Background: Tetrahydroxystilbene glucoside (TSG) is a main bioactive component of Polygonum multiflorum, a traditional Chinese medicine known for certain anti-aging effects. Since TSG has been found to extend lifespan in the nematode Caenorhabditis elegans, we hypothesized that TSG might produce anti-aging benefits in mammals. Objective: The aim was to evaluate the anti-aging potential of TSG and to explore its relative molecular mechanism. Methods: Mice were maintained on standard diet, high-calorie diet (HC), or high-calorie plus TSG diet. Survival rates and body weight changes were recorded weekly. Rotarod analysis was performed to assess the physical fitness of mice. Bone mineral density was assessed using micro-computed tomography. Hematoxylin and eosin staining was used for the histological examination of heart, liver, and kidney pathology. The mRNA and protein expression of target genes were analyzed by quantitative real-time polymerase chain reaction and western blotting, respectively. Mitotracker deep red staining and high-content analysis were used to quantify cellular mitochondrial mass and function. Results: In this study, we found that TSG improved the physiology of aged mice consuming excess calories and delayed senile symptoms. The anti-aging benefits of TSG were mediated at least in part by the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) signaling cascade, leading to significant improvement in motor function, bone mineral density, HC-induced organ pathology, and mitochondrial function. Conclusion: Our findings show that TSG could be a potential drug candidate for the treatment of aging- and high-calorie intake-associated disorders.

Keywords:
Tetrahydroxystilbene glucoside, Polygonum multiflorum, Traditional Chinese medicine, Aging, Senile symptoms
1.
Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G: The hallmarks of aging. Cell 2013; 153: 1194–1217.
2.
Lv G, Gu H, Chen S, Lou Z, Shan L: Pharmacokinetic profile of 2,3,5,4’-tetrahydroxystilbene-2-O-beta-D-glucoside in mice after oral administration of Polygonum multiflorum extract. Drug Dev Ind Pharm 2012; 38: 248–255.
3.
Xu C: Effect of the extract of Polygonum multiflorum Thunb. on the lifespan of Drosophila melanogaster. J Yantai Univ 2000; 13: 154–156.
4.
Wang W, Wang JH, Shi TR: Effect of Polygonum multiflorum on the life-span and lipid metabolism in senile Japanese quails (in Chinese). Zhong Xi Yi Jie He Za Zhi 1988; 8: 223–224, 198.
5.
Li X, Matsumoto K, Murakami Y, Tezuka Y, Wu Y, Kadota S: Neuroprotective effects of Polygonum multiflorum on nigrostriatal dopaminergic degeneration induced by paraquat and maneb in mice. Pharmacol Biochem Behav 2005; 82: 345–352.
6.
Buchter C, Zhao L, Havermann S, Honnen S, Fritz G, Proksch P, Watjen W: TSG (2,3,5,4’-tetrahydroxystilbene-2-O-β-D-glucoside) from the Chinese herb Polygonum multiflorum increases life span and stress resistance of Caenorhabditis elegans. Oxid Med Cell Longev 2015; 2015: 124357.
7.
Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA: Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006; 444: 337–342.
8.
Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA: Small molecule activators of sirtuins extend Saccharomyces cerevisiae life-span. Nature 2003; 425: 191–196.
9.
Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D: Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 2004; 430: 686–689.
10.
Viswanathan M, Kim SK, Berdichevsky A, Guarente L: A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. Dev Cell 2005; 9: 605–615.
11.
Jarolim S, Millen J, Heeren G, Laun P, Goldfarb DS, Breitenbach M: A novel assay for replicative lifespan in Saccharomyces cerevisiae. FEMS Yeast Res 2004; 5: 169–177.
12.
Wang T, Gu J, Wu PF, Wang F, Xiong Z, Yang YJ, Wu WN, Dong LD, Chen JG: Protection by tetrahydroxystilbene glucoside against cerebral ischemia: involvement of JNK, SIRT1, and NF-κB pathways and inhibition of intracellular ROS/RNS generation. Free Radic Biol Med 2009; 47: 229–240.
13.
Li C, Cai F, Yang Y, Zhao X, Wang C, Li J, Jia Y, Tang J, Liu Q: Tetrahydroxystilbene glucoside ameliorates diabetic nephropathy in rats: involvement of SIRT1 and TGF-β1 pathway. Eur J Pharmacol 2010; 649: 382–389.
14.
Lee HJ, Yang SJ: Aging-related correlation between serum sirtuin 1 activities and basal metabolic rate in women, but not in men. Clin Nutr Res 2017; 6: 18–26.
15.
Ingram DK, Anson RM, de Cabo R, Mamczarz J, Zhu M, Mattison J, Lane MA, Roth GS: Development of calorie restriction mimetics as a prolongevity strategy. Ann NY Acad Sci 2004; 1019: 412–423.
16.
Sinclair DA: Toward a unified theory of caloric restriction and longevity regulation. Mech Ageing Dev 2005; 126: 987–1002.
17.
Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P: Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 2005; 434: 113–118.
18.
Lerin C, Rodgers JT, Kalume DE, Kim SH, Pandey A, Puigserver P: GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1α. Cell Metab 2006; 3: 429–438.
19.
Golko-Perez S, Amit T, Bar-Am O, Youdim MB, Weinreb O: A novel iron chelator-radical scavenger ameliorates motor dysfunction and improves life span and mitochondrial biogenesis in SOD1G93A ALS mice. Neurotox Res 2017; 31: 230–244.
20.
Holloszy JO: Regulation by exercise of skeletal muscle content of mitochondria and GLUT4. J Physiol Pharmacol 2008; 59(suppl 7): 5–18.
21.
Lin L, Li H, Lin H, Zhang M, Qu C, Yan L, Yin X, Ni J: A new perspective on liver injury by traditional Chinese herbs such as Polygonum multiflorum: the geographical area of harvest as an important contributory factor. Front Pharmacol 2017; 8: 349.
22.
Jiao C, Gao F, Ou L, Yu J, Li M, Wei P, Miao F: Tetrahydroxy stilbene glycoside (TSG) antagonizes Aβ-induced hippocampal neuron injury by suppressing mitochondrial dysfunction via Nrf2-dependent HO-1 pathway. Biomed Pharmacother 2017; 96: 222–228.
23.
Cantó C, Gerharthines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J: AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 2009; 458: 1056–1060.
24.
Kemp BE, Stapleton D, Campbell DJ, Chen ZP, Murthy S, Walter M, Gupta A, Adams JJ, Katsis F, van Denderen B, Jennings IG, Iseli T, Michell BJ, Witters LA: AMP-activated protein kinase, super metabolic regulator. Biochem Soc Trans 2003; 31: 162–168.
25.
Mccarty MF: Chronic activation of AMP-activated kinase as a strategy for slowing aging. Med Hypotheses 2004; 63: 334–339.
26.
Guarente L, Picard F: Calorie restriction – the SIR2 connection. Cell 2005; 120: 473–482.
27.
Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, Tedesco L, Falcone S, Valerio A, Cantoni O, Clementi E: Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 2005; 310: 314–317.
28.
López-Lluch G, Hunt N, Jones B, Zhu M, Jamieson H, Hilmer S, Cascajo MV, Allard J, Ingram DK, Navas P, de Cabo R: Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci USA 2006; 103: 1768–1773.
29.
Cantó C, Menzies K, Auwerx J: Nad+ metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab 2015; 22: 31–53.
© 2018 S. Karger AG, Basel
2018
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.