of humans and animals, demonstrates the vital importance of vision. Studies of infants who are blind from birth show that vision is vital for early sensory-motor and psychosocial development, as it is the sense that co-ordinates the other sensory inputs. However, light energy is highly damaging to tissues, and the human eye has developed a range of mechanisms that protect its unique structures and functions from oxidative stress and other damaging insults. Failure of these mechanisms can lead to pathology and presentation of age-related ocular conditions such as cataract, primary open-angle glaucoma and age-related macular degeneration (AMD). Virtually all tissues of the eye are affected by ageing; the most well known pathologies are age-related development of opacification of the lens (cataract) and age-related macular degeneration. Indeed, epidemiological research has demonstrated that individuals with cataracts have a significantly higher mortality rate than those without, even after adjusting for known confounders. This suggests that biochemical mechanisms in ocular lens may reflect ageing processes elsewhere in the body (Hennis et al., 2001, Truscott, 2005, Truscott and Zhu, 2010, West et al., 2000). The retinal ganglion cells in the eye can also provide information relating to neuronal ganglion function in ageing and age-related disease such as Alzheimer's disease and glaucoma (Curcio and Drucker, 1993, Nag and Wadhwa, 2012, Osborne, 2008). Further examples of the age-related changes within the eye include loss of corneal endothelial cells, changes in the calibre of the retinal vasculature, loss of visual function (e.g. visual acuity; contrast sensitivity) and thinning of the retinal tissue layers, all of which can be measured easily, quickly, objectively and non-invasively. Many of these ocular age-related changes also have systemic associations or correlates with ageing in other end-organs or body systems, and these changes may be easier or less invasive to measure in the eye than other organs or systems (Table 1).

We present a comprehensive overview that proposes that the eye represents an ideal model for studying age-related processes at biological, clinical, epigenetic and molecular levels. The structural organization of the review leads the reader through (i) the rationale for the eye to be considered a model of ageing (ii) cellular and molecular mechanisms of ageing in the eye, (iii) epigenetic mechanisms and their role in age-related eye disease and (iv) ocular parameters that can be readily measured which might be of value in ageing research, using the eye as the translational “window to the rest of the body”. We conclude by discussing how the eye might represent a powerful new model for validating potential biomarkers of ageing and propose a research agenda to establish whether the eye is a suitable model.