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
Disruption of the mGsta4 Gene Increases Life Span of C57BL Mice
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
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Abstract |
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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