Two Opposing Functions of Angiotensin-Converting Enzyme (ACE) That Links Hypertension, Dementia, and Aging

Le, Duc Diana; Brown, Lindsay; Malik, Kundan; Murakami, Shin

doi:10.3390/ijms222413178

Cited by 28 publications

(28 citation statements)

References 68 publications

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“…The observation is consistent with the previous studies that a major hypertension target, angiotensin-converting enzyme (ACE) is also involved in AD (Le et al, 2020 and. Despite being less defined, AD may be classified as type 3 diabetes, which is a type of diabetes in the brain (Steen et al, 2005;Pilcher, 2006;de la Monte, 2014;Leszek et al, 2017). The vast majority of AD falls into LOAD, whose onset occurs starting at 65 years of age, while age-related diseases occur earlier than that.…”

Section: Discussionsupporting

confidence: 88%

Biological and Disease Hallmarks of Alzheimer’s Disease Defined by Alzheimer’s Disease Genes

Murakami

Lacayo

2022

Preprint

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An increasing number of genes associated with Alzheimer’s disease (AD) have been reported. However, despite previous studies, there is a lack of overview of the genetic relationship between AD and age-related comorbidities, such as hypertension, myocardial infarction, and diabetes, among others. Previously, we used Reactome analysis in conjunction with the genes that are associated with AD (AD genes) to identify both the biological pathways and the neurological diseases involved. Here we provide systematic updates on the genetic and disease hallmarks defined by AD genes. There are a total of 11 pathways (defined as genetic biological hallmarks) including 6 existing hallmarks and 5 newly updated hallmarks, the latter of which are developmental biology (axon and adipose development), gene expression (RNA transcription), metabolism of proteins (Amyloid formation, regulation of IGF-1/Insulin, and small ubiquitin-like modifiers/SUMOs), metabolism of RNA (mitochondrial tRNA and rRNA processing), and signal transduction (ErbB, NOTCH and p75 NTR death signaling). The AD genes further identified 20 diverse diseases that we define as disease hallmarks including: (1) existing hallmarks, including neurological diseases (Alzheimer’s disease, Amyotrophic Lateral Sclerosis, Parkinson’s Disease, and Schizophrenia); (2) as well as newly identified hallmarks, including Type 2 Diabetes, Cardiovascular diseases (Myocardial Infarction, Heart Disease, Hypertension, Cardiovascular system disease, Vascular Disease), Quantitative trait loci (lipoprotein and body mass index), Cancer (Breast cancer, Colorectal cancer, Prostate cancer, and Lung cancer); (3) and other health conditions; note that cancers reportedly have an inverse relation with AD. We previously suggested that a single gene is associated with multiple neurological diseases, and we are further extending the finding that AD genes are associated with common age-related comorbidities and others. This study indicates that heterogeneity of Alzheimer’s disease predicts complex clinical presentations in people living with AD. Taken together, the genes define AD as a part of age-related comorbidities with shared biological mechanisms and may raise awareness of a healthy lifestyle as potential prevention and treatment of the comorbidities.

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Section: Discussionsupporting

confidence: 88%

Biological and Disease Hallmarks of Alzheimer’s Disease Defined by Alzheimer’s Disease Genes

Murakami

Lacayo

2022

Preprint

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“…The authors call this result paradoxical (the genotype and allele associated with a high risk of cardiovascular diseases become more common with age), but they link these findings to the observation that an increase in the angiotensin-converting enzyme level prevents the onset of Alzheimer’s disease [ 31 ]. In addition, ACE being an amyloid-degrading enzyme, it can decrease amyloid toxicity [ 25 ]. The most recent findings regarding the Alu polymorphic locus in the ACE gene are related to the interaction of the human and viral genomes, and consider human longevity as a phenotype resistant to infectious agents.…”

Section: Discussionmentioning

confidence: 99%

“…Participating in the growth and development, control of metabolism, the immune response and apoptosis and being the blood plasma enzymes, components of extracellular matrix, as well as key transcription factors, these genes are interwoven and important for the physiological and pathological aging processes. Previous reports have linked the TEAD1 , HECW1 , SEMA6A , COL13A1 and LAMA2 genes with different age-related cancers [ 15 , 16 , 17 , 18 , 19 , 20 , 21 ], the PLAT and ACE genes with cardiovascular disease [ 22 , 23 , 24 , 25 ], the ACE and HECW1 genes with Alzheimer’s disease [ 25 , 26 ] and the SEMA6A gene with type 2 diabetes [ 27 ]. The STK38L and PKHD1L1 genes play an important role in the functioning of the immune system [ 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

Alu Deletions in LAMA2 and CDH4 Genes Are Key Components of Polygenic Predictors of Longevity

Erdman

Каримов

Tuktarova

et al. 2022

IJMS

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Longevity is a unique human phenomenon and a highly stable trait, characterized by polygenicity. The longevity phenotype occurs due to the ability to successfully withstand the age-related genomic instability triggered by Alu elements. The purpose of our cross-sectional study was to evaluate the combined contribution of ACE*Ya5ACE, CDH4*Yb8NBC516, COL13A1*Ya5ac1986, HECW1*Ya5NBC182, LAMA2*Ya5-MLS19, PLAT*TPA25, PKHD1L1*Yb8AC702, SEMA6A*Yb8NBC597, STK38L*Ya5ac2145 and TEAD1*Ya5ac2013 Alu elements to longevity. The study group included 2054 unrelated individuals aged from 18 to 113 years who are ethnic Tatars from Russia. We analyzed the dynamics of the allele and genotype frequencies of the studied Alu polymorphic loci in the age groups of young (18–44 years old), middle-aged (45–59 years old), elderly (60–74 years old), old seniors (75–89 years old) and long-livers (90–113 years old). Most significant changes in allele and genotype frequencies were observed between the long-livers and other groups. The search for polygenic predictors of longevity was performed using the APSampler program. Attaining longevity was associated with the combinations LAMA2*ID + CDH4*D (OR = 2.23, PBonf = 1.90 × 10−2) and CDH4*DD + LAMA2*ID + HECW1*D (OR = 4.58, PBonf = 9.00 × 10−3) among persons aged between 18 and 89 years, LAMA2*ID + CDH4*D + SEMA6A*I for individuals below 75 years of age (OR = 3.13, PBonf = 2.00 × 10−2), LAMA2*ID + HECW1*I for elderly people aged 60 and older (OR = 3.13, PBonf = 2.00 × 10−2) and CDH4*DD + LAMA2*D + HECW1*D (OR = 4.21, PBonf = 2.60 × 10−2) and CDH4*DD + LAMA2*D + ACE*I (OR = 3.68, PBonf = 1.90 × 10−2) among old seniors (75–89 years old). The key elements of combinations associated with longevity were the deletion alleles of CDH4 and LAMA2 genes. Our results point to the significance for human longevity of the Alu polymorphic loci in CDH4, LAMA2, HECW1, SEMA6A and ACE genes, involved in the integration systems.

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“…Pharmacological or genetic inhibition of members of the RAS can extend lifespan and delay age-related degenerative changes in mice and rats ( Figures 3C , 4C ) (reviewed in ( Basso et al, 2005 ; de Cavanagh et al, 2011 ; Capettini et al, 2012 ; Kamo et al, 2016 ; Mogi, 2020 ; Jaworska et al, 2021 ; Le et al, 2021 )). The study of ACE and the RAS in the context of aging is complicated in mammalian systems due to their pleiotropic effects not only on aging but also on vasoconstriction, renal, cardiovascular, and pulmonary health and function, and less understood functions in the brain (reviewed in ( Le et al, 2021 )). In contrast, non-mammalian organisms lacking closed circulatory systems can be used to distinguish the aging effects of the RAS from the cardiovascular functions.…”

Section: Introductionmentioning

confidence: 99%

Control of aging by the renin–angiotensin system: a review of C. elegans, Drosophila, and mammals

et al. 2022

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The free-living, non-parasitic nematode Caenorhabditis elegans is a premier model organism for the study of aging and longevity due to its short lifespan, powerful genetic tools, and conservation of fundamental mechanisms with mammals. Approximately 70 percent of human genes have homologs in C. elegans, including many that encode proteins in pathways that influence aging. Numerous genetic pathways have been identified in C. elegans that affect lifespan, including the dietary restriction pathway, the insulin/insulin-like growth factor (IGF) signaling pathway, and the disruption of components of the mitochondrial electron transport chain. C. elegans is also a powerful system for performing drug screens, and many lifespan-extending compounds have been reported; notably, several FDA-approved medications extend the lifespan in C. elegans, raising the possibility that they can also extend the lifespan in humans. The renin–angiotensin system (RAS) in mammals is an endocrine system that regulates blood pressure and a paracrine system that acts in a wide range of tissues to control physiological processes; it is a popular target for drugs that reduce blood pressure, including angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). Emerging evidence indicates that this system influences aging. In C. elegans, decreasing the activity of the ACE homolog acn-1 or treatment with the ACE-inhibitor Captopril significantly extends the lifespan. In Drosophila, treatment with ACE inhibitors extends the lifespan. In rodents, manipulating the RAS with genetic or pharmacological interventions can extend the lifespan. In humans, polymorphisms in the ACE gene are associated with extreme longevity. These results suggest the RAS plays a conserved role in controlling longevity. Here, we review studies of the RAS and aging, emphasizing the potential of C. elegans as a model for understanding the mechanism of lifespan control.

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Two Opposing Functions of Angiotensin-Converting Enzyme (ACE) That Links Hypertension, Dementia, and Aging

Cited by 28 publications

References 68 publications

Biological and Disease Hallmarks of Alzheimer’s Disease Defined by Alzheimer’s Disease Genes

Biological and Disease Hallmarks of Alzheimer’s Disease Defined by Alzheimer’s Disease Genes

Alu Deletions in LAMA2 and CDH4 Genes Are Key Components of Polygenic Predictors of Longevity

Control of aging by the renin–angiotensin system: a review of C. elegans, Drosophila, and mammals

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