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.
Highlights
The biological fitness of the human organism is supported by the phylogenetically conserved stress response, maintenance and repair pathways
In searching for the mechanisms underlying autophagy impairment in Age-related macular degeneration (AMD) retinal pigment epithelium (RPE) cells, Jang et al recently observed that activation of PARP1 by oxidative stress in ARPE-19 cells resulted in autophagy downregulation [139]
senescence-associated mitochondrial dysfunction (SAMD) may represent a mechanism of the involvement of impaired mitochondrial quality control (mtQC) in AMD pathogenesis as senescence of RPE cells plays an important role in AMD pathogenesis
Summary
The biological fitness of the human organism is supported by the phylogenetically conserved stress response, maintenance and repair pathways They include nutrients and energy signaling, proteostasis, DNA damage response (DDR), mitochondrial quality control (mtQC) and enzymes metabolizing toxic species [1]. The efficacy of these pathways declines with aging, but the process of aging is associated with diverse stresses that impose signals coming from the environment (reviewed in [2]). Oxidative stress is often considered a major risk factor in AMD [5] It is associated with increased levels of reactive oxygen and nitrogen species (ROS and RNS) that may damage cellular structures and macromolecules, including proteins and DNA. We show how these pathways are affected in AMD patients or models to justify that the aging stress response may be the key element in AMD pathogenesis
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