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

<h4>Background</h4>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.<h4>Methods</h4>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. 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.<h4>Results</h4>We obtained 194 target genes interacting 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 nine interacting genes of six 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, where 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, P_FDR = 3.37 × 10^-2, OR in nucleus accumbens = 1.02, 95% CI = 1.01-1.04, P_FDR = 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.<h4>Conclusions</h4>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.