Artificial Intelligence-Assisted Meta-Analysis of the Frequency of ACE I/D Polymorphisms in Centenarians and Other Long-Lived Individuals

Li, Lingxuan; Murakami, Shin

doi:10.3390/ijms24043411

Cited by 3 publications

(6 citation statements)

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“…A survivor or recruitment bias due to II males having died or been too frail to participate is unlikely given the body of literature indicating the association of the D allele with both morbidity and mortality [56][57][58][59][60][61][62]. However, although comparison with published UK studies where the individuals had average age over 75 did not affect our results, a recent meta-analysis of studies including centenarians, and older individuals as well as younger controls suggests a survivor advantage for DD individuals but not for ID individuals [63]. For this bias to account for our findings on the disproportionate number of DD men, the survivor effect would need to be greater and/or observed earlier in men as our observation of increased DD individuals was restricted to men.…”

Section: Discussionmentioning

confidence: 68%

ACE I/D genotype associates with strength in sarcopenic men but not with response to ACE inhibitor therapy in older adults with sarcopenia: Results from the LACE trial

Rossios,

Bashir,

Achison

et al. 2023

PLoS ONE

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Background Angiotensin II (AII), has been suggested to promote muscle loss. Reducing AII synthesis, by inhibiting angiotensin converting enzyme (ACE) activity has been proposed as a method to inhibit muscle loss. The LACE clinical trial was designed to determine whether ACE inhibition would reduce further muscle loss in individuals with sarcopenia but suffered from low recruitment and returned a negative result. Polymorphic variation in the ACE promoter (I/D alleles) has been associated with differences in ACE activity and muscle physiology in a range of clinical conditions. This aim of this analysis was to determine whether I/D polymorphic variation is associated with muscle mass, strength, in sarcopenia or contributed to the lack of response to treatment in the LACE study. Methods Sarcopenic individuals were recruited into a 2x2 factorial multicentre double-blind study of the effects of perindopril and/or leucine versus placebo on physical performance and muscle mass. DNA extracted from blood samples (n = 130 72 women and 58 men) was genotyped by PCR for the ACE I/D polymorphism. Genotypes were then compared with body composition measured by DXA, hand grip and quadriceps strength before and after 12 months’ treatment with leucine and/or perindopril in a cross-sectional analysis of the influence of genotype on these variables. Results Allele frequencies for the normal UK population were extracted from 13 previous studies (I = 0.473, D = 0.527). In the LACE cohort the D allele was over-represented (I = 0.412, D = 0.588, p = 0.046). This over-representation was present in men (I = 0.353, D = 0.647, p = 0.010) but not women (I = 0.458, D = 0.532, p = 0.708). In men but not women, individuals with the I allele had greater leg strength (II/ID = 18.00 kg (14.50, 21.60) vs DD = 13.20 kg (10.50, 15.90), p = 0.028). Over the 12 months individuals with the DD genotype increased in quadriceps strength but those with the II or ID genotype did not. Perindopril did not increase muscle strength or mass in any polymorphism group relative to placebo. Conclusion Our results suggest that although ACE genotype was not associated with response to ACE inhibitor therapy in the LACE trial population, sarcopenic men with the ACE DD genotype may be weaker than those with the ACE I/D or II genotype.

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Section: Discussionmentioning

confidence: 68%

ACE I/D genotype associates with strength in sarcopenic men but not with response to ACE inhibitor therapy in older adults with sarcopenia: Results from the LACE trial

Rossios,

Bashir,

Achison

et al. 2023

PLoS ONE

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“…For these reasons, it is important to assess interactions among genes and variants to define different phenotypes. This study using GSGA provides a general overview of major pathways as a blueprint of hallmarks relevant to phenotypic and disease ontology (e.g., AD, aging, and longevity in this study), while a personalized genetic overview, or direct-to-consumer genetic application for the assessment of health risks, would require a multidimensional analysis with genetic contributions of variants, epistatic effects, phenotypic and disease ontology, and other nongenetic effects in an individual [ 8 , 97 , 98 , 99 , 100 , 101 ].…”

Section: Discussionmentioning

confidence: 99%

“…(2) There are genes with controversial phenotypic effects [ 97 ]. The prediction has been supported by the observation that the genetic network and epistasis analysis estimates genetic effects better than single-gene effects [ 8 , 97 , 101 ].…”

Section: Conclusion and Future Directionmentioning

confidence: 99%

“…Gene profiling-based treatment would distinguish age-related comorbidities specific to AD and nonspecific to AD. Further studies on environmental and lifestyle factors may provide a genetic and epigenetic understanding of the development of Alzheimer’s disease and age-related comorbidities [ 101 , 105 ]. Moreover, AD genes are also associated with common age-related comorbidities, including diabetes, myocardial infarction, heart disease, hypertension, cardiovascular system disease, and vascular disease [ 8 ].…”

Section: Conclusion and Future Directionmentioning

confidence: 99%

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Genetic Networks of Alzheimer’s Disease, Aging, and Longevity in Humans

Balmorez

Sakazaki

Murakami

2023

IJMS

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Human genomic analysis and genome-wide association studies (GWAS) have identified genes that are risk factors for early and late-onset Alzheimer’s disease (AD genes). Although the genetics of aging and longevity have been extensively studied, previous studies have focused on a specific set of genes that have been shown to contribute to or are a risk factor for AD. Thus, the connections among the genes involved in AD, aging, and longevity are not well understood. Here, we identified the genetic interaction networks (referred to as pathways) of aging and longevity within the context of AD by using a gene set enrichment analysis by Reactome that cross-references more than 100 bioinformatic databases to allow interpretation of the biological functions of gene sets through a wide variety of gene networks. We validated the pathways with a threshold of p-value < 1.00 × 10−5 using the databases to extract lists of 356 AD genes, 307 aging-related (AR) genes, and 357 longevity genes. There was a broad range of biological pathways involved in AR and longevity genes shared with AD genes. AR genes identified 261 pathways within the threshold of p < 1.00 × 10−5, of which 26 pathways (10% of AR gene pathways) were further identified by overlapping genes among AD and AR genes. The overlapped pathways included gene expression (p = 4.05 × 10−11) including ApoE, SOD2, TP53, and TGFB1 (p = 2.84 × 10−10); protein metabolism and SUMOylation, including E3 ligases and target proteins (p = 1.08 × 10−7); ERBB4 signal transduction (p = 2.69 × 10−6); the immune system, including IL-3 and IL-13 (p = 3.83 × 10−6); programmed cell death (p = 4.36 × 10−6); and platelet degranulation (p = 8.16 × 10−6), among others. Longevity genes identified 49 pathways within the threshold, of which 12 pathways (24% of longevity gene pathways) were further identified by overlapping genes among AD and longevity genes. They include the immune system, including IL-3 and IL-13 (p = 7.64 × 10−8), plasma lipoprotein assembly, remodeling and clearance (p < 4.02 × 10−6), and the metabolism of fat-soluble vitamins (p = 1.96 × 10−5). Thus, this study provides shared genetic hallmarks of aging, longevity, and AD backed up by statistical significance. We discuss the significant genes involved in these pathways, including TP53, FOXO, SUMOylation, IL4, IL6, APOE, and CEPT, and suggest that mapping the gene network pathways provide a useful basis for further medical research on AD and healthy aging.

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“…However, there are conflicting results among a number of studies that addressed the effects of different ACE variants on human life duration. To settle this issue, a very recent work used an artificial intelligence‐assisted meta‐analysis to investigate the contribution of the ACE gene to human longevity (Li & Murakami, 2023 ) which confirmed that the D/D genotype is positively associated with extreme longevity, whereas the I/I genotype is negatively associated with the latter trait.…”

Section: The Renin–angiotensin Systemmentioning

confidence: 99%

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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Artificial Intelligence-Assisted Meta-Analysis of the Frequency of ACE I/D Polymorphisms in Centenarians and Other Long-Lived Individuals

Cited by 3 publications

References 56 publications

ACE I/D genotype associates with strength in sarcopenic men but not with response to ACE inhibitor therapy in older adults with sarcopenia: Results from the LACE trial

ACE I/D genotype associates with strength in sarcopenic men but not with response to ACE inhibitor therapy in older adults with sarcopenia: Results from the LACE trial

Genetic Networks of Alzheimer’s Disease, Aging, and Longevity in Humans

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

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