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).