Is the anti-aging effect of ACE2 due to its role in the renin-angiotensin system?—Findings from a comparison of the aging phenotypes of ACE2-deficient, Tsukuba hypertensive, and Mas-deficient mice—

Takeshita, Hikari; Yamamoto, Kōichi; Mogi, Masaki; Nozato, Satoko; Rakugi, Hiromi

doi:10.1038/s41440-023-01189-y

Cited by 5 publications

(5 citation statements)

References 86 publications

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“…Interestingly, cytokine IL-1β blocking reduced inflammation, and restored insulin secretion, suggesting that inflammation deteriorates pancreatic islet function and could lead to end-organ damage ( Sauter et al, 2015 ). On the other hand, scientific evidence has investigated the role of RAS in aging ( Takeshita et al, 2023 ). Ang II has been implicated in the senescence process.…”

Section: The Renin-angiotensin System and Its Counter-regulatory Armmentioning

confidence: 99%

“…Human ANG is a glycoprotein that is composed of 485 residue amino acids. The liver is considered the main source of ANG, but other organs and cells such as the heart, kidney, brain, and leukocytes can express ANG in pathophysiological conditions (Gomez et al, 1993;Tamura et al, 1998;Kobori et al, 2007;Klimov et al, 2012). Subsequently, the angiotensin-converting enzyme (ACE), expressed in many tissues, cleaves the C-terminal dipeptide from Ang I to produce Angiotensin II (Ang II) octapeptide.…”

Section: From Inflammation To Fibrosismentioning

confidence: 99%

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Counter-regulatory RAS peptides: new therapy targets for inflammation and fibrotic diseases?

Ávila-Martínez,

Mixtega-Ruiz,

Hurtado-Capetillo

et al. 2024

Front. Pharmacol.

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The renin-angiotensin system (RAS) is an important cascade of enzymes and peptides that regulates blood pressure, volume, and electrolytes. Within this complex system of reactions, its counter-regulatory axis has attracted attention, which has been associated with the pathophysiology of inflammatory and fibrotic diseases. This review article analyzes the impact of different components of the counter-regulatory axis of the RAS on different pathologies. Of these peptides, Angiotensin-(1–7), angiotensin-(1–9) and alamandine have been evaluated in a wide variety of in vitro and in vivo studies, where not only they counteract the actions of the classical axis, but also exhibit independent anti-inflammatory and fibrotic actions when binding to specific receptors, mainly in heart, kidney, and lung. Other functional peptides are also addressed, which despite no reports associated with inflammation and fibrosis to date were found, they could represent a potential target of study. Furthermore, the association of agonists of the counter-regulatory axis is analyzed, highlighting their contribution to the modulation of the inflammatory response counteracting the development of fibrotic events. This article shows an overview of the importance of the RAS in the resolution of inflammatory and fibrotic diseases, offering an understanding of the individual components as potential treatments.

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Section: The Renin-angiotensin System and Its Counter-regulatory Armmentioning

confidence: 99%

Section: From Inflammation To Fibrosismentioning

confidence: 99%

Counter-regulatory RAS peptides: new therapy targets for inflammation and fibrotic diseases?

Ávila-Martínez,

Mixtega-Ruiz,

Hurtado-Capetillo

et al. 2024

Front. Pharmacol.

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“…These observations indicate that Ang (1-7)'s antiaging effects are exerted through the Mas receptor. Based on present knowledge, the RAS-independent mechanisms of ACE2's antiaging actions were discussed in Takeshita et al (2023).…”

Section: Changes In the Activity And Responsiveness Of Ras During Agingmentioning

confidence: 99%

“…Interestingly, the distinctive early aging phenotype associated with ACE2 deficiency (ACE2 KO mice) was not observed in Ang (1–7) receptor deficient mice (Mas KO mice), which suggests that the antiaging actions of ACE2 are Mas independent. However, administration of Ang (1–7) to Mas KO mice did not mitigate age‐related muscle weakness, although it improved muscle strength in both aged wild‐type and ACE2 KO mice (Takeshita et al., 2023 ). These observations indicate that Ang (1–7)'s antiaging effects are exerted through the Mas receptor.…”

Section: The Renin–angiotensin Systemmentioning

confidence: 99%

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Renin–angiotensin system inhibitors positively impact on multiple aging regulatory pathways: Could they be used to protect against human aging?

de Cavanagh,

Inserra,

Ferder

2024

Physiological Reports

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The renin–angiotensin system (RAS)—a classical blood pressure regulator—largely contributes to healthy organ development and function. Besides, RAS activation promotes age‐related changes and age‐associated diseases, which are attenuated/abolished by RAS‐blockade in several mammalian species. RAS‐blockers also increase rodent lifespan. In previous work, we discussed how RAS‐blockade downregulates mTOR and growth hormone/IGF‐1 signaling, and stimulates AMPK activity (together with klotho, sirtuin, and vitamin D‐receptor upregulation), and proposed that at least some of RAS‐blockade's aging benefits are mediated through regulation of these intermediaries and their signaling to mitochondria. Here, we included RAS‐blockade's impact on other aging regulatory pathways, that is, TGF‐ß, NF‐kB, PI3K, MAPK, PKC, Notch, and Wnt, all of which affect mitochondria. No direct evidence is available on RAS/RAS‐blockade‐aging regulatory pathway–mitochondria interactions. However, existing results allow to conjecture that RAS‐blockers neutralize mitochondrial dysfunction by acting on the discussed pathways. The reviewed evidence led us to propose that the foundation is laid for conducting clinical trials aimed at testing whether angiotensin‐converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB)—even at subclinical doses—offer the possibility to live longer and in better health. As ACEi and ARB are low cost and well‐tolerated anti‐hypertension therapies in use for over 35 years, investigating their administration to attenuate/prevent aging effects seems simple to implement.

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Anthocyanins as natural bioactives with anti-hypertensive and atherosclerotic potential: Health benefits and recent advances

Xin,

Xu,

Tian

et al. 2024

Phytomedicine

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Is the anti-aging effect of ACE2 due to its role in the renin-angiotensin system?—Findings from a comparison of the aging phenotypes of ACE2-deficient, Tsukuba hypertensive, and Mas-deficient mice—

Cited by 5 publications

References 86 publications

Counter-regulatory RAS peptides: new therapy targets for inflammation and fibrotic diseases?

Counter-regulatory RAS peptides: new therapy targets for inflammation and fibrotic diseases?

Renin–angiotensin system inhibitors positively impact on multiple aging regulatory pathways: Could they be used to protect against human aging?

Anthocyanins as natural bioactives with anti-hypertensive and atherosclerotic potential: Health benefits and recent advances

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