antioxidants / ageing

Circ Res. 2004 Feb 12 [Epub ahead of print] Related Articles, Links

Antioxidants Inhibit Nuclear Export of Telomerase Reverse Transcriptase and Delay Replicative
Senescence of Endothelial Cells.

Haendeler J, Hoffmann J, Diehl JF, Vasa M, Spyridopoulos I, Zeiher AM, Dimmeler
S.

Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt,
Frankfurt, Germany.

Aging is associated with a rise in intracellular reactive oxygen species (ROS) and a loss of
telomerase reverse transcriptase activity. Incubation with H2O2 induced the nuclear export of
telomerase reverse transcriptase (TERT) into the cytosol in a Src-family kinase-dependent manner.
Therefore, we investigated the hypothesis that age-related increase in reactive oxygen species (ROS)
may induce the nuclear export of TERT and contribute to endothelial cell senescence. Continuous
cultivation of endothelial cells resulted in an increased endogenous formation of ROS starting after
29 population doublings (PDL). This increase was accompanied by mitochondrial DNA damage and
preceded the onset of replicative senescence at PDL 37. Along with the enhanced formation of ROS, we
detected an export of nuclear TERT protein from the nucleus into the cytoplasm and an activation of
the Src-kinase. Moreover, the induction of premature senescence by low concentrations of H2O2 was
completely blocked with the Src-family kinase inhibitor PP2, suggesting a crucial role for Src-
family kinases in the induction of endothelial cell aging. Incubation with the antioxidant N-
acetylcysteine, from PDL 26, reduced the intracellular ROS formation and prevented mitochondrial DNA
damage. Likewise, nuclear export of TERT protein, loss in the overall TERT activity, and the onset
of replicative senescence were delayed by incubation with N-acetylcysteine. Low doses of the statin,
atorvastatin (0.1 micro mol/L), had also effects similar to those of N-acetylcysteine. We conclude
that both antioxidants and statins can delay the onset of replicative senescence by counteracting
the increased ROS production linked to aging of endothelial cells.

PMID: 14963003 [PubMed - as supplied by publisher]

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