Impact of dietary omega-6 and omega-3 polyunsaturated fatty acids on retinal autophagy during aging in mice

Abstract

Purpose : Dietary lipids - particularly polyunsaturated fatty acids of the omega-3 series (n-3 PUFAs) - are important nutritional factors that regulate visual function and retinal homeostasis. Autophagy is a key cellular process involved in homeostasis maintenance whose regulation, initiation and machinery rely on lipids. Alterations in autophagy have been reported in the retina during aging and in age-related macular degeneration (AMD). In this study, we investigated whether dietary PUFAs can influence retinal autophagy during aging.

Methods : One-month-old GFP-LC3 transgenic mice (RIKEN BRC) were fed for 9 months and 18 months with diets that had a similar 5%-fat content but that were different regarding their ratio in n-6/n-3 PUFAs (complying with recommendations from health agencies or mimicking a Western diet) as well as the nature of n-3 PUFAs provided (precursor (alpha linolenic acid) or long chain (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)). Several aspects of the retinal physiology were studied: fatty acid composition (gas chromatography), function (electroretinography), and inflammation (immunostaining on cryosections). Autophagy was evaluated by several approaches: autophagy flux (ex-vivo using flux inhibitors and Western blot), expression of autophagy–related genes (RT-qPCR) and proteins (Western blot and immunostaining on cryosections).

Results : We showed that, whereas autophagy flux was maintained during aging in mice fed a diet that meets the recommendations of health agencies (low ratio of n-6/n-3 PUFA precursors), long-term consumption of a Western diet (high ratio in n-6/n-3 PUFA precursors) altered the retinal autophagy flux and impaired the response of the inner retina to light stimuli. Dietary supplementation with fish oil rich in DHA and EPA was not effective in preventing alterations in autophagy and in visual function induced by the Western diet. On the contrary, it led to earlier downregulation of the expression of several autophagy-related genes and proteins and was associated with an increased activation and migration of microglial cells in the retina.

Conclusions : Dietary PUFAs impact on retinal autophagy. Further investigation is needed to better characterize the origin of the autophagic alterations caused by modification of the fatty acid environment as well as their consequences on retinal physiology.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.