Positive oxidative stress in aging and aging-related disease tolerance☆

It is now well established that reactive oxygen species (ROS), reactive nitrogen species (RNS), and a basal level of oxidative stress are essential for cell survival. It is also well known that while severe oxidative stress often leads to widespread oxidative damage and cell death, a moderate level of oxidative stress, induced by a variety of stressors, can yield great beneficial effects on adaptive cellular responses to pathological challenges in aging and aging-associated disease tolerance such as ischemia tolerance. Here in this review, I term this moderate level of oxidative stress as positive oxidative stress, which usually involves imprinting molecular signatures on lipids and proteins via formation of lipid peroxidation by-products and protein oxidation adducts. As ROS/RNS are short-lived molecules, these molecular signatures can thus execute the ultimate function of ROS/RNS. Representative examples of lipid peroxidation products and protein oxidation adducts are presented to illustrate the role of positive oxidative stress in a variety of pathological settings, demonstrating that positive oxidative stress could be a valuable prophylactic and/or therapeutic approach targeting aging and aging-associated diseases.

Oxidative stress is a situation whereby cellular levels of ROS or RNS overwhelm the cellular antioxidant capacities [20]. This condition, when severe, usually leads to extensive modifications or damage to macromolecules including DNA, lipids and proteins [28,29]. Collectively, these damaged macromolecules, when beyond the cell 0 s reparative and degradative activities, can eventually induce cell death and tissue injury [22,25]. Nonetheless, increasing evidence has now established that many protein oxidation or lipid oxidation products can be beneficial for cell survival [29][30][31][32]. These oxidation products are usually caused by a moderate level of oxidative stress, which is termed here as positive oxidative stress. This is the type of oxidative stress that can induce or is part of an adaptive response that protects cells against subsequent severe challenges that otherwise would trigger widespread oxidative damage and cell death [23,27].
In order to create a positive oxidative stress condition, it is necessary to stress cells with a stressor [22,27]. Many stressors, when used at appropriate dosages, can elicit a moderate or nonlethal level of oxidative stress in the absence of cytotoxicity and cell death [27]. Nonetheless, it should be pointed out that if used at higher dosages; almost all stressors will inevitably yield toxicity that leads to cell death.
The best examples of positive oxidative stress would be ischemic tolerance including preconditioning and postconditioning, which are clinically-relevant approaches applied in a variety of animal models for protection of tissues against ischemia-induced injuries [33][34][35]. It has been well-demonstrated that a variety of stressors, such as, mitochondrial electron transport chain inhibitors [36], hypoxia [37], hyperoxia [38,39], hyperthermia [40] and hypothermia [41], as well as short episodes of ischemia [42] can induce positive oxidative stress via a transiently increased ROS production that is involved in an adaptive response for prophylactic purposes (Table 1) [43][44][45][46][47][48][49]. Accordingly, many studies have shown that antioxidants administered prior to or at the onset of preconditioning or postconditioning induction, can abolish the preconditioning or postconditioning effect [34,35,50,51], thus demonstrating that ROS and oxidative stress are essential for preconditioning or postconditioning to take effect [52][53][54]. Interestingly, the effects of preconditioning and postconditioning are only evident in severe pathological challenges such as an extended period of ischemia or reperfusion.
So how does positive oxidative stress work? As ROS and RNS are short-lived molecules, they themselves cannot impart a persistent beneficial effect [22]. It is thus believed that the targets of ROS and RNS would serve as molecular signatures [23] that relay and extend the beneficial effects of positive oxidative stress [22]. These molecular signatures are those of ROS/RNS modified oxidative products such as lipid peroxidation by-products and protein oxidation adducts. Chemically, numerous protein oxidative modifications involved in positive oxidative stress are reversible such as disulfide formation [55][56][57][58][59][60], S-glutathionylation [61][62][63][64], S-sulfenation [65][66][67], and S-nitrosylation [68][69][70][71]. These enhanced modifications usually play regulatory roles in protein function and thus can elicit great protective effects against cell death induced by a variety of severe stress conditions. As has been reported, all these reversible cysteine modifications can occur under basal conditions [72][73][74][75][76][77][78][79]. In the absence of positive oxidative stress, however, these basal level modifications may have no apparent protective effects owing to their low abundance.
Herein to demonstrate the role of positive oxidative stress in aging and aging-associated diseases, I would like to present a few selected representative examples of oxidative molecular signatures that are beneficial for cell survival. These examples include lipid peroxidation products and protein oxidation adducts.

Positive effect of lipid peroxidation products
Lipid peroxides in hemoglobin-modified low density lipoprotein are beneficial for cell survival Hemoglobin (Hb) can modify low density lipoproteins (LDL), and lipid oxidation of the latter is usually linked to pathogenesis of atherosclerosis [31]. However, while hemoglobin-binding of LDL renders the complex (Hb-LDL) highly susceptible to lipid peroxidation, such oxidation products are not cytotoxic [31]. The reason for this is that oxidized Hb-LDL could induce HO-1 (hemeoxygenase-1) expression, likely via the activation of the Nrf2 transcription factor [80]. Notably, when oxidized Hb-LDL was reduced by ebselen, HO-1 induction was inhibited [31]. Therefore, oxidized Hb-LDL can exhibit a beneficial effect via HO-1 induction. Beneficial effect of a cholesterol oxidation product 24-S-hydroxycholesterol (24-SOHC) is endogenously produced in the brain and plays an important role in brain cholesterol homeostasis. Okabe et al. recently showed that 24-SOHS could elicit an adaptive response in human neuroblastoma SH-SY5Y cells [81]. They found that cells treated with 24-SOHC at non-lethal levels could significantly attenuate cell death induced subsequently by 7-keto cholesterol (7KC). Furthermore, the attenuation of cell death occurred in both differentiated and non-differentiated cells, and could also be induced by other cholesterol oxidation by-products such as 25-hydroxycholesterol and 27-hydroxycholesterol. Moreover, 24-SOHC treatment upregulated the expression of liver X receptor (LXR) target genes, thereby inducing ATP-binding cassette transporter. When LXRβ was knocked down by siRNA, the adaptive response was greatly diminished. Therefore, 24-SOHC represents another example of positive oxidative stress; which works via transcriptional activation of LXR signaling pathway, leading to neuronal protection against further 7KCtriggered cellular toxicity.

Positive effects of protein oxidation products
Cardioprotection by S-nitrosylation of a single cysteine residue on the mitochondrial complex I subunit ND3 Mammalian mitochondrial complex I has at least 45 subunits and many of them are redox-sensitive proteins that can undergo redox modifications by ROS or RNS [82]. Recently, Chouchani et al. reported that S-nitrosylation of the ND3 subunit within complex I could protect cardiomyocytes against cell death induced by cardiac ischemia reperfusion injury [30]. As this S-nitrosylation occurred on cysteine-39 of ND3 and was induced by a mitochondriaselective S-nitrosylating agent (named mitoSNO) administered at the onset of reperfusion, the authors presented an excellent postconditioning paradigm whereby the nitrosylation of a single cysteine residue can trigger a positive oxidative stress condition that protects against cardiac ischemic injury.
S-cysteine sulfenation of the Parkinson 0 s disease-associated protein DJ-1 is neuroprotective Parkinson 0 s disease (PD) is an age-related neurodegenerative disorder. While it is known that mutations in the gene that encodes DJ-1, a PD-related protein, can abolish neuroprotective function, the underlying mechanisms have been elusive. Madian et al. have recently provided convincing evidence that DJ-1 0 s protective function in PD is due to the conversion of a cysteine 0 s sulfhydryl group (-SH) to an S-sulfenation product (-SOH) [32]. The authors further demonstrated that mutations occurring on the DJ-1 gene that disrupted or interfered with this -SH to -SOH conversion on cysteine residue 106 could abolish DJ-1 0 s neuroprotective function. This study thus provides another example of ROSinduced positive oxidative stress in age-related neurodegenerative disease.

Summary
The above representative examples demonstrate that lipid peroxidation by-products and protein oxidation adducts can have tremendous prophylactic effects on aging-related diseases. Fig. 1 shows the relative magnitudes of oxidative stress and the potential corresponding effects. Basically, while a basal level of ROS/RNS and oxidative stress is essential for cell survival [21,22], severe oxidative stress or damage associated with a highly elevated level of ROS/RNS production will inevitably impair the cells 0 self-repair ability and thus can lead to cell death [22]. Importantly, a moderate level of oxidative stress, i.e., positive oxidative stress, induced by a moderate level of ROS/RNS, can be triggered by a variety of stressors to protect against further lethal challenges that otherwise would cause cell death and tissue injury [22,23,27].

Perspectives
Given that ROS/RNS are short-lived molecules and that the molecular signatures imprinted by these ROS/RNS on lipids and proteins can actually execute the ultimate function of positive oxidative stress, including redox signaling and activation of transcriptional factors [27], further studies will need to be undertaken to identify more targets in a variety of stress settings. Moreover, the underlying mechanisms of such identified targets, especially their prophylactic roles in aging and aging-associated disease tolerance will also need to be elucidated. It is the author 0 s belief that induction of positive oxidative stress could serve as a valuable prophylactic or therapeutic approach targeting aging and aging-associated diseases.
Basal level oxidative stress that maintains homeostasis Positive oxidative stress induced purposely by non-lethal challenges Severe oxidative stress that induces damage and cell death Severity of oxidative stress Fig. 1. Levels of cellular oxidative stress and their differential effects. (A) basal level oxidative stress that is essential for cell survival and homeostasis; (B) positive oxidative stress that can be induced by a variety of non-lethal challenges that often induce protein oxidative modifications; (C) Severe oxidative stress that induces damage and cell death.