Elucidating causal relationships between circulating inflammatory factors and aging traits: Transcriptomics and...

Area of Science:

• Genetics and immunology
• Aging research
• Systems biology

Background:

• Chronic inflammation is associated with aging, but specific causal factors are unknown.
• Understanding the interplay between inflammation and aging is crucial for health span research.

Purpose of the Study:

• To investigate the bidirectional causal relationships between circulating inflammatory protein genes and aging traits.
• To identify specific inflammatory factors that influence aging and vice versa.

Main Methods:

• Bidirectional Mendelian randomization (Bi-MR) analysis of 91 inflammatory protein genes and aging traits (telomere length, epigenetic clocks, frailty, cognition, health span).
• Sensitivity analyses using MR-Egger, weighted median, Bayesian methods, and MR-RAPS.
• Transcriptomic validation using GTEx, GSE236927, GSE123697, and GSE237029 datasets with CIBERSORT and weighted gene coexpression network analysis.

Main Results:

• Identified 12 inflammatory factor genes with significant forward associations and 10 with reverse associations with aging traits.
• Found causal links between CASP8 and health span, IL1A/CXCL10 and telomere length.
• Demonstrated that telomere length causally influences Interleukin-10 (IL10) mRNA levels, with IL10 confirmed as an aging-related inflammatory gene.

Conclusions:

• Provides robust genetic and transcriptomic evidence for bidirectional causal links between inflammation and aging.
• Highlights IL10 as a significant molecular player mediating the relationship between immune regulation and aging biology.