Significantly altered peripheral blood cell DNA methylation profile as a result of immediate effect of metformin use in healthy individuals

Elbere, Ilze; Silamiķelis, Ivars; Ustinova, Monta; Kalniņa, Ineta; Zaharenko, Linda; Pečulis, Raitis; Konrāde, Ilze; Ciuculete, Diana M.; Zhukovsky, Christina; Gudrā, Dita; Radoviča-Spalviņa, Ilze; Fridmanis, Dāvids; Pīrāgs, Valdis; Schiöth, Helgi B.; Kloviņš, Jānis

doi:10.1186/s13148-018-0593-x

Cited by 24 publications

(22 citation statements)

References 102 publications

(86 reference statements)

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“…Metformin affects DNA methylation of cancer-associated MSCs in the tumor microenvironment. Metformin use has been associated with an immediate impact on blood cell DNA methylation (33). Metformin has also been reported to modify cancer cell DNA methylation (34)(35)(36).…”

Section: Translational Studiesmentioning

confidence: 99%

Phase II clinical trial of metformin as a cancer stem cell-targeting agent in ovarian cancer

et al. 2020

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Section: Translational Studiesmentioning

confidence: 99%

Phase II clinical trial of metformin as a cancer stem cell-targeting agent in ovarian cancer

et al. 2020

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“…For the majority of the CpG-sites investigated in the present study, the largest changes in DNA methylation status occurred within the first 3 days after PICU admission, whereas any further changes beyond day 3 progressed at a slower rate. Earlier research in other fields also documented short-term DNA methylation alterations in several CpG-sites, for instance within only hours after metformin administration [ 15 ], or within a few days after the start of a detoxification treatment in alcohol-dependent individuals [ 16 ]. Also, in physiologic conditions, DNA demethylation and methylation can occur rapidly, such as within a timeframe of several hours after fertilisation [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Time course of altered DNA methylation evoked by critical illness and by early administration of parenteral nutrition in the paediatric ICU

et al. 2020

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Background A genome-wide study identified de novo DNA methylation alterations in leukocytes of children at paediatric intensive care unit (PICU) discharge, offering a biological basis for their impaired long-term development. Early parenteral nutrition (early-PN) in PICU, compared with omitting PN in the first week (late-PN), explained differential methylation of 23% of the affected CpG-sites. We documented the time course of altered DNA methylation in PICU and the impact hereon of early nutritional management. Results We selected 36 early-PN and 36 late-PN matched patients, and 42 matched healthy children. We quantified DNA methylation on days 3, 5 and 7 for the 147 CpG-sites of which methylation was normal upon PICU admission in this subset and altered by critical illness at PICU discharge. Methylation in patients differed from healthy children for 64.6% of the 147 CpG-sites on day 3, for 72.8% on day 5 and for 90.5% on day 7 as revealed by ANOVA at each time point. Within-patients methylation time course analyses for each CpG-site identified different patterns based on paired t test p value and direction of change. Rapid demethylation from admission to day 3 occurred for 76.2% of the CpG-sites, of which 67.9% remained equally demethylated or partially remethylated and 32.1% further demethylated beyond day 3. From admission to day 3, 19.7% of the CpG-sites became hypermethylated, of which, beyond day 3, 34.5% remained equally hypermethylated or partially demethylated again and 65.5% further hypermethylated. For 4.1% of the CpG-sites, changes only appeared beyond day 3. Finally, for the CpG-sites affected by early-PN on the last PICU day, earlier changes in DNA methylation were compared for early-PN and late-PN patients, revealing that 38.9% were already differentially methylated by day 3, another 25.0% by day 5 and another 13.9% by day 7. Conclusions Critical illness- and early-PN-induced changes in DNA methylation occurred mainly within 3 days. Most abnormalities were at least partially maintained or got worse with longer time in PICU. Interventions targeting aberrant DNA methylation changes should be initiated early.

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“…As the cells were from healthy individuals, having ADAM8 in the result shows that metformin's anti-inflammatory effect is independent of diabetic status. 22 Treating yeast with rapamycin resulted in extended lifespan in a process that has been postulated to mimic CR. 23 Heterogeneous male mice that received a daily dosage of 2.24 mg of rapamycin per kg of body weight beginning at the age of 20 months had 9% extended lifespan while female mice had 14%.…”

Section: Longevitymentioning

confidence: 99%

“…Pathway enrichment analysis found association between the CpG sites and the unfolded protein response, which is involved in metformin-induced apoptosis in acute lymphoblastic leukemia. 22 In 2005, a case control study first discovered reduced risk of cancer associated with metformin in diabetic patients. 64 65 Diabetic patients who took metformin also had 7% less chance of getting hepatocellular cancer for each incremental year they took metformin, and it was attributed to inhibited proliferation and cell cycle arrest induced by metformin in the hepatocytes.…”

Section: Tumorsmentioning

confidence: 99%

Mechanisms under Metformin and Rapamycin as Anti-aging Drugs

Feng¹,

Chen²,

Wang³

et al. 2020

Preprint

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As percentages of elderly people rise in many societies, age-related diseases have become more prevalent. Research interests have been shifting to delaying age-related disease by delaying or reversing aging itself. We use metformin and rapamycin, two drugs at the center of anti-aging drug research, as an entry point to talk about important molecular and genetic anti-aging mechanisms that have been extensively studied with them, such as mTOR, AMPK, and epigenetic modifications. We also present a number of observational studies, animal studies, and clinical trials to reflect the potential and actual effects of the mechanisms. At the end, we list remaining concerns that not only apply to researches around metformin and rapamycin but also future researches to explore other anti-aging pathways and therapeutics.

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Significantly altered peripheral blood cell DNA methylation profile as a result of immediate effect of metformin use in healthy individuals

Cited by 24 publications

References 102 publications

Phase II clinical trial of metformin as a cancer stem cell-targeting agent in ovarian cancer

Phase II clinical trial of metformin as a cancer stem cell-targeting agent in ovarian cancer

Time course of altered DNA methylation evoked by critical illness and by early administration of parenteral nutrition in the paediatric ICU

Mechanisms under Metformin and Rapamycin as Anti-aging Drugs

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