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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences Advance Access published online on October 30, 2009
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, doi:10.1093/gerona/glp165
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© The Author 2009. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

Disruption of the mGsta4 Gene Increases Life Span of C57BL Mice

Sharda P. Singh1, Maciej Niemczyk1, Deepti Saini1,2, Vladimir Sadovov1, Ludwika Zimniak1 and Piotr Zimniak1,3

1 Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock
2 Present addresses: Department of Surgery, Washington University in St Louis, Missouri
3 Central Arkansas Veterans Healthcare System, Little Rock

Address correspondence to Piotr Zimniak, PhD, Department of Pharmacology and Toxicology, #638, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205. Email: zimniakpiotr{at}uams.edu


  Abstract

The lipid peroxidation product 4-hydroxynonenal (4-HNE) forms as a consequence of oxidative stress. By electrophilic attack on biological macromolecules, 4-HNE mediates signaling or may cause toxicity. A major route of 4-HNE disposal is via glutathione conjugation, in the mouse catalyzed primarily by glutathione transferase mGSTA4-4. Unexpectedly, mGsta4-null mice, in which 4-HNE detoxification is impaired, have an extended life span. This finding could be explained by the observed activation of the transcription factor Nrf2 in the knockout mice, which in turn leads to an induction of antioxidant and antielectrophilic defenses. Especially, the latter could provide a detoxification mechanism that contributes to enhanced longevity. We propose that disruption of 4-HNE conjugation elicits a hormetic response in which an initially increased supply of 4-HNE is translated into activation of Nrf2, leading to a new steady state in which the rise of 4-HNE concentrations is dampened, but life-extending detoxification mechanisms are concomitantly induced.

Keywords Aging; Life span; Mouse; 4-hydroxynonenal; Glutathione transferase

Received: July 23, 2009; Accepted: October 6, 2009

Decision Editor: Huber R. Warner, PhD


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