Authors: Ayyadevara S; Dandapat A; Singh SP; Siegel ER; Shmookler Reis RJ; Zimniak L; Zimniak P
Abstract: The lipid peroxidation product 4-hydroxynon-2-enal (4-HNE) forms as a consequence of oxidative stress, and acts as a signaling molecule or, at superphysiological levels, as a toxicant. The steady-state concentration of the compound reflects the balance between its generation and its metabolism, primarily through glutathione conjugation. Using an RNAi-based screen, we identified in Caenorhabditis elegans five glutathione transferases (GSTs) capable of catalyzing 4-HNE conjugation. RNAi knock-down of these GSTs (products of the gst-5, gst-6, gst-8, gst-10, and gst-24 genes) sensitized the nematode to electrophilic stress elicited by exposure to 4-HNE. However, interference with the expression of only two of these genes (gst-5 and gst-10) significantly shortened the life span of the organism. RNAi knock-down of the other GSTs resulted in at least as much 4-HNE adducts, suggesting tissue specificity of effects on longevity. Our results are consistent with the oxidative stress theory of organismal aging, broadened by considering electrophilic stress as a contributing factor. According to this extended hypothesis, peroxidation of lipids leads to the formation of 4-HNE in a chain reaction which amplifies the original damage. 4-HNE then acts as an "aging effector" via the formation of 4-HNE-protein adducts, and a resulting change in protein function.
Keywords: Aldehydes/chemistry/*metabolism/pharmacology; Animals; Caenorhabditis elegans/chemistry/drug effects/*physiology; Caenorhabditis elegans Proteins/genetics/*metabolism; Glutathione Transferase/genetics/*metabolism; Longevity/*physiology; RNA Interference; Stress, Psychological|
Journal: Mechanisms of ageing and development Volume: 128 Issue: 2 Pages: 196-205 Date: Dec. 13, 2006 PMID: 17157356 |
Ayyadevara S, Dandapat A, Singh SP, Siegel ER, Shmookler Reis RJ, Zimniak L, Zimniak P (2007) Life span and stress resistance of Caenorhabditis elegans are differentially affected by glutathione transferases metabolizing 4-hydroxynon-2-enal. Mechanisms of ageing and development 128: 196-205.
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