Recent Reassessment of the Role of Reactive Oxygen Species (ROS)

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Peer-reviewed | Manuscript received: February 21, 2013 | Revision accepted: July 02, 2013

Recent reassessment of the role of reactive oxygen species (ROS)

Sebastian Schmeißer, Jena; Michael Ristow, Zürich; Marc Birringer, Fulda

Summary Reactive oxygen species (ROS) are closely related to pathogenic age-associated diseases, such as arteriosclerosis, diabetes and cancer. Here, important macromolecules, such as proteins, lipids or genetic information in the form of DNA, are irreversibly altered. Apart from the intensively investigated negative properties of ROS, recent studies show that these molecules have signaling functions and that a balance must be maintained between the formation of ROS and the elimination by the antioxidative enzymes and antioxidants. This implies that an excess in ROS causes damage to the organism. However, complete elimination of ROS inhibits the organism’s capacity to react to external stress factors in the form of an adaptive stress response. This research is described here under the term hormesis or mitohormesis and a re-evaluation of reactive oxygen species is carried out. Keywords: reactive oxygen species (ROS), antioxidants, calorie restriction, ageing, extended life span, physical exercise, mitohormesis, hormesis © frank peters/Fotolia.com

162 Ernaehrungs Umschau international | 9/2013 Introduction ways apply. On the contrary, in re- (CAT), glutathionperoxidase (GPx) cent years there has been a change of and glutathione S-transferase. Non- The use of oxygen to oxidize macro- opinion in relation to the role of ROS enzymatic defense is comprised of molecules as part of an aerobic me- under physiological conditions. numerous anti-oxidative molecules, tabolism is considered a basic pre- The purpose of this article is there- such as uric acid, bilirubin, ascorbic requisite for the formation of higher fore to elucidate the current results acid (vitamin C), α tocopherol (vita- life forms. The transformation of in this area and to describe the phys- min E) and glutathione [2, 5]. nutritional energy to the available iological role of ROS in greater detail. cellular energy equivalents (for example ATP) is much more efficient Oxidative stress What are ROS? here than for the oxygen-free/anaer- Under physiological conditions, the obic generation of energy. Numerous ROS are instable oxygen compounds formation and elimination of ROS is biological processes can thus be sup- characterized by high reactivity and in equilibrium. However, if there is plied with sufficient energy, sup- therefore regarded as an activated an imbalance (that is if the equilib- porting cellular energy homeostasis. form of oxygen [1]. They belong in rium between formation and degra- However, the use of oxygen leads to part to the free radicals and result dation shifts in the direction of the the formation of so-called reactive primarily from the transfer of an generative process resulting in alter- oxygen species (ROS). Due to their electron to molecular oxygen [2]. ations to redox signaling pathways highly reactive nature, ROS are con- The resulting superoxide radical is and the occurrence of molecular sidered to be potentially toxic mole- quantitatively the most important damage) this leads to oxidative stress cules capable of damaging cellular ROS molecule [3]. Other ROS, such [6, 7]. It is generally known that components and thus restricting as hydrogen peroxide or the particu- long term exposure to oxidative their function. The discovery that larly reactive hydroxyl radical, may stress has pathological consequences cellular damage accumulates be formed in follow-on reactions. and thus correlates with an increased throughout life and ultimately leads Furthermore, so-called singlet oxy- risk of disease and death [3, 8]. One to the death of the cell or organism, gen also belongs to the ROS group. example of this is the occurrence of as well as the fact that ROS can Singlet oxygen describes a state of oxidatively modified LDL molecules cause damage, leads to the assump- oxygen which is significantly more which are significantly involved in tion that there is a causal relation. reactive than normal oxygen. the occurrence of vascular diseases Accordingly, numerous studies con- Due to their high reactivity, ROS are such as arteriosclerosis [9–11]. sider ROS formation to be one possi- capable of causing damage to nu- ble cause for the occurrence of age- merous biological molecules [4]. For Where do ROS occur? associated diseases, as well as for the example, the genetic substance DNA ageing process per se. This research is susceptible to ROS related damage. The energy providing metabolism has led to the wide-spread opinion Here, ROS can cause strand breakage has been identified as one of the main that ROS are invariably damaging and mutations. Lipid oxidation, i.e. sources of intracellular ROS [12]. In and that reduced occurrence or in- the oxidative modification of lipids, particular, it could be shown that in tervention is associated with positive can lead to extensive damage of mitochondria, which are also de- health effects. structure generating unsaturated scribed as the powerhouse of the cell, fatty acids in biological membranes. under physiological conditions un- Nevertheless, recent, largely contro- paired electrons are released during versial research in this area shows the generation of cellular energy (i. e. Cellular defense mechanisms that this relationship does not al- ATP). The subsequent transfer of In order to combat the potential these electrons to oxygen leads, as damage due to the presence of ROS, already elaborated, to the formation cells have manifold, highly effective of ROS (superoxide radical), so to say Citation: defense mechanisms. These can be as a by-product of the aerobic mito- Schmeißer S, Ristow M, Birringer grouped into enzymatic and non-en- chondrial metabolism [13]. M (2013) Recent reassessment of zymatic mechanisms. Enzymatic the role of reactive oxygen species detoxification includes all endoge- Quantitatively speaking, approxi- (ROS). Ernaehrungs Umschau in- nous enzymes which eliminate ROS mately 0.2–2 % of the overall oxy- ternational 60(9): 162–167 or play a role in eliminating the gen consumed is transformed into This article is available online: damage caused by the ROS. The ROS [14], corresponding to roughly DOI 10.4455/eu.2013.030 most important examples are super- 90 % of the overall amount of intra- oxide dismutase (SOD), catalase cellular ROS [15]. Ī

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Furthermore, granulocytes (white The discovery of the SOD enzyme in Consequently, effects which extend blood cells) form a targeted ROS de- 1969 by J. M. MCCORD and I. FRIDO- life span have already been observed fense against bacteria [2] by means of VICH, which serves only as a defense in simple organisms such as yeast NADPH oxidase. The release of super- mechanism against ROS, lends con- fungus, worms, flies, mice and pri- oxide radicals resulting from an in- siderable credibility to HARMAN’S the- mates [33, 34]. fection is considered, among others, ory [21]. In addition, the theory is to be an atherogenic risk factor. In ad- based on experiments which show It is not known whether CR can also dition to the endogenous energy me- that the formation of ROS and the extend the life span of humans. tabolism, ROS also result as a by- resulting damage increase with age However, we do know that CR can product of enzymatic reactions (for [14]. Furthermore, numerous stud- positively influence risk factors for example in the microsomal ethanol- ies based on different models lead to age-associated diseases [35–37]. oxidizing system [16]) and through the belief that there is a negative cor- Nevertheless, the hypothesis that re- environmental influences, such as en- relation between ROS formation and duced metabolic rate paired with re- vironmental toxins, cigarette smoke, life span [22–29]. duced ROS formation is responsible UV light, X-rays and Gamma rays for the positive characteristics of CR [17]. Modification of the aerobic could not be confirmed in recent re- metabolism, calorie restric- search [38, 39]. On the contrary, this indicated that CR increases the meta- The significance of ROS in tion and influence on ROS the ageing process bolic rate, observed in the form of formation increased mitochondrial cellular res- Mitochondrial free-radical Considering the assumption that piration and biogenesis [40–42]. In- theory of aging (FRTA/MFRTA) ROS represent by-products of the creased ROS formation could there- Ageing/senescence (lat. senescere aerobic metabolism, the reduction of fore also be measured on the basis of ‘ageing’) of an organism is under- the mitochondrial metabolism must CR [43–45]. stood as a progressive process lead- consequently be accompanied by a ing to a general restriction or reduc- decrease in overall ROS levels, and Furthermore, other indications con- tion of cellular and systemic func- therefore have a positive effect on life tradict the hypothesis of a simple re- tion [18]. span. This belief is based on the ob- lationship between ROS formation servation of Max RUBNER who postu- and ageing. One example of this is One of the most important theories lated an inverse connection between the naked mole rat, which has a life about the process of ageing is the the metabolic rate and life span [30]. expectancy of around 10 times free radical theory of ageing pre- longer than that of laboratory mice. sented by Denham HARMAN in the The realization that energetic metab- Interestingly, it was determined that 1950s and 1970s (FRTA), and the olism determines the life span was this long-living rodent demonstrated mitochondrial free radical theory of taken up again in the rate of living higher ROS formation as well as an ageing (MFRTA) [19, 20]. According hypothesis [31]. In combination increased level of oxidatively modi- to this, the ROS continuously pro- with FRTA, this hypothesis supplied fied macromolecules [46, 47]. In ad- duced in metabolic processes cause a plausible explanation for observa- dition, current studies on model or- permanent cellular damage, which tions in mice over the following ganisms have shown that targeted manifests itself particularly in the years which showed that a reduction mild ROS induction can extend life form of modified proteins, lipids and in calorie intake, that is the metabo- span [48–50]. nucleic acids. Over time, this damage lizable macronutrients for the pro- accumulates and leads to the loss of duction of energy, increases Along with this, numerous – in part cellular and systemic function and longevity [32]. large-scale – human intervention ultimately to the demise of the or- studies have been unable to corrob- ganism. In addition to this – accord- Calorie restriction (CR) refers to a re- orate the expected positive influence ing to HARMAN – the main source of duction of the ad libitum calorie in- of supplementation with antioxi- ROS, the mitochondria, at the same take by 10–50 % without the occur- dants (i.e. natural or synthetic sub- time represent the main point of at- rence of deficiency symptoms, such stances capable of eliminating ROS), tack. In this vicious circle, oxidative as a lack of vitamin supply or impor- as summarized elsewhere [51, 52]. damage to mitochondria not only tant trace elements. Up until now, Some of these studies even came to reduces the capacity to generate en- CR is the only convincing interven- the conclusion that supplementa- ergy, but also causes additionally ris- tion in relation to reducing age-as- tion with antioxidants has a nega- ing ROS levels, in turn leading to sociated diseases as well as increas- tive influence on health [53] and life further damage. ing life span. span [54].

164 Ernaehrungs Umschau international | 9/2013 Overall, this new knowledge indi- numerous stress-activated protein ciated with defense mechanisms, for cates that ROS, apart from their kinases. This signal transmission ul- example, antioxidative enzymes undisputed potentially damaging timately terminates in the cell nu- (SOD, catalase, GPx), redox regula- properties, also fulfill important cleus, where so-called transcription tors (thioredoxine, glutathion) or physiological functions. On the one factors (for example, NRF-2, FoxO phase 2 detoxification enzymes (glu- hand, this clearly demonstrates that transcription factors, HSF1), bring tathion S-transferases [GSt], UDP increased ROS formation can have about the expression of numerous glucuronosyl transferases [UDPGT]) positive effects. On the other hand, genes associated with defense mech- [63–67]. there is a danger of damage to health anisms [3, 61]. This high regulation The fact that ROS signaling mole- through the reduction of ROS levels of cellular defense systems, which cules are capable of inducing stress using antioxidant supplementation. not only incorporates the antioxida- resistance as a result of a complex tive protection systems, serves on adaptive response leads to the as- the one hand to defend against ini- ROS as important signaling sumption that they could also influ- tial stress and on the other increases molecules ence life span. This assumption is the general stress resistance. This cir- well supported by extensive research An increasing number of studies in cumstance makes the cell more re- which shows a correlation between this field prove that ROS function as sistant against a number of external longevity and increased stress resis- important signaling molecules influences and also possibly against tance [8, 68–73]. which play an important role in the the ageing process. regulation of cellular processes [55]. Under very high conditions of stress, They have typical properties which The transcription factor NRF-2 is that is circumstances which are un- predestine them as signaling mole- worthy of mention in this context. favorable for the maintenance of cel- cules. For example, certain ROS are It is part of a conserved oxidative lular functions, the result is an in- capable of permeating biological stress response, which means that it duction of substantial amounts of membranes. Their intracellular con- can also be found in other species ROS. This results in massive damage centration can be regulated (at the [62]. NRF-2 is coupled with a re- to the cellular components and the synthesis and elimination level) or pressor protein (KEAP-1) in the cy- demise of the cells, for example depending on external stimulants. tosol when in a state of rest, that is, through apoptosis (programmed cell Furthermore, there are numerous outside the cell nucleus, whereas death). functional cell components, known under stress this transcription factor as target molecules, which they can is directly activated by the previ- Hormesis/Mitohormesis activate or deactivate [3, 55]. Ac- ously mentioned stress-activated cordingly, it could be demonstrated protein kinases or by ROS. The bond The idea that a potentially damaging that ROS are involved, for example, to the repressor is triggered and NRF- substance can have a positive effect in the regulation of processes such as 2 moves into the nucleus. Here, it in low concentrations was first de- cellular growth (proliferation), in- binds to the DNA and initiates the scribed by two German researchers flammatory processes, glucose expression of numerous genes asso- in relation to the effect of medicines. homeostasis, programmed cell death and the induction of defense mechanisms [43, 44, 56–60]. homeostasis adaptive response cell death

As shown in v Figure 1, ROS carry out different functions depending on their concentration. Under normal physiological conditions, that is in ROS ROS the absence of cellular stress, they ROS- Level serve to maintain cellular homeostasis. With increased concentration, however, for example in the event of a moderately stressful state, they physiological level moderate induction high induction play a decisive role in what is called (no cellular stress) (mild cellular stress) (high cellular stress) the cellular stress response or adaptive response. Here, ROS function as Fig. 1: Different ROS functions as a function of concentration stress signals, which trigger signal (modified after [55]) cascades through the activation of ROS = reactive oxygen species Ī

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The ARNDT-SCHULZ law that they Nutrition and mitohormesis the basis of this knowledge from postulated describes the possibility of work with model organisms. On the In this respect, calorie restriction (CR) a non-linear dose-effect relationship contrary, further studies on humans is a well described example. As al- with pharmaceutical substances must define the role that of our nu- ready mentioned above, mitochon- [74]. This implies that the effect of tritional composition and the opti- drial biogenesis is activated by CR, the substance in low concentrations mal amount of, for example, carbo- followed by an increase in mito- is different from that in higher doses. hydrate intake. chondrial respiration [38, 40–43, The term hormesis was introduced 83]. Furthermore, it was demon- to describe this non-linear dose-ef- A further, possibly nutritionally rel- strated long ago that CR contributes fect relationship [75]. evant aspect results from the obser- to increased stress defense in organ- vation that the phytochemicals isms [84–93]. Accordingly, CR re- Accordingly, hormesis is defined as a found in fruit, vegetables and spices duces the risk factors for stress-as- biphasic dose effect, with a poten- are capable of inducing cellular de- sociated diseases, such as diabetes tially dangerous, non-lethal stressor fense mechanisms via the activation mellitus type 2 and cardiovascular in low concentrations resulting in a of the NRF-2 path. Classic antioxi- diseases [35–37]. Very recent investi- positive or stimulating effect, dants are found under the com- gations have now proven that in- whereas with high concentrations pounds described as hormetics or creased mitochondrial ROS forma- inhibitory or toxic effects are ob- hormetines, such as resveratol, cur- tion is responsible for increased stress served. cumin and also isothiocyanate [99]. resistance and thus also for the life- In pharmacological doses, some of prolonging potential of CR [44, 45, Here, the stimulating effect which these compounds offer life-prolong- 92, 93]. Consequently, it can be as- occurs with low doses refers to the ing potential, at least in model or- sumed that CR also represents an op- capability of cells in the organism to ganisms [100, 101]. timum intervention in humans for react to external signals. This enables healthy ageing. However, as CR is their activation as a result of an tantamount to a permanent state of Physical exercise and mito- adaptive response mechanism which hunger, this intervention is not an hormesis renders them capable of surviving option for the majority of the popu- more severe stress influences [76, Moderate physical activity is a gen- lation. 77]. The assumption that mitochon- erally recognized, health-promoting drial ROS formation also involves a Initial indications from work with intervention known to reduce the mild stressor serves as the basis for model organisms allow the conclu- risk of illness and death [102–107]. the formulation of the concept of sion that similar effects could also Here, regular physical activity leads mitochondrial hormesis, or mito- possibly be achieved by varying the to increased mitochondrial metabol- hormesis [78]. In relation to the reg- combination of macro-nutritional ics due to the high energy require- ulation of life span, the theory states components (that is, the fractions of ments and therefore to increased ROS that a slight increase in the mito- carbohydrates, proteins and lipids in formation and enhanced defense ca- chondrial ROS production (for ex- the overall nutritional intake). Here pacity [82, 102, 108–110]. Further- ample due to increased physical ac- it has been shown that glucose re- more, it has been reported that the tivity) may significantly extend life striction extends the life span of intake of antioxidative supplements span through a secondary induction model organisms through mito- parallel to physical exercise com- of defense mechanisms, whereas hormetic processes [40, 43, 94]. pletely inhibits the health-promoting high mitochondrial ROS levels reduce Conversely, an excess of glucose in- aspects [53, 111]. It therefore seems life span [44, 51, 60]. As already de- take in worms led to decreased life plausible that mitohormetic mecha- scribed, the oxidative, mitochondrial span [43, 95, 96]. Furthermore, nisms mediate the positive effect of metabolism permanently produces there are indications that diets low in physical activity. ROS. Here, increased mitochondrial carbohydrates decrease the risk of activity is associated with increased cardiovascular diseases in humans On the other hand, it is known that ROS formation [43, 79–81]. Accord- [97]. excessive training causes massive ingly, mitohormetic mechanisms oxidative stress which may exceed On the other hand, an increased sup- were observed, in particular, in life- the capacity of a positive hormetic ply of branched amino acids leads to prolonging interventions which ac- response and is therefore associated mitochondrial biogenesis and in- company an increase in mitochon- with health problems [112]. creased longevity in mice [98]. drial respiration, for example CR (see above) or moderate physical activity However, no clear nutritional rec- (see below) [53, 82]. ommendations can yet be derived on

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Recent reassessment of the role of reactive oxygen species (ROS)

Sebastian Schmeißer, Jena; Michael Ristow, Zürich; Marc Birringer, Fulda

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