8-Aminoguanine protects the retina from age-related degeneration.

Abstract

Purpose : Retinal thinning and declining vision are commonly associated with aging. As the human lifespan keeps increasing, an oral drug that delays age-related vision decline is desirable to improve the quality of life of the elderly. This study is to evaluate whether 8-aminoguanine (8-AG), an endogenous orally bioavailable purine metabolite, protects the retina against age-related degeneration.

Methods : Because Fischer 344 (F344) rats are a classic model of aging that shows age-related retinal degeneration featuring both thinning of the whole retina and declined visual function, aged F344 rats were obtained from the National Institute of Aging and used here. Rats were treated with oral 8-AG (5 mg/kg in the drinking water). Treatment was started at 22 m of age and continued for 8 or 17 wks. ERG and OCT were recorded at baseline and 7 or 16 wks of treatment, respectively. Retinae were collected at 8 or 17 wks of treatment, respectively, for purine analyses by UPLC-MS/MS, RNA-seq, immunoblots and immunohistochemistry. Non-treated age-matched animals served as controls. N= 4-6.

Results : Eight wks of daily oral treatment with 8-AG provided strong retinal protection in aged F344 rats as evidenced by thicker retinae and a higher number of nuclei in the outer nuclear and retinal ganglion layers. Higher ERG responses suggest improved retinal function by 8-AG treatment. 8-AG treatment also led to thicker OS, higher rhodopsin level, and more PNA+ cone cells, suggesting restored rod homeostasis and more cone cells. Purine metabolome analyses showed increased 8-AG concentrations in the retinae of treated animals; however, other purines were not affected by the treatment. Age-related accumulation of malondialdehyde and 8-hydroxydeoxyguanosine (biomarkers of oxidative stress) in retinae were significantly reduced in 8-AG-treated aged rats, compared to controls. Moreover, 8-AG significantly reduced retinal CD68+, IBA1+ microglia/macrophages, and RNA-seq and transcriptome analyses indicated reduced expression of pro-inflammatory genes by microglia. Strikingly, 17 wks of treatment preserved all retinal layers in the 26 m old animals, compared to controls that showed severe retinal deterioration.

Conclusions : We discovered an oral agent, 8-AG, that potently protects the retina against age-related degeneration. The potent anti-oxidative and anti-inflammatory effects of 8-AG likely mediate its retinal protection.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.