Research Paper Volume 10, Issue 9 pp 2338—2355
Antioxidant modifications induced by the new metformin derivative HL156A regulate metabolic reprogramming in SAMP1/kl (-/-) mice
- 1 Department of Biochemistry, School of Oriental Medicine, Dongguk University, Gyeongju 38066, Republic of Korea
- 2 Department of Pathology, School of Dentistry, Chosun University, Gwangju 61452, Republic of Korea
- 3 Department of Oral Pathology, College of Dentistry, Yonsei University, Seoul 03722, Republic of Korea
received: July 3, 2018 ; accepted: September 6, 2018 ; published: September 16, 2018 ;https://doi.org/10.18632/aging.101549
How to Cite
Copyright: Kim 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.
Aging is characterized by a reduced ability to defend against stress, an inability to maintain homeostasis, and an increased risk of disease. In this study, a metabolomics approach was used to identify novel metabolic pathways that are perturbed in a mouse model of accelerated aging (SAMP1/kl-/-) and to gain new insights into the metabolic associations of the metformin derivative HL156A. Extensive inflammation and calcification were observed in the tissues of the SAMP1/kl-/- mice with premature aging. In mouse embryonic fibroblasts (MEFs) obtained from SAMP1/kl-/- mice, we observed that HL156A induced FOXO1 expression through inhibition of the IGF-1/AKT/mTOR signaling pathways. Treatment of HL156A decreased reactive oxygen species production and enhanced mitochondrial transmembrane potential in SAMP1/kl-/- MEFs. A metabolomic profile analysis showed that HL156A increased the GSH/GSSG ratio in the kidneys of SAMP1/kl-/- mice (8-12 weeks old). In addition, treating SAMP1/kl-/- mice with HL156A (30 mg/kg) for 4 weeks improved survival and decreased the significant elevation of oxidized GSH (GSSG) that was observed in SAMP1/kl-/- mice. In histological sections, HL156A administered SAMP1/kl-/- mice exhibited a decrease in excessive calcification. Based on these findings, we conclude that the new metformin derivative HL156A may inhibit oxidative damage by inducing glutathione metabolism and antioxidant pathways.