Abstract
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.
Keywords: Ace2; COVID-19; DNA damage response; aging; telomere.
【저자키워드】 COVID-19, ACE2, aging, DNA damage response, telomere, 【초록키워드】 coronavirus disease, SARS-CoV-2, coronavirus, Hospitalization, Infection, DNA damage, mice, Lungs, death, ATM, in vivo, ACE2 expression, expression, Antisense oligonucleotide, Trigger, dysfunction, acute respiratory syndrome, Activation, higher risk, enzyme, upregulation, selective, promoter, transcriptional level, mammalian cell, pharmacological, susceptible, Prevent, cell receptor, cultured cell, increase, cause, contributing to, severe symptom, DDR, the SARS-CoV-2, 【제목키워드】 Transcription, SARS-CoV-2 receptor, DNA damage, boost, telomere,