Reaction of Carnosine with Aged Proteins

Another Protective Process?

Authors

  • ALAN R. HIPKISS,

    Corresponding author
    1. GKT School of Biomedical Sciences, King's College London, Guy's Campus, London Bridge, London SE1 1UL, United Kingdom
    • Address for correspondence: Alan Hipkiss, Henriette-Raphael House, GKT School of Biomedical Sciences, King's College London, Guy's Campus, London Bridge, London SE1 1UL, U.K. Voice: +44-(0)207-848-6071; +fax: 44-(0)207-848-6399; alan.hipkiss@kcl.ac.uk.

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  • CAROL BROWNSON,

    1. GKT School of Biomedical Sciences, King's College London, Guy's Campus, London Bridge, London SE1 1UL, United Kingdom
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  • MARIANA F. BERTANI,

    1. GKT School of Biomedical Sciences, King's College London, Guy's Campus, London Bridge, London SE1 1UL, United Kingdom
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  • EMILIO RUIZ,

    1. GKT School of Biomedical Sciences, King's College London, Guy's Campus, London Bridge, London SE1 1UL, United Kingdom
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  • ALBERT FERRO

    1. GKT School of Biomedical Sciences, King's College London, Guy's Campus, London Bridge, London SE1 1UL, United Kingdom
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Abstract

Cellular aging is often associated with an increase in protein carbonyl groups arising from oxidation- and glycation-related phenomena and suppressed proteasome activity. These “aged” polypeptides may either be degraded by 20S proteasomes or cross-link to form structures intractable to proteolysis and inhibitory to proteasome activity. Carnosine (β-alanyl-l-histidine) is present at surprisingly high levels (up to 20 mM) in muscle and nervous tissues in many animals, especially long-lived species. Carnosine can delay senescence in cultured human fibroblasts and reverse the senescent phenotype, restoring a more juvenile appearance. As better antioxidants/free-radical scavengers than carnosine do not demonstrate these antisenescent effects, additional properties of carnosine must contribute to its antisenescent activity. Having shown that carnosine can react with protein carbonyls, thereby generating “carnosinylated” polypeptides using model systems, we propose that similar adducts are generated in senescent cells exposed to carnosine. Polypeptide-carnosine adducts have been recently detected in beef products that are relatively rich in carnosine, and carnosine's reaction with carbonyl functions generated during amino acid deamidation has also been described. Growth of cultured human fibroblasts with carnosine stimulated proteolysis of long-labeled proteins as the cells approached their “Hayflick limit,” consistent with the idea that carnosine ameliorates the senescence-associated proteolytic decline. We also find that carnosine suppresses induction of heme-oxygenase-1 activity following exposure of human endothelial cells to a glycated protein. The antisenescent activity of the spin-trap agent α-phenyl-N-t-butylnitrone (PBN) towards cultured human fibroblasts resides in N-t-butyl-hydroxylamine, its hydrolysis product. As hydroxylamines are reactive towards aldehydes and ketones, the antisenescent activity of N-t-butyl-hydroxylamine and other hydroxylamines may be mediated, at least in part, by reactivity towards macromolecular carbonyls, analogous to that proposed for carnosine.

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