Topical cyclodextrin reduces amyloid beta and inflammation improving retinal function in ageing mice.

Retinal ageing results in chronic inflammation, extracellular deposition, including that of amyloid beta (Aß) and declining visual function. In humans this can progress into age-related macular degeneration (AMD), which is without cure. Therapeutic approaches have focused on systemic immunotherapies without clinical resolution. Here, we show using aged mice that 2-Hydroxypropyl-ß-cyclodextrin, a sugar molecule given as eye drops over 3 months results in significant reductions in Aß by 65% and inflammation by 75% in the aged mouse retina. It also elevates retinal pigment epithelium specific protein 65 (RPE65), a key molecule in the visual cycle, in aged retina. These changes are accompanied by a significant improvement in retinal function measured physiologically. 2-Hydroxypropyl-ß-cyclodextrin is as effective in reducing Aß and inflammation in the complement factor H knockout (Cfh(-/-)) mouse that shows advanced ageing and has been proposed as an AMD model. ß-cyclodextrin is economic, safe and may provide an efficient route to reducing the impact of retinal ageing.

Near-infrared light increases ATP, extends lifespan and improves mobility in aged Drosophila melanogaster.

Ageing is an irreversible cellular decline partly driven by failing mitochondrial integrity. Mitochondria accumulate DNA mutations and reduce ATP production necessary for cellular metabolism. This is associated with inflammation. Near-infrared exposure increases retinal ATP in old mice via cytochrome c oxidase absorption and reduces inflammation. Here, we expose fruitflies daily to 670 nm radiation, revealing elevated ATP and reduced inflammation with age. Critically, there was a significant increase in average lifespan: 100-175% more flies survived into old age following 670 nm exposure and these had significantly improved mobility. This may be a simple route to extending lifespan and improving function in old age.

Recharging mitochondrial batteries in old eyes. Near infra-red increases ATP.

Progressive accumulation of age related mitochondrial DNA mutations reduce ATP production and increase reactive oxygen species output, leading to oxidative stress, inflammation and degradation. The pace of this is linked to metabolic demand. The retina has the greatest metabolic demand and mitochondrial density in the body and displays progressive age related inflammation and marked cell loss. Near infra-red (670 nm) is thought to be absorbed by cytochrome c oxidase (COX), a key element in mitochondrial respiration and it has been demonstrated that it improves mitochondrial membrane potentials in aged eyes. It also significantly reduces the impact of experimental pathology and ameliorates age related retinal inflammation. We show ATP decline with ageing in mouse retina and brain. Also, in these tissues that ATP is significantly increased by 670 nm exposure in old mice. In the retina this was associated with increased COX and reduced acrolein expression. Acrolein, being a free radical marker of retinal oxidative stress, is up regulated in Alzheimer's and retinal degeneration. This is the first demonstration of ATP manipulation in vivo and may provide a simple non-invasive route to combating age related tissue decline.

Questioning photostasis.

Photostasis is a phenomenon where the photoreceptor outer segment (OS) length and its rhodopsin content vary depending on environmental lighting. When light is reduced for extended periods, it is argued that OS lengthen and its rhodopsin concentration rises to increase photon capture in darker environment. Increases in OS length may occur because the retinal pigment epithelium (RPE) cells reduce OS consumption in prolonged darkness. But sample sizes in assessing changes in OS length have been small, and results highly varied with no statistical analysis ever offered. Further, animals used were often albinos, which have abnormal RPE cells. Here we keep pigmented and albino mice for 21 days in darkness and compare OS length with those in a normal 12:12 light/dark environment. We measured approximately 1300 OS but found no statistically significant difference in their lengths between light and dark groups in either pigmentation phenotype, although there was a small trend in the data favoring OS extension in the dark. Given that earlier studies were undertaken on limited samples with no statistical analysis, our data pose serious questions for the notion of mammalian photostasis in terms of significant OS plasticity.

Treatment with 670 nm light up regulates cytochrome C oxidase expression and reduces inflammation in an age-related macular degeneration model.

Inflammation is an umbrella feature of ageing. It is present in the aged retina and many retinal diseases including age-related macular degeneration (AMD). In ageing and in AMD mitochondrial function declines. In normal ageing this can be manipulated by brief exposure to 670 nm light on the retina, which increases mitochondrial membrane potential and reduces inflammation. Here we ask if 670 nm exposure has the same ability in an aged mouse model of AMD, the complement factor H knockout (CFH(-/-)) where inflammation is a key feature. Further, we ask whether this occurs when 670 nm is delivered briefly in environmental lighting rather than directly focussed on the retina. Mice were exposed to 670 nm for 6 minutes twice a day for 14 days in the form of supplemented environmental light. Exposed animals had significant increase in cytochrome c oxidase (COX), which is a mitochondrial enzyme regulating oxidative phosphorylation.There was a significant reduction in complement component C3, an inflammatory marker in the outer retina. Vimetin and glial fibrillary acidic protein (GFAP) expression, which reflect retinal stress in Muller glia, were also significantly down regulated. There were also significant changes in outer retinal macrophage morphology. However, amyloid beta (Aß) load, which also increases with age in the outer retina and is pro-inflammatory, did not change. Hence, 670 nm is effective in reducing inflammation probably via COX activation in mice with a genotype similar to that in 50% of AMD patients even when brief exposures are delivered via environmental lighting. Further, inflammation can be reduced independent of Aß. The efficacy revealed here supports current early stage clinical trials of 670 nm in AMD patients.

Aged peripheral retinal lesions originating from the ciliary body sweep away the retinal pigmented epithelium.

AIMS: To investigate age-related lesions in the far-anterior retina that migrate from the ciliary body (CB) and how they affect the neural retina and retinal pigmented epithelium (RPE). METHODS: One eye from three healthy subjects aged 87, 92 and 93 years were used. Retinae were photographed, embedded in resin and then sectioned at 2 µm. RESULTS: Multiple elliptically shaped lesions were present in the CB. Larger lesions extended into the peripheral retina. Lesions resulted from deposits that had lenticular qualities. These develop centrally along Bruch's membrane sweeping away the RPE, such that piles of RPE cells were present around the deposits that resulted in retinal atrophy. The internal composition of the deposits revealed large numbers of spherical bodies, unlike those seen in drusen. RPE cells adjacent to these deposits and their underlying lesions became highly irregular, with melanin granules spacing themselves out within the cell and adopting similar orientations. This is a highly distinctive feature. CONCLUSIONS: These far-anterior deposits were different in nature from drusen in terms of morphology, composition and origin. They swept away the RPE, exposing the Bruch's membrane and isolating the retina, leading to atrophy. They appeared to originate from the CB and progressed centrally. The deposits may have developed from the ciliary muscle, which would account for their elongated orientation. Their impact on melanin distribution in RPE cells was unexpected and unusual, implying that they release a signal that influences melanin organisation.