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.