The tissue-specific effects of glucose-lowering drug targets on aging mediated through DNA methylation: a multi-omics genetic study

Background: DNA methylation plays a key role in mediating the anti-aging effects of glucose-lowering drugs. This study aims to systematically explore the potential anti-aging effects of target genes of FDA-approved glucose-lowering drugs and the underlying epigenetic mediators. Methods: We conducted a two-sample Mendelian randomization (MR) study to investigate the putative causal relationships between the gene expression levels of glucose-lowering drug targets and 10 aging-related phenotypes, followed by a two-step MR to estimate the mediation effect of DNA methylation. Drug candidates were selected according to the latest review of clinical drug use for type 2 diabetes, and their target genes were obtained from the DGIdb database. Tissue-specific cis-expression quantitative trait loci (eQTLs) from GTEx consortium were selected as genetic instruments to proxy the expression level of drug-target genes. Glycemic phenotypes were used as positive controls to validate the instruments. The cis- and trans-methylation QTLs of Cytosine-phosphate-Guanine sites near the drug target genes were obtained from GoDMC consortium. Additionally, we performed enrichment analyses focused on tissue specificity and aging pathways to further corroborate our findings. Results: We obtained 194 target genes interacted with 36 FDA-approved anti-diabetic drugs, of which the tissue-specific eQTLs were used to proxy the drug target effects. MR showed strong evidence that 9 interacting genes of 6 glucose-lowering drugs showed anti-aging potential on one or more aging-related phenotypes mediated by DNA methylation: EHMT2, HSPA4, IGF2BP2, IRS1, LPL, NDUFAF1, NDUFS3, SLC22A3 and TCF7L2. These genes were distributed in 17 tissues, especially in the central nervous system, suggesting a potential neural component in their anti-aging effects. For instance, expression of EHMT2 in several brain basal ganglia regions, which the gene interacted with Tolazamide, showed a protective effect on frailty (odds ratio[OR] in caudate =1.02, 95%CI=1.01-1.04, FDR adjusted P=1.69 × 10-2; OR in putamen=1.02, 95%CI=1.01-1.03, PFDR=3.37 × 10-2, OR in nucleus accumbens=1.02, 95%CI=1.01-1.04, PFDR=3.37 × 10-2). These associations were externally validated by searching literature evidence in existing EWAS and TWAS studies, as well as evidence from enrichment analyses. Conclusions: This study prioritizes nine glucose-lowering genes as anti-aging drug targets in specific tissues and prioritizes their epigenetic regulation through DNA methylation for future drug development.