Age-Related Surface Oxidases Shed into Body Fluids as Targets to Prevent Skin Aging and Reduce Cardiovascular Risk


Age-related Ecto-Nicotinamide Adenine Dinucleotide Oxidase Disulfide Thiol Exchangers 3 (ENOX3) or age-related NADH oxidases (arNOX) are expressed at the cell surface as five members of the TM-9 superfamily, initially membrane anchored, all functionally similar, with the N-termini exposed at the cell’s exterior. ECTO-NOXes are cell surface proteins with both time-keeping CoQH2 [NAD(P)H] oxidase and protein disulfidethiol interchange activities. They are designated as ECTO-NOX proteins because of their localization on the outer surface of the plasma membrane and to distinguish them from the phox-NOXes of host defense. A ca. 30 kDa N-terminal fragment is cleaved and accumulates in body fluids (serum, saliva, urine, perspiration). arNOXes appear around age 30 and increase steadily thereafter. Reduced quinones, i.e., reduced coenzyme Q, of the plasma membrane are natural substrates. NAD(P)H is oxidized as an artificial substrate. In one phase of the arNOX cycle electrons are transferred to oxygen to generate superoxide. Substrates for the shed forms of arNOX appear to be proteins of body fluids. Circulating lipoproteins and skin matrix proteins emerge as potentially important health-related targets. Through oxidation of collagen, elastin and other proteins of the skin matrix, arNOXes are major contributors to skin aging through tyrosine and thiol oxidation and subsequent cross linking. The main destructive action of arNOX, however, may be to directly oxidize circulating lipoproteins. arNOX in the blood is structured as an integral component of the LDL particle through site-specific binding. As such, arNOXes are implicated as major risk factors for cardiovascular disease due to specific oxidation of LDLs. The superoxide produced and its conversion to hydrogen peroxide would be one part of the potentially destructive properties by contribution to lipid oxidation. Inhibition of arNOX proteins provides a rational basis for anti-aging interventions and their elimination as a major risk factor of atherogenesis.

Share and Cite:

Morré, D. , Kern, D. , Meadows, C. , Knaggs, H. and Morré, D. (2014) Age-Related Surface Oxidases Shed into Body Fluids as Targets to Prevent Skin Aging and Reduce Cardiovascular Risk. World Journal of Cardiovascular Diseases, 4, 119-129. doi: 10.4236/wjcd.2014.43018.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Morré, D.J. and Morré, D.M. (2003) Cell Surface NADH Oxidases (ECTO-NOX proteins) with Roles in Cancer, Cellular Time-Keeping, Growth, Aging and Neurodegenerative Disease. Free Radical Research, 37, 795-808.
[2] Morré, D.M., Lenaz, G. and Morré, D.J. (2000) Surface Oxidize and Oxidative Stress Propagation in Aging. The Journal of Experimental Biology, 203, 1513-1521.
[3] Morré, D.J. and Morré, D.M. (2008) arNOX Activity of Saliva as a Non-Invasive Measure of Coenzyme Q10 Response in Human Trials. BioFactors, 32, 231-235.
[4] Morré, D.M, Meadows, C., Hostetler, B., Weston, N., Kern, D., Draelos, Z. and Morré, D. J. (2009) Age-Related ENOX Protein (arNOX) Activity Correlated with Oxidative Skin Damage in the Elderly. BioFactors, 34, 237-244.
[5] Morré, D.M., Meadows, C. and Morré, D.J. (2010) arNOX: Generator of Reactive Oxygen Species in the Skin and Sera of Aging Individuals Subject to External Modulation. Rejuvenation Research, 13, 162-164.
[6] Schmuck, A., Fuller, C. J., Devaraj, S. and Jialal, I. (1995) Effect of Aging on Susceptibility of Low-Density Lipoproteins to Oxidation. Clinical Chemistry, 41, 1628-1632.
[7] Morré, D.J. (2004) Quinone Oxidoreductases of the Plasma Membrane. Methods in Enzymology, 378A, 179-199.
[8] Morré, D.J. and Morré, D.M. (2013) ECTO-NOX Proteins. Springer, New York.
[9] Morré, D.J. and Morré, D.M. (2006) Aging-Related Cell Surface ECTO-NOX Protein, arNOX, a Preventive Target to Reduce Atherogenic Risk in the Elderly. Rejuvenation Research, 9, 231-236.
[10] Butler, J., Koppeol, W.H. and Margoliash, E. (1982) Kinetics and Mechanism of the Reduction of Ferricytochrome c by the Superoxide Anion. Journal of Biological Chemistry, 257, 10747-10750.
[11] Smith, J.B., Ingerman, C.M. and Silver, M.J. (1976) Malondialdehyde Formation as an Indicator of Prostaglandin Production by Human Platelets. Journal of Laboratory and Clinical Medicine, 88, 167-172.
[12] Tang, X., Parisi, D., Spicer, B., Morré, D.M. and Morré, D.J.(2013) Molecular Cloning and Characterization of Human Age-Related NADH Oxidase (arNOX) Proteins as Member of the TM-9 Super-family of Transmembrane Proteins. Adcances in Biological Chemistry, 3, 187-197.
[13] Kern, D.G., Draelos, Z.D., Meadows, C., Morré, D.J. and Morré, D.M. (2010) Controlling Reactive Oxygen Species in Skin at Their Source to Reduce Skin Aging. Rejuvenation Research, 13, 165-167.
[14] Rehmus, W.E., Kern, D., Janjua, R., Morré, D.M., Morré, D.J. and Knaggs, H. (2008) Appearance of Skin Ageing in Healthy Women. Correlation with arNOX Levels: A Potential New Mechanism in Ageing? Clinical Dermatology, Retinoids: Other Treatments, 24, 52-56.
[15] Reznick, A.Z. and Packer, L. (1994) Oxidative Damage to Proteins: Spectrophotometric Method for Carbonyl Assay. Methods in Enzymology, 233, 357-363.
[16] Terada, T., Takada, K., Yamanishi, H. and Ashida, Y. (2007) Inhibitory Effects of Coenzyme Q10 on Skin Aging. Abstracts. 5th Conference of the International Coenzyme Q10 Association, Kobe, 156.
[17] Knaggs, H. (2009) The arNOX Enzyme: Implications for Intrinsic Aging. Cosmetics and Toiletries, 124, 48-52.
[18] Holvoet, P. (1999) Endothelial Dysfunction, Oxidation of Low-Density Lipo-Protein, and Cardiovascular Disease. Therapeutic Apheresis and Dialysis, 3, 287-293.
[19] Bjelakovic, G., Nikolova, D., Gluud, L.L., Simonetti, R.G. and Gluud, C. (2007) Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention: Systematic Review and Meta-Analysis. JAMA, 297, 842-857.
[20] American Heart Association Statisitcal Update (2008) Heart Disease and Stroke Statistics-2008. Circulation, 117, e25-e146.
[21] Kannel, W.B. and Lavine, B.S. (2003) Coronary Heart Disease Risk in People 65 Years of Age and Older. Progress in Cardiovascular Nursing, 18, 135-140.
[22] Ferguson, E., Singh, R.J., Hagg, N. and Kalyanaraman, B. (1997) The mechanism of Apolipoprotein B-100 Thiol Depletion during Oxidative Modification of Low-Density Lipoprotein. Archives of Biochemistry and Biophysics, 341, 287-294.
[23] Gillotte, K.L., Hörkkö, S. Witztum, J.L. and Steinberg, D. (2001) Oxidized Phospholipids, Linked to Apolipoprotein B of Oxidized LDL, Are Ligands for Macrophage Scavenger Receptors. Journal of Lipid Research, 41, 824-833.
[24] Morré, D.M. and Morré, D.J. (2006) Coenzyme Q and Lipid Oxidation in Aging and Cardiovascular Disease. Absracts, 41st Annual South Eastern Regional Lipid Conference, Cashiers, 1-3 November 2006, 68.
[25] Nohl, H., Kozlov, V., Staniek, K. and Gille, L. (2001) The Multiple Functions of Coenzyme Q. Bioorganic Chemistry, 29, 1-13.
[26] Nohl, H., Gille, L. and Staniek, K. (2005) Intracellular Generation of Reactive Oxygen Species by Mitochondria. Biochemical Pharmacology, 69, 719-723.
[27] St. Pierre, J., Buckingham, J., Roebuck, S.J. and Brand, M.D. (2002) Topology of Superoxide Production from Different Sites in the Mitochondrial Electron Transport chain. Journal of Biological Chemistry, 277, 44784-44790.
[28] Morré, D.J., Morré, D.M. and Shelton, T.B. (2010) Aging-Related Nicotinamide Adenine Dinucleotide Oxidase Response to Dietary Supplementation: The French Paradox Revisited. Rejuvenation Research, 13, 159-161.
[29] Teissedre, P.L. and Waterhouse, A.L. (2000) Inhibition of Oxidation of Human Low-Density Lipoproteins by Phenolic Substances in Different Essential Oil Varieties. Journal of Agricultural and Food Chemistry, 48, 3801-3805.
[30] Walle, T., Hsieh, F., DeLegge, M.H., Oatis, Jr., J.E. and Walle, U.K. (2004) High Absorption But Very Low Bioavailability of Oral Resveratrol in Humans. Drug Metabolism and Disposition, 32, 1377-1382.
[31] Vitaglione, P., Sforza, S., Galaverna, G., Ghidini, C., Caporaso, N., Vescovi, P.P., Fogliano, V. and Marchelli, R. (2005) Bioavailability of Trans-Resveratrol from Red Wine in Humans. Molecular Nutrition & Food Research, 49, 495-504.

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.