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. 2023 Mar 8;24(6):5178.
doi: 10.3390/ijms24065178.

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

Timothy Balmorez  1 , Amy Sakazaki  1 , Shin Murakami  1
Affiliations

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

Timothy Balmorez et al. Int J Mol Sci. .

Abstract

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.

Keywords: age-related comorbidity; centenarian; dementia; epigenetics; hallmark of aging; life extension; longevity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic providing a breakdown of the methodology used in this study. We used the Reactome analysis for AD genes, AR genes, Longevity genes, overlapping AD and AR genes, and overlapping AD and Longevity genes.
Figure 2
Figure 2
Enriched pathway analysis. The entities colored purple are hits within the positive gene list. Proteins are rectangles whereas elongated hexagons are complexes. (A) Generic transcription pathway. (B) TP53 Regulates the transcription of death receptors and ligands. (C) SUMOylation of intracellular receptors.
Figure 3
Figure 3
The Reactome pathways from Figure 2 converted into a functional interaction network. Sub-pathways within the original pathway diagrams were extracted into the FI network as well. Hit genes are displayed in a thick purple border in the FI network view for a hit pathway. (A) Generic transcription pathway. (B) TP53 regulates the transcription of death receptors and ligands. (C) SUMOylation of intracellular receptors.
Figure 4
Figure 4
Enriched pathway analysis. The entities colored purple are hits within the positive gene list. Proteins are rectangles whereas elongated hexagons are complexes. (A) Generic transcription pathway. (B) TP53 regulates the transcription of death receptors and ligands.
Figure 5
Figure 5
The Reactome pathways from Figure 4 converted into a functional interaction network. Hit genes are displayed with a purple border. (A) FI network for the diagram of Interleukin-4, Interleukin-13, and Interleukin-10 signaling, (B) FI network for the diagram of plasma lipoprotein assembly, remodeling, and clearance.
Figure 6
Figure 6
Venn diagrams of overlapping pathways: (A) Alzheimer’s genes and aging-related genes and (B) overlapping Alzheimer’s genes and longevity genes. The pathways shown in Table 1, Table 2, Table 3, Table 5 and Table 6 were used.
Figure 7
Figure 7
Diagram of the Reactome pathway enrichment of AD genes. The results shown in Table 1 are summarized.
Figure 8
Figure 8
Diagram of the Reactome pathway enrichment of AR genes. The results shown in Table 2 are summarized.
Figure 9
Figure 9
Diagram of the Reactome pathway enrichment of longevity genes. The results shown in Table 3 are summarized. Two main pathways are shown out of twelve pathways identified.
Figure 10
Figure 10
A schematic illustrating proposed genetic pathways that contribute to aging and longevity.
Figure 11
Figure 11
Diagram of the Reactome pathway enrichment of AD–AR overlap genes. The results shown in Table 5 are summarized.
Figure 12
Figure 12
Diagram of the Reactome pathway enrichment of AD–longevity overlap genes. The results shown in Table 6 are summarized.
See this image and copyright information in PMC

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