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doi:10.1111/j.1600-0854.2010.01144.x
Review
Peroxisome Metabolism and Cellular Aging
Vladimir I. Titorenko1,∗ and Stanley
R. Terlecky2,∗
1 Department of Biology, Concordia University, 7141
Sherbrooke Street, West, SP Building, Office SP-501-9,
Montreal, Quebec, Canada H4B 1R6
2 Department of Pharmacology, Wayne State University
School of Medicine, 540 E. Canfield Avenue, Detroit, MI
48201, USA
∗ Corresponding authors: Vladimir I. Titorenko,
vtitor@alcor.concordia.ca and Stanley R. Terlecky,
srterlecky@med.wayne.edu
The essential role of peroxisomes in fatty acid oxidation,
anaplerotic metabolism, and hydrogen peroxide turnover
is well established. Recent findings suggest that these
and other related biochemical processes governed by
the organelle may also play a critical role in regulating
cellular aging. The goal of this review is to summarize
and integrate into a model the evidence that peroxi-
some metabolism actually helps define the replicative
and chronological age of a eukaryotic cell. In this model,
peroxisomal reactive oxygen species (ROS) are seen as
altering organelle biogenesis and function, and elicit-
ing changes in the dynamic communication networks
that exist between peroxisomes and other cellular com-
partments. At low levels, peroxisomal ROS activate an
anti-aging program in the cell; at concentrations beyond
a specific threshold, a pro-aging course is triggered.
Key words: anaplerotic metabolism, cell death, cellular
aging, fatty acid oxidation, hormesis, longevity, mito-
chondrial retrograde signaling, organelle biogenesis and
function, peroxisome, protein degradation, reactive oxy-
gen species, signal transduction
Received 27 October 2010, revised and accepted for
publication 16 November 2010, uncorrected manuscript
published online 18 November 2010, published online 7
December 2010
Aging of multicellular and unicellular eukaryotic organ-
isms is a highly complex, multifactorial biological phe-
nomenon (1). At the cellular level, declining function of
organelles and their elaborate communication systems
constitute both a cause and target of aging events (2–6).
Emergent studies have revealed that the peroxisome,
an organelle known for its essential role in lipid and
anaplerotic metabolism, as well as the production and
scavenging of hydrogen peroxide and other reactive oxy-
gen species (ROS) (7,8), can also function as an intracel-
lular signaling compartment and as an organizing platform
252 www.traffic.dk
© 2010 John Wiley & Sons A/S
that orchestrates important developmental decisions from
inside the cell (9–12). Moreover, peroxisomal dysfunction
has been shown to be associated with cellular aging as
well as with molecular pathologies that result in the devel-
opment and progression of specific age-related degener-
ative diseases (5,13–16). Here, we summarize growing
evidence in support of an essential role for the peroxi-
some in regulating age-related reactions within eukaryotic
cells and critically evaluate several molecular mechanisms
underlying its involvement in longevity-defining processes.
Mechanisms Linking Cellular Aging to Fatty
Acid Oxidation and Anaplerotic Reactions in
Peroxisomes
The well-established abilities of peroxisomes to oxidize
fatty acids to acetyl-coenzyme A (CoA) (7,8) and to use
it then in anaplerotic reactions to replenish tricarboxylic
acid (TCA) cycle intermediates destined for mitochon-
dria (17,18) are integrated into several longevity regula-
tion pathways within a cell. Such integration involves
dynamic communication between peroxisomes and other
organelles and is governed by the mechanisms outlined
here.
Role of non-esterified fatty acids and diacylglycerol
In yeast grown in glucose-containing media and in fat
storage tissues of multicellular eukaryotic organisms, the
non-esterified (‘free’) fatty acids that are oxidized in per-
oxisomes originate mainly from triacylglycerols (TAG) and
steryl esters (19–21). These neutral lipids are synthesized
in the endoplasmic reticulum (ER), and are then deposited
in the hydrophobic core of lipid bodies (21–23). In yeast,
the lipolytic conversion of neutral lipids to free fatty acids
within lipid bodies and the subsequent import of these
fatty acids by peroxisomes are driven by an extensive
physical contact between the two organelles (19). In fact,
peroxisomes are able to invade the hydrophobic core of
these stores of neutral lipids through synthesis of ‘pex-
opodia’ (19). Recently, we proposed a mechanism that
links yeast longevity to lipid dynamics in peroxisomes,
lipid bodies, and the ER (4,5). This mechanism may under-
lie the life-extending effect of caloric restriction (CR), a
low-calorie diet that increases life span in various organ-
isms and delays the onset, or reduces the incidence, of
many age-related diseases in rodent models (24). In the
proposed mechanism (Figure 1), short-lived non-CR yeast
accumulate ethanol, a product of glucose fermentation. By
repressing the synthesis of Fox1p, Fox2p and Fox3p, all of
which are the core enzymes of fatty acid β-oxidation in per-
oxisomes (25), ethanol suppresses peroxisomal oxidation

Figure 1: Peroxisomal fatty acid β-oxidation acts as a system controller regulating cellular aging by modulating levels of
non-esterified fatty acids and diacylglycerol. In yeast, the life-extending effect of a CR diet is due, in part, to a mechanism that links
longevity to lipid dynamics in peroxisomes, lipid bodies, and the ER. Please see text for details. Figure adapted from Goldberg et al.(5).
of free fatty acids that originate from TAGs synthesized
in the ER and deposited within lipid bodies (5). This leads
to the accumulation of electron-dense arrays of free fatty
acids (called ‘gnarls’) (19) within lipid bodies, and the ini-
tiation of several negative feedback loops. By reducing
lipolysis of TAGs in lipid bodies and their biosynthe-
sis in the ER, these feedback loops promote both the
accumulation of TAG in lipid bodies and the buildup of dia-
cylglycerol and free fatty acids in the ER (5). Because of
such remodeling of lipid dynamics, which is driven by the
diet-dependent changes in the efficiency of peroxisomal
fatty acid β-oxidation, yeast placed on a calorie-rich diet age
and die prematurely. The peroxisome-modulated prema-
ture death of non-CR yeast appears to be caused by their
(i) necrotic death, triggered by the inability of peroxisomes
to oxidize fatty acids which amass (26,27); (ii) caspase- and
mitochondria-independent lipoapoptotic death, initiated by
the accumulation of free fatty acids and diacylglycerol (28);
and (iii) response to a diacylglycerol-induced reorganiza-
tion of the protein kinase C-dependent signal transduction
network, known to affect multiple stress response- and
longevity-related processes (29,30).
Peroxisome metabolism and the mitochondrial
retrograde signaling pathway
In response to mitochondrial dysfunction, yeast cells
activate the mitochondrial retrograde (RTG) signaling path-
way (31,32). Controlled by a distinct set of regulatory
proteins, this signaling pathway responds to defects in
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Peroxisome Metabolism and Cellular Aging
mitochondria by activating transcription of a cassette of
nuclear genes (Figure 2). The protein products of these
genes cause a specific remodeling of carbohydrate and
nitrogen metabolism, activate peroxisome proliferation,
promote peroxisomal fatty acid β-oxidation and anaplerotic
reactions, stimulate stress responses, and enhance the
stability of nuclear and mitochondrial genomes (31–34).
The resulting changes in cell physiology compensate
for the mitochondrial dysfunction that prompted the
response (31,32,35).
The RTG pathway may be triggered in yeast cells by
inducing a complete loss of mitochondrial DNA (mtDNA),
introducing large deletions into mtDNA, or deleting the
nuclear COX4 gene encoding one of the subunits of mito-
chondrial cytochrome c oxidase (36–38). The resulting
loss of mitochondrial respiratory chain activity blocks the
TCA cycle at succinate dehydrogenase, a four-subunit
component of the chain (Figure 2) (32). Consequently,
the first three reactions of the cycle – all downstream
of the block – cannot convert pyruvate and acetyl-CoA
to α-ketoglutarate, the direct precursor of glutamate (32).
To meet the demand of nitrogen supply from glutamate
to most of the biosynthetic reactions, yeast cells need to
replenish acetyl-CoA, oxaloacetate and α-ketoglutarate. To
achieve this, they activate the RTG signaling pathway by a
yet-to-be-established mechanism. A collaborative effort of
multiple protein regulators in this pathway promotes relo-
cation of the Rtg1p–Rtg3p heterodimeric transcriptional
factor from the cytosol to the nucleus, where it activates
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Titorenko and Terlecky

Figure 2: Peroxisomal fatty acid oxidation and anaplerotic reactions drive the RTG signaling pathway of cellular aging
regulation. Functionally compromised mitochondria trigger the RTG pathway in replicatively aging yeast. Gene transcription ensues,
altering cell metabolism, stimulating peroxisome function, and maintaining cell viability. Please see text for details.

transcription of RTG-target genes (Figure 2) (31,32,35).
Among these are genes for the first three enzymes in
the TCA cycle, cytosolic enzymes involved in oxaloacetate
and acetyl-CoA biosynthesis, a mitochondrial transporter
for carnitine-dependent transfer of acetyl-CoA from the
cytosol and peroxisomes to mitochondria, mitochondrial
transporters for citrate and α-ketoglutarate, and plasma
membrane transporters for carnitine and glutamate. In
addition, RTG-target genes include a number that encode
proteins required for peroxisome biogenesis and func-
tion (31–34). Among these are the Pxa1p subunit of a
heterodimeric peroxisomal ATP-binding cassette trans-
porter complex required for import of long-chain fatty
acids into peroxisomes; Fox1p, Fox2p and Fox3p, the
core enzymes of fatty acid β-oxidation in peroxisomes;
Pex11p, a major positive regulator of peroxisome prolifer-
ation; and the citrate synthase Cit2p and acetyl-carnitine
synthase Cat2p – enzymes required for the conversion
of acetyl-CoA, a product of fatty acid oxidation, to cit-
rate and acetyl-carnitine, respectively (Figure 2) (33,34).
By promoting fatty acid oxidation and anaplerotic reactions
in peroxisomes that replenish TCA cycle intermediates to
be delivered to mitochondria, these peroxisomal proteins
are vital for the ability of the RTG pathway to maintain
viability of yeast cells harboring dysfunctional mitochon-
dria (31,32). In support of this notion, the signaling path-
way also responds to mitochondrial respiratory deficiency
(but not to the rate of mitochondrial ATP synthesis per
se) by greatly increasing peroxisome size and number
under conditions that normally do not induce peroxisome
assembly and proliferation (33). Moreover, in yeast cells
deficient in mitochondrial respiration, the RTG pathway
is mandatory for growth on oleate and for oleate-induced
expression of genes whose protein products play key
roles in peroxisome biogenesis and function (39,40).
It should be stressed that replicatively aging yeast gradu-
ally activate the RTG signaling pathway to compensate for
the age-associated decline in their mitochondrial function
which is manifest by a progressive deterioration of mito-
chondrial respiratory chain activity, loss of mitochondrial
membrane potential, and accumulation of mutations in
mtDNA (38,41–43). Importantly, the extent to which the
RTG pathway is activated in response to the accumulation
of dysfunctional mitochondria in yeast is directly correlated
with the resulting increase in their life span (31,35,38,44).

254 Traffic 2011; 12: 252–259


Thus, by being essential for the ability of the RTG signal-
ing pathway to maintain viability of yeast cells harboring
dysfunctional mitochondria, peroxisomes play a key role
in regulating yeast longevity.
Two other nutrient-status-activated signaling pathways
impact the peroxisome’s ability to modulate the RTG
reaction. One is the target of rapamycin (TOR) pathway,
which responds primarily to the quality of the nitrogen
source (45). The TOR pathway adjusts the RTG response
via Lst8p, a subunit of TOR Complex 1 (TORC1) and nega-
tive regulator of the mitochondrial pathway (Figure 2) (32).
Of note, a potent immunosuppressive drug, rapamycin,
extends the replicative and chronological lifespans of yeast
by inhibiting TORC1 (46) and, as a result, activating the
RTG pathway (45). In addition, the RTG response is mod-
ulated by the Ras2p/protein kinase A signaling pathway,
which responds primarily to the quality of the carbon
source available (45) and impacts the pathway at Mks1p
(Figure 2) (32,35).
The key point here is that the ability of peroxisomes to
modulate the RTG pathway is integrated into a nutritional
sensing network that regulates yeast longevity.
Mechanisms Linking Cellular Aging
to Peroxisomal ROS Homeostasis
By housing a number of ROS-producing oxidases as
well as the scavenging enzymes catalase and peroxire-
doxin, peroxisomes not only control the intraperoxisomal
homeostasis of ROS but can also contribute to the main-
tenance of extraperoxisomal ROS levels within the entire
cell (13,47). Here, we summarize the growing evidence
that ROS homeostasis and macromolecular oxidative dam-
age in peroxisomes govern several peroxisome-confined
anti-aging processes and control the dynamics of com-
munications between these organelles and other cellular
compartments, thereby helping to define the replicative
and chronological lifespan of a cell.
Peroxisome senescence
Peroxisomes manifest age-related changes to their
metabolism and biogenesis. Studies employing cultured
human cells reveal that peroxisomes senesce, with dra-
matic changes seen to their protein import capacities,
their ability to regulate organelle growth and division,
their functional integrity, and their capacity to process
ROS. Compromised trafficking of the hydrogen peroxide-
metabolizing enzyme catalase certainly contributes to the
latter effect, and may actually advance all the properties
listed (48). A method of re-establishing peroxisomal cata-
lase has been developed and dramatic effects on aging
cells observed. Indeed, old cells with newly established,
redox-balanced peroxisomes delay appearance of senes-
cence markers, re-establish mitochondrial integrity, and
enjoy oxidative equilibrium (15). The effects of altering
what is clearly age-related peroxisomal hypocatalasemia
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Peroxisome Metabolism and Cellular Aging
may have important health ramifications as there is com-
pelling epidemiological evidence that as the level of
catalase is reduced across a population, the incidence of
debilitating disease is dramatically increased (49). Thus, it
seems as if the intraperoxisomal concentration of ROS
cannot be actively maintained below a specific toxic
threshold, the organelle is damaged, oxidative balance
is lost, and both the organelle and the cell suffer the
consequences. It can also be imagined that as peroxi-
some function declines with age, its ability to participate
in the anti-aging processes described above (and outlined
in Figures 1 and 2) would be seriously impaired.
Mechanisms for minimizing buildup of oxidatively
damaged peroxisomes
Eukaryotic organisms have evolved several mechanisms
designed to minimize the buildup of peroxisomal macro-
molecules damaged by exposure to ROS in cells. These
include the selective elimination of oxidatively damaged
peroxisomal proteins and lipids, and prevention of poten-
tially damaging inheritance of functionally compromised
organelles by daughter cells during mitosis. Examples of
these mechanisms at work are considered here.
The insulin degrading enzyme (IDE) in mammalian perox-
isomes and the peroxisomal Lon (pLon) protease in yeast
peroxisomes carry out the intraperoxisomal degradation
of oxidatively damaged proteins (50,51). Interestingly, the
mitochondrial form of the Lon protease (mLon) is essen-
tial for metabolizing oxidatively damaged (mitochondrial)
proteins and its activity declines with age (52). It is tempt-
ing to speculate that its peroxisomal counterpart, pLon,
also plays a role in cellular aging by eliminating oxidatively
damaged proteins in peroxisomes of old or diseased cells.
Plant peroxisomes employ a peroxisome-associated pro-
tein degradation (PexAD) system – which appears to
function similar to the ER-associated protein degradation
(ERAD) system – for the export of oxidatively damaged
matrix proteins from the peroxisome to the cytosol where
they are subsequently degraded, perhaps by the ubiquitin-
proteasome system (53). PexAD involves the peroxisome-
bound ubiquitin-conjugating enzyme Pex4p, its membrane
tether Pex22p, and the peroxisome-associated ATPase
associated with diverse cellular activities (AAA) family
member, Pex6p. This system also requires the cycling
peroxisomal targeting signal 1 import receptor, Pex5p,
although its role in PexAD-driven protein degradation is
yet to be delineated (53).
A healthy population of peroxisomes in ‘young’ yeast cells
may also be maintained by pexophagy, an autophagy-
related process of selective degradation of whole
peroxisomes – perhaps, mainly dysfunctional organelles
containing oxidatively damaged proteins – following their
sequestration by vacuoles (51,54). Importantly, autophagy
is mandatory for the life-extending effects of a CR diet, as
well as of the anti-aging drugs rapamycin, resveratrol, and
spermidine. These interventions all stimulate autophagy
255

Titorenko and Terlecky
in aged cells and modulate the age-related dynamics of
ROS (55–60). Moreover, hydrogen peroxide serves as a
potent signaling molecule that initiates autophagy through
redox-sensitive proteases (61). It would be interesting to
know if age-related oxidative damage of the membrane-
bound peroxins, Pex3p and Pex14p, increases their affinity
for Atg30p, a protein whose Pex3p-dependent phosphory-
lation on the peroxisomal surface is required for targeting
the organelle to the autophagy machinery for degra-
dation (54). The increased size of dysfunctional, oxida-
tively damaged peroxisomes may also commit them for
autophagy through recruitment of two other pexophagy-
specific proteins, Atg11p and Atg26p (62).
In plant cells, an ER to peroxisome connectivity system
may contribute to the elimination of oxidatively damaged
peroxisomal proteins and lipids. It appears that in response
to endogenously induced hydroxyl radical stress, plant
peroxisomes produce dynamic tubular extensions called
‘peroxules’ which then elongate (63). Both peroxules and
elongated peroxisomes extend along path defined by
the ER tubules (63). Based on this observation, it has
been proposed that plant peroxisomes are continuous
with the ER and that the ER-peroxisome connectivity
system responds to conditions of oxidative stress by
enabling the retro-flow of oxidatively damaged matrix
proteins as well as of membrane proteins and lipids to
the ER. Such retro-flow would reduce the oxidative stress
to peroxisomes (63,64) and would allow undamaged
peroxisomal constituents (delivered either from the ER
or from the cytosol) to support the battery of peroxisome-
confined, anti-aging processes described above.
Finally, mechanisms exist to prevent inheritance of
dysfunctional, oxidatively damaged peroxisomes by the
daughter cell during mitosis. Indeed, two such pathways
have been identified in the yeasts Saccharomyces cere-
visiae and Yarrowia lipolytica (65,66).
Peroxisomal ROS may function as anti-aging
signaling molecules, akin to mitochondrial ROS
Growing evidence supports the view that in addition
to their pro-aging role postulated by the free radical
theory of aging – ROS at low, non-toxic levels can func-
tion as potent anti-aging signaling molecules that induce
‘stress-response hormesis’ (3,4,6,67–73). The molecular
mechanisms underlying the anti-aging potential of mito-
chondrial ROS (13,74) have begun to emerge; they involve
communication between mitochondria and the nucleus
via several signaling networks (3,6,75–77). Sub-lethal con-
centrations of hydrogen peroxide – following its diffusion
from mitochondria – appear to trigger the c -Jun amino-
terminal kinase signaling cascade that ultimately enables
the single forkhead box O transcriptional factor to activate
expression of critical anti-aging genes in the nucleus. It
is also possible that hormetic levels of ROS elicit partial
mitochondrial dysfunction, oxidative damage to specific
organellar constituents and ultimately trigger the RTG,
TOR, or AMPK signaling pathways described above.
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Importantly, in some animal tissues – such as rat liver –
peroxisomes can produce up to 35% of all cellular hydro-
gen peroxide (78). In addition to being able to control the
synthesis and degradation of ROS within the organelle,
peroxisomes also contribute to the maintenance of cel-
lular ROS homeostasis (13,47). It is not unreasonable to
speculate that if ROS are maintained below a specific
threshold level, peroxisomes could elicit an anti-aging cel-
lular program akin to that seen with mitochondria. In fact, a
recent study suggests that CR yeast induce hydrogen per-
oxide, presumably at non-toxic/pro-hormetic levels, and
experience extended chronological lifespans (79). Similar
effects are seen with catalase inactivation, even though
oxidative damage to macromolecules is increased under
such circumstances. Whether or not peroxisomal oxida-
tion/dysfunction caused by low concentrations of ROS
actually triggers the RTG, TOR, AMPK or other longevity-
defining signaling pathways remains to be determined.
Conclusions and a Model for the Integration
of Peroxisomal Processes that Regulate
Cellular Aging
A model for how peroxisome metabolism impacts cel-
lular aging emerges from our analysis and is depicted
schematically in Figure 3. The model includes the notion
that in replicatively and chronologically ‘young’ cells, effi-
cient Pex5p-dependent peroxisomal import of the ROS
scavenging enzymes catalase and peroxiredoxin enables
peroxisomes to minimize the oxidative damage to their
proteins and lipids. Quality control of the Pex5p-driven
reaction is assured by the receptor accumulation and
degradation in the absence of recycling (RADAR) path-
way (80). Inside the organelle, the IDE and pLon proteases
as well as the PexAD system for the degradation of
oxidatively damaged peroxisomal matrix proteins elim-
inate those molecules that are unable to support the
anti-aging processes orchestrated by functionally active
peroxisomes.
The efficient Pex5p- and Pex7p-dependent import of
Fox1p, Fox2p, and Fox3p into peroxisomes of ‘young’ cells
enhances their ability to oxidize fatty acids that originate
from TAGs synthesized in the ER and deposited within
lipid bodies. Such accelerated peroxisomal fatty acid oxi-
dation enables ‘young’ cells to maintain low levels of
non-esterified fatty acids and diacylglycerol, thereby pre-
venting their premature death by impairing necrosis and
lipoapoptosis and by maintaining stress resistance through
the attenuation of protein kinase C signaling (Figure 1).
Moreover, the efficient Pex5p-dependent import of the
citrate synthase Cit2p and acetyl-carnitine synthase Cat2p
into peroxisomes of ‘young’ cells – in conjunction with
the efficient peroxisomal import of Fox1p, Fox2p, and
Fox3p – enhances the life-extending ability of peroxi-
somes to drive the anti-aging RTG signaling pathway
of peroxisomes–mitochondria, mitochondria–nucleus and
nucleus–peroxisomes communications (Figure 2). The
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Peroxisome Metabolism and Cellular Aging

Figure 3: A model for the ROS-driven integration of peroxisomal processes that regulate cellular aging. A) In replicatively and
chronologically ‘young’ cells, the intraperoxisomal concentration of ROS is actively maintained below a toxic threshold. In these cells,
peroxisomes function both as a cellular compartment housing anti-aging processes (depicted in Figures 1 and 2) and as a signaling
platform for activating extraperoxisomal anti-aging processes within the cell. B) In replicatively and chronologically ‘old’ cells, the
intraperoxisomal concentration of ROS exceeds a toxic threshold. In these cells, the peroxisome switches from being a platform for
activating anti-aging processes to a staging area for the development of a pro-aging program within the cell. Not only is the peroxisome
unable to carry out intraorganellar anti-aging processes, but it now releases hydrogen peroxide and related ROS to the cytosol where it
contributes to oxidative damage throughout the cell. Please see text for additional details. H2 O2 = hydrogen peroxide; CAT = catalase;
PRX = peroxiredoxin.

peroxin Pex11p, a major positive regulator of peroxisome
proliferation, amplifies the RTG pathway by increasing the
number of peroxisomes carrying out fatty acid oxidation
and anaplerotic reactions. In our model, peroxisomes in
‘young’ cells not only efficiently import the protein compo-
nents constituting a cassette of anti-aging processes but
may also function as a signaling platform that maintains
ROS concentration at a certain optimal level. This level of
ROS is insufficient to damage cellular macromolecules but
can activate several redox signaling networks (75–77) that
induce stress-response hormesis by increasing the abun-
dance or activity of stress-protecting and other anti-aging
proteins.
Our model further posits that, over time, peroxisomes
senesce and begin to amass hydrogen peroxide and
related ROS. Import of critical proteins is compromised,
and an imbalance in peroxisomal (and cellular) ROS home-
ostasis is created. The organelle is oxidatively damaged,
metabolically compromised, and the dynamic communica-
tion networks that exist between itself and other organelle
systems are corrupted. The ability of the peroxisome
to function as a regulator of anti-aging metabolic and
signaling reactions is thereby dramatically reduced. As a
result, the cell adopts a pro-aging program.
The peroxisome is very clearly integrated into an
endomembrane system that governs cellular aging. The
challenge for the future is to define the nature of these
interactions, the basis of their regulation, and how, per-
haps, they can be manipulated pharmaceutically to extend
longevity.
Acknowledgments
VIT research was supported by grants from the CIHR, NSERC of Canada,
Canada Foundation for Innovation, and Concordia University Chair Fund.
VIT is a Concordia University Research Chair in Genomics, Cell Biology and
Aging. S. R. T. was supported by grants from the National Institutes of
Health (USA).
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