Mitochondrial free radical theory of aging: Who moved my premise?

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First proposed by D Harman in the 1950s, the Mitochondrial Free Radical Theory of Aging (MFRTA) has become one of the most tested and well-known theories ...
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Geriatr Gerontol Int 2014; 14: 740–749

REVIEW ARTICLE: BIOLOGY

Mitochondrial free radical theory of aging: Who moved my premise? Ye Liu, Jiangang Long and Jiankang Liu Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an, China

First proposed by D Harman in the 1950s, the Mitochondrial Free Radical Theory of Aging (MFRTA) has become one of the most tested and well-known theories in aging research. Its core statement is that aging results from the accumulation of oxidative damage, which is closely linked with the release of reactive oxygen species (ROS) from mitochondria. Although MFRTA has been well acknowledged for more than half a century, conflicting evidence is piling up in recent years querying the causal effect of ROS in aging. A critical idea thus emerges that contrary to their conventional image only as toxic agents, ROS at a non-toxic level function as signaling molecules that induce protective defense in responses to age-dependent damage. Furthermore, the peroxisome, another organelle in eukaryotic cells, might have a say in longevity modulation. Peroxisomes and mitochondria are two organelles closely related to each other, and their interaction has major implications for the regulation of aging. The present review particularizes the questionable sequiturs of the MFRTA, and recommends peroxisome, similarly as mitochondrion, as a possible candidate for the regulation of aging. Geriatr Gerontol Int 2014; 14: 740–749. Keywords: aging, mitochondria, Mitochondrial Free Radical Theory of Aging, peroxisome, reactive oxygen species.

Mitochondrial Free Radical Theory of Aging: A potent theory of aging Willy-nilly, we are living in an aging society. The past few decades have seen an unprecedented increase in the incidence of age-related diseases such as type 2 diabetes, osteoporosis and Alzheimer’s disease, affecting both the physical and mental health of human beings. Among theories that explain aging, the Mitochondrial Free Radical Theory of Aging (MFRTA)1 provides a plausible mechanism grounded on observations on ROS from mitochondria.2 This theory proposes that cellular aging is due to an increased level of ROS including superoxide, hydrogen peroxide and hydroxyl radical, byproducts of cellular metabolism through the mitochondrial electron transport chain (ETC).3 According to the MFRTA, the chemically reactive ROS can attack cellular macromolecules, such as proteins, lipids and nucleic acids.4 Under normal conditions, healthy cells are protected by a well-developed defense system against oxidative damage with enzymes (e.g. superoxide dismutase, catalase and peroxiredoxin) and small molAccepted for publication 9 March 2014. Correspondence: Dr Jiankang Liu PhD, Center for Mitochondrial Biology and Medicine, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi’an Jiaotong University, no. 28, West Xian-ning Road, Xi’an 710049, China. Email: [email protected]

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doi: 10.1111/ggi.12296

ecule anti-oxidants (e.g. vitamin C, vitamin E and glutathione) that scavenge free radicals and inhibit generation of ROS.5 Whereas in a pathological state where ROS cannot be swept off, oxidative stress will accumulate and cells will malfunction, which eventually triggers the switch of aging.6,7 Evidence in line with this theory includes: (i) that there exists a positive correlation between chronological age and the level of ROS production8,9 (i.e. older animals tend to suffer more from ROS damage than their younger counterparts and long-lived species leak less ROS from the ETC than short-lived ones); (ii) that mitochondrial deficiency is observed in several agerelated diseases and during the process of aging;10–12 and (iii) that some anti-oxidants have a positive effect in enhancing mitochondrial function and extending lifespan.13–16 As mitochondria are believed the main source and target of ROS,17 a vicious cycle is also predicted by the MFRTA: under abnormal conditions, oxidative damage accumulates as a result of an increased release of ROS; and this in turn leads to mitochondria malfunction and a succedent round of ROS burst.18

Can MFRTA always stand the test of experiments? Pervasive as it is, the MFRTA now faces challenges from various experiments that appear incompatible with its deductions.9,19 Contrary to what would be predicted by © 2014 Japan Geriatrics Society

MFRTA: Who moved my premise?

the MFRTA, mutant Drosophila melanogaster overexpressing the mitochondrial adenine nucleotide translocase had significantly lower ROS production, but their lifespan was not extended compared with the wild type.20 In the classical model of nematode Caenorhabditis elegans (C. elegans), deletion of the mitochondrial superoxide dismutase, (SOD)-2, failed to shorten the worm’s lifespan, but could surprisingly prolong it, although oxidative stress is increased anyway.21 Experiments in mice showed that deficiency in both Mn-SOD and glutathione peroxidase-1 increased oxidative damage, but did not reduce longevity.22 These findings suggest that reduced ROS level fails to exert a beneficial effect on the lifespan, whereas an accreted oxidative stress by the deletion of certain anti-oxidant enzymes does not imply a shortened lifespan. This questions the classic prediction of the MFRTA, and prompts us to seek other possible mechanisms that regulate aging and longevity.23 Probably the most striking counterexample comes from the naked mole rat, the longest-living rodent that can reach the venerable age of 28 years. With a life expectancy almost ninefold longer than the common mouse, the naked mole rat endures a higher level of oxidative stress and has lower levels of anti-oxidants.24 If oxidative status is a determinant of lifespan as MFRTA deduces, the exposure to a highly-oxidative cellular environment without sufficient anti-oxidative defense should become detrimental for the naked mole rat, and thus incompatible with its extended lifespan. In fact, long-lived species, whether it being the naked mole rat or pigeon, do not necessarily have higher levels of antioxidants or better repair systems.25,26 What they do have in common, though, is a more oxidation-resistant cell composition (for example, lower level of unsaturated fatty acids in membrane composition),27 which helps them cope with a more oxidative cellular environment. The aforementioned evidence suggests clearly that the accrued ROS level cannot be a consistent indicator or causal factor in aging. As aging is such a complicated process, it seems imprudent to simply conclude that ROS level correlates negatively or otherwise positively with maximum lifespan. However, oxidative stress does act as a selection pressure during evolution, and has witnessed the survival struggle of living organisms through their various life-extending strategies.

Does anti-oxidant mean anti-aging? The MFRTA holds that anti-oxidants are helpful in ensuring health and promoting longevity.28 On this ground, anti-oxidants appear in popular health products and have even been used as a preventive or curative measure for certain diseases.29 However, such a presumption is doubted by recent studies, which failed to notice neither an extended lifespan nor an improved physical fitness by anti-oxidant supplements in animal © 2014 Japan Geriatrics Society

studies, as well as in human epidemiological observations.30 Well-known mitochondrial anti-oxidants, alpha-lipoic acid or coenzyme Q10, had no impact on longevity or tumor patterns in mice compared with a control group fed with the same number of calories.31 Experts in the field of cancer found that vitamin C, vitamin E or beta carotene supplements showed no overall benefits in the prevention of cancer incidence and mortality.32 Ristow’s group proved that physical exercise could induce mild oxidative stress, which ameliorates insulin resistance and promotes endogenous anti-oxidant defense capacity, whereas supplementary anti-oxidants (vitamin C and vitamin E) precluded the health-promoting effects of exercise in humans.33 Epstein et al. pointed out that the overexpression of cytoplasmic anti-oxidants, metallothionein and catalase, in β-cells of the mouse pancreas actually accelerated β-cells death and sensitized the animal to diabetes.34 Bjelakovic et al. even found that treatment with several anti-oxidants (such as beta carotene, vitamin A and vitamin E) increased all-cause mortality in adults.35 All this evidence is contradictory to the prediction of the MFRTA that if ROS are eliminated by anti-oxidants, beneficial results would arise. Despite the common acknowledgement that oxidative stress results from enhanced ROS generation, mounting research has shown that ROS in small amounts and in particular locations represent important signaling components in various communication networks. Importantly, it should be mentioned that ROS constitute a heterogeneous group of species with varying chemical reactivity, making it likely that their contribution to biological processes vary as well.36 For example, excessive production of the negatively charged superoxide anion from the reduced nicotinamide adenine dinucleotide phosphate oxidase leads to the formation of the highly oxidizing agent peroxynitrite and the loss of nitric oxide bioavailability in the vascular system, contributing to various cardiovascular diseases.37 Hydroxyl radical and its derived molecules, known as the most biologically active free radicals, can almost instantly cause hydroxylation of any biomolecules in their vicinity, resulting in many diseases, such as atherosclerosis, cancer and neurological disorders.38 Interestingly, however, the uncharged non-radical hydrogen peroxide, another member of the ROS family, is evidenced to serve as an important second messenger at its low physiological concentrations through posttranslational protein modification.39 Thus, efforts should be made to clarify the individual effects of each ROS species, and it is important to determine exactly which type of ROS is involved in physiological and pathological processes. Hence, a possible explanation for the failure of antioxidant strategies could be that the indiscriminate metabolism of ROS by broad-acting, non-targeted | 741

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anti-oxidants can actually disrupt ROS homeostasis, which has profound effects on multiple signaling systems involved in longevity regulation.40 It is obvious that simple manipulation of ROS generation/ detoxification cannot achieve the expected results because of the complexity of cellular signaling networks. In this regard, our previous expectation for antioxidants supplements as magical anti-aging weapons should be carefully recorroborated with future studies.41

ROS: Evil curses or signaling molecules? The conclusion that ROS can exert deleterious effects comes from its correlation with chronological age observed in several species.42 Despite the close link between ROS and aging, however, simple correlation does not imply causation.43 An easy example is from diabetes: it is well acknowledged that the underlying metabolic cause of type 1 diabetes is the immune destruction of β-cells of the pancreas; whereas type 2 diabetes results from dysregulation of insulin secretion.44,45 Although both types of diabetes are characterized by hyperglycemia, we cannot conclude directly and superficially that it is the risen blood glucose that is responsible for this disease. Following the same logic, it is possible that ROS can be only an innocent accompaniment rather than a premier trigger during the aging process. In recent years, dysregulated ROS signaling has been reported in a host of diseases, and the contribution of ROS is becoming recognized in various cellular processes, such as hormone biosynthesis, cell proliferation and innate immunity.46–48 For example, in skeletal muscle and sciatic nerve of living mice, respiratory mitochondria showed spontaneous “superoxide flashes” that were able to decode metabolic status on systemic glucose challenge or insulin stimulation.49 Mice with reduced mitochondrial ROS production could not induce antigen-specific expansion of T cells, showing that specific ROS-dependent signaling was required for the activation of certain nuclear factors and subsequent interleukin-2 induction and so on.50 Therefore, it seems imprudent to regard ROS as a dangerous devil for living organisms as historically viewed.51,52 As said by Paracelsus (1493–1541), the pioneer of toxicology, “all substances are poisons: there is none which is not a poison. The right dose differentiates a poison and a remedy.” Consistent with this idea, some researchers developed the concept of “mitochondrial hormesis or mitohormesis.”53 The hormesis theory holds that ROS, depending on its intensity/duration of release, can actually serve as a stress signal in response to age-dependent damage, thus eliciting a positive effect on health and longevity.54 Research on rat glomerular cells showed that hydrogen peroxide could enhance Mn-SOD activity, protecting these cells against further 742 |

increases in stress.55 Similarly, calorie restricted yeast and yeast with reduced target of rapamycin (TOR) signaling had greater overall increases of ROS production, which supplied an adaptive signal that enhanced survival and extended chronological lifespan.56,57 Animals subjected to calorie restriction experienced a long-term reduction in the levels of oxidative damage to proteins, lipids and nucleic acids,53,58 similar to what occurs during moderate exercise. This long-term reduction in oxidative damage was probably a result of a short-term increase in ROS production, which elicited an adaptive response including enhanced catalase activity and increased oxidative stress resistance, and so on.59 Mclk1 knockout mice had elevated mitochondrial ROS accompanied with enhanced expression of hypoxia inducible factor-1α and inflammatory cytokines tumor necrosis factor-α; and they lived longer than wild-type siblings.60 Siegfried Hekimi’s group also confirmed an increased lifespan by an accrued superoxide generation in mutant C. elegans. According to them, elevated superoxide promoted longevity in these worms by triggering changes in gene expression that prevented or attenuated the effects of aging.61 They improved this hypothesis even further by proposing that there exists a threshold above which ROS levels become lethal. Obviously this threshold varies with the type of cells/tissues/species. At non-toxic levels, ROS can function as signaling molecules activating protective anti-aging pathways, which is beneficial to the viability of living beings.57 However, if such efforts of survival are not powerful enough in compensation for the age-related damages, a gradual net increase in ROS generation will result. Once it exceeds a certain threshold, ROS would become toxic, pro-death pathways would be induced and the trigger of aging would be switched on.9 This hypothesis is consistent with earlier studies that found that exhaustive exercise is harmful,62 whereas endurance or moderate excise enhanced fitness.63,64 The reason is probably that the former raises cellular ROS to a toxic level, whereas the latter increases ROS slightly, but well below the threshold value, thus it can upregulate anti-oxidant and anti-inflammatory systems as well as DNA and protein damage-repairing enzymes, and so on.65 Although many mysteries regarding details of the hormesis mechanism lay ahead awaiting to be deciphered, evidence of the ROS threshold has been corroborated in mounting studies. Persiyantseva’s team investigated the insulin receptor in rat cerebellar granule neurons, the autophosphorylation of which forms a key step for its activation under insulin stimulation. In their work, they showed that the autophosphorylation of the insulin receptor became possible only if mitochondrial hydrogen peroxide surpassed a certain threshold.66 Another convincing example is from Ming Li’s group showing that mammalian target of rapamycin complex 1 could be stimulated in vivo and in a variety of mammalian cell lines by © 2014 Japan Geriatrics Society

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low-dose or short-term ROS, but is inhibited by highdose or long-term ROS treatment. Obviously the ROS dose required for activation or inhibition of mammalian target of rapamycin complex 1 depended largely on cell type.67 In the contractile filaments of mammalian skeletal muscle, hydrogen peroxide levels that approximate the physiological range of 10–9–10–7 mol/L could decrease mean tetanic myoplasmic Ca2+ concentration and increase submaximal force, whereas an increase in intracellular ROS concentration beyond homeostatic boundaries, such as in fatigue, could cause increased Ca2+ release and impaired reuptake.68 From the discussion above, it is clear that ROS within a non-toxic level are more of signaling molecules than presumed evil curses. Then the question is, how does the ROS-induced signaling take place and what is the mechanism underlying it? First, the transduction of a signal is made possible only when a messenger molecule binds to its specific target proteins. ROS can regulate various cellular processes through the oxidation of thiol and thioether groups in cysteine and methionine residues present in redox-sensitive kinases, phosphatases and other regulatory factors, leading to the reversible modification of enzymatic activity.69 Indeed, the cell is populated with multiple intracellular oxygen sensors, such as prolyl hydroxylase70 for the degradation of HIF, Keap1 for the stabilization and translocation of Nrf2,71 and insulin for the activation of PI3K pathway72. Second, to be able to carry out the messenger activity, a molecule must show its stability under physiological conditions as well as a relatively large diffusion distance. In this regard, hydrogen peroxide seems the best candidate messenger compared with other forms of ROS; that is, superoxide and hydroperoxyl radical.23 Hydrogen peroxide is thought to signal through the chemoselective oxidation of deprotonated cysteine residues in target proteins. For example, hydrogen peroxide is found to be involved in the activation of the versatile protein kinase, p38 MAPK,73 and the induction of transcription factor NRF2,74 making it a significant mediator in the initiation of autophagy,75 the apoptosis of neuronal cells,76 the induction of anti-oxidative genes77 and the pathogenesis of aging.40. So in brief, the chemical reactivity of certain ROS with cysteine/methionine residues in target proteins, as well as the appropriate stability and diffusion distance they show as messenger molecules, allows for their signaling capacity in diverse signaling pathways.

Peroxisomes: A role to play in aging With mitochondria’s rise to the podium thanks to the MFRTA, the influence of peroxisomes on aging has long remained in the shade. Peroxisomes are famous for their essential role in the β-oxidation of long-chain fatty acid,78 during which process molecular oxygen is con© 2014 Japan Geriatrics Society

sumed and converted into hydrogen peroxide.79 Some of the substrates, such as acetyl-CoA, propionyl-CoA and 4, 8-dimethylnonanoyl-CoA, can then be shuttled to mitochondria and undergo more metabolic cycles.80 Mammalian peroxisomes also participate in the α-oxidation of phytanic acid, the breakdown of purines, polyamines and eicosanoids, the metabolism of steroid and peptide hormone as well as the synthesis of specific fatty acids, such as docosahexaenoic acid (DHA) and plasmalogens (PLGN).81,82 Many of these metabolites are involved in important signal transduction pathways or serve as cellular components indispensable to neural cell growth, retina function and brain development.83 It has been supported by various experiments that peroxisomal integrity and metabolism have great implications in the regulation of cellular aging, and the maintenance of neurological health.84 Yeast cells deprived of the PEX6 gene, which encodes a protein in a key step of peroxisomal protein import, showed markers of necrosis.85 Suppressed peroxisomal β-oxidation in yeast on a calorie-rich diet led to the accumulation of nonesterified fatty acids and diacylglycerol within cells, which eventually resulted in premature lipoapoptotic death.86 It was also found that myelin-associated peroxisomes are indispensable in maintaining paranodal loops and axonal integrity.87 Patients of rhizomelic chondrodysplasia punctate, clinically characterized by a disproportionally short stature and severe mental retardation, suffer from disorders of peroxisomal etherphospholipid biosynthesis and often die prematurely.88 Furthermore, there is compelling evidence that some age-related degenerative diseases are associated with peroxisome dysfunction.89 For example, peroxisome deficiency in neural cells was observed in diverse neurological anomalies leading to motor and cognitive disabilities.90 Mouse models with peroxisomal biogenesis disorders showed altered lipid metabolism and induced alpha-Synuclein abnormalities, which are critically involved in the cytopathology and genetics in Parkinson’s disease.91 Endogenous activation of the peroxisome proliferator-activated receptor alpha, a famous nuclear receptor that plays key roles in the metabolism of fatty acids, glucose and in other pathways92 could lead to sustained oxidative stress and cell proliferation in mouse liver, which eventually results in the development of hepatocellular carcinoma.93 The potential role of peroxisomes in the development of Alzheimer’s disease was also corroborated, especially in the part played by DHA, PLGN, carnitine and carnitinedependent peroxisomal enzymes.94 Peroxisomes can also influence longevity by participating in the maintenance of cellular redox balance. Although mitochondrion is a significant ROS generator, there is no solid experimental evidence in mammalian models to convince us that it is the main one.95 Other subcellular components, such as the nucleus, | 743

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endoplasmic reticulum (ER), peroxisomes and microsomes can serve as effective ROS sources as well. In the rat liver, for example, microsomes and peroxisomes (contributing relatively 45% and 35% to the cytosolic hydrogen peroxide) actually have a greater ROSgenerating capacity than mitochondria (contributing to 15% of the cytosolic hydrogen peroxide).96,97 The microsomes-generated ROS were discovered to be closely linked to drug reactions and lipid peroxidation;98,99 and the ER-generated ROS were found to influence protein folding.100 However, little attention was given to peroxisomes in the regulation of cellular ROS homeostasis. In fact, as a warehouse of ROS-producing oxidases (e.g. acyl-CoA oxidases, urate oxidase, 2-hydroxyacid oxidase etc.) and ROSscavenging enzymes (e.g. catalase, superoxide dismutase, peroxiredoxin V etc.), peroxisome is vital in ensuring the redox balance in intraperoxisomal levels as well as in extraperoxisomal levels.101 Furthermore, the mammalian peroxisomal membrane possesses poreforming channels facilitating ROS transit from the peroxisomal matrix to the cytosol (and vice versa).102,103 The most abundant peroxisomal ROS indicates hydrogen peroxide, the important secondary messenger active in various ROS signaling pathways.104 Peroxisomal enzymes, such as catalase and malate synthase, are sensitive to oxidative switches and become increasingly oxidized on hydrogen peroxide exposure in vivo. The modulation of their enzymatic properties can then be used to regulate intracellular processes.105 However, impairment of pexophagy in mice results in an accumulation of impaired peroxisomes with an imbalance between hydrogen peroxide-generating β-oxidation and hydrogen peroxide-detoxifying catalase, which eventually contributes to the continuously increased oxidative stress and aggravated kidney damage.106 All these studies provide evidence for the regulatory ability of peroxisomes in redox homeostasis.

Peroxisomes-mitochondria interference in the regulation of aging To better understand the subtle mechanisms that regulate aging, it is necessary to examine the peroxisomes– mitochondria interrelationship, which goes far beyond their metabolic cooperation in the β-oxidation of fatty acids.107 The cross-talk between peroxisomes and mitochondria in the maintenance of cellular ROS homeostasis has been widely recognized.108,109 Evidence exists that the redox-state of mitochondrion can be influenced by that of peroxisome, especially through the activity of peroxidase catalase.110 Catalase deficiency increased mitochondrial ROS and accelerated diabetic nephropathy through plasma free fatty acids-induced peroxisomal dysfunction.111 In contrast, aging cells with 744 |

restored peroxisomal catalase import saw a repolarization of mitochondria and a reduction in senescent markers.112 KillerRed-induced production of ROS in peroxisomes could lead to mitochondrial fragmentation and altered mitochondrial redox potential.113 In a PEX5 knockout-mouse model for Zellweger syndrome (cerebro-hepato-renal syndrome), the most severe form of the peroxisomal biogenesis disorders, and ultrastructural and functional mitochondrial alterations were observed in various organs and specific cell types where peroxisomal metabolism was defective.114 Another convincing experiment on mouse hepatocytes showed induced mitochondria abnormities as a result of the absence of peroxisomes.115 In this study, activities of complex I, III and V on mitochondrial ETC was severely reduced, and mitochondrial inner membrane structure was damaged in peroxisome-eliminated mouse hepatocytes, causing a collapse of the mitochondrial inner membrane potential. This evidence highlights the idea that peroxisomal alterations in metabolism, biogenesis, dynamics and proliferation could have the potential to influence mitochondrial function, morphology and redox balance.116 The functional interference between these two organelles is made possible by the mitochondria-toperoxisomes vesicular transport route described by Margaret Neuspiel’s group.117 Peroxisomes even share with mitochondria some key components, such as DLP1, Fis1 and Mff, for the fission machinery.118 Certain signaling pathway also shows a clear link between mitochondria and peroxisomes function. For example, the mitochondrial retrograde pathway is a protective mechanism in response to mitochondrial deficiency. It activates nuclear genes transcription whose protein products can induce changes in cell physiology and compensate for the mitochondrial dysfunction.119 Among target genes in this signal transduction are genes encoding peroxisomal proteins that promote peroxisome biogenesis and function.120 Reversely, peroxisomal fatty acid oxidation and anaplerotic reactions can also drive the retrograde pathway by replenishing the tricarboxylic acid cycle intermediates, such as citrate and acetyl-carnitine.121 It can be anticipated that once peroxisomal metabolism is slowed down in pathological conditions, critical intermediates cannot be properly produced and trafficked to mitochondria, which would adversely affect the metabolism in mitochondria.109 Thus, a normal function of peroxisomes is indispensable for mitochondria activity and vice versa. As mitochondria and peroxisomes are not isolated, but closely related, their interaction might have a significant implication in essential physiological processes, such as cellular aging and longevity regulation.122 The mitochondria–peroxisomes interference in the regulation of aging is schematically illustrated in Figure 1. © 2014 Japan Geriatrics Society

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TCA cycle

Fis1

LCFA/MCFA b-OX

O2

DLP1

Fission machinery

Mff VLCFA

Metabolites detoxification & biosynthesis

b-OX

O2

Fatty acids RC

H2O2 CAT

Acetyl-CoA ATP Anabolic reactions ROS metabolism

Mitochondrion

H2O+O2 RTG pathway Redox state: Hormesisor toxic?

Acyl-CoA Acetyl-CoA • • •

Cholesterol Bile acids ….. ROS metabolism

Peroxisome

Vesicular transport

Figure 1 Mitochondria–peroxisomes interference in regulation of aging. Mitochondria (left) and peroxisomes (right) in mammals cooperate with each other in a myriad of cellular pathways, including the β-oxidation of fatty acids, the maintenance of reactive oxygen species (ROS) homeostasis and regulation of certain signaling pathways (e.g. the retrograde pathway). The two organelles share key components for their fission machinery (e.g. DLP1, Mff, Fis1). Furthermore, there exists a vesicular transport route from mitochondria to peroxisomes, indicating their active interconnection. Indeed, a normal function of peroxisomes is indispensable for mitochondria activity and vice versa. β-OX, fatty acid β-oxidation; ATP, adenosine triphosphate; CAT, catalase; LCFA, long-chain fatty acids; MCFA, medium-chain fatty acids; RC, respiratory chain; RTG, retrograde pathway; TCA, tricarboxylic acid; VLCFA, very long-chain fatty acids.

Conclusions The MFRTA has become a well-acknowledged theory in aging research. However, it meets queries about its presumed causal relationship between ROS and aging. The conventional idea seems misleading that ROS should be scavenged in order to delay the onset of aging; and arising evidence shows that ROS might not be the initial trigger of aging, but can contribute to longevity by acting as signaling molecules that evoke a prosurvival adaptive responses. Thus, a serious rethink about the ROS-induced theory of aging is necessary. Further research is required to determine the particular effects of individual ROS species, and find out within which range ROS is non-toxic in vivo and above which level it becomes lethal. Although mitochondrion has been proved an important organelle in the regulation of aging, the function carried out by peroxisome should not be overlooked. Hopefully, a comprehensive understanding on the role peroxisome plays in aging will bring new insight into our efforts to prolong life. With the close cross-talk between mitochondria and peroxisomes corroborated, it is interesting to investigate the interaction between these two organelles through their extensive cooperation in lipid oxidation, the maintenance of cellular redox balance and their interorganelle metabolite transport, and so on. To take this effort one step further, future researchers can also expand their interest into the inter© 2014 Japan Geriatrics Society

connection of mitochondria and peroxisome with other crucial subcellular components, such as the nucleus and ER. As for clinical research, the use of anti-oxidants as an anti-aging panacea ought to be prudent. In order to achieve health-promoting benefits, it seems wiser to restore and maintain the redox homeostasis than to simply manipulate cellular ROS level. In our previous work, we have proposed the administration of specific mitochondrial nutrients that can prevent/delay mitochondrial decay as a strategy for preventing and treating some age-related cognitive dysfunction.123–128 Similarly, possible dietary nutrients that can enhance peroxisomal function or redox homeostasis could also be anticipated as potential life-extending supplements.

Acknowledgments The authors thank Ying Tang at the Center for Mitochondrial Biology and Medicine of Xi’an Jiaotong University for critical reading of this manuscript. This work was supported by “the Fundamental Research Funds for the Central Universities (2010 and 2013)”, the National Natural Science Foundation of China (30930105, 31070740, 31370844), New Century Excellent Talents of the Ministry of Education, National “Twelfth FiveYear” Plan for Science & Technology, and the 985 and 211 plans of Xi’an Jiaotong University. | 745

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Disclosure statement The authors declare no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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References 1 Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol 1956; 11: 298–300. 2 Breitenbach M, Laun P, Dickinson JR et al. The role of mitochondria in the aging processes of yeast. In: Breitenbach M, Jazwinski SM, Laun P, eds. Aging Research in Yeast. Dordrecht, The Netherlands: Springer, 2012; 55–78. 3 Shigenaga MK, Hagen TM, Ames BN. Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci USA 1994; 91: 10771–10778. 4 Sanders LH, Timothy Greenamyre J. Oxidative damage to macromolecules in human Parkinson disease and the rotenone model. Free Radic Biol Med 2013; 62: 111–120. 5 Gruber J, Fong S, Chen C-B et al. Mitochondria-targeted antioxidants and metabolic modulators as pharmacological interventions to slow ageing. Biotechnol Adv 2012; 31: 563–592. 6 Vavrova L, Kodydkova J, Zeman M, Dusejovska M et al. Altered activities of antioxidant enzymes in patients with metabolic syndrome. Obes Facts 2013; 6: 39–47. 7 Liu J, Mori A. Stress, aging, and brain oxidative damage. Neurochem Res 1999; 24: 1479–1497. 8 Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev 1998; 78: 547–581. 9 Hekimi S, Lapointe J, Wen Y. Taking a good look at free radicals in the aging process. Trends Cell Biol 2011; 21: 569–576. 10 Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science 2005; 307: 384–387. 11 Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006; 443: 787–795. 12 Liang FQ, Godley BF. Oxidative stress-induced mitochondrial DNA damage in human retinal pigment epithelial cells: a possible mechanism for RPE aging and age-related macular degeneration. Exp Eye Res 2003; 76: 397–403. 13 Long J, Gao F, Tong L, Cotman C, Ames B, Liu J. Mitochondrial decay in the brains of old rats: ameliorating effect of alpha-lipoic acid and acetyl-l-carnitine. Neurochem Res 2009; 34: 755–763. 14 Hao J, Shen W, Tian C et al. Mitochondrial nutrients improve immune dysfunction in the type 2 diabetic GotoKakizaki rats. J Cell Mol Med 2009; 13: 701–711. 15 Shen W, Hao J, Tian C et al. A combination of nutriments improves mitochondrial biogenesis and function in skeletal muscle of type 2 diabetic Goto–Kakizaki rats. PLoS ONE 2008; 3 (6): e2328. 16 Hagen TM, Liu J, Lykkesfeldt J et al. Feeding acetyl-lcarnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci USA 2002; 99: 1870–1875. 17 Moldovan L, Moldovan NI. Oxygen free radicals and redox biology of organelles. Histochem Cell Biol 2004; 4: 395–412. 18 Schütt T, Leuner K, Müller WE. S13.38 A vicious cycle-mitochondrial dysfunction leads to beta-amyloid

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accumulation. Biochim Biophys Acta 2008; 1777 (Suppl): S97. Gruber J, Ng LF, Fong S et al. Mitochondrial changes in ageing caenorhabditis elegans – what do we learn from superoxide dismutase knockouts? PLoS ONE 2011; 6: e19444. Miwa S, Riyahi K, Partridge L, Brand MD. Lack of correlation between mitochondrial reactive oxygen species production and life span in drosophila. Ann N Y Acad Sci 2004; 1019: 388–391. Van Raamsdonk JM, Hekimi S. Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans. PLoS Genet 2009; 5: e1000361. Zhang Y, Ikeno Y, Qi W et al. Mice deficient in both mn superoxide dismutase and glutathione peroxidase-1 have increased oxidative damage and a greater incidence of pathology but no reduction in longevity. J Gerontol A Biol Sci Med Sci 2009; 64A: 1212–1220. Scialo F, Mallikarjun V, Stefanatos R, Sanz A. Regulation of lifespan by the mitochondrial electron transport chain: reactive oxygen species-dependent and reactive oxygen species-independent mechanisms. Antioxid Redox Signal 2012; 19: 1953–1969. Andziak B, O’Connor TP, Qi W et al. High oxidative damage levels in the longest-living rodent, the naked mole-rat. Aging Cell 2006; 5: 463–471. Page M, Stuart J. Activities of DNA base excision repair enzymes in liver and brain correlate with body mass, but not lifespan. Age 2012; 34: 1195–1209. Salway K, Page M, Faure P, Burness G, Stuart J. Enhanced protein repair and recycling are not correlated with longevity in 15 vertebrate endotherm species. Age 2011; 33: 33–47. Hulbert AJ, Pamplona R, Buffenstein R, Buttemer WA. Life and death: metabolic rate, membrane composition, and life span of animals. Physiol Rev 2007; 87: 1175– 1213. Niki E. Role of vitamin E as lipid-soluble peroxyl radical scavenger: in vitro and in vivo evidence. Free Radic Biol Med 2013; 66: 3–12. Peake J, Suzuki K. Neutrophil activation, antioxidant supplements and exercise-induced oxidative stress. Exerc Immunol Rev 2004; 10: 129–141. Herrera E, Jimenez R, Aruoma OI, Hercberg S, Sanchez-Garcia I, Fraga C. Aspects of antioxidant foods and supplements in health and disease. Nutr Rev 2009; 67: S140–S144. Lee CK, Pugh TD, Klopp RG, Edwards J et al. The impact of alpha-lipoic acid, coenzyme Q10 and caloric restriction on life span and gene expression patterns in mice. Free Radic Biol Med 2004; 36: 1043–1057. Lin J, Cook NR, Albert C et al. Vitamins c and e and beta carotene supplementation and cancer risk: a randomized controlled trial. J Natl Cancer Inst 2009; 101: 14–23. Ristow M, Zarse K, Oberbach A et al. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci USA 2009; 106: 8665–8670. Li X, Chen H, Epstein PN. Metallothionein and catalase sensitize to diabetes in nonobese diabetic mice reactive oxygen species may have a protective role in pancreatic â-cells. Diabetes 2006; 55: 1592–1604. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention. JAMA 2007; 297: 842–857. den Hartog GJM, Qi S, van Tilburg JHO, Koek GH, Bast A. Superoxide anion radicals activate hepatic stellate cells © 2014 Japan Geriatrics Society

MFRTA: Who moved my premise?

37 38 39

40 41 42 43 44

45 46 47 48 49

50

51 52 53

54 55

56

after entry through chloride channels: a new target in liver fibrosis. Eur J Pharmacol 2014; 724: 140–144. Brandes RP, Weissmann N, Schröder K. NADPH oxidases in cardiovascular disease. Free Radic Biol Med 2010; 49: 687–706. Lipinski B. Hydroxyl radical and its scavengers in health and disease. Oxid Med Cell Longev 2011; 2011: Article ID 809696. doi:10.1155/2011/809696. Satoh K, Godo S, Saito H, Enkhjargal B, Shimokawa H. Dual roles of vascular-derived reactive oxygen species – with a special reference to hydrogen peroxide and cyclophilin A-. J Mol Cell Cardiol 2014. doi:org/10.1016/ j.yjmcc.2013.12.022. Giordano CR, Terlecky SR. Peroxisomes, cell senescence, and rates of aging. Biochim Biophys Acta 2012; 1822: 1358– 1362. Urso ML, Clarkson PM. Oxidative stress, exercise, and antioxidant supplementation. Toxicology 2003; 189: 41–54. Barja G. Mitochondrial free radical production and aging in mammals and birds. Ann N Y Acad Sci 1998; 854: 224–238. Lapointe J, Hekimi S. When a theory of aging ages badly. Cell Mol Life Sci 2010; 67: 1–8. Habener JF, Stoffers DA. A newly discovered role of transcription factors involved in pancreas development and the pathogenesis of diabetes mellitus. Proc Assoc Am Physicians 1998; 110: 12–21. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. â-cell deficit and increased â-cell apoptosis in humans with type 2 diabetes. Diabetes 2003; 52: 102–110. Rada B, Leto T. Oxidative innate immune defenses by Nox/Duox family NADPH oxidases. Contrib Microbiol 2008; 15: 164–187. Theopold U. Developmental biology: a bad boy comes good. Nature 2009; 461: 486–487. Wang X, Jian C, Zhang X et al. Superoxide flashes: elemental events of mitochondrial ROS signaling in the heart. J Mol Cell Cardiol 2012; 52: 940–948. Fang H, Chen M, Ding Y, Shang W et al. Imaging superoxide flash and metabolism-coupled mitochondrial permeability transition in living animals. Cell Res 2011; 21: 1295–1304. Sena Laura A, Li S, Jairaman A et al. Mitochondria are required for antigen-specific t cell activation through reactive oxygen species signaling. Immunity 2013; 38: 225– 236. Sanz A, Stefanatos RKA. The mitochondrial free radical theory of aging: a critical view. Curr Aging Sci 2008; 1: 10–21. Gruber J, Schaffer S, Halliwell B. The mitochondrial free radical theory of ageing – where do we stand? Front Biosci 2008; 13: 6554–6579. Ristow M, Zarse K. How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis). Exp Gerontol 2010; 45: 410–418. Ristow M, Schmeisser S. Extending life span by increasing oxidative stress. Free Radic Biol Med 2011; 51: 327–336. Yoshioka T, Homma T, Meyrick B et al. Oxidants induce transcriptional activation of manganese superoxide dismutase in glomerular cells. Kidney Int 1994; 46: 405– 413. Pan Y, Schroeder Elizabeth A, Ocampo A, Barrientos A, Shadel Gerald S. Regulation of yeast chronological life span by torc1 via adaptive mitochondrial ros signaling. Cell Metab 2011; 13: 668–678.

© 2014 Japan Geriatrics Society

57 Mesquita A, Weinberger M, Silva A et al. Caloric restriction or catalase inactivation extends yeast chronological lifespan by inducing H2O2 and superoxide dismutase activity. Proc Natl Acad Sci USA 2010; 107: 15123–15128. 58 Pamplona R, Portero-Otýìn M, Requena J, Gredilla R, Barja G. Oxidative, glycoxidative and lipoxidative damage to rat heart mitochondrial proteins is lower after 4 months of caloric restriction than in age-matched controls. Mech Ageing Dev 2002; 123: 1437–1446. 59 Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M. Glucose restriction extends caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab 2007; 6: 280– 293. 60 Wang D, Malo D, Hekimi S. Elevated mitochondrial reactive oxygen species generation affects the immune response via hypoxia-inducible factor-1á in long-lived mclk1+/− mouse mutants. J Immunol 2010; 184: 582–590. 61 Yang W, Hekimi S. A mitochondrial superoxide signal triggers increased longevity in caenorhabditis elegans. PLoS Biol 2010; 8: e1000556. 62 Appell HJ, Soares JM, Duarte JA. Exercise, muscle damage and fatigue. Sports Med 1992; 13: 108–115. 63 Nelson ME, Rejeski WJ, Blair SN et al. Physical activity and public health in older adults: recommendation from the American College of Sports Medicine and the American Heart Association. Med Sci Sports Exerc 2007; 39: 1423–1434. 64 Safdar A, Bourgeois JM, Ogborn DI et al. Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. Proc Natl Acad Sci USA 2011; 108: 4135–4140. 65 Radak Z, Chung H, Goto S. Exercise and hormesis: oxidative stress-related adaptation for successful aging. Biogerontology 2005; 6: 71–75. 66 Persiyantseva NA, Storozhevykh TP, Senilova YE, Gorbacheva LR, Pinelis VG, Pomytkin IA. Mitochondrial H2O2 as an enable signal for triggering autophosphorylation of insulin receptor in neurons. J Mol Signal 2013; 8: 1–11. 67 Li M, Zhao L, Liu J et al. Multi-mechanisms are involved in reactive oxygen species regulation of mTORC1 signaling. Cell Signal 2010; 22: 1469–1476. 68 Andrade FH, Reid MB, Westerblad H. Contractile response of skeletal muscle to low peroxide concentrations: myofibrillar calcium sensitivity as a likely target for redox-modulation. FASEB J 2001; 15: 309–311. 69 Finkel T. Signal transduction by reactive oxygen species. J Cell Biol 2011; 194: 7–15. 70 Aragonés J, Fraisl P, Baes M, Carmeliet P. Oxygen sensors at the crossroad of metabolism. Cell Metab 2009; 9: 11–22. 71 Niecknig H, Tug S, Reyes BD, Kirsch M, Fandrey J, Berchner-Pfannschmidt U. Role of reactive oxygen species in the regulation of HIF-1 by prolyl hydroxylase 2 under mild hypoxia. Free Radic Res 2012; 46: 705–717. 72 Ray PD, Huang B-W, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal 2012; 24: 981–990. 73 Bretón-Romero R, Lamas S. Hydrogen peroxide signaling mediator in the activation of p38 MAPK in vascular endothelial cells. Methods Enzymol 2013; 528: 49–59. 74 Fourquet S, Guerois R, Biard D, Toledano MB. Activation of nrf2 by nitrosative agents and H2O2 involves keap1 disulfide formation. J Biol Chem 2010; 285: 8463–8471. 75 Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z. Reactive oxygen species are essential for

| 747

Y Liu et al.

76 77

78 79 80 81 82

83

84 85 86 87

88 89 90

91 92

93 94

autophagy and specifically regulate the activity of Atg4. EMBO J 2007; 26: 1749–1760. Chen L, Xu B, Liu L et al. Hydrogen peroxide inhibits mTOR signaling by activation of AMPKá leading to apoptosis of neuronal cells. Lab Invest 2010; 90: 762–773. Jian Z, Li K, Liu L et al. Heme oxygenase-1 protects human melanocytes from H2O2-induced oxidative stress via the Nrf2-ARE pathway. J Invest Dermatol 2011; 131: 1420–1427. Islinger M, Grille S, Fahimi HD, Schrader M. The peroxisome: an update on mysteries. Histochem Cell Biol 2012; 137: 547–574. Antonenkov VD, Grunau S, Ohlmeier S, Hiltunen JK. Peroxisomes are oxidative organelles. Antioxid Redox Signal 2010; 13: 525–537. Van Veldhoven PP. Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism. J Lipid Res 2010; 51: 2863–2895. Reddy JK, Mannaerts GP. Peroxisomal lipid metabolism. Annu Rev Nutr 1994; 14: 343–370. Weinhofer I, Kunze M, Forss-Petter S, Berger J. Involvement of human peroxisomes in biosynthesis and signaling of steroid and peptide hormones. In: del Río LA, ed. Peroxisomes and Their Key Role in Cellular Signaling and Metabolism. Dordrecht, The Netherlands: Springer, 2013; 101–110. Wanders RA. Peroxisomes in human health and disease: metabolic pathways, metabolite transport, interplay with other organelles and signal transduction. In: del Río LA, ed. Peroxisomes and Their Key Role in Cellular Signaling and Metabolism. Dordrecht, The Netherlands: Springer, 2013; 23–44. Manivannan S, Scheckhuber CQ, Veenhuis M, van der Klei IJ. The impact of peroxisomes on cellular aging and death. Front Oncol 2012; 2: 50. Jungwirth H, Ring J, Mayer T et al. Loss of peroxisome function triggers necrosis. FEBS Lett 2008; 582: 2882– 2886. Low CP, Liew LP, Pervaiz S, Yang H. Apoptosis and lipoapoptosis in the fission yeast Schizosaccharomyces pombe. FEMS Yeast Res 2006; 5: 1199–1206. Kassmann CM, Quintes S, Rietdorf J et al. A role for myelin-associated peroxisomes in maintaining paranodal loops and axonal integrity. FEBS Lett 2011; 585: 2205– 2211. Wanders RJA. Peroxisomes, lipid metabolism, and peroxisomal disorders. Mol Genet Metab 2004; 83: 16–27. Masters CJ, Crane DI. On the role of the peroxisome in ontogeny, ageing and degenerative disease. Mech Ageing Dev 1995; 80: 69–83. Bottelbergs A, Verheijden S, Van Veldhoven PP, Just W, Devos R, Baes M. Peroxisome deficiency but not the defect in ether lipid synthesis causes activation of the innate immune system and axonal loss in the central nervous system. J Neuroinflammation 2012; 9: 1–21. Yakunin E, Moser A, Loeb V, Saada A et al. alphaSynuclein abnormalities in mouse models of peroxisome biogenesis disorders. J Neurosci Res 2010; 88: 866–876. Vamecq J, Cherkaoui-Malki M, Andreoletti P, Latruffe N. The human peroxisome in health and disease: the story of an oddity becoming a vital organelle. Biochimie 2013; 98: 4–11. Pyper SR, Viswakarma N, Yu S, Reddy JK. PPARalpha: energy combustion, hypolipidemia, inflammation and cancer. Nucl Recept Signal 2010; 8: e002. Lizard G, Rouaud O, Demarquoy J, Cherkaoui-Malki M, Iuliano L. Potential roles of peroxisomes in Alzheimer’s

748 |

95 96 97 98 99 100 101

102 103

104 105 106

107 108 109

110 111 112 113

114

disease and in dementia of the Alzheimer’s type. J Alzheimers Dis 2012; 29: 241–254. Brown GC, Borutaite V. There is no evidence that mitochondria are the main source of reactive oxygen species in mammalian cells. Mitochondrion 2012; 12: 1–4. Chance B, Sies H, Boveris A. Hydroperoxide metabolism in mammalian organs. Physiol Rev 1979; 59: 527–605. Boveris A, Oshino N, Chance B. The cellular production of hydrogen peroxide. Biochem J 1972; 128: 617–630. Gillette JH, Brodie BB, La Du BN. The oxidation of drugs by liver microsomes: on the role of tpnh and oxygen. J Pharmacol Exp Ther 1957; 119: 532–540. Morehouse LA, Tien M, Bucher JR, Aust SD. Effect of hydrogen peroxide on the initiation of microsomal lipid peroxidation. Biochem Pharmacol 1983; 32: 123–127. Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 2010; 140: 900–917. Fransen M, Nordgren M, Wang B, Apanasets O. Role of peroxisomes in ROS/RNS-metabolism: implications for human disease. Biochim Biophys Acta 2012; 1822: 1363– 1373. Antonenkov VD, Hiltunen JK. Peroxisomal membrane permeability and solute transfer. Biochim Biophys Acta 2006; 1763: 1697–1706. Antonenkov VD, Sormunen RT, Hiltunen JK. The rat liver peroxisomal membrane forms a permeability barrier for cofactors but not for small metabolites in vitro. J Cell Sci 2004; 117: 5633–5642. Groeger G, Quiney C, Cotter TG. Hydrogen peroxide as a cell-survival signaling molecule. Antioxid Redox Signal 2009; 11: 2655–2671. Anand P, Kwak Y, Simha R, Donaldson RP. Hydrogen peroxide induced oxidation of peroxisomal malate synthase and catalase. Arch Biochem Biophys 2009; 491: 25–31. Vasko R, Ratliff BB, Bohr S et al. Endothelial peroxisomal dysfunction and impaired pexophagy promotes oxidative damage in lipopolysaccharide-induced acute kidney injury. Antioxid Redox Signal 2013; 19: 211–230. Le Borgne F, Demarquoy J. Interaction between peroxisomes and mitochondria in fatty acid metabolism. Open J Mol Integr Physiol 2012; 2: 27–33. Schrader M, Yoon Y. Mitochondria and peroxisomes: are the “Big Brother” and the “Little Sister” closer than assumed? Bioessays 2007; 29: 1105–1114. Ivashchenko O, Van Veldhoven PP, Brees C, Ho Y-S, Terlecky SR, Fransen M. Intraperoxisomal redox balance in mammalian cells: oxidative stress and interorganellar cross-talk. Mol Biol Cell 2011; 22: 1440–1451. Koepke JI, Wood CS, Terlecky LJ, Walton PA, Terlecky SR. Progeric effects of catalase inactivation in human cells. Toxicol Appl Pharmacol 2008; 232: 99–108. Hwang I, Lee J, Huh JY, Park J et al. Catalase deficiency accelerates diabetic renal injury through peroxisomal dysfunction. Diabetes 2012; 61: 728–738. Koepke JI, Nakrieko K-A, Wood CS et al. Restoration of peroxisomal catalase import in a model of human cellular aging. Traffic 2007; 8: 1590–1600. Wang B, Van Veldhoven PP, Brees C et al. Mitochondria are targets for peroxisome-derived oxidative stress in cultured mammalian cells. Free Radic Biol Med 2013; 65: 882– 894. Baumgart E, Vanhorebeek I, Grabenbauer M, Borgers M et al. Mitochondrial alterations caused by defective peroxisomal biogenesis in a mouse model for Zellweger syndrome (PEX5 knockout mouse). Am J Pathol 2001; 159: 1477–1494. © 2014 Japan Geriatrics Society

MFRTA: Who moved my premise? 115 Dirkx R, Vanhorebeek I, Martens K, Schad A et al. Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities. Hepatology 2005; 41: 868–878. 116 Bonekamp NA, Völkl A, Fahimi HD, Schrader M. Reactive oxygen species and peroxisomes: struggling for balance. Biofactors 2009; 35: 346–355. 117 Neuspiel M, Schauss AC, Braschi E et al. Cargo-selected transport from the mitochondria to peroxisomes is mediated by vesicular carriers. Curr Biol 2008; 18: 102–108. 118 Camões F, Bonekamp N, Delille H, Schrader M. Organelle dynamics and dysfunction: a closer link between peroxisomes and mitochondria. J Inherit Metab Dis 2009; 32: 163–180. 119 Liu Z, Butow RA. Mitochondrial retrograde signaling. Annu Rev Genet 2006; 40: 159–185. 120 Chelstowska A, Butow RA. RTG genes in yeast that function in communication between mitochondria and the nucleus are also required for expression of genes encoding peroxisomal proteins. J Biol Chem 1995; 270: 18141– 18146. 121 Titorenko VI, Terlecky SR. Peroxisome metabolism and cellular aging. Traffic 2011; 12: 252–259. 122 Delille HK, Alves R, Schrader M. Biogenesis of peroxisomes and mitochondria: linked by division. Histochem Cell Biol 2009; 131: 441–446.

© 2014 Japan Geriatrics Society

123 Liu J, Atamna H, Kuratsune H, Ames BN. Delaying brain mitochondrial decay and aging with mitochondrial antioxidants and metabolites. Ann N Y Acad Sci 2002; 959: 133–166. 124 Liu J, Ames BN. Reducing mitochondrial decay with mitochondrial nutrients to delay and treat cognitive dysfunction, Alzheimer’s disease, and Parkinson’s disease. Nutr Neurosci 2005; 8: 67–89. 125 Aksenov V, Long J, Liu J et al. A complex dietary supplement augments spatial learning, brain mass, and mitochondrial electron transport chain activity in aging mice. Age 2013; 35: 23–33. 126 Long J, Aksenov V, Rollo CD, Liu J. A complex dietary supplement modulates nitrative stress in normal mice and in a new mouse model of nitrative stress and cognitive aging. Mech Ageing Dev 2012; 133: 523–529. 127 Aksenov V, Long J, Lokuge S, Foster JA, Liu J, Rollo CD. Dietary amelioration of locomotor, neurotransmitter and mitochondrial aging. Exp Biol Med 2010; 235: 66– 76. 128 Liu J, Killilea DW, Ames BN. Age-associated mitochondrial oxidative decay: improvement of carnitine acetyltransferase substrate-binding affinity and activity in brain by feeding old rats acetyl-l- carnitine and/or R-á-lipoic acid. Proc Natl Acad Sci USA 2002; 99: 1876– 1881.

| 749