Marra, P. S. | Search bioRxiv

bioRxiv2022

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

BackgroundWhile 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 metformins potential mechanism of action for longevity is through its epigenetic modifications. MethodsTo 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. ResultsEnrichment analysis from the Kyoto Encyclopedia of Genes and Genome (KEGG) showed pathways relevant to metformins 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-1 pathways. However, no individual CpG site showed genome-wide statistical significance (p<5E-08). ConclusionThis study may elucidate metformins potential role in longevity through epigenetic modifications and other possible mechanisms of action.

genetics↗

bioRxiv2022

Epigenetics of post-operative delirium: A genome-wide DNA methylation study of neurosurgery patients

AimsThere is no previous study demonstrating the differences of genome-wide DNA methylation (DNAm) profiles between patients with and without postoperative delirium (POD). We aimed to discover epigenetic (DNAm) markers that are associated with POD in blood obtained from patients before and after neurosurgery. MethodsPre- and post-surgical blood DNA samples from 37 patients, including 10 POD cases, were analyzed using the Illumina EPIC array genome-wide platform. We examined DNAm differences in blood from patients with and without POD. Enrichment analysis with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes terms were also conducted. ResultsWhen POD cases were tested for DNAm change before and after surgery, enrichment analyses showed many relevant signals with statistical significance in immune response related-pathways and inflammatory cytokine related-pathways such as "cellular response to cytokine stimulus", "regulation of immune system process", "regulation of cell activation", and "regulation of cytokine production". Furthermore, after excluding the potential effect of common factors related to surgery and anesthesia between POD cases and non-POD controls, the enrichment analyses showed significant signals such as "immune response" and "T cell activation", which are same pathways previously identified from an independent non-surgical inpatient cohort. Conclusions: Our first genome-wide DNAm investigation of POD showed promising signals related to immune response, inflammatory response and other relevant signals considered to be associated with delirium pathophysiology. Our data supports the hypothesis that epigenetics are playing an important role in pathophysiological mechanism of delirium and suggest the potential usefulness of epigenetics based biomarker of POD.

neuroscience↗