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Biochimica et Biophysica Acta xx (2006) xxx – xxx
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Review
Peroxisomes 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
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 hemecontaining tetrameric enzyme, catalase. 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; Peroxisome; Protein import; Reactive oxygen specie; Senescence
1. Introduction
How peroxisomes are formed has been a topic of great
interest to many investigators for several years now. Proteins
involved in various aspects of membrane assembly, protein
import, and organelle maintenance and inheritance have been
identified and how these molecules function mechanistically
elucidated in many cases. Although important questions remain,
it is clear that overall, peroxisome biogenesis is relatively well
understood.
There is also a rich understanding of peroxisome biochemistry and function as well as of how the organelle is turned over
during the processes known collectively as “pexophagy.”
Furthermore, the molecular basis of many devastating peroxisomal diseases has been delineated. Of no less importance, but
far less studied, are the questions of how the peroxisome
functions in cells and organisms of advancing age and what
⁎ Corresponding author. Tel.: +1 313 577 3557; fax: +1 313 577 6739.
E-mail address: [email protected] (S.R. Terlecky).
contribution the organelle makes to the course of cellular aging.
It is these latter questions that are the focus of this review.
Human cellular aging is multifactorial (see [1–3] and references therein); telomeres shorten, proteins are aberrantly glycated, DNA is damaged and inefficiently or improperly repaired,
epigenetic events occur, protein expression is altered and reactive oxygen species accumulate and damage cellular constituents. No one process dominates under all circumstances—
rather they appear to conspire in some, perhaps varying,
combination. An important open question is what initiates the
aging cascade. One possibility is reactive oxygen species;
molecules with the capacity to damage, inactivate, and even
destroy cellular DNA, proteins, and lipids including biological
membranes.
Falling under the heading of reactive oxygen species and
related compounds are singlet oxygen, superoxide anion,
hydrogen peroxide, and the hydroxyl radical. These cellular
reactive oxygen species are produced primarily by mitochondria
and peroxisomes [4]. Although peroxisomes probably do not
generate near the amount of reactive oxygen species that mito-
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chondria do [1,5], they may very well be making them earlier—
an important point to be considered further below.
Peroxisome aging was initially investigated using a rat liver
model. These important studies documented, for the first time,
age-related differences in peroxisomal enzyme activities and
overall organelle function (see detailed summary [6]). Important
follow-up work by Badr and colleagues confirmed the reduced
activities of peroxisomal β-oxidation enzymes and catalase in
aging rat liver, and suggested that with respect to the former,
diminished levels of the peroxisome proliferator-activated
receptor alpha (PPARα)-binding partner, retinoid X receptor
alpha (RXRα), may be responsible [7].
More recently, human fibroblasts have been employed to
study the specific relationship of peroxisomes and cellular
aging. These somatic cells may be cultured to various
population doubling levels (PDL), with advancing PDLs
being viewed as akin to aging. At a certain point, these cells
experience an irreversible cell cycle arrest and are termed
“senescent”. Characteristic biochemical and morphological
changes accompany cells' entry into the end of their replicative
lifespan. Perhaps the best validation of the model system comes
from recent studies performed in primates demonstrating the
presence of senescent cells at high frequencies in aged tissue
[8].
A final note regarding cellular senescence; it has been
suggested and evidence obtained to support the idea that cells
enter replicative senescence to avoid transformation and
becoming cancerous [9]. Interestingly, the very environment
that promotes senescence—that is, the presence of reactive
oxygen species both within cells and in the surrounding stroma,
also potentiates initiation and progression of cancerous
transformation.
2. PTS1 protein import in aging
The overwhelming majority of peroxisomal enzymes, including most oxidases which produce hydrogen peroxide,
contain a carboxy-terminal tripeptide closely related or identical
to serine–lysine–leucine (SKL) [10]. Called peroxisomal
targeting signal 1 (PTS1), this sequence and residues just
upstream determine the enzymes' capacities to be recognized by
the import receptor, Pex5p [10–12]. Conventional wisdom in
the field is that the strength of Pex5p's binding to a given
substrate determines its import efficiency. “PTS1 predictor” (see
http://mendel.imp.ac.at/mendeljsp/sat/pts1/PTS1predictor.jsp),
a powerful tool for the in silico analysis of relative PTS1
strength, indicates that human peroxisomal oxidases consistently score in the 10–15 range—a point to be returned to
shortly.
Using biochemically-defined in vitro assays, peroxisomal
import of a PTS1 (SKL)-containing reporter protein was found
to drop in cells of advancing age [13]. Interestingly, this import
defect appears first in cells of middle passage and is then
exacerbated in late passage and senescent cells. Extensive
follow-up studies indicate that irrespective of the human cell
line examined or the import assay employed, the results were
similar; aging compromises peroxisomal protein import.
As pointed out above, catalase levels are found to be reduced
in peroxisomes of aged rat livers [6,7,14]. Coupled with early
reports that catalase was a rather poor substrate of the peroxisomal
protein import apparatus [15], a more detailed examination of
catalase's import properties as a function of age was prompted.
Perhaps not surprisingly, catalase's import capacity too declined
significantly with age (Terlecky, S.R., Koepke, J.I., and Walton, P.
A., unpublished results]. Catalase is a PTS1-containing enzyme
whose import is mediated by Pex5p [16]. However, its PTS1 is a
tetrapeptide, lysine–alanine–asparagine–leucine (KANL) [16],
largely unrelated to the consensus motif described above. This
sequence is an extremely weak PTS1, only poorly directing
catalase or other reporter proteins to which it is appended, to the
organelle [13,17]. Combined with its upstream amino acids (in
catalase), its “PTS1 predictor” score is a paltry 1.5. A weak import
substrate even in early passage cells, catalase's import is severely
compromised in middle and late passage cells. Thus it appears
that although aging acts on all PTS1 enzymes with respect to their
import capacities, it is catalase with its weak KANL signal that is
the most dramatically affected.
3. Pex5p
3.1. Binding
One straightforward explanation for the distinct import capacities of SKL-containing enzymes as compared to catalase is
differential binding by Pex5p. Several experimental approaches
were brought to bear on the issue including fluorescence
anisotropy, ligand blots, solid-phase (ELISA-type) assays, twohybrid analysis, and surface plasmon resonance, among others
[12,13,18]. The results were clear and consistent—proteins
containing an SKL PTS1 were far better recognized and bound
by Pex5p than the KANL-containing catalase molecule.
Importantly, appending an SKL sequence in lieu of KANL
increased catalase's recognition by Pex5p to the level seen with
other SKL-containing enzymes [13]. Catalase-SKL was not only
recognized more avidly by Pex5p, but its import into peroxisomes was also enhanced (Terlecky, S.R., Koepke, J.I., and
Walton, P.A., unpublished results).
What happens to Pex5p with age? Preliminary results
suggest its affinity for PTS1 sequences is reduced (Terlecky,
S.R., Koepke, J.I., and Walton, P.A., unpublished results). As
will be discussed below, aging cells accumulate hydrogen
peroxide and other reactive oxygen species. Perhaps Pex5p is
oxidatively damaged in that environment. The observation that
hydrogen peroxide-treated Pex5p binds PTS1 less well supports
this notion. Investigation in this area continues.
Most of the binding studies described above involve measurement of direct protein–protein interactions between receptor and
ligand. Such interactions may very well be facilitated or modulated
in the cell by molecular chaperones or other factors. Hsp70 is one
such factor—shown to regulate Pex5p's binding to PTS1 [19] and
be a necessary component of (PTS1) protein import [20]. Since its
expression is reduced in aging [21], hsp70, or more accurately, its
absence, may contribute to the processes associated with
peroxisome senescence.
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3.2. Trafficking
4.2. Hydrogen peroxide production
Pex5p is a cycling receptor, binding PTS1 cargo in the cytosol
and ferrying it to the peroxisome membrane. The receptor docks
with the peroxisomal membrane protein Pex14p [22], and through
a rather poorly understood series of steps, releases its cargo, is
freed from Pex14p and then either enters the organelle (in whole or
in part), or engages other membrane peroxins and recycles back to
the cytosol. Pex5p cycling is critical—under certain conditions
(e.g. ATP depletion or reduced temperatures) Pex5p accumulates
on the peroxisome membrane and PTS1 protein import is slowed
[23]. Increased membrane-associated Pex5p is also seen in certain
mutant backgrounds—for example, when the peroxisomal
membrane proteins Pex2p, Pex10p, or Pex12p are defective or
absent [23], or when activity of the AAA proteins Pex1p and
Pex6p are reduced or eliminated [24,25]. Of relevance here is the
fact that Pex5p's cycling is reduced and accumulation on the
peroxisome membrane enhanced in middle and late passage cells
[13]. Again, such slowing of Pex5p cycling is most certainly
associated with reduced import rates. Pointing to the oxidative
environment of aging cells as potentially once more eliciting these
effects are the observations that treating (early passage) cells with
hydrogen peroxide not only causes Pex5p to amass on the
organelle membrane, but also significantly reduces PTS1 protein
import [13].
In early passage cells, peroxisomes exist in oxidative
balance—the organelle's oxidases consume molecular oxygen
and convert it to hydrogen peroxide, while catalase decomposes
the potentially toxic metabolite back to oxygen and water. A
balance of peroxisomal pro- and antioxidants exists. With
advancing age and the accompanying effects on peroxisomal
protein import described above, this homeostatic balance is
upset. Peroxisomal catalase in particular is reduced or lost. The
result of this uncoupling is the net production of hydrogen
peroxide and related reactive oxygen species. Specific oxidation-sensitive fluorescent dyes and enzymatic assays have been
used to document dramatic increases in hydrogen peroxide and
other reactive oxygen species in late passage cells [13]. That
these molecules amass in aged cells was well established in the
literature [1]; that the peroxisome contributes to this oxidative
burden has only recently come to light.
Metal ion-catalyzed conversion of hydrogen peroxide to the
hydroxyl radical via the Fenton reaction serves to increase the
destructive capacity of the peroxisomal metabolic by-products
formed. These molecules are quite clearly capable of damaging
DNA, proteins, and lipids including biological membranes.
Recent evidence suggests peroxisome-derived hydrogen peroxide and downstream reactive oxygen species may also
damage mitochondria causing them to depolarize and produce
damaging oxidants of their own (Terlecky, S.R., Koepke, J.I.,
and Walton, P.A., unpublished results).
Hydrogen peroxide and related reactive oxygen species
initiate a negative spiral of molecular events resulting in
oxidative damage to cellular constituents. Cell growth rates are
reduced, perhaps due to effects on the mitogenic cell-signaling
extracellular signal–regulated protein kinase 1/2 (“Erk 1/2”)
pathway, known to be sensitive to hydrogen peroxide [27].
Ames and colleagues demonstrated a direct connection
between accumulation of reactive oxygen species and aging by
showing non-toxic concentrations of hydrogen peroxide drove
(early passage) cells to a senescent-like state [28]. Cell morphology, growth, and function were all affected. Similar
approaches employed recently revealed that hydrogen peroxide
actually damages the PTS1-protein import machinery suggesting the notion of a self-sustaining “peroxisome deterioration
spiral” as illustrated in Fig. 1. In this model, age-related
peroxisomal hypocatalasemia results in increased cellular
concentrations of hydrogen peroxide. Other more damaging
reactive oxygen species may form and harm cellular components and functions. Peroxisomes themselves are a target of
oxidant-induced damage—further exacerbating the problem by
potentially perpetuating the spiral.
4. Peroxisomes of aging cells
4.1. Proliferation
Detailed immunocytochemical analysis of middle and late
passage human cells revealed progressively less intense staining
of SKL-containing proteins [13]. Rather, these molecules
appeared to accumulate in ever-increasing amounts in the
cytosol. Catalase was also mislocalized in aging cells, although
to a far greater extent. Indeed, some late passage cells appeared
completely devoid of peroxisomal catalase. Biochemical (latency)
analysis confirmed the immunofluorescence work—catalase was
clearly accumulating in the cytosol of aging cells [13].
As if the aging cell senses a reduced concentration of
peroxisomal enzymes (or the accumulation of unmetabolized
substrates), it responds by increasing peroxisome number—that
is, the organelle proliferates [13]. As compared to early passage
cells, middle and late passage cells contain approximately twice
as many punctate structures that may be immunodecorated with
antibodies to the peroxisomal membrane protein of 70 kDa
(PMP70) or Pex14p, appropriate membrane markers.
Similarly, peroxisomes proliferate in human retinal epithelia
of aged individuals or those suffering from (age-related)
macular degeneration [26].
Peroxisome biogenesis is thought to be a delicate balance of
organelle/membrane formation and assembly, protein import,
and growth and division of the nascent structure. In aging, this
balance is upset and organelle formation or division occurs even
when protein import is corrupted. It is not clear what elicits this
response (Pex11p involved?) and whether or not it represents
some type of rescue mechanism.
5. Hypocatalasemia and disease
Many individuals worldwide are hypocatalasemic, not due to
aging's effects, but rather to a reduction in cellular catalase
expression [29,30] or stability [29,31]. Detailed epidemiological studies suggest these individuals experience the premature
onset of age-related disease, including anemia, atherosclerosis,
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tumors, and type 2 diabetes as well as the eye disorders,
cataracts and macular degeneration [32–35]. Cells from a
hypocatalasemic patient (expressing approximately 25% of
normal catalase levels) were found to have accumulated
hydrogen peroxide and harbored age-associated pathologies
[17]. These cells were oxidatively damaged-proteins were
excessively carbonylated, DNA contained oxidative lesions,
and growth rates were reduced. Peroxisome function was
compromised as was PTS1 protein import. Presumably one or
both of the latter phenomena explain the reduced activity
measured of dihydroxyacetone-phosphate acyl-transferase, the
rate-limiting enzyme in plasmalogen biosynthesis. This is an
important point as plasmalogens are a critical class of cellular
lipids found in virtually all membranes within the cell. They
serve to protect the cell against various damaging agents
including reactive oxygen species [36]. Their relative absence
would render the cell and its constituent membranes that much
more susceptible to toxic insult. What other peroxisomal
enzyme activities are reduced or lost potentially further
jeopardizing cell physiology remain to be determined.
Absent from these analyses was any evidence that these cells
were genuinely senescent. It appears cells from hypocatalasemic patients enter the “peroxisome deterioration spiral” not due
to mislocalized catalase, but rather because of its relative
absence. Oxidative damage is the price paid—which once again
only serves to further ratchet down all peroxisomal protein
import, but especially of catalase.
Cells may also be rendered hypocatalasemic by inhibiting the
enzyme with 3-amino-1,2,4-triazole (aminotriazole). In experiments where aminotriazole is added to cells continuously for
several passages at a concentration that reduces catalase activity to
approximately 35% of normal, the cells behave rather predictably
(Terlecky, S.R., Koepke, J.I., and Walton, P.A., unpublished
results). They amass hydrogen peroxide and other reactive oxygen
species, contain oxidatively damaged protein and DNA, and
exhibit slowed growth rates. Their peroxisomes proliferate and are
Fig. 1. Peroxisome deterioration spiral. See text for further explanation.
less import competent; senescence markers appear. In short, the
cells have entered the peroxisome deterioration spiral. Quite
clearly, catalase inactivation accelerates aging in human cells.
6. Peroxisomal catalase
6.1. Other model systems
To this point, the review has focused on hypocatalasemia as
it relates to the human condition. However, the effects of altered
peroxisomal catalase levels have been examined in a number of
other model systems. For example, in the nematode Caenorhabditis elegans, loss of peroxisomal catalase results in the
organism manifesting a progeric phenotype [37]. (Note that
these animals contain distinct cytosolic and peroxisomal forms
of catalase; loss of the cytosolic enzyme has no effect on aging
parameters.) Generation and processing of reactive oxygen
species appears altered, peroxisome morphology is changed,
and the organism's lifespan is shortened. Similarly, lifespan of
the yeast Saccharomyces cerevisiae is significantly reduced
when its (peroxisomal) catalase is knocked out [37].
In rats and mice, a general trend emerges. Cellular catalase
levels drop with age, accompanied by an increase in reactive
oxygen species and resultant oxidative stress [14,38,39].
Calorically restricted animals reverse this trend—they express
elevated levels of catalase and are more long-lived [40].
6.2. Restoration
To directly evaluate the role of catalase in organismal longevity, Schriner and coauthors [41] created a series of transgenic
mice overexpressing catalase in various subcellular organelles.
They directed the catalase to mitochondria, to the nucleus, and
to peroxisomes by engineering the enzyme with appropriate
organellar targeting signals. (With respect to the peroxisomallytargeted enzyme, the naturally occurring KANL PTS1 was
employed.) Their results were dramatic-overexpression of mitochondrial catalase increased lifespan by nearly 20%. An antiaging strategy based on “antioxidant prophylaxis” was a viable
one. Nuclear-targeted catalase showed only insignificant
increases while peroxisomally-directed catalase increased lifespan only some 10%. Perhaps these results reflect the importance 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 hypocatalasemic 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
higher than that seen in normal (early passage) fibroblasts.
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Catalase-KANL similarly introduced into hypocatalasemic cells
quenched less than 50% of the hydrogen peroxide and related
reactive oxygen species. If hypocatalasemic cells are in fact
generating hydrogen peroxide and other reactive oxygen
species in peroxisomes, then catalase directed to the organelle
(via an SKL-PTS1) might be expected to be the most effective
strategy. Supporting this idea is the observation that in aging
human cells nuclear microinjected with plasmids encoding
catalase-SKL or catalase-KANL derivatives, it is the catalaseSKL molecule that is far more effective at eliminating hydrogen
peroxide and related reactive oxygen species.
7. Concluding comments/future considerations
One of the questions that arises regarding peroxisomal
hypocatalasemia and cellular and organismal aging is why does
human catalase have a “weak” targeting signal? A difficult
question to answer—however, it does not appear to be an
anomaly specific to humans. That is, examination of PTS1
sequences of at least 10 other animals including dogs, pigs,
cows, and orangutans, reveals low PTS1-predictor scores (range
of 1.5–4.4) for all. It is probably not likely that cells missort
catalase by design—consider the patient with Zellweger-like
neurological impairment described by Singh and colleagues
[42]. This individual's cells simply do not traffic catalase, in
contrast to other peroxisomal enzymes that appear correctly
targeted. Coupled with the evidence summarized here regarding
the association of catalase mislocalization and age-related
cellular pathologies, there must be another explanation. The
more likely reason that catalase contains a weak targeting signal
is that there was no evolutionary pressure to select against it. In
humans, where due to environmental conditions, food supplies,
disease, and other factors, life expectancy was not far beyond
reproductive age, the naturally occurring catalase signal was
sufficient. Only recently as humans have started to live longer
has the issue of peroxisomal trafficking efficiency and
accumulation of cellular reactive oxygen species become a
concern. Mice die in the wild largely of hypothermia, not from
the accumulated effects of cellular aging.
Going forward, basic and translational scientists will continue
to try to understand the cellular factors and molecular mechanisms
contributing to aging and related degenerative disease. Such
understanding will foster the development of pharmaceutical
therapeutics designed not only to treat aging, but also to slow it
down or indeed, prevent it. Oxidant-induced damage accumulates
over years—facilitating the development and progression of agerelated disease. The work summarized herein identifies a new
source of reactive oxygen species in cells and a potential new
target for intervention. Reducing the oxidative load contributed to
the cells by peroxisomal hypocatalasemia may prove to be very
beneficial in treating aging pathologies and, importantly, be an
attainable goal.
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Please cite this article as: Stanley R. Terlecky et al., Peroxisomes and aging, Biochimica et Biophysica Acta (2006), doi:10.1016/j.bbamcr.2006.08.017