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Considering Angiotensin II and Aging


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Posted 04 May 2015 - 10:19 PM


When reading about research into any particular gene or protein and its influence on aging it is important to keep in mind that our biochemistry is a network of connections. Nothing happens in isolation, and any change in the amount of a particular protein or interference in its activities will cause a cascade of consequences though its interactions with other proteins. Thus there are probably comparatively few important mechanisms involved in determining natural variations in longevity but many distinct ways to manipulate those mechanisms.

Decades of research focused on treating cardiovascular disease and hypertension has resulted in a range of drugs that interfere with the activities of angiotensin II and the broader renin-angiotensin system it is a part of. These biological systems have a fairly direct role in determining blood pressure, and hence have long been a target for efforts to slow down the onset of hypertension. Thanks to the easy availability of drugs targeting the renin-angiotensin system, a fair amount of research has taken place into the effects of these interventions on aging in mice. Disrupting an angiotensin II receptor increases mouse life span, for example, as does a reduction in levels of ACE, the angiotensin I-converting enzyme responsible for transforming angiotensin I into angiotensin II. These interventions may work to extend life by reducing blood pressure, and may have other important effects involving enhanced mitochondrial function.

Definitive answers as to how specific approaches to alter the operation of metabolism actually work under the hood so as to extend life span are slow in arriving, however. Cellular biochemistry is enormously complex, so much so that it is par for the course for a decade or more to come and go without too much progress being made in understanding how a particular mechanism influences longevity. This is the case for angiotensin II and the systems it participates in. Below are linked a few recent papers on the topic; they don't add a great deal over similar papers published ten years ago, beyond reinforcing the point that high blood pressure is a potent source of tissue damage in old age, and being more openly enthusiastic about building treatments for aging:

The Intrarenal Renin-Angiotensin System in Hypertension

The renin-angiotensin system (RAS) is a well-studied hormonal cascade controlling fluid and electrolyte balance and blood pressure through systemic actions. The classical RAS includes renin, an enzyme catalyzing the conversion of angiotensinogen to angiotensin (Ang) I, followed by angiotensin-converting enzyme (ACE) cleavage of Ang I to II, and activation of AT1 receptors, which are responsible for all RAS biologic actions.

Recent discoveries have transformed the RAS into a far more complex system with several new pathways. Instead of a simple circulating RAS, several independently functioning tissue RASs exist, the most important of which is the intrarenal RAS. Several physiological characteristics of the intrarenal RAS differ from those of the circulating RAS, autoamplifying the activity of the intrarenal RAS and leading to hypertension.

Angiotensin II Blockage: How its Molecular Targets May Signal to Mitochondria and Slow Aging

Caloric restriction (CR), rapamycin-mediated mTOR inhibition and renin angiotensin system blockade (RAS-bl) increase survival and retard aging across species. Previously, we have summarized CR and RAS-bl's converging effects, and the mitochondrial function changes associated to their physiological benefits. mTOR-inhibition and enhanced sirtuin and Klotho signaling contribute to the benefits of CR in aging. mTORC1/mTORC2 complexes contribute to cell growth and metabolic regulation. Prolonged mTORC1 activation may lead to age-related disease progression; thus, rapamycin-mediated mTOR inhibition and CR may extend lifespan and retard aging through mTORC1 interference.

Here we review how mTOR-inhibition extends lifespan, Klotho functions as an aging-suppressor, sirtuins mediate longevity, Vitamin-D loss may contribute to age-related disease, and how they relate to mitochondrial function. Also, we discuss how RAS-bl downregulates mTOR, upregulates Klotho, sirtuin and VitaminD-receptor expression, suggesting that at least some of RAS-bl benefits in aging are mediated through the modulation of mTOR, klotho and sirtuin expression and Vitamin-D signaling, paralleling CR actions in age retardation.

Concluding, the available evidence endorses the idea that RAS-bl is among the interventions that may turn out to provide relief to the spreading issue of age-associated chronic disease.

Pleiotropic Effects of Angiotensin II Receptor Signaling in Cardiovascular Homeostasis and Aging

Most of the pathophysiological actions of angiotensin II (Ang II) are mediated through the Ang II type 1 (AT1) receptor, a member of the seven-transmembrane G protein-coupled receptor family. Essentially, AT1 receptor signaling is beneficial for organismal survival and procreation, because it is crucial for normal organ development, and blood pressure and electrolyte homeostasis. On the other hand, AT1 receptor signaling has detrimental effects, such as promoting various aging-related diseases that include cardiovascular diseases, diabetes, chronic kidney disease, dementia, osteoporosis, and cancer. Pharmacological or genetic blockade of AT1 receptor signaling in rodents has been shown to prevent the progression of aging-related phenotypes and promote longevity. In this way, AT1 receptor signaling exerts antagonistic and pleiotropic effects according to the ages and pathophysiological conditions.

View the full article at FightAging




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