Society is ageing rapidly, with the US Census Bureau’s 2017 National Population Projections forecasting that 1 in 5 residents will be of retirement age by 2030. As a consequence, more individuals will experience age-related diseases like cancer and dementia. Treatments aimed at these diseases, such as chemotherapy or radiotherapy, only delay the disease’s progression and do not provide a cure. As a result, there is increasing interest in treating ageing itself as a disease.
Several interventions, including exercise, intermittent fasting, and the consumption of certain compounds, have been shown to extend lifespan in basic and pre-clinical models. Promising compounds include rapamycin, resveratrol, NAD, and metformin. It was found that patients taking metformin had improved three-year survival rates and a lower prevalence of delirium than those who did not use metformin.
The mechanisms behind how these interventions prolong lifespan or delay ageing have been heavily investigated, with epigenetics being identified as one of the most critical molecular mechanisms of ageing in animals and plants. It is plausible that the “life-prolonging” effects of many interventions are due to their modification of epigenetic processes. For example, exercise, fasting, rapamycin, resveratrol, and NAD have all been shown to induce epigenetic changes. However, there are limited studies investigating the direct influence of metformin on epigenetic changes, highlighting a gap in knowledge.
To address this gap, a study was conducted to investigate the potential influence of metformin on the epigenetic profile by analysing genome-wide DNA methylation (DNAm) in whole blood samples from inpatients with and without a history of metformin use. The findings were published in the journal Aging.
Metformin, a commonly prescribed anti-diabetic medication, has repeatedly been shown to hinder ageing 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.
In this recent study, researchers Pedro S. Marra, Takehiko Yamanashi, Kaitlyn J. Crutchley, Nadia E. Wahba, Zoe-Ella M. Anderson, Manisha Modukuri, Gloria Chang, Tammy Tran, Masaaki Iwata, Hyunkeun Ryan Cho, and Gen Shinozaki from Stanford University School of Medicine, University of Iowa, Tottori University Faculty of Medicine, the University of Nebraska Medical Center College of Medicine, and Oregon Health and Science University School of Medicine hypothesised that metformin’s potential mechanism of action for longevity is through its epigenetic modifications.
“To test our hypothesis, we conducted a posthoc analysis of available genome-wide DNA methylation (DNAm) data obtained from whole blood collected from inpatients with and without a history of metformin use.”
The researchers assessed the methylation profile of 171 patients (first run) and only 63 diabetic patients (second run) and compared the DNAm rates between metformin users and nonusers. 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. They also identified several pathways related to delirium whose risk factor is ageing. Moreover, top hits from the Gene Ontology (GO) included HIF-1α pathways. However, no individual CpG site showed genome-wide statistical significance.
“This study may elucidate metformin’s potential role in longevity through epigenetic modifications and other possible mechanisms of action,” explained the researchers.
The study was the largest of its kind, and it aimed to investigate the potential influence of metformin on the epigenetic profile in human peripheral blood. The research team discovered the longevity pathway from a hypothesis-free approach, which supported their hypothesis that metformin might exhibit its potential benefits for longevity through epigenetic processes. Furthermore, they identified other relevant pathways associated with metformin’s mechanisms of action, such as the AMPK signalling pathway and HIF-1α signalling pathway.
But the study has several limitations. Although 171 subjects were analyzed retrospectively in the study, a controlled prospective study with a larger sample size would provide a better picture of the epigenetic mechanism of metformin on longevity. Additionally, none of the individual CpG sites reached genome-wide significance. Thus, their findings should be interpreted as exploratory and hypothesis-generating.
The diabetes and metformin use status of the subjects was determined based on a retrospective chart review of electronic medical records, which might lead to misclassification. Moreover, the duration of metformin use was not precisely assessed, making their definition of “metformin history use” broad. They did not investigate the influence of other diabetic medications, such as sulfonylureas and glinide drugs, as past literature showed that diabetic medications other than metformin did not show benefits for survival.
The findings support their hypothesis that epigenetics, especially DNA methylation, may be altered by metformin use, and such epigenetic processes potentially contribute to molecular mechanisms leading to longevity. But further careful investigation with a larger sample size is warranted to provide more robust evidence.