T
Telomere-SubtelomereTelomerase System
Giacinto Libertini
ASL NA2 Nord, Italian National Health Service,
Frattamaggiore, Italy
Department of Translational Medical Sciences,
Federico II University, Naples, Italy
Synonyms
Telomere-telomerase system; TST system
Definition
The expression telomere-subtelomere-telomerase
system, or shortly TST system, describes the morphologic and functional complex consisting of
telomere, subtelomere, and telomerase (which
are composed of various distinct molecular
parts) and the interactions between them, their
parts, and the other cellular components.
Overview
For aging, defined as age-related decreasing fitness
(or increasing mortality), there are two opposite
explanations. They are mutually incompatible, radically different and with so many diverse assumptions and implications that may deserve the
definition of distinct “paradigms” (Libertini
2015a) in the meaning proposed by Kuhn (1962).
The first paradigm, defined as the “nonadaptive or non-programmed aging paradigm,”
justifies aging as the cumulative effect of many
degenerative factors that natural selection cannot sufficiently oppose (mutation accumulation,
antagonistic pleiotropy, disposable soma, and
damage accumulation hypotheses [Libertini
2015a, b]).
The second paradigm, defined as the “adaptive
or programmed aging paradigm,” explains aging
as a physiological phenomenon evolutionarily
favoured in terms of supra-individual natural
selection (Libertini 2015a). For this paradigm,
aging is a form of phenoptosis (Skulachev 1997;
Libertini 2012), i.e., “programmed death of an
organism” (Skulachev 1999, p. 1418), which is a
very common type of phenomena in the biological
world, well known as physiological events
favored and modeled by natural selection (Finch
1990).
An important and opposite implication of the
two paradigms is that: (1) according to the nonadaptive aging paradigm, senescence cannot be
caused by specific genetically determined and
regulated mechanisms, and (2) on the contrary,
according to the adaptive aging paradigm, such
mechanisms must exist, and indeed their existence
is indispensable in order to consider this paradigm
valid (Libertini 2015a).
Although the nonadaptive aging paradigm still
represents the group of theories presented as the
© Springer Nature Switzerland AG 2019
D. Gu, M. E. Dupre (eds.), Encyclopedia of Gerontology and Population Aging,
https://doi.org/10.1007/978-3-319-69892-2_59-1
2
correct explanation of aging (Olshansky et al.
2002; Kirkwood and Melov 2011; Kowald and
Kirkwood 2016; Fedarko 2018), on the basis of
the results of numerous and qualified works, it is
possible to describe the mechanisms that appear to
determine aging and that are certainly genetically
determined and modulated and not the simplistic
effect of random accumulation of harmful events
(Fossel 2004; Libertini 2015a, b). These mechanisms, which will be briefly described here, have
as their core the telomere-subtelomere-telomerase
(TST) system. It determines (i) the gradual cell
senescence, (ii) the cell senescence, (iii) the
slowing down of the cellular turnover, and
(iv) the atrophic syndrome of all tissues and
organs, phenomena that constitute the substrate
of aging (Fossel 2004; Libertini 2009, 2015a, b).
The Machinery of the TST System
After a long period in which it was erroneously
believed that cells could duplicate themselves an
unlimited number of times, limits in cellular
duplication capabilities were shown in 1961
(Hayflick and Moorhead 1961). However, for
some time, it was not understood why the cells
had these limits. In 1971, the observation that the
DNA polymerase enzyme, which allows DNA
duplication, fails to duplicate a small part of the
terminal region of the molecule (the telomere),
suggested the hypothesis that the progressive
shortening of the telomere at each duplication
could explain the limits in cell duplication
(Olovnikov 1971). Subsequently, as germ and
stem cells appeared capable of unlimited or very
many duplications, respectively, the existence of
an enzyme, then called telomerase, capable of
restoring the part of the telomere not duplicated
was predicted (Olovnikov 1973). This enzyme
was isolated and described a few years later
(Greider and Blackburn 1985).
It was also demonstrated that the telomere is a
repetitive nucleotide sequence, TTAGGG in
humans, and other mammals (Moyzis et al.
1988), which was highly conserved during evolution and present in many species that were phylogenetically distant (Blackburn 1991).
Telomere-Subtelomere-Telomerase System
Subsequently, valuable information was provided by the study of the yeast (Saccharomyces
cerevisiae), a single-celled eukaryotic species. In
S. cerevisiae, the telomerase enzyme is always
active, and the length of the telomeres remains
the same after each duplication (D’Mello and
Jazwinski 1991). The yeast reproduces by division of a mother cell that gives rise to a “daughter”
cell and another “mother” cell. The cells of daughter lineage may duplicate themselves an unlimited
number of times, while those of the mother lineage may reproduce only a limited number of times
(25–35 duplications in about 3 days) and show a
progressive decline in the ability to sustain stress
(Jazwinski 1993). The main difference between
the cells of the two lines, apart from a functional
decline in the cells of the mother line, was that the
mother cells showed, in proportion to the number
of duplications, a progressive accumulation of
particular substances, extrachromosomal ribosomal DNA circles (ERCs), on the portion of
DNA adjacent to the telomere (the subtelomere)
(Sinclair and Guarente 1997).
It was then observed that in the strains of
particular yeast mutants, the tlc1D mutants,
which exhibited deficient telomerase activity,
aside from the fact that both mother and daughter
cells showed telomere shortening at each generation, individuals of the daughter line while not
showing ERC accumulation as individuals of the
wild-type strain, showed a decline in the ability to
resist stress and a transcriptome similar to that of
older individuals of the mother lineage of the wild
strain (Lesur and Campbell 2004).
These facts suggested that the alterations
shown by the cells of the mother lineage in the
wild strain and also by the daughter cells in tlc1D
mutant strain were always due to the repression of
the subtelomeric region, although determined by
two different mechanisms: (i) accumulation of
ERCs in the mother cells of wild strains and
(ii) shortening of the telomere in the daughter
cells of the mutant strain. This also suggested
that the decline of cell functions and the replicative senescence observed in multicellular eukaryotic organisms could have a mechanism similar to
that explaining the alterations in the daughter cells
of tlc1D mutants (Libertini 2009).
Telomere-Subtelomere-Telomerase System
In fact, it had already been proposed that the
telomere was covered by a heterochromatin
“hood” and that the progressive shortening of
the telomere caused a proportional sliding of the
hood with the repression of the adjacent subtelomere: “One model of telomere-gene expression linkage is an altered chromosomal structure
(Ferguson et al. 1991), such as a heterochromatin
‘hood’ that covers the telomere and a variable
length of the subtelomeric chromosome (Fossel
1996; Villeponteau 1997; Wright et al. 1999). As
the telomere shortens, the hood slides further
down the chromosome (the heterochromatin
hood remains invariant in size and simply
moves with the shortening terminus) . . . the
result is an alteration of transcription from portions of the chromosome immediately adjacent
to the telomeric complex, usually causing transcriptional silencing, although the control is
doubtless more complex than merely telomere
effect through propinquity (Aparicio and
Gottschling 1994; Singer et al. 1998; Stevenson
and Gottschling 1999). These silenced genes
may in turn modulate other, more distant genes
(or sets of genes). There is some direct evidence
for such modulation in the subtelomere . . .”
(Fossel 2004, p. 50).
As hinted by Fossel, this model necessarily
required a hood with a fixed length, defined in
the germ cell of an organism, and that this length
remained unchanged in all subsequent duplications (Libertini and Ferrara 2016a). These concepts are illustrated in Fig. 1.
Subtelomere repression has general consequences on cell functions, including extracellular
secretions. This phenomenon was first described
in yeast in 1990 and was called telomere “position
effect” (Gottschling et al. 1990, p. 751). Subsequently, to describe the manifestations of this
phenomenon on the cell, the name “gradual cell
senescence” was proposed (Libertini 2014,
p. 1006; 2015b).
As the subtelomere is increasingly repressed
by the sliding of the hood caused by telomere
shortening, another effect of the gradual cell
senescence is a growing probability of activation
of a particular program, “cell senescence,” a
3
“fundamental cellular program” (Ben-Porath and
Weinberg 2005, p. 962), which has two main
effects: (i) blocking of replication capabilities
and (ii) manifestations of the gradual cell senescence at the highest level.
A simplistic model could be that cell senescence program is activated when telomere shortening reaches a critical value. However, in
synchronized cell cultures, that is, with an equal
number of duplications in all cells, the duplication
capacity did not stop simultaneously in all the
cells but showed a progressive decrease in the
whole culture related to the number of duplications, that is to say related to telomere length
reduction. The explanation for this phenomenon
was proposed by Blackburn (2000).
The telomere is covered by a cap (probably the
same hood involved in the explanation of gradual
cell senescence [Libertini 2015b]). This cap does
not permanently cover the telomere, and therefore
the telomere continuously oscillates between two
states, “capped” and “uncapped.” The duration of
the second state is related to telomere shortening,
and in this state, the cell is vulnerable to the
passage to replicative senescence, i.e., to the activation of cell senescence program. Even when
telomeres have their maximum length and telomerase is active, a small percentage of cells pass
to the replicative senescence (Blackburn 2000).
Since the fraction of time in which the telomere
is uncapped and vulnerable is proportional to telomere shortening and therefore to the level of subtelomere repression, it has been hypothesized that
the percentage of time in which the telomere is
uncapped is somehow regulated by subtelomeric
repetitive sequences, defined as “r,” which would
also have general regulatory action over the functions altered in gradual cell senescence (Libertini
and Ferrara 2016a).
The possible existence of “r” sequences is
supported by the description of subtelomere structure as an “unusual structure: patchworks of blocks
that are duplicated” (Mefford and Trask 2002, p. 91)
and “long arrays of tandemly repeated satellite
sequences” (Torres et al. 2011, p. 85).
These concepts are illustrated in Fig. 2.
4
Telomere-Subtelomere-Telomerase System
Telomere-Subtelomere-Telomerase
System,
Fig. 1 (A) Yeast, normal stock, daughter lineage; (B)
yeast, normal stock, old individuals of mother lineage;
(C) yeast, tlc1D mutants, daughter lineage; (D) multicellular eukaryotes, cells of the germinal line; (E) multicellular eukaryotes, somatic cells. In A and D, telomeres
are not shortened, and subtelomeric DNA is not repressed.
In B, subtelomeric DNA is repressed by ERC accumulation. In C and E, telomeres are shortened, and the subtelomeric DNA is repressed by the proteinic hood.
(Figure from Libertini 2015a, modified and redrawn)
Absence of a Relationship Between
Initial Telomere Length and Longevity
correlation between age of the individual and cell
duplication capacities (Martin et al. 1970;
Libertini 2009). The reduction of these capacities
was anticipated by Olovnikov (1971, 1973) as
related to telomere shortening. From this, a
It is well known that in the comparison between
individuals of the same species, there is an inverse
Telomere-Subtelomere-Telomerase System
5
Telomere-Subtelomere-Telomerase System, Fig. 2 Scheme of telomere sequences (“r”) with regulatory actions
(through likely intermediate molecules) and of their repression by the sliding of telomere hood. (Figure from Libertini
2017, modified and redrawn)
possible relation, in the comparison among species, between telomere length in germ line cells
and longevity has been hypothesized (Gorbunova
et al. 2008). However, this expected relation is
denied by strong contrary evidence (Gorbunova
et al. 2008; Libertini and Ferrara 2016a), and this
could induce to doubt the hypothesis that aging
alterations are determined by telomere shortening.
Similarly, it could be hypothesized that in the
comparison among species, there is a correlation
between longevity and a greater activity of telomerase, but also this possible relation is contradicted by
evidence (Gorbunova et al. 2008).
The topic was discussed elsewhere, highlighting that the aforesaid two correlations falsified by
the evidence do not have a theoretical foundation
(Libertini and Ferrara 2016a).
In the germ cell, in a phase definable as “reset”
phase, the hood is modeled on the length of the
telomere, and its size does not change in all subsequent duplications. As far as longevity is
concerned, the absolute “telomere length is irrelevant” (Fossel 2004, p. 36), provided that the
telomere length is not less than a critical value
(Fossel 2004). In subsequent duplications, the
telomere is shortened, and the hood slides on the
subtelomeric region. The critical element is the
proportion of subtelomere that is inhibited as a
consequence of the relative shortening of the telomere. Therefore, if, other things being equal, in
case 1 we have a long telomere but a short
subtelomere, while in case 2, we have a short
telomere but a long subtelomere, it is easy to
predict that after an equal number of duplications,
we will have a degree of subtelomere repression
that is greater in case 1. A similar concept is
shown in Fig. 3, where the case of two mutant
strains of mice is considered, with telomeres long
the first 20 kb and the second 10 kb (or also the
case of a donor animal and a cloned animal),
which showed equal longevity and aging rates
(Fossel 2004). In this case, we have telomeres of
different lengths but equal subtelomeres: an identical sliding of the hood causes in the cells of the
two strains an identical repression of the subtelomere and therefore identical manifestations
related to aging.
Similarly, a lower/higher telomerase activity
could be balanced by a lower/greater length of
the subtelomere (Libertini and Ferrara 2016a).
The Effect of the TST System on the
Whole Organism
The effects of the TST system, which vary
according to how it is regulated in each species,
are extremely important for the whole body.
In mammals, even in the absence of diseases or
traumatic lesions, most of the cells are subjected
to continuous turnover. In fact, cells die of various
types of programmed cell death (PCD), e.g.:
6
Telomere-Subtelomere-Telomerase System
Telomere-Subtelomere-Telomerase
System,
Fig. 3 Case 1, Mus strain with 20 kb telomeres; case 2,
Mus strain with 20 kb telomeres (or case 1, donor animals;
case 2, cloned animals). In case 1, cells have longer telomeres and heterochromatin hoods than in case 2, but the
longevity is the same: the progressive gradual cell
senescence and the increasing probability of cell senescence activation are not a function of telomere absolute
initial length but of progressive subtelomere repression,
caused by relative telomere shortening (Fossel 2004).
(Figure from Libertini and Ferrara 2016a, modified and
redrawn)
– Keratinization of epidermis and hair cells.
– Detachment of cells of mucous membrane
from the lining of intestines or other body
cavities.
– Osteocytes phagocytized by osteoclasts.
– Transformation of erythroblasts in erythrocytes
with subsequent removal by macrophages.
– Apoptosis, an ordinate process of selfdestruction for the first time described in the
study of normal epatocytes (Kerr et al. 1972),
well documented for many tissues and organs
(e.g., biliary epithelial cells, gliocytes, kidneys,
pancreatic b-cells, liver, thyroid, type II alveolar
epithelial cells, cartilage, prostate, adipocytes,
bone, skeletal muscle [Libertini 2009]).
The cells eliminated by PCD are replaced by
duplication of appropriate stem cells. Cell turnover rates vary greatly depending on cell types
(Richardson et al. 2014). While some cell types
are renewed in a few days (e.g., in the intestinal
epithelium, “cells are replaced every 3–6 days”
[Alberts et al. 2013, p. 705]), for others, the
renewal takes place over a period of years (e.g.,
“bone has a turnover time of about 10 years in
humans” [Alberts et al. 2013, p. 705], and “the
heart is replaced approximately every 4.5 years”
[Anversa et al. 2006, p. 1457]).
Cell turnover is slackened and finally stopped
by cell duplication limits determined by the TST
system. The decline in cell turnover causes a
Telomere-Subtelomere-Telomerase System
reduction in the number of functional cells and
their replacement with nonspecific cells. This
determines a decline in the function of tissues
and organs increased by the dysfunction of cells
in gradual cell senescence and in cell senescence
(which involves the gradual cell senescence at the
highest level). These cells also show alterations of
extracellular secretion that cause dysfunctions in
other cells that otherwise would be perfectly functional (Libertini and Ferrara 2016a).
It should be noted that this functional decline
also affects perennial cells, i.e., not subject to cell
turnover, which therefore would not seem to have to
suffer from the aforementioned phenomena. However, as these cells depend for their functionality and
vitality from other cells that are subject to turnover,
the phenomena of gradual cell senescence, cell
senescence, and decline in cell turnover affecting
their satellite cells cause dysfunction and death in
perennial cells (Libertini and Ferrara 2016b). These
two types of decline, the first caused by direct
7
impairment of the functional cells of a tissue and
the second caused by impairment of the perennial
cells as a result of that of their satellite trophic cells
(which anyway may have other important functions), may be distinguished with the terms “direct”
and “indirect” aging.
This decline in the functionality of tissues and
organs determines a general fitness decline, that is
to say a lower ability to overcome difficulties
caused by external factors and, in the most
advanced stages, the sure death of the organism
(Libertini 2009).
In order to describe this set of phenomena, to
which it is necessary to add the greater vulnerability to cancer caused by telomere dysfunction
(DePinho 2000; Meena et al. 2015; Bernal and
Tusell 2018), the definition “atrophic syndrome”
has been proposed (Libertini 2009, p. 95).
A general scheme of these alterations is shown
in Fig. 4 and Table 1.
Telomere-Subtelomere-Telomerase System, Fig. 4 A scheme of aging phenomenon
8
Telomere-Subtelomere-Telomerase System
Telomere-Subtelomere-Telomerase System, Table 1 Atrophic syndrome of various tissues and organs due to direct
and indirect aging
Direct aging
Endothelial cells
►
Dermis and epidermis cells
Hair follicle cells
Oral cavity
Intestinal cells
Alveolar type II cells
Hepatocytes
Glomerular cells
Pancreatic b-cells
Myocytes
Cardiac myocytes
Osteoblasts
Spermatogonia
►
►
►
►
►
►
►
►
►
►
►
►
Bone marrow
Olfactory receptor cells
►
►
Other sensory neuronal cells with turnover
Indirect aging
Microglia cells that serve neurons
►
►
Astrocytes that serve neurons
►
Retina-pigmented cells that serve retina
photoreceptors
Deiters’ cells that serve hair cells of cochlea
►
►
Lens epithelial cells
►
Atherosclerosis and vascular
diseases
Skin atrophy
Baldness
Atrophy of oral mucosa
Intestinal and gastric atrophy
Emphysema
Hepatic atrophy
Renal insufficiency
Latent or mild diabetes
Muscle atrophy
Cardiac insufficiency
Osteoporosis
Diminished fertility, testicular
atrophy
Reduction of various cell types
Age-related olfactory
dysfunction
Function decline
Neuronal impairment and
death
Neuronal impairment and
death
Photoreceptor impairment
and death
Hair cell impairment and
death
Eye crystalline lens
impairment
It should be noted that cell turnover is not a
feature of all animals (e.g., the adult stage of the
worm Caenorhabditis elegans does not show cell
turnover and has a fixed number of cells) (Finch
1990).
The TST System and the Limits in Cell
Turnover as a General Defense Against
Cancer
TST system, cell turnover, and its progressive
decline appear as a very sophisticated machinery,
certainly determined and regulated by genes,
which reduce the fitness of the organism and,
►
Alzheimer’s disease
►
Parkinson’s disease
►
►
Age-related macular
degeneration
Presbycusis
►
Cataract
ultimately, favors the death of the individual.
These phenomena appear incompatible with the
thesis of nonadaptive aging, while on the contrary,
they are perfectly compatible with the opposite
paradigm of adaptive aging, for which they are
indispensable to allow its validity (Libertini
2015a, b).
As these phenomena invalidate the paradigm
of nonadaptive aging, the proponents of this thesis
have somehow tried to justify their existence by
attributing to cell senescence and to the limits
imposed on cell turnover the aim, favored by
natural selection, of a general defense against
cancer (Campisi 2000).
Telomere-Subtelomere-Telomerase System
This explanation is contradicted by many facts,
which, for the sake of brevity, cannot be explained
in detail here. However, we will mention some of
them, e.g., (i) existence of animals without any
age-related increase in mortality (animals with
“negligible senescence” [Finch 1990, p. 206])
and with no increase in cancer mortality in the
older ages (as it is implicitly demonstrated by the
invariability of mortality rates at any age);
(ii) gradual cell senescence, i.e., a mechanism
that reduces cell functionality and consequently
the fitness of the organism and does not make
sense as a defense against cancer; (iii) telomere
shortening that determines DNA instability and so
increases the chances of cancer (DePinho 2000);
and (iv) in mice, the selective elimination of
senescent cells (p16Ink4a+ cells), i.e., with functions altered by cell senescence, contrasts various
age-dependent manifestations, delays the progression of neoplastic diseases, and increased
lifespan, and this is against the possibility that
cell senescence might be a defense against cancer
(Libertini and Ferrara 2016a).
Consequently, the hypothesis that the TST and
the consequent phenomena might be a general
defense against cancer appears completely untenable because falsified by evidence (Libertini 2009;
Mitteldorf 2013; Libertini and Ferrara 2016a).
However, this thesis remains common in the
scientific community and supported by authoritative researchers (Campisi and Robert 2014), perhaps because its rejection would also imply the
rejection of the nonadaptive aging paradigm and
the transition to the adaptive aging paradigm:
“The hypothesis that telomerase is restricted to
achieve a net increase in lifespan via cancer prevention is certainly false. Were it not for the
unthinkability of the alternative – programmed
death – the theory would be dead in the water”
(Mitteldorf 2013, p. 1058). In fact, a paradigm
shift is always a difficult and of slow gestation
event (Kuhn 1962).
Conclusion
Gradual cell senescence, cell senescence, and
limits in cell duplication capacity appear to have
9
their main mechanisms and regulations in the TST
system. As these phenomena are the likely determinants of aging manifestations, the study of TST
system is essential to understand aging mechanisms. About the widespread idea that aging is
due to the accumulation of oxidized substances or
even of altered mitochondria, in a sort of modern
repetition of old theories that explain aging on the
basis of “wear and tear” phenomena, it is important to highlight an authoritative opinion: “Cells
do not senesce because of wear and tear, but
because they permit wear and tear to occur
because of an altered pattern of gene expression”
(Fossel 2004, p. 53) and that this altered gene
expression is under the control of telomere, telomerase, and subtelomere (Fossel 2004), i.e., the
STS system.
Cross-References
▶ Cell Senescence
▶ Effects of Telomerase Activation
▶ Gradual Cell Senescence
▶ Subtelomere
▶ Telomerase
▶ Telomeres
▶ Timeline of Aging Research
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