Brain Renin–Angiotensin System at the Intersect of Physical and Cognitive Frailty

Abstract

The renin-angiotensin system (RAS) was initially considered to be part of the endocrine system regulating water and electrolyte balance, systemic vascular resistance, blood pressure, and cardiovascular homeostasis. It was later discovered that intracrine and local forms of RAS exist in the brain apart from the endocrine RAS. This brainspecific RAS plays essential roles in brain homeostasis by acting mainly through four angiotensin receptor subtypes; AT 1 R, AT 2 R, MasR, and AT 4 R. These receptors have opposing effects; AT 1 R promotes vasoconstriction, proliferation, inflammation, and oxidative stress while AT 2 R and MasR counteract the effects of AT 1 R. AT 4 R is critical for dopamine and acetylcholine release and mediates learning and memory consolidation. Consequently, aging-associated dysregulation of the angiotensin receptor subtypes may lead to adverse clinical outcomes such as Alzheimer's disease and frailty via excessive oxidative stress, neuroinflammation, endothelial dysfunction, microglial polarization, and alterations in neurotransmitter secretion. In this article, we review the brain RAS from this standpoint. After discussing the functions of individual brain RAS components and their intracellular and intracranial locations, we focus on the relationships among brain RAS, aging, frailty, and specific neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and vascular cognitive impairment, through oxidative stress, neuroinflammation, and vascular dysfunction. Finally, we discuss the effects of RAS-modulating drugs on the brain RAS and their use in novel treatment approaches.

Sex-specific DNA methylation changes in Alzheimer’s disease pathology

“…The comparison with gene ontology (GO) terms showed at 25% FDR, signi cant methylation changes in females were enriched in 25 GO biological processes (Table 4, Supplementary Table 10), many of which are involved in in ammatory responses associated with AD pathology including CD8 positive alpha beta T cell activation and interferon alpha production, as well as other biological processes critical for AD pathogenesis such as response to platelet derived growth factor and positive regulation of axon extension. For males, we did not identify any signi cant GO terms at 25% FDR; the strongest enrichment with nominal Pvalue less than 0.001 involved immune responses to the accumulation of amyloid-β (Aβ) in the brain, such as regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell, and other biological processes recently implicated in AD such as response to angiotensin [42,43] and cell redox homeostasis [44,45].…”

Sex-specific DNA methylation changes in Alzheimer’s disease pathology

“…For males, we did not identify any significant GO terms at 25% FDR; the strongest enrichment with nominal P-value less than 0.001 involved immune responses to the accumulation of amyloid-β (Aβ) in the brain, such as regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell, and other biological processes recently implicated in AD such as response to angiotensin [42,43] and cell redox homeostasis [44,45].…”

Can Blood-Circulating Factors Unveil and Delay Your Biological Aging?

“…A decline in the number of neurons regulating the vasomotor response of vessels due to a decrease in expression of NGF and other factors leads to a reduction of the maximum lumen size of capillaries and weakens the response to stress. Along with hormonal changes, the attenuation of the renin–angiotensin system [ 24 , 238 , 259 , 260 ], impaired growth and regulation of the vasculature also cause a decline in muscle activity, an increase in blood clotting (also due to the high vWF level), and a rise in blood pressure with age [ 260 ]. In addition, a decrease in hemoglobin concentration in erythrocytes results in hypoxic disorders in peripheral tissues, which in turn increases the likelihood of pathological disorders in the organism.…”

“…It also induces angiogenesis by activating the synthesis of VEGF-A, bFGF, and can modulate the inflammatory response by enhancing the synthesis of metalloproteases and the expression of sICAM-1 and sVCAM-1. Long-term presence of both molecules in blood plasma is a signal of local inflammation and a sign of metastasis in cancer [ 24 , 237 , 238 ].…”