Journal
JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES
Volume 65, Issue 1, Pages 14-23Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/gerona/glp165
Keywords
Aging; Life span; Mouse; 4-hydroxynonenal; Glutathione transferase
Categories
Funding
- National Institutes of Health [R01 ES07804, R01 AG18845]
- VA Research Career Scientist Award
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [R01ES007804] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG018845] Funding Source: NIH RePORTER
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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.
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