Telomeric aging: mitotic clock or stress indicator?

Citation: Koliada AK, Krasnenkov DS and Vaiserman AM (2015) Telomeric aging: mitotic clock or stress indicator? Front. Genet. 6:82. Telomeres are regions of tandem arrays of TTAGGG repeats and associated proteins located at chromosomal ends that allow cells to distinguish chromosome ends from double-strand breaks and protect chromosomes from end-to-end fusion, recombination, and degradation (Houben et al., 2008). Telomeres are not linear structures, telomeric DNA is maintained in a loop structure due to many key proteins. This structure serves to protect the ends of chromosomes (Neidle and Parkin-son, 2003). Telomeres are subjected to shortening at each cycle of cell division due to incomplete synthesis of the lagging strand during DNA replication owing to the inability of DNA polymerase to completely replicate the ends of chromosome DNA (" end-replication problem ") (Muraki et al., 2012). Therefore, they assume to limit the number of cell cycles and act as a " mitotic clock " (Olovnikov, 1996). Shortened telomeres cause decreased proliferative potential, thus triggering senescence (Blackburn et al., 2006). Telomere length (TL) is highly heterogeneous in somatic cells, but generally decreases with age in proliferating tissues thereby constituting a barrier to tumorigenesis but also contributing to age-related loss of stem cells. Repair of critically short (" uncapped ") telomeres by telomerase enzyme, which elongates chromosomal ends by synthesizing new telomeric repeats, is limited in somatic cells, and cellular senescence, apoptosis and/or a permanent cell cycle arrest in G1 phase are triggered by a critical accumulation of uncapped telomeres (D'Souza et al., 2013). Telomerase maintains TL by adding telomeric DNA repeats to chromosome ends in prenatal tissues, gametes, stem cells, and cancerous cells. In proliferative somatic cells, it is usually inactive or expressed at levels that are not high enough to maintain the stable TL (Hiyama and Hiyama, 2007). Alternative lengthening of telomeres (ALT) pathway is a recombination-mediated process, which can increase telomere length by thousands of base-pairs within a few somatic cell cycles (Liu et al., 2007). Telomere-initiated cellular senescence is a mechanism of eliminating cells with damaged DNA and protection against cancerogenesis (through the activation mechanisms of cell cycle arrest or double-strand breaks-induced apoptosis), but it may also impair the cell function contributing to degenerative organ failure and organismal aging (Chen et al., 2007; Campisi, 2013). Cellular senes-cence (a state of irreversible cell cycle arrest) occurring in response to a telomere shortening may be regulated by immune surveillance. In this process, …