Global Single Clustering of Phenotype-Associated Human Aging Genes in the Co-Expression and Physical Interaction Networks: An OMIM-Based Investigative Review.

• The first investigative review to propose human aging pathways and networks based on OMIM-extracted phenotype-associated aging genes. • Proposed single-clustering of the OMIM-extracted aging (ageing) genes in the co-expression and physical interaction networks. • Three genes, TP53, APP, and SIRT1 were the consistent hub genes co-expressed across multiple selected human tissues frequently affected by age-related phenotypes. BACKGROUND: While a large wealth of literature on aging pertains to in silico, experimental, and predicted genes, many of those genes do not have validated phenotypic consequences in human. Online Mendelian Inheritance in Man (OMIM) provides an exceptional compendium of authoritative, validated aging genes and phenotypes, the interactions among which may enhance the overall perspective of aging mechanisms in human. METHODS: Here, we reviewed and investigated the global clustering pattern of the OMIM-indexed aging genes (until April 2021) in the gene co-expression and physical interaction networks, using the two keywords “aging” and “ageing”. To allow for validity check, we randomly selected six sets of genes from the human genome as control genes, each set consisting of a similar number of genes obtained from the OMIM search. STRING was implemented in the weighted setting and using the edge betweenness parameter, to construct the integrated and tissue-specific networks of the age-related and control genes. RESULTS: 286 aging (ageing) genes and a wide spectrum of 96 associated phenotypes were detected, including late-onset neurodegenerative disorders, cancers, osteoarthritis, and longevity. Despite the general terms used and the vast range of age-related phenotypes, we detected single clustering of the OMIM-extracted aging (ageing) genes in each of the integrated weighted co-expression and physical interaction networks (p<0.0005), as opposed to multiple clustering of the control genes (p≥0.04). TP53 was the overlapping hub gene in each of the networks. Three genes, TP53, APP , and SIRT1 were the consistent hub genes co-expressed across eleven selected human tissues frequently affected by age-related phenotypes. CONCLUSION: We propose predominant single clustering of the human phenotype-associated aging genes in the co-expression and physical interaction networks, and list the top pathways and genes involved.