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{at}kcl.ac.uk
Ann. N.Y. Acad. Sci. 959: 285-294 (2002).
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 (ß-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
-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.
