Isotschimgine Promotes Lifespan, Healthspan and Neuroprotection of Caenorhabditis Elegans Via the Activation of Nuclear Hormone Receptors

Overview

Journal Biogerontology

Specialty Geriatrics

Date 2024 Oct 29

PMID 39470855

Authors

Hang Shi

Xiaoyan Gao

Jing Yu

Lijun Zhang

Bingbing Fan

Ying Liu

Xinyi Wang

Shengjie Fan

Cheng Huang

Affiliations

Soon will be listed here.

Abstract

Isotschimgine (ITG) is a bornane-type monoterpenoid derivative naturally occurring in genus Ferula plants and propolis. Its effects on aging and the underlying mechanisms are not yet well understood. This study employed Caenorhabditis elegans (C. elegans) as a model organism to evaluate the potential of ITG in extending lifespan, enhancing healthspan, and promoting neuroprotection, while exploring the underlying mechanisms involved. The results showed that ITG extended the lifespan and healthspan of C. elegans, significantly enhanced stress resistance and detoxification functions. Studies on mutants and qPCR data indicated that ITG-mediated lifespan extension was modulated by the insulin/IGF-1 signaling pathway and nuclear hormone receptors. Furthermore, ITG markedly increased stress-responsive genes, including daf-16 and its downstream genes sod-3 and hsp-16.2, as well as NHR downstream detoxification-related genes cyp35a1, cyp35b3, cyp35c1, gst-4, pgp-3 and pgp-13. Additionally, ITG alleviated β-amyloid-induced paralysis and behavioral dysfunction in transgenic C. elegans strains. The neuroprotective efficacy of ITG was weakened by RNAi knockdown of nuclear hormone receptors daf-12 and nhr-8. Overall, our study identifies ITG as a potential compound for promoting longevity and neuroprotection, mediated through nuclear hormone receptors.

References

Antebi A . Nuclear receptor signal transduction in C. elegans. WormBook. 2015; :1-49. PMC: 5402207. DOI: 10.1895/wormbook.1.64.2. View

Banerjee A, Khemka V, Ganguly A, Roy D, Ganguly U, Chakrabarti S . Vitamin D and Alzheimer's Disease: Neurocognition to Therapeutics. Int J Alzheimers Dis. 2015; 2015:192747. PMC: 4553343. DOI: 10.1155/2015/192747. View

Bazzari F, Abdallah D, El-Abhar H . Chenodeoxycholic Acid Ameliorates AlCl-Induced Alzheimer's Disease Neurotoxicity and Cognitive Deterioration via Enhanced Insulin Signaling in Rats. Molecules. 2019; 24(10). PMC: 6571973. DOI: 10.3390/molecules24101992. View

Biglou S, Bendena W, Chin-Sang I . An overview of the insulin signaling pathway in model organisms Drosophila melanogaster and Caenorhabditis elegans. Peptides. 2021; 145:170640. DOI: 10.1016/j.peptides.2021.170640. View

Castellani R, Plascencia-Villa G, Perry G . The amyloid cascade and Alzheimer's disease therapeutics: theory versus observation. Lab Invest. 2019; 99(7):958-970. DOI: 10.1038/s41374-019-0231-z. View

Chamoli M, Singh A, Malik Y, Mukhopadhyay A . A novel kinase regulates dietary restriction-mediated longevity in Caenorhabditis elegans. Aging Cell. 2014; 13(4):641-55. PMC: 4326946. DOI: 10.1111/acel.12218. View

Collins J, Evason K, Kornfeld K . Pharmacology of delayed aging and extended lifespan of Caenorhabditis elegans. Exp Gerontol. 2006; 41(10):1032-9. DOI: 10.1016/j.exger.2006.06.038. View

Daujat-Chavanieu M, Gerbal-Chaloin S . Regulation of CAR and PXR Expression in Health and Disease. Cells. 2020; 9(11). PMC: 7692647. DOI: 10.3390/cells9112395. View

Fan S, Yan Y, Xia Y, Zhou Z, Luo L, Zhu M . Pregnane X receptor agonist nomilin extends lifespan and healthspan in preclinical models through detoxification functions. Nat Commun. 2023; 14(1):3368. PMC: 10250385. DOI: 10.1038/s41467-023-39118-9. View

10.

Fontana L, Partridge L, Longo V . Extending healthy life span--from yeast to humans. Science. 2010; 328(5976):321-6. PMC: 3607354. DOI: 10.1126/science.1172539. View

11.

Friedman D, Johnson T . A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics. 1988; 118(1):75-86. PMC: 1203268. DOI: 10.1093/genetics/118.1.75. View

12.

Gao X, Yu J, Zhang L, Shi H, Yan Y, Han Y . Mulberrin extends lifespan in Caenorhabditis elegans through detoxification function. J Appl Toxicol. 2024; 44(6):833-845. DOI: 10.1002/jat.4578. View

13.

Hardy J, Higgins G . Alzheimer's disease: the amyloid cascade hypothesis. Science. 1992; 256(5054):184-5. DOI: 10.1126/science.1566067. View

14.

Hayes P, Bouchier I, Beckett G . Glutathione S-transferase in humans in health and disease. Gut. 1991; 32(7):813-8. PMC: 1379001. DOI: 10.1136/gut.32.7.813. View

15.

Herndon L, Schmeissner P, Dudaronek J, Brown P, Listner K, Sakano Y . Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans. Nature. 2002; 419(6909):808-14. DOI: 10.1038/nature01135. View

16.

Hibshman J, Webster A, Baugh L . Liquid-culture protocols for synchronous starvation, growth, dauer formation, and dietary restriction of . STAR Protoc. 2021; 2(1):100276. PMC: 7811050. DOI: 10.1016/j.xpro.2020.100276. View

17.

Hobert O . Behavioral plasticity in C. elegans: paradigms, circuits, genes. J Neurobiol. 2002; 54(1):203-23. DOI: 10.1002/neu.10168. View

18.

Hoffmann J, Partridge L . Nuclear hormone receptors: Roles of xenobiotic detoxification and sterol homeostasis in healthy aging. Crit Rev Biochem Mol Biol. 2015; 50(5):380-92. DOI: 10.3109/10409238.2015.1067186. View

19.

Hou Y, Dan X, Babbar M, Wei Y, Hasselbalch S, Croteau D . Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol. 2019; 15(10):565-581. DOI: 10.1038/s41582-019-0244-7. View

20.

Huang C, Wang J, Hu W, Wang C, Lu X, Tong L . Identification of functional farnesoid X receptors in brain neurons. FEBS Lett. 2016; 590(18):3233-42. DOI: 10.1002/1873-3468.12373. View