MOLECULAR ATLAS OF AGING. META-GROUP 10. RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM AND VASOACTIVE PEPTIDES: LATENT DICTATOR OF PRESSURE AND FIBROSIS. INTEGRATIVE APPROACH IN THE CONTEXT OF META-MEDIUM THEORY AND META-REGULATORS

Relevance. The renin-angiotensin-aldosterone system (RAAS) is a hormonal system that regulates blood pressure, water-salt balance, and vascular tone. In youth, it works as a precise tool for maintaining homeostasis. However, with age, under the influence of inflammation, oxidative stress, and endothelial damage, RAAS gets out of control. Its key effectors, angiotensin II and endothelin-1, become chronically elevated, causing vasoconstriction, sodium retention, fibrosis activation, and cardiac hypertrophy. Add to this an imbalance of natriuretic peptides (ANP, BNP), which limit this process in youth, but their protective potential weakens with age. Chronic activation of RAAS is strongly associated with age-related cardiovascular diseases, including hypertension, atherosclerosis, atrial fibrillation, and heart failure. Aim. To present age-related dysregulation of RAAS and vasoactive peptides as the tenth level of molecular aging, the main executive mechanism that turns age-related damage into irreversible hypertension, fibrosis, and organ failure. To substantiate the need for systemic restoration of the balance of RAAS through the tuning of meta-regulators. Results. It has been shown that with age, circulating levels of renin and angiotensin II increase in healthy elderly mice, and in the heart and blood vessels, the expression of mRNA and angiotensin II protein significantly increases. Angiotensin II β, through AT1R-mediated activation of macrophages and T-lymphocytes, stimulates the production of pro-inflammatory cytokines (IL-6, TNF-α, IL-17A), forming a self-sustaining pro-inflammatory circuit. Chronic exposure to low-dose angiotensin II induces senescence in renal tissue and endothelium, contributing to the formation of an inflammatory microenvironment through SASP factors. Endothelin-1, the level of which increases with aging, enhances vasoconstriction and promotes senescence of skeletal stem cell progenitor cells through ETBR-mediated ROS production. Senescent endothelial cells enhance vascular resistance through an imbalance between reduced bioavailability of NO and increased levels of vasoconstrictors ET-1 and angiotensin II. Expression of mineralocorticoid receptors in vascular smooth muscle cells gradually increases with age, contributing to vasoconstriction, oxidative stress, and vascular stiffness. A multimodal approach (Quatotron technique) to physiologically restore RAAS balance through normalization of endothelial function, reduction of inflammation, and restoration of sensitivity to natriuretic peptides has been proposed. Conclusion. RAAS and vasoactive peptides are the tenth level of molecular aging — the main executive mechanism that turns age-related damage into irreversible structural degradation. Their systemic recovery through the control of meta-regulators opens up new opportunities for the prevention of cardiovascular diseases and healthy longevity.