Telomeres play a vital role in many cellular processes because they protect chromosomes from end-to-end fusions and chromosomal instability ( Aksenova and Mirkin, 2019 ). The repetitive TTAGGG sequences that make up telomeric DNA are bound by a protective protein complex called Shelterin. This complex, together with proteins involved in chromatin remodeling, forms the structure of telomeres, thereby protecting the ends of chromosomes ( Tomita, 2018 ). Two key features of telomeres are the formation of DNA loops at the ends of chromosomes (T-loops) and transcription of telomeres to form G-rich RNA (TERRA). In the t-loop structure, the 3′-end of the G-rich strand protrudes as a single-stranded protrusion known as the G-loop ( Turner et al., 2019). This protruding end of the G strand curls backward, forming a T-loop, and intrudes into the 5′-duplex of the double-stranded telomere duplex, thereby forming the so-called D-loop. This structure ensures the placement of free DNA ends within the nucleoprotein structure ( Turner et al., 2019 ). The formation of such loop structures is an important mechanism that protects telomeres from premature degradation. Despite their heterochromatin state, telomeres are able to be actively transcribed, resulting in the production of long noncoding RNAs called TERRA (telomere repeats containing RNA). TERRA molecules play crucial roles in telomere biology, including regulation of telomerase activity and heterochromatin formation at the ends of chromosomes ( Bettin et al., 2019 ; Lalonde and Chartrand, 2020 ).

In each division cycle of a somatic cell, telomeres are shortened by 50-200 bp due to incomplete synthesis of the lagging strand during DNA replication ( Srinivas et al., 2020 ). This is due to the inability of DNA polymerase to completely replicate the 3′-end of the DNA chain (a phenomenon commonly referred to as the “end replication problem”) ( Watson, 1972 ; Olovnikov, 1973 ). Moreover, since the G-rich telomere repeat sequence is known to be very susceptible to oxidative damage ( Oikawa and Kawanishi, 1999 ), telomeres can be directly damaged by oxidative stress, leading to cell aging ( Barnes et al., 2019.). Given this, it has recently been suggested that telomere-induced aging of postmitotic cells may be a key factor in aging ( von Zglinicki et al., 2020 ).

In culture, somatic cells have a limited replication potential, reaching a point in time when cell division ceases. This point in time is characterized by the shortening (“depletion”) of certain telomeres to a critical size incompatible with their function, leading to cell cycle arrest and cell aging. Therefore, TL is thought to limit the number of cell divisions and act as a “mitotic clock” in the cell ( Olovnikov, 1996 ), and telomere shortening may cause a decrease in proliferative potential and be a marker of cellular aging ( Liu et al., 2019a). In multicellular organisms, TLs are very heterogeneous in different tissues and cell types, depending at least in part on the rate of tissue-specific proliferation, but they generally tend to decrease with age in all proliferating tissues ( Demanelis et al., 2020 ).

The size of critically short (“unclosed”) telomeres can be stabilized by telomerase, a reverse transcriptase enzyme that can lengthen the ends of chromosomes de novo . The two major components of human telomerase are telomerase reverse transcriptase (TERT) and telomerase RNA-component (TERC), which serve as the matrix for telomere elongation (Rubtsova and Dontsova, 2020). In humans, this enzyme is known to be expressed early in intrauterine development, is inactivated in most adult cells except germline cells, embryonic stem cells, and immune cells, and is reactivated in most cancers ( Shay and Wright, 2019 ) .) Telomerase has been shown to be insufficient to maintain normal TL even in proliferating stem cells that can express it; consequently, these cells also experience gradual telomere shortening ( Lai et al., 2018 ; Celtikci et al., 2020 ) ( Figure 1 ) . Since most human somatic cells have low or no telomerase activity, this leads to age-related telomere erosion and related pathological processes. Thus, telomerase activation is considered by some authors as a promising therapeutic method for the treatment of degenerative aging disorders (Bernardes de Jesus and Blasco, 2011 ; Prieto-Oliveira, 2020). However, although telomerase does have potential in anti-aging medicine, the fact that it is overexpressed in approximately 90% of human cancers raises doubts about the applicability of telomerase activators in clinical practice (Smith-Sonneborn, 2020).