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Accepted Manuscript

Title: DNA, the central molecule of aging

Author: Peter Lenart Lumir Krejci

PII: S0027-5107(16)30007-0
DOI: http://dx.doi.org/doi:10.1016/j.mrfmmm.2016.01.007
Reference: MUT 11531

To appear in: Mutation Research

Received date: 17-12-2015


Revised date: 16-1-2016
Accepted date: 30-1-2016

Please cite this article as: Peter Lenart, Lumir Krejci, DNA, the central molecule of
aging, Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
http://dx.doi.org/10.1016/j.mrfmmm.2016.01.007

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Journal Name, Year, Volume 1

Title: DNA, the Central Molecule of Aging

Peter Lenart1 and Lumir Krejci*1,2,3

1
Department of Biology, Masaryk University, Brno, Czech Republic; 2International Clinical
Research Center, Center for Biomolecular and Cellular Engineering, St. Anne’s University Hospital
Brno, Brno, Czech Republic; 3National Centre for Biomolecular Research, Masaryk University,
Brno, Czech Republic
Abstract: Understanding the molecular mechanism of aging could have enormous medical
implications. Despite a century of research, however, there is no universally accepted
theory regarding the molecular basis of aging. On the other hand, there is plentiful evidence
suggesting that DNA constitutes the central molecule in this process. Here, we review the
roles of chromatin structure, DNA damage, and shortening of telomeres in aging and
propose a hypothesis for how their interplay leads to aging phenotypes.
Keywords: DNA; aging; chromatin structure, telomeres; DNA damage, DNA repair; mutagenesis

1. INTRODUCTION

Aging is a complex biological process resulting in the decline of almost all physiological functions,
which in turn leads to a time-dependent increase in mortality. Many theories have tried to explain the
aging process, but none is universally accepted [1, 2]. Although many biomolecules could play a role in
aging, DNA seems to be the most relevant. This is supported by several arguments. First, syndromes of
accelerated aging are often associated with defects in DNA repair genes [3, 4]. Second, changes of
chromatin structure, shortening of telomeres and accumulation of DNA damage are all associated with
aging and life span [5-9]. These chromosomal changes do not act in isolation but are rather tightly
interconnected. Changes of chromatin structure can accelerate shortening of telomeres [10] alter
susceptibility to DNA damage [11] and modify transcription [12] thus influencing almost all cellular
functions. Vice versa, DNA damage can lead to changes of chromatin structure [13] and accelerate
telomere shortening [14]. Here we review how these three types of chromosomal changes and their
interplay influence the aging process.
1.1. Chromatin Structure
Chromatin is a nucleoprotein complex that can be understood as a dynamic, three-dimensional, higher-
order structural state of a chromosome. The basic unit of chromatin is a nucleosome consisting of four
pairs of core histones (H2A, H2B, H3, H4) around which 147 bases of DNA are wrapped [15]. Higher-
order chromatin structure is also formed by linker H1 histone and other non-histone proteins. There exists
two basic types of chromatin: highly condensed heterochromatin or loosly condensed euchromatin,
characterized by typically transcriptional inactivity and resistance to DNA damage or transcriptional
activity and susceptibility to DNA damage, respectively [11].
*Address correspondence to this author at the Department of Biology, Faculty of Medicine, Masaryk
University, Kamenice 5/A7, Brno 62500, Czech Republic, Telephone: +420-549-493-767; Fax:
+420-549-492-556; E-mail: lkrejci@chemi.muni.cz
Therefore, it is not surprising that several studies have shown depletion of core histones to be associated
with aging. In yeast, histone concentration decreases with age and seems to be directly related to aging,
since their overexpression leads to a 65 % increase in replicative life span [8]. The possible mechanism
might be changes in transcription, as loss of nucleosome in yeast was reported to cause globally increased
gene expression [16]. In addition, decreases in H3 and H4 histone levels also have been observed in
human senescent fibroblasts, where their concentrations were reported as reduced by half compared to
2 Journal Name, 2015, Vol. 0, No. 0 Lenart and Krejci

levels in young cells [5, 17]. Although synthesis of new histones diminishes with age, it is notable that
their expression actually increases [18]. Even as cells are trying to stabilize histone levels, therefore, this
might be counteracted by an increased rate of mRNA degradation or increasingly ineffective translation. It
would therefore be interesting to test whether overexpression of histones would extend the life span of
human cells.
Chromatin structure can be altered not only by changes in the number of histones but also by their post-
translational modifications. More than 60 modification sites have been identified on histones, which,
together with the 8 basic types of modifications, means the number of specific modifications (type and
position) is immense. Histone modifications are known to play important roles in regulation of many
cellular processes such as replication, transcription, and DNA repair [19], and so it is not surprising that
types and amounts of modifications change with age. For instance, acetylation of lysine 16 on histone 4
(H4K16ac) increases with age in yeast [5, 20]. Other examples include increases in H3K9ac and
reductions in H3K56ac [5]. Acetylation in general removes positive charge from lysine and could be
expected to weaken the binding of DNA to histone and, in turn, make chromatin structure looser. Indeed,
H4K16ac has been implicated in determining chromatin structure and influencing the interaction between
non-histone proteins and chromatin [21, 22]. In addition, the dynamic status of the modification plays an
important role, as Sir2, the main deacetylase regulating this modification, is also known to extend life
span in several invertebrates such as Saccharomyces cerevisiae [23], Caenorhabditis elegans [24], and
Drosophila melanogaster [25]. It is not clear, however, if SIRT1, the human Sir2 orthologue [26, 27], can
extend life span in mammals, since overexpressing SIRT1 in all mouse tissues was shown to have no life-
extending effects despite its having a positive effect on several pathologies associated with aging [28].
Surprisingly, another study overexpressing SIRT1 in mouse brains reported 11 % elongation of life span
[29]. It can therefore be speculated that SIRT1 is beneficial to life span only in certain tissues or only at
low concentrations.
Strong evidence for a connection of histone acetylation with chromatin maintenance and aging can be
seen in the effect of the polyamine known as spermidine on life span and aging. In general, polyamines
are associated with cell growth [30], their depletion inhibits apoptosis [31], and they are also implicated in
carcinogenesis inasmuch as their concentrations are elevated in cancer cells [32]. In addition, it has been
shown that yeast as well as mammalian cells synthesize less polyamines with age. Eisenberg et al. have
shown that spermidine supplementation extends life span in yeast, nematodes, flies, mice, and also human
cells and that this effect is accompanied by hypoacetylation of H3K9, H3K14 and H3K18. Accordingly,
inactivation of acetyltransferases responsible for acetylation of these lysines also extended the life span of
yeast and decreased the effect of spermidine treatment [33].
Histones modification by methylation of their lysine or arginine residues plays also important role. In
contrast to the histone acetylation, methylation can be associated with either active or repressed
transcription, depending on the affected residue [34]. While trimethylation of lysine 4 on histone 3 is
associated with active transcription [35], trimethlyation of lysine 27 on the same histone is associated with
repressed transcription [34]. Both of these modifications are linked to aging. In human senescent
fibroblasts H3K4me3 is enriched and occupies new parts of genome [36]. Spreading of H3K4me3 during
aging has bean also observed in mouse hematopoietic stem cells [37]. The most direct evidence of role of
H3K4me3 in aging comes from C. elegans, where overexpression of RBR-2, the H3K4me3 demethylase,
increase life span, while its knockdown has opposite effect. Furthermore knockdown or mutation of genes
encoding H3K4 methyltransferases increases life span [38]. In contrast to H3K4me3 mark, H3K27me3
decreases during aging and knockdown of UTX-1, H3K27me3 demethylase extends life span of C.
elegans [39]. However, role of H3K27me3 in aging is not as clear, as experiments in D. melanogaster
have shown that mutation in H3K27-specific methyltransferase E(Z) increases life span of flies and reduce
amount of H3K27me3 [40].
Other histone modifications are less characterized, but may nevertheless influence aging. For example
low levels of ubiquitination of H2B were found to be necessary for yeast cells to attain normal life span
possibly trough regulating Sir2 recruitment [41].
DNA methylation is also relevant in determining chromatin structure [42, 43] and regulating gene
expression [44]. Changes in methylation are typical for cancer cells, but similar changes have been
observed also in senescent cells [45–47]. Aging cells exhibit global hypomethylation and local
hypermethylation. While hypomethylation is typical for noncoding parts of the genome, sequences near
the promotors of several genes regulating the cell cycle are often hypermethylated [48]. Several authors
DNA, central molecule of aging. Journal Name, 2015, Vol. 0, No. 0 3

have been able recently to use methylation patterns to successfully predict the age of several different
tissues, mostly by analyzing methylation of different CpG sites as an aging clock [49–51]. Furthermore,
the methylation patterns of genomic DNA were also shown to predict mortality regardless of current
health status, life style, and known genetic predispositions [52], thus suggesting a direct relationship
between DNA methylation and aging. A causal role of DNA methylation in aging is also suggested by the
ability of methionine restriction – a well-known dietary intervention – to prolong the life span of various
model organisms [53–56] and human fibroblast [57]. It is expected that this is due to methionine’s serving
as a substrate for methyl-transferases and thus affecting the methylation state [58].
1.2. Telomeres Shortening
Telomeres are nucleoprotein complexes protecting coding sequences from replicative shortening of
chromosomes. Telomeric DNA consists of a G-rich repetitive sequence (TTAGGG in mammals) bound
by numerous proteins forming a shelterin complex which also blocks these ends from being recognized as
DNA double-strand breaks (DSBs) [59]. Telomeres progressively shorten after each cell division, limiting
the number of divisions of somatic cells. They can be extended by a special enzyme termed telomerase,
which in humans is active mostly in embryonic stem cells [60]. Telomeres and telomerase have long been
implicated in the aging process, as introduction of telomerase to cells in vitro is able to postpone
senescence and promote immortalization [6]. It was later proven that transient telomerase expression did
extend the life span of human cells, but this did not result in their immortalization [61]. This led to the
hypothesis that telomere shortening is the primary cause of aging and sparked many studies analyzing the
impact of telomere length on human health.
The first studies defining the role of telomeres in aging of mammals involved mice with knock-out of
the genes necessary for telomerase synthesis (Terc or Tert genes). Surprisingly, first-generation mice from
these knock-out lines are healthy with no significant changes in phenotype [62, 63], thus indicating that
telomerase is not necessary for life and that a lack of phenotype might be due to residual telomerase
activity in the organism. Accordingly, the phenotype should be more visible in future generations. Indeed,
from the third generation onward these mice have significantly shorter telomeres, decreased fertility,
overall frailty, and atrophy of tissues leading to organ malfunctions [64]. Aging is exacerbated in mice
defective for the WRN helicase, mutated in Werner syndrome and responsible for telomere maintenance
[65, 66]. This is interesting since Werner syndrome is a well-known progeria in humans showing an
interaction with different genome maintenance mechanisms [67].
Telomerase is often expressed in cancer cells, since it can allow unrestricted proliferation, and it is
therefore not surprising that classical transgenesis increases the incidence of cancer [68–70]. Nevertheless,
overexpression of telomerase in mice genetically modified to be more resistant to cancer by increased
expression of tumor-suppressor genes led to slower aging and increase in median life span by 40 % [71].
Additionally, cancer incidence is not increased if the telomerase is transduced into adult mice and
transduction of telomerase into 1-year-old mice extended their life by 24 % [72].
While the aforementioned findings clearly demonstrate that telomere shortening and accordingly
telomerase activity influence aging, the results of comparative studies show that telomere shortening is
almost certainly not the primary cause of aging. For example, a study comparing telomerase activity in
different rodents found no correlation between this enzyme’s activity and rodent life span. On the other
hand, a significant negative correlation with body weight was observed and suggests a possible cancer-
protective strategy of organisms [73]. An identical relationship between telomerase activity and body
weight was also observed in a study comparing more than 60 mammalian species [74]. Interestingly, a
negative correlation between telomere length and life span was found. On the other hand, telomere length
can be used to predict the life span of individual zebra finches [75]. Although this seemingly contradictory
data could be used to argue that telomeres are rather downstream effectors of aging, in species that
evolved to use their proliferation-limiting potential as a protection mechanism against cancer their
telomere shortening speed can determine individual life span.
Studies in humans analyzing the relationship between telomere length and health and mortality have
led to findings no less interesting. The initial study analyzing 143 subjects older than 60 showed a strong
correlation between shorter telomeres in leukocytes from periphery blood and increased mortality [76].
This result was not confirmed, however, by more recent studies involving considerably larger cohorts.
While a study on a cohort of 3,075 healthy men and women aged 70–79 found no significant correlation
between telomere length and mortality, it did show a correlation between telomere length and years of
healthy life span [77]. Short telomeres were also associated with risks of many illnesses such as various
types of cancer [78], renal dysfunction [79], autism [80], mortality from cancer in patients with chronic
obstructive pulmonary disease [81], and many others. In principle, however, this kind of study is only
correlative and cannot prove a causal relationship. The situation is also complicated by the fact that longer
telomeres were also associated with risks of deadly diseases. While one study found a correlation between
4 Journal Name, 2015, Vol. 0, No. 0 Lenart and Krejci

long telomeres and a risk of lung cancer in never-smoking women [82], another associated longer
telomeres with susceptibility to colorectal carcinoma [83]. Telomere length greater than average was also
correlated with a risk of breast cancer [84]. This brief overview illustrates that within the current state of
knowledge it remains very difficult or even impossible to objectively evaluate the influence of telomere
length on human health. Therefore, a large meta-analysis is needed that could provide more clear
evidence.
1.3. DNA Damage
As a consequence of endogenous or exogenous influences, the chemical structure of DNA can be
altered or lead to breakage of one or both DNA strands. A causal role of DNA damage in aging is strongly
suggested by its role in progeria syndromes [3] as well as other indications. One of these is that many life-
span-extending strategies lead to enhanced DNA repair or decreased DNA damage. For example, caloric
restriction, the oldest known intervention able to prolong life span, has been reported to decrease age-
related decline of base excision repair (BER) [85], nucleotide excision repair [86], and non-homologous
end joining [87]. It also increases expression of SIRT1 [88, 89], which enhances function of homologous
recombination [90]. Furthermore the mTOR inhibitor, rapamycin was shown in mice to increase life span
[91] and reduce DNA damage and cancer in skin exposed to a DNA damaging agent [92].
DNA adducts are a common type of DNA damage. Formation of DNA adducts is caused mainly by
reactive-oxygen species, with 8-oxoguanine (8-oxoG) being commonly used as a marker of oxidative
stress [93]. Current data suggest that DNA adducts do not play an important role in aging since even a 20-
fold increase in 8-oxoG levels in mice did not result in visibly accelerated aging [94]. Another frequent
type of DNA damage involves apurinic/apyrimidinic-sites (AP sites), which arise from spontaneous
depurination or through repair of modified bases via BER. Creation of AP sites eventually leads to base
replacements, frame shift mutations and DNA breaks, and accumulation of AP sites with age is supported
by their 7-fold increase in leukocytes from old donors when compared to young donors [95]. In addition,
BER is required for yeast to attain a full chronological life span [96], supporting its role in aging. Single-
strand breaks (SSBs) are the most common type of DNA damage, with more than 10,000 lesions arising
per cell per day [97]. This important type of DNA damage is probably not connected to aging, however,
since studies analyzing SSBs in mice have found no age-dependent derivation in SSB levels [98, 99].
DSBs are the most dangerous type of damage and arguably are also the most associated with aging.
Unrepaired or incorrectly repaired DSBs can lead to loss of a part of a chromosome or to gross
chromosomal reengagements and genomic instability, which processes are linked with many diseases
including those related to advanced age and DSB repair defects can lead to early aging in mice [100].
DSBs increases with age both in vitro and in vivo [101, 7], as does the time within which cells respond to
DSBs, thus indicating the gradual loss of DNA repair efficiency [102]. Accordingly, it was recently shown
that inducing DSBs in mice livers by expression of the restriction enzyme Sac1 accelerated this organ’s
aging [9].
DNA damage response (DDR) is a mechanism by which cells sense damage and trigger corresponding
repair. This response includes modification of histones near the damage site. Specifically, H2AX histones
are phosphorylated (γ–H2AX) [103–105]. These changes can span as many as even several megabases
from the DSBs [106] and as a consequence can also inhibit transcription [107, 108]. However,
heterochromatin, which is also induced by aging, limits DDR [109, 110], and this can be attributed to an
inability of cells to recognize DNA damage. Such assumption has been challenged, however, since γ–
H2AX can be generated successfully even in the very dense structure of mitotic chromosomes [111].
Another possible explanation might be that this reflects changes in chromatin structure rather than
recognition of DNA damage itself by DNA repair proteins [112, 113].

A variety of other chromatin modifications also accumulate at sites of DNA damage. Very important is
ubiquitination of H2A and H2B that further stimulates cell response to DNA damage [114, 115]. These
modifications not only play a role in DNA repair but also influence transcription both locally and globally,
and many changes in transcription caused by DNA damage are transitional [116]. In some cases, however,
inability to restore a normal chromatin structure after DNA repair can significantly deregulate
transcription. One such example is delocalization of the histone deacetylase SIRT1. In response to DNA
damage, SIRT1 binds to the damaged site. There, it plays a role in repair, although this leads to its
deficiency in other parts of the genome and the depression of SIRT1 regulated genes [13]. This process is
similar to changes observed in aging and it seems to be evolutionarily conserved inasmuch as binding of
SIR proteins to DNA damage sites also leads to their depression in other parts of the genome and
manifestation of an aging phenotype [117].
DNA, central molecule of aging. Journal Name, 2015, Vol. 0, No. 0 5

Other proteins, too, are implicated in DNA repair and chromatin structure that also regulate life span.
Both SIRT1 and yeast Sir2 have important roles in DDR, for example, as they bind to the DNA damage
site and there deacetylate several proteins involved in DNA repair and stimulate their activity [118]. DSB
repair leads to acetylation of the N-terminal lysines of histones H3 and H4 [117]. This is very intriguing
with regard to aging because, as mentioned above, hypoacetylation of the N-terminal lysines of histones is
at least partially responsible for the life-extending effects of spermidine [33]. Sirtuins also play an
important role in maintaining heterochromatin on repetitive sequences of rDNA and telomeres and
prevent aberrant recombination between these repetitive sequences [90, 119]. As would be expected, mice
with inactive SIRT6 have increased genomic instability and show accelerated aging [120]. In addition,
overexpression of pch-2, which modulates meiotic recombination and helps to maintain ribosomal DNA
stability [121] was recently shown to extend the life span of C. elegans and increase resistance to multiple
stressors, thereby affecting both DNA and protein integrity. Furthermore, even though the effect of pch-2
modulation is sir-2 independent, the same authors propose a mechanism of pch-2 and sir-2 interaction
leading to life extension [122]. In addition, deletion of Exo1, nuclease involved in mismatch repair and
recombination, is able to prolong the life span of telomere-dysfunctional mice, possibly by impairing
DNA damage signals at DNA breaks [123].
Mutations arise as a consequence of nonfunctional DNA repair or mistakes during replication.
Mutations were first mentioned as the primary cause of aging in the middle of the 20th century [124, 125].
It was nevertheless impossible for decades directly to compare mutation rate in differently aged cells.
Finally, several studies showed that mutations are indeed accumulating with age and reflect the
proliferative capacity of tissues [126–128]. Despite this, small mutations that result from improper repair
of base lesions, base mismatches or indels are unlikely to constitute one of the primary causes of aging
since transgenic mice with defects in mismatch repair [129] or antioxidant defense [130] exhibit an
increase in spontaneous mutation rate, but do not shown any signs of accelerated aging apart from
increased cancer incidence. Similarly mice, with defective transcription-coupled repair exhibited early
ageing without an increase in mutation frequency [131]. A recent study also confirmed that aging in S.
cerevisiae is not caused by an increase in small mutations, since old yeast cells with few or no mutations
were dying even though young cells mutated in eight thiol peroxidases, which are enzymes detoxifying
hydroperoxides, had twice as many mutations and continued dividing [132]. By contrast, defective repair
of DNA DSBs could accelerate aging since mutations in multiple DSB repair genes leads to early aging in
mice and people and since chromosomal abnormalities correlate with age [100]. Thus, the accumulation of
chromosomal rearrangements might be a good indicator for some age-associated pathologies, such as
cancer.
Conclusion
It is unlikely for such a complex process as aging to be driven just by one specific kind of disturbance.
Accordingly, we suggest that aging is caused by the interplay of several types of damage. Even though their
relationship may form complex network which is yet to be fully understood, we believe that there is already a
traceable pattern suggesting a possible order of their interaction (Fig. 1).
We propose that DNA damage serves as trigger of aging. Accumulation of DNA damage, mainly DSBs,
leads to chromatin modifications and chromatin’s loosening, which in turn makes chromatin more prone to
additional DNA damage. These changes of chromatin structure then affect transcription, and accelerate
telomere shortening. Faster telomere shortening may then lead to quicker depletion of stem cells in organisms
thus reducing regenerative capacity of tissues. In addition, we suggest that changes in transcription can lead to
age-related decrease in physiological functions, since cells with progressively more deregulated transcription
can scarcely maintain optimal biological function. Moreover, this notion is strongly supported by fact that
changing levels of specific histone modification also influences life span. Finally, unrepaired or incorrectly
repaired DNA damage can also lead to mutations, and these can inversely affect all the aforementioned
processes. Even though accumulation of small mutations probably does not play a causal role in aging, it can
influence any of the individual processes and thus manifest some age-related pathologies, and especially
increased incidence of cancer. The accumulation of chromosomal rearrangements could impact aging by
directly impairing cell homeostasis or inducing cell senescence. Most importantly, this model indicates not
only the possible importance of these processes individually but in particular their combination that eventually
leads to aging. It might be this combination that gives to the entire process the complexity that would lead to a
determination of direct causality.
Nevertheless, it can be expected that future research in this area will shed more light on how changes
relating to the DNA molecule affect the aging process. A better understanding of the mechanism will enable us
6 Journal Name, 2015, Vol. 0, No. 0 Lenart and Krejci

to identify appropriate targets for intervention, generate new compounds, and develop new strategies to
counteract aging phenotypes. Furthermore, it could be expected that aging research will continue to capture the
attention of an ever-increasing number of scientists, since mathematical models clearly demonstrate that to
delay aging will have enormous health and economic benefits greatly outweighing the potential benefits of
separately addressing heart disease or cancer [133].

Conflict Of Interest
The authors declare no conflict of interest.

Acknowledgements
This work was supported by Czech Science Foundation grants GACR13-26629S and
GACR207/12/2323, European Regional Development Fund [Project FNUSA-ICRC, no.
CZ.1.05/1.1.00/02.0123] and Research Support Programme [GAMU] - MUNI/M/1894/2014.

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DNA, central molecule of aging. Journal Name, 2015, Vol. 0, No. 0 13

Fig. (1). Interaction between different types of molecular damage and their relationship to aging. DNA damage arises as a
consequence of intrinsic or extrinsic influences and when not repaired correctly can lead to mutations. Mutations alone probably do not play a
causal role in aging, but they can lead to other biological changes and pathologies, including cancer development. On the other hand, the
actual repair process leads to changes in chromatin structure, which can, in turn, make chromatin structure more prone to additional DNA
damage. The main result of changes in chromatin structure, however, is deregulation of transcription, which may result in modification of
tissue-specific expression patterns and thereby decrease the biological functions of tissues and lead to accelerated aging. Deregulated
transcription can also impair DNA damage response machinery and chromatin structure maintenance, because specific expression profiles are
needed for these processes to ensure maximum efficiency. Most importantly, it is not the effect of these individual processes alone, but rather
their combination that might result in the aging phenotype.