A. Seluanov, C. Hine, M. Bozzella, A.A. Ribeiro, K.C. Catania, D.C. Presgraves, V. Gorbunova

In multicellular organisms, telomerase is required to maintain telomere length in the germline but is dispensable in the soma. Mice, for example, express telomerase in somatic and germline tissues, while humans express telomerase almost exclusively in the germline. As a result, when telomeres of human somatic cells reach a critical length the cells enter irreversible growth arrest called replicative senescence. Replicative senescence is believed to be an anti-cancer mechanism that limits cell proliferation. We tested whether regulation of telomerase activity coevolves with lifespan and body mass using comparative analysis of 15 rodent species with highly diverse lifespans and body masses. Here we showed that telomerase activity does not coevolve with lifespan but instead coevolves with body mass: larger rodents repress telomerase activity in somatic cells. Consistent with repressed telomerase activity, fibroblasts from large rodents undergo replicative senescence accompanied by telomere shortening and overexpression of p16 and p21 cycline dependent kinase inhibitors. Large, long-lived species experience more lifetime cell divisions - and hence a greater risk of spontaneous tumor formation - than smaller, short-lived species. Our findings therefore suggested that repression of telomerase activity mitigates the increased risk of cancer in larger bodied species but not necessarily longer-lived ones. These findings imply that other tumor suppressor mechanisms must mitigate increased cancer risk in long-lived species. Interestingly, small rodents with different lifespans show a striking difference: cells from small, short-lived species display rapid and continuous proliferation, whereas cells from small, long-lived species display a novel slow-proliferation pattern. We hypothesize that cells of small long-lived rodents, which do not use replicative senescence, evolve alternative tumor-suppressor mechanisms, which prevent inappropriate cell division in vivo and slow cell growth in vitro. Thus, large-bodied species and small but long-lived species have evolved distinct tumor suppressor mechanisms.

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