Role of reactive oxygen species-mediated signaling in aging

Abstract

Significance: Redox biology is a rapidly developing area of research due to the recent evidence for general importance of redox control for numerous cellular functions under both physiological and pathophysiological conditions. Understanding of redox homeostasis is particularly relevant to the understanding of the aging process. The link between reactive oxygen species (ROS) and accumulation of age-associated oxidative damage to macromolecules is well established, but remains controversial and applies only to a subset of experimental models. In addition, recent studies show that ROS may function as signaling molecules and that dysregulation of this process may also be linked to aging.

Recent advances: Many protein factors and pathways that control ROS production and scavenging, as well as those that regulate cellular redox homeostasis, have been identified. However, much less is known about the mechanisms by which redox signaling pathways influence longevity. In this review, we discuss recent advances in the understanding of the molecular basis for the role of redox signaling in aging.

Critical issues: Recent studies allowed identification of previously uncharacterized redox components and revealed complexity of redox signaling pathways. It would be important to identify functions of these components and elucidate how distinct redox pathways are integrated with each other to maintain homeostatic balance.

Future directions: Further characterization of processes that coordinate redox signaling, redox homeostasis, and stress response pathways should allow researchers to dissect how their dysregulation contributes to aging and pathogenesis of various age-related diseases, such as diabetes, cancer and neurodegeneration.

FIG. 1.

ROS production in mammalian mitochondria. Superoxide anion radical O₂^•− is a major source of intracellular ROS. It is formed mainly in mitochondria as a result of electron leakage from the electron transport chain at complex I and complex III. O₂^•− can be also produced by several enzymes that catalyze one-electron transfer reactions, such as monoamine oxidase (MAO) and the cytochrome P450 components. Superoxide is unstable and is dismutated spontaneously or by the activity of mitochondrial manganese superoxide dismutase (MnSOD), into H₂O₂. In addition to hydrogen peroxide produced by MnSOD, H₂O₂ can be also produced by p66sch protein through 2-electron transfer from cytochrome C (Cyt C). Once hydrogen peroxide is formed, it is further degraded by enzymes such as catalase (CAT) in peroxisomes and glutathione peroxidases (GPx) and peroxiredoxins (Prx) in various cellular compartments.

FIG. 2.

Redox-dependent cysteine modifications. During oxidative stress, reactive Cys residues can be oxidized by H₂O₂ to form cysteine sulfenic acid (R-SOH). R-SOH can be further oxidized by H₂O₂ to cysteine sulfinic acid (R-SO₂H) and cysteine sulfonic acid (R-SO₃H). Alternatively, R-SOH can covalently interact with adjacent Cys-SH groups and form disulfide bonds (either intra- or intermolecular), or can be converted to sulfenyl amide (R-SN).

FIG. 3.

A model for the role of yeast thiol peroxidases in regulation of gene expression in response to H₂O₂. Due to their high specificity toward hydroperoxides, Tsa1, Tsa2, and other thiol peroxidases serve as the proximal H₂O₂ sensors. These proteins are initially oxidized by H₂O₂ and then oxidize regulatory and signaling proteins. Upon activation, regulatory proteins interact with their specific substrates (S1, S2, etc.), resulting in the transcriptional response and activation of various signaling pathways. Although this model does not exclude direct oxidation of transcription factors and other regulatory proteins by H₂O₂ (dashed arrow), at physiological H₂O₂ concentrations it likely plays a minimal role.

FIG. 4.

Functions of thiol oxidoreductases.

FIG. 5.

Computational methods for high-throughput identification of reactive Cys residues. (A) Redox-active Cys residues in thiol oxidoreductases are highly conserved, and in some organisms a functionally similar amino acid, selenocysteine (one letter designation is U), can replace the catalytic Cys. Detection of such Cys/selenocysteine pairs in homologous sequences using TBLASTN could predict the location of redox-active Cys residues in proteins. (B) Proteins containing redox-active Cys can sometimes form fusions with thiol oxidoreductases. Thus, catalytic Cys residues can be predicted by searching for conserved Cys in protein domains fused to known thiol oxidoreductases. (C) Distant homologs of known thiol oxidoreductases containing conserved catalytic redox-active Cys could also be identified in an iterative approach by PSI-BLAST.

FIG. 6.

Model for Tsa1-dependent lifespan extension by caloric restriction. (A) At high concentration, glucose stimulates the activity of cyclic AMP-dependent protein kinase A (PKA), leading to inhibition of translation of the SRX1 gene. As a result of decreased production of Srx1, Tsa1 is inactivated by H₂O₂-induced hyperoxidation. (B) During caloric restriction, low PKA activity stimulates Tsa1 activity by enhancing Gcn2-dependent translation of Srx1, which reactivates hyperoxidized Tsa1.

FIG. 7.

Model for the effect of ROS on lifespan in wild-type and sod-12345 worms. (A) ROS may have a dual function in regulating longevity: (i) they can cause oxidative stress (toxicity), and (ii) activate prosurvival signaling. At low concentrations of superoxide, produced by addition of low levels of paraquat, ROS extend lifespan of wild-type worms in a dose-dependent manner, as the prosurvival signaling effect of ROS is greater than the toxic effect. At high concentrations, superoxide leads to a dose-dependent decrease in lifespan due to its toxicity. (B) ROS levels in sod-12345 worms exceed the optimum concentration required for signaling. Decreasing superoxide levels in these animals through addition of antioxidants leads to lifespan extension, whereas treatment with paraquat shortens the lifespan.