Ezetimibe increases resistance to oxidative stress and extends lifespan mimicking dietary restriction in Caenorhabditis elegans

Authors

DOI:

https://doi.org/10.14393/BJ-v39n0a2023-65305

Keywords:

Caenorhabditis elegans, Ezetimibe, Dietary Restriction, Lifespan, Stress Response.

Abstract

Ezetimibe is an approved drug for lowering plasma LDL (low-density lipoprotein) level via inhibition of cholesterol absorption. Derivatives of ezetimibe reduce inflammatory response and oxidative stress. In the present study, we investigated the effect of dietary supplementation with ezetimibe in response to environmental stressors and found that ezetimibe increases resistance to oxidative stress and ultraviolet irradiation. Ezetimibe also significantly extended lifespan accompanying reduced fertility, which is a common trade-off for longevity in C. elegans. Cellular level of reactive oxygen species was increased and the expression of stress-responsive genes, hsp-16.2 and sod-3, was induced by dietary supplementation with ezetimibe, suggesting a hormetic effect on oxidative stress response and lifespan. Ezetimibe also significantly prevented amyloid beta-induced toxicity and completely reversed increased mortality by high-glucose diet. Nuclear localization of DAF-16 required for the prevention of amyloid beta-induced toxicity was enhanced by ezetimibe supplementation. Lifespan assay using known long-lived mutants, age-1, clk-1, and eat-2, revealed that lifespan extension by ezetimibe specifically overlapped with that of eat-2 mutants, which are genetic models of dietary restriction. Effect of ezetimibe on lifespan of worms fed with diluted bacteria suggested that ezetimibe mimics the effect of dietary restriction on lifespan. These findings suggest that ezetimibe exhibits anti-oxidative and anti-aging effects through hormesis and works as a dietary-restriction mimetic on lifespan extension.

Downloads

Download data is not yet available.

References

ANISIMOV, V.N. Metformin for aging and cancer prevention. Aging (Albany NY). 2010, 2(11), 760-774. https://doi.org/10.18632/aging.100230

AZAMI, S.H., et al. The antioxidant curcumin postpones ovarian aging in young and middle-aged mice. Reproduction, Fertility and Development. 2020, 32(3), 292-303. https://doi.org/10.1071/RD18472

BARGER, J.L., et al. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One. 2008, 3(6), e2264. https://doi.org/10.1371/journal.pone.0002264

CALABRESE, E.J., BALDWIN, L.A. and HOLLAND, C.D. Hormesis: a highly generalizable and reproducible phenomenon with important implications for risk assessment. Risk Analysis : an official publication of the Society for Risk Analysis. 1999, 19(2), 261-281. https://doi.org/10.1111/j.1539-6924.1999.tb00404.x

COHEN, E. and DILLIN, A. The insulin paradox: aging, proteotoxicity and neurodegeneration. Nature Reviews. Neuroscience. 2008, 9(10), 759-767. https://doi.org/10.1038/nrn2474

CYPSER, J.R., TEDESCO, P. and JOHNSON, T.E. Hormesis and aging in Caenorhabditis elegans. Experimental Gerontology. 2006, 41(10), 935-939. https://doi.org/10.1016/j.exger.2006.09.004

DHAHBI, J.M., et al. Identification of potential caloric restriction mimetics by microarray profiling. Physiological Genomics. 2005, 23(3), 343-350. https://doi.org/10.1152/physiolgenomics.00069.2005

ERNST, I.M., et al. Vitamin E supplementation and lifespan in model organisms. Ageing Research Reviews. 2013, 12(1), 365-375. https://doi.org/10.1016/j.arr.2012.10.002

FONTANA, L., PARTRIDGE, L. and LONGO, V.D. Extending healthy life span--from yeast to humans. Science. 2010, 328(5976), 321-326. https://doi.org/10.1126/science.1172539

FOSSEL, M. Telomerase and the aging cell: implications for human health. Journal of the American Medical Association. 1998, 279(21), 1732-1735. https://doi.org/10.1001/jama.279.21.1732

GRUBER, J., TANG, S.Y. and HALLIWELL, B. Evidence for a trade-off between survival and fitness caused by resveratrol treatment of Caenorhabditis elegans. Annals of the New York Academy of Sciences. 2007, 1100, 530-542. https://doi.org/10.1196/annals.1395.059

HARMAN, D. Aging: a theory based on free radical and radiation chemistry. Joural of Gerontology. 1956, 11(3), 298-300. https://doi.org/10.1093/geronj/11.3.298

HOWITZ, K.T., et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003, 425(6954), 191-196. https://doi.org/10.1038/nature01960

JOHNSON, T.E. Increased life-span of age-1 mutants in Caenorhabditis elegans and lower Gompertz rate of aging. Science. 1990, 249(4971), 908-912. https://doi.org/10.1126/science.2392681

KIRKWOOD, T.B. Evolution of ageing. Nature. 1977, 270(5635), 301-304. https://doi.org/10.1038/270301a0

LI, Y.M., et al. Green tea catechins upregulate superoxide dismutase and catalase in fruit flies. Molecular Nutrition and Food Research. 2007, 51(5), 546-554. https://doi.org/10.1002/mnfr.200600238

LONG, J., et al. Grape extract protects mitochondria from oxidative damage and improves locomotor dysfunction and extends lifespan in a Drosophila Parkinson's disease model. Rejuvenation Research. 2009, 12(5), 321-331. https://doi.org/10.1089/rej.2009.0877

MANCINI, E., et al. Green tea effects on cognition, mood and human brain function: A systematic review. Phytomedicine : International Journal of Phytotherapy and Phytopharmacology. 2017, 34, 26-37. https://doi.org/10.1016/j.phymed.2017.07.008

OH, S.I. and PARK, S.K. N-acetyl-L-cysteine mimics the effect of dietary restriction on lifespan and reduces amyloid beta-induced toxicity in Caenorhabditis elegans. Food Science and Biotechnology. 2017, 26(3), 783-790. https://doi.org/10.1007/s10068-017-0079-1

ONKEN, B. and DRISCOLL, M. Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1. PLoS One. 2010, 5(1), e8758. https://doi.org/10.1371/journal.pone.0008758

PATHATH, A.W. Theories of aging. The International Journal of Indian Psychology. 2017, 4(4), 15-22. https://doi.org/10.25215/0403.142

PEARSON, T.A., et al. A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the ezetimibe add-on to statin for effectiveness (EASE) trial. Mayo Clinic Proceedings. 2005, 80(5), 587-595. https://doi.org/10.4065/80.5.587

PENG, C., et al. Black tea theaflavins extend the lifespan of fruit flies. Experimental Gerontology. 2009, 44(12), 773-783. https://doi.org/10.1016/j.exger.2009.09.004

PETO, R. and PETO, J. Asymptotically efficient rank invariant test procedures. Journal of the Royal Statistical Society. Series A. 1972, 135(2), 185-207. https://doi.org/10.2307/2344317

RATTAN, S.I. Hormesis in aging. Ageing Research Reviews. 2008, 7(1), 63-78. https://doi.org/10.1016/j.arr.2007.03.002

ROBIDA-STUBBS, S., et al. TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metabolism. 2012, 15(5), 713-724. https://doi.org/10.1016/j.cmet.2012.04.007

SUDHOP, T., et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation. 2002, 106(15), 1943-1948. https://doi.org/10.1161/01.CIR.0000034044.95911.DC

TATAR, M., BARTKE, A. and ANTEBI, A. The endocrine regulation of aging by insulin-like signals. Science. 2003, 299(5611), 1346-1351. https://doi.org/10.1126/science.1081447

TROCHA, M., et al. Influence of ezetimibe on selected parameters of oxidative stress in rat liver subjected to ischemia/reperfusion. Archives of Medical Science. 2014, 10(4), 817-824. https://doi.org/10.5114/aoms.2013.38087

WOOD, J.G., et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004, 430(7000), 686-689. https://doi.org/10.1038/nature02789

Downloads

Published

2023-02-24

How to Cite

PARK, S., PARK, J.-S. and PARK, S.-K., 2023. Ezetimibe increases resistance to oxidative stress and extends lifespan mimicking dietary restriction in Caenorhabditis elegans. Bioscience Journal [online], vol. 39, pp. e39027. [Accessed21 April 2024]. DOI 10.14393/BJ-v39n0a2023-65305. Available from: https://seer.ufu.br/index.php/biosciencejournal/article/view/65305.

Issue

Section

Biological Sciences