G Model
ARR-371; No. of Pages 24
ARTICLE IN PRESS
Ageing Research Reviews xxx (2012) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Ageing Research Reviews
journal homepage: www.elsevier.com/locate/arr
Review
The role of DNA damage and repair in aging through the prism of
Koch-like criteria
Alexey A. Moskalev a,∗ , Mikhail V. Shaposhnikov a , Ekaterina N. Plyusnina a ,
Alex Zhavoronkov b,c , Arie Budovsky d,e , Hagai Yanai e , Vadim E. Fraifeld e
a
Laboratory of Molecular Radiobiology and Gerontology, Institute of Biology, Komi Science Center of Russian Academy of Sciences, Syktyvkar 167982, Russia
Bioinformatics Laboratory, Center for Pediatric Hematology, Oncology, Immunology, Moscow 119296, Russia
c
The Biogerontology Research Foundation, Reading, UK
d
Judea Regional Research & Development Center, Carmel 90404, Israel
e
The Shraga Segal Department of Microbiology and Immunology, Center for Multidisciplinary Research on Aging, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
b
a r t i c l e
i n f o
Article history:
Received 31 May 2011
Received in revised form 27 January 2012
Accepted 6 February 2012
Available online xxx
Keywords:
Aging
Longevity
DNA damage
DNA repair
DNA mutations
a b s t r a c t
Since the first publication on Somatic Mutation Theory of Aging (Szilárd, 1959), a great volume of knowledge in the field has been accumulated. Here we attempted to organize the evidence “for” and “against”
the hypothesized causal role of DNA damage and mutation accumulation in aging in light of four Kochlike criteria. They are based on the assumption that some quantitative relationship between the levels
of DNA damage/mutations and aging rate should exist, so that (i) the longer-lived individuals or species
would have a lower rate of damage than the shorter-lived, and (ii) the interventions that modulate the
level of DNA damage and repair capacity should also modulate the rate of aging and longevity and vice
versa. The analysis of how the existing data meets the proposed criteria showed that many gaps should
still be filled in order to reach a clear-cut conclusion. As a perspective, it seems that the main emphasis
in future studies should be put on the role of DNA damage in stem cell aging.
© 2012 Elsevier B.V. All rights reserved.
1. Introduction
Various types of errors in DNA sequences are regular events
throughout the lifetime of any given organism. They result from
either spontaneous or damage-induced mutagenesis. The DNA
defects may include nucleotide deletions or insertions, nucleotide
substitutions, cross-linking with other nucleotides and proteins,
chemical modifications, single- or double-stranded DNA breaks,
and chromosomal rearrangements (see Appendix A). At the genome
architecture level such events may lead to aneuploidy, gene amplifications, loss of heterozygosity, and eventually to partial or full
loss of gene functions, alterations in gene expression and genome
instability (Vijg, 2000). To counteract DNA damage, the cell has
a powerful repair system, with often overlapping and redundant
pathways (see Appendices A and B). Whatever the case, accumulation of mutations is a result of misbalance between DNA damage
and repair, when the repair mechanisms are not sufficient enough
to cope with a given level of damage. Once a certain level of DNA
damage is reached, cells may undergo a wide range of phenotypic
changes, from cell cycle arrest, apoptosis, or cellular senescence
∗ Corresponding author. Tel.: +7 8212 430 650, fax: +7 8212 240 163.
E-mail address: [email protected] (A.A. Moskalev).
to malignant transformation (Erol, 2011). In fact, elimination of
cells with damaged DNA or cessation of their proliferation may be
considered the cellular protective responses to unresolved or
excessive DNA damage, aimed at preventing a spread or “neutralizing” of potentially dangerous cells.
Since the first publication on Somatic Mutation Theory of Aging
(Szilárd, 1959), a great volume of knowledge in the field has been
accumulated and intensively discussed (Rattan, 1989; Vijg, 2000;
Kyng and Bohr, 2005; Best, 2009; Hoeijmakers, 2009; Seviour and
Lin, 2010; Freitas and de Magalhaes, 2011). Up to date, around
10,000 articles dealing with mutations and aging are deposited in
PubMed, of them, almost two thousand are reviews. Yet, to what
extent accumulation of mutations contributes to the aging process
still remains an open question. In view of the massive amount of
information, we attempted to analyze the existing data using a set
of logical “Koch-like” criteria (in 1890, Koch proposed postulates
designed to establish an etiological role of a pathogen in an infectious disease). So, here we evaluate how the current knowledge in
the field meets the following criteria,1 without detailed discussion
of the underlying mechanisms:
1
Proposed by V.E. Fraifeld.
1568-1637/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.arr.2012.02.001
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
G Model
ARR-371; No. of Pages 24
ARTICLE IN PRESS
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
2
Criterion 1: DNA damage and mutations accumulate with age.
Criterion 2: (i) Premature aging is accompanied by increased
DNA damage/mutations; (ii) agents increasing the DNA damage/mutation rate cause a premature aging.
Criterion 3: (i) Longevity phenotype is associated with lower levels of DNA damage/mutations; (ii) pro-longevity interventions
decrease the DNA damage/mutation load; (iii) reduction of DNA
damage/mutations increases lifespan.
Criterion 4: Species differing in DNA damage/mutation load, differ
in longevity and vice versa, so that the longer-lived species have a
lower mutation load than the shorter-lived species.
In this study we addressed these criteria for nuclear DNA. They
could also be applied for mitochondrial DNA, but this important
issue is beyond the scope of this work (for reviews see Yang et al.,
2008; Gredilla et al., 2010). We postulate that fulfillment of at least
one of the above criteria may point to the involvement of the DNA
damage/mutation accumulation in mechanisms of aging, but only
by meeting all criteria, it would be considered a universal (“public”) determinant of aging. It should also be taken into account
that the extent to which DNA damage/mutations contribute to
the aging process could differ between species, i.e., to be speciesspecific (“private”). Finally, compliance to these criteria does not
exclude the contribution of other putative mechanisms, but rather
puts somatic mutations as one of the major (or at least important)
mechanisms of aging.
2. Do DNA damage and somatic mutations accumulate with
age?
It is quite obvious that before considering any possible (including causative) role of the DNA damage/mutation accumulation in
aging, it should be shown that it does indeed accumulate. Thus, our
first step was to evaluate to what extent the existing data meet
Criterion 1, focusing primarily on humans and mammalian species.
2.1. DNA damage
Several types of DNA damage have been investigated in respect
to aging. These data are presented in Table 1.
One of the most common types of spontaneous DNA damage is
the breakage of the glycosidic bonds between purine or pyrimidine
bases and carbohydrates, resulting in apurinic/apyrimidinic sites
(AP-sites) (Talpaert-Borle, 1987). The formation of AP-sites leads
to base replacements, frameshift mutations, and subsequent DNA
breaks. A dramatic (7-fold) increase in the number of AP-sites was
observed in the leukocytes of elderly humans compared with young
individuals (Atamna et al., 2000).
Another common type of damage is DNA adducts in which DNA
fragments covalently bind to certain chemical compounds. Reactive oxygen species (ROS) are the major inducers of DNA adducts.
Among these adducts, 8-oxoguanine (8-oxoG), commonly used as
a marker of oxidative DNA damage, is a frequently oxidized base
which formation leads to GC → TA transversions after the DNA
replication (Kasai, 1997). Age-related accumulation of 8-oxoG was
found in several organs of humans and model organisms (Table 1).
Of note, high 8-oxoG content was also observed in premature
aging syndromes (Xeroderma pigmentosum, Ataxia telangiectasia,
Bloom syndrome, and Fanconi anemia) (Degan et al., 1995; Machwe
et al., 2000) (see Section 3). Nevertheless, the impact of 8-oxoG
accumulation on aging is far from clear as OGG1-deficient mice,
with severalfold increase in the level of 8-oxoG in both nuclear and
mitochondrial DNA, did not display any gross phenotypical abnormalities and had normal respiratory functions (Stuart et al., 2005;
Miwa et al., 2008).
Endogenous aldehydes including malonaldehyde, crotonaldehyde, acrolein, and N-hydroxynonenal, products of lipid peroxidation, may cross-link with DNA bases to form exocyclic adducts
(De Bont and van Larebeke, 2004). Alkylating agents (among them,
many chemotherapeutic drugs), UV light, and ionizing radiation
induce formation of covalent bonds between DNA and chromatin
proteins, which in turn can lead to breaks in DNA strands (Lai et al.,
2008). The number of DNA adducts was shown to increase with
age, contributing to carcinogenesis, atherosclerosis, and other agerelated pathologies (Izzotti et al., 1999; Voulgaridou et al., 2011).
Single-strand DNA breaks (SSB) are also a frequent type of DNA
damage which occurs tens of thousands of times per cell per day
(Caldecott, 2008). Surprisingly, studies of SSB in the mouse brain,
liver, and kidneys and in human peripheral blood mononuclear cells
did not show any age-dependent deviations from the spontaneous
damage level (Fu et al., 1991; Trzeciak et al., 2012). The number of
SSB did not increase with age in the case of house flies either, but it
was higher in old animals after ␥- or UV-irradiation (Newton et al.,
1989a) (see Section 2.5).
The most dangerous type of DNA damage is double-strand DNA
breaks (DSB) since their repair requires both a convergence of
homologous chromosomes and a very large amount of energy.
Unrepaired DSB result in the loss of chromosome segments and
endanger the cell survival, while the incorrectly repaired DSB cause
chromosomal rearrangements and genomic instability. In contrast
to SSB, the DSB are frequently observed in the elderly (Morgan
et al., 1998) and in cancer (Gorbunova et al., 2007). High level of
DSB was also observed in aged rats (4-fold increase vs. young mice)
(Mandavilli and Rao, 1996).
2.2. Somatic mutations
If a damaged cell has not been eliminated, an unrepaired
or incorrectly repaired DNA damage results in mutations (see
Appendix A for possible outcomes of insufficient repair). The data
showing the accumulation (or lack of accumulation) of various
mutations with age are summarized in Table 2.
The direct quantitative measurements of the impact of age on
frequency and spectra of spontaneous somatic mutations became
possible due to the transgenic mice containing a LacZ plasmid rescue system developed by Vijg’s group (Gossen et al., 1989). Using
this model, they found that the largest age-related accumulation
of mutations (11.0 × 10−5 in the young and up to 25.6 × 10−5 in
the old mice) was in the small intestine, an organ with extremely
high proliferative capacity (Dollé et al., 2000). In contrast, the brain
which is mostly a postmitotic organ not only had the lowest level
of mutations but also displayed insignificant changes in mutation
frequency during aging (from 4.8 × 10−5 and 5.0 × 10−5 in young
and old mice, respectively) (Dollé et al., 1997). The intermediate
levels of age-related accumulation of mutations were observed for
the heart (postmitotic organ) and liver (slowly proliferating organ)
(Dollé et al., 2000; Vijg and Dollé, 2002). Not only the total mutation load but also the frequency of each type of mutations changes
as a function of age in a tissue-specific manner. In the young
age, the mutation spectra are nearly identical in all organs examined, mainly consisting of GC-to-AT transitions and 1-bp deletions.
In the old age, only point mutations (transitions and transversions) accumulate in the small intestine, whereas in the heart and
liver, a remarkable amount of the accumulated mutations are large
genomic rearrangements (Dollé et al., 2000; Vijg and Dollé, 2002;
Busuttil et al., 2007).
What factors may stand behind this diversity? Among the most
probable ones is the rate of proliferation. While large genomic
rearrangements are not related to the replication process and are
more common in postmitotic organs (heart and liver) (Vijg and
Dollé, 2002; Busuttil et al., 2007) and also in postmitotic organisms
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
G Model
ARR-371; No. of Pages 24
ARTICLE IN PRESS
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
3
Table 1
Age-dependent alterations in the levels of different types of DNA damage in mammals.
Type of DNA damage
Age-dependent
alteration
Species/cells or organs
Reference
Increase
Increase
No change
Human leukocytes
Rat liver
Rat brain
Atamna et al. (2000)
Atamna et al. (2000)
Atamna et al. (2000)
Increase
Increase
Increase
Increase
Increase
No change
Human neurons (gene promoters)
Human skeletal muscles
Rat and mouse liver, heart, brain, kidney,
skeletal muscle, and spleen
Rat liver, kidney, and intestine
Rat brain and testes
Lu et al. (2004)
Mecocci et al. (1999)
Hamilton et al. (2001)
Thymine glycol (TG)
8-Hydroxyadenine (8-OHAde)
Increase
Increase
Rat liver and lung
Rat liver and lung
Wang et al. (1995)
Wang et al. (1995)
DNA alkylation:
O6 -Methyldeoxyguanine (O6 -medG)
7-Methylguanine (m7Gua)
No change
Increase
Rat thymus, forestomach, and small intestine
Rat liver
Mizoguchi et al. (1993)
Park and Ames (1988)
DNA glycation:
N2 -carboxyethyl-2 -deoxyguanosine (CEdG)
Increase
Mouse senescent embryonic fibroblasts
NIH3T3
Breyer et al. (2011)
DNA cross-linkages:
DNA–DNA crosslinks (DDXL)
DNA–protein crosslinks (DPXL)
Increase
Increase
Rabbit liver
Mouse liver, brain, and heart
Yamamoto et al. (1988)
Izzotti et al. (1999)
Indigenous DNA adducts (I-compounds):
Deoxyguanosine malondialdehyde adduct (dG-MDA)
Increase
Rat liver, brain, and kidney
Draper et al. (1995), Cai et al. (1996)
No change
No change
Increase
Mouse brain, liver, and kidney
Human peripheral blood mononuclear cells
Rat brain (max in cerebral cortex)
Fu et al. (1991)
Trzeciak et al. (2012)
Mandavilli and Rao (1996)
Increase
Rat brain (max in cerebral cortex and
hippocampus)
Mandavilli and Rao (1996)
Formation of abasic sites:
Apurinic/apyrimidinic
sites (AP-sites)
DNA oxidation:
8-Oxoguanine (8-oxoG)
DNA strand breaks:
Single-strand breaks (SSB)
Double-strand breaks (DSB)
(fruitflies) (Garcia et al., 2010), the point mutations depend predominantly on the replication accuracy and therefore are common
in proliferating organs (intestine). In line with this are observations on age-related accumulation of point mutations in the mouse
hippocampus and hypothalamus, where neurogenesis continues
throughout life, in contrast to the lack of the mutation accumulation
in the brain overall (Busuttil et al., 2007).
Apart from point mutations, chromosomal aberrations may also
happen in peripheral blood lymphocytes cells, though their rate
is relatively low (Vorobtsova et al., 2001). Dicentric and acentric chromosomal defects in human lymphocytes were found to
be thrice more frequent in old vs. young individuals. Even more
pronounced (10-fold) increase with age was observed for translocations and insertions (Ramsey et al., 1995). Similar results were
reported by Vorobtsova et al. (2001), who found that the number
of translocation-containing cells increase as a quadratic function of age. Unstable chromosomal aberrations (dicentrics, rings,
and fragments) generally result in cell death, while the stable
ones (translocations, insertions) predispose the cell to malignant
transformation (Wojda and Witt, 2003). The number of cells that
accumulate chromosomal aberrations increases with age in proliferating tissues as a result of repair disruptions in the G2 phase of
the cell cycle (Wojda and Witt, 2003).
The loss of chromosomes, known as hypoploidy (primarily in
sex chromosomes) and aneuploidy, has been observed in peripheral lymphocytes and skin fibroblasts of the elderly (Nowinski
et al., 1990; Guttenbach et al., 1995; Mukherjee and Thomas,
1997). The FISH-analysis of interphase nuclei further revealed a
loss of autosomes 1, 4, 6, 8, 10 and 15 in aneuploid cells (Mukherjee
and Thomas, 1997). Of note, many of these chromosomes carry
the genes whose disruption is associated with premature aging
syndromes such as the Werner syndrome (see Section 3). The
Fraga et al. (1990)
Fraga et al. (1990)
aneuploidy is directly related to the formation of micronuclei
which number in human lymphocytes increases thrice with age
(Fenech and Morley, 1985).
Collectively, the majority of observations obtained thus far are
in favor of age-related accumulation of DNA damage and somatic
mutations. This seems to be a public phenomena since it was also
observed in lower organisms such as yeast (Wei et al., 2011) and
fruitflies (Garcia et al., 2010). However, it is still unclear to what
extent this accumulation influences the functional capacity of cells
and organs with age. Besides, some types of DNA damage and mutations do not accumulate with age, at least in certain organs (for
example, AP-sites, large genomic rearrangements in the brain) (see
Tables 1 and 2).
The rate of mutations largely depends on epigenetic regulation and activity of mobile genetic elements (MGEs), which are
discussed in the next sections.
2.3. Epigenetic regulation and epimutations
Gene expression and integrity of the genome are under a
strict epigenetic regulation through the heritable mechanisms
that do not change the DNA sequence. In fact, these changes are
chemical modifications of DNA nucleotides (e.g., DNA methylation) or chromatin remodeling (mainly, histone modifications)
that effect transcription both at the level of individual genes
and genome-wide scale. They may be either spontaneous or
enzymatically mediated (for example, DNA methylation by DNA
methyltransferase enzymes). Whatever the case, these changes
largely determine the phenotypical differences between the
normal cells of a given organism, but after exceeding a certain
threshold may have far reaching consequences (Holliday, 1987,
1999; Feinberg, 2008; Bartova et al., 2010). According to Holliday’s
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
G Model
ARR-371; No. of Pages 24
ARTICLE IN PRESS
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
4
Table 2
Age-related alterations in the levels of different types of DNA mutations.
Type of mutation
Age-dependent
alteration
Species/cells, tissues or
organs
Reference
Point mutations:
GC → AT transitions
GC → TA, GC → CG, and T → CG transversions
Deletions (1-bp)
Accumulation
Accumulation
Accumulation
Mouse small intestine (mucosa),
brain (hypothalamus and
hippocampus), heart
Dollé et al. (2000),
Busuttil et al. (2007)
Expanded simple
tandem repeats (ESTR)
No change
Accumulation
Mouse brain
Mouse sperm and bone
marrow
Hardwick et al. (2009)
Hardwick et al. (2009)
Transpositions of MGE:
IAP retrotransposon transcription activity
Increase
Mouse liver
Tc1 element somatic excision
Increase
Tc1 element mobility
Increase
C. elegans somatic
tissues
S. cerevisae
Dupressoir et al.
(1995), Barbot et al.
(2002)
Egilmez and
Shmookler Reis (1994)
Maxwell et al. (2011)
Large genomic rearrangements:
Deletions and
translocations
Accumulation
Mouse heart, liver, and
small intestine (serosa)
Accumulation
No change
Drosophila somatic
tissues
Mouse brain and testes
Accumulation
Accumulation
Human lymphocytes
Human lymphocytes
Dicentric, acentric
Accumulation
No change
Human lymphocytes
Human lymphocytes
Hypoploidy
Accumulation
Human lymphocytes
Aneuploidy
Accumulation
Human skin fibroblasts
Micronuclei
Accumulation
Accumulation
Human lymphocytes
Human lymphocytes
Chromosomal aberrations:
Translocations, insertions
concept, accumulation of epimutations with age alters a normal
epigenotype, leading to a destabilization of the genome.
The most studied epigenetic modification with regard to aging
and age-related diseases (ARDs) is DNA methylation (Lu et al.,
2006; Calvanese et al., 2009), a process of adding the methyl group
to the 5 -CpG cytosine dinucleotide by DNA methyltransferases
(DNMT1, DNMT3a and DNMT3b) (Donkena et al., 2010). This
epigenetic modification causes gene silencing, especially when the
methylated cytosines are found in the gene promoters. In various
tissues, DNA tends to become demethylated with age (Wilson et al.,
1987; Lu et al., 2006; Calvanese et al., 2009). Among other factors,
DNA damage contributes to this process by hindering the DNMT
activity (Donkena et al., 2010). In turn, a global DNA demethylation
promotes DNA damage in a vicious cycle mode. For example,
hypomethylation caused by methyl-deficient diet increased the
amount of 8-oxoG and DNA strand breaks in the rat liver (Pogribny
et al., 2009). Hypomethylation of MGEs and CpG sites in promoter
regions causes genome instability, chromosomal aberrations,
and increases the risk of carcinogenesis and cellular senescence
(Barbot et al., 2002; Dimauro and David, 2009; Donkena et al.,
2010). In parallel to global hypomethylation, a number of genes
undergo age-related hypermethylation at their regulatory CpG
sites. Notably, among them are certain DNA repair genes and
tumor suppressors (for example, hMLN, LMNA, MGMT, ERCC1,
RAD50, BRCA1, and WRN), which epigenetic inactivation may
result in impaired DNA damage response, mutation accumulation,
accelerated aging and cancer (Esteller, 2002; Fraga and Esteller,
2007; Christensen et al., 2009).
Other epigenetic modifications such as covalent modification
of N-termini of the chromatin histone proteins, incorporation
Dollé et al. (1997),
Dollé et al. (2000),
Busuttil et al. (2007)
Garcia et al. (2010)
Dollé et al. (1997, 2000)
Ramsey et al. (1995)
Vorobtsova et al.
(2001)
Ramsey et al. (1995)
Vorobtsova et al.
(2001)
Guttenbach et al.
(1995)
Mukherjee and Thomas
(1997)
Nowinski et al. (1990)
Fenech and Morley
(1985)
of histone variants into chromatin, chromatin remodeling, and
microRNA interference are also susceptible to DNA damage
(Holliday, 2005; Feinberg, 2008; Wolfson et al., 2008; RodríguezRodero et al., 2010). Ultimately, disruptions in epigenetic control
lead to reactivation of previously silenced MGEs (see Section
2.4) and proto-oncogenes, silencing of tumor suppressors, loss of
imprinting, and DNA repair disorders (Krishnan et al., 2011a,b;
Schumacher, 2011; Han and Brunet, 2012). Epigenetic reactivation
of genes which are normally silenced in postdevelopmental period
or epigenetic inactivation of housekeeping genes may explain how
“good” genes may become “bad” later in life. With this in mind, we
have proposed to widen a classic idea of antagonistic pleiotropy
(Williams, 1957) to “epigenetic antagonistic pleiotropy” (Budovsky
et al., 2006).
2.4. Mobile genetic elements as a source of mutations and
genome instability
Mobile genetic elements are cellular genome segments ranging in size from thousands to tens of thousands of base pairs that
can “jump” both within and between chromosomes. They cover
approximately 30–50% of the human genome and have been identified to be involved in more than 100 human genetic disorders
as well as in different forms of cancer (Xing et al., 2007; Belancio
et al., 2010). Transposition of MGEs may be extremely mutagenic
and toxic to somatic cells, accounting for a significant part of spontaneous genome damage. In both in vitro and in vivo, activation
of MGEs was shown to induce DSB, large genomic rearrangements
and genome instability (Engels and Preston, 1984; Dupressoir et al.,
1995; Zainullin and Moskalev, 2000; Barbot et al., 2002; Wallace
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
G Model
ARR-371; No. of Pages 24
ARTICLE IN PRESS
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
et al., 2008; Belancio et al., 2010; Maxwell et al., 2011). As shown
in Table 2, it appears that transposition of MGE increases with age.
It should be stressed that even low but consistent activity of MGEs
could lead to progressive accumulation of DNA damage with possible implication to human aging (St. Laurent et al., 2010).
Silencing of MGEs is largely attributed to epigenetic regulation
(Slotkin and Martienssen, 2007). However, a global demethylation
of MGE promoters during aging and cancer may lead to a significant
increase in MGE re-activation which is often accompanied by the
loss of critical DNA sensing and repair pathways (Belancio et al.,
2010). Importantly, changes in the diet of the elderly people have
the potential to reduce age-related activation of MGEs by modifying
their epigenetic regulation (Chew et al., 2008; Schernhammer et al.,
2010).
A potential importance of MGEs for aging has been reflected
in two hypotheses. In 1990, V. Murray hypothesized that amplification and uncontrolled movement of MGEs in the genome may
silence the expression of important genes and in such a way contribute to cell death and organismal aging (Murray, 1990). As a
continuation of this concept, St. Laurent et al. (2010) proposed their
LINEage hypothesis of human aging placing a special emphasis on
deleterious effects of the LINE-1element on somatic stem cells (see
also Sections 5 and 6.1). By analyzing mortality rates (in Gomperz
coordinates) of fruitflies differing in abundance of MGEs, Frolkis and
Muradian (1991) concluded that MGEs increase survival at early
age but decrease survival later in life, thus behaving as antagonistic
pleiotropy factors.
2.5. DNA repair pathways
Accumulation of mutations is eventually a result of misbalance
between the levels of DNA damage and efficiency of repair processes (relative insufficiency of DNA repair mechanisms). For the
reader’s convenience, a brief overeview of DNA repair pathways is
given in Appendix B.
In humans, the DNA repair pathways comprise over 200 genes
(Milanowska et al., 2011), involved in detection of a damage site in
the DNA, several steps of enzymatic transformation of the damaged
DNA, and recombination of the DNA strands (see Suppl. Table 1). In
most cases, the original sequence is restored, but in some cases DNA
damage is repaired via lesion bypass which assures continuation of
replication even at the price of incorrect repair.
Data on age-related changes in DNA repair pathways are presented in Table 3. As seen in the table, apart from the human
brain cortex where an increased expression of the BER components
8-oxoguanine DNA glycosylase and uracil DNA glycosylase (apparently, as a response to an increased oxidative damage to DNA)
were found (Lu et al., 2004), the activity of most other pathways
decline with age in different cells and organs examined thus far
in humans and model organisms. Moreover, age-related shifts in
usage of different DNA repair pathways were also observed (Engels
et al., 2007). Using a transgenic Drosophila repair reporter construct,
Preston et al. (2006) discovered that the spectrum of DSB repair
pathways changes from SSA and NHEJ in the younger flies to HR
in older ones. Given the fact that DNA damage accumulates with
age, this observation seems paradoxical and even confusing since
a greatly increased usage of the more accurate HR mechanisms
is expected to reduce the DNA damage. This could be interpreted
in terms of antagonistic pleiotropy. Indeed, using the error-prone
NHEJ and SSA pathways for repairing the DNA strand breaks allows
avoiding a time- and energy-consuming DNA synthesis which is
required for HR. This in turn may ensure a more rapid development, thus offering a significant competitive advantage at the early
stages of life. However, the predominant use of these error-prone
pathways at early ages may result in a faster accumulation of DNA
damage and deleterious consequences later in life, which could not
5
be compensated by a rise in the HR activity (Engels et al., 2007).
A putative relevance of these findings to mammals is discussed in
detail elsewhere (Gorbunova et al., 2007).
On the whole, a decrease in total DNA repair capacity coincides well with the age-related accumulation of DNA damage and
mutations. Yet, it is not always possible to point out the cause-andeffect relationships between them. Generally, there are no clear-cut
connections between a given impaired DNA repair pathway and
accumulation of specific types of DNA damage or mutations. For
example, there are at least three different pathways for repair of
DSB (Lieber, 2010).
Further complicating this issue is that the activation of DNA
repair pathways in the course of DNA damage response induces
transcription of thousands of genes regulating the cell fate, which
are also highly interconnected (Begley and Samson, 2004). In particular, DNA repair genes are tightly connected with the genes
involved in DNA replication, DNA-replication checkpoint signaling,
and oxidative stress by forming a continuous interaction network
(Pan et al., 2006). Analysis of this network in S. cerevisae showed
that different repair pathways not only have overlapping functions
and compensate one another, but also enhance the activity of DNA
replication machinery and genes involved in repair of oxidative
damage.
3. Is premature aging accompanied by an increased
mutation load? Do agents increasing the mutation load
cause a premature aging?
The most prominent examples of how the accumulated DNA
damage and defective DNA repair pathways affect the organism are
premature aging (progeroid) syndromes (Table 4). In fact, mutations in DNA repair genes were found in all human progeroid
syndromes described thus far (Hoeijmakers, 2009; Freitas and de
Magalhaes, 2011). Even in the case of the Hutchinson–Gilford syndrome which is not directly related to mutations in DNA repair
genes, there is a delayed access of repair enzymes to the DNA damage sites, eventually leading to genomic instability (Musich and
Zou, 2009; Krishnan et al., 2011a,b).
It is important to stress that in most cases, monogenic
(Mendelian) diseases have rather distinct phenotypes and effect
distinct organismal functions. According to the OMIM Gene Map
Statistics, mutation(s) of 2702 genes have thus far been established to cause disease (Hamosh et al., 2000; http://omim.org/
statistics/geneMap). None of them (except for the DNA repair
genes and DNA repair-associated LMNA) has been reported to
cause a premature aging phenotype. By contrast, the monogenic
syndromes of premature aging are caused almost exclusively by
mutations in DNA repair genes. Although they belong to various
DNA repair pathways, their disruption results in similar and overlapping phenotypes which to a great extent resemble a “normal”
aging (graying and loss of hair, abnormal pigmentation and thinning and of skin, hypersensitivity to sunlight, cataract, sarcopenia,
osteoporosis, kyphosis, endocrine, reproductive and immune disorders, and increased incidence of major ARDs). Of note, there are
numerous evidence for the involvement of DNA repair genes in
ARDs and aging-associated conditions such as chronic inflammation, oxidative stress and cellular senescence (Tacutu et al., 2010;
Suppl. Table 1).
The links between premature aging and impaired DNA repair
gained further support from the studies on model organisms
(Budovsky et al., 2007; de Magalhães et al., 2009). As seen in Table 5,
in the majority of cases, partial or full inactivation of DNA repair
genes resulted in mutation accumulation and the development of
progeroid-like phenotypes.
An important and counterintuitive point is that short-lived
(progeroid) mice and long-lived mouse strains were found to
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
ARTICLE IN PRESS
G Model
ARR-371; No. of Pages 24
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
6
Table 3
Age-related changes in DNA repair pathways.
DNA repair pathway
Age-related changes
Effects
Species/cells or organs
Reference
Direct reversal
Reduced activity of the
O6 -methylguanine DNA
methyltransferase
Deficiency of DNA polymerase
␤ and DNA ligase
Alkylation-related mutagenesis and
carcinogenesis
Human brain
Silber et al. (1996)
Increase in mismatched base pairs,
modified bases, abasic sites, and
oxidative DNA damage
Accumulation of AP-sites
Rat neurons
Krishna et al. (2005),
Rao et al. (2000)
Human leukocytes
Atamna et al. (2000)
Accumulation of mtDNA mutations
and age-related cataract pathogenesis
Rat lenses
Zhang et al. (2010)
Reduced BER and damage response
Mouse liver
Cabelof et al. (2006)
Increased levels of DNA damage and
mutagenesis
Response to unresolved oxidative DNA
damage (?)
Mouse brain and liver
nuclear extracts
Human brain (cortex)
Intano et al. (2003)
Reduction in nucleotide excision of
dimer photoproducts
Human fibroblasts and
lymphocytes
Decrease
Reduction in nucleotide excision of
dimer photoproducts
Rat fibroblasts and
hepatocytes
Mismatch repair
Decrease
Human peripheral
blood cells
Neri et al. (2005)
Human normal colonic
cells
Toyota et al. (1999)
SSBR
Hypermethylation of hMLH1
promoter with inhibition of its
expression
Decrease
Increased microsatellite instability and
accumulation of mutations involved in
carcinogenesis
Sporadic tumors with mismatch repair
deficiency
Increase in SSB and/or alkali-labile
sites after X irradiation
Postmitotic cells from
houseflies, Musca
domestica
Human lymphocytes
Newton et al. (1989a)
BER
NER
Reduced 3-methyladenine
DNA glycosylase activity
Decrease in 8-oxoguanine DNA
glycosylase 1, AP endonuclease
1, and DNA polymerase ␥
expression
Reduced inducibility of DNA
polymerase ␤ and AP
endonuclease in response to
the DNA damage
Decreased abundance of DNA
polymerase-␤
Increased expression of
8-oxoguanine DNA glycosylase
and uracil DNA glycosylase
Decrease
Decrease
HR
Increase
SSA
Decrease
NHEJ
Decrease
Decrease
Decrease Ku70/80 levels,
changes in Ku intracellular
distribution, and the loss of
appropriate response of Ku to
DNA damage
Decrease in Ku70/80 levels
Decrease in Ku70/80 DNA
binding in response to X-ray
Decrease in Ku70 and Mre11
levels
Impaired Ku activity in testes,
unaffected in liver. Altered
expression in kidney and lungs
Increase in SSB and/or alkali-labile
sites after X irradiation
Age-dependent shift from SSA and
NHEJ to HR
Age-dependent shift from SSA and
NHEJ to HR
Age-dependent shift from SSA and
NHEJ to HR
Neuronal aging
Drosophila premeiotic
germ cells
Drosophila premeiotic
germ cells
Drosophila premeiotic
germ cells
Rat neurons
Lu et al. (2004)
Annett et al. (2004),
Boyle et al. (2005),
Grossman and Wei
(1995), Kruk et al.
(1995), Moriwaki et al.
(1996), Wei et al.
(1993)
Guo et al. (1998), Vijg
et al. (1985)
Singh et al. (1990)
Preston et al. (2006)
Preston et al. (2006)
Preston et al. (2006)
Vyjayanti and Rao
(2006)
Seluanov et al. (2004,
2007)
NHEJ becomes less efficient and more
error-prone. NHEJ in old cells was
associated with extended deletions
Human fibroblasts
Increased nuclear oxidative DNA
damage and relatively higher
susceptibility to aging
Decrease in X-ray induced DSB repair
Rat testis
Um et al. (2003)
Human peripheral
blood mononuclear
cells
Human lymphocytes
Frasca et al. (1999)
Decrease in DSB repair and
age-dependent telomere shortening
Increased expression of mtHSP70.
Increase in the amount of nuclear
oxidative DNA damage in the testes
display a high similarity in gene expression profiles (Schumacher
et al., 2008) and share some features typical for the long-lived
mutants (van de Ven et al., 2006, 2007; Susa et al., 2009; Botter
et al., 2010), in particular, an increased resistance to oxidative
stress (Susa et al., 2009). This apparent paradox could in part be
attributed to inhibition of insulin/IGF-1 signaling pathway in both
mouse groups (Schumacher et al., 2008). However, the nature
Rat kidney, lungs,
testes and liver
Ju et al. (2006)
Um et al. (2003)
of this inhibition differ dramatically between the long-lived and
progeroid mice as in progeroid mice it is induced by the persistent
DNA damage response (Hinkal and Donehower, 2008; Garinis and
Schumacher, 2009; Garinis et al., 2009). This may explain why
in case of the similar gene expression patterns, there are such
drastically different outcomes in aging and longevity. While providing some adaptive benefits (for example, resistance to stress),
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
ARTICLE IN PRESS
G Model
ARR-371; No. of Pages 24
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
7
Table 4
Segmental progeroid syndromes in humans.
Syndrome
Phenotype
Disrupted gene
Encoded protein
Function
References
Hutchinson–Gilford syndrome
Short lifespan (<13 years),
retarded growth, lipoatrophy,
bone disorders, small
beak-shaped nose, receding
chin, complete loss of hair,
spotty hypopigmentation of
skin
Reduced lifespan (40–50
years), cataract, hair graying,
sclerodermal and degenerative
vascular changes,
atherosclerosis, diabetes,
osteoporosis, cancer
LMNA
Structural protein
of nuclear envelope
Lamin A
Nuclear structure,
genomic stability,
regulation of gene
expression
Eriksson et al.
(2003), Scaffidi and
Misteli (2005)
WRN
RecQ 3 –5 helicase
and exonuclease
Goto et al. (1992),
Yu et al. (1996),
Opresko et al.
(2003), Muftuoglu
et al. (2008)
RECQL4
RecQ 3 –5 DNA
helicase
Single-strand DNA
annealing,
homologous
recombination,
repair of DNA
crosslinks, and
reactivation of the
blocked replication
forks
Reactivation of the
blocked replication
forks
BLM
RecQ 3 –5 DNA
helicase
Reactivation of the
blocked replication
forks
Rassool et al.
(2003), Cheok et al.
(2005)
XPA, -B, -C, -D, -F, and
-G
Structure-specific
endonucleases,
helicases, subunits
of the TFIIH
transcription factor
Transcriptioncoupled
NER
CSA and CSB
Subunits of TFIIH
transcription/repair
factor
Subunit of TFIIH
transcription/repair
factor
Transcriptioncoupled
NER
Harada et al.
(1999), Coppede
and Migliore
(2010), Oksenych
and Coin (2010),
Wu et al. (2011)
Licht et al. (2003)
Transcriptioncoupled
NER
Egly and Coin
(2011)
ATM
Serine-protein
kinase
DNA damage
sensing
Derheimer and
Kastan (2010)
NBS1
ATM kinase
cofactor
DNA damage
sensing
Antoccia et al.
(2006), Kanu and
Behrens (2008)
FANCA, -B, -C, -D1, -D2,
-E, -F, -G, -I, -J, -L, and
-M
Components of
multiproteins
complexes,
involved in DNA
repair
Grillari et al.
(2007), Kee and
D’Andrea (2010)
LigIV
DNA ligase IV
Interstrand
cross-link repair,
sensing and repair
of DNA replicationblocking lesions,
DSB repair
NHEJ
Werner syndrome
Rothmund-Thompson syndrome
Bloom syndrome
Xeroderma pigmentosum
Cockayne syndrome
Trichothiodystrophy
Ataxia telangiectasia
Nijmegen breakage syndrome
Fanconi anemia
LigIV syndrome
Unaltered lifespan, stunted
growth, hair growth problems,
juvenile cataract, skin
pigmentation, hypersensitivity
to sunlight, hypogonadotropic
hypogonadism, anemia, soft
tissue contracture, hypodontia,
osteosarcoma
Reduced lifespan (<30 years),
stunted growth,
UV-hypersensitivity,
immunodeficiency,
osteosarcoma
Reduced lifespan (by ∼30
years) hypersensitivity to light,
abnormal pigmentation, and
predisposition to skin cancer
Reduced lifespan (20–40
years), dwarfism, skeletal
abnormalities, neurological
dysfunction
Reduced lifespan, ichthyosis,
brittle hair and nails, impaired
intelligence, decreased fertility
and short stature, UVsensitivity
Reduced lifespan, cerebellar
ataxia, ocular apraxia,
telangiectasias of the eyes and
skin, immunodeficiency,
radiosensitivity, ovarian
dysgenesis, neuronal
degeneration, increased
incidence of tumors
Reduced lifespan,
microcephaly, special face
shape, short stature,
immunodeficiency,
radiosensitivity, predisposition
to lymphoid types of cancer
Reduced lifespan,
developmental defects (e.g.
absence of fingers), bone
marrow dysfunction, acute
myeloid leukemia
Reduced lifespan, growth
defects, immunodeficiency,
hitherto unexplained
pancytopenia
TTDA
the downregulation of insulin/IGF-1 signaling cannot compensate
for the overwhelming accumulation of DNA damage in progeroid
mice.
It is important to note that in several mouse models, shortened
lifespan with some progeroid phenotypical features was achieved
Larizza et al. (2010)
Nijnik et al. (2007)
by genetic interventions that do not directly affected the DNA repair
pathways and were mostly associated with excessive production
of damaging factors (data not shown). Nevertheless, the accumulated findings strongly indicate that defective DNA repair offers the
potential of being a primary determinant of premature aging. In
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
Model
organism
Role in DNA
repair
Intervention
Phenotype
References
APEX1
exo-3
C. elegans
RNAi
ATM
Atm
M. musculus
Apurinic/apyrimidinic
endonuclease
Cell response
to DNA damage
Schlotterer
et al. (2010)
Barlow et al.
(1996), Elson
et al. (1996), Xu
et al. (1996)
ATR
Atr
M. musculus
Reduced mean (by 20%) and
maximum (by 10%) lifespan
Growth retardation, neurologic
dysfunctions, male and female
infertility, defects in T lymphocyte
maturation, extreme sensitivity to
gamma-irradiation. The majority of
animals developed malignant
thymic lymphomas between 2 and
4 months of age.
Defects in tissue homeostasis (cell
loss in continuously proliferating
tissues, depletion of stem and
progenitor cells), hair graying,
alopecia, kyphosis, osteoporosis,
thymic involution, fibrosis
Reduced size of the brain, ovaries,
testes and all tissues of the
hematopoietic compartment, hair
graying, decreased density of hair
follicles and thinner epidermis.
kyphosis, osteoporosis,
accumulation of fat in the bone
marrow, Mutant mice died in less
than half a year.
Random mutant phenotypes due to
an increased number of insertions
and deletions leading to genomic
instability. A low brood size,
disbalance in sexes (a high
incidence of males), increased
amount of apoptosis in germ cells.
Reduced mean lifespan (by 20%).
30% of mice developed lymphoma
and died before 7 months. Starting
from 8 mo-old, the majority of
mutant mice exhibited kyphosis,
osteoporosis, thinner skin and
reduction in body fat.
Reduced median lifespan (by 8%).
An increase in incidence of
spontaneous and
irradiation-induced tumors.
About 20% decrease in median
lifespan in daf-2 and daf-2/daf-16
mutant backgrounds.
Mean lifespan extension by
15–25%.
Remarkable lifespan extension,
attenuation of growth defects and
delay in the development of
tumors in Brca1−/− /Chk2 +/− mice
vs. Brca1−/− /p53 +/− mice.
Cell response to DNA
damage
Knockout
Conditional knockout
in adults
BLM
him-6
C. elegans
ATP-dependent
DNA helicase
Mutation
BRCA1
Brca1
M. musculus
DNA damage sensor
Knockout of full-length
isoform
Brca1+/−
CDK7
cdk-7
C. elegans
DNA damage
sensor
RNAi
CHEK1
chk-1
C. elegans
RNAi
CHEK2
Chek2
M. musculus
DNA damage
sensor
DNA damage
sensor
Mutations on Brca1
deficiency background
Murga et al.
(2009)
Grabowski
et al. (2005)
Cao et al.
(2003)
Jeng et al.
(2007)
Samuelson
et al. (2007)
Olsen et al.
(2006)
Cao et al.
(2006)
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
Mutations
Ruzankina
et al. (2007)
G Model
Gene in model
organism
ARTICLE IN PRESS
Human ortholog
ARR-371; No. of Pages 24
8
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
Table 5
Aging/longevity phenotypes resulting from genetic manipulations with the DNA repair genesa in model organismsb .
Model
organism
Role in DNA
repair
Intervention
Phenotype
References
EEF1E1
Eef1e1
M. musculus
Cell response
to DNA damage
Overexpression
Oh et al. (2010)
ERCC1
Ercc1
M. musculus
Catalyzes the 5
incision in the
process of
excising the
DNA lesion
Mutations
ERCC2
Ercc2
M. musculus
ATP-dependent
DNA helicase
Mutations
ERCC4
Ercc4
M. musculus
Forms a
complex with
ERCC1 and is
involved the 5
incision in the
process of
excising the
DNA lesion
Double knockout
EXO1
Exo1
M. musculus
5 –3
exonuclease
activity in
mismatch
repair and
recombination
Knockout
FEN1
RAD27
S. cerevisae
Removes 5 overhanging
flaps in DNA repair and
processes the 5 ends of
Okazaki fragments in
lagging strand DNA
synthesis
Mutation
20% survival at 2 years vs. ∼80% in
WT. Transgenic mice exhibited
pronounced lordokyphosis,
reduction in cortical bone
thickness, alopecia, wrinkles and
reduced subcutaneous fat. The
human cell lines overexpressing
Eef1e1 showed accelerated
senescence and defects in nuclear
morphology.
Compromised NER, DSBR, and
cross-link repair, gross
abnormalities of ploidy and
cytoplasmic invaginations in nuclei
of liver and kidney. An absence of
subcutaneous fat, early onset of
ferritin deposition in the spleen,
kidney malfunction, cognitive
decline and neurodegeneration.
Ercc1-mutant mouse embryonic
fibroblasts undergo premature
replicative senescence.
Reduced mean lifespan (by 50%).
Osteoporosis, kyphosis,
osteosclerosis, early graying,
cachexia, infertility.
Ercc4-Ercc1-deficient mice
typically died by four weeks.
Embryonic and early post-natal
development is mildly retarded.
Growth arrests dramatically in the
second week after the birth.
Neurodegenerative disorders
(dystonia and progressive ataxia),
renal insufficiency, sarcopenia,
kyphosis. Primary embryonic
fibroblasts underwent premature
replicative senescence and showed
an increased sensitivity to
oxidative stress.
Reduced survival (at 17 months:
50% of Exo1−/− and 80% of Exo1+/−
mice vs. 90% of wild-type mice
were alive). Increased incidence of
lymphomas. Exo1−/− male and
female mice were sterile because
of meiotic defects.
Reduced mean replicative lifespan
(by 40%).
Reduced mean chronological
lifespan in the “a” strain (by over
50%).
Knockout
Weeda et al.
(1997),
Borgesius et al.
(2011)
de Boer et al.
(2002)
Niedernhofer
et al. (2006)
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
Gene in model
organism
Tian et al.
(2004)
Hoopes et al.
(2002)
Laschober et al.
(2010)
ARTICLE IN PRESS
Human ortholog
G Model
ARR-371; No. of Pages 24
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
Table 5 (Continued)
9
Role in DNA
repair
Intervention
Phenotype
References
GADD45G
Gadd45
D. melanogaster
Structural
component in
excision repair
Constitutive or
conditional
overexpression in the
nervous system
Plyusnina et al.
(2011)
HDAC1
Rpd3
D. melanogaster
Cell response
to DNA damage
Heterozygous partial or
full-of- loss mutations
HUS1
hus-1
C. elegans
RNAi
MRE11A
MRE11
S. cerevisae
MSH2
Msh2
M. musculus
MSH6
MSH6
S. cerevisae
NEIL1
Neil1
M. musculus
Cell response
to DNA damage
3 –5
exonuclease
activity and
endonuclease
activity
Binds to DNA
mismatches to
initiate the
mismatch
repair process
Forms a
complex with
Msh2 to repair
both
single-base &
insertiondeletion
mispairs
Glycosylase
that initiates
the first step in
base excision
repair by
cleaving bases
damaged by
reactive
oxygen species
A considerable decrease (by
approximately 25%) in the number
of single-stranded breaks in DNA of
Drosophila larvae neuroblast.
Lifespan extension, without
affecting fertility or physical
activity. The median lifespan of
flies with constitutive dGadd45
overexpression was extended by
77 and 73% in males and by 22 and
46% in females vs. two parental
strains, respectively.
Partial or full loss-of-function
resulted in extended median
lifespan (33% for males and 55% for
females, and ∼45% for both sexes,
respectively). Lifespan extension
was accompanied by Sir2 (homolog
of human SIR1) upregulation and
was not augmented by CR
Extension of mean lifespan by 11%.
Knockout
Reduced mean chronological
lifespan in the “a” strain by 15–50%.
Knockout
About 50% of KO mice died by 8
month of age and all KO died by 12
month of age (∼80% of WT mice
were alive at 14 months). Increased
incidence of multiple cancers.
Reduced mean chronological
lifespan in the “a” strain (by over
50%).
Knockout
Knockout
Increased levels of mtDNA damage,
severe obesity, dyslipidemia, fatty
liver disease, a tendency to
hyperinsulinemia
Rogina et al.
(2002)
Arum and
Johnson (2007)
Laschober et al.
(2010)
Reitmair et al.
(1996)
Laschober et al.
(2010)
Vartanian et al.
(2006)
G Model
Model
organism
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
Gene in model
organism
ARTICLE IN PRESS
Human ortholog
ARR-371; No. of Pages 24
10
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
Table 5 (Continued)
Model
organism
Role in DNA
repair
Intervention
Phenotype
References
PARP1
Parp1
M. musculus
DNA damage
sensor and
mediator for
BER, NER, HR
and NHEJ
Overexpression
(hPARP-1)
Mangerich
et al. (2010),
Bürkle (2006)
Parp
D. melanogaster
PMS2
PMS1
S. cerevisae
Decrease in mean lifespan (by
25%), with no difference in
maximal lifespan vs. WT. Reduced
hair growth, adiposity, kyphosis,
nephropathy, dermatitis,
pneumonitis, cardiomyopathy,
hepatitis, and anemia. Transgenic
male mice showed impaired
glucose tolerance, without
manifested diabetes.
In males, constitutive PARP-1
overexpression results in reduced
median (by 14%) and maximum
(by 8%) lifespan, whereas in
females the median (by 14%) and
maximum (by 20%) lifespan
increases. Conditional PARP-1
overexpression results in extension
of the median (by 3–16%) and the
maximum (by 10–15%) lifespan in
females and males, respectively.
The lifespan increase in females
with PARP-1 conditional
overexpression was accompanied
by decrease of fertility.
Reduced mean chronological
lifespan in the “a” strain.
POLD1
Pold1
M. musculus
Reduced median, mean and
maximum lifespan (by 18, 15 and
10%, respectively in allele L604 K).
Genomic instability and
accelerated tumorigenesis (allele
L604 K) or increased incidence of
cancer (alleles L604 K and L604G).
A high mutation rate in cultured
embryonic fibroblasts.
Venkatesan
et al. (2007)
Constitutive or
conditional
overexpression in the
nervous system
Binds to DNA
mismatches
and
participates in
the mismatch
repair process
The DNA
polymerase
delta complex
is involved in
DNA
replication and
repair
Knockout
Mutations
Shaposhnikov
et al. (2011)
Matecic et al.
(2010)
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
Gene in model
organism
ARTICLE IN PRESS
Human ortholog
G Model
ARR-371; No. of Pages 24
11
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
Table 5 (Continued)
Model
organism
Role in DNA
repair
Intervention
Phenotype
References
POLG
Polg
M. musculus
Catalytic subunit of
mitochondrial DNA
polymerase-gamma
Mutation (expression of
a proof-reading-deficient
version of Polg)
A 3–5-fold increase in the levels of
mtDNA point mutations and
increased frequency of mtDNA
deletions. Reduced median (4
months) and maximum (61 weeks)
lifespan. Weight loss, reduced
subcutaneous fat, alopecia,
kyphosis, osteoporosis, anemia,
reduced fertility and heart
enlargement.
Accumulation of mtDNA
mutations. Reduced median (416
days) and maximum (460 days)
lifespan (WT 90% survived). Hair
graying, weight loss, sarcopenia,
loss of bone mass, kyphosis, thymic
involution, testicular atrophy, loss
of intestinal crypts, anemia, severe
hearing loss, and presbycusis.
Reduced mean replicative lifespan
(by 70%).
Trifunovic et al.
(2004)
Mutation
Reduced mean replicative lifespan
(by about 40%).
Park et al.
(1999)
Mutation
Reduced mean replicative life span
(by 70%).
Park et al.
(1999)
Knockout
Almost 2-fold decrease in mean
and maximum chronological
lifespan vs. WT in nutrient
depletion condition.
Reduced replicative lifespan of
mother cells. Enlargement of
mother cells and buds, mitotic
arrest due to defective
recombination, sterility
Weinberger
et al. (2007)
RAD50
S. cerevisae
RAD51
RAD51
S. cerevisae
RAD52
RAD52
S. cerevisae
RAD9A
RAD9
S. cerevisae
RECQL
SGS1
S. cerevisae
Involved in DNA
double-strand
break repair
Strand exchange
protein involved
in the
recombinational
repair of DNA
double-strand
breaks
Protein that
stimulates strand
exchange during
the repair of DNA
double-strand
breaks
3 –5 exonuclease
activity
A member of the
RecQ DNA
helicase family
involved in
various types of
DNA repair,
including
mismatch repair,
nucleotide
excision repair
and direct repair
Mutation
Mutations
Park et al.
(1999)
Sinclair et al.
(1997), McVey
et al. (2001)
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
RAD50
Kujoth et al.
(2005)
G Model
Gene in model
organism
ARTICLE IN PRESS
Human ortholog
ARR-371; No. of Pages 24
12
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
Table 5 (Continued)
Model
organism
Role in DNA
repair
Intervention
Phenotype
References
RECQL5
rcq-5
C. elegans
RNAi
Reduced mean lifespan (by 37%).
Jeong et al.
(2003)
RRM1
RNR3
S. cerevisae
Knockout
SETMAR
SET2
S. cerevisae
Reduced mean chronological life
span in the “a” strain (by 15–50%).
Reduced replicative lifespan in the
“alpha” strain (by 15%).
Laschober et al.
(2010)
Smith et al.
(2008)
SIRT1
Sirt1
M. musculus
Helicase which is
important for
genome stability
DNA damage
sensor
Histone
methylase
involved in
nonhomologous
end-joining
repair of DNA
double-strand
breaks
DNA damage
sensor
Cheng et al.
(2003)
SIRT6
Sirt6
M. musculus
DNA damage
sensor
Knockout
TP53
Trp53
M. musculus
DNA damage sensor
Haploid loss of p53
Small body size, notable
developmental defects of the
retina and heart; only infrequently
survived postnatally.
Sirt6-deficient mice are small and
at 2–3 weeks of age develop
abnormalities that include
profound lymphopenia, loss of
subcutaneous fat, lordokyphosis,
and severe metabolic defects,
eventually dying at about 4 weeks.
Reduced lifespan (mutant mice
died by one year of age). Decrease
in body fat, osteoporosis, skin
atrophy, and decreased rate of skin
wound healing.
Super p53 mice do not show any
indication of premature aging. p53
is under a normal regulatory
control.
Overexpression of p44 upsets the
balance between the full-length
and short forms of p53. Reduced
maximum lifespan (by 40%).
Growth suppression, proliferation
deficits, abnormal insulin/IGF-1
signaling, accelerated cellular
senescence of primary embryonic
fibroblasts.
Reduced median (by 19%; 96 and
118 weeks, for p53+/m and p53+/+
mice, respectively) and maximum
(by 17%; 136 and 164 weeks, for
p53+/m and p53+/+ mice,
respectively) lifespan. Weight loss,
kyphosis, osteoporosis, sarcopenia,
generalized organ atrophy, delayed
wound healing in skin, diminished
stress resistance, and enhanced
resistance to spontaneous
tumorigenesis vs. WT.
Knockout
Knockout
Overexpression
Overexpression of the
p44 isoform
Mutations
Mostoslavsky
et al. (2006)
Cao et al.
(2003)
García-Cao
et al. (2006)
Maier et al.
(2004)
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
Gene in model
organism
Tyner et al.
(2002)
ARTICLE IN PRESS
Human ortholog
G Model
ARR-371; No. of Pages 24
13
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
Table 5 (Continued)
Table 5 (Continued)
Intervention
Phenotype
References
TP53BP1
Trp53bp1
M. musculus
DNA damage
sensor
Deletion in the Brca1
mutant (Brca111/11 )
background
Cao et al.
(2009)
UBE2N
ubc-13
C. elegans
RNAi
XPA
Xpa
M. musculus
XPC
RAD4
S. cerevisae
XRCC3
RAD57
S. cerevisae
XRCC5
Xrcc5
M. musculus
XRCC6
Xrcc6
M. musculus
DNA damage
sensor
Zinc finger
protein involved
in DNA excision
repair
XPC plays an
important role in
the early steps of
global genome
NER, especially in
damage
recognition, open
complex
formation, and
repair protein
complex
formation
Participates in
homologous
recombination to
maintain
chromosome
stability and
repair DNA
damage
ATP-dependant
DNA helicase II
(heterodimer
with Xrcc6)
involved in
repairing DNA
double-strand
breaks by NHEJ
ATP-dependant
DNA helicase II
(heterodimer
with Xrcc5)
involved in
repairing DNA
double-strand
breaks by NHEJ
p53bp1-deficiency restored
survival of Brca111/11 mutant
mice decreased by heterozygous
deletion of p53 to the near-WT
level. As opposed to
Brca111/11 /p53+/− mice, whose
maximal life span was roughly 1
year, nearly 80% of
Brca111/11 /p53bp1−/− and 100%
WT were still alive at 20 months of
age.
Reduced median lifespan (19%) in
daf-2 background
Osteopenia, atrophic skin,
hepatocellular degeneration,
hepatocellular inclusions, and
hepatic hyperplastic foci.
Reduced mean chronological
lifespan in the “a” strain
Mutations
Matecic et al.
(2010)
Mutations
Reduced mean replicative life span
(by 40%).
Park et al.
(1999)
Knockout
Reduced median (by 65%), mean
(by 62%) and maximum (by 32%)
lifespan. Osteopenia, epiphyseal
closure, skin and follicular atrophy,
liver damage, chronic
inflammation in various tissues,
fewer incidence but early onset of
cancer.
Reduced median (by 68%), mean
(by 66%) and maximum (by 50%)
lifespan for both Xrcc6−/− and
Xrcc5−/− /Xrcc6−/− mice. Kyphosis,
decrease in cortical wall and
trabecular surface areas, a rough
fur coat, alopecia, rectal prolapsed,
early onset of inflammatory
responses fewer incidence but
early onset of cancer.
Vogel et al.
(1999)
Single Xrcc6 and
double Xrcc5/Xrcc6
knockout
Li et al. (2007)
a
DNA repair genes were extracted from http://repairtoire.genesilico.pl/ (Milanowska et al., 2011) and overlapped with longevity-associated genes, extracted from http://genomics.senescence.info/species/ (de Magalhães et al.,
2009).
b
Phenotypes are described for mouse when available; otherwise, for lower organisms.
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
Knockout
Samuelson
et al. (2007)
de Boer et al.
(2002)
G Model
Role in DNA
repair
ARTICLE IN PRESS
Model
organism
ARR-371; No. of Pages 24
Gene in model
organism
14
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
Human ortholog
G Model
ARR-371; No. of Pages 24
ARTICLE IN PRESS
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
line with this are also the aging-accelerating effects of several nongenetic interventions causing genotoxic stress (for a recent review
see Moskalev et al., 2012).
4. Is longevity phenotype associated with a lower
mutational load? Do pro-longevity interventions decrease
the mutation load and vice versa?
Lifespan extension due to interventions specifically decreasing
the DNA damage and mutation load would be the strongest evidence in favor of their causative role in aging. It seems that one of
the reasonable ways to achieve this is the activation of the enzymes
or components of DNA repair pathways. However, a very limited
number of studies into this matter have been carried out, and the
results are rather confusing (see Table 5). Transgenic model organisms overexpressing O6 -methylguanine-DNA methyltransferase,
PARP-1, ATR, EEF1E1, SIR1, HDACI and GADD45 have been examined thus far. Of them, 5 genes (PARP-1, EEF1E1, SIR1, HDACI and
GADD45) were identified as longevity-associated (Table 5).
Overexpression of O6 -methylguanine-DNA methyltransferase
which repairs the product of DNA alkylation O6 -methylguanine did
not extend the mouse lifespan (Walter et al., 2001). It should however be noted that O6 -methylguanine does not accumulate with age
and apparently does not play a significant role in aging (Mizoguchi
et al., 1993).
The activity of poly(ADP-ribose) polymerase-1 (PARP-1), an
important component of BER and a sensor for DNA strand breaks,
significantly decreases with age (Grube and Bürkle, 1992; Bürkle,
2006). However, transgenic mice carrying an additional copy of
hPARP-1 exhibited impaired survival and early onset of aging phenotype (Mangerich et al., 2010). An additional copy of hPARP-1
not only failed to improve DNA repair but even caused its delay
as well as upregulation of pro-inflammatory cytokines (Mangerich
et al., 2010). Overexpression of PARP in the fungal aging model
Podospora anserine also led to reduced lifespan (Müller-Ohldach
et al., 2011). In a Drosophila model, constitutive overexpression of
PARP-1 in the nervous system throughout the lifetime reduced the
lifespan in males (both median and maximum) but had the opposite
effect in females (Shaposhnikov et al., 2011). However, a conditional overexpression in imagos resulted in a moderate lifespan
extension in both sexes, without alterations in locomotor activity
(Shaposhnikov et al., 2011).
Overexpression of the tumor suppressor and DNA repair gene
EEF1E1 in mice is another example for the adverse effect on lifespan caused by modulating the DNA damage response with a single
player. These transgenic mice developed a clear progeroid phenotype (Oh et al., 2010).
There are also examples when increased activity of repair
mechanisms positively affected lifespan. Additional copies of the
Drosophila homolog of ATR, mei-41 (a mediator of EEF1E1) slightly
increased the imago survival (Symphorien and Woodruff, 2003). A
much more pronounced longevity-promoting effect was observed
in nematodes and Drosophila overexpressing the SIRT1 homolog
(a histone deacetylase class III) which is essential for the DNA
damage response (Rogina and Helfand, 2004; Tissenbaum and
Guarente, 2001). A similar effect was also found in case of a partial or full loss-of-function mutation of Rpd3 (homolog of HDACI, a
histone deacetylase class I) accompanied by upregulation of SIRT1 homolog in Drosophila (Rogina et al., 2002). Our recent study
showed that overexpression of the stress response and DNA repairassociated gene Gadd45 decreased the number of spontaneous SSB
and significantly extended the Drosophila lifespan (Plyusnina et al.,
2011).
It seems plausible that the negative effects of a single DNA repair
gene overexpression could stem from an imbalance in the DNA
15
repair machinery. As suggested by Gorbunova et al. (2007), the
manipulations of upstream DNA repair regulators might induce a
more coordinated response and thus would be preferable to downstream players.
Of certain relevance to Criterion 3 are also the results obtained
in non-genetic models of extended lifespan. Among them, dietary
restriction (DR) is the most investigated. Its longevity-promoting
effect has been shown in diverse species including yeast, worms,
flies, fish, rodents and primates (Fontana et al., 2010). It has
been suggested that DR extends lifespan and reduces age-related
pathologies by lowering the levels of DNA damage and mutations
that accumulate with age (Haley-Zitlin and Richardson, 1993). This
suggestion has since been supported by numerous studies on rats
and mice (for example, see: Kaneko et al., 1997; Hamilton et al.,
2001; Aidoo et al., 2003), being at least in part attributed to resisting the age-related decline in BER (Cabelof et al., 2003), NER (Guo
et al., 1998), and NHEJ (Um et al., 2003) pathways. The “universality” of the positive effect of DR on DNA maintenance has recently
been challenged by the work of Edman et al. (2009), who showed
that DR extended the Drosophila melanogaster lifespan without any
impact on the age-dependent accumulation of spontaneous mutations. Also, a supplementation of ␣-Tochopherol to mice from 4
months of age, increased their median (by 15%) and maximum (by
10%) lifespan, but had no effect on age-related accumulation of
oxidative DNA damage in lymphocytes and hepatocytes (Selman
et al., 2008).
Other interventions, such as lowering temperature (Garcia et al.,
2010) and reduction in physical activity (Agarwal and Sohal, 1994),
extended lifespan and inhibited the accumulation of oxidative DNA
damage and mutations in flies. A similar though less pronounced
effect was also shown for several pharmacological compounds in a
variety of model organisms (Table 6).
Increasing evidence indicates that low doses of potentially
harmful factors (e.g., radiation) may exert a longevity-promoting
(hormetic) effect (reviewed by Rattan, 2001, 2008; Schumacher,
2009; Vaiserman, 2011). Though the exact mechanisms of this
effect remain elusive, the activation of DNA repair pathways was
suggested as one of the hormetic “channels”. Indeed, a recent
genome-wide analysis of low-dose irradiated male D. melanogaster
revealed that the DNA repair and DNA damage response GO categories were among the enriched biological processes compared to
the untreated flies (Seong et al., 2011). Moreover, mutations in the
DNA repair and DNA damage response genes (such as homologs
of human ATM, ATR, FOXO, and p53) in Drosophila cancelled the
pro-longevity effects induced by low doses of radiation (Moskalev,
2007; Moskalev et al., 2011).
Of special interest would be an evaluation whether a longevity
phenotype within a given population is associated with lower
levels of DNA damage and mutations. Only several studies have
as yet been conducted with respect to that. While studying the
human peripheral blood mononuclear cells, Trzeciak et al. (2012)
found that females have higher SSB levels than males. This result
is quite unexpected in view of a higher female life expectancy.
As far as the humans with exceptional longevity (centenarians)
are concerned, the relevant data is scarce. Chevanne et al. (2003)
found that the amount of SSB in H2 O2 -treated fibroblasts from
centenarians was lower than in the cells of old donors from the general population. Also, the levels of PARP enzymes in Epstein–Barr
virus-immortalized B lymphocyte cells from centenarians were significantly higher than in old individuals and comparable to those
of the young (Chevanne et al., 2007). It seems that centenarians
are less sensitive to oxidative DNA damage due to a well-preserved
DNA repair capacity. In support of this suggestion are the experiments on house flies of the same genetic background, showing that
a more efficient DNA damage response to ␥-irradiation positively
correlates with life expectancy (Newton et al., 1989b).
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
G Model
ARR-371; No. of Pages 24
16
ARTICLE IN PRESS
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
Table 6
Pharmacological longevity-promoting interventions affecting DNA damage/repair.
Compound
Protective effect against DNA damage
Anti-aging and lifespan
effects
Reference
Aspirin
Inhibits oxidative DNA damage induced by
H2 O2 /Cu(II) or hydroquinone/Cu(II)
Inhibited the peroxynitrite-induced DNA strand
breakage
Protects against Fenton reaction-mediated oxidative
damage to DNA
Decreases the level of H2AX phosphorylation on
Ser139 and constitutivly activates of ATM
Stimulates the repair of DNA damage induced by UV
irradiation, N-methyl-N -nitro-N-nitroso guanidine,
dimethyl sulfate, or N-nitrosobis
(2-oxopropyl)amine
Suppresses the homologous recombination (HR) and
nonhomologous end joining (NHEJ) in MCF7 breast
cancer cells. Inhibits yeast transcription-coupled
nucleotide excision repair in a gene transcribed by
RNA polymerase II
Decreases the frequencies of micronuclei induced by
mitomycin C, ethyl nitrosourea or 4-nitroquinoline
1-oxide
Inhibits free radical formation and activation of
endonuclease that can be triggered by intracellular
oxidative stress, and by increasing the rate of
removal of damaged DNA
Extended lifespan of
male mice
Extended lifespan in C.
elegans
Extended lifespan of
Zaprionus fruitflies
Extended lifespan of
female SHR mice
Extended lifespan in
yeast
Hsu and Li (2002),
Strong et al. (2008)
Jia et al. (2010), Wang
et al. (2010)
Sharma et al. (1997),
Olsen et al. (1999)
Anisimov et al. (2011),
Halicka et al. (2011)
Berger and Sikorski
(1980), Lawson (1989),
Tsuchiya et al. (2006)
Extended lifespan in
genetically
heterogeneous mice
Harrison et al. (2009),
Limson and Sweder
(2010), Chen et al.
(2011)
Extended lifespan in C.
elegans
Sasaki et al. (1990a),
Saul et al. (2010)
Increased median
lifespan in rodents
Claycombe and
Meydani (2001), Banks
et al. (2010)
Dimethyl sulfoxide
Kinetin
Metformin
Nicotinamide
Rapamycin
Tannic acid
Vitamin E
5. Do species differing in mutation load also differ in
longevity and vice versa?
Compliance to Criterion 4 is a sufficient but not necessary condition for approving a causative role for accumulation of DNA damage
and mutations in aging. It rather points to a possibility that this
accumulation could be a public mechanism of aging. If so, it implies
a correlation between species-specific lifespan and the level of DNA
damage/mutations or DNA repair capacity. This was the subject of
several comparative studies on mammals.
As seen in Table 7, a positive correlation of maximum lifespan
(MLS) with damage-induced DNA repair capacity (mostly, excision
repair) was found. Moreover, the ability to recognize DNA damage
sites appears to be higher in longer-lived species. Such a correlation
was not observed when the basal levels of DNA repair enzymes (APE
and Pol␤) were measured (Page and Stuart, 2011). However, the
lack of significant correlation in this study could be attributed to the
relatively narrow range of MLS (from 3.9 years in Syrian hamsters
to only 27 years in pig).
It could be expected that the positive correlation of MLS with
DNA repair capacity would result in the opposite trend between
MLS and the level of DNA damage/mutations. The expected negative correlation was indeed found for the level of damage-induced
micronuclei (Fink et al., 2011). However, the levels of 8-oxoG in
brain and heart did not correlate significantly with MLS (Barja and
Herrero, 2000). A much more surprising result was brought about
by the comparison between the naked mole rat, a rodent with
exceptional longevity, and a mouse (8-fold difference in MLS). It
was found that the level of 8-oxoG in the liver of the young naked
mole rats was 8-fold higher than in the young mice (Andziak et al.,
2006). These findings put into question the functional significance
of age-related accumulation of 8-oxoG (see Section 2.1).
There is a remarkable difference in the abundance of the
LINE-1 transposable element between mammalian species (St.
Laurent et al., 2010). In mouse, the number of LINE-1 copies is
approximately 50-fold greater than in humans. Even when comparing humans and chimpanzees with relatively close lifespans, a
significant difference still exists. This offers a much higher probability for DNA to be damaged in the short-lived vs. long-lived
species.
While the above data indicates some trend in which longer-lived
species have better capabilities for a proper DNA maintenance, the
current knowledge in the field is yet insufficient to meet Criterion 4.
Clearly, a substantially wider range of species is called for in future
studies. The same is also true for the types of DNA damage/repair,
and the cells or organs to be tested. Besides, one of the limitations of
such comparative studies is that the comparison is commonly made
on young adults with no consideration for possible species-specific
differences in the rate of age-related changes. For example, we did
not find any significant differences in expression profile of DNA
repair genes between young mice of a long-lived ␣MUPA strain
and their parental WT, but they did differ when compared in old
age (unpublished data). Interestingly, the same age-related pattern
was demonstrated by us for the rate of skin wound healing (Yanai
et al., 2011). Such a factor was indeed considered in the study of
Grube and Bürkle (1992), who compared the rate of age-related
changes in maximum PARP-1 activity in rats and humans. They
found that not only was the PARP-1 activity at the young age 4-fold
lower in rats, but the decline per year was also 4-fold faster in rats
than in humans.
6. Other relevant issues
6.1. Stem cells
The impact of DNA damage accumulation in stem cells on tissue
and organismal aging is a newly evolving and rapidly developing
field. As such, the ability of stem cells to withstand accumulating
DNA damage and maintain their regenerative capacity over time
has been proposed to be a fundamental factor determining the
rate of tissue aging (Nijnik et al., 2007; Rossi et al., 2007; Charville
and Rando, 2011). In contrast to other somatic cells, the stem cells
are able to defend themselves from DNA damage by using nonrandom chromosome segregation during asymmetric mitosis (for
recent reviews see Charville and Rando, 2011; Mandal et al., 2011).
Under asymmetric strand segregation, the replicated DNA strand is
preferentially targeted to the “daughter” (differentiating) cell after
each round of DNA replication, while the original DNA molecule is
kept in the “mother” stem cell. This reduces the risk of replicationdependent DNA errors, although cannot avoid the accumulation
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
G Model
ARR-371; No. of Pages 24
ARTICLE IN PRESS
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
17
Table 7
Correlations between maximum lifespan (MLS) and DNA repair/damage in mammals.
Organ/cells tested
Type of DNA
repair/damage
Correlation with maximum
lifespan
Reference
Primary skin fibroblasts
Excision repair after
UV-irradiation
Excision repair after
UV-irradiation
Excision repair after
UV-irradiation
PARP activity
Positive correlationa
n=7
Positive correlationa
(n = 21; p < 0.05)
Positive correlationa
(n = 7 primates)
Positive correlation
(n = 13; r = 0.84; p < 0.001)
Positive correlation
(n = 12; r2 = 0.845; p < 0.001)
Negative correlation for
mtDNA
(brain: n = 6; r = −0.88;
p = 0.016; Heart: n = 8;
r = −0.92, p < 0.001)
No significant correlation with
nDNA
Positive correlation
(n = 12; r = 0.9; p < 0.0001)
Negative correlation
(n = 6; r = −0.8; p = 0.006)
Hart and Setlow (1974)
Primary skin fibroblasts
Primary skin fibroblasts and peripheral blood lymphocytes
Mononuclear leukocytes
Recalculation of the results from 5 comparative studies
Brain and heart
Standardized DNA
repair activity
Accumulation of
8-oxoG in nDNA and
mtDNA
Primary skin fibroblasts
DSB recognition
Primary skin fibroblasts
Micronuclei formation
after neocarzinostatin
treatment
AP endonuclease and
polymerase ␤ activities
(BER)
Brain and liver
a
No significant correlation with
MLS.
Negative correlation with body
mass
(n = 13 mammals and 2 avians)
Francis et al. (1981)
Hall et al. (1984)
Grube and Bürkle (1992)
Cortopassi and Wang (1996)
Barja and Herrero (2000)
Lorenzini et al. (2009)
Fink et al. (2011)
Page and Stuart (2011)
Values of correlation coefficient not available.
of replication-independent DNA damage with advanced age, such
as oxidized or deaminated bases and strand breaks (Charville and
Rando, 2011). Indeed, the level of the DSB markers gamma H2AXfoci in CD34+ and CD34− stem/progenitor cells along with a decline
in the repair of DSB was higher in individuals >50-years old compared with the younger group (<50-years old) and this difference
increased with the donor age after exposure to ␥-irradiation (Rube
et al., 2011). In another study on human hematopoietic stem cells,
the persistent oxidative DNA damage was also found to accumulate with the age of donors, restricting their self-renewal capacity
(Yahata et al., 2011). Similar age-related decrease in the functional
capacity of hematopoietic stem cells (Rossi et al., 2007) and musclederived stem/progenitor cells (Lavasani et al., 2012) was observed
in wild-type mice.
Notably, in a variety of premature aging syndromes, the stem
cell compartment is affected by DNA damage which is primarily connected to the defects in DNA repair (reviewed by Park and
Gerson, 2005). Recent studies on mouse models have clearly shown
that this has a profound impact on functional capacity and viability of stem cells (Nijnik et al., 2007; Rossi et al., 2007; Ruzankina
et al., 2007; Wang et al., 2011). For example, mice deficient in
the DNA damage response ATR gene showed a considerable agerelated loss of stem and progenitor cells in the thymus and hair
follicles, which strongly correlates with a reduced tissue renewal
and homeostatic capacity (Ruzankina et al., 2007). Another prominent example includes the Ligase IV syndrome mouse model with
defective NHEJ repair. These mice exhibited the accelerated agerelated loss of hematopoietic stem cells (Nijnik et al., 2007). In
four mouse models of premature aging, Rossi et al. (2007) showed
that hematopoietic stem cells are particularly susceptible to stress
leading to loss of their reconstitution and proliferative potential,
diminished self-renewal, and increased apoptosis.
Collectively, the presented data suggest an important role of
accumulated DNA damage in age-related deterioration of the
somatic stem cell pool, which could greatly affect the tissue regenerative potential and eventually contribute to organismal aging.
Highly supporting this notion is the recent study on progeroid mice
transplanted with stem cells from young wild-type mice, which
resulted in lifespan and healthspan extension (Lavasani et al., 2012).
6.2. Cell-nonautonomous effects
The harmful effects of mutations are not limited only to the cells
of origin but may also affect neighboring cells and even distant
ones. The most extensively studied cell-nonautonomous effects
are those associated with insulin/IGF-1 signaling, a well-known
aging/longevity pathway (Rincon et al., 2005), which is involved in
regulation of DNA repair. This regulation is mediated through FOXO
transcription factor and its effector GADD45, which participates
in the DNA damage response (Moskalev et al., 2012). In turn, the
insulin/IGF-1 signaling is activated by the DNA damage response
(Niedernhofer et al., 2006). However, an excessive DNA damage
has an opposite effect resulting in inhibition of the insulin/IGF1 pathway (Niedernhofer et al., 2006). Taking into account the
pleiotropic effects of insulin/IGF-1 signaling, including cell-cell and
cell-extracellular matrix interactions, any changes in its activity
would have far-reaching consequences for both mutant cell and
its environment (Hinkal and Donehower, 2008).
Another important example of cell-nonautonomous effects
is the formation of senescence-associated secretory phenotype
(SASP). It is initiated in senescent cells by a persistent signal of unrepaired DNA damage, which is mediated through the DNA damage
response proteins ATM, NBS1 and CHK2 (Rodier et al., 2009). The
SASP-bearing cells secrete increased amounts of pro-inflammatory
molecules and promote inflammation, carcinogenesis and fibroproliferative responses in the surrounding tissue (“senescent”
microenvironment) (Rodier and Campisi, 2011). Of note, cellular
senescence could be induced by transposition or expression of
MGEs (see Section 2.4) as was shown in cultured fibroblasts and
adult stem cells (Zainullin and Moskalev, 2000; Belancio et al.,
2010). Our recent analysis showed that in addition to SASP, there
are multiple molecular links between cellular senescence, aging
and ARDs (Tacutu et al., 2011). Highlighting this point is the recent
study of Baker et al. (2011) who showed that the drug-induced
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
G Model
ARR-371; No. of Pages 24
18
ARTICLE IN PRESS
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
Fig. 1. Is accumulation of DNA damage and mutations a causal factor of aging? The fulfillment of the criteria is marked in color intensity. Lighter intensity may indicates
either inconsistent data or small amounts of data.
clearance of senescent cells from progeroid mice delayed the onset
of several age-related conditions.
7. Concluding remarks
This work is an attempt to organize the evidence “for” and
“against” the hypothesized causal role of DNA damage and mutation accumulation in aging. For this purpose, we propose four
logical “Koch-like” criteria, presented in Fig. 1 (see also Section
1). The hypothesis could be considered proven, once the necessary
(Criterion 1) and sufficient (Criteria 2–4) conditions are met (“if and
only if”). As seen in Fig. 1, many gaps should still be filled in order
to reach a clear-cut conclusion.
Is there a strong evidence for the accumulation of DNA damage and mutations with age? The data compiled thus far indicates
that it is true for many but not all types of DNA damage/mutations.
Although this accumulation appears to be cell-type/organ-specific,
still many cell types and organs remain to be examined. Also, it
is still unclear to what extent the accumulated DNA damage is
functionally meaningful, for example, as in the case of 8-oxoG (see
Sections 2.1 and 5). Thus, while the age-related accumulation of
DNA damage and mutations is apparently not a ubiquitous phenomenon, the evidence obtained for at least several cell types and
organs amply meet Criterion 1.
Given that Criterion 1 is at least partially fulfilled, some quantitative relationship between the levels of DNA damage/mutations and
aging rate could be predicted (Criteria 2–4), so that (i) the longerlived individuals or species would have a lower rate of damage
than the shorter-lived, and (ii) the interventions that modulate DNA
damage should also modulate aging/longevity and vice versa. Perhaps, the most consistent evidence supporting a plausible role of
DNA damage accumulation in aging is the connection of progeroid
syndromes to defects in DNA repair (Criterion 2). Also, interventions
that increase DNA damage, such as high doses of ionizing radiation,
often result in accelerated aging.
Lifespan extension due to interventions decreasing the DNA
damage and mutations would stand as the strongest evidence in
support of the major role of their accumulation in aging (Criterion
3). However, the results of such attempts were rather inconsistent,
in the case of overexpressed DNA repair genes in particular.
Positive correlation between MLS and damage-induced DNA
repair capacity, found in several comparative studies on mammals,
suggests that the DNA of longer-lived species may be better protected. However, the relevant data on interspecies differences in the
levels of DNA damage/mutations are too scarce to reach a definite
conclusion regarding Criterion 4.
Further research is definitely warranted to determine to what
extent accumulation of DNA damage and mutations contribute to
the aging process. The steps toward filling the current gaps would
include wide comparative studies addressing wide spectra of DNA
damage/mutations and repair pathways in a variety of cell types
and organs. This will also shed light on whether and to what extent
the age-related accumulation of DNA damage/mutations is a “public” or “private” phenomenon. Finally, a functional significance and
survival value of such an accumulation should be addressed for
better understanding its role in the mechanisms of aging. As a
promising perspective, it seems that a special emphasis in future
studies should be put on the role of DNA damage in stem cell aging.
Presuming that future studies will confirm the accumulation
of DNA damage/mutations as a major determinant of aging, what
would be the preferable anti-aging strategy? Obviously, a complete prevention of DNA damage is unrealistic because it occurs
as a natural by-product of cell activity and exposures to exogenous
hazards. It is however a realistic task to attempt decreasing the level
of damaging factors or counteracting their action, in particular by
enhancing the efficiency of DNA repair. Would it be sufficient to
completely resist the aging process? In fact, DNA is important but
not the only target of damaging insults. Accumulation of insoluble
protein aggregates (Dillin and Cohen, 2011) and modified proteins,
oxidation of cell membrane lipids (Hyun et al., 2006), impaired
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
G Model
ARR-371; No. of Pages 24
ARTICLE IN PRESS
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
autophagy (Cuervo, 2008) and many others could all essentially
impair the normal cell functions and turn the cell into a danger
to its surrounding and to the whole organism. Importantly, these
processes are commonly coupled to the induction of DNA damage
which may serve as a sensor, signaling the need for elimination of
such a cell. From the perspective of energy allocation and an optimal outcome, to eliminate the damaged cell and replace it by a new
one from a pool of stem/progenitor cells may be a simpler and more
effective way than to massively recruit the DNA repair machinery
at any cost. A complicating point is that DNA damage accumulates
also in adult stem cells, leading to their depletion and functional
decline over time (see Section 6.1). It seems therefore reasonable
to put a major emphasis on how to preserve a healthy pool of adult
stem/progenitor cells as a main anti-aging strategy. The promising
results of the recent study by Lavasani et al. (2012) further reinforce
this notion.
Acknowledgments
19
Science (to A.B.), and by the European Commission FP7 Health
Research Grant number HEALTH-F4-2008-202047 (to V.E.F.). M.V.
Shaposhnikov, E.N. Plyusnina, A. Budovsky, and H. Yanai equaly
contributed to this work; A.A. Moskalev and V.E. Fraifeld hold equal
responsibility. We apologize to those whose work we could not cite
due to a huge number of publications in the field.
Appendix A. Types of DNA damage, the relevant DNA repair
mechanisms and possible outcomes (mutations)
Abbreviations: AP-sites – abasic (apurinic/apyrimidinic) sites;
BER – base excision repair; NER – nucleotide excision repair;
8-oxoG – 8-oxoguanine; CPD photolyase – cyclobutane pyrimidine dimer photolyase; DSB – double-strand DNA breaks; HR –
homologous recombination; SSA – single-strand annealing; SSB –
single-strand DNA breaks; NHEJ – nonhomologous DNA end joining; RNS – reactive nitrogen species; ROS – reactive oxygen species;
SSBR – single-strand DNA repair.
This work was supported from the Presidium of the Russian
Academy of Science (to A.A.M.) grant from Israeli Ministry of
Damaging process
DNA damage
DNA repair mechanism
Mutations
UV-induced photochemical
reactions between thymine or
cytosine bases
Cyclobutane pyrimidine
dimers
Pyrimidine (6–4) pyrimidone
photoproducts
O6 - methylguanine
Light-dependent repair by CPD
photolyase or NER
Light-dependent repair by
(6–4)photolyase or NER
Direct reversal by
O6 -methylguanine DNA
methyltransferase
BER
T → C transition, T → G
transversion; deletions
T → C transition; deletions
DNA alkylation
3-methyladenine
GC → AT transversion
AT → GC transitions, AT → CG
transversion; deletions
Nucleotide base replacements;
frameshift mutations; DNA
strand breaks
Glycosidic bond breaking
between purine or
pyrimidine bases and
carbohydrates
Oxidation of DNA by ROS and
RNS
Covalent bond formation
between DNA and aldehydes,
ketones, epoxides
AP-sites
Short-patch and long-patch
BER pathway
8-oxoG, 8-nitroguanine
Long-patch BER
GC → TA transversions
DNA adducts
BER, NER, mismatch repair
Deamination of DNA
bases
Guanine → xanthine
Adenine → hypoxanthine
Cytosine → Uracil
5-Methylcytosine → Thymine
Mismatches (G/T or A/C
pairing)
Single-strand DNA breaks (SSB)
Long-patch BER
Long-patch BER
Long-patch BER
Long-patch BER
Mismatch repair
Transitions and transversions;
deletions; sister chromatid
exchanges; chromosomal
aberrations
GC → AT transition
AT → GC transition
GC → AT transition
GC → AT transition
Base substitutions
BER, SSBR
Double-strand DNA breaks
(DSB)
Double-strand DNA breaks
(DSB)
HR, SSA, DNA-PK-dependent
NHEJ, and reverse NHEJ
Cross-linking in DNA
(intrastrand and interstrand
crosslinks)
DNA–protein crosslinks
Fanconi anemia and WRN
proteins, NER, HR
Loss of chromosome
fragments; dicentric or acentric
chromosomal fragments;
chromosomal aberrations
DNA strand breaks
DNA replication errors
Exposure to peroxynitrite
and/or hydroxyl radicals;
BER/NER intermidiates;
excessive activity of
topoisomerase I
Ionizing radiation or
radio-mimetic chemicals;
V(D)J recombination
intermediates
Exposure to methylglyoxal,
malondialdehyde, UV or
ionizing radiation
Covalent bond formation
between DNA and proteins
induced by alkylating agents,
UV light or ionizing radiation
HR
DNA strand breaks
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
G Model
ARR-371; No. of Pages 24
ARTICLE IN PRESS
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
20
Appendix B. Brief overview of DNA repair pathways
Currently, seven major DNA repair pathways are recognized:
(1) Direct reversal repair which involves enzymes that directly
restore the native nucleotide residue by removing the nonnative chemical modification. Selected examples include direct
reduction of UV-induced pyrimidine dimers by photolyase
(Sancar, 2003), and of alkylated guanine by O6 -methylguanine
DNA methyltransferase (Kaina et al., 2007).
(2) Base excision repair (BER) which excises modified bases from
the DNA. In particular, BER plays a role in the correction of
AP-sites, oxidized, reduced, alkylated, and deaminated bases,
mismatches, and SSB (reviewed by Wilson and Bohr, 2007).
(3) More extensive DNA damage is corrected by nucleotide excision repair (NER) which includes transcriptional-coupled NER
(TC-NER) and global genome NER (GG-NER) (Hanawalt, 2001).
TC-NER repairs the damages in the actively transcibed genes,
while GG-NER takes care of the non-transcribed genome
(Hanawalt, 2002). Each of these mechanisms involves specific
repair enzymes.
(4) Mismatch repair is a postreplicational DNA repair that
removes errors introduced during the replication (misinserted nucleotides, small loops, insertions, deletions) (Clark
et al., 2000).
(5) Homologous recombination (HR), including single strand DNA
annealing, is an accurate post-replicative repair of DSB based on
the use of an undamaged sister chromatid as a repair template
and functions only after DNA replication (Mahaney et al., 2009).
(6) Non-homologous end joining repair (NHEJ) is characterized
by ligation of ends resulting from DSB without use of the
homologous template (Collis et al., 2005). This repair pathway
also includes the more error-prone microhomology end joining
(MMEJ) repair.
(7) Translesion synthesis is an error accumulating pathway that
employs specialized polymerases to replicate across lesions
in order to finish replication despite a severe DNA damage
(Waters et al., 2009).
Appendix C. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.arr.2012.02.001.
References
Agarwal, S., Sohal, R.S., 1994. DNA oxidative damage and life expectancy in houseflies. Proc. Natl. Acad. Sci. U.S.A. 91, 12332–12335.
Aidoo, A., Mittelstaedt, R.A., Bishop, M.E., Lyn-Cook, L.E., Chen, Y.J., Duffy, P., Heflich,
R.H., 2003. Effect of caloric restriction on Hprt lymphocyte mutation in aging
rats. Mutat. Res. 527, 57–66.
Andziak, B., O’Connor, T.P., Qi, W., DeWaal, E.M., Pierce, A., Chaudhuri, A.R.,
Van Remmen, H., Buffenstein, R., 2006. High oxidative damage levels
in the longest-living rodent, the naked mole-rat. Aging Cell 5, 463–
471.
Anisimov, V.N., Berstein, L.M., Popovich, I.G., Zabezhinski, M.A., Egormin, P.A.,
Piskunova, T.S., Semenchenko, A.V., Tyndyk, M.L., Yurova, M.N., Kovalenko, I.G.,
Poroshina, T.E., 2011. If started early in life, metformin treatment increases
life span and postpones tumors in female SHR mice. Aging (Albany NY) 3,
148–157.
Annett, K., Hyland, P., Duggan, O., Barnett, C., Barnett, Y., 2004. An investigation of
DNA excision repair capacity in human CD4+ T cell clones as a function of age
in vitro. Exp. Gerontol. 39, 491–498.
Antoccia, A., Kobayashi, J., Tauchi, H., Matsuura, S., Komatsu, K., 2006. Nijmegen
breakage syndrome and functions of the responsible protein, NBS1. Genome
Dyn. 1, 191–205.
Arum, O., Johnson, T.E., 2007. Reduced expression of the Caenorhabditis elegans p53
ortholog cep-1 results in increased longevity. J. Gerontol. A Biol. Sci. Med. Sci.
62, 951–959.
Atamna, H., Cheung, I., Ames, B.N., 2000. A method for detecting abasic sites in living
cells: age-dependent changes in base excision repair. Proc. Natl. Acad. Sci. U.S.A.
97, 686–691.
Baker, D.J., Wijshake, T., Tchkonia, T., LeBrasseur, N.K., Childs, B.G., van de Sluis, B.,
Kirkland, J.L., van Deursen, J.M., 2011. Clearance of p16Ink4a-positive senescent
cells delays ageing-associated disorders. Nature 479, 232–236.
Banks, R., Speakman, J.R., Selman, C., 2010. Vitamin E supplementation and mammalian lifespan. Mol. Nutr. Food Res. 54, 719–725.
Barbot, W., Dupressoir, A., Lazar, V., Heidmann, T., 2002. Epigenetic regulation of
an IAP retrotransposon in the aging mouse: progressive demethylation and
de-silencing of the element by its repetitive induction. Nucleic Acids Res. 30,
2365–2373.
Barja, G., Herrero, A., 2000. Oxidative damage to mitochondrial DNA is inversely
related to maximum life span in the heart and brain of mammals. FASEB J. 14,
312–318.
Barlow, C., Hirotsune, S., Paylor, R., Liyanage, M., Eckhaus, M., Collins, F., Shiloh, Y.,
Crawley, J.N., Ried, T., Tagle, D., Wynshaw-Boris, A., 1996. Atm-deficient mice: a
paradigm of ataxia telangiectasia. Cell 86, 159–171.
Bartova, E., Galiova, G., Legartova, S., Stixova, L., Jugova, A., Kozubek, S., 2010. Genome
instability in the context of chromatin structure and fragile sites. Crit. Rev.
Eukaryot. Gene Expr. 20 (3), 181–194.
Begley, T.J., Samson, L.D., 2004. Network responses to DNA damaging agents. DNA
Repair (Amst.) 3, 1123–1132.
Belancio, V.P., Roy-Engel, A.M., Pochampally, R.R., Deininger, P., 2010. Somatic
expression of LINE-1 elements in human tissues. Nucleic Acids Res. 38,
3909–3922.
Berger, N.A., Sikorski, G.W., 1980. Nicotinamide stimulates repair of DNA damage in
human lymphocytes. Biochem. Biophys. Res. Commun. 95, 67–72.
Best, B.P., 2009. Nuclear DNA damage as a direct cause of aging. Rejuvenation Res.
12, 199–208.
Borgesius, N.Z., de Waard, M.C., van der Pluijm, I., Omrani, A., Zondag, G.C., van
der Horst, G.T., Melton, D.W., Hoeijmakers, J.H., Jaarsma, D., Elgersma, Y., 2011.
Accelerated age-related cognitive decline and neurodegeneration, caused by
deficient DNA repair. J. Neurosci. 31, 12543–12553.
Botter, S.M., Zar, M., van Osch, G.J., van Steeg, H., Dolle, M.E., Hoeijmakers, J.H.,
Weinans, H., van Leeuwen, J.P., 2010. Analysis of osteoarthritis in a mouse model
of the progeroid human DNA repair syndrome trichothiodystrophy. Age (Dordr.)
33, 247–260.
Boyle, J., Kill, I.R., Parris, C.N., 2005. Heterogeneity of dimer excision in young and
senescent human dermal fibroblasts. Aging Cell 4, 247–255.
Breyer, V., Becker, C.M., Pischetsrieder, M., 2011. Intracellular glycation of nuclear
DNA, mitochondrial DNA, and cytosolic proteins during senescence-like growth
arrest. DNA Cell Biol. 30, 681–689.
Budovsky, A., Abramovich, A., Cohen, R., Chalifa-Caspi, V., Fraifeld, V., 2007. Longevity
network: construction and implications. Mech. Ageing Dev. 128, 117–124.
Budovsky, A., Muradian, K.K., Fraifeld, V.E., 2006. From disease-oriented to
aging/longevity-oriented studies. Rejuvenation Res. 9, 207–210.
Bürkle, A., 2006. DNA repair and PARP in aging. Free Radic. Res. 40, 1295–1302.
Busuttil, R.A., Garcia, A.M., Reddick, R.L., Dolle, M.E., Calder, R.B., Nelson, J.F., Vijg, J.,
2007. Intra-organ variation in age-related mutation accumulation in the mouse.
PLoS ONE 2, e876.
Cabelof, D.C., Raffoul, J.J., Ge, Y., Van Remmen, H., Matherly, L.H., Heydari, A.R., 2006.
Age-related loss of the DNA repair response following exposure to oxidative
stress. J. Gerontol. A Biol. Sci. Med. Sci. 61, 427–434.
Cabelof, D.C., Yanamadala, S., Raffoul, J.J., Guo, Z., Soofi, A., Heydari, A.R., 2003. Caloric
restriction promotes genomic stability by induction of base excision repair and
reversal of its age-related decline. DNA Repair 2, 295–307.
Cai, Q., Tian, L., Wei, H., 1996. Age-dependent increase of indigenous DNA adducts
in rat brain is associated with a lipid peroxidation product. Exp. Gerontol. 31,
373–385.
Caldecott, K.W., 2008. Single-strand break repair and genetic disease. Nat. Rev.
Genet. 9, 619–631.
Calvanese, V., Lara, E., Kahn, A., Fraga, M.F., 2009. The role of epigenetics in aging
and age-related diseases. Ageing Res. Rev. 8, 268–276.
Cao, L., Kim, S., Xiao, C., Wang, R.H., Coumoul, X., Wang, X., Li, W.M., Xu, X.L., De Soto,
J.A., Takai, H., Mai, S., Elledge, S.J., Motoyama, N., Deng, C.X., 2006. ATM-Chk2p53 activation prevents tumorigenesis at an expense of organ homeostasis upon
Brca1 deficiency. EMBO J. 25, 2167–2177.
Cao, L., Li, W., Kim, S., Brodie, S.G., Deng, C.X., 2003. Senescence, aging, and malignant
transformation mediated by p53 in mice lacking the Brca1 full-length isoform.
Genes Dev. 17, 201–213.
Cao, L., Xu, X., Bunting, S.F., Liu, J., Wang, R.H., Cao, L.L., Wu, J.J., Peng, T.N., Chen, J.,
Nussenzweig, A., Deng, C.X., Finkel, T., 2009. A selective requirement for 53BP1
in the biological response to genomic instability induced by Brca1 deficiency.
Mol. Cell 35, 534–541.
Charville, G.W., Rando, T.A., 2011. Stem cell ageing and non-random chromosome
segregation. Philos. Trans. R. Soc. Lond. B Biol. Sci. 366, 85–93.
Chen, H., Ma, Z., Vanderwaal, R.P., Feng, Z., Gonzalez-Suarez, I., Wang, S., Zhang,
J., Roti Roti, J.L., Gonzalo, S., Zhang, J., 2011. The mTOR inhibitor rapamycin
suppresses DNA double-strand break repair. Radiat. Res. 175, 214–224.
Cheng, H.L., Mostoslavsky, R., Saito, S., Manis, J.P., Gu, Y., Patel, P., Bronson, R., Appella,
E., Alt, F.W., Chua, K.F., 2003. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc. Natl. Acad. Sci. U.S.A. 100,
10794–10799.
Cheok, C.F., Bachrati, C.Z., Chan, K.L., Ralf, C., Wu, L., Hickson, I.D., 2005. Roles of the
Bloom’s syndrome helicase in the maintenance of genome stability. Biochem.
Soc. Trans. 33, 1456–1459.
Chevanne, M., Caldini, R., Tombaccini, D., Mocali, A., Gori, G., Paoletti, F., 2003. Comparative levels of DNA breaks and sensitivity to oxidative stress in aged and
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
G Model
ARR-371; No. of Pages 24
ARTICLE IN PRESS
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
senescent human fibroblasts: a distinctive pattern for centenarians. Biogerontology 4, 97–104.
Chevanne, M., Calia, C., Zampieri, M., Cecchinelli, B., Caldini, R., Monti, D., Bucci,
L., Franceschi, C., Caiafa, P., 2007. Oxidative DNA damage repair and parp 1
and parp 2 expression in Epstein–Barr virus-immortalized B lymphocyte cells
from young subjects old subjects, and centenarians. Rejuvenation Res. 10,
191–204.
Chew, Y.C., West, J.T., Kratzer, S.J., Ilvarsonn, A.M., Eissenberg, J.C., Dave, B.J., Klinkebiel, D., Christman, J.K., Zempleni, J., 2008. Biotinylation of histones represses
transposable elements in human and mouse cells and cell lines and in Drosophila
melanogaster. J. Nutr. 138, 2316–2322.
Christensen, B.C., Houseman, E.A., Marsit, C.J., Zheng, S., Wrensch, M.R., Wiemels,
J.L., Nelson, H.H., Karagas, M.R., Padbury, J.F., Bueno, R., Sugarbaker, D.J., Yeh,
R.F., Wiencke, J.K., Kelsey, K.T., 2009. Aging and environmental exposures alter
tissue-specific DNA methylation dependent upon CpG island context. PLoS
Genet. 5, e1000602.
Clark, A.B., Valle, F., Drotschmann, K., Gary, R.K., Kunkel, T.A., 2000. Functional interaction of proliferating cell nuclear antigen with MSH2-MSH6 and MSH2-MSH3
complexes. J. Biol. Chem. 275, 36498–36501.
Claycombe, K.J., Meydani, S.N., 2001. Vitamin E and genome stability. Mutat. Res.
475, 37–44.
Collis, S.J., DeWeese, T.L., Jeggo, P.A., Parker, A.R., 2005. The life and death of DNA-PK.
Oncogene 24, 949–961.
Coppede, F., Migliore, L., 2010. DNA repair in premature aging disorders and neurodegeneration. Curr. Aging Sci. 3, 3–19.
Cortopassi, G.A., Wang, E., 1996. There is substantial agreement among interspecies
estimates of DNA repair activity. Mech. Ageing. Dev. 91, 211–218.
Cuervo, A.M., 2008. Autophagy and aging: keeping that old broom working. Trends
Genet. 24, 604–612.
de Boer, J., Andressoo, J.O., de Wit, J., Huijmans, J., Beems, R.B., van Steeg, H., Weeda,
G., van der Horst, G.T., van Leeuwen, W., Themmen, A.P., Meradji, M., Hoeijmakers, J.H., 2002. Premature aging in mice deficient in DNA repair and transcription.
Science 296, 1276–1279.
De Bont, R., van Larebeke, N., 2004. Endogenous DNA damage in humans: a review
of quantitative data. Mutagenesis 19, 169–185.
de Magalhães, J.P., Budovsky, A., Lehmann, G., Costa, J., Li, Y., Fraifeld, V., Church,
G.M., 2009. The human ageing genomic resources: online databases and tools
for biogerontologists. Aging Cell 8, 65–72.
Degan, P., Bonassi, S., De Caterina, M., Korkina, L.G., Pinto, L., Scopacasa, F.,
Zatterale, A., Calzone, R., Pagano, G., 1995. In vivo accumulation of 8-hydroxy2 -deoxyguanosine in DNA correlates with release of reactive oxygen species in
Fanconi’s anaemia families. Carcinogenesis 16, 735–741.
Derheimer, F.A., Kastan, M.B., 2010. Multiple roles of ATM in monitoring and maintaining DNA integrity. FEBS Lett. 584, 3675–3681.
Dillin, A., Cohen, E., 2011. Ageing and protein aggregation-mediated disorders: from
invertebrates to mammals. Philos. Trans. R. Soc. Lond. B Biol. Sci. 366, 94–98.
Dimauro, T., David, G., 2009. Chromatin modifications: the driving force of senescence and aging? Aging (Albany NY) 1, 182–190.
Dollé, M.E., Giese, H., Hopkins, C.L., Martus, H.J., Hausdorff, J.M., Vijg, J., 1997. Rapid
accumulation of genome rearrangements in liver but not in brain of old mice.
Nat. Genet. 17, 431–434.
Dollé, M.E., Snyder, W.K., Gossen, J.A., Lohman, P.H., Vijg, J., 2000. Distinct spectra
of somatic mutations accumulated with age in mouse heart and small intestine.
Proc. Natl. Acad. Sci. U.S.A. 97, 8403–8408.
Donkena, K.V., Young, C.Y., Tindall, D.J., 2010. Oxidative stress and DNA methylation
in prostate cancer. Obstet. Gynecol. Int. 2010, 302051.
Draper, H.H., Agarwal, S., Nelson, D.E., Wee, J.J., Ghoshal, A.K., Farber, E., 1995.
Effects of peroxidative stress and age on the concentration of a deoxyguanosinemalondialdehyde adduct in rat DNA. Lipids 30, 959–961.
Dupressoir, A., Puech, A., Heidmann, T., 1995. IAP retrotransposons in the mouse
liver as reporters of ageing. Biochim. Biophys. Acta. 1264, 397–402.
Edman, U., Garcia, A.M., Busuttil, R.A., Sorensen, D., Lundell, M., Kapahi, P., Vijg, J.,
2009. Lifespan extension by dietary restriction is not linked to protection against
somatic DNA damage in Drosophila melanogaster. Aging Cell 8, 331–338.
Egilmez, N.K., Shmookler Reis, R.J., 1994. Age-dependent somatic excision of transposable element Tc1 in Caenorhabditis elegans. Mutat. Res. 316, 17–24.
Egly, J.M., Coin, F., 2011. A history of TFIIH: two decades of molecular biology on a
pivotal transcription/repair factor. DNA Repair (Amst.) 10, 714–721.
Elson, A., Wang, Y., Daugherty, C.J., Morton, C.C., Zhou, F., Campos-Torres, J., Leder,
P., 1996. Pleiotropic defects in ataxia-telangiectasia protein-deficient mice. Proc.
Natl. Acad. Sci. U.S.A. 93, 13084–13089.
Engels, W.R., Johnson-Schlitz, D., Flores, C., White, L., Preston, C.R., 2007. A third link
connecting aging with double strand break repair. Cell Cycle 6, 131–135.
Engels, W.R., Preston, C.R., 1984. Formation of chromosome rearrangements by P
factors in Drosophila. Genetics 107, 657–678.
Eriksson, M., Brown, W.T., Gordon, L.B., Glynn, M.W., Singer, J., Scott, L., Erdos, M.R.,
Robbins, C.M., Moses, T.Y., Berglund, P., Dutra, A., Pak, E., Durkin, S., Csoka, A.B.,
Boehnke, M., Glover, T.W., Collins, F.S., 2003. Recurrent de novo point mutations
in lamin A cause Hutchinson–Gilford progeria syndrome. Nature 423, 293–298.
Erol, A., 2011. Deciphering the intricate regulatory mechanisms for the cellular
choice between cell repair apoptosis or senescence in response to damaging
signals. Cell. Signal. 23, 1076–1081.
Esteller, M., 2002. CpG island hypermethylation and tumor suppressor genes: a
booming present, a brighter future. Oncogene 21, 5427–5440.
Feinberg, A.P., 2008. Epigenetics at the epicenter of modern medicine. JAMA 299,
1345–1350.
21
Fenech, M., Morley, A.A., 1985. The effect of donor age on spontaneous and induced
micronuclei. Mutat. Res. 148, 99–105.
Fink, L.S., Roell, M., Caiazza, E., Lerner, C., Stamato, T., Hrelia, S., Lorenzini, A., Sell,
C., 2011. 53BP1 contributes to a robust genomic stability in human fibroblasts.
Aging (Albany NY) 3, 836–845.
Fontana, L., Partridge, L., Longo, V.D., 2010. Extending healthy life span—from yeast
to humans. Science 328, 321–326.
Fraga, C.G., Shigenaga, M.K., Park, J.W., Degan, P., Ames, B.N., 1990. Oxidative damage
to DNA during aging: 8-hydroxy-2 -deoxyguanosine in rat organ DNA and urine.
Proc. Natl. Acad. Sci. U.S.A. 87, 4533–4537.
Fraga, M.F., Esteller, M., 2007. Epigenetics and aging: the targets and the marks.
Trends Genet. 23, 413–418.
Francis, A.A., Lee, W.H., Regan, J.D., 1981. The relationship of DNA excision repair
of ultraviolet-induced lesions to the maximum life span of mammals. Mech.
Ageing Dev. 16, 181–189.
Frasca, D., Barattini, P., Tirindelli, D., Guidi, L., Bartoloni, C., Errani, A., Costanzo, M.,
Tricerri, A., Pierelli, L., Doria, G., 1999. Effect of age on DNA binding of the ku
protein in irradiated human peripheral blood mononuclear cells (PBMC). Exp.
Gerontol. 34, 645–658.
Freitas, A.A., de Magalhaes, J.P., 2011. A review and appraisal of the DNA damage
theory of ageing. Mutat. Res. 728, 12–22.
Frolkis, V.V., Muradian, K.K., 1991. Life Span Prolongation. CRC Press, Boca Raton.
Fu, C.S., Harris, S.B., Wilhelmi, P., Walford, R.L., 1991. Lack of effect of age and
dietary restriction on DNA single-stranded breaks in brain, liver, and kidney
of (C3H × C57BL/10)F1 mice. J. Gerontol. 46, B78–B80.
Garcia, A.M., Calder, R.B., Dollé, M.E., Lundell, M., Kapahi, P., Vijg, J., 2010. Ageand temperature-dependent somatic mutation accumulation in Drosophila
melanogaster. PLoS Genet. 6, e1000950.
García-Cao, I., García-Cao, M., Tomás-Loba, A., Martín-Caballero, J., Flores, J.M., Klatt,
P., Blasco, M.A., Serrano, M., 2006. Increased p53 activity does not accelerate
telomere-driven ageing. EMBO Rep. 7, 546–552.
Garinis, G.A., Schumacher, B., 2009. Transcription-blocking DNA damage in aging
and longevity. Cell Cycle 8, 2134–2135.
Garinis, G.A., Uittenboogaard, L.M., Stachelscheid, H., Fousteri, M., van Ijcken, W.,
Breit, T.M., van Steeg, H., Mullenders, L.H., van der Horst, G.T., Bruning, J.C.,
Niessen, C.M., Hoeijmakers, J.H., Schumacher, B., 2009. Persistent transcriptionblocking DNA lesions trigger somatic growth attenuation associated with
longevity. Nat. Cell Biol. 11, 604–615.
Gorbunova, V., Seluanov, A., Mao, Z., Hine, C., 2007. Changes in DNA repair during
aging. Nucleic Acids Res. 35, 7466–7474.
Gossen, J.A., de Leeuw, W.J., Tan, C.H., Zwarthoff, E.C., Berends, F., Lohman, P.H.,
Knook, D.L., Vijg, J., 1989. Efficient rescue of integrated shuttle vectors from
transgenic mice: a model for studying mutations in vivo. Proc. Natl. Acad. Sci.
U.S.A. 86, 7971–7975.
Goto, M., Rubenstein, M., Weber, J., Woods, K., Drayna, D., 1992. Genetic linkage of
Werner’s syndrome to five markers on chromosome 8. Nature 355, 735–738.
Grabowski, M.M., Svrzikapa, N., Tissenbaum, H.A., 2005. Bloom syndrome ortholog
HIM-6 maintains genomic stability in C. elegans. Mech. Ageing Dev. 126,
1314–1321.
Gredilla, R., Bohr, V.A., Stevnsner, T., 2010. Mitochondrial DNA repair and association
with aging—an update. Exp. Gerontol. 45, 478–488.
Grillari, J., Katinger, H., Voglauer, R., 2007. Contributions of DNA interstrand crosslinks to aging of cells and organisms. Nucleic Acids Res. 35, 7566–7576.
Grossman, L., Wei, Q., 1995. DNA repair and epidemiology of basal cell carcinoma.
Clin. Chem. 41, 1854–1863.
Grube, K., Bürkle, A., 1992. Poly(ADP-ribose) polymerase activity in mononuclear
leukocytes of 13 mammalian species correlates with species-specific life span.
Proc. Natl. Acad. Sci. U.S.A. 89, 11759–11763.
Guo, Z., Heydari, A., Richardson, A., 1998. Nucleotide excision repair of actively transcribed versus nontranscribed DNA in rat hepatocytes: effect of age and dietary
restriction. Exp. Cell Res. 245, 228–238.
Guttenbach, M., Koschorz, B., Bernthaler, U., Grimm, T., Schmid, M., 1995. Sex chromosome loss and aging: in situ hybridization studies on human interphase
nuclei. Am. J. Hum. Genet. 57, 1143–1150.
Haley-Zitlin, V., Richardson, A., 1993. Effect of dietary restriction on DNA repair and
DNA damage. Mutat. Res. 295, 237–245.
Halicka, H.D., Zhao, H., Li, J., Traganos, F., Zhang, S., Lee, M., Darzynkiewicz, Z., 2011.
Genome protective effect of metformin as revealed by reduced level of constitutive DNA damage signaling. Aging (Albany NY) 3, 1028–1038.
Hall, K.Y., Hart, R.W., Benirschke, A.K., Walford, R.L., 1984. Correlation between
ultraviolet-induced DNA repair in primate lymphocytes and fibroblasts and
species maximum achievable life span. Mech. Ageing Dev. 24, 163–173.
Hamilton, M.L., Van Remmen, H., Drake, J.A., Yang, H., Guo, Z.M., Kewitt, K., Walter,
C.A., Richardson, A., 2001. Does oxidative damage to DNA increase with age?
Proc. Natl. Acad. Sci. U.S.A. 98, 10469–10474.
Hamosh, A., Scott, A.F., Amberger, J., Valle, D., McKusick, V.A., 2000. Online Mendelian
inheritance in man (OMIM). Hum. Mutat. 15, 57–61.
Hanawalt, P.C, 2001. Controlling the efficiency of excision repair. Mutat. Res. 485,
3–13.
Hanawalt, P.C., 2002. Subpathways of nucleotide excision repair and their regulation.
Oncogene 21, 8949–8956.
Han, S., Brunet, A., 2012. Histone methylation makes its mark on longevity. Trends
Cell Biol. 22, 42–49.
Harada, Y.N., Shiomi, N., Koike, M., Ikawa, M., Okabe, M., Hirota, S., Kitamura, Y.,
Kitagawa, M., Matsunaga, T., Nikaido, O., Shiomi, T., 1999. Postnatal growth
failure, short life span, and early onset of cellular senescence and subsequent
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
G Model
ARR-371; No. of Pages 24
22
ARTICLE IN PRESS
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
immortalization in mice lacking the xeroderma pigmentosum group G gene.
Mol. Cell. Biol. 19, 2366–2372.
Hardwick, R.J., Tretyakov, M.V., Dubrova, Y.E., 2009. Age-related accumulation of
mutations supports a replication-dependent mechanism of spontaneous mutation at tandem repeat DNA loci in mice. Mol. Biol. Evol. 26, 2647–2654.
Harrison, D.E., Strong, R., Sharp, Z.D., Nelson, J.F., Astle, C.M., Flurkey, K., Nadon,
N.L., Wilkinson, J.E., Frenkel, K., Carter, C.S., Pahor, M., Javors, M.A., Fernandez,
E., Miller, R.A., 2009. Rapamycin fed late in life extends lifespan in genetically
heterogeneous mice. Nature 460, 392–395.
Hart, R.W., Setlow, R.B., 1974. Correlation between deoxyribonucleic acid excisionrepair and life-span in a number of mammalian species. Proc. Natl. Acad. Sci.
U.S.A. 71, 2169–2173.
Hinkal, G., Donehower, L.A., 2008. How does suppression of IGF-1 signaling by DNA
damage affect aging and longevity? Mech. Ageing Dev. 129, 243–253.
Hoeijmakers, J.H., 2009. DNA damage, aging, and cancer. N. Engl. J. Med. 361,
1475–1485.
Holliday, R., 1987. The inheritance of epigenetic defects. Science 238, 163–170.
Holliday, R., 1999. Understanding Aging. Cambridge, Cambridge University Press.
Holliday, R., 2005. DNA methylation and epigenotypes. Biochemistry (Mosc.) 70,
500–504.
Hoopes, L.L., Budd, M., Choe, W., Weitao, T., Campbell, J.L., 2002. Mutations in DNA
replication genes reduce yeast life span. Mol. Cell. Biol. 22, 4136–4146.
Hsu, C.S., Li, Y., 2002. Aspirin potently inhibits oxidative DNA strand breaks: implications for cancer chemoprevention. Biochem. Biophys. Res. Commun. 293,
705–709.
Hyun, D.H., Hernandez, J.O., Mattson, M.P., de Cabo, R., 2006. The plasma membrane
redox system in aging. Ageing Res. Rev. 5, 209–220.
Intano, G.W., Cho, E.J., McMahan, C.A., Walter, C.A., 2003. Age-related base excision
repair activity in mouse brain and liver nuclear extracts. J. Gerontol. A Biol. Sci.
Med. Sci. 58, 205–211.
Izzotti, A., Cartiglia, C., Taningher, M., De Flora, S., Balansky, R., 1999. Agerelated increases of 8-hydroxy-2 -deoxyguanosine and DNA–protein crosslinks
in mouse organs. Mutat. Res. 446, 215–223.
Jeng, Y.M., Cai-Ng, S., Li, A., Furuta, S., Chew, H., Chen, P.L., Lee, E.Y., Lee, W.H., 2007.
Brca1 heterozygous mice have shortened life span and are prone to ovarian
tumorigenesis with haploinsufficiency upon ionizing irradiation. Oncogene 26,
6160–6166.
Jeong, Y.S., Kang, Y., Lim, K.H., Lee, M.H., Lee, J., Koo, H.S., 2003. Deficiency of
Caenorhabditis elegans RecQ5 homologue reduces life span and increases sensitivity to ionizing radiation. DNA Repair (Amst.) 2, 1309–13019.
Jia, Z., Zhu, H., Li, Y., Misra, H.P., 2010. Potent inhibition of peroxynitrite-induced
DNA strand breakage and hydroxyl radical formation by dimethyl sulfoxide at
very low concentrations. Exp. Biol. Med. (Maywood) 235, 614–622.
Ju, Y.J., Lee, K.H., Park, J.E., Yi, Y.S., Yun, M.Y., Ham, Y.H., Kim, T.J., Choi, H.M., Han, G.J.,
Lee, J.H., Lee, J., Han, J.S., Lee, K.M., Park, G.H., 2006. Decreased expression of DNA
repair proteins Ku70 and Mre11 is associated with aging and may contribute to
the cellular senescence. Exp. Mol. Med. 38, 686–693.
Kaina, B., Christmann, M., Naumann, S., Roos, W.P., 2007. MGMT: key node in the
battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating
agents. DNA Repair (Amst.) 6, 1079–1099.
Kaneko, T., Tahara, S., Matsuo, M., 1997. Retarding effect of dietary restriction on
the accumulation of 8-hydroxy-2 -deoxyguanosine in organs of Fischer 344 rats
during aging. Free Radic. Biol. Med. 23, 76–81.
Kanu, N., Behrens, A., 2008. ATMINistrating ATM signalling: regulation of ATM by
ATMIN. Cell Cycle 7, 3483–3486.
Kasai, H., 1997. Analysis of a form of oxidative DNA damage, 8-hydroxy-2 deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis.
Mutat. Res. 387, 147–163.
Kee, Y., D’Andrea, A.D., 2010. Expanded roles of the Fanconi anemia pathway in
preserving genomic stability. Genes Dev. 24, 1680–1694.
Krishna, T.H., Mahipal, S., Sudhakar, A., Sugimoto, H., Kalluri, R., Rao, K.S., 2005.
Reduced DNA gap repair in aging rat neuronal extracts and its restoration by
DNA polymerase beta and DNA-ligase. J. Neurochem. 92, 818–823.
Krishnan, V., Chow, M.Z., Wang, Z., Zhang, L., Liu, B., Liu, X., Zhou, Z., 2011a. Histone
H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice. Proc. Natl. Acad. Sci. U.S.A. 108,
12325–12330.
Krishnan, V., Liu, B., Zhou, Z., 2011b. ‘Relax and Repair’ to restrain aging. Aging
(Albany NY) 3, 943–954.
Kruk, P.A., Rampino, N.J., Bohr, V.A., 1995. DNA damage and repair in telomeres:
relation to aging. Proc. Natl. Acad. Sci. U.S.A. 92, 258–262.
Kujoth, G.C., Hiona, A., Pugh, T.D., Someya, S., Panzer, K., Wohlgemuth, S.E., Hofer, T.,
Seo, A.Y., Sullivan, R., Jobling, W.A., Morrow, J.D., Van Remmen, H., Sedivy, J.M.,
Yamasoba, T., Tanokura, M., Weindruch, R., Leeuwenburgh, C., Prolla, T.A., 2005.
Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian
aging. Science 309, 481–484.
Kyng, K.J., Bohr, V.A., 2005. Gene expression and DNA repair in progeroid syndromes
and human aging. Ageing Res. Rev. 4, 579–602.
Lai, C., Cao, H., Hearst, J.E., Corash, L., Luo, H., Wang, Y., 2008. Quantitative analysis of
DNA interstrand cross-links and monoadducts formed in human cells induced
by psoralens and UVA irradiation. Anal. Chem. 80, 8790–8798.
Larizza, L., Roversi, G., Volpi, L., 2010. Rothmund–Thomson syndrome. Orphanet. J.
Rare Dis. 5, 2.
Laschober, G.T., Ruli, D., Hofer, E., Muck, C., Carmona-Gutierrez, D., Ring, J., Hutter, E., Ruckenstuhl, C., Micutkova, L., Brunauer, R., Jamnig, A., Trimmel, D.,
Herndler-Brandstetter, D., Brunner, S., Zenzmaier, C., Sampson, N., Breitenbach,
M., Fröhlich, K.U., Grubeck-Loebenstein, B., Berger, P., Wieser, M., GrillariVoglauer, R., Thallinger, G.G., Grillari, J., Trajanoski, Z., Madeo, F., Lepperdinger,
G., Jansen-Dürr, P., 2010. Identification of evolutionarily conserved genetic regulators of cellular aging. Aging Cell 9, 1084–1097.
Lavasani, M., Robinson, A.R., Lu, A., Song, M., Feduska, J.M., Ahani, B., Tilstra, J.S.,
Feldman, C.H., Robbins, P.D., Niedernhofer, L.J., Huard, J., 2012. Muscle-derived
stem/progenitor cell dysfunction limits healthspan and lifespan in a murine
progeria model. Nat. Commun. 3, 608.
Lawson, T., 1989. Nicotinamide and selenium stimulate the repair of DNA damage
produced by N-nitrosobis (2-oxopropyl) amine. Anticancer Res. 9, 483–486.
Li, H., Vogel, H., Holcomb, V.B., Gu, Y., Hasty, P., 2007. Deletion of Ku70 Ku80, or
both causes early aging without substantially increased cancer. Mol. Cell. Biol.
27, 8205–8214.
Licht, C.L., Stevnsner, T., Bohr, V.A., 2003. Cockayne syndrome group B cellular and
biochemical functions. Am. J. Hum. Genet. 73, 1217–1239.
Lieber, M.R., 2010. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu. Rev. Biochem. 79, 181–211.
Limson, M.V., Sweder, K.S., 2010. Rapamycin inhibits yeast nucleotide excision repair
independently of TOR kinases. Toxicol. Sci. 113, 77–84.
Lorenzini, A., Johnson, F.B., Oliver, A., Tresini, M., Smith, J.S., Hdeib, M., Sell, C.,
Cristofalo, V.J., Stamato, T.D., 2009. Significant correlation of species longevity
with DNA double strand break recognition but not with telomere length. Mech.
Ageing Dev. 130, 784–792.
Lu, T., Pan, Y., Kao, S.Y., Li, C., Kohane, I., Chan, J., Yankner, B.A., 2004. Gene regulation
and DNA damage in the ageing human brain. Nature 429, 883–891.
Lu, Q., Qiu, X., Hu, N., Wen, H., Su, Y., Richardson, B.C., 2006. Epigenetics, disease, and
therapeutic interventions. Ageing Res. Rev. 5, 449–467.
Machwe, A., Ganunis, R., Bohr, V.A., Orren, D.K., 2000. Selective blockage of the
3 –>5 exonuclease activity of WRN protein by certain oxidative modifications
and bulky lesions in DNA. Nucleic Acids Res. 28, 2762–2770.
Mahaney, B.L., Meek, K., Lees-Miller, S.P., 2009. Repair of ionizing radiation-induced
DNA double-strand breaks by non-homologous end-joining. Biochem. J. 417,
639–650.
Maier, B., Gluba, W., Bernier, B., Turner, T., Mohammad, K., Guise, T., Sutherland, A.,
Thorner, M., Scrable, H., 2004. Modulation of mammalian life span by the short
isoform of p53. Genes Dev. 18, 306–319.
Mandal, P.K., Blanpain, C., Rossi, D.J., 2011. DNA damage response in adult stem cells:
pathways and consequences. Nat. Rev. Mol. Cell. Biol. 12, 198–202.
Mandavilli, B.S., Rao, K.S., 1996. Neurons in the cerebral cortex are most susceptible
to DNA-damage in aging rat brain. Biochem. Mol. Biol. Int. 40, 507–514.
Mangerich, A., Herbach, N., Hanf, B., Fischbach, A., Popp, O., Moreno-Villanueva, M.,
Bruns, O.T., Burkle, A., 2010. Inflammatory and age-related pathologies in mice
with ectopic expression of human PARP-1. Mech. Ageing Dev. 131, 389–404.
Matecic, M., Smith, D.L., Pan, X., Maqani, N., Bekiranov, S., Boeke, J.D., Smith, J.S.,
2010. A microarray-based genetic screen for yeast chronological aging factors.
PLoS Genet. 6, e1000921.
Maxwell, P.H., Burhans, W.C., Curcio, M.J., 2011. Retrotransposition is associated
with genome instability during chronological aging. Proc. Natl. Acad. Sci. U.S.A.
108, 20376–20381.
McVey, M., Kaeberlein, M., Tissenbaum, H.A., Guarente, L., 2001. The short life span
of Saccharomyces cerevisiae sgs1 and srs2 mutants is a composite of normal
aging processes and mitotic arrest due to defective recombination. Genetics 157,
1531–1542.
Mecocci, P., Fano, G., Fulle, S., MacGarvey, U., Shinobu, L., Polidori, M.C., Cherubini,
A., Vecchiet, J., Senin, U., Beal, M.F., 1999. Age-dependent increases in oxidative
damage to DNA, lipids, and proteins in human skeletal muscle. Free Radic. Biol.
Med. 26, 303–308.
Milanowska, K., Krwawicz, J., Papaj, G., Kosinski, J., Poleszak, K., Lesiak, J., Osinska, E.,
Rother, K., Bujnicki, J.M., 2011. REPAIRtoire—a database of DNA repair pathways.
Nucleic Acids Res. 39, D788–D792 (Database issue).
Miwa, S., Beckman, K.B., Muller, F.L., 2008. Oxidative Stress in Aging: From Model
Systems to Human Diseases. Totowa, NJ, Humana Press.
Mizoguchi, M., Naito, H., Kurata, Y., Shibata, M.A., Tsuda, H., Wild, C.P., Montesano,
R., Fukushima, S., 1993. Influence of aging on multi-organ carcinogenesis in rats
induced by N-methyl-N-nitrosourea. Jpn. J. Cancer Res. 84, 139–146.
Morgan, W.F., Corcoran, J., Hartmann, A., Kaplan, M.I., Limoli, C.L., Ponnaiya, B.,
1998. DNA double-strand breaks chromosomal rearrangements, and genomic
instability. Mutat. Res. 404, 125–128.
Moriwaki, S., Ray, S., Tarone, R.E., Kraemer, K.H., Grossman, L., 1996. The effect of
donor age on the processing of UV-damaged DNA by cultured human cells:
reduced DNA repair capacity and increased DNA mutability. Mutat. Res. 364,
117–123.
Moskalev, A., 2007. Radiation-induced life span alteration of Drosophila lines with
genotype differences. Biogerontology 8, 499–504.
Moskalev, A.A., Plyusnina, E.N., Shaposhnikov, M.V., 2011. Radiation hormesis and
radioadaptive response in Drosophila melanogaster flies with different genetic
backgrounds: the role of cellular stress-resistance mechanisms. Biogerontology
12, 253–263.
Moskalev, A.A., Smit-McBride, Z., Shaposhnikov, M.V., Plyusnina, E.N., Zhavoronkov,
A., Budovsky, A., Tacutu, R., Fraifeld, V.E., 2012. Gadd45 proteins: relevance to
aging, longevity and age-related pathologies. Ageing Res. Rev. 11, 51–66.
Mostoslavsky, R., Chua, K.F., Lombard, D.B., Pang, W.W., Fischer, M.R., Gellon, L.,
Liu, P., Mostoslavsky, G., Franco, S., Murphy, M.M., Mills, K.D., Patel, P., Hsu, J.T.,
Hong, A.L., Ford, E., Cheng, H.L., Kennedy, C., Nunez, N., Bronson, R., Frendewey,
D., Auerbach, W., Valenzuela, D., Karow, M., Hottiger, M.O., Hursting, S., Barrett,
J.C., Guarente, L., Mulligan, R., Demple, B., Yancopoulos, G.D., Alt, F.W., 2006.
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
G Model
ARR-371; No. of Pages 24
ARTICLE IN PRESS
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
Genomic instability and aging-like phenotype in the absence of mammalian
SIRT6. Cell 124, 315–329.
Muftuoglu, M., Kulikowicz, T., Beck, G., Lee, J.W., Piotrowski, J., Bohr, V.A., 2008.
Intrinsic ssDNA annealing activity in the C-terminal region of WRN. Biochemistry 47, 10247–10254.
Mukherjee, A.B., Thomas, S.A., 1997. Longitudinal study of human age-related chromosomal analysis in skin fibroblasts. Exp. Cell. Res. 235, 161–169.
Müller-Ohldach, M., Brust, D., Hamann, A., Osiewacz, H.D., 2011. Overexpression of
PaParp encoding the poly(ADP-ribose) polymerase of Podospora anserina affects
organismal aging. Mech. Ageing Dev. 132, 33–42.
Murga, M., Bunting, S., Montaña, M.F., Soria, R., Mulero, F., Cañamero, M., Lee, Y.,
McKinnon, P.J., Nussenzweig, A., Fernandez-Capetillo, O., 2009. A mouse model
of ATR-Seckel shows embryonic replicative stress and accelerated aging. Nat.
Genet. 41, 891–898.
Murray, V., 1990. Are transposons a cause of ageing? Mutat. Res. 237, 59–63.
Musich, P.R., Zou, Y., 2009. Genomic instability and DNA damage responses in
progeria arising from defective maturation of prelamin A. Aging (Albany NY) 1,
28–37.
Neri, S., Gardini, A., Facchini, A., Olivieri, F., Franceschi, C., Ravaglia, G., Mariani, E.,
2005. Mismatch repair system and aging: microsatellite instability in peripheral
blood cells from differently aged participants. J. Gerontol. A Biol. Sci. Med. Sci.
60, 285–292.
Newton, R.K., Ducore, J.M., Sohal, R.S., 1989a. Effect of age on endogenous DNA
single-strand breakage, strand break induction and repair in the adult housefly,
Musca domestica. Mutat. Res. 219, 113–120.
Newton, R.K., Ducore, J.M., Sohal, R.S., 1989b. Relationship between life expectancy
and endogenous DNA single-strand breakage strand break induction and DNA
repair capacity in the adult housefly, Musca domestica. Mech. Ageing Dev. 49,
259–270.
Niedernhofer, L.J., Garinis, G.A., Raams, A., Lalai, A.S., Robinson, A.R., Appeldoorn, E.,
Odijk, H., Oostendorp, R., Ahmad, A., van Leeuwen, W., Theil, A.F., Vermeulen, W.,
van der Horst, G.T., Meinecke, P., Kleijer, W.J., Vijg, J., Jaspers, N.G., Hoeijmakers,
J.H., 2006. A new progeroid syndrome reveals that genotoxic stress suppresses
the somatotroph axis. Nature 444, 1038–1043.
Nijnik, A., Woodbine, L., Marchetti, C., Dawson, S., Lambe, T., Liu, C., Rodrigues, N.P.,
Crockford, T.L., Cabuy, E., Vindigni, A., Enver, T., Bell, J.I., Slijepcevic, P., Goodnow,
C.C., Jeggo, P.A., Cornall, R.J., 2007. DNA repair is limiting for haematopoietic stem
cells during ageing. Nature 447, 686–690.
Nowinski, G.P., Van Dyke, D.L., Tilley, B.C., Jacobsen, G., Babu, V.R., Worsham, M.J.,
Wilson, G.N., Weiss, L., 1990. The frequency of aneuploidy in cultured lymphocytes is correlated with age and gender but not with reproductive history. Am.
J. Hum. Genet. 46, 1101–1111.
Oh, Y.S., Kim, D.G., Kim, G., Choi, E.C., Kennedy, B.K., Suh, Y., Park, B.J., Kim, S., 2010.
Downregulation of lamin A by tumor suppressor AIMP3/p18 leads to a progeroid
phenotype in mice. Aging Cell 9, 810–822.
Oksenych, V., Coin, F., 2010. The long unwinding road: XPB and XPD helicases in
damaged DNA opening. Cell Cycle 9, 90–96.
Olsen, A., Siboska, G.E., Clark, B.F., Rattan, S.I., 1999. N(6)-Furfuryladenine, kinetin,
protects against Fenton reaction-mediated oxidative damage to DNA. Biochem.
Biophys. Res. Commun. 265, 499–502.
Olsen, A., Vantipalli, M.C., Lithgow, G.J., 2006. Checkpoint proteins control survival
of the postmitotic cells in Caenorhabditis elegans. Science 312, 1381–1385.
Opresko, P.L., Cheng, W.H., von Kobbe, C., Harrigan, J.A., Bohr, V.A., 2003. Werner
syndrome and the function of the Werner protein; what they can teach us about
the molecular aging process. Carcinogenesis 24, 791–802.
Page, M.M., Stuart, J.A., 2011. Activities of DNA base excision repair enzymes
in liver and brain correlate with body mass, but not lifespan. Age (Dordr.),
doi:10.1007/s11357-011-9302-9.
Pan, X., Ye, P., Yuan, D.S., Wang, X., Bader, J.S., Boeke, J.D., 2006. A DNA integrity
network in the yeast Saccharomyces cerevisiae. Cell 124, 1069–1081.
Park, J.W., Ames, B.N., 1988. 7-Methylguanine adducts in DNA are normally present
at high levels and increase on aging: analysis by HPLC with electrochemical
detection. Proc. Natl. Acad. Sci. U.S.A. 85, 7467–7470.
Park, Y., Gerson, S.L., 2005. DNA repair defects in stem cell function and aging. Annu.
Rev. Med. 56, 495–508.
Park, P.U., Defossez, P.A., Guarente, L., 1999. Effects of mutations in DNA repair genes
on formation of ribosomal DNA circles and life span in Saccharomyces cerevisiae.
Mol. Cell. Biol. 19, 3848–3856.
Plyusnina, E.N., Shaposhnikov, M.V., Moskalev, A.A., 2011. Increase of Drosophila
melanogaster lifespan due to D-GADD45 overexpression in the nervous system.
Biogerontology 12, 211–226.
Pogribny, I.P., Shpyleva, S.I., Muskhelishvili, L., Bagnyukova, T.V., James, S.J., Beland,
F.A., 2009. Role of DNA damage and alterations in cytosine DNA methylation
in rat liver carcinogenesis induced by a methyl-deficient diet. Mutat. Res. 669,
56–62.
Preston, C.R., Flores, C., Engels, W.R., 2006. Age-dependent usage of double-strandbreak repair pathways. Curr. Biol. 16, 2009–2015.
Ramsey, M.J., Moore 2nd, D.H., Briner, J.F., Lee, D.A., Olsen, L., Senft, J.R., Tucker, J.D.,
1995. The effects of age and lifestyle factors on the accumulation of cytogenetic
damage as measured by chromosome painting. Mutat. Res. 338, 95–106.
Rao, K.S., Annapurna, V.V., Raji, N.S., Harikrishna, T., 2000. Loss of base excision repair
in aging rat neurons and its restoration by DNA polymerase beta. Mol. Brain Res.
85, 251–259.
Rassool, F.V., North, P.S., Mufti, G.J., Hickson, I.D., 2003. Constitutive DNA damage is
linked to DNA replication abnormalities in Bloom’s syndrome cells. Oncogene
22, 8749–8757.
23
Rattan, S.I., 1989. DNA damage and repair during cellular aging. Int. Rev. Cytol. 116,
47–88.
Rattan, S.I., 2001. Hormesis in biogerontology. Crit. Rev. Toxicol. 31, 663–664.
Rattan, S.I., 2008. Hormesis in aging. Ageing Res. Rev. 7, 63–78.
Reitmair, A.H., Redston, M., Cai, J.C., Chuang, T.C., Bjerknes, M., Cheng, H., Hay, K.,
Gallinger, S., Bapat, B., Mak, T.W., 1996. Spontaneous intestinal carcinomas and
skin neoplasms in Msh2-deficient mice. Cancer Res. 56, 3842–3849.
Rincon, M., Rudin, E., Barzilai, N., 2005. The insulin/IGF-1 signaling in mammals and
its relevance to human longevity. Exp. Gerontol. 40, 873–877.
Rodier, F., Campisi, J., 2011. Four faces of cellular senescence. J. Cell Biol. 192,
547–556.
Rodier, F., Coppe, J.P., Patil, C.K., Hoeijmakers, W.A., Munoz, D.P., Raza, S.R., Freund, A.,
Campeau, E., Davalos, A.R., Campisi, J., 2009. Persistent DNA damage signalling
triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol.
11, 973–979.
Rodríguez-Rodero, S., Fernández-Morera, J.L., Fernandez, A.F., Menéndez-Torre, E.,
Fraga, M.F., 2010. Epigenetic regulation of aging. Discov. Med. 52, 225–233.
Rogina, B., Helfand, S.L., 2004. Sir2 mediates longevity in the fly through a pathway
related to calorie restriction. Proc. Natl. Acad. Sci. U.S.A. 101, 15998–16003.
Rogina, B., Helfand, S.L., Frankel, S., 2002. Longevity regulation by Drosophila Rpd3
deacetylase and caloric restriction. Science 298, 1745.
Rossi, D.J., Bryder, D., Seita, J., Nussenzweig, A., Hoeijmakers, J., Weissman, I.L., 2007.
Deficiencies in DNA damage repair limit the function of haematopoietic stem
cells with age. Nature 447, 725–729.
Rube, C.E., Fricke, A., Widmann, T.A., Furst, T., Madry, H., Pfreundschuh, M., Rube, C.,
2011. Accumulation of DNA damage in hematopoietic stem and progenitor cells
during human aging. PLoS ONE 6, e17487.
Ruzankina, Y., Pinzon-Guzman, C., Asare, A., Ong, T., Pontano, L., Cotsarelis, G., Zediak,
V.P., Velez, M., Bhandoola, A., Brown, E.J., 2007. Deletion of the developmentally
essential gene ATR in adult mice leads to age-related phenotypes and stem cell
loss. Cell Stem Cell 1, 113–126.
Samuelson, A.V., Carr, C.E., Ruvkun, G., 2007. Gene activities that mediate increased
life span of C. elegans insulin-like signaling mutants. Genes Dev. 21, 2976–2994.
Sancar, A., 2003. Structure and function of DNA photolyase and cryptochrome bluelight photoreceptors. Chem. Rev. 103, 2203–2237.
Sasaki, Y.F., Matsumoto, K., Imanishi, H., Watanabe, M., Ohta, T., Shirasu, Y., Tutikawa,
K., 1990a. In vivo anticlastogenic and antimutagenic effects of tannic acid in
mice. Mutat. Res. 244, 43–47.
Saul, N., Pietsch, K., Menzel, R., Sturzenbaum, S.R., Steinberg, C.E., 2010. The longevity
effect of tannic acid in Caenorhabditis elegans: disposable soma meets hormesis.
J. Gerontol. A Biol. Sci. Med. Sci. 65, 626–635.
Scaffidi, P., Misteli, T., 2005. Reversal of the cellular phenotype in the premature aging disease Hutchinson–Gilford progeria syndrome. Nat. Med. 11,
440–445.
Schernhammer, E.S., Giovannucci, E., Kawasaki, T., Rosner, B., Fuchs, C.S., Ogino, S.,
2010. Dietary folate, alcohol and B vitamins in relation to LINE-1 hypomethylation in colon cancer. Gut 59, 794–799.
Schlotterer, A., Hamann, A., Kukudov, G., Ibrahim, Y., Heckmann, B., Bozorgmehr, F.,
Pfeiffer, M., Hutter, H., Stern, D., Du, X., Brownlee, M., Bierhaus, A., Nawroth, P.,
Morcos, M., 2010. Apurinic/apyrimidinic endonuclease 1, p53, and thioredoxin
are linked in control of aging in C. elegans. Aging Cell 9, 420–432.
Schumacher, A., 2011. Aging epigenetics. In: Tollefsbol, T. (Ed.), Handbook of Epigenetics: The New Molecular and Medical Genetics. Elsevier/Academic Press,
Amsterdam, Boston, pp. 405–425.
Schumacher, B., 2009. Transcription-blocking DNA damage in aging: a mechanism
for hormesis. Bioessays 31, 1347–1356.
Schumacher, B., van der Pluijm, I., Moorhouse, M.J., Kosteas, T., Robinson, A.R., Suh,
Y., Breit, T.M., van Steeg, H., Niedernhofer, L.J., van Ijcken, W., Bartke, A., Spindler,
S.R., Hoeijmakers, J.H., van der Horst, G.T., Garinis, G.A., 2008. Delayed and accelerated aging share common longevity assurance mechanisms. PLoS Genet. 4,
e1000161.
Selman, C., McLaren, J.S., Mayer, C., Duncan, J.S., Collins, A.R., Duthie, G.G., Redman,
P., Speakman, J.R., 2008. Lifelong alpha-tocopherol supplementation increases
the median life span of C57BL/6 mice in the cold but has only minor effects on
oxidative damage. Rejuvenation Res. 11, 83–96.
Seluanov, A., Danek, J., Hause, N., Gorbunova, V., 2007. Changes in the level and
distribution of Ku proteins during cellular senescence. DNA Repair (Amst.) 6,
1740–1748.
Seluanov, A., Mittelman, D., Pereira-Smith, O.M., Wilson, J.H., Gorbunova, V., 2004.
DNA end joining becomes less efficient and more error-prone during cellular
senescence. Proc. Natl. Acad. Sci. U.S.A. 101, 7624–7629.
Seong, K.M., Kim, C.S., Seo, S.W., Jeon, H.Y., Lee, B.S., Nam, S.Y., Yang, K.H., Kim, J.Y.,
Min, K.J., Jin, Y.W., 2011. Genome-wide analysis of low-dose irradiated male
Drosophila melanogaster with extended longevity. Biogerontology 12, 93–107.
Seviour, E.G., Lin, S.Y., 2010. The DNA damage response: balancing the scale between
cancer and ageing. Aging (Albany NY) 2, 900–907.
Shaposhnikov, M.V., Moskalev, A.A., Plyusnina, E.N., 2011. Effect of PARP-1 overexpression and pharmacological inhibition of NF-␬B on the lifespan of Drosophila
melanogaster. Adv. Gerontol. 24, 405–419.
Sharma, S.P., Kaur, J., Rattan, S.I., 1997. Increased longevity of kinetin-fed Zaprionus fruitflies is accompanied by their reduced fecundity and enhanced catalase
activity. Biochem. Mol. Biol. Int. 41, 869–875.
Silber, J.R., Blank, A., Bobola, M.S., Mueller, B.A., Kolstoe, D.D., Ojemann, G.A., Berger,
M.S., 1996. Lack of the DNA repair protein O6-methylguanine-DNA methyltransferase in histologically normal brain adjacent to primary human brain tumors.
Proc. Natl. Acad. Sci. U.S.A. 93, 6941–6946.
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001
G Model
ARR-371; No. of Pages 24
24
ARTICLE IN PRESS
A.A. Moskalev et al. / Ageing Research Reviews xxx (2012) xxx–xxx
Sinclair, D.A., Mills, K., Guarente, L., 1997. Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants. Science 277, 1313–1316.
Singh, N.P., Danner, D.B., Tice, R.R., Brant, L., Schneider, E.L., 1990. DNA damage and
repair with age in individual human lymphocytes. Mutat. Res. 237, 123–130.
Slotkin, R.K., Martienssen, R., 2007. Transposable elements and the epigenetic regulation of the genome. Nat. Rev. Genet. 8, 272–285.
Smith, E.D., Tsuchiya, M., Fox, L.A., Dang, N., Hu, D., Kerr, E.O., Johnston,
E.D., Tchao, B.N., Pak, D.N., Welton, K.L., Promislow, D.E., Thomas, J.H.,
Kaeberlein, M., Kennedy, B.K., 2008. Quantitative evidence for conserved
longevity pathways between divergent eukaryotic species. Genome Res. 18,
564–570.
St. Laurent 3rd, G., Hammell, N., McCaffrey, T.A., 2010. A LINE-1 component to human
aging: Do LINE elements exact a longevity cost for evolutionary advantage?
Mech. Ageing Dev. 131, 299–305.
Strong, R., Miller, R.A., Astle, C.M., Floyd, R.A., Flurkey, K., Hensley, K.L., Javors, M.A.,
Leeuwenburgh, C., Nelson, J.F., Ongini, E., Nadon, N.L., Warner, H.R., Harrison,
D.E., 2008. Nordihydroguaiaretic acid and aspirin increase lifespan of genetically
heterogeneous male mice. Aging Cell 7, 641–650.
Stuart, J.A., Bourque, B.M., de Souza-Pinto, N.C., Bohr, V.A., 2005. No evidence of
mitochondrial respiratory dysfunction in OGG1-null mice deficient in removal
of 8-oxodeoxyguanine from mitochondrial DNA. Free Radic. Biol. Med. 38,
737–745.
Susa, D., Mitchell, J.R., Verweij, M., van de Ven, M., Roest, H., van den Engel, S.,
Bajema, I., Mangundap, K., Ijzermans, J.N., Hoeijmakers, J.H., de Bruin, R.W., 2009.
Congenital DNA repair deficiency results in protection against renal ischemia
reperfusion injury in mice. Aging Cell 8, 192–200.
Symphorien, S., Woodruff, R.C., 2003. Effect of DNA repair on aging of transgenic
Drosophila melanogaster: I. mei-41 locus. J. Gerontol. A Biol. Sci. Med. Sci. 58,
B782–B787.
Szilárd, L., 1959. On the nature of the aging process. Proc. Natl. Acad. Sci. U.S.A. 45,
30–45.
Tacutu, R., Budovsky, A., Fraifeld, V.E., 2010. The NetAge database: a compendium of
networks for longevity, age-related diseases and associated processes. Biogerontology 11, 513–522.
Tacutu, R., Budovsky, A., Yanai, H., Fraifeld, V.E., 2011. Molecular links between
cellular senescence, longevity and age-related diseases—a systems biology perspective. Aging (Albany NY) 3, 1178–1191.
Talpaert-Borle, M., 1987. Formation, detection and repair of AP sites. Mutat. Res.
181, 45–56.
Tian, M., Shinkura, R., Shinkura, N., Alt, F.W., 2004. Growth retardation, early death,
and DNA repair defects in mice deficient for the nucleotide excision repair
enzyme XPF. Mol. Cell. Biol. 24, 1200–1205.
Tissenbaum, H.A., Guarente, L., 2001. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410, 227–230.
Toyota, M., Ahuja, N., Ohe-Toyota, M., Herman, J.G., Baylin, S.B., Issa, J.P., 1999. CpG
island methylator phenotype in colorectal cancer. Proc. Natl. Acad. Sci. U.S.A. 96,
8681–8686.
Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J.N., Rovio, A.T., Bruder, C.E.,
Bohlooly-Y., M., Gidlöf, S., Oldfors, A., Wibom, R., Törnell, J., Jacobs, H.T., Larsson,
N.G., 2004. Premature ageing in mice expressing defective mitochondrial DNA
polymerase. Nature 429, 417–423.
Trzeciak, A.R., Mohanty, J.G., Jacob, K.D., Barnes, J., Ejiogu, N., Lohani,
A., Zonderman, A.B., Rifkind, J., Evans, M.K., 2012. Oxidative damage to DNA and single strand break repair capacity: Relationship to
other measures of oxidative stress in a population cohort. Mutat. Res.,
http://dx.doi.org/10.1016/j.mrfmmm.2012.01.002.
Tsuchiya, M., Dang, N., Kerr, E.O., Hu, D., Steffen, K.K., Oakes, J.A., Kennedy, B.K.,
Kaeberlein, M., 2006. Sirtuin-independent effects of nicotinamide on lifespan
extension from calorie restriction in yeast. Aging Cell 5, 505–514.
Tyner, S.D., Venkatachalam, S., Choi, J., Jones, S., Ghebranious, N., Igelmann, H., Lu, X.,
Soron, G., Cooper, B., Brayton, C., Hee Park, S., Thompson, T., Karsenty, G., Bradley,
A., Donehower, L.A., 2002. p53 mutant mice that display early ageing-associated
phenotypes. Nature 415, 45–53.
Um, J.H., Kim, S.J., Kim, D.W., Ha, M.Y., Jang, J.H., Chung, B.S., Kang, C.D., Kim, S.H.,
2003. Tissue-specific changes of DNA repair protein Ku and mtHSP70 in aging
rats and their retardation by caloric restriction. Mech. Ageing Dev. 124, 967–975.
van de Ven, M., Andressoo, J.O., Holcomb, V.B., Hasty, P., Suh, Y., van Steeg, H., Garinis, G.A., Hoeijmakers, J.H., Mitchell, J.R., 2007. Extended longevity mechanisms
in short-lived progeroid mice: identification of a preservative stress response
associated with successful aging. Mech. Ageing Dev. 128, 58–63.
van de Ven, M., Andressoo, J.O., Holcomb, V.B., von Lindern, M., Jong, W.M., Zeeuw,
C.I., Suh, Y., Hasty, P., Hoeijmakers, J.H., van der Horst, G.T., Mitchell, J.R., 2006.
Adaptive stress response in segmental progeria resembles long-lived dwarfism
and calorie restriction in mice. PLoS Genet. 2, e192.
Vartanian, V., Lowell, B., Minko, I.G., Wood, T.G., Ceci, J.D., George, S., Ballinger, S.W.,
Corless, C.L., McCullough, A.K., Lloyd, R.S., 2006. The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase. Proc. Natl. Acad. Sci. U.S.A.
103, 1864–1869.
Vaiserman, A.M., 2011. Hormesis and epigenetics: is there a link? Ageing Res. Rev.
10, 413–421.
Venkatesan, R.N., Treuting, P.M., Fuller, E.D., Goldsby, R.E., Norwood, T.H., Gooley,
T.A., Ladiges, W.C., Preston, B.D., Loeb, L.A., 2007. Mutation at the polymerase
active site of mouse DNA polymerase delta increases genomic instability and
accelerates tumorigenesis. Mol. Cell. Biol. 27, 7669–7682.
Vijg, J., 2000. Somatic mutations and aging: a re-evaluation. Mutat. Res. 447,
117–135.
Vijg, J., Dollé, M.E., 2002. Large genome rearrangements as a primary cause of aging.
Mech. Ageing. Dev. 123, 907–915.
Vijg, J., Mullaart, E., Lohman, P.H., Knook, D.L., 1985. UV-induced unscheduled DNA
synthesis in fibroblasts of aging inbred rats. Mutat. Res. 146, 197–204.
Vogel, H., Lim, D.S., Karsenty, G., Finegold, M., Hasty, P., 1999. Deletion of Ku86
causes early onset of senescence in mice. Proc. Natl. Acad. Sci. U.S.A. 96, 10770–
10775.
Vorobtsova, I., Semenov, A., Timofeyeva, N., Kanayeva, A., Zvereva, I., 2001. An
investigation of the age-dependency of chromosome abnormalities in human
populations exposed to low-dose ionising radiation. Mech. Ageing Dev. 122,
1373–1382.
Voulgaridou, G.P., Anestopoulos, I., Franco, R., Panayiotidis, M.I., Pappa, A., 2011. DNA
damage induced by endogenous aldehydes: current state of knowledge. Mutat.
Res. 711, 13–27.
Vyjayanti, V.N., Rao, K.S., 2006. DNA double strand break repair in brain: reduced
NHEJ activity in aging rat neurons. Neurosci. Lett. 393, 18–22.
Wallace, N.A., Belancio, V.P., Deininger, P.L., 2008. L1 mobile element expression
causes multiple types of toxicity. Gene 419, 75–81.
Walter, C.A., Zhou, Z.Q., Manguino, D., Ikeno, Y., Reddick, R., Nelson, J., Intano, G., Herbert, D.C., McMahan, C.A., Hanes, M., 2001. Health span and life span in transgenic
mice with modulated DNA repair. Ann. N. Y. Acad. Sci. 928, 132–140.
Wang, J., Geiger, H., Rudolph, K.L., 2011. Immunoaging induced by hematopoietic
stem cell aging. Curr. Opin. Immunol. 23, 532–536.
Wang, X., Li, L., Wang, D., 2010. Lifespan extension in Caenorhabditis elegans by
DMSO is dependent on sir-2.1 and daf-16. Biochem. Biophys. Res. Commun.
400, 613–618.
Wang, Y.J., Ho, Y.S., Lo, M.J., Lin, J.K., 1995. Oxidative modification of DNA bases in rat
liver and lung during chemical carcinogenesis and aging. Chem. Biol. Interact.
94, 135–145.
Waters, L.S., Minesinger, B.K., Wiltrout, M.E., D’Souza, S., Woodruff, R.V., Walker,
G.C., 2009. Eukaryotic translesion polymerases and their roles and regulation in
DNA damage tolerance. Microbiol. Mol. Biol. Rev. 73, 134–154.
Weeda, G., Donker, I., de Wit, J., Morreau, H., Janssens, R., Vissers, C.J., Nigg, A.,
van Steeg, H., Bootsma, D., Hoeijmakers, J.H., 1997. Disruption of mouse ERCC1
results in a novel repair syndrome with growth failure, nuclear abnormalities
and senescence. Curr. Biol. 7, 427–439.
Wei, M., Madia, F., Longo, V.D., 2011. Studying age-dependent genomic instability
using the S. cerevisiae chronological lifespan model. J. Vis. Exp. 55, e3030.
Wei, Q., Matanoski, G.M., Farmer, E.R., Hedayati, M.A., Grossman, L., 1993. DNA repair
and aging in basal cell carcinoma: a molecular epidemiology study. Proc. Natl.
Acad. Sci. U.S.A. 90, 1614–1618.
Weinberger, M., Feng, L., Paul, A., Smith Jr., D.L., Hontz, R.D., Smith, J.S., Vujcic, M.,
Singh, K.K., Huberman, J.A., Burhans, W.C., 2007. DNA replication stress is a
determinant of chronological lifespan in budding yeast. PLoS ONE 2, e748.
Williams, G.C., 1957. Pleiotropy, natural selection, and the evolution of senescence.
Evolution 11, 398–411.
Wilson 3rd, D.M., Bohr, V.A., 2007. The mechanics of base excision repair, and its
relationship to aging and disease. DNA Repair 6, 544–559.
Wilson, V.L., Smith, R.A., Ma, S., Cutler, R.G., 1987. Genomic 5-methyldeoxycytidine
decreases with age. J. Biol. Chem. 262, 9948–9951.
Wojda, A., Witt, M., 2003. Manifestations of ageing at the cytogenetic level. J. Appl.
Genet. 44, 383–399.
Wolfson, M., Tacutu, R., Budovsky, A., Aizenberg, N., Fraifeld, V.E., 2008. MicroRNAs:
relevance to aging and age-related diseases. Open Longevity Sci. 2, 66–75.
Wu, Y., Jin, M., Liu, B., Liang, X., Yu, Y., Li, Q., Ma, X., Yao, K., Chen, K., 2011. The
association of XPC polymorphisms and tea drinking with colorectal cancer risk
in a Chinese population. Mol. Carcinog. 50, 189–198.
Xing, J., Witherspoon, D.J., Ray, D.A., Batzer, M.A., Jorde, L.B., 2007. Mobile DNA elements in primate and human evolution. Am. J. Phys. Anthropol. (Suppl.) 45,
2–19.
Xu, Y., Ashley, T., Brainerd, E.E., Bronson, R.T., Meyn, M.S., Baltimore, D., 1996.
Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev.
10, 2411–2422.
Yahata, T., Takanashi, T., Muguruma, Y., Ibrahim, A.A., Matsuzawa, H., Uno, T., Sheng,
Y., Onizuka, M., Ito, M., Kato, S., Ando, K., 2011. Accumulation of oxidative DNA
damage restricts the self-renewal capacity of human hematopoietic stem cells.
Blood 118, 2941–2950.
Yamamoto, O., Fuji, I., Yoshida, T., Cox, A.B., Lett, J.T., 1988. Age dependency of base
modification in rabbit liver DNA. J. Gerontol. 43, B132–B136.
Yanai, H., Budovsky, A., Tacutu, R., Fraifeld, V.E., 2011. Is rate of skin wound healing
associated with aging or longevity phenotype? Biogerontology 12, 591–597.
Yang, J.L., Weissman, L., Bohr, V.A., Mattson, M.P., 2008. Mitochondrial DNA damage
and repair in neurodegenerative disorders. DNA Repair (Amst.) 7, 1110–1120.
Yu, C.E., Oshima, J., Fu, Y.H., Wijsman, E.M., Hisama, F., Alisch, R., Matthews, S.,
Nakura, J., Miki, T., Ouais, S., Martin, G.M., Mulligan, J., Schellenberg, G.D., 1996.
Positional cloning of the Werner’s syndrome gene. Science 272, 258–262.
Zainullin, V.G., Moskalev, A.A., 2000. The role of genetic instability in cell aging.
Genetika 36, 1013–1016.
Zhang, Y., Zhang, L., Bai, J., Ge, H., Liu, P., 2010. Expression changes in DNA
repair enzymes and mitochondrial DNA damage in aging rat lens. Mol. Vis. 16,
1754–1763.
Please cite this article in press as: Moskalev, A.A., et al., The role of DNA damage and repair in aging through the prism of Koch-like criteria.
Ageing Res. Rev. (2012), doi:10.1016/j.arr.2012.02.001