Revisiting renin-angiotensin-aldosterone system in aging: translational insights from bench to bedside and back

The renin-angiotensin-aldosterone system (RAAS) is a central regulator of cardiovascular, renal, and fluid homeostasis. Over the past century, our understanding of RAAS has evolved from a unidimensional circulatory hormone system to a complex network that includes local and intracellular signaling pathways. Aging profoundly impacts this system, influencing both systemic and tissue-specific RAAS activity. While levels of systemic RAAS components, such as plasma renin and aldosterone, decline with age, local RAAS components, particularly the proinflammatory angiotensin (Ang)II/AngII type 1 receptor (AT1R) axis, are upregulated in aging tissues, contributing to vasoconstriction, oxidative stress, inflammation, and fibrosis. Conversely, the protective arms of RAAS, the AngII/AT2R and Ang-(1-7)/Mas receptor pathways, are downregulated. Recent advances in geroscience have further illuminated how RAAS intersects with fundamental aging mechanisms, providing a mechanistic framework for understanding RAAS not only as a driver of age-related disease but also as a modifiable contributor to the aging process itself. In this Review, we summarize the evolution of RAAS biology, examine the molecular and functional consequences of aging on RAAS activity, and discuss the translational relevance of these findings. Finally, we explore emerging therapeutic strategies targeting RAAS components as potential interventions to promote healthy aging and reduce age-related disease burden, emphasizing a translational arc moving from bedside to bench and back, with the ultimate goal of improving patient outcomes.