IFOM Foundation-FIRC Institute of Molecular Oncology Foundation, Milan, Italy.
Tumor Immunology Unit, Department of Health Sciences, University of Palermo, Palermo, Italy.
EMBO Rep. 2022 Feb 3;23(2):e53658. doi: 10.15252/embr.202153658. Epub 2021 Dec 2.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19), known to be more common in the elderly, who also show more severe symptoms and are at higher risk of hospitalization and death. Here, we show that the expression of the angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 cell receptor, increases during aging in mouse and human lungs. ACE2 expression increases upon telomere shortening or dysfunction in both cultured mammalian cells and in vivo in mice. This increase is controlled at the transcriptional level, and Ace2 promoter activity is DNA damage response (DDR)-dependent. Both pharmacological global DDR inhibition of ATM kinase activity and selective telomeric DDR inhibition by the use of antisense oligonucleotides prevent Ace2 upregulation following telomere damage in cultured cells and in mice. We propose that during aging telomere dysfunction due to telomeric shortening or damage triggers DDR activation and this causes the upregulation of ACE2, the SARS-CoV-2 cell receptor, thus contributing to make the elderly more susceptible to the infection.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）引起 2019 年冠状病毒病（COVID-19），已知在老年人中更为常见，老年人的症状更为严重，住院和死亡的风险更高。在这里，我们表明，血管紧张素转换酶 2（ACE2）的表达，即 SARS-CoV-2 细胞受体，在小鼠和人类肺部衰老过程中增加。在培养的哺乳动物细胞中和体内的小鼠中，端粒缩短或功能障碍都会导致 ACE2 的表达增加。这种增加受转录水平控制，Ace2 启动子活性依赖于 DNA 损伤反应（DDR）。ATM 激酶活性的药理学全局 DDR 抑制以及使用反义寡核苷酸对端粒 DDR 的选择性抑制，均可防止端粒损伤后培养细胞和小鼠中 ACE2 的上调。我们提出，在衰老过程中，由于端粒缩短或损伤导致的端粒功能障碍会触发 DDR 激活，从而导致 SARS-CoV-2 细胞受体 ACE2 的上调，从而使老年人更容易感染。
