ISSN 0006-2979, Biochemistry (Moscow), 2023, Vol. 88, No. 11, pp. 1704-1718 © The Author(s) 2023. This article is an open access publication.
Published in Russian in Biokhimiya, 2023, Vol. 88, No. 11, pp. 2066-2083.
1704
REVIEW
Olovnikov, Telomeres, and Telomerase.
Is It Possible to Prolong a Healthy Life?
Yegor E. Yegorov
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
e-mail: yegorov58@gmail.com
Received July 20, 2023
Revised August 29, 2023
Accepted August 31, 2023
Abstract— The science of telomeres and telomerase has made tremendous progress in recent decades. In this review, we
consider it first in a historical context (the Carrel–Hayflick–Olovnikov–Blackburn chain of discoveries) and then review
current knowledge on the telomere structure and dynamics in norm and pathology. Central to the review are consequences
of the telomere shortening, including telomere position effects, DNA damage signaling, and increased genetic instability.
Cell senescence and role of telomere length in its development are discussed separately. Therapeutic aspects and risks of
telomere lengthening methods including use of telomerase and other approaches are also discussed.
DOI: 10.1134/S0006297923110032
Keywords: telomeres, telomerase, aging, carcinogenesis, Olovnikov, telomere crisis, cell senescence, inflammatory aging,
genetic instability
HISTORICAL INTRODUCTION
The end regions of chromosomes visible in a light
microscope have been termed by cytologists telomeres.
These are very large structures covering regions of mil-
lions of DNA base pairs. Descriptions of telomeres as
special structures that ensure integrity of chromosomes
first appeared in the Muller’s work performed on the
Drosophila chromosomes in 1938 [1], and in the works
of McClintock performed on the maize chromosomes
in 1938-1941 [2-4]. The essence of these early observa-
tions is that a broken chromosome remains unstable un-
til it acquires a new telomere either by recombination or
de novo. Modern biologists consider the much smaller
end regions of chromosomes, thousands of nucleotide
pairs long, as telomeres.
Although the idea that the ends of linear chromo-
some require special stabilization has been recognized
by the scientific community, it had not been especially
fruitful until it was connected to the cell senescence and
cell immortalization.
Back in the 19th century, after numerous proofs of
cell theory, it became clear that there are mortal and
immortal cells in multicellular organisms, including hu-
mans. Immortal cells must exist because living organ-
isms, being the product of long evolution, are still alive.
At the same time, our cells die, including via pro-
grammed death. Early experiments on the cell cultiva-
tion pointed to the potential immortality of cells. Ex-
periments on serial transplantation of tumor cells in
peritoneal cavities of rats (end of the XIX century) [5],
then the famous experiment of Alexis Carrel, when
chicken cells were continuously multiplied for 30 years,
created a false belief that all cells are immortal [6].
Retrospectively, we realize that experiments demon-
strating cell death in culture are of little informative
value. Such result can always be attributed to a technical
error. A prime example is the hard-won published paper
by Leonard Hayflick, who claimed that “in our hands,
cells are not capable of infinite division” [7]. Future
Nobel laureate Peyton Rous wrote just one word as a
review – “nonsense” [8]. Nevertheless, the “Hayflick
limit” turned out to be real, and the term became gen-
erally accepted.
The main reason for persistence of the view that
cultured cells are immortal was Carrel’s reputation.
Author of the idea of making organs from the patient
cells to avoid rejection (even before the discovery of
blood groups), author of the vascular suture (Nobel Prize
in1912), inventor of masses of devices for transplantation
and sterile work– he was extremely authoritative. Infact,
he developed technology for primary surgical wound
care during World War I, saving thousands of lives.
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At the same time, he was the man who proposed “ahu-
mane and economical way of disposing of inferior hu-
man beings in gas chambers” (“should be humanely and
economically disposed of in small euthanasic institutions
supplied with proper gases”), which was realized already
during the Second World War. After 1945 in 20French
cities streets named after Carrel were renamed back.
TheFrench disliked very much those who collaborated
with the Nazis [9-11].
Limited proliferative capacity of cells found in the
Hayflick’s experiments had to be explained. After the
mechanisms of DNA replication became clear in gener-
al terms, a hypothesis on the mechanism of functioning
of a cell division counter was suggested. In 1971, Alexey
Olovnikov proposed the “principle of marginotomy in
template synthesis of polynucleotides”, which claims
that DNA polymerase is unable to fully replicate a lin-
ear template; the replica is always shorter in its initial
part [12]. Gradual shortening of DNA (underreplication)
limits proliferative potential of the cells and can serve as
the basis of the cell division counter in the Hayflick’s
experiments. In the same work it was postulated that
immortal cells should possess an enzyme that completes
chromosome ends.
This enzyme, later called telomerase, was first dis-
covered in 1985 in the protozoan cells [13]. At that time,
the authors thought that the enzyme they found in infu-
soria cells was necessary only for replication of the spe-
cial telomeres of this protozoan. Later they (Nobel lau-
reates Elizabeth Blackburn and Carol Greider) recalled:
“We did not know about Olovnikov’s ideas until 1988,
when Calvin Harley told Greider about them. Intrigued,
Greider, Harley, and their colleagues decided to find
out if the chromosome shortening in human cells occurs
over time.” [14].
The very next year, 1989, telomerase was detected
in human cells and the length of human telomeres was
found to change during development. A year later, telo-
mere shortening during the cell aging was revealed. In
1998, it was proved that telomerase expression induced
by gene insertion leads to cell immortalization.
In addition to Olovnikov’s visionary articles of 1971
and 1973, several of his other important works should
be mentioned. A few months ago, Alexei Matveyevich
passed away, and in writing the historical part of the re-
view, I would like to touch on some of his hypotheses,
both confirmed and not confirmed.
First, few people remember that Olovnikov suggest-
ed that in addition to underreplication, underrepair may
also lead to telomere shortening [15, 16]. Indeed, it was
subsequently found that telomeres shorten at different
rates (per division) depending on the conditions of cell
cultivation [17,18]. Thus, telomere shortening turns not
into a simple division count, but into a total index that
takes into account various factors, including oxidative
stress conditions.
Second, around the millennium boundary,
Olovnikov hypothesized existence of perichromosomal
particles, which are copies of chromosome segments[19].
It was assumed that transcription of these particles yields
some short RNAs controlling many processes related to
spatial and temporal regulation of genes and chromatin
rearrangement. The terms were introduced: redusomes,
chronomers, printomers, fountain RNA, etc. This hy-
pothesis is still waiting for its confirmation. TERRA
(TElomeric Repeat-containing RNAs) could be consid-
ered as distant analogs of such particles (see below).
It should be noted that scientific events related to
the study of cellular immortality have gained wide pub-
licity due to their intensive coverage by the mass me-
dia. The author of this article learned about the noto-
rious 50 divisions that human cells are capable of from
the popular in USSR weekly review of the foreign press
“Za rubezhom (Abroad)”. The term “Hayflick limit”
has entered the encyclopedias. Unlike the Hayflick
and Carrel works, Olovnikov’s work was little known,
also due to the relative isolation of Soviet science from
the world. Only translation of the Olovnikov’s paper
published in Russian in 1971 into English (2 years lat-
er) [20], made it possible to acquaint the world com-
munity with it. And it received a well-deserved recog-
nition 15 years later, leading to an explosive growth in
the number of papers on the role of telomeres in aging
all over the world and, as a result, to the Nobel Prize,
but not to A.M. Olovnikov.
TELOMERS
Telomeres are the ends of chromosomes, and
they must be packaged so that the repair systems do
not confuse them with the double-stranded breaks in
DNA. This is achieved through the ability of telomere
sequences to fold in a special way and through special-
ized proteins that protect these “breaks.” In humans
and all vertebrates, telomeric DNA is represented by the
5′-(TTAGGG)
n
-3′ sequence [21]. At the ends of human
telomeres, there are single-stranded 3′ regions about
100-150 nucleotides long [22] (Fig.1).
This single-stranded region is present both in the
cells with and without telomerase, so it cannot be ex-
plained by telomerase activity. Presence of this free
3′-end is a direct consequence of underreplication of
the end, namely, removal of the 5′-end RNA primer on
the opposite strand and its inability to be filled by DNA
polymerase during replication.
As the structure suggests, this single-stranded site
contains repetitive clusters of three guanines (GGG).
Calculations show that this sequence easily forms non-ca-
nonical structures (triplexes, quadruplexes). G-4 struc-
tures (quadruplexes) can be intramolecular, bimolecular,
and even tetramolecular, i.e., connecting 4DNA strands.
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Fig. 1. A simplified scheme of telomere organization.
The strands in them can be parallel and antiparallel. It is
believed that at least 12 guanines are required to form a
quadruplex [23].
There is an alternative, more widely accepted mod-
el of the behavior of the single-stranded 3′-end of DNA.
The results of experiments of De Lange and coworkers
allowed to propose a telomere model based on the telo-
meric loop [24]. According to it, the single-stranded
end together with the proteins interacts with the dou-
ble helix of telomeric DNA. Thus, a telomeric loop is
formed. Length of this loop correlates with the length of
the telomeric repeat measured by independent methods.
Six proteins present in telomeres form a complex
called shelterin. Two proteins (TRF1 and TRF2) bind
the double-stranded regions of telomeric DNA, two
proteins (POT1 and TPP1) bind the single-stranded
DNA, and two more proteins (TIN2 and Pap1) have no
(at least in humans) DNA-binding sites [25, 26] (Fig.1).
Despite the fact that the telomeric regions of DNA
are devoid of protein-coding sequences, they are tran-
scribed. A long noncoding RNA TERRA (TElomeric
Repeat-containing RNA) is formed [27, 28]. TERRA
expression is initiated in subtelomeric regions [29].
Thus, it contains subtelomeric sequences at the 5′-end
and telomeric UUAGGG repeats at the 3′-end [30].
Various events leading to the changes in TERRA ex-
pression are strongly associated with the telomere length
[31, 32]. For example, TERRA expression is highly sen-
sitive to stress [33,34] and depends on epigenetic chang-
es in subtelomeric regions [35]. Interestingly, TERRA is
abundantly detected as part of plasma exosomes and is
able to modulate the inflammatory response [36]. Also,
TERRA expression is altered in Hutchinson–Gilford
progeria [37]. Overall, however, a clear picture of TERRA
function has not yet emerged. It is obvious that TERRA
expression affects numerous heterogeneous cellular
responses, including telomere maintenance, chroma-
tin state, stress response, and inflammation induction.
Involvement of TERRA in carcinogenesis is being inten-
sively studied. Recent articles [38-42] on this subject
can be recommended to the reader.
TELOMERASE
Telomerase is a reverse transcriptase with an in-
tegrated RNA template for telomeric repeat synthe-
sis. The enzyme is based on the protein part of human
telomerase reverse transcriptase (hTERT) and the RNA
component (hTERC). A small part of hTERC contains
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Fig. 2. Partial interactome in hTERT regulation (from [49] with permission).
a template for telomeric DNA synthesis [43]. The en-
zyme works as a large complex with molecular mass
of about 0.5 × 10
6
Da. The complex includes hTERT,
hTERC, dyskerin, TCAB1, as well as temporally asso-
ciated proteins pontin, reptin, and chaperones HSP90
and TRiC [44].
As predicted in the Olovnikov’s hypothesis, telo-
merase is expressed in germ, stem, and cancer cells.
Inthe latter case, activation of hTERT, which is prac-
tically absent in normal somatic cells, is observed. In a
relatively small percentage of cases (depending on the
tissue origin of cancer), cancer cells activate an alterna-
tive mechanism of telomere maintenance (ALT) based
on recombination.
The rate-limiting component of telomerase func-
tioning in humans is the hTERT protein. The hTERT
gene has a total length of about 37 kb and consists of
16 exons and 15 introns. In humans, 20 hTERT splicing
variants have been described [45], some of which strong-
ly influence telomerase activity [46]. Splicing of hTERT
changes not only during development, but also during
carcinogenesis [47].
Another level of regulating telomerase activity is
transcriptional. The hTERT promoter contains many
transcription factors binding sites. Among the most
studied regulators are c-Myc, estrogen receptor, HIF-1,
NF-B, Menin, STAT3/5, MAD1, ETS, Sp1/3, USF,
NFX1, etc. [48]. Presence of the sites for numerous ac-
tivators and repressors suggests a very complex system
of gene expression regulation (Fig.2).
In addition to transcription and splicing, regula-
tion of telomerase activity can occur through posttrans-
lational modifications, including phosphorylation [50].
The ability of telomerase to elongate telomeres also de-
pends on many factors, including localization within the
nucleus or in the cytoplasm, and the state of chroma-
tin [51]. Telomerase must undergo a maturation step in
Cajal bodies, where TCAB1 is contained [52,53]. Sup-
pression of activity can be achieved by delaying telomer-
ase in the nucleolus.
Regulation of hTERT is mainly associated with the
cell cycle. It involves cyclin/cyclin-dependent kinase
(cdk) complexes, which regulate transcription factors
that bind to the hTERT promoter. E2F-1 plays a dual
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role in the cyclin regulation, acting both as repressor
and as activator. PI3K/Akt, NF-kB, and MAP kinase
cascades activate hTERT. Phosphorylation of the p107
cyclin/cdk complexes as well as binding of estrogen
to its receptor Era relieve the inhibitory effects of the
TGF-b cascade. Through the positive feedback, hTERT
expression activates the PI3K/Akt cascade, which, in
turn, activates the cell cycle via MAD1 and p53 deg-
radation, activates the NF-kB cascade, and blocks the
TGF-β cascade.
EXTRACHROMOSOMAL
FUNCTIONS OF TELOMERASE
Over time, the data on the action of telomerase be-
gan to accumulate, which are difficult to explain only
through its effect on chromosomes. For example, en-
hanced expression of mTERT (murine telomerase) pro-
motes carcinogenesis and wound healing [54]. Enhanced
expression of telomerase alters stem cell functions [55].
A surprising result was obtained when the hTERT gene
was introduced into the cells of a patient suffering from
Niemann-Pick disease, a rare inherited disease char-
acterized by impaired lipid metabolism. Insertion of
hTERT normalized the cell phenotype [56]. Telomerase
has also been shown to affect activity of the glycolysis
genes [57], stimulate transcription of the genes associ-
ated with epithelial-mesenchymal transition (vimentin
and snail1) [58]. Telomerase was shown to influence the
work of NF-kappaB-dependent genes, i.e., participate
in the regulation of inflammation [59]. Mutual effects
of hTERT on the Wnt cascade and vice versa have been
described [60].
Under conditions of oxidative stress, hTERT acts
as a redox regulator, moving into mitochondria, where
it protects mitochondrial DNA and helps maintain the
level of anti-oxidative enzymes [61]. It is not entirely
clear whether hTERT moves from the nucleus to mito-
chondria or whether the newly synthesized protein goes
directly to mitochondria.
Expression of hTERT is involved in epigenetic reg-
ulation by influencing the STAT3 factor, which activates
DNA methyltransferase I [62]. In 2009, it was discovered
that hTERT protein is able to form complex not only
with hTERC, but also with RMRP (RNA component of
mitochondrial RNA-processing endoribonuclease) [63].
Such complex has the RNA-dependent RNA poly-
merase activity, producing long double-stranded RNA.
RMRP mutations are associated with cartilage and hair
hypoplasia disease in humans [64]. It has been suggest-
ed that hTERT may form similar complexes with other
RNAs [65]. We have previously shown that even with-
out RNA, the telomerase protein has non-template DNA
polymerase activity [66]. Subsequently, these data were
confirmed [67].
WHAT HAPPENS
WHEN TELOMERES SHORTEN?
The Olovnikov’s theory of marginotomy suggested
that the trigger for stopping cell divisions and cell death
was impairment of the subtelomeric genes critical for
cell function. This assumption was not explicitly con-
firmed, which was one of the points that prompted him
to create a new hypothesis of aging. Nevertheless, DNA
shortening occurs as a result of end underreplication and
this phenomenon has clear physiological consequences.
What is the mechanism connecting terminal underrep-
lication of chromosomes and cessation of cell growth?
So far, we can clearly see at least three different mecha-
nisms for the effects of telomere shortening on the cells,
which do not agree with each other.
Telomere position effect. In 2001, the effect of
changing expression of the genes located near the telo-
mere when its length changes was first described [68].
As an explanation, the hypothesis of “heterochromatin
stocking” was proposed, which in general can be de-
scribed as follows: telomeric sequences have a special
chromatin packing and special epigenetic changes, and
the effect of this packing extends to nearby genes.
Later, a similar effect was described, but already for
the genes located at a distance [69,70]. A similar expla-
nation has been suggested here: telomeres affect expres-
sion of the genes located in the space next to them as a
result of chromosomal loop formation.
The results of the studies of telomere position effect
are still mostly not very convincing, although a num-
ber of findings are of interest. For example, the hTERT
gene is a subject to the telomere position effect, which
opens up a number of hypothetical mechanisms for how
the telomere length may be maintained in aging and
cancer [71]. At least three mechanisms have been de-
scribed for regulation of the hTERT expression through
formation of chromatin or telomeric loops [72]. Finally,
it should be noted that telomere shortening increases
expression of the ISG15 gene (interferon stimulated
gene 15), which is able to increase inflammation by
stimulating IFNγ production [69]. Thus, there is a di-
rect link between aging and inflammation, which pro-
vides support to the inflammaging theory.
DNA damage signal emergence. After a critical short-
ening of telomeres, a DNA damage signal appears.
Human cells stop proliferation at an average telomere
length of a few thousand nucleotides (i.e., not their
complete shortening) and enter a special state, which is
called cell senescence in English-language literature.
Probably, there is some minimal telomere length
that allows to properly pack the chromosome end so that
it differs from the DNA break. As early as 1997, two years
before the discovery of telomere loops [24], we suggested
a hypothesis about the loop structure of telomeres [73]
(Fig.3).
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Fig. 3. Telomere looping hypothesis. Telomeric DNA together with telomere-binding proteins can form loops. Due to restriction of free rotation
of DNA and interaction with a variety of proteins, DNA in a loop has a tense conformation. In the process of telomeric DNA shortening there is
a point when the length of telomeric repeat is not already sufficient for formation of a loop. The telomeric end of DNA acquires a free conforma-
tion, which is perceived by the cell as a signal of damage.
There is a great heterogeneity in the telomere length
not only between the cells but also within a single cell.
Therefore, critical shortening, which causes DNA dam-
age response (DDR), usually concerns only a small part
of telomeres. This is sufficient to induce cellular senes-
cence [74,75].
In most studies on the telomere length, however,
data on some average telomere lengths are mostly re-
ported. Such measurements are made using different
methods: Southern blot analysis of restriction fragments,
PCR, digital PCR, quantitative FISH, FISH cytometry.
Occasionally, more sophisticated methods are used that
allow to record the lengths of individual, including the
shortest telomeres (STELA, TeSLA) [76-78]. Advances
in technology already allow sequencing of long sequenc-
es, including individual telomeres [79].
Presence of critically shortened telomeres and av-
erage telomere length are not strictly related values. Itis
also worth noting that in the vast majority of geronto-
logical studies telomeres of white blood cells are mea-
sured, which also introduces additional ambiguities [80].
There is direct evidence that the cellular senescence
arises as a result of DDR signaling from telomeres [81].
At the same time, the signal must be long-lasting, indi-
cating that DNA cannot be repaired [82]. It was proved
that a single double-stranded DNA break (if it is not re-
paired) is sufficient for the induction of senescence [83].
The concept of cellular senescence has changed over
the past 60 years, and the generally recognized meaning
of this term is still not fully established [84]. There is
even an opinion that the term should be replaced [85].
At first, the term was used only for the cells that reached
the Hayflick limit, then it was extended to the cells with
DNA damage in general [86]. The term ‘oncogene-in-
duced senescence’ appeared and then others no longer
related to DNA. In 2019, leading scientists agreed on
what exactly should be considered as a senescence [87],
and the following definition emerged. Cellular senes-
cence is a state of the cell caused by stressors and cer-
tain physiological processes, characterized by prolonged
and generally irreversible cell cycle arrest with secretion
changes, macromolecular damage, and altered metabo-
lism. By trying to explain all heterogeneous phenomena,
such definition looks too general and does not improve
our understanding of the essence of the process.
In simple words, we can define senescence as an
ineffective cell response to any type of stress. Based on
this definition, it becomes clear why no unique (char-
acteristic only for senescence) features have been found
so far[88]. It is clear that both complex and simplified
definitions can be applied to any cells, including post-
mitotic and cancer cells.
The difficulty in determining cellular senescence
is aggravated by the fact that the senescent phenotype
depends on the initial cell type and changes over time;
senescence deepens and different mechanisms become
involved [89,90]. Recently, a very interesting phenome-
non has been described: increase in activity of the endog-
enous retrotransposons during senescence [91-93]. Most
likely, epigenetic changes are the signal for this [94].
Asa result of retroelement activation, in addition to the
increase in genetic instability, innate immunity systems
are activated and inflammation develops [95,96].
In the beginning, senescence is an entirely intracel-
lular process. In its development it acquires a specific
secretory phenotype (senescence associated secretory
phenotype, SASP). The cell begins to affect the life of
neighboring cells and further of the whole organism.
Mitochondria somehow start to participate in the devel-
opment of cellular senescence, possibly through redox
regulation [97,98].
In the senescent cells, resistance to apoptosis in-
creases, metabolism shifts towards glycolysis, and pro-
duction of reactive oxygen species increases. SASP in-
cludes DAMPs (damage associated molecular patterns),
various proinflammatory cytokines and chemokines that
attract immune cells, as well as proteases that alter the
extracellular matrix, etc. [99, 100].
Dramatic increase in genetic instability. Telomere
fusions and their consequences. The third mechanism
of the impact of telomere shortening on the cell fate is
the most complex, and leads to sharp increase in the
genetic instability. This mechanism is one of the path-
ways leading to formation of immortal cancer cells.
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Fig. 4. Chromosome bridge in 3T3 Swiss cells. The cell(s) resemble Siamese twins. Mitosis ended long ago (no chromosomes visible) and
thenuclei (cells) started moving away from each other, with the nucleus (and the cells themselves) not separating from each other (the nucleus that
did not separate is circled in yellow). DNA of the cells was pre-labelled with
3
H-thymidine. Radioautography. Photo by the author.
The mechanism begins to work only in the partially
transformed cells, in which, for some reason, the usu-
al mechanism of stopping proliferation upon reaching
the Hayflick limit does not work. Such cells, despite
the telomere shortening, continue proliferation and can
divide dozens of times before reaching the so-called
telomere or replicative crisis. About 30 years ago, the ex-
istence of two barriers that a normal cell needs to over-
come to achieve replicative immortality was theoretically
postulated: cellular senescence (M1) and telomere cri-
sis (M2) [101].
Experimentally, the study of telomere crisis is per-
formed on the cells in which p53 or pRb activity is sup-
pressed. For example, in 2023 [102], this was done by
introducing genetic constructs encoding human papillo-
mavirus antigens E6 and E7 or the large antigen SV40
into normal fibroblasts. Such cells have an increased
proliferative potential, during which telomeres continue
to shorten; after that, the cells begin to die enmasse as
a result of catastrophic cell cycle but continue to divide.
The outcome of the experiment can be either complete
death of all cells or emergence of a replicatively immor-
tal clone, most often with reactivation of the hTERT
gene. As recent studies show, cells undergo autophagic
death in the process of crisis [103].
If the Hayflick limit is overcome as a result of inac-
tivation of the cell cycle arrest mechanisms in response
to DNA damage, the DNA damage repair systems con-
tinue to operate. If underreplication continues, DNA
damage accumulates, and, at some point, there are
options for repairing incorrect DNA ends by means of
telomeric fusions.
Either different chromosomes or sister chromatids
may undergo fusion. In subsequent mitosis, these di-
centrics either mis-segregate or break off. A sequence of
events called fusion-bridge-breakage occurs (Fig.4).
It can be repeated many times. As a result of such
seemingly simple processes, a wide variety of mutations
can be formed [104]:
1. Aneuploidy, which is lack of a chromosome or
acquisition of an extra chromosome.
2. Non-reciprocal translocations resulting from
gap-induced replication.
3. Loss of Heterozygosity (LOX) due to terminal
deletion. Can become fixed in the genome of cancer
cells due to the loss of tumor suppressor genes.
4. General increase in ploidy.
5. During chromatid fusion, local amplification
may occur, followed by formation of a homogeneously
stained region (HSR) or double minute chromosomes
(DM chromosomes).
6. Chromothripsis – dozens of rearrangements
within one chromosome segment. It is formed when
a chromosome fragment is trapped in the cytoplasm
during nuclear envelope rupture and is severely frag-
mented under the influence of TREX1 exonuclease.
7. Kataegis is editing of the DNA fragments formed
during chromothripsis by APOBEC3 deaminase, which
converts cytosine residues to uracil. Activity of this en-
zyme normally limits infection by the DNA and RNA
viruses.
In the process of breaking the “bridge”, the DNA
in its middle is strongly stretched, it is devoid of nu-
cleosomes [105]. After rupture of the nuclear envelope,
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DNA becomes a target of cytoplasmic nucleases and
deaminases. In recent years, it has become clear that
the components of innate immunity responsible for
antiviral defense are involved in these processes. When
DNA is present in the cytoplasm, the cGAS-STING
pathway is activated, inducing ZBP1 (Z-DNA binding
protein 1), which binds to the TERRA transcript, the
amount of which increases with telomere dysfunction.
The TERRA–ZBP1 complexes oligomerize as filaments
on the surface of the outer mitochondrial membrane,
where they contribute to formation of MAVS (mito-
chondrial antiviral signaling complex). An interferon re-
sponse is initiated [102]. Eventually, the severely damaged
DNA with single-strand breaks is incorporated into the
nucleus, leading to the phenomena of chromothripsis
and kataegis.
The details of the processes of chromosome rear-
rangement and telomere crisis are too extensive and are
not the subject of this review. It should be emphasized,
however, that the traces of the above-described events
are found with varying frequency in many types of can-
cer cells. Thus, the impairment of telomere function is
involved in carcinogenesis [106-113].
Thus, we see that the telomere shortening (lack of
telomerase activity) leads to the appearance of senes-
cent cells, which promotes aging both locally (decreased
tissue functionality) and systemically (development of
inflammatory aging in the whole organism). The same
processes contribute to the growth of genetic instability,
which is an important part of carcinogenesis. It has long
been observed that despite telomerase activity, cancer
cells usually have shortened telomeres [114]. It has been
hypothesized that the cancer cells benefit from main-
taining short telomeres in order to ensure an increased
level of genetic instability.
TELOMERASE,
REJUVENATION, AND CANCER
Since telomerase prevents cellular senescence
caused by underreplication and enables cell proliferation
to maintain normal tissue function, its use for therapeu-
tic purposes for rejuvenation (healthspan) has long been
considered. In recent decades, the concept of longevity
(lifespan) has been gradually replaced by healthspan as a
target for scientists and physicians. The main aspect of
telomerase use in medical practice is safety.
On the one hand, telomerase expression does not
necessarily lead to cancer-related changes [115, 116] and
many normal (non-cancerous) cells have telomerase
activity. These include cells of the developing embryo,
various stem cells and progenitors, and germline cells in
males. At the beginning of the century, Calvin Harley,
wishing to emphasize safety of telomerase, wrote an
article entitled “Telomerase Is Not an Oncogene” [117].
On the other hand, telomerase activation is the most
common feature of cancer cells (about 90%), and, in this
regard, purely phenomenologically, we should attribute
it to oncogenes [118]. Telomerase activation during car-
cinogenesis occurs in different ways: these are mutations
of the hTERT promoter, genomic rearrangements, and
gene amplification. There are positions within the pro-
moter that are most frequently altered [119]. Mutations
in the hTERT promoter are the most frequent non-cod-
ing mutations in the human cancer cells [120]. In tissues
with slow cell self-renewal (tumors of the central ner-
vous system, liver, and melanocytes), mutations in the
hTERT promoter are more frequent and appear earlier
than in the intestinal and blood tumors [121-123].
Hepatitis B virus (HBV) is able to integrate into the
host genome near the hTERT promoter and enhance its
expression [124]. Genomic rearrangements that enhance
hTERT expression are often observed in neuroblastomas
[125, 126]. Amplifications of hTERT have been observed
in ovarian tumors and lung adenocarcinomas [127].
In addition to the functional link between telomer-
ase and cancer, namely frequent acquisition of telomer-
ase activity by the cancer cells, various non-canonical
telomerase activities unrelated to telomere maintenance
but somehow beneficial to cancer cells have been de-
scribed [128, 129].
It is known that a cancer cell must have a number
of changes, one of which is immortalization. In an age-
ing body there are many cells in which many precancer-
ous changes have already occurred and these cells lack
only immortality. Expression of telomerase allows them
to pass this stage and turn them into real cancer cells.
Consequently, mass acquisition of unregulated telomer-
ase activity by many cells is obviously dangerous.
It is known that cancer cells are characterized by
high telomerase activity and tumor malignancy cor-
relates with the level of telomerase activity [130, 131];
the level of activity can vary hundredfold [132]. It could
be hypothesized that if telomerase activity is relatively
low or erratic, it will only ‘heal’ dysfunctional, critically
shortened telomeres, thereby reducing DDR and SASP
and reducing inflammation, but not enabling long-term
growth [133]. The protective effect of telomerase under
oxidative stress is also likely to be beneficial [61, 134-135].
How can we assess the possible positive health
outcomes of telomerase activation? When the telomer-
ase gene was introduced into aging mice using adeno-
associated viruses, significant improvement of biomark-
ers associated with aging was observed [136]. A similar
result in mice was achieved by the same authors using the
low molecular weight telomerase activator TA-65 instead
of AAV9 [137].
TA-65 is a natural product derived from a tradi-
tional Chinese medicinal plant (Astragalus). Extracts of
this plant have been used for centuries with no report-
ed side effects. Dosage of the drug is easy to control
YEGOROV1712
BIOCHEMISTRY (Moscow) Vol. 88 No. 11 2023
and it is afairly weak telomerase activator. In human tri-
als, TA-65 has recently been shown to improve key risk
markers for cardiovascular diseases, the leading cause
of death in the developed countries. Plasma TNF levels
also decreased. The authors conclude that there were
changes associated with the reduced inflammation [138].
Reduction of inflammation and normalization of the
lymphocyte profile were also shown in another long-
term trial of TA-65 conducted on the age-matched pa-
tients after a heart attack [139].
Reducing inflammation becomes increasingly im-
portant as aging progresses [140, 141]. Therefore, in-
terventions aimed at blocking inflammatory senescence
may be justified.
In recent years, the exosome pathway of intercellu-
lar communication has attracted special interest. It has
been shown that the cells can transfer hTERT transcripts
through exosomes, which makes donor cells temporarily
telomerase-positive [142, 143].
In addition to the two known ways of telomere
maintenance (telomerase-dependent and alternative),
a method of direct cell-to-cell telomere transfer during
the immune response development has recently been dis-
covered [144]. Upon contact with a T-lymphocyte, the
antigen-presenting cell degrades shelterin and cuts off
telomeres with participation of the TZAP factor. After
that telomeres together with Rad51 (necessary for recom-
bination) are packed into vesicles, which are transferred
to the T-lymphocyte via immunological synapse. As a re-
sult, the telomeres of the T-lymphocyte are lengthened by
on average 3000 base pairs, while those of the presenting
cell are shortened. Possible mastering of the direct telo-
mere transfer in medicine would open new opportunities
for fighting aging of the immune system, increasing ef-
fectiveness of vaccination, and, in future, for the devel-
opment of new technologies of cellular rejuvenation, in
particular, the cells of the vascular wall. Also, the issue
of using telomerase for treatment of aging-related pathol-
ogies, which has gone out of fashion, requires further
study, and we may expect a next, more productive wave
of interest in this important enzyme [80, 145].
CONCLUSION
The history of telomerase research, which began with
prediction of the enzyme’s existence by A. M. Olovnikov
in 1971, continues.
The problem of underreplication, as it has been
called in the past, is probably not so much a problem,
but a mechanism adapted by evolution to control the fate
of individual cells in an organism. To date, three ways of
maintaining telomere length in humans are known: use
of telomerase, alternative, and direct transfer of telomeric
DNA. All three methods are utilized by the organism in
normal development. Restrictions associated with sup-
pression of telomerase in development are of preventive
nature and related to protection against cancer. When
these limitations interfere with normal function, the
body uses telomerase activation in a limited way (in stem
cells and some progenitor cells), or an alternative way to
lengthen telomeres (in embryogenesis, prior to implanta-
tion). When an ultra-urgent increase in the proliferative
potential of lymphocytes is required, there is a method
of direct telomere transfer that provides the necessary
speed to the immune system functioning.
In the process of organism aging, increase of sterile
inflammation plays a growing role. There is a direct link
between the state of telomeres and activation of immune
antiviral defenses. What was once called a replicome-
ter (telomere shortening as a counter of the number of
passed divisions) turned out to be a part of a complex
mechanism that largely determines the state of our health
and its importance increases with age.
Acknowledgments. I am grateful to I. A. Olovnikov
for editing the manuscript.
Ethics declarations. The author declares no con-
flicts of interest in financial or any other sphere.
This article does not contain any studies with human
participants or animals performed by the author.
Open access. This article is licensed under a Cre-
ative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution, and
reproduction in any medium or format, as long as you
give appropriate credit to the original author(s) and the
source, provide a link to the Creative Commons license,
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your intended use is not permitted by statutory regula-
tion or exceeds the permitted use, you will need to obtain
permission directly from the copyright holder. To view
a copy of this license, visit http://creativecommons.org/
licenses/by/4.0/.
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