Telomeres as a component of organismal aging
Aging theories are classified
into two types based on the molecular and cellular mechanisms associated
with biological aging: non-programmed (stochastic) and programmed
(Davidovic et al. 2010; Jin 2010; Fathi et al. 2019). Stochastic
theories propose that aging is the result of accumulating random changes
that negatively affect biological systems and are a result of natural
processes such as effects of toxic byproducts, telomere shortening,
various other molecular damage, etc. The programmed theory of aging
proposes that aging is the result of a progression of changes in
expression of specific genes, such as those of the immune system or
telomerase activity, both of which decline over time (Davidovic et al.
2010; Jin 2010; Fathi et al. 2019). Accumulating evidence indicate 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 eukaryotic chromosome
ends that consist of short DNA repeats with well-defined sequence
composition and telomere-specific protein complexes (Blackburn 1990).
Through a multiprotein structure called a telomere cap, telomeres allow
cells to distinguish natural chromosome ends from chromosome breaks, and
formation of telomere caps requires a satisfactory length of telomeric
DNA (Blackburn 1991; Capkova Frydrychova et al. 2009; Mason et al.
2011). Due to the limitations of semiconservative DNA replication and
the inability of conventional DNA polymerase to fully replicate the end
of linear DNA strands, telomere length is shortened with each round of
cell division. When telomeres become critically short, a DNA damage
checkpoint response induces cell senescence (Greenberg 2005), which not
only acts as a major determinant of organismal development (Ulaner and
Giudice 1997; Jiang et al. 2007) but also aging and age-related diseases
such as dyskeratosis congenita, pulmonary fibrosis, and aplastic anemia
(Kong et al. 2007). In a variety of mammal and avian species, a positive
correlation has been observed between telomere shortening rate or
telomere length early in life and realized lifespan, which is consistent
with the fact that critically short telomeres limit replicative
potential and, thus, tissue or organ regeneration potential. As a
result, telomere length and, more importantly, the rate of telomere
shortening may be used to predict lifespan (Heidinger et al. 2011;
Whittemore et al. 2019). In this regard, it is worth noting that the
species’ ability to defend against some DNA damaging agents, such as
ultraviolet light or oxidative stress, that can cause telomere
shortening correlates with the species’ lifespan (Hart and Setlow 1974;
Hall et al. 1984; von Zglinicki 2002; Ma et al. 2012). Telomere length
has been linked to a variety of stressor exposures, and telomere length
is thought to be a potential molecular-level measure of allostatic load,
which is the cumulative burden of chronic stress and life events (Law et
al. 2016; Guidi et al. 2021). Because allostatic load includes
dysregulation of multiple physiological systems, telomere length and
attrition rate may provide an index of cumulative damage inputs from
multiple regulatory systems and cellular structures (Tomiyama et al.
2012) and can act as somatic integrity biomarkers (Young 2018).
Telomere shortening can be circumvented by the extension of telomeric
DNA via special telomere maintenance mechanisms such as the activity of
telomerase, retrotransposition of special telomeric elements, or gene
conversion (Mason et al. 2011, 2016), and the most common mechanism of
telomere elongation involves telomerase activity. Telomerase is a
specialized reverse transcriptase that uses an RNA template to
repeatedly synthesize a short telomeric sequence onto the chromosome
ends (Blackburn 2005; Mason et al. 2015). Telomerase activity is tightly
regulated. In humans, telomerase activity is highest during
embryogenesis and gradually decreases in most somatic cells later in
development, suggesting that telomerase may play a role in fetal tissue
differentiation and development (Wright et al. 1996; Ulaner and Giudice
1997). In adult humans, most somatic cell types are telomerase-negative;
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 cell
senescence (Hiyama and Hiyama 2007; Choudhary et al. 2012). Telomerase
in adult humans is, however, 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 cells are, due to their high telomerase activity,
considered immortal having the capacity of indefinite self-renewal and
proliferation (Hiyama and Hiyama 2007).