Am J Physiol Regul Integr Comp Physiol-2007-Kregel-R18-36

An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations
Kevin C. Kregel and Hannah J. Zhang

Am J Physiol Regul Integr Comp Physiol 292:R18-R36, 2007. First published 17 August 2006; doi: 10.1152/ajpregu.00327.2006 You might find this additional info useful... This article cites 279 articles, 99 of which you can access for free at: http://ajpregu.physiology.org/content/292/1/R18.full#ref-list-1 This article has been cited by 22 other HighWire-hosted articles: http://ajpregu.physiology.org/content/292/1/R18#cited-by Updated information and services including high resolution figures, can be found at: http://ajpregu.physiology.org/content/292/1/R18.full Additional material and information about American Journal of Physiology - Regulatory, Integrative and Comparative Physiology can be found at: http://www.the-aps.org/publications/ajpregu This information is current as of November 12, 2012.
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American Journal of Physiology - Regulatory, Integrative and Comparative Physiology publishes original investigations that illuminate normal or abnormal regulation and integration of physiological mechanisms at all levels of biological organization, ranging from molecules to humans, including clinical investigations. It is published 12 times a year (monthly) by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright 2007 the American Physiological Society. ISSN: 0363-6119, ESSN: 1522-1490. Visit our website at http://www.the-aps.org/.
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Am J Physiol Regul Integr Comp Physiol 292: R18 R36, 2007. First published August 17, 2006; doi:10.1152/ajpregu.00327.2006.
An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations
Kevin C. Kregel and Hannah J. Zhang
Department of Integrative Physiology and Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa
Submitted 15 May 2006; accepted in nal form 16 August 2006
Kregel KC, Zhang HJ. An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations. Am J Physiol Regul Integr Comp Physiol 292: R18 R36, 2007; First published August 17, 2006; doi:10.1152/ajpregu.00327.2006.Aging is an inherently complex process that is manifested within an organism at genetic, molecular, cellular, organ, and system levels. Although the fundamental mechanisms are still poorly understood, a growing body of evidence points toward reactive oxygen species (ROS) as one of the primary determinants of aging. The oxidative stress theory holds that a progressive and irreversible accumulation of oxidative damage caused by ROS impacts on critical aspects of the aging process and contributes to impaired physiological function, increased incidence of disease, and a reduction in life span. While compelling correlative data have been generated to support the oxidative stress theory, a direct cause-and-effect relationship between the accumulation of oxidatively mediated damage and aging has not been strongly established. The goal of this minireview is to broadly describe mechanisms of in vivo ROS generation, examine the potential impact of ROS and oxidative damage on cellular function, and evaluate how these responses change with aging in physiologically relevant situations. In addition, the mounting genetic evidence that links oxidative stress to aging is discussed, as well as the potential challenges and benets associated with the development of antiaging interventions and therapies. oxidative damage; antioxidants; free radicals; reactive oxygen species; hyperthermia; caloric restriction
If Id known I was going to live this long, I would have taken better care of myself. Eubie Blake, American ragtime musician, who lived well into his 90s
HEIGHTENED INTEREST IN THE aging process, both in scientic and public settings, has been stimulated by a number of factors. One key observation, the impressive increase in average life expectancy in humans over recent centuries, lends some import to the pronouncement made by renowned jazz musician Eubie Blake as he neared 100 years of age. In addition, the growing percentage of elderly making up the population base in most developed countries (212) and the large health care expenditures that are committed to the elderly (42) have stimulated both scientic inquiry and heightened public awareness on issues related to aging. Harman denes aging as the progressive . . . accumulation of diverse deleterious changes in cells and tissues with advancing age that increase the risk of disease and death. (95). This denition illustrates two widely recognized and equally important aspects of the aging process: 1) aging is characterized as a progressive decline in biological functions with time, and 2) aging results in a decreased resistance to multiple forms of
Address for reprint requests and other correspondence: K. C. Kregel, Dept. of Integrative Physiology, 532 FH, The Univ. of Iowa, Iowa City, IA 52242 (e-mail: kevin-kregel@uiowa.edu). R18
stress, as well as an increased susceptibility to numerous diseases. Even with a well-described denition and a familiar set of characteristics, aging remains one of the most poorly understood of all biological phenomena, due in large part to its inherently complex and integrative nature, as well as the difculty in dissociating the effects of normal aging from those manifested as a consequence of age-associated disease conditions. As a result, while disciplines ranging from physiology and genetics to epidemiology and demography have developed a large number of theories that attempt to explain why we age (152), denitive mechanisms to explain the process across species and systems remain equivocal. One of the prevalent theories in the current literature revolves around free radicals, which are molecules containing unpaired, highly reactive electrons, as causal agents in the process of aging. In the 1950s, Harman proposed the free radical theory, postulating that damage to cellular macromolecules via free radical production in aerobic organisms is a major determinant of life span (94). It was subsequently discovered that reactive oxygen species (ROS), some of which are not free radicals (because they do not have an unpaired electron in their outer shell), contribute to the accumulation of oxidative damage to cellular constituents. Thus, a more modern version of this tenet is the oxidative stress theory of aging, which holds that increases in ROS accompany aging, leading to functional alterations, pathological conditions, and even
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death (91). Oxidative stress in a physiological setting can be dened as an excessive bioavailability of ROS, which is the net result of an imbalance between production and destruction of ROS (with the latter being inuenced by antioxidant defenses). Over the past two decades, many reviews have been published that contain extensive information regarding the oxidative stress theory of aging (7, 12, 21, 33, 57, 96, 142). However, despite a large body of evidence supporting the notion that ROS are produced in cells and can manifest damage, a causal link between ROS and aging has still not been clearly established. In recent years, several related theories containing an ROS component have also been proposed (283). One that has been extensively studied is the mitochondrial theory of aging, which hypothesizes that mitochondria are the critical component in control of aging. It is proposed that electrons leaking from the electron transport chain (ETC) produce ROS and that these molecules can then damage ETC components and mitochondrial DNA, leading to further increases in intracellular ROS levels and a decline in mitochondrial function (276). In support of a mitochondrial theory of aging, evidence suggests that mitochondrial DNA damage is increased with aging (90, 93). Another consideration is the cellular senescence theory of aging, which emphasizes the importance of cellular signal responses to stress and damage. These signaling responses subsequently stimulate pathways related to cell senescence and death (20). At the cellular level, ROS have been found to modulate various signals leading to accelerated mitogenesis and premature cellular senescence (106). An additional theory that has gained more attention in recent years is the molecular inammatory theory of aging, whereby the activation of redox-sensitive transcriptional factors by age-related oxidative stress causes the upregulation of proinammatory gene expression. As a result, various proinammatory molecules are generated, leading to inammation processes in various tissues and organs. This inammatory cascade is exaggerated during aging and has been linked with many ageassociated pathologies, such as cancer, various cardiovascular diseases, arthritis, and several neurodegenerative diseases (47). Interestingly, a common phenomenon in agingrelated pathologies is the discovery of ROS as a potential unifying mechanism contributing to many of these diseases (72, 150, 176, 205). Despite much investigation in recent years, no single theory has been completely successful in explaining the aging process. In fact, while many investigators focus on a limited number of genes in selected model organisms, current evidence has led to the suggestion that it is impossible for aging to be accounted for by a single theory (127). The purpose of this minireview is to discuss recent evidence that links oxidative stress to biological aging at molecular, cellular, and organismal levels. A primary focus will be to provide an integrated view of the involvement of oxidative stress in normal aging processes. The authors recognize that the role of oxidative stress in numerous age-related pathologies is another important aspect of the aging process; however, providing a detailed assessment of this broad topic is outside the scope of this article and many reviews are currently available in this particular area (153, 187, 214, 249, 284).
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Basics of ROS Sources of ROS. ROS are metabolites of molecular oxygen (O2) that have higher reactivity than O2. ROS can include unstable oxygen radicals such as superoxide radical (O2 ) and hydroxyl radical (HO ), and nonradical molecules like hydrogen peroxide (H2O2). These ROS, which are continually generated as byproducts of normal aerobic metabolism, can also be produced to a greater extent under stress and pathological conditions, as well as taken up from the external environment. Thus, all organisms living in an aerobic environment are exposed to ROS on a continual basis. As noted in the previous section, one of the primary intracellular sites for in vivo ROS production is the mitochondion (19). This organelle generates ATP through a series of oxidative phosphorylation processes that ultimately involve a fourelectron reduction of O2 to water. However, during this process, one- or two-electron reductions of O2 can occur, leading to the formation of O2 or H2O2, and these species can be converted to other ROS. Additional examples of intracellular sources of ROS production include reactions involving peroxisomal oxidases (236), cytochrome P-450 enzymes (293), NAD(P)H oxidases (143), or xanthine-xanthine oxidase (220). A variety of exogenous stimuli, such as radiation (222), pathogen infections (238), and exposure to xenobiotics (196) can also cause in vivo ROS production. Additionally, several specic types of environmental stress can lead to the production of ROS, including heat stress (297), herbicide/insecticide contamination (3), environmental toxins (240), and ultraviolet light exposure (235). ROS generation via these various sources can be specic for particular tissues, cells, and organelles. Oxidative damage to macromolecules by ROS. It has long been recognized that high levels of ROS can inict direct damage to macromolecules, such as lipids, nucleic acids, and proteins (32). Due to the bis-allylic structures of polyunsaturated fatty acids, lipids are one of the most sensitive oxidation targets for ROS. Once lipid peroxidation is initiated, a propagation of chain reactions will take place until termination products are produced. Therefore, end products of lipid peroxidation, such as malondialdehyde (MDA), 4-hydroxy-2-nonenol (4-HNE), and F2-isoprostanes are accumulated in biological systems. DNA bases are also very susceptible to ROS oxidation, and the predominant detectable oxidation product of DNA bases in vivo is 8-hydroxy-2-deoxyguanosine. Oxidation of DNA bases can cause mutations and deletions in both nuclear and mitochondrial DNA. Mitochondrial DNA is especially prone to oxidative damage due to its proximity to a primary source of ROS and its decient repair capacity compared with nuclear DNA. Almost all amino acid residues in a protein can be oxidized by ROS. Some widely studied oxidative products of amino acid residues include the formation of disulde bonds at cysteine residues, carbonyl derivatives, and many others oxidized residues, such as methionine sulfoxide. These oxidative modications lead to functional changes in various types of proteins, which can have substantial physiological impact. For instance, oxidative damage to enzymes can cause a modication of their activity, while oxidant-derived injury to structural proteins and chaperones produces protein aggregation. Similarly, redox modulation of transcription factors, as detailed in the next section, can produce an increase or decrease in their specic DNA binding activities, which stim292 JANUARY 2007
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Fig. 1. Reactive oxygen species (ROS) can play a role in cell signaling. Oxidative stress can activate numerous intracellular signaling pathways via ROS-mediated modulation of various enzymes and critical transcription factors. In one scenario, transcription factors activated in response to an increase in ROS or oxidative damage travel from the cytoplasm to the nucleus within a cell and bind to promoter regions of particular genes. As a result, these stress-activated pathways can have a signicant impact on gene expression, which will ultimately affect the fate of a cell (e.g., apoptosis, proliferation, cytokines). The balance between ROS production, cellular antioxidant defenses, activation of stress-related signaling pathways, and the production of various gene products, as well as the effect of aging on these processes, will determine whether a cell exposed to an increase in ROS will be destined for survival or death.
ulates gene expression changes that impact on cell survival, death, and senescence pathways (Fig. 1). Redox modulation of transcriptional factors by ROS. While ROS are known to function as harmful products of aerobic metabolism, especially when present at high concentrations, low levels of these prooxidant molecules have more recently been discovered to modulate transcription factor activation (66, 155). A growing number of molecules, such as many kinases (147, 210), phosphatases (123), and transcription factors (63, 67, 185, 253, 270, 296), in a wide range of signal transduction pathways, are thought to be modulated by intracellular redox status. Moreover, a few transcription factors, such as the small GTP-binding protein Rac, are known to activate ROS-generating enzymes (e.g., NADPH oxidase) and produce ROS as a modulator of downstream molecules (9, 277). ROS regulation of transcription factors can occur by direct modication of critical amino acid residues, primarily through the formation of disulde bonds, at DNA-binding domains or via indirect phosphorylation/dephosphorylation as a result of changes in redox-modulated signaling pathways. The consequences of redox modulation are bidirectional, producing either activation or inactivation of affected transcription factors. Examples of aging-related transcription factors known to be redox-regulated include tumor suppressor p53, Forkhead transcription factors, activator protein-1 (AP-1), and NF-B. Tumor suppressor p53 is a 53-kD protein that controls cell cycle arrest, cell apoptosis, and senescence (97). Forkhead transcription factors encompass a large family of proteins characterized by a conserved DNA-binding domain termed Forkhead box (118). These proteins are ubiquitous in eukaryotic cells and thought to be critical in regulating cell cycle arrest, cellular stress responses, apoptosis, and longevity (86).
AP-1 and NF-B are two of the early-response transcriptional factors that have been shown to suppress apoptosis and induce cellular transformation, proliferation, stress resistance, and inammation (119, 208). We have shown that the activation of AP-1 by in vivo adenovirus administration is redox-modulated and involves the participation of redox factor-1 (Ref-1). Ref-1 is a unique molecule that has two distinct enzymatic functions: it serves as both a DNA repair enzyme and a redox regulatory transcription factor (296). Under oxidative stress conditions, the Ref-1 molecule also undergoes major conformation changes while two critical cysteines, Cys65 and Cys93 at the NH2-terminal region of Ref-1, interact with conserved cysteine residues (e.g., Fos cys-154 and Jun cys-272) in the AP-1 DNA binding domain to stimulate the activation of AP-1 (287). Similarly, reduced cysteines in the zinc-nger domain of p53 are critical for its DNA binding ability. ROS inhibits site-specic p53 binding while Ref-1 can reactivate DNA binding of oxidized p53 in vitro and stimulate p53 transactivation in vivo (115). Furthermore, it is thought that the phosphorylation of IB, the inhibitory subunit of NF-B, is the key step in NF-B redox activation. ROS-mediated phosphorylation of IB, leading to its ubiquitination and degradation, allows the NF-B complex to be translocated to the nucleus and act as a transcriptional activator (208). On the other hand, direct oxidation of critical cysteine residues in the p50 subunit of NF-B is believed to signicantly decrease its DNA binding ability (209). Although the ROS-targeted protein kinases remain to be identied for the redox-regulation of Forkhead transcription factors, there are some data indicating that oxidative stress caused by H2O2, menadione, or heat shock stimulates the phosphorylation and translocation of Forkhead proteins and activation of Akt, a serine/threonine kinase also known as protein kinase B. This protein is directly responsible for the phosphorylation of Forkhead protein in the phosphatidylinositol 3-Akt signaling pathway (76). In addition, oxidative stress promotes the acetylation of Forkhead proteins at several critical lysine residues by acetylases, such as p300, and cAMPresponse element-binding protein-binding protein (160, 204). The acetylation of Forkhead proteins results in an inhibition of the transactivation activity of Forkhead transcription factors. Antioxidant systems. A number of sophisticated antioxidant systems exist in aerobic organisms, and they function to balance the cellular production of ROS that has been described in the previous sections. Endogenous antioxidant defenses include a network of compartmentalized antioxidant enzymes that are usually distributed within the cytoplasm and among various organelles in cells. A variety of small nonenzymatic molecules present in the internal milieu are also capable of scavenging ROS. In eukaryotic organisms, several ubiquitous primary antioxidant enzymes, such as SOD, catalase, and different forms of peroxidases work in a complex series of integrated reactions to convert ROS to more stable molecules, such as water and O2. Besides the primary antioxidant enzymes, a large number of secondary enzymes act in concert with small molecular-weight antioxidants to form redox cycles that provide necessary cofactors for primary antioxidant enzyme functions. Small molecular-weight antioxidants (e.g., GSH, NADPH, thioredoxin, vitamins E and C, and trace metals, such as selenium) can also function as direct scavengers of ROS. These enzymatic and nonenzymatic antioxidant
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systems are necessary for sustaining life by their ability to both maintain a delicate intracellular redox balance and reduce or prevent cellular damage caused by ROS (284). Oxidative Stress in Cellular Senescence and Death Cellular aging is characterized by an accumulation of damage that results in cell senescence and death. In recent years, pathways leading to cell senescence and death have been implicated as important factors contributing to organismal aging due to critical and irreplaceable cell loss. Therefore, this section will focus on the involvement of ROS and ROSmodied molecules in the activation of several signaling cascades related to cell death and senescence. Oxidative stress and cellular responses. At the cellular level, oxidative stress generated by ROS and ROS-modied molecules can inuence a wide range of cellular functions. The direct consequence of oxidative stress is damage to various intracellular constituents. For example, when lipid peroxidation occurs, changes in cellular membrane permeability and even membrane leakage can be manifested (233). Oxidative damage to both nuclear and mitochondrial DNA has detrimental effects, leading to uncontrolled cell proliferation or accelerated cell death (64). As would be expected, protein oxidation has many important physiological consequences that affect normal cellular functions (248). There is evidence that oxidative stress-mediated protein aggregation may be the primary cause of the neuronal death in several forms of aging-related neurodegenerative diseases (85). Furthermore, redox modication of transcriptional factors, as discussed in the previous section, leads to the activation or inactivation of signaling pathways that will subsequently produce changes in gene expression proles (155), including those affecting cellular proliferation, differentiation, senescence, and death (Fig. 1). It is important to note that many oxidatively damaged macromolecules also act as regulatory molecules in cell-signaling pathways. For instance, several lipid peroxidation products have been implicated in the activation of stress-response signal transduction pathways (114, 140, 267), while DNA damage by oxidative stress triggers the activation of cell apoptosis and senescence cascades via p53 activation (87, 125). Oxidative stress in apoptosis Apoptosis, also known as programmed cell death, plays an important role in all stages of an organisms development. While there are controversies in the literature regarding the role of apoptosis in aging, ageassociated increases in apoptosis have been observed in several physiological systems, including the human immune system, human hair follicle, and rat skeletal muscle (2, 5, 247). Apoptotic cell death is executed via two major signaling pathways, the intrinsic and extrinsic pathways, in either caspase-dependent or caspase-independent manners (44). The intrinsic pathway involves the induction of various protein responses, such as posttranslational modications, conformational changes and interorganelle translocation of specic proteins. These responses can produce an alteration in mitochondrial membrane potential and the release of apoptogenic factors, such as cytochrome c and apoptosis-inducing factor, from the mitochondria to the cytoplasm. A cascade of downstream signals, including caspases, is then stimulated to orchestrate apoptotic responses. In contrast, the induction of apoptosis by extrinsic pathways requires the binding of ligands to membrane
receptors and recruitment of cytosolic adaptor proteins, which will, in turn, activate a series of initiator and effector caspases. It has been clearly established that ROS and ROS-modulated molecules participate in both intrinsic and extrinsic apoptotic pathways (161). Some well-known exogenous ROS-generating stressors, such as radiation, proinammatory cytokine treatment, growth factor withdrawal, and physiological challenges, such as heat stress, will stimulate apoptosis (8, 89, 124, 215). One example of oxidative stress involvement in extrinsic apoptotic signaling pathways is the redox activation of the MAPK cascade upon sustained oxidative stress. A novel protein in the mitogen-activated-kinase-kinase-kinase family, known as apoptosis signal-regulating kinase 1 (ASK1), has recently been identied as a critical redox sensor in the MAPK pathway (83, 262, 268). Thioredoxin, a small enzyme that participates in redox reactions, can have a negative regulatory inuence on ASK1 and, subsequently, apoptosis (229, 298). Oxidative stress-induced apoptosis can also be reduced by a dominant-negative mutation of ASK1 (110). Another example involving the extrinsic apoptotic pathway is the downregulation of signaling pathways associated with growth factor receptor stimulation in response to oxidative stress (299). In the intrinsic apoptotic pathway, it has been shown that proteins in the mitochondrial permeability transition pore complex, which controls mitochondrial membrane potential, are the direct targets of ROS (135). These proteins include the adenine nucleotide translocator in the inner membrane (82), the voltage-dependent anion channel in the outer membrane (151), and cyclophilin D at the matrix (11). Prooxidants capable of induction of mitochondrial permeability potential include not only chemicals, such as t-butyl hydroperoxide and diamide (207) but also lipid peroxidation products such as 4-hydroxynonenal (217). Moreover, it has been increasingly recognized that oxidative damage to organelles, such as lysosomes and the endoplasmic reticulum, stimulates crosstalk between these organelles and mitochondria and induction of apoptosis via intrinsic signaling pathway (122, 256). More importantly, recent studies on p66Shc redox protein may provide a link between oxidative stress-mediated apoptosis and biological aging (169). The p66Shc redox protein is the third isoform discovered in the Shc protein family, and this group of proteins was initially identied as signal transduction adapters involved in mitogenic signaling through Ras, a small GTP-binding protein. Evidence has suggested that p66Shc is an atypical signal transducer that can be regulated by oxidative stress and also plays a role in H2O2 generation (80, 168). While mice lacking p66Shc (p66Shc/) live 30% longer than the control animals, p66Shc/ cells from knockout mice are resistant to ROS-induced apoptosis (168, 181). Several lines of evidence indicate that p66Shc potentially acts at sites upstream of the mitochondrial permeability transition pore in oxidative stress-mediated apoptosis (80, 192, 203). Oxidative stress in autophagy. Autophagy is characterized by the sequestration of bulk proteins, membrane fragments, and organelles into autophagic vesicles and the subsequent infusion and degradation of these vesicles in lysosomes. Cellular autophagy was discovered in the early 1960s, but renewed interests were recently triggered by the rst genetic evidence suggesting that autophagy is essential in the life span extension of the nematode Caenorhabditis elegans (166). Specic inhibition of autophagy by RNAi techniques abolished the life292 JANUARY 2007
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extension effect in C. elegans that carried a mutated gene in the insulin-like signaling pathway. While it has often been regarded as a housekeeping system for cells, autophagy is also a major pathway for the degradation and recycling of damaged cellular components to ensure cell survival under stress conditions, such as nutrition deprivation (178). However, recently it has been suggested that autophagy is not only important for cellular survival but can also induce cell death. For instance, there is evidence indicating that autophagy is directly involved in both cytokine- and chemical-induced cell death (216, 286). It appears that the dual roles played by autophagy, involving cell survival as well as cell death, are both important during aging process. On one hand, reports have shown that autophagic function declines with age in in vivo and in vitro settings (52, 158, 260). In support of these observations, cells from old rodents subjected to caloric restriction (CR), a life-extension intervention, have similar levels of autophagic function as their young counterparts (24, 55). Conversely, excessive activation of autophagy, leading to cell death, was observed in neurons with increased protein aggregation, suggesting that autophagy may play an important role in aging-related neurodegenerative diseases (71, 292). Although the regulation of autophagy is not yet completely understood, ROS have been implicated in the process. There is some evidence suggesting that aging-related increases in ROS production can result in elevated oxidative damage to proteins, including lysosomal proteins and proteins in autophagic pathways (38). However, more direct evidence for ROS involvement in autophagy comes from a recent report showing that cellular autophagy induced by caspase inhibition can lead to catalase degradation, resulting in ROS accumulation, lipid peroxidation, and loss of membrane integrity (291). Oxidative stress in cellular senescence. Cellular senescence was rst observed in cultured primary cells that ceased proliferation after a nite number of divisions. This concept of cellular senescence, termed replicative senescence, was later identied in primary cells under acute stress conditions and is also known as premature senescence (263). Two tumor suppressor proteins that are involved in cell cycle regulation, p53 and Rb protein, play central roles in the molecular mechanisms of cellular senescence. Evidence has shown that both p53 and Rb protein are activated when cells are in a senescent state (131, 182), while inactivation of these two proteins prevents senescence of human lung broblasts (280) and allows senescent cells to resume proliferation (81, 228). It is now known that several factors contribute to the activation of p53 and Rb protein and initiate senescence processes. Telomere shortening, acting through a pathway involving p53, is one of the most well-documented triggers for cellular senescence (101). Oxidative stress is another important cell senescence trigger. Exogenous treatment with hydrogen peroxide or inhibition of antioxidant enzymes initiates premature senescence in human broblasts (29). Similarly, senescence is routinely observed in cells grown in a high ambient oxygen concentration, while the proliferation life span of cells is extended when they were grown under physiologically relevant low oxygen tension (43, 195, 200). Based on a wide range of observations, it appears that oxidative stress participates in multiple steps of senescence signaling pathways, functioning at sites either upstream or downstream of p53 activation. For example, ROS can cause DNA damage and also accelerate telomere shortening (13,
273). In addition, ROS released by the activation of Ras oncogene can induce cell senescence via p53 activation (136), while the overexpression of Akt, an important cell-signaling molecule, led to an inhibition of Foxo3a transcription activity and an elevation of intracellular ROS that later induced a senescence-like cell growth arrest in a p53 dependent manner (172). Moreover, increased p53 activation can trigger a senescence response that is accompanied by increased levels of intracellular ROS (41), and p53-mediated cell fate also appears to correlate with the levels of intracellular ROS (149). Elevations in p53 are associated with high levels of ROS and cell apoptosis, while slight increases in p53 expression induce cell senescence that is reminiscent of a small increase in oxidative stress. The relevance of cellular senescence to in vivo aging has not yet been clearly delineated. Whether the mechanisms underlining premature senescence reect the mechanisms of organismal aging is also a controversy. However, a recent study indicated that cellular markers of senescence, such as telomere shortening, are exponentially increased with age in skin broblasts of primates (100). Furthermore, hematopoietic stem cells obtained from mice that develop ataxia telangiectasia syndrome, which is characterized by premature aging, neurodegenerative diseases, immunodeciency and cancers, showed increased levels of ROS and signs of cellular premature senescence (14, 113). Therefore, developing a better understanding of the molecular mechanisms of cellular senescence may provide some insight into the biology of organismal aging and potential sites for therapeutic interventions involving senescence pathways. Oxidative Stress in Normal Organismal Aging One of the central themes of the oxidative stress hypothesis is that ROS are the primary causal factor underlying agingassociated declines in physiological function. Several lines of direct and indirect evidence generated over the past two decades have demonstrated a positive relationship between increased in vivo oxidative stress and biological aging. While the majority of these correlative studies have been supportive of the oxidative stress hypothesis of aging, one controversial aspect of the hypothesis has been the lack of data clearly demonstrating a cause-and-effect relationship between the accumulation of oxidation-mediated cellular damage and aging. In the following sections, we discuss evidence related to ROS accumulation and changes in cellular redox status with aging, the potential to modulate oxidative damage via antioxidant enzyme manipulation, and current models being utilized to test the oxidative stress hypothesis. Increased in vivo ROS levels and a shift in redox status with age. One signicant challenge that investigators face in their attempt to directly assess oxidant levels in vivo are the low concentrations of ROS present within a cell and the extremely transient nature of these species. The only analytical approach that is currently available to directly detect radical species in biological systems is electron paramagnetic resonance (EPR) spectroscopy (also known as electron spin resonance) (132). The EPR approach takes advantage of the magnetic properties of unpaired electrons, and the energy states of these species produce characteristic footprints that are detectable on the electromagnetic spectrum. As summarized in a
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Fig. 2. DNA binding activities of the early response transcriptional factors activator protein-1 (AP-1) and NF-B are higher in old rats. Liver samples were obtained from young and old rats in euthermic control conditions. Nuclear extracts were analyzed by EMSA using AP-1-specic (A) or NF-Bspecic (B) 32P-labeled oligonucleotides. In both assays, DNA binding activities were greater in all old rats examined. AP-1 and NF-B DNA binding activities were supershifted by specic c-Jun or p50 antibodies reacting with nuclear extracts from old control animals to verify that the bands produced in the EMSA procedure represented the AP-1 and NF-B complexes. Each nuclear extract (5 g) was incubated with 5 l of antibody specic for AP-1 (c-Jun; A) or NF-B (p50 and p65; B) 2 h before the EMSA procedure. The experiments were repeated 3 times, and representative images are presented. FP, free probe. Adapted from Zhang et al. (297).
review by Tarpey et al. (257), some other techniques specic for individual types of ROS, such as the reaction of dihydroethidium with O2 to produce a red uorescence, have also been developed in recent years. Using these techniques, recent studies have shown that ROS levels are increased with age in major organ systems such as liver, heart, brain, and skeletal muscle (22, 23, 56, 84, 297). Due to the technical difculties of directly assessing oxidant levels in vivo, investigators have generally had to rely on more indirect measurements of oxidative stress. In particular, redox status is considered an important parameter for assessing the prooxidant environment in an in vivo system (213, 234). Several indicators of in vivo redox status are available, including the ratios of GSH to GSSG, NADPH to NAPD, and NADH to NAD, as well as the balance between reduced and oxidized thioredoxin. Among these redox pairs, the GSH-toGSSG ratio is thought to be one of most abundant redox buffer systems in mammalian species (234). A decrease in this ratio, indicating a relative shift from a reduced to an oxidized form of GSH, suggests the presence of oxidative stress at the cellular or tissue level. Experimentally, a progressive change to a more prooxidant environment has been noted in many species during aging (58, 245, 294, 297). In this scenario, an age-related shift from a cellular environment that is in redox balance to one with an oxidative prole would likely result in a blunted ability to buffer ROS that are generated in both normal conditions and at times of challenge. As demonstrated in recent studies from our laboratory in which rodents were exposed to a hyperthermic challenge (297), a primary outcome of this diminished buffering capability would be an increase in oxidative stress and widespread cellular damage. Thus, a progressive shift in cellular redox status could potentially be one of the primary molecular mechanisms contributing to the aging process and accompanying functional declines. Accumulation of oxidative damage with age. In addition to elevations in in vivo ROS levels and redox balance in aged organisms, one of the most common types of evidence presented by investigators is the strong correlation between aging and an increase in oxidative damage to tissues throughout the body in species ranging from C. elegans to humans (21, 33, 183, 184, 245). Studies of oxidant-associated damage during aging have been focused on oxidative modication of intracellular macromolecules, primarily lipids, proteins and DNA (1, 4, 25, 294, 297). In the case of DNA, oxidative damage to
mitochondrial and nuclear nucleic acids is signicantly increased in all major tissues in aged organisms, including mice (93), rats (93, 269), hamsters (255), and humans (79, 241). Substantially higher levels of lipid peroxidation products (e.g., MDA, 4-HNE, and F2-isoprostanes) have been observed in aged compared with young organisms in tissues, such as kidney (194, 279), brain (211, 223, 285), liver (194, 279), lung (139, 285), and muscle (117, 197). Moreover, investigators have discovered age-related oxidative modications to a large variety of proteins, including changes in structural proteins (88), enzymes, and proteins important in signal transduction pathways (27). Many investigators believe this increase in oxidized protein is the consequence of increased ROS production and impairment in protein turnover (65, 73). Removal of damaged proteins is mainly achieved by proteolytic degradation pathways including proteasome proteases, lysosome proteases, and mitochondrial proteases. Age-associated impairment has generally been reported in the function of all these proteolytic pathways (40, 74). It is important to point out that the extent of this age-associated increase in oxidative damage to macromolecules varies greatly among different tissues, species, and detection methods. Aberrant regulation of redox-sensitive signal pathways with age. Although the original concept of the oxidative stress theory suggested that ROS-induced accumulation of random macromolecular damage results in functional alterations and pathological conditions in old organisms, studies over the past decade have demonstrated that aging is associated with the regulation of several known redox-sensitive signal transduction pathways. For instance, as shown in Fig. 2, our laboratory has demonstrated an aging-associated increase in the DNA binding activities of NF-B and AP-1 in livers of old animals (294). Similar observations were made in many species by other investigators (126, 142, 155, 297). In two of the predominant animal models of longevity, C. elegans and Drosophila, it has been found that extension of life span is dependent on the activation of members of the Forkhead transcription factor family (107, 278). Moreover, transgenic mice containing an endogenous superactive form of p53 have a shortened life span and show signs of accelerated aging (266). However, in another strain of super p53 transgenic mice, increased activation of p53 did not affect life span (77). Investigators are now attempting to understand whether there is a direct causal link between oxidative stress and the
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modulation of aging processes via specic signal transduction pathways. As an example, mutations in the DAF-16 signaling pathway, a homologue of the mammalian Forkhead protein pathway, have been shown to extend life span in C. elegans. However, the manifestation of this result requires the expression of ctl-1, a gene coding for the cytosolic form of catalase. Mutation of the ctl-1 gene, which led to a decrease in catalase activity, abolished the life-extension effects in worms with daf-16 mutations (259). Furthermore, Nemoto and Finkel (185) have identied a pathway for peroxide modulation of the Forkhead protein in p66shc null mice broblasts and Migliaccio et al. (168) demonstrated that mice lacking p66shc exhibit an extended life span phenotype. Taken together, these results provide additional support for the possibility that intracellular oxidants play a key role in modulating in vivo aging processes. Studies along these lines have pointed toward new areas of inquiry related to oxidative stress and aging that could provide more detailed insight into the role of redox-sensitive transcription factor activation in modulating gene expression. Moreover, while many studies have documented the accumulation of oxidative markers with advancing age, only a limited amount of research, in a diverse range of species, such as worms, ies, mice, rats, and humans, has been conducted with regard to potential changes in gene expression proles (102, 137, 138, 224, 295, 300). Thus, it will be necessary to gain more detailed insight into the mechanisms governing agerelated changes in cell-signaling pathways with oxidative stress to better understand the integrative processes of aging, as well as to more carefully assess genes and metabolic pathways that may be directly involved in life span extension. Effects of antioxidant manipulation on aging. Although numerous studies have demonstrated a correlation between in vivo oxidative damage and aging, a more insightful test of the oxidative stress theory would be to assess the direct effects of antioxidants on aging processes. Two approaches have been widely applied in this area of study. The rst, which involves the evaluation of changes in antioxidant proles of older compared with young organisms, has proven difcult to generalize. On one hand, it is reasonable to postulate that the increase in oxidative stress and damage to cellular constituents associated with aging could be due to a decline in antioxidant defense systems. However, the pattern of aging-related changes in antioxidants in many tissues and species has been inconsistent. There are certainly studies supporting the notion that a decline in antioxidant defenses occurs with aging (91), but substantial data also exist indicating that there is no generalized decrease in antioxidant enzyme function (159, 221, 243). When viewed broadly over a range of different species, tissues, and conditions, the lack of a consistent decline in antioxidant enzyme activities suggests that antioxidant enzymes may not be a primary limiting factor governing the degree of cellular oxidative damage with aging. The second approach has been to directly determine whether experimental interventions can ameliorate oxidative damage or slow the rate of aging. This remains an active area of inquiry, as investigators attempt to increase intracellular antioxidant defenses, either by dietary supplementation of antioxidants or by overexpressing genes encoding antioxidant enzymes (e.g., SOD, catalase). Early attempts at antioxidant intervention as a means to delay aging were initiated soon after the free radical theory of
aging was proposed, but these pursuits failed to extend life span in most cases (28, 261). In recent years, some impressive successes have been achieved in nonmammalian models using synthetic antioxidant enzyme mimetics, and these results have stimulated additional interest in aging research. In one of the rst studies of this type, Melov et al. (167) showed that C. elegans treated with EUK-8 and EUK-134, antioxidant enzyme mimetics with both SOD and catalase activity, had signicantly longer life spans than untreated nematodes. However, the same conclusions could not be drawn from subsequent studies involving house ies treated with similar agents (17). Moreover, Keaney et al. (121) recently found that administration of these antioxidant enzyme mimetics to C. elegans, while increasing cellular SOD activity in a dose-dependent manner, did not extend life span. As advancements in genetic manipulation of animals have progressed, studies involving gene transfer of antioxidant enzymes, such as CuZnSOD, MnSOD, and catalase have been conducted in Drosophila. However, as noted by Sohal et al. (244), the results obtained from these studies have been difcult to reconcile. For example, overexpression of CuZnSOD and MnSOD by an inducible promoter in adult Drosophila was associated with extended life span (199, 251, 252), while overexpression of catalase in Drosophila had no effect on longevity (173, 191). Furthermore, other investigations using different strains of Drosophila and different promoters for antioxidant enzyme gene transfer have also yielded mixed results (18, 189). It is important to note that there can be substantial variation in both life span and effects of antioxidant enzymes in different y strains. Moreover, Sohal et al. (243) have suggested that the magnitude of any extension of life span in these types of studies could be attributed to the utilization of relatively short-lived control ies in the different experimental designs. Thus, extrapolation of these ndings in lower species such as Drosophila to more complex mammalian species should be carefully scrutinized. The direct impact of antioxidant enzyme treatment on life span is even less clearly dened in mammalian models. Some studies have failed to demonstrate improvements in life span with antioxidant enzyme manipulation, while others showed positive effects on longevity in mouse models. For instance, transgenic mice that constitutively overexpress human CuZnSOD did not live longer than control animals (105), while heterozygous mice with reduced MnSOD activity have a life expectancy that is similar to wild-type mice, although these animals have increased oxidative damage to DNA (272). In contrast to these negative results, a recent study provides some of the rst direct evidence in support of the oxidative stress theory of aging in mammals. Schriner et al. (237) showed that transgenic mice overexpressing human catalase in mitochondria had increases in both median and maximum life span by averages of 5 and 5.5 mo, respectively. It was also signicant that this extension of life span was accompanied by reductions in selected markers of oxidative damage, such as attenuated H2O2 production and H2O2-sensitive aconitase inactivation in heart and skeletal muscle. The expression of other antioxidant enzymes has also affected life span in a variety of animal models. In Drosophila, overexpression of glutamate-cysteine ligase, a rate-limiting enzyme for de novo GSH biosynthesis, extended mean and maximum life span by 50% (190). Similarly, overexpression of
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methionine sulfoxide reductase, a enzyme that catalyzes the reduction of methionine sulfoxide back to methionine, extended life span by 70% in Drosophila (227), while mice with reduced activity of methionine sulfoxide reductase have an increased sensitivity to oxidative stress (179). Furthermore, transgenic mice overexpressing human thioredoxin, a small protein with important redox regulatory properties, exhibited extended median and maximum life span values compared with their wild-type counterparts (171). These controversial and sometimes contradictory outcomes from experiments involving the manipulation of antioxidants by either pharmacological or genetic approaches add further support for the postulate that aging is a complicated and multifaceted phenomenon that cannot be accounted for by a single theory. Future research should focus some efforts on delineating common pathways that contribute to the aging process, especially among longer-lived species. These types of studies will provide more mechanistic insight into potential therapeutic targets and approaches for modulating aging, agerelated diseases, and longevity. Oxidative stress in aging models. Many of the in vivo aging models currently being utilized by investigators involve animals with an altered life span that has been produced by either pharmacological intervention or gene manipulation. Such studies have provided signicant insights into aging processes and, signicantly, are now progressing to include higher mammalian species. There are generally two types of aging models: long-lived animals with retarded aging processes or short-lived animals with accelerated aging processes. CR, an intervention involving a prolonged reduction in caloric intake while maintaining adequate nutrition, is known to increase life span and retard age-associated physiological deterioration in species ranging from yeast to mammals (111, 129, 156, 245, 282, 289). One potential mechanism contributing to these benecial effects associated with CR is a reduction in oxidative stress (129, 245). Currently, several pieces of evidence support this postulation. For instance, CR can blunt the increase in lipid peroxidation, accumulation of oxidized proteins, and oxidative damage to DNA that occurs with aging (59, 159, 242). This reduction in oxidative damage by CR has been attributed to a decline in the rate of ROS generation and an enhanced ability to repair oxidative damage in CR animals (148, 231). Moreover, recent ndings have demonstrated that CR can enhance some aspects of antioxidant enzyme function (6, 49, 92), although other studies that focused on the activities of individual antioxidant enzymes in a variety of tissues during aging or in response to CR have generated conicting results (92, 159, 221, 245). In addition, our laboratory demonstrated that a long-term reduction in caloric intake also improves tolerance to heat stress and reduces heat-induced oxidative damage in aged rodents (92). Information obtained from several long-lived animal models has been supportive of the oxidative stress theory. For instance, growth hormone deciency leads to extended life span in several strains of mice, including Ames dwarf, Snell dwarf, and genetically modulated, growth-hormone receptor knockout mice, and most of these strains have shown an increased resistance to oxidative stress (16). Specically, Ames dwarf mice exhibit upregulation of antioxidant enzyme expression (35, 36, 98), reduced mitochondrial ROS production, and decreased oxidative damage (34, 230) in several tissue types.
Importantly, these physiological changes are associated with life span increases of over 50% compared with their wild-type littermates. Another category of long-lived animals involves species defective in the insulin/IGF-I signaling pathway. Not surprisingly, life-extension in these animals is generally accompanied by increased antioxidant defenses and resistance to oxidative stress (15, 103, 144, 258, 271). Studies by Nemoto and Finkel (181) have demonstrated that p66sch, a protein involved in the transduction of mitogenic and apoptotic signals, participates in the regulation of intracellular oxidant levels. In these experiments, immortalized broblasts from p66sch/ mice subjected to the stress of serum deprivation had lowered levels of ROS than their wild-type counterparts as measured by a redox sensitive probe. Consistent with these ndings, p66sch gene knock-out in mice increases life span by 30% and reduces in vivo oxidative damage and ROS production (181, 265). Evidence from an animal model with a shortened life span has also been supportive of the oxidative stress theory. Senescence-accelerated mice have shown hastened declines in mitochondrial function (188), GSH-to-GSSG ratios (219), and antioxidant enzyme activities, along with increased lipid peroxidation (198) and enhanced sensitivity to oxidative stress (146) in multiple types of tissues. Alternatives to the oxidative stress theory: evidence in animal models. While substantial evidence from various animal models provides a strong link between aging and oxidative stress, it is important to note that data from some aging models also suggest alternatives to the oxidative stress theory of aging. As an example, studies attempting to understand the effects of CR on aging have produced results implicating other causal factors for changes in aging processes, such as neuroendocrine alterations, a decrease in protein glycation, a lowering of body temperature and associated hypometabolic state, and alterations in gene expression (111, 156, 193). In addition, mice expressing a defective form of mitochondrial DNA polymerase, an enzyme important in repairing mitochondrial DNA damage, showed reduced mean and maximum life span and evidence of premature aging (264). However, no signicant increases in markers of oxidative damage were found in these animals compared with their wild-type counterparts. Thus, results obtained from experiments performed in this animal model suggest that the accumulation of mitochondrial DNA damage that is independent of oxidative stress may also be important in the aging process. Despite some contradictory results, animal models produced during the past decade have provided valuable information on biological systems that impact on aging. As more animal models are developed to study aging mechanisms, it will be important to carefully evaluate the relevance of these models to normal aging processes. For instance, a genetic manipulation that accelerates aging can yield important insight into the function of an intracellular signaling pathway on specic aging processes. However, it may be valid to question to what extent an accelerated aging model is relevant to normal biological aging. The same is true for life span extension models that are currently being utilized. Furthermore, the only intervention that has been consistently successful in extending life span in mammals is CR, and it is well documented that CR yields a vast array of physiological changes that impact on multiple systems. Therefore, one of the current challenges for researchers is to incorporate the information obtained from genetic
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Invited Review R26

manipulation studies into a broader context that focuses on integrated mechanisms of aging, with a particular eye on applications that are relevant to humans. Oxidative stress in age-related stress tolerance. As noted in preceding sections, aging is linked to an increase in ROS generation and oxidative damage. In addition, many types of stressors, such as hyperthermia (297) and hypoxia (31), have been associated with an increased production of prooxidants and induction of oxidative stress. Recently, several studies have demonstrated that young organisms are capable of initiating an array of regulatory processes in response to oxidative stress, including the activation of stress-gene expression and modication of stress-responsive signal transcription pathways. In contrast, there is compelling evidence that these regulatory processes are altered in old organisms (39, 92, 108, 109, 128, 130, 142, 177, 270, 297). Therefore, stress-induced cellular injury appears to be exaggerated with advancing age. This failure to effectively respond to cellular challenge has been postulated to contribute to a reduction in stress tolerance and the development of various pathologies and diseases (155). Consistent with this view, Lithgow and colleagues (145, 162) have shown that extension of life span in C. elegans through genetic mutations was associated with an increase in resistance to a variety of insults. Moreover, Miller (170) has speculated that enhanced resistance to oxidative stress, through both antioxidant mechanisms and the engagement of multiple cellular signaling pathways associated with stress resistance, will be integral in explaining the mechanism of life span extension. Studies from the authors laboratory have addressed the issue of stress tolerance in detail in a series of experiments by investigating the effects of hyperthermia on old compared with young rodents (294, 296, 297). For instance, repeated heat challenge produces extensive injury in the liver of older rats, whereas young rats tolerate the stress very well. In the old cohort, this injury pattern is associated with increases in steady-state levels of ROS and substantial oxidative damage to hepatocellular macromolecules (e.g., lipids, DNA), along with alterations in intracellular redox status and aberrant activation of stress-response transcription factors (297). These data demonstrate that young animals can effectively cope with oxidative stress in response to environmental challenge. In contrast, in older animals, a decline in cellular redox potential, along with exaggerated ROS generation, leads to extensive oxidative damage and alterations in intracellular signal transduction. Factors such as these are likely to contribute to the cellular dysfunction and reductions in stress tolerance that are hallmarks of aging. In subsequent experiments, in an effort to determine whether a therapeutic intervention that reduces the degree of oxidative damage can protect old animals from heat-stress induced liver injury, young and old rats were chronically administered a continuous, low-dose infusion of the synthetic catalytic ROS scavenger EUK-189 via an implanted osmotic pump and then were exposed to a heat stress protocol (294). Widespread oxidative injury to the liver (e.g., hepatocyte vacuolization, necrosis, monocyte inltration) was present in old but not young vehicle-treated animals in response to hyperthermic challenge. However, SOD/catalase mimetic treatment markedly decreased the liver injury associated with heat stress in old animals. The reversal of histopathologic damage with EUK189 in the old cohort was also associated with a striking reduction in hepatocellular lipid peroxidation (Fig. 3A) and an
improvement in intracellular redox status, as evidenced by an increase in GSH-to-GSSG ratios within liver tissue (Fig. 3B). Cell-signaling changes were also noted with EUK-189 treatment. AP-1, which is a redox-sensitive early response transcription factor involved in the regulation of cellular stress responses, was elevated following heat stress in old rats. With chronic antioxidant enzyme mimetic treatment, DNA binding activity of AP-1 was reduced back to control levels (Fig. 3C). Finally, plasma alanine aminotransferase (ALT), which is a systemic marker for hepatocellular damage, was measured in animals after the heating protocol to assess in vivo functional changes in relation to the alterations in oxidative stress and organ damage that were observed to accompany the modulation in cellular redox status with EUK-189 treatment (Fig. 3D). ALT concentrations were markedly increased in older but not young animals following heating, consistent with the histological and oxidative damage observed. Conversely, heat-stressed old animals that received chronic antioxidant mimetic treatment had circulating ALT levels that were similar to those in young and old nonheated control animals. These results suggest that either a decline in redox potential or an exaggerated production of ROS will lead to extensive hepatocellular oxidative damage and alterations in intracellular signal transduction in older animals, which subsequently contribute to cellular and organ dysfunction and age-related reductions in stress tolerance. Based on these and other observations, it could be postulated that antioxidants would be therapeutically effective in an aged mammal exposed to a stressor that generates exaggerated oxidative injury. The ndings from these studies also implicate an imbalance in intracellular redox status as having a direct causal role in the reduced stress tolerance that accompanies aging. ROS, inammation, and aging. Developing a clearer understanding of the basic mechanisms of biological aging certainly has long-term implications for improving both longevity and quality of life in humans. However, along with the desire to understand the hows of aging at a molecular level, there is also a compelling need to delineate why the aging process is accompanied by an increased incidence of various chronic diseases. This type of knowledge should allow scientists to develop more comprehensive therapeutic strategies to offset the increased vulnerability of aged individuals to a wide range of degenerative conditions. As outlined in previous sections, the free radical theory of aging is currently among the most plausible explanations for the aging process in mammalian species. This theory serves not only to explain basic mechanisms of aging, but also the pathogenesis of a range of disease processes that consistently accompany aging, including atherosclerosis and other cardiovascular disorders, dementia, diabetes, arthritis, and osteoporosis (21, 51). In evaluating the free radical theory and its possible link to numerous age-related maladies, investigators have focused attention on the possibility that an increase in ROS, along with a concomitant disruption in redox balance, leads to a state of chronic inammation (Fig. 4) (45, 47, 134, 232). Along these lines, Yu and colleagues (46) have proposed the molecular inammation hypothesis of aging as a possible mechanistic link between biological aging and pathological conditions associated with aging. An age-related disruption in intracellular redox balance appears to be a primary causal factor in producing a chronic
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Fig. 3. Impact of an environmental insult on age-related oxidative stress responses and the effect of redox modulation with chronic antioxidant enzyme mimetic treatment. Liver samples were obtained from young and old rats in euthermic control conditions and 2 h after a heat stress protocol. Prior to the heating protocol, some young and old rats were chronically treated (4 wk) with either the SOD/catalase mimetic EUK-189 (heat EUK) or vehicle (heat alone), both of which were delivered via an implanted miniosmotic pump (n 59 rats/age group for each treatment). A: EUK supplementation prevented heat-induced hepatic oxidative damage. The lipid peroxidation marker malondialdehyde was elevated in old rats after heat stress, but not young rats. Chronic supplementation with EUK signicantly reduced the oxidative damage associated with heat stress in old rats. B: EUK supplementation improved redox status in old rats. The ratio of GSH and GSSG was utilized to evaluate cellular redox status. In control conditions, a more prooxidative environment was present in the liver of old vs. young controls as indicated by the lower GSH/GSSG ratio in the old animals. Following heat stress, there was an increase in oxidative stress in liver samples from young rats, whereas the GSH-to-GSSG ratio remained low in the old rats. EUK supplementation reduced the oxidative environment in the liver of both young and old rats after heat stress as evidenced by an increase in the GSH-to-GSSG ratio. C: EUK-189 supplementation normalized DNA binding activity of the redox-sensitive transcription factor AP-1. Heat stress produced an increase in AP-1 DNA binding activity in the liver of old rats, but EUK supplementation resulted in a decrease in this activity back to control levels. D: EUK-189 supplementation prevented hepatic alanine aminotransferase (ALT) release after heat stress. ALT, a systemic marker for hepatocellular damage, was measured in plasma samples from young and old rats. Heat stress produced an increase in ALT levels in old but not young rats. However, old rats supplemented with EUK and, subsequently, heat stressed had ALT levels similar to control conditions. *P 0.05 vs. young rats within a treatment group; P 0.05 vs. old control and old heat EUK groups; P 0.05 vs. old control and old heat. Adapted from Zhang et al. (294).
state of inammation (Fig. 4). Besides impairing a cells ability to effectively remove ROS, this redox imbalance leads to an activation of redox-sensitive transcription factors and the subsequent generation of numerous proinammatory mediators [e.g., cytokines, chemokines, inducible nitric oxide (NO) synthase]. These molecules, acting both systemically and at the tissue level, can produce products that include both reactive oxygen and reactive nitrogen species (153, 187, 214, 249, 284), and it is postulated that the accumulation of these reactive species contributes to the pathogenesis of age-related diseases (47, 232). In this scenario, a positive feedback loop is also activated with the generation of these reactive species, which serves to further augment the cascade of inammatory processes and exacerbate inammation-induced cellular and tissue damage. There is substantial evidence, in a range of systems and species, supporting the link between aging and chronic inammation, as well as the integrated molecular and cellular signaling processes depicted in Fig. 4. Chronic inammation is typically assessed by measuring various inammatory biomarkers, and at the tissue level, the primary marker of chronic inammation is the inltration of macrophages, which is posAJP-Regul Integr Comp Physiol VOL
itively correlated to several age-associated diseases. For instance, investigators have observed activated macrophages in the brain of patients with various neurodegenerative diseases (163, 164), as well as in plaques obtained from patients with atherosclerosis (288). These activated macrophages generate reactive species, which can subsequently produce oxidative and nitrosative injury in specic tissues. In the systemic circulation, biomarkers include inammatory cytokines and acute phase proteins such as C-reactive protein, and it is welldocumented that circulating levels of these proinammatory proteins are increased with advancing age. In humans, IL-1, IL-6, and TNF- are generally higher in the plasma of older individuals compared with their young counterparts (10, 37, 54, 61, 70, 202). However, it is important to note that this chronic inammatory condition in aged populations is associated with substantially lower circulating levels of these inammatory markers than would be generated during an acute inammatory condition. Evidence from both animal and human studies indicates that there are also positive correlations between chronic inammation and the development of age-associated diseases (47, 232). Although many of these diseases involve a chronic inamma292 JANUARY 2007
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Invited Review R28

Fig. 4. Relationship between ROS, inammation, and aging. An increase in ROS levels and a redox imbalance stimulates an intracellular signaling cascade that can potentially stimulate a state of chronic inammation and contribute to both aging processes and the manifestation of aging-associated diseases. iNOS, inducible nitric oxide synthase, O , positive feedback.
tory state, it is unclear whether inammation is an integral component in the pathogenesis of a particular disease or an underlying secondary event. However, long-term inammation can clearly inuence the pathogenesis and progression of these diseases. Attempts to delineate basic mechanisms responsible for the pathogenesis of these disease conditions are currently being undertaken in a wide array of disciplines and will necessitate an integrative approach that includes an understanding of the entire inammatory cascade. Relevant to this minireview, it appears that increased ROS levels, accompanying cellular redox imbalance, and related oxidative damage are key contributors to the pathogenesis of many age-related maladies. Therefore, knowledge gained concerning the role of oxidative stress in the pathogenesis of specic diseases and chronic inammatory conditions may prove insightful to scientists pursuing more basic questions related to the causal agents of biological aging and issues of longevity in mammalian species. Studies in human and nonhuman primates. A vast majority of studies addressing the role of oxidative stress in aging processes over the past half century have been performed in a wide range of animal species, and the results obtained have certainly shed a great deal of light on basic molecular mechanisms of aging. However, extrapolating ndings from ies,
worms, and rodents to humans, while useful as a potential means to optimize human health and longevity, should also be approached with caution. Given our complex genetic and physiological make-up, it is important to directly assess the role of oxidative stress in human aging processes. At the present time, only limited experimental data are available regarding oxidation status in older humans, due in part to the difculties of assessing aging per se compared with age-related disease effects. An increased presence of oxidative damage to mitochondrial DNA has been found in skeletal muscle and brain of older individuals (165, 241), and these observations are consistent with recent ndings demonstrating a decline in mitochondrial function in older humans (48, 206). Some survey data evaluating plasma antioxidant levels and dietary intake of antioxidant nutrients in human populations as a function of age can be found in the literature (53, 75), although this type of information has only limited utility. However, as noted in a previous section, one of the more signicant developments in this area over the past decade has been the accumulation of evidence to suggest that oxidative stress is a primary or secondary causal factor in many agedependent human diseases (21, 26, 30, 50, 51, 69, 116, 250, 281). Some potential insights into the impact of oxidative stress on aging processes in humans can also be drawn from the CR literature. Numerous studies have demonstrated that a decrease in caloric intake of 40% throughout the life span of laboratory animals can eliminate or retard numerous age-associated chronic diseases, improve stress tolerance, and prolong both average and maximal life span. Several hypotheses have been proposed to explain the mechanisms by which CR functions to produce these benecial effects, but a decrease in energy expenditure, along with concomitant reductions in ROS production and oxidative damage, appear to be key components in many studies (92, 129, 157, 245). Investigations involving nonhuman primates, which are ongoing, have reported benecial effects of CR on overall health status. In rhesus monkeys, low calorie diets have impacted on several morphological and physiological parameters (112, 218, 226), including a reduction in skeletal muscle oxidative damage (226). However, the expression of genes involved in oxidative stress from skeletal muscle samples of monkeys was not affected by CR in a study by Kayo et al. (120). In addition, primate life span data are not yet available. In humans, experimental data on the effects of CR is quite limited. Some studies suggest that health benets can be manifested from short-term reductions in caloric intake (68, 99, 274, 275), but there are currently no results from well-controlled studies involving long-term CR. One emerging area of research that has important clinical ramications is the potential role of ROS on vascular dysfunction that accompanies human aging (46, 154, 186, 201, 246, 290). Blood vessels are critically important to overall physiological homeostasis due to their role in supplying cells throughout the body with oxygen and nutrients. Thus, damage to these vessels can have a profound impact on organ function and contribute to a myriad of diseases that are typically associated with aging (e.g., diabetes, atherosclerosis, hypertension). Endothelial cells that line blood vessels, because of their location, are especially vulnerable to potentially damaging circulatory factors, such as oxidized macromolecules and proinammatory cytokines, and endogenous ROS generation within endothelial
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cells can also lead to oxidative damage and cellular dysfunction. Yu and colleagues (46, 47, 290) have postulated that vascular aging may be a primary factor in the overall aging process; thus, alterations at cellular, tissue, and organ levels may be secondary to age-related vascular dysfunction. In such a scenario, therapeutic interventions aimed at reducing oxidative stress and accompanying damage to the vasculature could have benecial effects on a range of age-associated pathologies. Most antioxidant intervention studies have involved longterm treatments as a potential means to eliminate age-related oxidative damage. However, there is a developing literature focused on the use of acute or short-term administration of antioxidants as a method to determine the tonic inuence of oxidative stress on altered physiological function in aged humans. Relevant examples can be found in studies that have examined the link between oxidative stress, endothelial dysfunction, and the potential development of cardiovascular diseases (e.g., atherosclerosis, hypertension). The endothelium functions to modulate both vascular tone and structure, primarily through the production of NO, which serves as a relaxing factor the vasculature. Endothelial dysfunction, which is increased with aging (60, 78, 254), can arise when oxidative stress reduces NO availability. Moreover, arterial endothelial dysfunction is a key component of many cardiovascular disorders (174, 225). Based on the link established between oxidative stress and age-related vascular dysfunction, investigators have begun to view the vasculature as a key target for antioxidant therapeutic intervention with regard to aging and age-associated diseases. Initial studies in this area demonstrated that the acute administration of ascorbic acid (vitamin C) improved brachial artery blood ow in patients with coronary artery disease (141) or congestive heart failure (104). More recent studies in older humans have shown that vascular function (specically, ischemia-induced increases in brachial artery blood ow) was reduced in old, compared with young, sedentary men, but acute ascorbic acid infusion restored arterial blood ow responses in the older group. However, ascorbic acid supplementation for a relatively short duration (30 days) did not have the same effect on age-related vascular responsiveness (62). These ndings, along with supporting data from postmenopausal women treated acutely with ascorbic acid (175), suggest that the impairment in arterial vascular function that accompanies aging may be mediated by an increase in vascular oxidative stress. These results are some of the rst evidence to implicate oxidative stress as an important contributor to vascular dysfunction with human aging. While it is unclear whether longerterm antioxidant treatments might prove effective in dealing with aging and conditions, such as vascular aging, provocative results from acute-treatment studies suggest that the vasculature should be viewed as a key target for therapeutic intervention (133, 180, 239). Integrative Mechanisms While the ultimate causes of aging are complex and multifaceted, it is clear that knowledge regarding the cellular, biochemical, and genetic changes that accompany aging is steadily growing. There is now strong correlative evidence implicating the formation of ROS and the accompanying inAJP-Regul Integr Comp Physiol VOL
Fig. 5. A schematic summary of proposed mechanisms by which ROS and oxidative stress could contribute to the process of aging. A variety of exogenous and endogenous factors can stimulate an increase in ROS production at the cellular level. ROS can stimulate signal transduction pathways, resulting in changes in gene expression that can modulate numerous responses that impact on cellular function and survival. In addition to activating intracellular signaling pathways, elevations in ROS can produce oxidative damage at molecular levels (DNA, proteins, lipids), if repair processes are insufcient. One result is organelle damage, which can directly affect key cellular responses. In both scenariosthe modulation of expression of various stress-response genes and the intracellular damage to macromoleculesthere are subsequent responses at cellular levels (e.g., inammation, proliferation, apoptosis, necrosis) that can stimulate additional ROS generation from endogenous sources. ROS-induced changes at cellular levels can also lead to an integrated array of systemic responses that can impact, with the passage of time, on aging processes, as well as organ dysfunction, frailty, and age-related diseases.
crease in oxidative stress as key contributors to the process of aging in cells and tissues. This correlation is found in a wide range of species both short- and long-lived. While the oxidative stress theory remains a viable hypothesis, a direct casual link between oxidative stress and either aging pathologies or life span has not yet been denitively proven, which has hindered the widespread acceptance of this theory as the primary explanation for the aging process. Therefore, at the current time, a more appropriate explanation would likely include an increase in ROS levels and subsequent oxidative stress/damage as key features of more complex physiological changes that contribute to aging. One possible integrative scenario by which ROS and oxidative stress could contribute to aging is proposed in Fig. 5. As illustrated in this gure, the aging process involves multifaceted changes that are affected by both exogenous conditions and endogenous factors at molecular, cellular, tissue, organ, and systemic levels. Aging effects are revealed rst at molecular levels and include the accumulation of macromolecular damage and changes in signal transduction pathways. These alterations subsequently impact on cellular responses, such as organelle dysfunction, inammation, cell proliferation, survival, and death. Eventually, dysfunction is manifested at systemic levels, which would likely include a decline in organ function, reduced stress tolerance, frailty, increased incidence of diseases, and death. With this model has come a greater appreciation of the important roles played by ROS and the profound physiological impact that an acute or chronic shift in cellular redox environ292 JANUARY 2007
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OXIDATIVE STRESS IN AGING 3. Ali S, Jain SK, Abdulla M, Athar M. Paraquat induced DNA damage by reactive oxygen species. Biochem Mol Biol Int 39: 63 67, 1996. 4. Ames B, Shinenaga MK, Hagen TM. Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci USA 90: 79157922, 1993. 5. Arck PC, Overall R, Spatz K, Liezman C, Handjiski B, Klapp BF, Birch-Machin MA, Peters EM. Towards a free radical theory of graying: melanocyte apoptosis in the aging human hair follicle is an indicator of oxidative stress induced tissue damage. FASEB J 20: 1567 1569, 2006. 6. Armeni T, Pieri C, Marra M, Saccucci F, Principato G. Studies on the life prolonging effect of food restriction: glutathione levels and glyoxylase enzymes in the liver. Mech Ageing Dev 101: 101110, 1998. 7. Ashok BT, Ali R. The aging paradox: free radical theory of aging. Exp Gerontol 34: 293303, 1999. 8. Assefa Z, Van Laethem A, Garmyn M, Agostinis P. Ultraviolet radiation-induced apoptosis in keratinocytes: on the role of cytosolic factors. Biochim Biophys Acta 1755: 90 106, 2005. 9. Bae YS, Sung JY, Kim OS, Kim YJ, Hur KC, Kazlauskas A, Rhee SG. Platelet-derived growth factor-induced H2O2 production requires the activation of phosphatidylinositol 3-kinase. J Biol Chem 275: 10527 10531, 2000. 10. Baggio G, Donazzan S, Monti D, Mari D, Martini S, Gabelli C, Dalla Vestra M, Previato L, Guido M, Pigozzo S, Cortella I, Crepaldi G, Franceschi C. Lipoprotein(a) and lipoprotein prole in healthy centenarians: a reappraisal of vascular risk factors. FASEB J 12: 433 437, 1998. 11. Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, Robbins J, Molkentin JD. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434: 658 662, 2005. 12. Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, aging. Cell 120: 483 495, 2005. 13. Bar-Or D, Thomas GW, Rael LT, Lau EP, Winkler JV. Asp-AlaHis-Lys (DAHK) inhibits copper-induced oxidative DNA double strand breaks and telomere shortening. Biochem Biophys Res Commun 282: 356 360, 2001. 14. Barlow C, Dennery PA, Shigenaga MK, Smith MA, Morrow JD, Roberts LJ, 2nd Wynshaw-Boris A, Levine RL. Loss of the ataxiatelangiectasia gene product causes oxidative damage in target organs. Proc Natl Acad Sci USA 96: 99159919, 1999. 15. Bartke A. Mutations prolong life in ies; implications for aging in mammals. Trends Endocrinol Metab 12: 233234, 2001. 16. Bartke A, Brown-Borg H. Life extension in the dwarf mouse. In: Current Topics in Developmental Biology, edited by Schatten GP. New York: Academic, 2004, p. 189 225. 17. Bayne ACV, Sohal RS. Effects of superoxide dismutase/catalase mimetics on life span and oxidative stress resistance in the housey, Musca domestica. Free Radic Biol Med 32: 1229 1234, 2002. 18. Bayne AC, Mockett RJ, Orr WC, Sohal RS. Enhanced catabolism of mitochondrial superoxide/hydrogen peroxide and aging in transgenic Drosophila. Biochem J 391: 277284, 2005. 19. Beal MF. Less stress, longer life. Nat Med 11: 598 599, 2005. 20. Beausejour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, Campisi J. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J 22: 4212 4222, 2003. 21. Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev 78: 547581, 1998. 22. Bejma J, Ji LL. Aging and acute exercise enhance free radical generation in rat skeletal muscle. J Appl Physiol 87: 465 470, 1999. 23. Bejma J, Ramires P, Ji LL. Free radical generation and oxidative stress with ageing and exercise: differential effects in the myocardium and liver. Acta Physiol Scand 169: 343351, 2000. 24. Bergamini E, Cavallini G, Donati A, Gori Z. The anti-ageing effects of caloric restriction may involve stimulation of macroautophagy and lysosomal degradation, and can be intensied pharmacologically. Biomed Pharmacother 57: 203208, 2003. 25. Berlett BS, Stadtman ER. Protein oxidation in aging, disease, and oxidative stress. J Biol Chem 272: 2031320316, 1997. 26. Berliner JA, Heinecke JW. The role of oxidized lipoproteins in atherogenesis. Free Radic Biol Med 20: 707727, 1996.
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ment can have on an organism, especially as it grows older. As reviewed in previous sections, intracellular ROS production is increased with exposure to many environmental stress conditions. While increased oxidative stress and other factors trigger an array of alterations at molecular levels that contribute to aging, genetic factors, as well as lifestyle, can accelerate or reverse the aging process by either sensitizing or preventing and repairing the defects. As the molecular and cellular defects accumulate during the life span of an organism, the resulting perturbation in redox balance and the endogenous generation of ROS will further inuence the regulation of a number of physiological functions (e.g., metabolism and stress tolerance) and, ultimately, accelerate the aging process. Perspectives While it remains unclear whether reactive species derived from oxygen molecules are the primary cause of aging in mammalian species, there is substantial evidence from a variety of species demonstrating that in vivo oxidative damage is highly correlated with biological aging. However, to date, interventions aimed at reducing oxidative damage in mammals, primarily through manipulations of antioxidant enzyme systems, have yielded disappointing results. Another issue that must be carefully scrutinized as this eld of research moves forward is whether insights gained from relatively short-lived mammalian species, such as mice with an average life span of 2 to 4 yr, are applicable to humans, who can live well beyond 100 years. If oxidative stress is a key component of biological aging, researchers must consider whether there are differences in ROS generation, cellular responses to these molecular species, or antioxidant defenses that explain the disparity in longevity of various mammalian species. Despite these concerns, substantial progress has been made toward an integrative understanding of aging, and attempts to delineate mechanisms to explain the biology of aging should include ROS and oxidative stress as potential key participants. With the successes being achieved through genetic manipulations and the development of drug therapies that can modulate oxidative processes and antioxidant defenses, it may be possible in the near future to more clearly delineate the integrative mechanisms of aging that are common between a broad range of species. By gaining more detailed knowledge of specic pathways affected by aging, investigators will be provided with additional opportunities to impact both life span and agerelated diseases in humans.
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An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations

Kevin C. Kregel and Hannah J. Zhang

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