Department of Research and Postgraduate in Food, University of Sonora, Blvd. Luis Encinas y Rosales S/N, Col. Centro, Hermosillo 83000, Mexico.
Catalytic Longevity Foundation, San Diego, CA 92109, USA.
Nutrients. 2022 May 9;14(9):1985. doi: 10.3390/nu14091985.
In patients with age-related macular degeneration (AMD), the crucial retinal pigment epithelial (RPE) cells are characterized by mitochondria that are structurally and functionally defective. Moreover, deficient expression of the mRNA-editing enzyme Dicer is noted specifically in these cells. This Dicer deficit up-regulates expression of Alu RNA, which in turn damages mitochondria-inducing the loss of membrane potential, boosting oxidant generation, and causing mitochondrial DNA to translocate to the cytoplasmic region. The cytoplasmic mtDNA, in conjunction with induced oxidative stress, triggers a non-canonical pathway of NLRP3 inflammasome activation, leading to the production of interleukin-18 that acts in an autocrine manner to induce apoptotic death of RPE cells, thereby driving progression of dry AMD. It is proposed that measures which jointly up-regulate mitophagy and mitochondrial biogenesis (MB), by replacing damaged mitochondria with "healthy" new ones, may lessen the adverse impact of Alu RNA on RPE cells, enabling the prevention or control of dry AMD. An analysis of the molecular biology underlying mitophagy/MB and inflammasome activation suggests that nutraceuticals or drugs that can activate Sirt1, AMPK, Nrf2, and PPARα may be useful in this regard. These include ferulic acid, melatonin urolithin A and glucosamine (Sirt1), metformin and berberine (AMPK), lipoic acid and broccoli sprout extract (Nrf2), and fibrate drugs and astaxanthin (PPARα). Hence, nutraceutical regimens providing physiologically meaningful doses of several or all of the: ferulic acid, melatonin, glucosamine, berberine, lipoic acid, and astaxanthin, may have potential for control of dry AMD.
在与年龄相关的黄斑变性（AMD）患者中，关键的视网膜色素上皮（RPE）细胞的特点是结构和功能有缺陷的线粒体。此外，这些细胞中特定存在 mRNA 编辑酶 Dicer 的表达不足。这种 Dicer 缺陷会上调 Alu RNA 的表达，进而损害线粒体，导致膜电位丧失、氧化生成增加，并使线粒体 DNA 易位到细胞质区域。细胞质中的 mtDNA 与诱导的氧化应激一起，触发 NLRP3 炎性小体激活的非经典途径，导致白细胞介素-18 的产生，以自分泌方式诱导 RPE 细胞凋亡死亡，从而推动干性 AMD 的进展。有人提出，通过用“健康”的新线粒体取代受损的线粒体，共同上调自噬和线粒体生物发生（MB）的措施，可能会减轻 Alu RNA 对 RPE 细胞的不利影响，从而能够预防或控制干性 AMD。对自噬/MB 和炎性小体激活的分子生物学分析表明，激活 Sirt1、AMPK、Nrf2 和 PPARα 的营养保健品或药物在这方面可能有用。这些包括阿魏酸、褪黑素、尿石素 A 和氨基葡萄糖（Sirt1）、二甲双胍和黄连素（AMPK）、硫辛酸和西兰花芽提取物（Nrf2）以及贝特类药物和虾青素（PPARα）。因此，提供几种或所有阿魏酸、褪黑素、氨基葡萄糖、黄连素、硫辛酸和虾青素的生理上有意义剂量的营养保健品方案，可能具有控制干性 AMD 的潜力。
