Abstract
It is currently believed that aging is closely linked with mitochondrial dysfunction, and that resveratrol exhibits anti-aging and neuroprotective effects by improving mitochondrial function, even though the mechanisms are not well defined. This study explored mitochondrial quality (mitochondrial DNA integrity and copy number), mitochondrial function (fusion/fission, mitophagy/autophagy), antioxidant system and activity of the Akt/mTOR and Ampk/Sirt1/Pgc1α pathways, and inflammation in aging zebrafish retinas to identify the probable mechanisms of resveratrol’s anti-aging and neuroprotective effects. mtDNA integrity, mtDNA copy number, mitochondrial fusion regulators, mitophagy, and antioxidant-related genes were all decreased whereas Akt/mTOR activity and inflammation was increased upon aging in zebrafish retinas. Resveratrol was shown to not only increase mitochondrial quality and function, but also to suppress Akt/mTOR activity in zebrafish retinas. These results support the notion that mitochondrial dysfunction and increased Akt/mTOR activity are major players in age-related retinal neuropathy in zebrafish, and demonstrate a trend towards mitochondrial fragmentation in the aging retina. Importantly, resveratrol promoted mitochondrial function, up-regulating Ampk/Sirt1/Pgc1α, and down-regulated Akt/mTOR pathway activity in zebrafish retinas, suggesting that it may be able to prevent age-related oculopathy.
Highlights
Aging is the biological process characterized by the accumulation of damage in structure and decline in function of cells and tissues over time, leading to organismal death [1]
Zebrafish retinal mitochondrial DNA (mtDNA) quality at different ages and after resveratrol treatment To investigate the mitochondrial quality in aging zebrafish retinas, we first analyzed the ratio of mitochondrial long chain to mitochondrial short chain DNA which reflects the mitochondrial integrity and the ability to repair mitochondrial damage
While mitochondrial integrity was higher at 1 and 4 months compared to 5 days old, at 19 months old the mitochondrial integrity had returned to the level of the 5-day old retinas (Figure 1A). mtDNA copy number is proportional to mitochondrial mass, and we observed that at 4 months old the mtDNA copy number of retinas was substantially increased compared to 5-day and 1month old retinas, at 19 months it had returned to the level of 5-day old retinas (Figure 1B)
Summary
Aging is the biological process characterized by the accumulation of damage in structure and decline in function of cells and tissues over time, leading to organismal death [1]. The causes of aging are complex but include abnormal mitochondria, epigenetic alterations, increased reactive oxygen species (ROS), increased DNA methylation, and decreased telomere length [2–4]. Both dysfunctional mitochondria that overproduce ROS [5] and abnormal mitochondrial dynamics have been recognized as crucial contributors to the aging process as well as age-related neuronal diseases and age-related oculopathies such as glaucoma, www.aging-us.com age-related macular degeneration (AMD), and cataracts [6–8]. A potential reason for this alteration in mitochondrial dynamics is that accumulated ROS damage reduces mitochondrial output, and in response the cell promotes mitochondrial fission to help cope with the decline in mitochondrial function [11]
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