RAS pathway in aging and COVID-19
The RAS pathway undergoes major physiological changes during development and aging. In fish models, PRR has been found to play a role in embryogenesis, with PRR knockouts exhibiting developmental defects. In adults, however, PRR is known to increase levels of pro-inflammatory cytokines independent of the angiotensin II pathway.12
Fetal and neonatal mice kidneys have a higher expression of AT2 receptors than AT1 receptors. In adult mice, however, AT1 receptors are more widely distributed with AT2 having a selective and minor role.13 There is an upregulation of AT1 receptors with aging in non-human primates.14 Sheep studies have demonstrated that the ACE/ACE2 receptor expression ratio is significantly lower in male neonatal sheep than in adult sheep.15 It has also been shown that ACE2 levels may decrease in the lungs of aged rats.16
The low ACE2 levels in addition to the downregulation of ACE2 by SARS CoV-2 might be the tipping point in the pathogenesis of COVID-19. The consequent increase in angiotensin II might make the AT1 predominant elderly prone to severe disease. This effect might be tempered in the AT2 predominant neonates and children leading to less severe disease.