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Severe COVID-19 in the Elderly May Be Caused by ACE2 Cell Receptor in the Lungs

Higher ACE2 expression may explain why elderly people experience more severe COVID-19.

COVID-19 infection is known to affect elderly persons more severely. A new study, published in EMBO Reports, finds this may be due to the increasing of the virus’s cell receptor, ACE2.

During the aging process, telomere dysfunction gradually builds and activates a DNA damage response, leading to an increase of the SARS-CoV-2 receptor, ACE2. Increased ACE2 expression in the lungs may explain the heightened severity of COVID-19 infection in elderly people.

The study, conducted by Italian and American investigators, confirmed the presence of elevated ACE2 protein expression in aging human and mouse lungs. ACE2 is predominantly found in alveolar epithelial type II cells (ATII), which COVID-19 infection likely targets. The investigators noted that the virus first attacks the lungs, and the most common complication among COVID-19 patients is pneumonia (91% incidence).

Using in vitro and in vivo models, the investigators replicated aspects of aging, including telomere shortening and tissue damage. Telomeres that become too short activate DNA damage response pathways. The investigators inhibited DNA damage by targeting ATM with telomeric antisense oligonucleotides (tASO). 

To confirm ACE2 increase in ATII cells, the investigators conducted double-marker immunofluorescence for ACE2 and markers identifying ATII cells (pro-SP-C in mice or TTF-1 in humans) in lung samples at varying ages. The immunofluorescence showed that ACE2 expression in ATII pneumocytes increased with age; similar increases were observed in other types of cells. The findings indicated that it was likely the DNA damage response activation, not telomeric shortening, that cause ACE2 gene and protein upregulation.

The study noted that further research is needed to understand whether reducing ACE2 expression also reduces COVID-19 infection and severity. Because ACE2 is typically expressed in other organs as well as the lungs, the investigators saw the potential for their findings to extend beyond COVID-19.