Abstract
Age-related macular degeneration (AMD), the main cause of vision loss in the elderly, is associated with oxidation in the retina cells promoting telomere attrition. Activation of telomerase was reported to improve macular functions in AMD patients. The catalytic subunit of human telomerase (hTERT) may directly interact with proteins important for senescence, DNA damage response, and autophagy, which are impaired in AMD. hTERT interaction with mTORC1 (mTOR (mechanistic target of rapamycin) complex 1) and PINK1 (PTEN-induced kinase 1) activates macroautophagy and mitophagy, respectively, and removes cellular debris accumulated over AMD progression. Ectopic expression of telomerase in retinal pigment epithelium (RPE) cells lengthened telomeres, reduced senescence, and extended their lifespan. These effects provide evidence for the potential of telomerase in AMD therapy. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may be involved in AMD pathogenesis through decreasing oxidative stress and senescence, regulation of vascular endothelial growth factor (VEGF), and improving autophagy. PGC-1α and TERT form an inhibitory positive feedback loop. In conclusion, telomerase activation and its ectopic expression in RPE cells, as well as controlled clinical trials on the effects of telomerase activation in AMD patients, are justified and should be assisted by PGC-1α modulators to increase the therapeutic potential of telomerase in AMD.
Highlights
Age-related macular degeneration (AMD) is the main cause of legal blindness and vision loss in the elderly in developed countries
We present the potential of telomere dynamics in AMD pathogenesis and the role of telomerase in telomere maintenance in early AMD and its interactions with proteins important for pathways that are frequently impaired in AMD—senescence, DNA damage response (DDR), and autophagy
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Summary
Age-related macular degeneration (AMD) is the main cause of legal blindness and vision loss in the elderly in developed countries It is a complex, multilateral disease with many confirmed or putative factors involved in its etiology, but the mechanism of pathogenic action of these factors is not completely clear. We present the potential of telomere dynamics in AMD pathogenesis and the role of telomerase in telomere maintenance in early AMD and its interactions with proteins important for pathways that are frequently impaired in AMD—senescence, DNA damage response (DDR), and autophagy. These interactions are underlined by activities of telomerase that are different from its canonical telomere-maintenance functions. We show that peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a protein essential in AMD pathogenesis, may be a master regulator of telomerase
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