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\begin{document}

\title{Telomerase as a possible key to bypass the cost of reproduction effect}



\author[1]{Radmila Capkova Frydrychova}%
\affil[1]{Biology Centre Czech Academy of Sciences}%


\vspace{-1em}



  
  \date{May 04, 2024}


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\selectlanguage{english}
\begin{abstract}
Telomerase activity and telomere restoration in certain somatic cells of
human adults maintain the proliferative capacity of these cells and
contribute to their regenerative potential, and telomerase activity and
telomere length are commonly considered lifespan predictors. Eusocial
insects provide excellent model systems for aging research based on
their extraordinary caste-related lifespan differences that contradict
the typical fecundity/lifespan trade-off. In agreement with the common
presumption, telomerase activity is upregulated in the reproductive,
long-lived individuals of eusocial insects such as queens and kings,
proposing that telomerase activity acts as a key factor in their
extended longevity. But, as documented by the presence of telomerase in
somatic tissues of numerous invertebrate and vertebrate species, the
connection between telomerase activity and the predicted lifespan is not
clear. Here, I ask whether somatic telomerase activity in eusocial
reproductives may serve its non-canonical function to protect its
individuals against the exacerbated metabolic stress upon reproduction
and be a reflection of a more common phenomenon among species. I propose
a hypothesis that the presence of telomerase activity in somatic cells
reflects a different reproduction strategy of the species.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Social behavior is a set of interactions among individuals within a
species and is displayed in a wide spectrum of forms, and eusociality
represents the most intimate and complex degree of social organization.
Eusociality is defined by the presence of distinct reproductive and
non-reproductive castes, overlapping generations, and cooperative care
for the brood within a colony (Engels 1990; Kocher and Paxton 2014).
Reproductives (kings and queens) and non-reproductives (workers or
soldiers) in the colonies are differentiated morphologically,
physiologically, and behaviorally (Wilson 1971; Sherman et al. 1994;
Engel 2012). Although the most well-characterized eusocial species are
represented by termites and hymenopteran insect species (such as
honeybees or ants), eusociality has been reported in several other
insect, non-insect, or even vertebrate species (Sherman et al. 1994;
Duffy et al. 2000).

Although taxonomically rare, eusocial insect species exhibit great
ecological importance, as approximately 50 \% of the world insect
biomass is represented by eusocial insect species (Wilson 1971; Kocher
and Paxton 2014). Despite their abundance and renown, little is known
regarding the ability of eusocial insects to offer an appealing
opportunity for the scientific community to uncover mechanisms
underlying how the social environment can alter the rate of organism
aging. Due to their extraordinary caste-related lifespan differences,
their plasticity in the rate of aging in the social context, and their
contradiction of the usual fecundity/lifespan trade-off, eusocial
insects provide an excellent model system for research on aging. This
article proposes the possible role of telomerase and telomere biology in
life-span regulation concerning the reproduction strategy of animal
species.

\textbf{Eusociality contradicts a reversed reproduction-longevity
trade-off}

The evolution theory according to natural selection attempts to explain
how organisms maximize their fitness to achieve maximal genetic
contribution within the future genetic pool. However, fitness
maximization is limited by certain evolutionary constraints such as
multiple life-history trade-offs. Based on the competitive allocation of
limited resources, trade-offs act as negative correlations between the
fitness components when an improvement of one component is associated
with a decrement of the other (Fabian and Flatt 2014). One of the major
trade-offs is the cost of reproduction, which is the phenomenon where
the increased rate of reproduction reduces the longevity of the parent
(Reznick 1985; Harshman and Zera 2006). However, the reversed
reproduction-longevity trade-off is contradicted by eusocial insects,
whose reproductive individuals, which are highly fecund compared to
solitary insects, typically exhibit longer lifespans than do
non-reproductives within their colonies or solitary insect individuals.
Comparative analysis between the lifespan of eusocial reproductives and
solitary insects has indicated that the evolution of eusociality is
associated with a 100-fold increase in insect longevity (Jemielity et
al. 2005). The reproductive individuals of many termite or ant species
may live for many decades (Laurent and Genoud 1997; Keller 1998). For
example, the mean average lifespans of honeybee queens is 5.6 years,
while adults of solitary insect species exhibit lifespans of only 0.1 \selectlanguage{ngerman}±
0.2 years (Keller and Genoud 1997; Keller 1998). The mechanisms
underlying the extraordinary lifespan extension of eusocial
reproductives are not fully understood.

\textbf{The aging explanation theories}

Aging is characterized by a series of cellular and tissue damage events
that accumulate with age and result in impaired functioning of the
organism that eventually leads to death. Although countless theories
have been proposed as universal explanations for the aging process, none
of these theories are entirely satisfactory. Instead, to explain the
aging process these theories are applied in a complex way to provide a
combinatorial explanation (Jin 2010).

Aging theories exist in two primary categories that include programmed
and damage theories. The most established theory of aging is the
mitochondrial free radical theory of aging, proposing that aging is a
result of accumulating cellular damage caused by free radicals, and
mitochondria act as the primary source of reactive oxygen species (ROS)
(Harman 1956; Harman 1972). Generation of mitochondrial ROS such as
hydroxyl radicals, hydrogen peroxide, and superoxide radicals primarily
occurs during electron transport during oxidative phosphorylation.
According to this theory, mitochondrial DNA (mtDNA) due to its proximity
to ROS generation is considered the prime ROS target, and this targeting
of mtDNA leads to the accumulation of ROS-induced damage in mitochondria
and loss of functionality with age (Murphy 2009).

The programmed theory of aging proposes that aging is the result of a
program that acts through gene expression where certain genes are
switched on or off such as genes of the immune system or telomerase
activity, both of which decline over time (Davidovic et al. 2010; Jin
2010; Fathi et al. 2019). Alternatively, aging is explained as a
continuation of the program for developmental growth (acting as a
quasi-program) that exerts a deleterious effect on adult individuals.
Together with the antagonistic pleiotropy hypothesis, this theory is
based on the assumption that evolution favors genes that increase
fitness in early life despite the knowledge that they are harmful in
later life (Blagosklonny 2010).

Regardless of any theory, aging is linked to multiple cellular processes
that are interconnected and act in numerous cell organelles (Zheng et
al. 2019). It has been demonstrated that the aging process is associated
with changes in epigenomic information (Chittka and Chittka 2010; Lyko
et al. 2010; Ben-Avraham et al. 2012; Herb et al. 2012; He et al. 2017)
that affect the expression levels of aging-related genes (Kaiwen et al.
2018) and lead to alterations in numerous aging-related factors such as
antioxidant protection (Kurz et al. 2004; Corona et al. 2005),
nutrient-sensing pathways, energy homeostasis, and mitochondrial
functioning (Ozawa 1997; Aamodt 2009; Blagosklonny 2010; Cui et al.
2012; Antikainen et al. 2017).

\textbf{Telomeres as a component of organismal aging}

Accumulating evidence exists indicating that stem cell function,
regeneration, and organ maintenance, all of which largely contribute to
the aging process, are connected to telomere biology. Telomeres are
nucleoprotein structures located at chromosome ends that consist of
short DNA repeats with well-defined sequence composition and
telomere-specific protein complexes. Through a multiprotein structure
called a telomere cap, telomeres allow cells to distinguish natural
chromosome ends from chromosome breaks, and the formation of telomere
caps requires a satisfactory length of telomeric DNA (Blackburn 1991;
Capkova Frydrychova et al. 2009; Mason et al. 2011). Disruption of
telomere cap function that can occur either by loss of telomeric DNA or
telomere-binding proteins activates the DNA damage response, and this
response, in turn, induces a permanent proliferation arrest known as
cell senescence (Greenberg 2005).

Due to the limitations of semiconservative DNA replication and the
inability of conventional DNA polymerase to fully replicate the end of
linear DNA strands, telomeres are gradually shortened with each round of
cell division. This shortening can be circumvented by the extension of
telomeric DNA via special telomere maintenance mechanisms, and the most
common mechanism of telomere elongation involves telomerase activity.
Telomerase is a specialized reverse transcriptase that uses its RNA
template to repeatedly synthesize a short telomeric sequence onto the
chromosome ends (Blackburn 2005; Mason et al. 2015). Telomerase activity
is strictly controlled. In humans, the highest telomerase activity is
observed during embryogenesis, and telomerase activity is downregulated
in most somatic cells during later development. This suggests an
important role for telomerase in fetal tissue differentiation and
development (Wright et al. 1996; Ulaner and Giudice 1997). In adult
humans, the majority of somatic cell types are telomerase-negative, and
telomerase activity is primarily present in germ, stem, and cancer
cells. In contrast to germ and cancer cells, the level of telomerase in
most stem cells of human adults is low and insufficient to prevent
replicative senescence (Hiyama and Hiyama 2007; Choudhary et al. 2012).
Telomerase in adult humans is also upregulated in cells with high
reproducible activity such as hematopoietic progenitor cells,
endometrial and intestinal cells, activated lymphocytes, or
keratinocytes (Wright et al. 1996; Razgonova et al. 2020). In contrast
to other cell types, embryonic stem cells and cancer stem cells are, due
to their high telomerase activity, considered immortal having the
capacity of indefinite self-renewal and proliferation (Hiyama and Hiyama
2007).

The absence of or low activity of telomerase in somatic cells results in
significant telomere shortening throughout the lifespan, and this limits
the replicative capacity of the cells and acts not only as a major
determinant of organismal development but also aging and age-related
diseases (Ulaner and Giudice 1997; Jiang et al. 2007; Razgonova et al.
2020). Also, as documented in zebra finches, there is a positive
correlation between telomere length early in life and the length of
realized lifespan, thus indicating that the length of telomeres may act
even as a predictor of lifespan predisposition (Heidinger et al. 2011).

\textbf{Telomerase is upregulated in the long-lived eusocial
reproductives}

The common presumption that telomerase activity is a marker of aging and
advancing organismal development even in insects is supported by
observations in hemimetabolous insects such as cockroaches and termites
(Korandová et al. 2014; Koubová and \selectlanguage{polish}Č\selectlanguage{english}apkov\selectlanguage{ngerman}á Frydrychová 2021).
Hemimetabolous insects exhibit incomplete metamorphosis, where during
development the insects lack larval and pupal stages and instead undergo
several nymphal stages before their final molt into adults. Recent
phylogenetic studies indicate that termites evolved from cockroaches,
and along with cockroaches, they form the order Blattodea. But, in
contrast to cockroaches, termites are eusocial insects. Both cockroaches
and termites exhibit upregulated telomerase activity in young instars,
and this activity gradually declines in later development. However,
there were two exceptions for the decline: the germline cells in both
insects and somatic tissues in the long-lived reproductives, exhibiting
high telomerase activity throughout the duration of their lives
(Korandová et al. 2014; Koubová and \selectlanguage{polish}Č\selectlanguage{english}apkov\selectlanguage{ngerman}á Frydrychová 2021). A similar
finding, which contradicts the common scheme of telomerase decline in
adult somatic tissues, was obtained in the long-lived honeybee and ant
queens (Korandová and Frydrychová 2016; our unpublished data),
representing holometabolous insects (adult growth in holometabolous
insects is largely determined and ended by metamorphosis). These
observations suggest that the upregulation of telomerase activity may be
a key factor in the caste differentiation process in eusocial insects
and in the extended longevity of their reproductive individuals.

It is well established that if telomerase is required for the
maintenance of telomeres, it must be active during the DNA replication
stage (S-phase), and while the highest levels of telomerase activity are
found in the S-phase, telomerase activity is virtually absent in the
G2/M or G0 phases (Zhu et al. 1996; Holt et al. 1997). Surprisingly, no
DNA synthesis was detected in any of the telomerase-positive somatic
tissues of eusocial reproductive insects (Koubová and \selectlanguage{polish}Č\selectlanguage{english}apkov\selectlanguage{ngerman}á
Frydrychová 2021), and no differences were observed in telomere length
between the long-lived and short-lived castes (Jemielity et al. 2005;
Korandová and Frydrychová 2016; Koubová et al. 2021a).

To explain the role of telomerase in the caste system of eusocial
insects and to identify its possible engagement in the disparity between
fertility and life expectancy, research was further conducted examining
the bumblebee \emph{Bombus terrestris} . Bumblebees are members of the
group of insects possessing a primitive social organization, and there
are significant differences in the life expectancy of their female
castes. Workers of the bumblebee species \emph{B. terrestris} typically
live for 2-3 months; however, the queens can live up to one year.
Nevertheless, the lifespan comparison is not unbiased, as the bumblebee
queens spend the majority of their lives (approximately 6-9 months) in a
diapause in which most biological processes take place at only low-cost
levels. Thus, the bumblebee queens cannot provide an example of a
full-bodied extension of life expectancy, or at least they cannot
provide it in the way that exists in advanced eusocial species. In
contrast to eusocial reproductive individuals, the only adult somatic
tissue of \emph{B. terrestris} showing upregulated telomerase was the
fat body of very young and pre-diapause queens (Koubová et al. 2019).
Additionally, telomerase activity was co-localized with the DNA
endoreduplication cycles that were followed by a massive increase in fat
body mass and nutrient content, which suggests that the upregulation of
telomerase activity in the fat body mass in \emph{B. terrestris} is
tightly linked to the ability of queens to survive upcoming diapause
(Koubová et al. 2019). A similar observation was obtained in honeybee
workers, where telomerase activity, DNA synthesis, and nutrient content
were reinforced in the fat body cells of winter-generation workers
(Koubová et al. 2021b).

Collectively, these findings suggest that the caste-related differences
in telomerase activity in eusocial insects such as honeybees or termites
are not linked to telomere maintenance mechanisms, and instead, they are
associated with some non-canonical telomerase roles without the typical
telomerase catalytic activity that directly serves to elongate
telomeres.

\textbf{Non-canonical functions of telomerase in oxidative defense}

An increasing body of evidence indicates that non-canonical telomerase
functions participate in a variety of biological pathways related to DNA
repair and stress resistance. In addition to the regulation of cell
growth and the cell cycle, the induction of apoptosis, or changes in
global patterns of gene expression or chromatin status, telomerase and
telomeres are involved in protecting cells against oxidative stress
(Saretzki 2009; Ségal-Bendirdjian et al. 2019; Zheng et al. 2019). The
impact of telomere biology in regard to cell functions under oxidative
stress is documented by the crosstalk between telomeres/telomerase and
mitochondria. It was determined that mitochondrial dysfunctions
accelerate telomere shortening, thus indicating that mitochondrial ROS
may act as a determinant of telomere-dependent senescence (Liu et al.
2002; Passos et al. 2007) and that telomere shortage and dysfunction can
lead to the reprogramming of mitochondrial biosynthesis and alterations
in mitochondrial functioning (Guo et al. 2011; Sahin et al. 2011).
Additionally, it has been reported that in response to oxidative stress
induced by hyperoxia, 80-90\% of TERT (the catalytic subunit of
telomerase) is transported from the nucleus into the mitochondria,
ultimately resulting in a dramatic acceleration of telomere shortening.
When the cellular conditions are shifted from hyperoxia back to
normoxia, TERT is re-transported back to the nucleus, and telomere
length is restored (Santos et al. 2006; Ahmed et al. 2008; Saretzki
2009). Telomerase may also exert a protective effect on mitochondrial
functions. Under oxidative stress, it binds to mitochondrial DNA,
increases respiratory chain activity, and protects against oxidative
stress-induced damage (Haendeler et al. 2009). Finally, different
tissues of the bank vole \emph{Myodes glareolus} from the Chernobyl
Exclusion Zone displayed reduced telomere length but upregulated
telomerase activity. The upregulation of telomerase, in this case,
appears to be associated with functions other than telomere maintenance,
perhaps protection against a stressful environment (Kesäniemi et al.
2019).

\textbf{Stress as a key player in telomere homeostasis maintenance}

Although organisms have evolved a set of stress responses to protect
against adverse environmental conditions, protracted stressful
conditions and long-term activation of the stress response negatively
impact health and lifespan (Monaghan 2014). It is now broadly accepted
that chronic stress and lifestyle factors such as oxidative stress,
psychosocial stress, and improper health conditions can affect telomere
dynamics (Epel et al. 2004; Kotrschal et al. 2007; Lin et al. 2012;
Monaghan 2014; Korandová et al. 2018). Reproduction is an energetically
costly activity that increases metabolic rates, ROS production, and
susceptibility to oxidative stress, and it is hypothesized that
oxidative stress may represent a mechanistic link for the inverse
relationship between reproduction and lifespan in both vertebrate and
invertebrate models that acts independently of energy allocation
(Alonso-Alvarez et al. 2004; Wiersma et al. 2004; Kr\selectlanguage{polish}ůč\selectlanguage{english}ek et al. 2015;
Sharick et al. 2015; Colominas-Ciur\selectlanguage{ngerman}ó et al. 2017; Costantini 2018). It
has been demonstrated that resistance to oxidative stress is decreased
during reproduction and that breeding activity increases susceptibility
to oxidative stress (Alonso-Alvarez et al. 2004; Wiersma et al. 2004).
Additionally, resistance to oxidative stress plays a significant role in
shaping fecundity, as a higher fecundity rate was observed in
individuals with higher oxidative protection (Bize et al. 2008). It is
well established that oxidative stress in humans is implicated in
pathological processes in the reproductive tract that contribute to
infertility and poor pregnancy outcomes, and treatments based on
strategies to boost the exhausted antioxidant defense of the
reproductive microenvironment have been suggested (Adeoye et al. 2018).

DNA molecules represent an important target of oxidative damage in
cells, and the most common DNA damage caused by free oxygen radicals is
oxidative modifications of DNA bases such as the formation of
8-oxoguanin. Oxidative DNA lesions are associated with the production of
single-strand breaks that are induced directly or as an intermediate
step in the repair of oxidative base modifications. Due to their high
content of guanine, telomeres are highly sensitive to oxidative damage
and induction of single-strand breaks that interfere with the
replication fork and thus lead to telomere attrition (von Zglinicki
2002; Houben et al. 2007; Coluzzi et al. 2019). In agreement with the
assumption that breeding individuals are more susceptible to oxidative
damage, engaging organisms in reproduction accelerates telomere loss
(Kotrschal et al. 2007; Heidinger et al. 2011).

Bypassing the common negative association between fecundity and
longevity in eusocial reproductives may explain their enhanced oxidative
protection coupled with the fecundity rate. As demonstrated in ants,
young founding queens exhibit immunity and resistance against
environmental and physiological stress, while established older queens
exhibit stimulated oxidative protection (Lucas and Keller 2018; Negroni
et al. 2019). Similarly, data suggesting a role for antioxidant genes in
modulating the lifespan of long-lived reproductives were identified in
Adélie penguins that exhibit an increased antioxidant defense in
response to breeding efforts, while oxidative damage and telomere length
remained unchanged (Beaulieu et al. 2011). When we compared a
few-day-old termite reproductives (with no or very low mating
experience) to greater than 1-year-old reproductives, the old
individuals exhibited highly upregulated oxidative defenses in their
somatic tissues in combination with telomerase activity (Koubová et al.
2021a; our unpublished data).

\textbf{What is the real purpose of telomerase activity in somatic cells
?}

To sum up, telomere shortening and lack of telomerase in most human
somatic cells result in an irreversible cell cycle arrest termed
replicative senescence, which is one of determinants of organismal
development, an anticancer mechanism, and a marker of organismal aging.
The presence of telomerase activity and telomere restoration in certain
somatic cells of human adults maintains the proliferative capacity of
these cells and contributes to their regenerative potential, and
telomerase activity and telomere length in these cells both are commonly
considered lifespan predictors (Blasco 2007; Tan et al. 2012).

However, from a broad perspective, the connection between the length of
telomeres and the predicted lifespan or the reason of telomerase
activity in somatic tissues of numerous animal species are not clear,
which has been documented by series studies reviewed in (Gomes et al.
2010; Smith et al. 2021). For example, telomerase activity and telomere
length have been studied in sea urchins in the context of the
long-lived\emph{Strongylocentrotus franciscanus} (live over 100 years)
and the short-lived \emph{Lytechinus variegatus} (with an estimated
lifespan of only 3-4 years). While both species exhibit telomerase
activity in their somatic tissues, \emph{L. variegatus} possessed longer
telomeres (average length of approximately 21 kb) compared to those of
\emph{S. franciscanus} (average telomere length of approximately 5.5
kb). Moreover, no differences in telomere length were observed between
the young and old individuals. This suggests that sea urchins do not
utilize telomerase repression as a mechanism to suppress neoplastic
transformation (as a decline of telomerase is hypothesized to prevent
tumor development), and the continuous telomerase activity in somatic
tissues of the sea urchins is explained by the undetermined growth of
these organisms throughout their lifespan (Francis et al. 2006).
Similarly, the presence of telomerase activity throughout the lifespan
or a lack of a positive correlation between the predicted lifespan,
telomerase activity, and telomere length have been reported in numerous
other invertebrate and vertebrate species (Gomes et al. 2010). Studies
have provided no detailed information relating telomerase activity to
the proliferation status of the tissues, and the presence of telomerase
in the tissues was hypothetically explained by the existence of
telomerase function that differs from that involved in the elongation of
telomeres (Lau et al. 2008; Gomes et al. 2010).

Also, the existence of different patterns of telomerase regulation has
been documented in mammals. While adult humans express telomerase almost
exclusively in the germline and a few specialized cell types and possess
short telomeres (\textless{}20 kb), most rodents express telomerase in
both germline and a wide array of somatic tissues and possess long
telomeres (25-150 kb) (Gomes et al. 2010). It indicates that rodents do
not use telomere length to control their replicative aging. A similar
lack of telomere-based replicative aging is predicted in lagomorphs
(rabbits, pikas, and hares) as prolonged tissue cultures derived from
different lagomorph species displayed no growth arrest or a decrease in
doubling time but show either very long telomere arrays or detectable
telomere activity (Forsyth et al. 2005). A comparative study examining
telomerase activity and telomere length in mammals revealed that
telomere length inversely correlates with lifespan (longer telomeres are
present in short-lived mammal species), and telomerase activity in
somatic cells inversely correlates with body mass (small mammal species
such as small rodents exhibit telomerase activity in somatic cells)
(Seluanov et al. 2007; Gomes et al. 2010). It has been suggested that
larger and longer-lived mammals protectively repress telomerase activity
in somatic cells, as their large body masses and longer lifespans
contribute to an increased risk of cancer development (Seluanov et al.
2007).

\textbf{A role of telomerase to eliminate the cost of reproduction
depending on the type of reproduction strategy?}

Although telomerase has been widely demonstrated to be present in
somatic tissues of numerous animal species, no detailed information is
available relating telomerase to the proliferation status of the tested
tissues or other biological traits that could better identify the
purpose of telomerase activity in such cases. The reason for telomerase
activity in non-proliferative cells remains unclear. It is speculated
that in the somatic tissues of large mammals, telomerase activity is
reduced as protection against tumor development, and in small mammals,
telomerase is widely active, as there is no need to repress it. This
``purposiveness without purpose' can be questioned in regard to why it
is worthy for cells to express telomerase (or anything else) if there is
no need for it. It is widely known that body mass in terrestrial mammals
is negatively correlated with the fecundity rate of the species (Allainé
et al. 1987; Werner and Griebeler 2011). Therefore, it is tempting to
ask whether somatic telomerase activity in eusocial kings and queens as
well as in small but highly fecund mammal species such as lagomorphs or
rodents may serve its non-canonical function to protect its individuals
against reactive oxygen species produced due to the exacerbated
metabolic stress upon reproduction and may only be a reflection of a
more common and broader phenomenon. We can speculate whether the
necessity to maintain telomerase activity in somatic cells of some
species reflects a different reproduction strategy of the species rather
than their body size.

\textbf{Conflicts of Interest Statement} Author declares no conflict of
interest.

\textbf{Acknowledgements} This study was supported by grant no.
18-21200S from the Grant Agency of the Czech Republic and by Strategy
AV21, Diversity of Life and Health of Ecosystems.

\textbf{Data availability statement}

Data sharing not applicable to this article as no data sets were
generated or analyzed during the current study.

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