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Antioxidant modifications induced by the new metformin derivative HL156A regulate metabolic reprogramming in SAMP1/kl (-/-) mice

 Soo-A Kim  ;  Thuy Giang Lam  ;  Jong-In Yook  ;  Sang-Gun Ahn 
 Aging, Vol.10(9) : 2338-2355, 2018 
Journal Title
Issue Date
HL156A ; SAMP1/ Klotho ; aging ; antioxidant ; glutathione ; metabolic profiling
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.
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2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실) > 1. Journal Papers
Yonsei Authors
Yook, Jong In(육종인) ORCID logo https://orcid.org/0000-0002-7318-6112
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