The frail renin-angiotensin system

Abstract

Over the last few decades, the understanding of the renin-angiotensin system (RAS) has advanced dramatically. RAS is now thought to play a crucial role in physiologic and pathophysiologic mechanisms in almost every organ system and is a key regulator of hypertension, cardiovascular disease, and renal function. Angiotensin II (Ang II) promotes inflammation and the generation of reactive oxygen species and governs onset and progression of vascular senescence, which are all associated with functional and structural changes, contributing to age-related diseases. Although the vast majority of the actions of Ang II, including vascular senescence, are mediated by the Ang II type 1 receptor (AT1R), the identification, characterization, and cloning of the angiotensin type 2 receptor has focused attention on this receptor and to its antagonistic effect on the detrimental effects of AT1R. This review provides an overview of the changes in RAS with aging and age-disease interactions culminating in the development of frailty.

Fig. 1

The steps in the biochemical pathway that is involved in the formation of the most biologically potent angiotensin peptide Ang II and its interaction with angiotensin receptors. The enzymes renin converts angiotensinogen to angiotensin I, which in turn is converted via angiotensin converting enzyme to Angiotensin II. Other enzymes that facilitate alternative pathways for the formation of Ang II are tPA, cathepsin G, and tonin. tPA, tissue plasminogen activator.

Fig. 2

A hypothetical model for changes in the angiotensin receptors with aging and/or frailty, resulting in increased production of cytokines, pathologic changes, and development/worsening of diseases. Note that with robust aging, the balance is maintained between the angiotensin receptors despite decrease in both AT1R (blue circles) and AT2R (red circles). With development of frailty that balance is tipped toward more expression of AT1R and less AT2R predisposing to increased cytokine production, which further widens the gap by increasing the expression of AT1R and reducing expression of AT2R. ACEi, ACE inhibitor; ARBs, Ang II receptor blockers.