Detoxification reactions: relevance to aging

Abstract

It is widely (although not universally) accepted that organismal aging is the result of two opposing forces: (i) processes that destabilize the organism and increase the probability of death, and (ii) longevity assurance mechanisms that prevent, repair, or contain damage. Processes of the first group are often chemical and physico-chemical in nature, and are either inevitable or only under marginal biological control. In contrast, protective mechanisms are genetically determined and are subject to natural selection. Life span is therefore largely dependent on the investment into protective mechanisms which evolve to optimize reproductive fitness. Recent data indicate that toxicants, both environmental and generated endogenously by metabolism, are major contributors to macromolecular damage and physiological dysregulation that contribute to aging; electrophilic carbonyl compounds derived from lipid peroxidation appear to be particularly important. As a consequence, detoxification mechanisms, including the removal of electrophiles by glutathione transferase-catalyzed conjugation, are major longevity assurance mechanisms. The expression of multiple detoxification enzymes, each with a significant but relatively modest effect on longevity, is coordinately regulated by signaling pathways such as insulin/insulin-like signaling, explaining the large effect of such pathways on life span. The major aging-related toxicants and their cognate detoxification systems are discussed in this review.

Fig. 1

Schematic representation of the formation and functions of the lipid peroxidation product 4-HNE. Electrons leaking from the mitochondrial respiratory chain to molecular oxygen lead to the formation of superoxide which can be converted to other ROS. ROS can be generated by other processes (e.g., Krause, 2006) but mitochondria are their major source. Via the Fenton reaction, transition metals catalyze the conversion of H₂O₂ to the hydroxyl radical which can abstract a hydrogen from a polyunsaturated fatty acid (PUFA) molecule (denoted as LH), generating a carbon-centered radical. The latter initiates a chain reaction provided there is a supply of oxygen and additional PUFAs (yellow highlight). The resulting lipid hydroperoxides (LOOH) can be converted to electrophilic aldehydes such as 4-HNE. These aldehydes are metabolized (green lettering) by glutathione conjugation or redox reactions (reduction of the aldehyde group or of the carbon-carbon double bond, or oxidation of the aldehyde group). Otherwise, 4-HNE can react with cellular macromolecules, chiefly proteins (Fig. 2), changing their activity. This can modulate signaling or cause toxicity. Targets of 4-HNE include mitochondrial proteins, leading to either a negative or positive feedback loop (orange highlight): activation of mitochondrial uncoupling proteins by 4-HNE decreases ROS production (Echtay and Brand, 2007; Echtay et al., 2003; Wolkow and Iser, 2006), but damage to components of the respiratory chain increases generation of ROS (Lee et al., 2006; Uchida, 2003). The latter process could additionally amplify the action of 4-HNE by triggering a higher level of lipid peroxidation. The concentration of 4-HNE may determine whether negative or positive feedback predominates.

Fig. 2

Major reactions of 4-HNE with proteins. Upper part of scheme: the predominant reaction is a Michael addition of a nucleophilic center (side chain of cysteine, histidine, or lysine) in a protein to the double bond of 4-HNE. Subsequently, the resulting adduct can cyclize to a hemiacetal, or the aldehyde group of the 4-HNE moiety of the adduct can form a Schiff base with an amino group on the same or another protein, causing protein cross-linking. Lower part of scheme: a less common reaction is the formation of a Schiff base of the aldehyde group of 4-HNE with a lysine side chain in a protein, followed by dehydration and cyclization to a pentylpyrrole adduct. The scheme is based on (Liu et al., 2003).

Fig. 3

Composite figure illustrating the effect of 4-HNE on median life span of C. elegans. Worms were either subjected to RNAi against gst-10 (Ayyadevara et al., 2005a) or made transgenic for murine mGsta4 or for gst-10 (Ayyadevara et al., 2005b). Panel A shows 4-HNE-conjugating activity in worm homogenates; panel B, the level of 4-HNE-protein adducts; and panel C, the median life span of the lines. Asterisks denote statistical significance versus control.