Research Paper Volume 15, Issue 3 pp 601—616

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

Pedro S. Marra1,2, , Takehiko Yamanashi1,3, , Kaitlyn J. Crutchley1,2,4, , Nadia E. Wahba2,5, , Zoe-Ella M. Anderson2, , Manisha Modukuri2, , Gloria Chang2, , Tammy Tran2, , Masaaki Iwata3, , Hyunkeun Ryan Cho6, , Gen Shinozaki1,2, ,

  • 1 Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94304, USA
  • 2 Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
  • 3 Department of Neuropsychiatry, Tottori University Faculty of Medicine, Yonago-shi, Tottori 680-8550, Japan
  • 4 University of Nebraska Medical Center College of Medicine, Omaha, NE 68131, USA
  • 5 Department of Psychiatry, Oregon Health and Science University School of Medicine, Portland, OR 97239, USA
  • 6 Department of Biostatistics, University of Iowa College of Public Health, Iowa City, IA 52242, USA

Received: December 10, 2022       Accepted: January 16, 2023       Published: February 2, 2023
How to Cite

Copyright: © 2023 Marra et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Background: 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. 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.


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.