Metformin use history and genome-wide DNA methylation profile: potential molecular mechanism for aging and longevity

Background While there are medications that treat and manage age-related diseases, a compound that prolongs lifespan is yet to be discovered. Nonetheless, metformin, a commonly prescribed anti-diabetic medication, has repeatedly been shown to hinder aging in pre-clinical models and to be associated with lower mortality for humans, even among cancer patients. It is, however, not well understood how metformin can potentially prolong lifespan from a biological standpoint. We hypothesized that metformin’s potential mechanism of action for longevity is through its epigenetic modifications. Methods To test our hypothesis, we conducted a post-hoc analysis of available genome-wide DNA methylation (DNAm) data obtained from whole blood collected from inpatients with and without a history of metformin use. We assessed the methylation profile of 171 patients (first run) and only among 63 diabetic patients (second run) and compared the DNAm rates between metformin users and nonusers. Results Enrichment analysis from the Kyoto Encyclopedia of Genes and Genome (KEGG) showed pathways relevant to metformin’s mechanism of action, such as longevity, AMPK, and inflammatory pathways. We also identified several pathways related to delirium whose risk factor is aging. Moreover, top hits from the Gene Ontology (GO) included HIF-1α pathways. However, no individual CpG site showed genome-wide statistical significance (p<5E-08). Conclusion This study may elucidate metformin’s potential role in longevity through epigenetic modifications and other possible mechanisms of action. ### Competing Interest Statement Gen Shinozaki is co-founder of Predelix Medical LLC and has pending patents as follows: "Non-invasive device for predicting and screening delirium", PCT application no. PCT/US2016/064937 and US provisional patent no. 62/263,325; "Prediction of patient outcomes with a novel electroencephalography device", US provisional patent no. 62/829,411; "Epigenetic Biomarker of Delirium Risk" in the PCT Application No. PCT/US19/51276, and in U.S. Provisional Patent No. 62/731,599. Pedro S. Marra, Takehiko Yamanashi, Kaitlyn J. Crutchley, Nadia E. Wahba, Zoe-Ella M. Anderson, Manisha Modukuri, Gloria Chang, Tammy Tran, Masaaki Iwata, and Hyunkeun Ryan Cho have declared that no conflict of interest exists. * DM : diabetes mellitus non-Met : patient without a history of metformin use Met : patient with a history of metformin use DM(−)Met : diabetic patients without a history of metformin use DM(+)Met : diabetic patients with a history of metformin use.