The lipid peroxidation product 4-hydroxynon-2-enal (4-HNE) is a reactive electrophile able to modify proteins, aminophospholipids and, to a lesser extent, nucleic acids. Derivatization by 4-HNE of Cys, His, and Lys side chains of proteins often changes protein function; both inhibition and activation have been observed. 4-HNE is considered to be a signaling molecule that conveys the information that an oxidative event has occurred. The signal then coordinates an appropriate cellular response. We have previously found that conditions that lower the steady-state 4-HNE concentration, such as overexpression of 4-HNE-metabolizing enzyme
gst-10, extend C. elegans lifespan, whereas elevated 4-HNE leads to a shorter lifespan. We now report that expression (driven by the
gst-10 promoter) of human GSTA4-4, an enzyme with high catalytic efficiency toward 4-HNE, curtails C. elegans lifespan, whereas expression of a GSTA4-4 mutant in which 4-HNE-conjugating activity is selectively abrogated, has no effect on longevity. Together, these results indicate that moderate depletion of 4-HNE extends life, while excessive depletion of 4-HNE by the highly active human enzyme has the opposite effect. This conclusion is consistent with our finding that overexpression of the
gst-10 gene product in a wild-type background prolongs life (as previously reported), but expression of
gst-10 in a
ins-7 null mutant shortens lifespan. Ins-7 is an insulin-like peptide that is a Daf-2 agonist; disruption of Ins-7 expression has been shown by others to extend life. A possible interpretation of our result is that moderate depletion of 4-HNE (by
gst-10 overexpression) in wild-type worms has two countervailing effects on lifespan: extension, possibly mediated by limiting Ins-7 activity, and shortening due to loss of 4-HNE signaling. The sum of these two effects is a moderate gain in longevity. In
ins-7 null background, limiting of Ins-7 activity is no longer possible, but a detrimental loss of 4-HNE functions remains, resulting in a net decrease of lifespan. While further work is necessary to confirm this hypothesis, at present, our results are consistent with at least two distinct functions of 4-HNE that have opposing effects on life span. This would result in the existence of an optimal 4-HNE concentration with regard to lifespan; 4-HNE levels either higher or lower than this optimum reduce longevity.