Abstract
Terpenes and their derivatives have been used conventionally as potential dietary supplements to boost the nutritional value of endless food products. Several plant-based complex terpenoid and their derivatives have been reported for a wide range of medicinal and nutritional properties. However, their simple counterparts, whose production is relatively easy, sustainable, and economic from food-grade microbial sources, have not been studied yet for any such biological activities. The present study aimed to investigate the longevity-promoting property and neuromodulatory effects of 3,3-dimethylallyl alcohol (Prenol), one of the simplest forms of terpenoid and a constituent of fruit aroma, in the animal model Caenorhabditis elegans. Prenol supplementation (0.25 mM) augmented the lifespan of wild-type nematodes by 22.8% over the non-treated worms. Moreover, a suspended amyloid-β induced paralysis and reduced α-synuclein aggregation were observed in Prenol-treated worms. The lifespan extending properties of Prenol were correlated with ameliorated physiological parameters and increased stress (heat and oxidative) tolerance in C. elegans. In silico and gene-specific mutant studies showed that pro-longevity transcription factors DAF-16, HSF-1, and SKN-1 were involved in the improved lifespan and health-span of Prenol-treated worms. Transgenic green fluorescent protein-reporter gene expression analysis and relative mRNA quantification (using real-time PCR) demonstrated an increase in the expression of DAF-16, HSF-1, and SKN-1 transcription factors and their downstream target genes in Prenol-treated worms. Together, the findings suggest that small molecules, like Prenol, could be explored as a potential alternate to develop therapeutics against aging and age-related ailments.
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Abbreviations
- AD:
-
Alzheimer’s disease
- Aβ:
-
Amyloid-β
- BCP:
-
β-caryophyllene
- BLAST:
-
Basic local alignment search tool
- CI :
-
Chemotaxis index
- DR:
-
Dietary restriction
- FOXO:
-
Forkhead box protein O
- FUdR:
-
2′-Deoxy-5-fluorouridine
- GFP:
-
Green fluorescent protein
- GRAS:
-
Generally regarded as safe
- H2DCF-DA:
-
7-dichlorodihydrofluoresceindiacetate
- IIS:
-
Insulin/insulin like signaling
- NDs:
-
Neurodegenerative disorders
- NGM:
-
Nematode Growth Medium
- PD:
-
Parkinson’s disease
- ROS:
-
Reactive oxygen species
- TFs:
-
Transcription factors
- YFP:
-
Yellow fluorescent protein
- αS:
-
α-Synuclein
References
Ahmad W, Ebert PR. Metformin attenuates Aβ pathology mediated through levamisole sensitive nicotinic acetylcholine receptors in a C. elegans model of Alzheimer’s disease. Mol Neurobiol. 2017;54:5427–39. https://doi.org/10.1007/s12035-016-0085-y.
Asthana J, Yadav AK, Pant A, Pandey S, Gupta MM, Pandey R. Specioside ameliorates oxidative stress and promotes longevity in Caenorhabditis elegans. Comp Biochem Physiol Part - C Toxicol Pharmacol. 2015;169:25–34. https://doi.org/10.1016/j.cbpc.2015.01.002.
Bargmann CI (1998) Neurobiology of the Caenorhabditis elegans genome. Science (80- ) 282:2028–2033.
Bargmann CI, Hartwieg E, Horvitz HR. Odorant-selective genes and neurons mediate olfaction in C. elegans. Cell. 1993;74:515–27. https://doi.org/10.1016/0092-8674(93)80053-H.
Blackwell TK, Steinbaugh MJ, Hourihan JM, Ewald CY, Isik M. SKN-1/Nrf, stress responses, and aging in <i>Caenorhabditis elegans<i>. Free Radic Biol Med. 2015;88:290–301.
Bodhicharla R, Nagarajan A, Winter J, Adenle A, Nazir A, Brady D, et al. Effects of α-synuclein overexpression in transgenic Caenorhabditis elegans strains. CNS Neurol Disord Drug Targets. 2012;11:965–75. https://doi.org/10.2174/1871527311211080005.
Brown MK, Evans JL, Luo Y. Beneficial effects of natural antioxidants EGCG and α-lipoic acid on life span and age-dependent behavioral declines in Caenorhabditis elegans. Pharmacol Biochem Behav. 2006;85:620–8. https://doi.org/10.1016/j.pbb.2006.10.017.
Brunquell J, Morris S, Lu Y, Cheng F, Westerheide SD. The genome-wide role of HSF-1 in the regulation of gene expression in Caenorhabditis elegans. BMC Genomics. 2016;17:559. https://doi.org/10.1186/s12864-016-2837-5.
Chalorak P, Jattujan P, Nobsathian S, Poomtong T, Sobhon P, Meemon K. Holothuria scabra extracts exhibit anti-Parkinson potential in C. elegans: a model for anti-Parkinson testing. Nutr Neurosci. 2017;8305:1–12. https://doi.org/10.1080/1028415X.2017.1299437.
Cohen E, Bieschke J, Perciavalle RM, et al (2006) Opposing activities protect against age-onset Proteotoxicitye. Science (80- ) 313:1604–1610.
Dues DJ, Schaar CE, Johnson BK, et al (2017) Uncoupling of oxidative stress resistance and lifespan in long-lived isp-1 mitochondrial mutants in Caenorhabditis elegans. Elsevier B.V.
Edwards C, Canfield J, Copes N, et al. D-beta-hydroxybutyrate extends lifespan in C. elegans. Aging (Albany NY). 2014;6:621–44. https://doi.org/10.18632/aging.100683.
Feng S, Cheng H, Xu Z, Yuan M, Huang Y, Liao J, et al. Panax notoginseng polysaccharide increases stress resistance and extends lifespan in Caenorhabditis elegans. J Funct Foods. 2018;45:15–23. https://doi.org/10.1016/j.jff.2018.03.034.
George KW, Thompson MG, Kang A, et al. Metabolic engineering for the high-yield production of isoprenoid-based C 5 alcohols in E . coli. Sci Rep. 2015;5:11128. https://doi.org/10.1038/srep11128.
Govindan S, Amirthalingam M, Duraisamy K, Govindhan T, Sundararaj N, Palanisamy S. Phytochemicals-induced hormesis protects Caenorhabditis elegans against α-synuclein protein aggregation and stress through modulating HSF-1 and SKN-1/Nrf2 signaling pathways. Biomed Pharmacother. 2018;102:812–22. https://doi.org/10.1016/j.biopha.2018.03.128.
Gruber J, Soon YT, Halliwell B. Evidence for a trade-off between survival and fitness caused by resveratrol treatment of Caenorhabditis elegans. Ann N Y Acad Sci. 2007;1100:530–42. https://doi.org/10.1196/annals.1395.059.
Gulia KK, Kumar VM. Sleep disorders in the elderly: a growing challenge. Psychogeriatrics. 2018;18:155–65. https://doi.org/10.1111/psyg.12319.
He L, Mo H, Hadisusilo S, Qureshi AA, Elson CE. Isoprenoids suppress the growth of murine B16 melanomas in-vitro and in-vivo. J Nutr. 1997;127:668–74.
Honda Y, Tanaka M, Honda S. Modulation of longevity and diapause by redox regulation mechanisms under the insulin-like signaling control in Caenorhabditis elegans. Exp Gerontol. 2008;43:520–9. https://doi.org/10.1016/j.exger.2008.02.009.
Hwang O. Role of oxidative stress in Parkinson’s disease. Exp Neurobiol. 2013;22:11–7. https://doi.org/10.5607/en.2013.22.1.11.
Ishii N, Fujii M, Hartman PS, Tsuda M, Yasuda K, Senoo-Matsuda N, et al. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature. 1998;394:694–7. https://doi.org/10.1038/29331.
Ishii T, Miyazawa M, Hartman PS, Ishii N. Mitochondrial superoxide anion (O2•-) inducible “mev-1” animal models for aging research. BMB Rep. 2011;44:298–305. https://doi.org/10.5483/BMBRep.2011.44.5.298.
Jimbo D, Kimura Y, Taniguchi M, et al. Effect of aromatherapy on patients with Alzheimer’s disease. Psychogeriatrics. 2009;9:173–9. https://doi.org/10.1111/j.1479-8301.2009.00299.x.
Kenyon CJ. The genetics of ageing. Nature. 2010;464:504–12. https://doi.org/10.1038/nature08980.
Lasekan O. Identification of the aroma compounds in Vitex doniana sweet: free and bound odorants. Chem Cent J. 2017;11:19. https://doi.org/10.1186/s13065-017-0247-7.
Li J, Chotiko A, Chouljenko A, Gao C, Zheng J, Sathivel S (2018) Delivery of alpha-tocopherol through soluble dietary fibre-based nanofibres for improving the life span of Caenorhabditis elegans. Int J Food Sci Nutr 0:1–10. https://doi.org/10.1080/09637486.2018.1489785, 70.
Link CD. Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans. Proc Natl Acad Sci U S A. 1995;92:9368–72. https://doi.org/10.1073/PNAS.92.20.9368.
Link CD, Taft A, Kapulkin V, et al. Gene expression analysis in a transgenic Caenorhabditis elegans Alzheimer’s disease model. Neurobiol Aging. 2003;24:397–413. https://doi.org/10.1016/S0197-4580(02)00224-5.
Liu J, Banskota AH, Critchley AT, Hafting J, Prithiviraj B. Neuroprotective effects of the cultivated Chondrus crispus in a C. elegans model of Parkinson’s disease. Mar Drugs. 2015;13:2250–66. https://doi.org/10.3390/md13042250.
Ma X, Cui X, Li J, Li C, Wang Z. Peptides from sesame cake reduce oxidative stress and amyloid-β-induced toxicity by upregulation of SKN-1 in a transgenic Caenorhabditis elegans model of Alzheimer’s disease. J Funct Foods. 2017;39:287–9. https://doi.org/10.1016/j.jff.2017.10.032.
Mo H, Elson CE. Apoptosis and cell-cycle arrest in human and murine tumor cells are initiated by isoprenoids. J Nutr. 1999;129:804–13. https://doi.org/10.1093/jn/129.4.804.
Negi H, Shukla A, Khan F, Pandey R. 3β-Hydroxy-urs-12-en-28-oic acid prolongs lifespan in C. elegans by modulating JNK-1. Biochem Biophys Res Commun. 2016;480:539–43.
Pandey S, Tiwari S, Kumar A, Niranjan A, Chand J, Lehri A, et al. Antioxidant and anti-aging potential of Juniper berry (Juniperus communis L.) essential oil in Caenorhabditis elegans model system. Ind Crop Prod. 2018;120:113–22. https://doi.org/10.1016/j.indcrop.2018.04.066.
Pandey S, Phulara SC, Jha A, Chauhan PS, Gupta P, Shukla V. 3-Methyl-3-buten-1-ol (isoprenol) confers longevity and stress tolerance in Caenorhabditis elegans 3-methyl-3-buten-1-ol (isoprenol) confers longevity and stress tolerance in Caenorhabditis elegans. Int J Food Sci Nutr. 2019a;70:595–602. https://doi.org/10.1080/09637486.2018.1554031.
Pandey S, Phulara SC, Mishra SK, Bajpai R, Kumar A, Niranjan A, et al. Betula utilis extract prolongs life expectancy, protects against amyloid-β toxicity and reduces Alpha Synuclien in Caenorhabditis elegans via DAF-16 and SKN-1. Comp Biochem Physiol Part C Toxicol Pharmacol. 2019b;228:108647. https://doi.org/10.1016/J.CBPC.2019.108647.
Pant A, Saikia SK, Shukla V, et al. Beta-caryophyllene modulates expression of stress response genes and mediates longevity in Caenorhabditis elegans. Exp Gerontol. 2014;57:81–95. https://doi.org/10.1016/j.exger.2014.05.007.
Phulara SC, Shukla V, Tiwari S, Pandey R. Bacopa monnieri promotes longevity in Caenorhabditis elegans under stress conditions. Pharmacogn Mag. 2015;11:410–6. https://doi.org/10.4103/0973-1296.153097.
Phulara SC, Chaturvedi P, Gupta P. Isoprenoid-based biofuels: homologous expression and heterologous expression in prokaryotes. Appl Environ Microbiol. 2016;82:5730–40. https://doi.org/10.1128/AEM.01192-16.
Phulara SC, Chaturvedi P, Chaurasia D, Diwan B, Gupta P. Modulation of culture medium confers high-specificity production of isopentenol in Bacillus subtilis. J Biosci Bioeng. 2018a;127:458–64. https://doi.org/10.1016/j.jbiosc.2018.10.002.
Phulara SC, Chaurasia D, Diwan B, Chaturvedi P, Gupta P. In-situ isopentenol production from Bacillus subtilis through genetic and culture condition modulation. Process Biochem. 2018b;72:47–54. https://doi.org/10.1016/j.procbio.2018.06.019.
Powolny AA, Singh SV, Melov S, Hubbard A, Fisher AL. The garlic constituent diallyl trisulfide increases the lifespan of C. elegans via skn-1 activation. Exp Gerontol. 2011;46:441–52. https://doi.org/10.1016/j.exger.2011.01.005.
Rathor L, Pant A, Awasthi H, Mani D, Pandey R. An antidiabetic polyherbal phytomedicine confers stress resistance and extends lifespan in Caenorhabditis elegans. Biogerontology. 2017;18:131–47. https://doi.org/10.1007/s10522-016-9668-2.
Rizki G, Picard CL, Pereyra C, Lee SS. Host cell factor 1 inhibits SKN-1 to modulate oxidative stress responses in Caenorhabditis elegans. Aging Cell. 2012;11:717–21. https://doi.org/10.1111/j.1474-9726.2012.00831.x.
Roullet JB, Luft UC, Xue H, Chapman J, Bychkov R, Roullet CM, et al. Farnesol inhibits L-type Ca2+ channels in vascular smooth muscle cells. J Biol Chem. 1997;272:32240–6. https://doi.org/10.1074/JBC.272.51.32240.
Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative CT method. Nat Protoc. 2008;3:1101–8. https://doi.org/10.1038/nprot.2008.73.
Senchuk MM, Dues DJ, Van Raamsdonk JM (2017) Measuring oxidative stress in Caenorhabditis elegans: Paraquat and Juglone sensitivity assays. Bio-protocol 7: https://doi.org/10.21769/BIOPROTOC.2086
Shukla V, Phulara SC, Yadav D, Tiwari S, Kaur S, Gupta MM, et al. Iridoid compound 10-O-trans-p-coumaroylcatalpol extends longevity and reduces α synuclein aggregation in Caenorhabditis elegans. CNS Neurol Disord Drug Targets. 2012a;11:984–92.
Shukla V, Yadav D, Phulara SC, Gupta MM, Saikia SK, Pandey R. Longevity-promoting effects of 4-hydroxy-E-globularinin in Caenorhabditis elegans. Free Radic Biol Med. 2012b;53:1848–56. https://doi.org/10.1016/j.freeradbiomed.2012.08.594.
Szeto WY, Yang L, Wong RCP, Li YC, Wong SC. Spatio-temporal travel characteristics of the elderly in an ageing society. Travel Behav Soc. 2017;9:10–20. https://doi.org/10.1016/j.tbs.2017.07.005.
Tiwari S, Lata C, Chauhan PS, Nautiyal CS. Pseudomonas putida attunes morphophysiological, biochemical and molecular responses in Cicer arietinum L. during drought stress and recovery. Plant Physiol Biochem. 2016;99:108–17. https://doi.org/10.1016/j.plaphy.2015.11.001.
Trojanowski NF, Raizen DM, Fang-Yen C. Pharyngeal pumping in Caenorhabditis elegans depends on tonic and phasic signaling from the nervous system. Sci Rep. 2016;6:22940. https://doi.org/10.1038/srep22940.
Tullet JMA, Hertweck M, An JH, Baker J, Hwang JY, Liu S, et al. Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell. 2008;132:1025–38. https://doi.org/10.1016/j.cell.2008.01.030.
United Nations, Department of Economic and Social Affairs PD (2019) World Population Ageing 2019: Highlights (ST/ESA/SER.A/430).
van Ham TJ, Thijssen KL, Breitling R, Hofstra RMW, Plasterk RHA, Nollen EAA. C. elegans model identifies genetic modifiers of α-synuclein inclusion formation during aging. PLoS Genet. 2008;4:e1000027. https://doi.org/10.1371/journal.pgen.1000027.
Wei CC, Chang CH, Liao VHC. Anti-Parkinsonian effects of β-amyrin are regulated via LGG-1 involved autophagy pathway in Caenorhabditis elegans. Phytomedicine. 2017;36:118–25.
Wilson MA, Shukitt-Hale B, Kalt W, Ingram DK, Joseph JA, Wolkow CA. Blueberry polyphenols increase lifespan and thermotolerance in Caenorhabditis elegans. Aging Cell. 2006;5:59–68. https://doi.org/10.1111/j.1474-9726.2006.00192.x.
World Health Organization (2016) Global Health Observatory (GHO) Data.
Wu Y, Wu Z, Butko P, Christen Y, Lambert MP, Klein WL, et al. Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J Neurosci. 2006;26:13102–13. https://doi.org/10.1523/JNEUROSCI.3448-06.2006.
Zhang J, Shi R, Li H, Xiang Y, Xiao L, Hu M, et al. Antioxidant and neuroprotective effects of Dictyophora indusiata polysaccharide in Caenorhabditis elegans. J Ethnopharmacol. 2016;192:413–22. https://doi.org/10.1016/j.jep.2016.09.031.
Zhi D, Wang D, Yang W, et al. Dianxianning improved amyloid β-induced pathological characteristics partially through DAF-2/DAF-16 insulin like pathway in transgenic C. elegans. Sci Rep. 2017;7:11408. https://doi.org/10.1038/s41598-017-11628-9.
Acknowledgments
The authors are grateful to the Caenorhabditis elegans Genetics Center (Minneapolis, MN, USA) for providing nematode strains. Authors also heartily acknowledge Director, CSIR-National Botanical Research Institute, Lucknow, Uttar Pradesh, India and Director, National Institute of Technology, Raipur, Chhattisgahr, India for their kind support. Authors also show their sincere gratitude to Ms. Neetu Phulara, Child Development Project Officer, Uttarakhand Govetment, Chakrata, Dehradun, Uttarakhand, India for critically reading the manuscript and providing grammar check.
Funding
SP was financially supported by Indian Council of Medical Research (ICMR), New Delhi, India (Grant Id- 45/11/2018-PHA/BMS/OL) through Senior Research Fellowship grant.
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SCP, SP, and VS conceived, designed, and performed in vivo and in vitro experiments; AJ performed in silico analysis; SCP, SP, and VS analyzed the data; PG and PSC contributed reagents/materials/analysis tools; SCP, SP, and AJ wrote the manuscript. PSC, VS, and PG critically reviewed and edited the manuscript. All authors have critically gone through the manuscript and approved it.
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Phulara, S.C., Pandey, S., Jha, A. et al. Hemiterpene compound, 3,3-dimethylallyl alcohol promotes longevity and neuroprotection in Caenorhabditis elegans. GeroScience 43, 791–807 (2021). https://doi.org/10.1007/s11357-020-00241-w
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DOI: https://doi.org/10.1007/s11357-020-00241-w