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Aging and disease    2017, Vol. 8 Issue (6) : 760-777     DOI: 10.14336/AD.2016.0620
Review |
Rhizoma Coptidis and Berberine as a Natural Drug to Combat Aging and Aging-Related Diseases via Anti-Oxidation and AMPK Activation
Xu Zhifang1,2,*, Feng Wei3, Shen Qian4, Yu Nannan1, Yu Kun1, Wang Shenjun1,2, Chen Zhigang4, Shioda Seiji5, Guo Yi1,2,*
1Acu-moxibustion and Tuina Department, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
2Acupuncture Research Center, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
3South Branch of Guang’anmen Hospital, China Academy of Chinese Medical Science, Beijing 102618, China
4Dongfang hospital, Beijing University of Chinese Medicine, Beijing 100078, China
5Peptide Drug Innovation, Global Research Center for Innovative Life Science, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa, Tokyo 142-8501, Japan
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Abstract  

Aging is the greatest risk factor for human diseases, as it results in cellular growth arrest, impaired tissue function and metabolism, ultimately impacting life span. Two different mechanisms are thought to be primary causes of aging. One is cumulative DNA damage induced by a perpetuating cycle of oxidative stress; the other is nutrient-sensing adenosine monophosphate-activated protein kinase (AMPK) and rapamycin (mTOR)/ ribosomal protein S6 (rpS6) pathways. As the main bioactive component of natural Chinese medicine rhizoma coptidis (RC), berberine has recently been reported to expand life span in Drosophila melanogaster, and attenuate premature cellular senescence. Most components of RC including berberine, coptisine, palmatine, and jatrorrhizine have been found to have beneficial effects on hyperlipidemia, hyperglycemia and hypertension aging-related diseases. The mechanism of these effects involves multiple cellular kinase and signaling pathways, including anti-oxidation, activation of AMPK signaling and its downstream targets, including mTOR/rpS6, Sirtuin1/ forkhead box transcription factor O3 (FOXO3), nuclear factor erythroid-2 related factor-2 (Nrf2), nicotinamide adenine dinucleotide (NAD+) and nuclear factor-κB (NF-κB) pathways. Most of these mechanisms converge on AMPK regulation on mitochondrial oxidative stress. Therefore, such evidence supports the possibility that rhizoma coptidis, in particular berberine, is a promising anti-aging natural product, and has pharmaceutical potential in combating aging-related diseases via anti-oxidation and AMPK cellular kinase activation.

Keywords Rhizoma coptidis      berberine      aging      aging-related diseases      AMPK      anti-oxidation     
Corresponding Authors: Xu Zhifang,Guo Yi   
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These authors contributed equally to this study

Issue Date: 01 December 2017
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Xu Zhifang
Feng Wei
Shen Qian
Yu Nannan
Yu Kun
Wang Shenjun
Chen Zhigang
Shioda Seiji
Guo Yi
Cite this article:   
Xu Zhifang,Feng Wei,Shen Qian, et al. Rhizoma Coptidis and Berberine as a Natural Drug to Combat Aging and Aging-Related Diseases via Anti-Oxidation and AMPK Activation[J]. Aging and disease, 2017, 8(6): 760-777.
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http://www.aginganddisease.org/EN/10.14336/AD.2016.0620     OR     http://www.aginganddisease.org/EN/Y2017/V8/I6/760
Figure 1.  The photographs of RC dried root and rhizome.
Figure 2.  The structures of berberine and other key protoberberine-type alkaloids contained in RC.
Refs.Cell type, animal modelEffect of BBRIndex
[37]wild-type Drosophila melanogasterboosts life-span and health-spanmean, median and maximum life span, locomotor activity (vertical climbing), lethality, kynurenine, tryptophan
[39]wild-type Drosophila melanogasterboosts life-spankynurenine, tryptophan
[49]premature senescence in pulmonary adenocarcinoma A549 cells induced by persistent DNA replication stressanti-senescencecell morphology; the ratio of mean intensity of maximal pixels to nuclear area; cyclin kinase inhibitors, phosphorylation of ribosomal protein S6 (rpS6)
[41]normal human keratinocytesanti-skin agingTPA, MMP-9, IL-6, ERK, AP-1 DNA binding activity
[42]human dermal fibroblastsanti-skin agingMMP-1, type I procollagen
[83]hydrogen peroxide-induced senescent cellsanti-oxidation, promote autophagy,p62, NAD(+), mTOR, Sirt1
Table 1  Anti-aging effect of bererine.
ComponentRefs.Patient, cell type, animal modelIndex
anti-hyperlipidemia
Berberine[52]hyperlipidemic patientsTC, TG, LDL-c, LDLR
[53]diabetic hyperlipidemic ratTC, TG, LDL-c, apolipoprotein B, apolipoprotein AI
Coptisine[54]HepG2 cellsTC, TG, LDL-c, HDL-c, LDLR, HMGCR, CYP7A1
[55]HFHC-induced hyperlipidemic hamstersbody weight gain, TC, TG, LDL-c, HDL-c, TBA
Jatrorrhizine[55]hyperlipidemic miceTC, TG, LDL-c, HDL-c, SREBP-1c, FAS, PPAR-α, CPT1A
[56]HFHC-induced hyperlipidemic hamstersTC, TG, and LDL-c, HDL-c, TBA,LDLR, CYP7A1, HMGR, ASBT
[57]high-fat and high-cholesterol (HFHC) miceTC, TG, LDL-c,
anti-hyperglycemia
Berberine[59]type 2 diabetes mellitus patientsblood glucose, insulin receptor
Palmatine[62]alloxan-induced diabetic miceblood glucose
Jatrorrhizine[63]high-fat diet-induced obesity and hyperglycemic micebody weight, blood glucose, insulin receptor
anti-hypertensive activity
Berberine[64]spontaneously hypertensive ratsBlood pressure, IL-6, IL-17 and IL-23
Alzheimer’ disease
Berberine[68]human neuroglioma H4 cellsAPP
Coptisine[44]AβPP/PS1 transgenic micecognition, neuron loss, amyloid plaque formation, IDO
Table 2  Effect of RC major components (bererine, coptisine, jatrorrhizine and palmatine) on aging-related disease.
Figure 3.  Schematic illustration of the molecular mechanisms and pathways of <i>RC</i>/berberine anti-aging and aging-related diseases

(1) RC/berberine could activate AMPK signaling pathway in the cellular mitochondria. (2) The activation of AMPK by RC/berberine inhibits the oxidative stress in mitochondria via down-regulating ROS production and up-regulating anti-oxidative enzymes. (3) The downstream targets of the AMPK signaling regulated by RC/berberine include the activation of mitochondrial biogenesis, SIRT1/FOXO and Nrf2 signaling, and inhibition mTOR/S6K, NADPH and NF-??B pathways. (4) Via regulating the downstream productions of the signaling pathways mentioned above, RC/berberine could activate cellular autophagy which finally inhibits cellular senescence, aging process and the pathological process of aging-related diseases.

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