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Biochimica et Biophysica Acta 1763 (2006) 1749–1754 www.elsevier.com/locate/bbamcr

Review and aging ⁎ Stanley R. Terlecky a, , Jay I. Koepke a, Paul A. Walton b

a Department of Pharmacology, Wayne State University School of Medicine, 540 E. Canfield Avenue, Detroit, Michigan 48201, USA b Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada N6A 5C1

Received 23 May 2006; received in revised form 14 August 2006; accepted 18 August 2006 Available online 23 August 2006

Abstract

Peroxisomes are indispensable for proper functioning of human cells. They efficiently compartmentalize enzymes responsible for a number of metabolic processes, including the absolutely essential β-oxidation of specific fatty acid chains. These and other oxidative reactions produce hydrogen peroxide, which is, in most instances, immediately processed in situ to water and oxygen. The responsible peroxidase is the heme- containing tetrameric enzyme, . What has emerged in recent years is that there are circumstances in which the tightly regulated balance of hydrogen peroxide producing and degrading activities in peroxisomes is upset—leading to the net production and accumulation of hydrogen peroxide and downstream reactive oxygen species. The factor most essentially involved is catalase, which is missorted in aging, missing or present at reduced levels in certain disease states, and inactivated in response to exposure to specific xenobiotics. The overall goal of this review is to summarize the molecular events associated with the development and advancement of peroxisomal hypocatalasemia and to describe its effects on cells. In addition, results of recent efforts to increase levels of peroxisomal catalase and restore oxidative balance in cells will be discussed. © 2006 Elsevier B.V. All rights reserved.

Keywords: Aging; Catalase; ; Protein import; Reactive oxygen specie; Senescence

1. Introduction contribution the organelle makes to the course of cellular aging. It is these latter questions that are the focus of this review. How peroxisomes are formed has been a topic of great Human cellular aging is multifactorial (see [1–3] and refer- interest to many investigators for several years now. Proteins ences therein); telomeres shorten, proteins are aberrantly gly- involved in various aspects of membrane assembly, protein cated, DNA is damaged and inefficiently or improperly repaired, import, and organelle maintenance and inheritance have been epigenetic events occur, protein expression is altered and reac- identified and how these molecules function mechanistically tive oxygen species accumulate and damage cellular constitu- elucidated in many cases. Although important questions remain, ents. No one process dominates under all circumstances— it is clear that overall, peroxisome biogenesis is relatively well rather they appear to conspire in some, perhaps varying, understood. combination. An important open question is what initiates the There is also a rich understanding of peroxisome biochem- aging cascade. One possibility is reactive oxygen species; istry and function as well as of how the organelle is turned over molecules with the capacity to damage, inactivate, and even during the processes known collectively as “pexophagy.” destroy cellular DNA, proteins, and lipids including biological Furthermore, the molecular basis of many devastating perox- membranes. isomal diseases has been delineated. Of no less importance, but Falling under the heading of reactive oxygen species and far less studied, are the questions of how the peroxisome related compounds are singlet oxygen, superoxide anion, functions in cells and organisms of advancing age and what hydrogen peroxide, and the hydroxyl radical. These cellular reactive oxygen species are produced primarily by mitochondria ⁎ Corresponding author. Tel.: +1 313 577 3557; fax: +1 313 577 6739. and peroxisomes [4]. Although peroxisomes probably do not E-mail address: [email protected] (S.R. Terlecky). generate near the amount of reactive oxygen species that mito-

0167-4889/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.bbamcr.2006.08.017 1750 S.R. Terlecky et al. / Biochimica et Biophysica Acta 1763 (2006) 1749–1754 chondria do [1,5], they may very well be making them earlier— As pointed out above, catalase levels are found to be reduced an important point to be considered further below. in peroxisomes of aged rat livers [6,7,14]. Coupled with early Peroxisome aging was initially investigated using a rat liver reports that catalase was a rather poor substrate of the peroxisomal model. These important studies documented, for the first time, protein import apparatus [15], a more detailed examination of age-related differences in peroxisomal enzyme activities and catalase's import properties as a function of age was prompted. overall organelle function (see detailed summary [6]). Important Perhaps not surprisingly, catalase's import capacity too declined follow-up work by Badr and colleagues confirmed the reduced significantly with age (Terlecky, S.R., Koepke, J.I., and Walton, P. activities of peroxisomal β-oxidation enzymes and catalase in A., unpublished results]. Catalase is a PTS1-containing enzyme aging rat liver, and suggested that with respect to the former, whose import is mediated by Pex5p [16]. However, its PTS1 is a diminished levels of the peroxisome proliferator-activated tetrapeptide, lysine–alanine–asparagine–leucine (KANL) [16], receptor alpha (PPARα)-binding partner, retinoid X receptor largely unrelated to the consensus motif described above. This alpha (RXRα), may be responsible [7]. sequence is an extremely weak PTS1, only poorly directing More recently, human fibroblasts have been employed to catalase or other reporter proteins to which it is appended, to the study the specific relationship of peroxisomes and cellular organelle [13,17]. Combined with its upstream amino acids (in aging. These somatic cells may be cultured to various catalase), its “PTS1 predictor” score is a paltry 1.5. A weak import population doubling levels (PDL), with advancing PDLs substrate even in early passage cells, catalase's import is severely being viewed as akin to aging. At a certain point, these cells compromised in middle and late passage cells. Thus it appears experience an irreversible cell cycle arrest and are termed that although aging acts on all PTS1 enzymes with respect to their “senescent”. Characteristic biochemical and morphological import capacities, it is catalase with its weak KANL signal that is changes accompany cells' entry into the end of their replicative the most dramatically affected. lifespan. Perhaps the best validation of the model system comes from recent studies performed in primates demonstrating the 3. Pex5p presence of senescent cells at high frequencies in aged tissue [8]. 3.1. Binding A final note regarding cellular senescence; it has been suggested and evidence obtained to support the idea that cells One straightforward explanation for the distinct import ca- enter replicative senescence to avoid transformation and pacities of SKL-containing enzymes as compared to catalase is becoming cancerous [9]. Interestingly, the very environment differential binding by Pex5p. Several experimental approaches that promotes senescence—that is, the presence of reactive were brought to bear on the issue including fluorescence oxygen species both within cells and in the surrounding stroma, anisotropy, ligand blots, solid-phase (ELISA-type) assays, two- also potentiates initiation and progression of cancerous hybrid analysis, and surface plasmon resonance, among others transformation. [12,13,18]. The results were clear and consistent—proteins containing an SKL PTS1 were far better recognized and bound 2. PTS1 protein import in aging by Pex5p than the KANL-containing catalase molecule. Importantly, appending an SKL sequence in lieu of KANL The overwhelming majority of peroxisomal enzymes, in- increased catalase's recognition by Pex5p to the level seen with cluding most oxidases which produce hydrogen peroxide, other SKL-containing enzymes [13]. Catalase-SKL was not only contain a carboxy-terminal tripeptide closely related or identical recognized more avidly by Pex5p, but its import into peroxi- to serine–lysine–leucine (SKL) [10]. Called peroxisomal somes was also enhanced (Terlecky, S.R., Koepke, J.I., and targeting signal 1 (PTS1), this sequence and residues just Walton, P.A., unpublished results). upstream determine the enzymes' capacities to be recognized by What happens to Pex5p with age? Preliminary results the import receptor, Pex5p [10–12]. Conventional wisdom in suggest its affinity for PTS1 sequences is reduced (Terlecky, the field is that the strength of Pex5p's binding to a given S.R., Koepke, J.I., and Walton, P.A., unpublished results). As substrate determines its import efficiency. “PTS1 predictor” (see will be discussed below, aging cells accumulate hydrogen http://mendel.imp.ac.at/mendeljsp/sat/pts1/PTS1predictor.jsp), peroxide and other reactive oxygen species. Perhaps Pex5p is a powerful tool for the in silico analysis of relative PTS1 oxidatively damaged in that environment. The observation that strength, indicates that human peroxisomal oxidases consis- hydrogen peroxide-treated Pex5p binds PTS1 less well supports tently score in the 10–15 range—a point to be returned to this notion. Investigation in this area continues. shortly. Most of the binding studies described above involve measure- Using biochemically-defined in vitro assays, peroxisomal ment of direct protein–protein interactions between receptor and import of a PTS1 (SKL)-containing reporter protein was found ligand. Such interactions may very well be facilitated or modulated to drop in cells of advancing age [13]. Interestingly, this import in the cell by molecular chaperones or other factors. Hsp70 is one defect appears first in cells of middle passage and is then such factor—shown to regulate Pex5p's binding to PTS1 [19] and exacerbated in late passage and senescent cells. Extensive be a necessary component of (PTS1) protein import [20]. Since its follow-up studies indicate that irrespective of the human cell expression is reduced in aging [21], hsp70, or more accurately, its line examined or the import assay employed, the results were absence, may contribute to the processes associated with similar; aging compromises peroxisomal protein import. peroxisome senescence. S.R. Terlecky et al. / Biochimica et Biophysica Acta 1763 (2006) 1749–1754 1751

3.2. Trafficking 4.2. Hydrogen peroxide production

Pex5p is a cycling receptor, binding PTS1 cargo in the cytosol In early passage cells, peroxisomes exist in oxidative and ferrying it to the peroxisome membrane. The receptor docks balance—the organelle's oxidases consume molecular oxygen with the peroxisomal membrane protein Pex14p [22],andthrough and convert it to hydrogen peroxide, while catalase decomposes a rather poorly understood series of steps, releases its cargo, is the potentially toxic metabolite back to oxygen and water. A freed from Pex14p and then either enters the organelle (in whole or balance of peroxisomal pro- and exists. With in part), or engages other membrane peroxins and recycles back to advancing age and the accompanying effects on peroxisomal the cytosol. Pex5p cycling is critical—under certain conditions protein import described above, this homeostatic balance is (e.g. ATP depletion or reduced temperatures) Pex5p accumulates upset. Peroxisomal catalase in particular is reduced or lost. The on the peroxisome membrane and PTS1 protein import is slowed result of this uncoupling is the net production of hydrogen [23]. Increased membrane-associated Pex5p is also seen in certain peroxide and related reactive oxygen species. Specific oxida- mutant backgrounds—for example, when the peroxisomal tion-sensitive fluorescent dyes and enzymatic assays have been membrane proteins Pex2p, Pex10p, or Pex12p are defective or used to document dramatic increases in hydrogen peroxide and absent [23], or when activity of the AAA proteins Pex1p and other reactive oxygen species in late passage cells [13]. That Pex6p are reduced or eliminated [24,25]. Of relevance here is the these molecules amass in aged cells was well established in the fact that Pex5p's cycling is reduced and accumulation on the literature [1]; that the peroxisome contributes to this oxidative peroxisome membrane enhanced in middle and late passage cells burden has only recently come to light. [13]. Again, such slowing of Pex5p cycling is most certainly Metal ion-catalyzed conversion of hydrogen peroxide to the associated with reduced import rates. Pointing to the oxidative hydroxyl radical via the Fenton reaction serves to increase the environment of aging cells as potentially once more eliciting these destructive capacity of the peroxisomal metabolic by-products effects are the observations that treating (early passage) cells with formed. These molecules are quite clearly capable of damaging hydrogen peroxide not only causes Pex5p to amass on the DNA, proteins, and lipids including biological membranes. organelle membrane, but also significantly reduces PTS1 protein Recent evidence suggests peroxisome-derived hydrogen per- import [13]. oxide and downstream reactive oxygen species may also damage mitochondria causing them to depolarize and produce 4. Peroxisomes of aging cells damaging oxidants of their own (Terlecky, S.R., Koepke, J.I., and Walton, P.A., unpublished results). 4.1. Proliferation Hydrogen peroxide and related reactive oxygen species initiate a negative spiral of molecular events resulting in Detailed immunocytochemical analysis of middle and late oxidative damage to cellular constituents. Cell growth rates are passage human cells revealed progressively less intense staining reduced, perhaps due to effects on the mitogenic cell-signaling of SKL-containing proteins [13]. Rather, these molecules extracellular signal–regulated protein kinase 1/2 (“Erk 1/2”) appeared to accumulate in ever-increasing amounts in the pathway, known to be sensitive to hydrogen peroxide [27]. cytosol. Catalase was also mislocalized in aging cells, although Ames and colleagues demonstrated a direct connection to a far greater extent. Indeed, some late passage cells appeared between accumulation of reactive oxygen species and aging by completely devoid of peroxisomal catalase. Biochemical (latency) showing non-toxic concentrations of hydrogen peroxide drove analysis confirmed the immunofluorescence work—catalase was (early passage) cells to a senescent-like state [28]. Cell mor- clearly accumulating in the cytosol of aging cells [13]. phology, growth, and function were all affected. Similar As if the aging cell senses a reduced concentration of approaches employed recently revealed that hydrogen peroxide peroxisomal enzymes (or the accumulation of unmetabolized actually damages the PTS1-protein import machinery suggest- substrates), it responds by increasing peroxisome number—that ing the notion of a self-sustaining “peroxisome deterioration is, the organelle proliferates [13]. As compared to early passage spiral” as illustrated in Fig. 1. In this model, age-related cells, middle and late passage cells contain approximately twice peroxisomal hypocatalasemia results in increased cellular as many punctate structures that may be immunodecorated with concentrations of hydrogen peroxide. Other more damaging antibodies to the peroxisomal membrane protein of 70 kDa reactive oxygen species may form and harm cellular compo- (PMP70) or Pex14p, appropriate membrane markers. nents and functions. Peroxisomes themselves are a target of Similarly, peroxisomes proliferate in human retinal epithelia oxidant-induced damage—further exacerbating the problem by of aged individuals or those suffering from (age-related) potentially perpetuating the spiral. macular degeneration [26]. Peroxisome biogenesis is thought to be a delicate balance of 5. Hypocatalasemia and disease organelle/membrane formation and assembly, protein import, and growth and division of the nascent structure. In aging, this Many individuals worldwide are hypocatalasemic, not due to balance is upset and organelle formation or division occurs even aging's effects, but rather to a reduction in cellular catalase when protein import is corrupted. It is not clear what elicits this expression [29,30] or stability [29,31]. Detailed epidemiologi- response (Pex11p involved?) and whether or not it represents cal studies suggest these individuals experience the premature some type of rescue mechanism. onset of age-related disease, including anemia, atherosclerosis, 1752 S.R. Terlecky et al. / Biochimica et Biophysica Acta 1763 (2006) 1749–1754 tumors, and type 2 diabetes as well as the eye disorders, less import competent; senescence markers appear. In short, the cataracts and macular degeneration [32–35]. Cells from a cells have entered the peroxisome deterioration spiral. Quite hypocatalasemic patient (expressing approximately 25% of clearly, catalase inactivation accelerates aging in human cells. normal catalase levels) were found to have accumulated hydrogen peroxide and harbored age-associated pathologies 6. Peroxisomal catalase [17]. These cells were oxidatively damaged-proteins were excessively carbonylated, DNA contained oxidative lesions, 6.1. Other model systems and growth rates were reduced. Peroxisome function was compromised as was PTS1 protein import. Presumably one or To this point, the review has focused on hypocatalasemia as both of the latter phenomena explain the reduced activity it relates to the human condition. However, the effects of altered measured of dihydroxyacetone-phosphate acyl-transferase, the peroxisomal catalase levels have been examined in a number of rate-limiting enzyme in plasmalogen biosynthesis. This is an other model systems. For example, in the nematode Caenor- important point as plasmalogens are a critical class of cellular habditis elegans, loss of peroxisomal catalase results in the lipids found in virtually all membranes within the cell. They organism manifesting a progeric phenotype [37]. (Note that serve to protect the cell against various damaging agents these animals contain distinct cytosolic and peroxisomal forms including reactive oxygen species [36]. Their relative absence of catalase; loss of the cytosolic enzyme has no effect on aging would render the cell and its constituent membranes that much parameters.) Generation and processing of reactive oxygen more susceptible to toxic insult. What other peroxisomal species appears altered, peroxisome morphology is changed, enzyme activities are reduced or lost potentially further and the organism's lifespan is shortened. Similarly, lifespan of jeopardizing cell physiology remain to be determined. the yeast Saccharomyces cerevisiae is significantly reduced Absent from these analyses was any evidence that these cells when its (peroxisomal) catalase is knocked out [37]. were genuinely senescent. It appears cells from hypocatalase- In rats and mice, a general trend emerges. Cellular catalase mic patients enter the “peroxisome deterioration spiral” not due levels drop with age, accompanied by an increase in reactive to mislocalized catalase, but rather because of its relative oxygen species and resultant oxidative stress [14,38,39]. absence. Oxidative damage is the price paid—which once again Calorically restricted animals reverse this trend—they express only serves to further ratchet down all peroxisomal protein elevated levels of catalase and are more long-lived [40]. import, but especially of catalase. Cells may also be rendered hypocatalasemic by inhibiting the 6.2. Restoration enzyme with 3-amino-1,2,4-triazole (aminotriazole). In experi- ments where aminotriazole is added to cells continuously for To directly evaluate the role of catalase in organismal long- several passages at a concentration that reduces catalase activity to evity, Schriner and coauthors [41] created a series of transgenic approximately 35% of normal, the cells behave rather predictably mice overexpressing catalase in various subcellular organelles. (Terlecky, S.R., Koepke, J.I., and Walton, P.A., unpublished They directed the catalase to mitochondria, to the nucleus, and results). They amass hydrogen peroxide and other reactive oxygen to peroxisomes by engineering the enzyme with appropriate species, contain oxidatively damaged protein and DNA, and organellar targeting signals. (With respect to the peroxisomally- exhibit slowed growth rates. Their peroxisomes proliferate and are targeted enzyme, the naturally occurring KANL PTS1 was employed.) Their results were dramatic-overexpression of mito- chondrial catalase increased lifespan by nearly 20%. An anti- aging strategy based on “ prophylaxis” was a viable one. Nuclear-targeted catalase showed only insignificant increases while peroxisomally-directed catalase increased life- span only some 10%. Perhaps these results reflect the impor- tance both of catalase as a critical cellular anti-oxidant and mitochondria as the major source of damaging reactive oxygen species. However, based on what is now known regarding peroxisomal trafficking of catalase with age, it would be very interesting to know what happens to animals overexpressing catalase with an SKL-targeting signal. Such animals have been created and longitudinal aging studies begun (Terlecky, S.R., Koepke, J.I., and Walton, P.A., unpublished results). Restoration of peroxisomal catalase has been achieved at the cellular level ([16] and Terlecky, S.R., Koepke, J.I., and Walton, P.A., unpublished results). Human fibroblasts from a hypoca- talasemic individual transduced with catalase-SKL had their levels of hydrogen peroxide and related oxidants reduced nearly 80%. In fact, their oxidant level after treatment was only slightly Fig. 1. Peroxisome deterioration spiral. See text for further explanation. higher than that seen in normal (early passage) fibroblasts. S.R. Terlecky et al. / Biochimica et Biophysica Acta 1763 (2006) 1749–1754 1753

Catalase-KANL similarly introduced into hypocatalasemic cells [2] D. Harman, Aging: phenomena and theories, Ann. N. Y. Acad. Sci. 854 – quenched less than 50% of the hydrogen peroxide and related (1998) 1 7. [3] F.B. Johnson, D.A. Sinclair, L. Guarente, Molecular biology of aging, Cell reactive oxygen species. If hypocatalasemic cells are in fact 96 (1999) 291–302. generating hydrogen peroxide and other reactive oxygen [4] L. Moldovan, N.I. Moldovan, Oxygen free radicals and redox biology of species in peroxisomes, then catalase directed to the organelle organelles, Histochem. Cell Biol. 122 (2004) 395–412. (via an SKL-PTS1) might be expected to be the most effective [5] H.-C. Lee, Y.-H. Wei, Mitochondrial alterations, cellular response to strategy. Supporting this idea is the observation that in aging oxidative stress and defective degradation of proteins in aging, Biogerontology 2 (2001) 231–244. human cells nuclear microinjected with plasmids encoding [6] R. Perichon, J.M. Bourre, J.F. Kelly, G.S. Roth, The role of peroxisomes in catalase-SKL or catalase-KANL derivatives, it is the catalase- aging, Cell. Mol. Life Sci. 54 (1998) 641–652. SKL molecule that is far more effective at eliminating hydrogen [7] C. Chao, J. Youssef, M. Rezaiekhaleigh, L. Birnbaum, M. Badr, peroxide and related reactive oxygen species. Senescence-associated decline in hepatic peroxisomal activities corre- sponds with diminished levels of retinoid X receptor alpha, but not peroxisome proliferator-activated receptor alpha, Mech. Ageing Dev. 123 7. Concluding comments/future considerations (2002) 1469–1476. [8] U. Herbig, M. Ferreira, L. Condel, D. Carey, J.M. Sedivy, Cellular One of the questions that arises regarding peroxisomal senescence in aging primates, Science 311 (2006) 1257. hypocatalasemia and cellular and organismal aging is why does [9] J. Campisi, Suppressing cancer: the importance of being senescent, – human catalase have a “weak” targeting signal? A difficult Science 309 (2005) 886 887. — [10] S. Subramani, Components involved in peroxisome import, biogenesis, question to answer however, it does not appear to be an proliferation, turnover and movement, Physiol. Rev. 78 (1998) anomaly specific to humans. That is, examination of PTS1 171–180. sequences of at least 10 other animals including dogs, pigs, [11] S. Subramani, A. Koller, W.B. Snyder, Import of peroxisomal matrix and cows, and orangutans, reveals low PTS1-predictor scores (range membrane proteins, Annu. Rev. Biochem. 69 (2000) 399–418. of 1.5–4.4) for all. It is probably not likely that cells missort [12] G. Lametschwandtner, C. Brocard, M. Fransen, P. Van Veldhoven, — J. Berger, A. Hartig, The difference in recognition of terminal tri- catalase by design consider the patient with Zellweger-like peptides as peroxisomal targeting signal 1 between yeast and human is neurological impairment described by Singh and colleagues due to different affinities of their receptor Pex5p to the cognate signal [42]. This individual's cells simply do not traffic catalase, in and to residues adjacent to it, J. Biol. Chem. 273 (1998) contrast to other peroxisomal enzymes that appear correctly 33635–33643. targeted. Coupled with the evidence summarized here regarding [13] J.E. Legakis, J.I. Koepke, C. Jedeszko, F. Barlaskar, L.J. Terlecky, H.J. Edwards, P.A. Walton, S.R. Terlecky, Peroxisome senescence in human the association of catalase mislocalization and age-related fibroblasts, Mol. Biol. Cell 13 (2002) 4243–4255. cellular pathologies, there must be another explanation. The [14] K. Beier, A. Volkl, H.D. Fahimi, The impact of aging on enzyme proteins more likely reason that catalase contains a weak targeting signal of rat liver peroxisomes: quantitative analysis by immunoblotting and is that there was no evolutionary pressure to select against it. In immunoelectron microscopy, Virchows Arch., B Cell Pathol. Incl. Mol. – humans, where due to environmental conditions, food supplies, Pathol. 63 (1993) 139 146. [15] P.B. Lazarow, M. Robbi, Y. Fujiki, L. Wong, Biogenesis of peroxisomal disease, and other factors, life expectancy was not far beyond proteins in vivo and in vitro, in: H. Kindl, P.B. Lazarow (Eds.), Peroxisomes reproductive age, the naturally occurring catalase signal was and Glyoxysomes, vol. 386, Annals of the New York Academy of Sciences, sufficient. Only recently as humans have started to live longer New York, NY, 1982, pp. 285–300. has the issue of peroxisomal trafficking efficiency and [16] P.E. Purdue, P.B. Lazarow, Targeting of human catalase to peroxisomes is accumulation of cellular reactive oxygen species become a dependent upon a novel COOH-targeting sequence, J. Cell Biol. 134 (1996) 849–862. concern. Mice die in the wild largely of hypothermia, not from [17] C.S. Wood, J.I. Koepke, H. Teng, K.K. Boucher, S. Katz, P. Chang, L.J. the accumulated effects of cellular aging. Terlecky, I. Papanayotou, P.A. Walton, S.R. Terlecky, Hypocatalasemic Going forward, basic and translational scientists will continue fibroblasts accumulate hydrogen peroxide and display age-associated to try to understand the cellular factors and molecular mechanisms pathologies, Traffic 7 (2006) 97–107. contributing to aging and related degenerative disease. Such [18] G.J. Gatto Jr., E.L. Maynard, A.L. Guerrerio, B.V. Getsbrecht, S.J. Gould, J.M. Berg, Correlating structure and affinity for Pex5:PTS2 complexes, understanding will foster the development of pharmaceutical Biochemistry 42 (2003) 1660–1666. therapeutics designed not only to treat aging, but also to slow it [19] T. Harano, S. Nose, R. Uezu, N. Shimizu, Y. Fujiki, Hsp70 regulates the down or indeed, prevent it. Oxidant-induced damage accumulates interaction between the peroxisome targeting signal type 1 (PTS1)-receptor over years—facilitating the development and progression of age- Pex5p and PTS1, Biochem. J. 357 (2001) 157–165. related disease. The work summarized herein identifies a new [20] P.A. Walton, M. Wendland, S. Subramani, R.A. Rachubinski, W.J. Welch, Involvement of 70 kDa heat-shock proteins in peroxisomal import, J. Cell source of reactive oxygen species in cells and a potential new Biol. 125 (1994) 1037–1046. target for intervention. Reducing the oxidative load contributed to [21] C.-K. Lee, R.G. Klopp, R. Weindruch, T.A. Prolla, Gene expression profile the cells by peroxisomal hypocatalasemia may prove to be very of aging and its retardation by caloric restriction, Science 285 (1999) beneficial in treating aging pathologies and, importantly, be an 1390–1393. attainable goal. [22] M. Fransen, S.R. Terlecky, S. Subramani, Identification of a human PTS1 receptor docking protein directly required for peroxisomal protein import, Proc. Natl. Acad. Sci. U. S. A. 95 (1998) 8087–8092. References [23] G. Dodt, S.J. Gould, Multiple PEX genes are required for proper subcellular distribution and stability of Pex5p, the PTS1 import receptor: [1] K.B. Beckman, B.N. Ames, The free radical theory of aging matures, evidence that PTS1 protein import is mediated by a cycling receptor, J. Cell Physiol. Rev. 78 (1998) 547–581. Biol. 135 (1996) 1763–1774. 1754 S.R. Terlecky et al. / Biochimica et Biophysica Acta 1763 (2006) 1749–1754

[24] H.W. Platta, S. Grunau, K. Rosenkranz, W. Girzalsky, R. Erdmann, [34] L. Goth, M. Vitai, Hypocatalesemia in hospital patients, Clin. Chem. 42 Functional role of the AAA peroxins in dislocation of the cycling PTS1 (1996) 341–342. receptor back to the cytosol, Nat. Cell Biol. 7 (2005) 817–822. [35] O. Yildirim, N.A. Ates, L. Tamer, N. Musler, B. Ercan, U. Atik, A. Kanik, [25] N. Miyata, Y. Fujiki, Shuttling mechanism of peroxisome targeting signal Changes in antioxidant enzyme activity and malondialdehyde level in Type 1 receptor Pex5: ATP-independent import and ATP-dependent patients with age-related macular degeneration, Ophthalmologica 218 export, Mol. Cell. Biol. 25 (2005) 10822–10832. (2004) 202–206. [26] J. Feher, I. Kovacs, M. Artrico, C. Cavallotti, A. Papale, C. Balacco- [36] O.H. Morand, R.A. Zoeller, C.R.H. Raetz, Disappearance of plasmalogens Gabriel, Mitochondrial alterations of retinal pigment epithelium in age- from membranes of animal cells subjected to photosensitized oxidation, J. related macular degeneration, Neurobiol. Aging 27 (2005) 983–993. Biol. Chem. 263 (1988) 11597–11606. [27] H.S. Kim, M.-C. Song, I.H. Kwak, T.J. Park, I.K. Lim, Constitutive [37] O.I. Petriv, R.A. Rachubinsky, Lack of peroxisomal catalase causes a induction of p-Erk1/2 accompanied by reduced activities of protein progeric phenotype in Caenorhabditis elegans, J. Biol. Chem. 279 (2004) phosphatases 1 and 2A and MKP3 due to reactive oxygen species during 19996–20001. cellular senescence, J. Biol. Chem. 278 (2003) 37497–37510. [38] K. Ishii, L.X. Zhen, D.H. Wang, Y. Funamori, K. Ogawa, K. Taketa, [28] Q. Chen, B.N. Ames, Senescent-like growth arrest induced by hydrogen Prevention of mammary tumorigenesis in acatalasemic mice by vitamin E peroxide in human diploid fibroblasts, Proc. Natl. Acad. Sci. U. S. A. 91 supplementation, Jpn. J. Cancer Res. 87 (1996) 680–684. (1994) 4130–4134. [39] A. Ito, H. Watanabe, H. Aoyama, Y. Nakagawa, M. Mori, Effect of 1,2- [29] J.W. Eaton, M. Ma, Acatalasemia, in: C.R. Scriver, A.L. Beaudet, W.S. dimethylhydrazine and hydrogen peroxide for the duodenal tumorigenesis Sly, D. Valle (Eds.), The Metabolic and Molecular Bases of Inherited in relation to blood catalase activity in mice, Hiroshima, J. Med. Sci. 35 Disease, McGraw-Hill, New York, 1995, pp. 2371–2383. (1986) 197–200. [30] J.K. Wen, T. Osimi, T. Hashimoto, M. Ogata, Diminished synthesis of [40] G. Rao, E. Xia, M.J. Nadakavukaren, A. Richardson, Effect of dietary catalase due to the decrease in catalase mRNA in Japanese-type restriction on the age-dependent changes in the expression of antioxidant acatalasemia, Physiol. Chem. Phys. Med. NMR 20 (1988) 171–176. enzymes in rat liver, J. Nutr. 120 (1990) 602–609. [31] D.R. Crawford, M.E. Mirault, R. Moret, I. Zbinden, P.A. Cerutti, [41] S. Schriner, N.J. Linfor, G.M. Martin, P. Treuting, C.E. Ogburn, M. Emond, P. Molecular defect in human fibroblasts, Biochem. Biophys. E. Coskun, W. Ladiges, N. Wolf, H. Van Remmen, D.C. Wallace, P.S. Res. Commun. 153 (1988) 59–66. Rabinovitch, Extension of murine life span by overexpression of catalase [32] L. Goth, J.W. Eaton, Hereditary catalase deficiencies and increased risk of targeted to mitochondria, Science 308 (2005) 1909–1911. diabetes, Lancet 356 (2000) 1820–1821. [42] F.G. Sheikh, K. Pahan, M. Khan, E. Barbosa, I. Singh, Abnormality in [33] L. Goth, Lipid and carbohydrate chemistry in acatalasemia, Clin. Chem. 46 catalase import into peroxisomes leads to a severe neurological disorder, (2000) 564–566. Proc. Natl. Acad. Sci. U. S. A. 95 (1998) 2961–2966.