The Aging Stress Response and Its Implication for AMD Pathogenesis

Abstract

Aging induces several stress response pathways to counterbalance detrimental changes associated with this process. These pathways include nutrient signaling, proteostasis, mitochondrial quality control and DNA damage response. At the cellular level, these pathways are controlled by evolutionarily conserved signaling molecules, such as 5’AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), insulin/insulin-like growth factor 1 (IGF-1) and sirtuins, including SIRT1. Peroxisome proliferation-activated receptor coactivator 1 alpha (PGC-1α), encoded by the PPARGC1A gene, playing an important role in antioxidant defense and mitochondrial biogenesis, may interact with these molecules influencing lifespan and general fitness. Perturbation in the aging stress response may lead to aging-related disorders, including age-related macular degeneration (AMD), the main reason for vision loss in the elderly. This is supported by studies showing an important role of disturbances in mitochondrial metabolism, DDR and autophagy in AMD pathogenesis. In addition, disturbed expression of PGC-1α was shown to associate with AMD. Therefore, the aging stress response may be critical for AMD pathogenesis, and further studies are needed to precisely determine mechanisms underlying its role in AMD. These studies can include research on retinal cells produced from pluripotent stem cells obtained from AMD donors with the mutations, either native or engineered, in the critical genes for the aging stress response, including AMPK, IGF1, MTOR, SIRT1 and PPARGC1A.

Interactions Between Genes From Aging Pathways May Influence Human Lifespan and Improve Animal to Human Translation

“…To explore the possibility that genes from the major aging pathways (IGF1/AKT/FOXO3, TP53/P21/P16, and mTOR/S6K mediated) may influence human lifespan as result of their interplay rather than independently, we selected the set of candidate genes ( Table 1B ) that belong to these pathways and have also been featured in aging research, as genes or their products ( Braeckman and Vanfleteren, 2007 ; Feng et al, 2007 ; Tsai et al, 2008 ; Ghosh et al, 2010 ; Kenyon, 2010 ; Johnson et al, 2013 ; Nojima et al, 2013 ; Ortega-Molina and Serrano, 2013 ; Tran et al, 2014 ; Cetrullo et al, 2015 ; Pavlatou et al, 2016 ; Uno and Nishida, 2016 ; Yuan et al, 2016 ; Donlon et al, 2017 ; Bartke and Quainoo, 2018 ; Morris et al, 2019 ; Singh et al, 2019 ; Blasiak et al, 2020 ; Zhang et al, 2020 ; Tabibzadeh, 2021 ). Majority of these genes are involved in cell/tissue responses to stress and damage that can contribute to the body’s ability to recover (resilience) and through this to its ability to survive to the oldest old age ( Ukraintseva et al, 2021 ).…”

Oxidative and Nitrosative Stress in Age-Related Macular Degeneration: A Review of Their Role in Different Stages of Disease

“…High numbers of mitochondria are present in metabolically active cells like RPE cells, while their number decreases with age and disease [ 100 , 101 ]. Decreased mitochondrial number, function and ATP production have been demonstrated in RPE cells isolated from human AMD eyes [ 102 ] and previous reports showed mitochondrial depolarization, with reduced energy production and an increase in Cytochrome C release and ROS generation, to precede RPE cell death caused by peroxidation [ 103 , 104 , 105 ], thus highlighting the existence of a link between mitochondrial impairment, RPE degeneration and an unbalanced cellular redox system. Mitochondrial electron transport chain (ETC) complexes are a major source of ROS as a byproduct of respiration [ 106 , 107 , 108 ] and, under pathologic conditions involving ETC components, ROS production and leakage into the cytoplasm are significantly increased and not balanced by the local anti-oxidative stress metabolism [ 109 ].…”

Potential of Telomerase in Age-Related Macular Degeneration—Involvement of Senescence, DNA Damage Response and Autophagy and a Key Role of PGC-1α

“…Mitochondria also specifically produce reactive aldehydes that can form adducts with mtDNA [76]. Several reports suggest increased levels of DNA damage, both nuclear and mitochondrial, in AMD as well as impairments to its repair, and these effects are mainly attributed to oxidative stress and mutations/polymorphisms of DDR-related genes (reviewed in [62,77]).…”