The retina, an extreme model of ageing

Photoreceptors in the retina demand more energy than any other tissue in the body. Because of this they can be viewed as the body's sports car. They demand excess energy, produce polluting by products and tend to have a relatively short lifespan. Hence they age fast, with progressive levels of inflammation, extra-cellular deposition and cell loss. 30% of our photoreceptors are lost over normal life because of these processes. Hence, the retina is a special case in the area of ageing. This was not a problem for our ancestors whose historic lifespan was relatively short. But now it is a major problem, as in Western Europe our average lifespans is >80 years. It will also become a problem in the third world as improved health case pushed the average lifespan back further and further and healthy ageing becomes a major issue.

There are many factors driving retinal ageing but two are significant. First, we run out of energy. The energy producing units in our cells called mitochondria become less efficient and produce less energy in the form of ATP. Reduced ATP is associated with inflammation and ageing, so this is problematic. Second, photoreceptors are associated with the build up of extra-cellular debris because their tips are removed each day and have to be cleared away while new ones are made to replace them. The clearing up process appears to become less efficient with age and the system gets clogged up. This also restricts the blood supply to the outer retina which carries the oxygen needed for mitochondrial function and ATP production. So in age, the retina can not breath as well as it could when it was young.

Lack of energy and deposited waste material are key problems in retinal ageing. However, we can do something about this. We can provide more energy. Mitochondrial production of ATP can be increased by specific near infrared (NIR) wavelengths including 670nm. Mitochondria absorb these wavelengths and this lifts their respiration increasing ATP. In old mice this also reduces age related inflammation significantly. So we will expose old mice to this light for short and long periods and test their retinal function and examine age related changes in retinal metabolism and inflammation. This light is very safe in terms of its energy and wavelength. In fact there are clinical trials for its use in pathological eye inflammation at Moorfields Eye Hospital. Our hypothesis is that we will reduce age related cell death with this treatment. As this is procedure is safe we will extend such light exposures to normal aged human subjects and subsequently test their retinal function

We can also clear waste material. Cyclodextrin is a sugar that can be given as eye drops. It has been used for many years as a food additive and as a vehicle for drug delivery. It has a long safety profile. However, it has a unique and largely overlooked property. It has the ability to scoop up waste products within its ring structure particularly those that can not normally be made soluble. It has recently been used in Alzheimer mouse models where the brain accumulates a lot of waste in the form of amyloid beta and also deposits in the retina. We propose that removing waste material will allow the retina to breath and improve its function. We already know that it can improve retinal function in a pilot study. We will employ cyclodextrin in aged mice and subsequently, as above, test their retinal function and probe their retinal metabolism and levels of inflammation.

The key advantages of this proposal are that we know that NIR and cyclodextrin work in animals models, but not if it combats ageing over the longer term and in respect of a comprehensive series of measures. Further, both agents are highly economic and known to be safe. They represent a highly compelling route to addressing a unique problem in ageing that undermines the quality of life.

The outer retina has the greatest energy demand in the body reflected in the high concentration of mitochondria in photoreceptors and their ATP output. With age mitochondrial function and ATP decline. This is associated with progressive inflammation. The outer retina also suffers from excess extra-cellular deposition with age, probably related to the continual turnover of photoreceptor outer segments. The deposited material is pro-inflammatory and restricts the outer retinal oxygen supply, further undermining mitochondrial function. These factors make the retina unique in terms of the pace of ageing. The consequence is a highly significant photoreceptor loss over normal life of 30%. With increased life expectancy this will become an major problem impacting on the quality of life of millions.

It is known that cytochrome c oxidase (COX) in mitochondria absorb certain wavelengths in the red and infrared. We have recently shown that this increases mitochondrial membrane potentials, COX and ATP. Further that this significantly reduces age related inflammation in mice. We will examine the sort and long term impact of 670nm on mouse retinal function (ERG), metabolic profile (Seahorse), inflammation and retinal cell death. Our application of Seahorse technology for profiling mitochondrial function will be a powerful tool in analysis of retinal ageing. As 670nm is safe we will examine its impact on aged human retinal function.

Cyclodextrin clears cellular deposits from retina and brain. It is FDA approved as a food additive and a drug vehicle. We will employ this in old mice clearing deposits, improving retinal respiration and examine changes in the ERG, metabolic profile (Seahorse), inflammation and cell death.

NIR and cyclodextrin have been shown to be effective in mice and are highly economic and safe. They represent a route to combat ageing processes in an organ that is highly susceptible to these factors that undermine the quality of life.

Ageing impacts on everyone. 10 million people in the UK are over 65 years old. The latest projections are for >5.5 million more in 20 years time and the number will almost double to around 19 million by 2050. The pace of retinal ageing will increase as life expectancy extends. There is little or no photoreceptor cell death in early midlife, but significant amounts later when inflammation and extra-cellular deposition are established. Hence the pace of ageing is likely to increase disproportionally as lifespan moves towards 100. The impact of this is significant as it reduces our ability to read normal print and undertake fine manipulations. Consequently, some elderly face increased difficulty in working and all will have problems reading whether for work or leisure.

There are multiple factors driving ageing and our ability to intervene is limited. It is unlikely that we will be able to change the genetic platform on which ageing takes place. However, it is now clear that we can improve mitochondrial function once it has declined and we are also able to clear deposits in the retina and brain that contribute to age related decline. The application of near infrared (NIR) lifts ATP production after it has declined with age and reduces age related inflammation. This is with limited exposures of around 1 min 5 times a week (Kokkinopoulos et al 2013; Gkotsi et al 2014). This light can be delivered via supplemented lighting (Begum et al 2014). We have been able to sustain reduced inflammation for >4 months in old mice (Submitted). Hence, this is a sustainable way to reduce the impact of ageing on mitochondria in the retina and is very economic. Incandescent light bulbs have a significant 670nm component but new low energy blubs and white LEDs do not. Hence, simply replacing the NIR element in domestic lighting may have a profound impact on the ageing process in the retina and could impact on a large number of individuals.

Cyclodextrin is economic and we know that it can be used in the form of eye drops. It enters the retina rapidly via the ciliary body. It is economic, FDA approved as a food additive and as a drug vehicle and can be self administered. In old mice reductions in amyloid beta and inflammation are obtained over 3 months with dosing three times a week (ARVO Abs submitted). There is no reason why cyclodextrin should not be given on a regular basis to "decoke" the aged retina. This very simple procedure is likely to increase mitochondrial respiration as well as remove age related inflammatory deposits. Hence, this may also be a driver to improve ATP production.

There is no obvious reason why NIR and cyclodextrin can not be used to combat the rapid ageing that the retina experiences. Consequently the potential impact on the ageing population could be enormous and impact on society and the economy. This could be delivered within 5-7 years as there are no safety concerns, only a need to enrich our understanding of their underlying mechanisms and influences.

We have an industrial partner in Polyphtonix (PPX) with whom we have had TSB funding for light delivery masks. These were initially designed for clinical use but such lighting with NIR is now being developed for domestic use. PPX is an award winning SME and they have recently won the 2014 National Business Award (http://www.polyphotonix.com/news.php). They are an expanding UK leader in specialised lighting. Our ability to monitor the age related decline in the retina in vivo is being exploited with Dr Tachtsidis from Biomedical Engineering at UCL. With Dr Tachtsidis, we are able to measure COX optically in the living retina which is tightly linked to ATP production. This is with a relatively simple device in a few minutes. Our aim is to develop commercial units that can do this with white light so that we are able to monitor the ageing process in the human living eye.