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Nobiletin Delays Aging and Enhances Stress Resistance of Caenorhabditis Elegans

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Nobiletin Delays Aging and Enhances Stress Resistance of Caenorhabditis Elegans International Journal of Molecular Sciences Article Nobiletin Delays Aging and Enhances Stress Resistance of Caenorhabditis elegans Xueyan Yang 1, Hong Wang 1,2,* , Tong Li 3, Ling Chen 2, Bisheng Zheng 1,4 and Rui Hai Liu 3,* 1 Overseas Expertise Introduction Center for Discipline Innovation of Food Nutrition and Human Health (111 Center), School of Food Science and Engineering, South China University of Technology, Guangzhou 510641, China; [email protected] (X.Y.); [email protected] (B.Z.) 2 Ministry of Education Engineering Research Centre of Starch & Protein Processing, Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, South China University of Technology, Guangzhou 510641, China; [email protected] 3 Department of Food Science, Stocking Hall, Cornell University, Ithaca, NY 14853, USA; [email protected] 4 Guangdong ERA Food & Life Health Research Institute, Guangzhou 510670, China * Correspondence: [email protected] (H.W.); [email protected] (R.H.L.) Received: 9 December 2019; Accepted: 29 December 2019; Published: 4 January 2020 Abstract: Nobiletin (NOB), one of polymethoxyflavone existing in citrus fruits, has been reported to exhibit a multitude of biological properties, including anti-inflammation, anti-oxidation, anti-atherosclerosis, neuroprotection, and anti-tumor activity. However, little is known about the anti-aging effect of NOB. The objective of this study was to determine the effects of NOB on lifespan, stress resistance, and its associated gene expression. Using Caenorhabditis elegans, an in vivo nematode model, we found that NOB remarkably extended the lifespan; slowed aging-related functional declines; and increased the resistance against various stressors, including heat shock and ultraviolet radiation. Also, NOB reduced the effects of paraquat stressor on nematodes and scavenged reactive oxygen species (ROS). Furthermore, gene expression revealed that NOB upregulated the expression of sod-3, hsp-16.2, gst-4, skn-1, sek-1, and sir-2.1, which was suggested that anti-aging activity of NOB was mediated most likely by activation of the target genes of the transcription factors including dauer formation (DAF)-16, heat-shock transcription factor (HSF)-1, and skinhead (SKN)-1. In summary, NOB has potential application in extension of lifespan, and its associated healthspan and stress resistances. Keywords: nobiletin; aging; stress resistance; Caenorhabditis elegans 1. Introduction The global population is stepping into the stage of aging. By 2050, 16% of people in the world will be over the age of 65, up from 9% in 2019, and the number of persons aged 80 years or over is projected to triple, from 143 million in 2019 to 426 million in 2050 [1]. With an increasing proportion of the elderly in society and, consequently, rising incidences of aging-associated diseases, it has become more and more urgent to seek nutraceuticals, not only to prolong lifespan, but also to improve healthspan as well as stress resistance. Thousands of phytochemicals, present in plant-derived food, such as vitamin C, phenolics, and flavonoids, play an important physiological role in the maintenance of human health. Epidemiological studies have shown that increasing the intake of fruits and vegetables rich in phytochemicals can protect the body from chronic diseases such as cancer, atherosclerosis, and neurodegenerative diseases in an age-dependent manner [2–4]. In addition, similar improvement on cognitive performance in the elderly could be achieved through consumption of flavonoid-rich food like wine, tea, and chocolate [5]. Int. J. Mol. Sci. 2020, 21, 341; doi:10.3390/ijms21010341 www.mdpi.com/journal/ijms Int.Int. J. J. Mol. Mol. Sci. Sci. 20192020, ,2021, ,x 341 2 2of of 19 18 The short-lived model organism Caenorhabditis elegans (C. elegans) offers promising possibilities for studyingThe short-lived the influence model of organism bioactiveCaenorhabditis compounds on elegans the process(C. elegans of aging,) offers given promising that its possibilities longevity- associatedfor studying signaling the influence pathways of are bioactive highly conservative compounds to on higher the processmammals, of including aging, given humans that [6]. its Additionally,longevity-associated some aging-related signaling pathways physiological are highlyindexes conservative occurring in this to higher kind of mammals, worm, are includingsimilar to thosehumans found [6]. in Additionally, higher mammals. some aging-related In C. elegans physiological, the insulin/- indexesinsulin-like occurring growth in thisfactor kind signaling of worm, (IIS), are heat-shocksimilar to those transcription found in higher factor mammals. (HSF-1), Inmitogen-activatedC. elegans, the insulin protein/- insulin-like kinase (MAPK), growth factor and signaling dietary restriction(IIS), heat-shock (DR) pathways transcription have factor been proved (HSF-1), to mitogen-activated be involved in aging protein and the kinase onset (MAPK), of aging-associated and dietary diseasesrestriction [7,8]. (DR) The pathways IIS pathway, have been an evolutionarily proved to beinvolved conserved in agingcentral and contro thel onset pathway of aging-associated similar to the humandiseases aging [7,8]. process, The IIS pathway,plays an important an evolutionarily role in the conserved regulation central of lifespan control in pathway both nematodes similar to and the mammalshuman aging by process,regulating plays the ancons importanterved transcription role in the regulationfactor DAF-16 of lifespan [9–11]. in The both HSF-1 nematodes pathway and prolongsmammals longevity by regulating by activating the conserved heat transcriptionshock gene expression factor DAF-16 [12], [9 while–11]. TheMAPK HSF-1 upregulates pathway prolongs SKN-1, thelongevity nuclear by factor-E2-related activating heat shock factor gene 2 (Nrf-2) expression homologue [12], while transcription MAPK upregulates factor, SKN-1,to combat the nuclearstress- inducedfactor-E2-related aging [13]. factor These 2 (Nrf-2)three transcription homologue transcriptionfactors are critical factor, for to stress combat resistance stress-induced and longevity aging [via13]. promotingThese three expression transcription of factorsantioxidan are criticalt or detoxifying for stress resistance enzymes. and Previous longevity studies via promoting have reported expression that variousof antioxidant flavonoids or detoxifying and extracts enzymes. rich in flavonoids Previous exert studies life-prolonging have reported effects that various through flavonoids the inhibition and ofextracts the IIS rich pathway. in flavonoids For instance, exert life-prolonging quercetin [14,15] eff wasects found through to theprolong inhibition the lifespan of the IIS of pathway.C. elegans Forby 10–15%,instance, and quercetin promote [14 stress,15] was resistance found tothrough prolong rapid the lifespantranslocation of C. elegansof DAF-16by 10–15%,and activation and promote of the downstreamstress resistance targets through of DAF-16. rapid Similarly, translocation the anti-a of DAF-16ging effect and of activation myricetin of was the partly downstream dependent targets on DAF-16of DAF-16. through Similarly, a nuclear the anti-aging translocation effect of of DAF-16, myricetin but was not partlyof SKN-1[16]. dependent Previously, on DAF-16 our through lab [17] a reportednuclear translocation that blueberry of DAF-16,extract rich but notin polyphenol of SKN-1 [16s ].extended Previously, lifespan our lab and [17 increased] reported survival that blueberry rates afterextract acute rich stress in polyphenols through the extended regulation lifespan of downstream and increased gene survival of daf-16 rates in after C. elegans acute stress. Besides, through the oxidativethe regulation stress of resistance downstream promoted gene ofbydaf-16 pasteurizedin C. elegans orange. Besides,juice (POJ) the treatment oxidative in stress C. elegans resistance has beenpromoted reported by pasteurized as a result of orange the transcription juice (POJ) treatment factor SKN-1 in C. action elegans [18].has been reported as a result of the transcriptionNobiletin factor (5,6,7,8,3 SKN-1′,4′-hexamethoxyflavone, action [18]. NOB, Figure 1), one of polymethoxylated flavones (PMFs)Nobiletin extracted (5,6,7,8,3 exclusively0,40-hexamethoxyflavone, in citrus fruits, is abundant NOB, Figure in 1Citrus), one reticulate of polymethoxylated (mandarin oranges), flavones Citrus(PMFs) tangerine extracted (tangerines), exclusively Citrus in citrus sinensis fruits, (oranges), is abundant and in CitrusCitrus aurantium reticulate (grapefruits)(mandarin oranges), (Table 1)Citrus [19– 21],tangerine and as(tangerines), reported, CitrusCitrus tangerine sinensis (oranges), contains the and highestCitrus aurantiumthe content(grapefruits) of NOB. After (Table undergoing1)[ 19–21], metabolismand as reported, or autohydrolysis,Citrus tangerine containsmany different the highest derivatives the content will of be NOB. generated, After undergoing the most common metabolism of whichor autohydrolysis, are the following many difour:fferent 3′-demethylnobiletin derivatives will be (3 generated,′-DMN), 4 the′-DMN, most common3′,4′-DMN, of whichand 5–DMN are the (Figurefollowing 1) four:[22–24]. 30-demethylnobiletin Recently, NOB has (3 become0-DMN), a 4hots0-DMN,pot as 30 ,4one0-DMN, of candidates and 5–DMN for the (Figure prevention1)[ 22–24 of]. Alzheimer’sRecently, NOB disease has become (AD), a hotspotwhich asis onea chronic of candidates and fordevastating the prevention
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