Telomerase as non-functional phylogenetic relict in small and short-lived animals?
While most mammalian adults, including humans, express telomerase almost exclusively in the germline and a few specialized cell types and have short telomeres (< 25 kb), most rodents express telomerase in both the germline and a wide range of somatic tissues and have long telomeres (25-150 kb) (Gomes et al. 2011). It suggests that rodents do not use telomere length to regulate replicative aging. A similar lack of telomere-based replicative aging is predicted in Lagomorpha (rabbits, pikas, and hares), as prolonged tissue cultures derived from various lagomorph species show no growth arrest or decrease in doubling time but have either very long telomere arrays or detectable telomere activity (Forsyth et al. 2005). Similarly, very long telomeres and expression of telomerase were observed in adult tissues in species of Afrosoricida (golden moles and tenrecs), Didelphimorphia (opossums), and Macroscelidea (elephant shrew) (Gomes et al. 2011). A comparative study of telomerase activity and telomere length revealed that the ancestral mammalian phenotype had human-like telomeres with repressed telomerase activity, and the human-type of telomeres was switched to rodent-type at least 5-7 times during mammalian evolution. Furthermore, it was discovered that telomere length in mammals inversely correlates with lifespan (longer telomeres are found in short-lived mammal species) and telomerase activity in somatic cells inversely correlates with body mass (telomerase activity in somatic cells is found in small mammal species such as small rodents) (Seluanov et al. 2007; Gomes et al. 2010).
Body size and lifespan are factors that influence cancer risk because cancer develops through somatic evolution with genetic and epigenetic instability causing fitness variation among cells. Therefore, one can assume that larger organisms, which typically have longer lifespans, are more susceptible to cancer. In fact, however, there is no correlation between the body size, longevity, and cancer across species (known as Peto’s Paradox) (Caulin and Maley 2011).
To explain the Peto’s paradox, it has been suggested that larger and longer-lived mammals repress telomerase activity in their somatic cells as protective mechanism against cancer development, and accordingly, small short-lived mammals have telomerase widely active, as there is no need to repress it (Seluanov et al. 2007). On the other hand, this assumption may evoke the idea that telomerase in these species is present only as non-functional phylogenetic relict, and this “presence without purpose’ can be questioned regarding why it is worthy for cells to express telomerase (or anything else) if there is no need for it. Furthermore, there is substantial evidence that cancer incidence is a taxonomically widespread phenomenon, observed both in captivity and in wild populations, with no increase in cancer incidence in the long-lived indeterminate growers (Athena Aktipis et al. 2015; Olsson et al. 2018; Kitsoulis et al. 2020). For example, neoplasia was found at necropsy in 2.75 % of mammals, 1.89 % of birds, and 2.19 % of reptiles. Additionally, neoplasia has not been reported in Galapagos giant tortoises (Effron et al. 1977), which live for more than 150 years and, like many other reptile species, are ectotherms with indeterminate growth (Hariharan et al. 2016; Hoekstra et al. 2020). This collectively indicates that the risk of cancer is not elevated in the species with indeterminate growth and somatic telomerase activity, and that the proposed telomerase repression as a cancer protection is less straightforward than was previously believed (Olsson et al. 2018). Finally, a plenty of evidence suggests that numerous anti-cancer mechanisms other than telomere attrition have evolved (Caulin and Maley 2011; Tian et al. 2018).