Metformin treatment of juvenile mice alters aging-related developmental and metabolic phenotypes

Zhu, Yun; Fang, Yimin; Medina, David; Bartke, Andrzej; Yuan, Rong

doi:10.1016/j.mad.2021.111597

Cited by 12 publications

(5 citation statements)

References 86 publications

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“… 233 Nevertheless, metformin relieves many aging-related diseases in rodent models, including cognitive impairment and neurodegeneration, 229 , 234 – 237 depression, 238 chronic kidney disease, 239 thymus degeneration, 240 aging-related cataract, 228 aging-related hearing loss, 241 mitochondrial dysfunction in aged hearts, 230 adipose tissue senescence and metabolic abnormalities, 242 , 243 and aging-related developmental and metabolic phenotypes. 244 …”

Section: Epigenetic Regulation Of Agingmentioning

confidence: 99%

Epigenetic regulation of aging: implications for interventions of aging and diseases

Wang

Liu

et al. 2022

Sig Transduct Target Ther

194

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Aging is accompanied by the decline of organismal functions and a series of prominent hallmarks, including genetic and epigenetic alterations. These aging-associated epigenetic changes include DNA methylation, histone modification, chromatin remodeling, non-coding RNA (ncRNA) regulation, and RNA modification, all of which participate in the regulation of the aging process, and hence contribute to aging-related diseases. Therefore, understanding the epigenetic mechanisms in aging will provide new avenues to develop strategies to delay aging. Indeed, aging interventions based on manipulating epigenetic mechanisms have led to the alleviation of aging or the extension of the lifespan in animal models. Small molecule-based therapies and reprogramming strategies that enable epigenetic rejuvenation have been developed for ameliorating or reversing aging-related conditions. In addition, adopting health-promoting activities, such as caloric restriction, exercise, and calibrating circadian rhythm, has been demonstrated to delay aging. Furthermore, various clinical trials for aging intervention are ongoing, providing more evidence of the safety and efficacy of these therapies. Here, we review recent work on the epigenetic regulation of aging and outline the advances in intervention strategies for aging and age-associated diseases. A better understanding of the critical roles of epigenetics in the aging process will lead to more clinical advances in the prevention of human aging and therapy of aging-related diseases.

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Section: Epigenetic Regulation Of Agingmentioning

confidence: 99%

Epigenetic regulation of aging: implications for interventions of aging and diseases

Wang

Liu

et al. 2022

Sig Transduct Target Ther

194

View full text Add to dashboard Cite

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“…Neither drug significantly affected the weight of female mice at 18 months (Figure S1B). The sex‐specific weight reduction effect of metformin has been previously reported 21 . Liver tissue was collected for histological study and scored for steatosis (Figure S2A) and DNA adduct frequency (Figure S2B), but this revealed only a modest (nonsignificant) increase in DNA damage in the liver cells of mutant mice.…”

Section: Resultsmentioning

confidence: 53%

Long‐term combination therapy with metformin and oxymetholone in a Fanconi anemia mouse model

Dorrell,

Peters,

Zhang

et al. 2024

Pediatric Blood & Cancer

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Fanconi anemia (FA) is a disease caused by defective deoxyribonucleic acid (DNA) repair that manifests as bone marrow failure, cancer predisposition, and developmental defects. We previously reported that monotherapy with either metformin (MET) or oxymetholone (OXM) improved peripheral blood (PB) counts and the number and functionality of bone marrow hematopoietic stem progenitor cells (HSPCs) number in Fancd2−/− mice. To evaluate whether the combination treatment of these drugs has a synergistic effect to prevent bone marrow failure in FA, we treated cohorts of Fancd2−/− mice and wildtype controls with either MET alone, OXM alone, MET+OXM, or placebo diet from age 3 weeks to 18 months. The OXM treated animals showed modest improvements in blood parameters including platelet count (p = .01) and hemoglobin levels (p < .05). In addition, the percentage of quiescent hematopoietic stem cell (HSC) (LSK [Lin−Sca+c‐Kit+]) was significantly increased (p = .001) by long‐term treatment with MET alone. The combination of metformin and oxymetholone did not result in a significant synergistic effect in any hematopoietic parameter. Gene expression analysis of liver tissue from these animals showed that some of the expression changes caused by Fancd2 deletion were partially normalized by metformin treatment. Importantly, no adverse effects of the individual or combination therapies were observed, despite the long‐term administration. We conclude that androgen therapy is not a contraindication to concurrent metformin administration in clinical trials.Highlights Long‐term coadministration of metformin in combination with oxymetholone is well tolerated by Fancd2−/− mice. Hematopoietic stem cell quiescence in mutant mice was enhanced by treatment with metformin alone. Metformin treatment caused a partial normalization of gene expression in the livers of mutant mice.

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“…The rationale for the dosage and approach of metformin treatment was elucidated in previous report. 15 Peripheral blood was collected from the submandibular vein plexus of the mice for following experiments. A priori power analysis using Gpower estimated that the animal sample size would be at least 52 in total, and the Gpower computation details were as followed: effect size f=0.4; alpha error=0.05; power=0.8; numerator df=1; number of groups=2.…”

Section: Methodsmentioning

confidence: 99%

Metformin treatment of juvenile mice potentiates innate immune response to bacterial lipopolysaccharide in males

Sun,

Zhu,

Bartke

et al. 2023

Eur J Inflamm

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Objective: Metformin is a widely used drug, with a good safety profile, for treatment of type 2 diabetes. Recently, it has been found to also exhibit immunomodulatory potential. We aim to preliminarily explore the potential role of metformin in regulating innate immunity using UM-HET3 mice. Methods: In this study, we treated juvenile UM-HET3 mice with metformin and investigated the alteration of the innate immune response. Peripheral blood of HET3 mice was treated with ex-vivo lipopolysaccharide (LPS) stimulation to induce a leukocyte inflammatory response, which was detected by analyzing the expression of LPS receptors TLR4 and CD14 on leukocytes with flow cytometry. Furthermore, cytokine release induced by LPS was measured in isolated cell culture supernatants with ELISA. Results: In this study LPS treatment triggered a downregulation of TLR4 as well as an upregulation of CD14 expressed on the cell surface. Besides, it enhanced the secretion of pro-inflammatory cytokines TNF-α, IL-1β and IL-6. The results showed that metformin treatment led to a significant ( p < .05) increase in the expression of CD14 and pro-inflammatory cytokines, including IL-1β and IL-6, as well as increased proportion of TLR4 downregulation on the cell surface in response to LPS, specifically in males. Conclusions: This study indicates that treating juvenile mice with metformin enhances the innate immune response to bacterial endotoxin in males, but not in females.

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Metformin treatment of juvenile mice alters aging-related developmental and metabolic phenotypes

Cited by 12 publications

References 86 publications

Epigenetic regulation of aging: implications for interventions of aging and diseases

Epigenetic regulation of aging: implications for interventions of aging and diseases

Long‐term combination therapy with metformin and oxymetholone in a Fanconi anemia mouse model

Metformin treatment of juvenile mice potentiates innate immune response to bacterial lipopolysaccharide in males

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