Identification of human age-associated gene co-expressions in functional modules using liquid association

Abstract

Aging is a major risk factor for age-related diseases such as certain cancers. In this study, we developed Age Associated Gene Co-expression Identifier (AAGCI), a liquid association based method to infer age-associated gene co-expressions at thousands of biological processes and pathways across 9 human tissues. Several hundred to thousands of gene pairs were inferred to be age co-expressed across different tissues, the genes involved in which are significantly enriched in functions like immunity, ATP binding, DNA damage, and many cancer pathways. The age co-expressed genes are significantly overlapped with aging genes curated in the GenAge database across all 9 tissues, suggesting a tissue-wide correlation between age-associated genes and co-expressions. Interestingly, age-associated gene co-expressions are significantly different from gene co-expressions identified through correlation analysis, indicating that aging might only contribute to a small portion of gene co-expressions. Moreover, the key driver analysis identified biologically meaningful genes in important function modules. For example, IGF1, ERBB2, TP53 and STAT5A were inferred to be key genes driving age co-expressed genes in the network module associated with function “T cell proliferation”. Finally, we prioritized a few anti-aging drugs such as metformin based on an enrichment analysis between age co-expressed genes and drug signatures from a recent study. The predicted drugs were partially validated by literature mining and can be readily used to generate hypothesis for further experimental validations.