An integrated computational model of human outer retinal bioenergetics and effects of ageing

The biology of ageing is of growing importance as the elderly population grows. This project seeks to further understanding of how the back of the eye ages. The 'system' to be investigated is the layer of light sensitive cells (rods and cones) in the outer retina, the remarkably dense, supporting vascular bed (choriocapillaris) that lies beneath it and the connective tissue layer known as Bruch's membrane that sits between the choriocapillaris and the rods and cones.

Rods and cones require large amounts of energy to function normally and the very highly vascular choriocapillaris provides the necessary oxygen. This needs to be precisely controlled as too low an oxygen supply impairs rod and cone function and potentially leads to cell death. Conversely, too high a concentration of oxygen can also be toxic.

From published data, we know that with increasing age rod numbers drop, Bruch's membrane gets thicker and the choriocapillaris degrades in a way that reduces blood flow. It is possible that in healthy ageing these changes interact in a way maintains the health of rods and cones (photoreceptors).

It is not possible to make the direct measurements necessary to explore this phenomenon in more detail in patients or healthy volunteers, particularly as the anatomy of the back of the human eye varies markedly from one area to another. Also, it is very difficult to explore how changes in blood pressure and other factors might impact on photoreceptor health. Even direct measurements of choriocapillaris blood flow are challenging as a layer of pigmented cells lies just in front of it.

For these reasons we have developed a computer simulation of choriocapillaris blood flow and already identified some unexpected properties of this vascular bed. By drawing together published data and additional morphological data from post-mortem eyes donated for research purposes we intend to extend this model to describe how oxygen is delivered from the choriocapillaris to the outer retina and how much oxygen the outer retina (photoreceptors) need.

Having established the model we will be able to use it to determine how the integrated system of blood vessels, Bruch's membrane and photoreceptors behaves in healthy ageing. We predict that oxygen supply and demand will be closely matched and that, paradoxically, reduction of blood flow is beneficial as it keeps photoreceptors at an optimal concentration of oxygen. It is possible that similar combinations of age-related changes are a feature of healthy ageing at other sites, a phenomenon for which we have coined the term 'graceful ageing'.

The proposed study seeks to explore the factors that determine photoreceptor oxygen tension and in particular to further understanding of how ageing of the choriocapillaris, Bruch's membrane and photoreceptor populations may combine in healthy ageing to maintain optimal oxygen concentrations at the photoreceptor inner segments.

The methodology will centre on computational models informed by anatomical and physiological datasets. The starting point will be a recently developed, novel model of human choriocapillaris blood flow. This will be coupled with a 3-dimensional model of mass transfer that will use a validated finite element code (ACEsim). In this way we will be able to model oxygen delivery to photoreceptor inner segments. In order to estimate outer retinal oxygen demand we will modify estimates of murine rod energy requirements for human rods, conventional cones and the specialised cones that are found in the fovea. By generating maps of photoreceptor density from donor eyes of differing ages we will then be able to estimate outer retinal oxygen demand. Combining this with the oxygen supply model it will be possible to estimate inner segment oxygen tension and determine whether it is likely to be optimal or adversely low (hypoxia) or high (likely to generate damaging reactive oxygen species).

The final model will allow us to explore how varying various parameters (age, choroidal blood flow, completeness of choriocapillaris network, Bruch's membrane thickness, age-related photoreceptor cell loss) are likely to alter inner segment pO2.

The model not only has relevant to ageing. It will also inform studies of drug delivery to the outer retina and pathogenesis of conditions such as age-related macular degeneration and diabetic retinopathy.

The impact of this study falls into several different areas:

1) The biopharmaceutical industry will benefit from the modelling of choroidal blood flow and exchange between the choroid and outer retina for assessing delivery of therapeutics.

2) Insights into healthy ageing will help define 'unhealthy' ageing and in particular inform understanding of the pathogenesis of age-related blinding conditions. Such understanding will in turn lead to the development of new therapies.

3) The approach to be taken in this proposal is likely to deliver impact in other age-related disorders. The applicants believe that part of the relative failure to achieve therapeutic success in age-related degenerative conditions is that the interplay between different components of the system under investigation has not been taken into account. In the eye, this has led to approaches that target either the microcirculation, or Bruch's membrane or retinal pigment epithelium or photoreceptors. We consider it critical to model the system in an integrated manner, as proposed here.