Mechanisms of Ageing and Development

123 (2002) 207 – 213

Protein turnover plays a key role in aging

Alexey G. Ryazanov *, Bradley S. Nefsky

Department of Pharmacology, Uni

6ersity of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School,

675

Hoes Lane, Piscataway, NJ

08854

, USA

Abstract

Although the molecular mechanism of aging is unknown, a progressive increase with age in the concentration of

damaged macromolecules, especially proteins, is likely to play a central role in senescent decline. In this paper, we
discuss evidence that the progressive decrease in protein synthesis and turnover can be the primary cause of the
increase in the concentration of damaged proteins with age. Conversely, protein damage itself is likely to be the cause
of the decrease in protein turnover. This could establish a positive feedback loop where the increase in protein damage
decreases the protein turnover rate, leading to a further increase in the concentration of damaged proteins. The
establishment of such a feedback loop should result in an exponential increase in the amount of protein damage — a
protein damage catastrophe — that could be the basis of the general deterioration observed in senescent organisms.
© 2002 Published by Elsevier Science Ireland Ltd.

Keywords

:

Senescent decline; Protein damage; Protein turnover; Aging; Protein oxidation; Protein damage catastrophe

www.elsevier.com/locate/mechagedev

1. Increase in the concentration of damaged
proteins during aging

Various genes have been identified in worms,

flies and mammals whose mutation can drastically
affect life span. For example, mutations in the
insulin signaling pathway, such as age-

1

and daf-

2

, can double life span in Caenorhabditis elegans

(Friedman and Johnson, 1988; Kenyon et al.,
1993), the Methuselah mutation can significantly
increase life span in Drosophila (Lin et al., 1998),
and mutation of p66

shc

can increase life span in

mice (Migliaccio et al., 1999). However, the

molecular mechanism by which any of these genes
affects life span remains unknown. Similarly, the
molecular mechanism of aging in general remains
a mystery. It is also unclear whether there is a
general, or ‘public’, as George Martin called it,
mechanism of aging that is common to various
organisms, or if each type of organism ages in its
own way (Martin et al., 1996).

There is extensive evidence, however, that dam-

age to macromolecules, especially oxidative dam-
age, plays an important role in aging (Martin et
al., 1996). Increase in the concentration of dam-
aged proteins seems particularly important be-
cause it would lead to the malfunction of virtually
all biological processes. An increase in the concen-
tration of damaged intracellular proteins as well
as an increase in the concentration of inactive or

* Corresponding author. Tel.: + 1-732-235-5526; fax: + 1-

732-235-4073.

E-mail address

:

[e-mail] (A.G. Ryazanov).

0047-6374/02/$ - see front matter © 2002 Published by Elsevier Science Ireland Ltd.

PII: S 0 0 4 7 - 6 3 7 4 ( 0 1 ) 0 0 3 3 7 - 2

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partially active forms of various enzymes in aging
organisms is well-documented (reviewed in Stadt-
man, 1988, 1992; Rothstein, 1979, 1989; Rattan,
1996; Gershon, 1979; Rosenberger, 1991; Gafni,
1990). Extensive damage to extracellular proteins
such as collagen, elastin and proteoglycans is also
observed during aging (reviewed in Sell and Mon-
nier, 1995). The age-related increase in protein
damage is due to various post-translational mod-
ifications that include oxidation of amino acid
side chains, racemization of aspartyl and as-
paraginyl residues, deamidation of asparaginyl
and

glutaminyl

residues,

and

oxidation

of

sulfhydry groups (reviewed in Stadtman, 1988,
1992). Protein misfolding is also likely to con-
tribute to the increase in the concentration of
abnormal enzymes and proteins in senescent tis-
sues (Gafni, 1990).

Oxidation by free radicals is particularly impor-

tant in generating damaged proteins during aging
(Harman, 1956; Stadtman, 1992). There is exten-
sive evidence that the increased concentration of
oxidatively damaged proteins, can be a major
contributing factor in aging (Sohal et al., 1993;
Forster et al., 1996; Oliver et al. 1987; Carney et
al., 1991; Smith et al., 1991; Dubey et al., 1996;
Youngman et al., 1992).

The extent of protein damage observed during

aging is quite remarkable. Roughly 20 – 30% of all
cellular proteins are carbonylated in aged individ-
uals (Starke-Reed and Oliver, 1989; Stadtman,
1992). If all other forms of oxidative damage are
included, this number probably increases to 40 –
50% (Stadtman, 1992). If we consider other forms
of damage, it seems likely that most protein
molecules in senescent tissues contain some form
of damage.

What causes the increase in the concentration

of damaged proteins during aging? There are two
possible mechanisms: an increase in the rate at
which damage is generated or a decrease in the
rate at which damage is removed. Both mecha-
nisms appear to be involved in aging. For exam-
ple, an increase in the amount of oxidatively
damaged proteins during aging may be due to an
increase in the production of free radicals (re-
viewed in Sohal and Weindruch, 1996). On the
other hand, increased accumulation of damaged

proteins can result from an age-dependent de-
crease in the removal of protein damage by either
repair or replacement of the damaged protein.
The cells ability to repair protein damage, how-
ever, seems rather limited and most forms of
protein damage appear to be irreversible. The
only mechanism cells have to deal with irre-
versibly damaged proteins is to replace them
through protein turnover. The decrease in protein
turnover with age (see below) could therefore be a
major cause of the increased concentration of
damaged proteins.

2. Protein turnover in aging

The rate of protein turnover is determined by

the combined rates of protein synthesis and degra-
dation. Once growth is complete, organisms reach
a steady state in which the rate of protein synthe-
sis equals the rate of protein degradation. Most
studies of protein metabolism in aging were fo-
cused on protein synthesis, and there is over-
whelming evidence that the rate of protein
synthesis declines with age. This decrease in
protein synthesis appears to be a universal phe-
nomenon (reviewed in Makrides, 1983; Richard-
son and Cheung, 1982; Van Remmen et al., 1995;
Rattan, 1996). Since there is no pronounced de-
crease in protein mass with age, the age-depen-
dent decrease in protein synthesis must be
counterbalanced by a corresponding decrease in
protein degradation. In fact, there is experimental
evidence that certain proteolytic activities associ-
ated with both the lysosome and proteasome de-
crease with age (reviewed in Van Remmen et al.,
1995; Cuervo and Dice, 2000; Grune, 2000;
Friguet et al., 2000; Keller et al., 2000). The
age-dependent decrease in the rate of protein
turnover is quite significant and leads to a drastic
increase in protein half-life (see e.g. Sharma et al.,
1979; Prasanna and Lane, 1979). As is shown in
Fig. 1, the half-life of an average protein increases
exponentially with age in the nematode Turbatrix
aceti, and is increased 10-fold in old nematodes in
comparison to young worms (Prasanna and Lane,
1979). The drastic decrease in protein synthesis
with age in C. elegans (Johnson and McCaffrey,

A.G. Ryazano

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123 (2002) 207 – 213

209

1985) suggests a similar increase in protein half-
life occurs during aging in this organism. Whole
body protein turnover is also significantly de-
creased during aging in rats (Lewis et al., 1985)
and humans (Young et al., 1975). It is striking
that despite a very significant decrease in protein
turnover during aging, there are no dramatic
changes in the spectrum of proteins synthesized in
C. elegans (Vanfleteren and DeVreese, 1994; John-
son and McCaffrey, 1985) or in the spectrum of
mRNA expressed in mammalian tissues (Goyns et
al., 1998; Lee et al., 1999). Therefore, the several-
fold decrease in overall protein turnover implies
that the rate of turnover of most proteins are
decreased several-fold.

As was suggested by Richardson and Cheung

(1982), an increase in protein half-life can signifi-
cantly decrease the rate at which protein expres-
sion is induced. This can significantly increase the

Fig. 2. Model for the positive feedback loop between the
increase in the concentration of damaged proteins and de-
creased protein turnover leading to a protein damage catastro-
phe.

time needed for cells to respond to external stim-
uli, and can explain diminished stress resistance
observed with age.

Decrease in protein turnover can also con-

tribute to the development of neurodegenerative
disorders that are associated with the deposition
of protein aggregates such as Parkinson’s disease
and Alzheimer’s disease (Alves-Rodriguez et al.,
1998; Andersen, 2000).

3. Protein damage catastrophe

Although the age-dependent decrease in protein

turnover is well-documented, the mechanism re-
sponsible for this decrease is unclear. Analysis of
the literature suggests that the activities of various
components of both the protein synthesis and
degradation machinery decline with age (reviewed
in Van Remmen et al., 1995; Cuervo and Dice,
2000; Grune, 2000; Friguet et al., 2000; Keller et
al., 2000). A possible cause of such age-dependent
decline in protein turnover can be the cumulative
effect of non-specific damage to various compo-
nents involved in protein synthesis and degrada-
tion. This could establish a positive feedback loop
where increase in protein damage decreases
protein synthesis and degradation rates, and this
decrease in protein turnover leads to a further
increase in the concentration of damaged proteins
(Fig. 2).

Fig. 1. Exponential increase of average protein half-life with
age in the nematode Turbatrix aceti. The graph was plotted
using data from Prasanna and Lane, 1979. In the inset, the ln
of protein half-life is plotted against age demonstrating a
linear relationship.

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Increase in protein damage in this model can be

described by the following equations. Let

w be the

rate of protein turnover and q be the concentra-
tion of damaged proteins.

Then,

w=g−aq

dq/dt =

d−bn

Where

a, b, d and g are constants. From these

two equations, the rate of the increase in the
concentration of damaged proteins can be de-
scribed as:

dq/dt =

d−b(g−aq)=d−bg+baq

or, since

d−bg is a constant, (C):

dq/dt =

baq+C;

One can see that when q is small, dq/dt is

constant, while if q

\C/ab, then q#e

abt

and,

therefore, the concentration of damaged proteins
increases exponentially.

Therefore, the establishment of such a feedback

loop could result in an exponential increase in the
amount of protein damage, leading to a protein
damage catastrophe. An exponential increase in
the amount of damaged proteins with age was in
fact observed in several studies (Oliver et al.,
1987; Starke-Reed and Oliver, 1989; Stadtman,
1992). A decrease in the rate of protein turnover
with age also appears to be exponential (see Fig.
1), which is consistent with the idea that it is
caused by an exponential increase in damage to
the components of the protein synthesis and
degradation machinery. We suggest that this posi-
tive feedback loop between increasing protein
damage and decreasing protein turnover leading
to a protein damage catastrophe may be the ma-
jor cause of senescence.

Our model is reminiscent of Orgel’s error

catastrophe hypothesis that suggested aging is due
to an accumulation of abnormal proteins arising
from transcriptional and translational errors
(Orgel, 1963, 1970). He suggested that the accu-
mulation of errors in the transcriptional and
translational machinery would decrease their
fidelity, establishing a positive feedback loop,
which would further increase the accumulation of

errors in proteins leading to an ‘error catastro-
phe’. This hypothesis was widely discussed during
the 1970s and 1980s, and several mathematical
models of ‘error catastrophe’ have been devel-
oped. Although a number of studies (particularly
in tissue culture cells) found no evidence of an
‘error catastrophe’ during aging, in the absence of
a direct test we cannot determine the extent to
which transcriptional and translational errors
contribute to senescence. Our ‘protein damage
catastrophe’ model proposes a similar feedback
loop in which damage to the protein synthesis and
degradation machinery accelerates the accumula-
tion of abnormal proteins resulting in senescence.
Unlike the ‘error catastrophe’ model, however, we
propose that protein damage (covalent modifica-
tions and misfolding) instead of translational er-
rors gives rise to the abnormal proteins and that it
is the resulting decrease in protein turnover,
rather than a decrease in translational fidelity,
that leads to the increase in the concentration of
abnormal proteins.

Although our model assumes that the decrease

of protein turnover rate with age is the result of
cumulative damage to the various components of
the protein synthesis and degradation machinery,
it is possible that damage to some rate-limiting
components is particularly important in the over-
all decline in protein turnover. For example, there
is a consensus in the literature that the elongation
stage of protein synthesis is predominantly af-
fected by aging (reviewed in Van Remmen et al.,
1995). In addition, there is evidence that elonga-
tion factor-2 is particularly sensitive to oxidative
damage, and is one of the major carbonylated
proteins observed during oxidative stress in rat
liver as well as in yeast (Cabiscol et al., 2000;
Parrado et al., 1999; Ayala et al., 1996). There-
fore, it is possible that the overall exponential
decrease in protein turnover with age is due pre-
dominantly to damage to a rate-limiting compo-
nent such as an elongation factor, while damage
to other components that are not rate-limiting do
not affect the overall decline. If this is the case,
and there is a particular component whose decline
in activity is responsible for the overall decrease in
protein turnover, then this would suggest an obvi-
ous strategy for intervention that can increase
protein turnover and extend life span.

A.G. Ryazano

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Is it possible that mutations or interventions

that extend life span act through an increase in
protein turnover? Dietary restriction is a well
established intervention which can extend the life
span of various organisms (Sohal and Weindruch,
1996). It was demonstrated in rats that an in-
crease in protein synthesis and degradation are
among the most prominent effects of dietary re-
striction (Lewis et al., 1985; Holehan and Merry,
1986; D’Costa et al., 1993). In their comprehen-
sive review on the mechanism of the anti-aging
effect of dietary restriction, Holehan and Merry
(1986) concluded that ‘‘protein turnover, both
directly and through amplification by adjustments
in endocrine feedback, is the primary effect of
underfeeding’’.

A

detailed

study

of

protein

turnover in rat liver revealed that protein turnover
is elevated throughout most of the life span of
dietary restricted versus ad libidum fed animals
(Ward, 1988a,b). This data, together with the data
that

an

increase

in

protein

degradation

is

observed shortly after the onset of dietary
restriction (Ishigami and Goto, 1990), argues that
an increase in protein turnover can play a
causative role in the anti-aging effect of dietary
restriction.

It was recently found that dwarf mice have a

significantly increased life span (Brown-Borg et
al., 1996; Bartke et al., 2001; Flurkey et al., 2001),
and it was argued that small size in animals was
associated

with

longevity

(Miller,

1999;

Bartke, 2000; Miller et al., 2000). Intriguingly, it
was reported that mice selected for small size
have

increased

protein

turnover

in

various

organs

(Priestley

and

Robertson,

1973).

It

will be interesting in the future to analyze whether
various

long-lived

mutants

of

C.

elegans,

Drosophila and mice have increased protein
turnover rates.

Overall, we suggest that the exponential in-

crease in the concentration of damaged proteins
with age in conjunction with the decrease in
protein turnover — protein damage catastrophe —
is the major mechanism underlying senescent de-
cline

during

aging,

and

increasing

protein

turnover can be a plausible strategy to retard
aging and extend life span.

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