Research Papers: Gerotarget (Focus on Aging):
A steroid like phytochemical Antcin M is an anti-aging reagent that eliminates hyperglycemia-accelerated premature senescence in dermal fibroblasts by direct activation of Nrf2 and SIRT-1
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Abstract
Kumar K.J. Senthil1, Vani M. Gokila1,2, Jeng-Leun Mau2,3, Chin-Chung Lin4, Fang-Hua Chu5, Chia-Cheng Wei6, Vivian Hsiu-Chuan Liao6 and Sheng-Yang Wang1,2,7
1 Department of Forestry, National Chung Hsing University, Taichung, Taiwan
2 National Chung Hsing University/University of California at Davis, Plant and Food Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
3 Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan
4 Taiwan Leader Biotech Company, Taipei, Taiwan
5 School of Forestry and Resource Conservation, National Taiwan University, Taipei, Taiwan
6 Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, Taiwan
7 Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan
Correspondence to:
Sheng-Yang Wang, email:
Keywords: Antcin M, antrodia salmonea, hyperglycemia, stress-induced premature senescence, SIRT-1, Gerotarget
Received: February 18, 2016 Accepted: July 27, 2016 Published: August 11, 2016
Abstract
The present study revealed the anti-aging properties of antcin M (ANM) and elucidated the molecular mechanism underlying the effects. We found that exposure of human normal dermal fibroblasts (HNDFs) to high-glucose (HG, 30 mM) for 3 days, accelerated G0/G1 phase arrest and senescence. Indeed, co-treatment with ANM (10 µM) significantly attenuated HG-induced growth arrest and promoted cell proliferation. Further molecular analysis revealed that ANM blocked the HG-induced reduction in G1-S transition regulatory proteins such as cyclin D, cyclin E, CDK4, CDK6, CDK2 and protein retinoblastoma (pRb). In addition, treatment with ANM eliminated HG-induced reactive oxygen species (ROS) through the induction of anti-oxidant genes, HO-1 and NQO-1 via transcriptional activation of Nrf2. Moreover, treatment with ANM abolished HG-induced SIPS as evidenced by reduced senescence-associated β-galactosidase (SA-β-gal) activity. This effect was further confirmed by reduction in senescence-associated marker proteins including, p21CIP1, p16INK4A, and p53/FoxO1 acetylation. Also, the HG-induced decline in aging-related marker protein SMP30 was rescued by ANM. Furthermore, treatment with ANM increased SIRT-1 expression, and prevented SIRT-1 depletion. This protection was consistent with inhibition of SIRT-1 phosphorylation at Ser47 followed by blocking its upstream kinases, p38 MAPK and JNK/SAPK. Further analysis revealed that ANM partially protected HG-induced senescence in SIRT-1 silenced cells. A similar effect was also observed in Nrf2 silenced cells. However, a complete loss of protection was observed in both Nrf2 and SIRT-1 knockdown cells suggesting that both induction of Nrf2-mediated anti-oxidant defense and SIRT-1-mediated deacetylation activity contribute to the anti-aging properties of ANM in vitro. Result of in vivo studies shows that ANM-treated C. elegens exhibits an increased survival rate during HG-induced oxidative stress insult. Furthermore, ANM significantly extended the life span of C. elegans. Taken together, our results suggest the potential application of ANM in age-related diseases or as a preventive reagent against aging process.
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