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 anticancer mechanism that limits cell proliferation. The difference between mice and humans led to the hypothesis that repression of telomerase in somatic cells has evolved as a tumor-suppressor adaptation in large, long-lived organisms. 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 show that telomerase activity does not coevolve with lifespan but instead coevolves with body mass: larger rodents repress telomerase activity in somatic cells. These results suggest that large body mass presents a greater risk of cancer than long lifespan, and large animals evolve repression of telomerase activity to mitigate that risk.
The study is discussed pretty well in this University of Rochester press release:
"Mice express telomerase in all their cells, which helps them heal dramatically fast," says Gorbunova. "Skin lesions heal much faster in mice, and after surgery a mouse's recovery time is far shorter than a human's. It would be nice to have that healing power, but the flip side of it is runaway cell reproduction -- cancer."
Up until now, scientists assumed that mice could afford to express telomerase, and thereby benefit from its curative powers, because their natural risk of developing cancer is low -- they simply die before there's much likelihood of one of their cells becoming cancerous.
"Most people don't know that if you put mice in a cage so the cat can't eat them, 90 percent of them will die of cancer," says Gorbunova.
I for one didn't know that. Of course, there is no paradox here -- early reproduction in mice has a much higher impact on their fitness than late reproduction, and they really shouldn't live long enough to compete reproductively with their daughters -- if they can devote that late reproductive effort to earlier reproduction, they certainly should do so.
But isn't it interesting that cancer in particular should be a high risk for late-living mice, and that it might be linked to the facility for healing early injuries?
Telomerase has long been recognized as one of the big baddies behind most cancers. Here's a paragraph from a 2001 review by Shay and colleagues:
Telomerase, a eukaryotic ribonucleoprotein (RNP) complex (26-33), helps to stabilize telomere length in human stem cells, reproductive cells (34) and cancer cells (35,36) by adding TTAGGG repeats onto the telomeres using its intrinsic RNA as a template for reverse transcription (37). Telomerase activity has been found in almost all human tumors but not in adjacent normal cells (35,36). The most prominent hypothesis is that maintenance of telomere stability is required for the long-term proliferation of tumors (38-42). Thus, escape from cellular senescence and becoming immortal by activating telomerase, or an alternative mechanism to maintain telomeres (43), constitutes an additional step in oncogenesis that most tumors require for their ongoing proliferation. This makes telomerase a target not only for cancer diagnosis but also for the development of novel anti-cancer therapeutic agents.
The study of telomerase knockout mice has shown that they get messed up in some ways characteristic of aging (e.g., grey hair, hair loss) and that they start having wounds in places with chronic mechanical stresses, like the distal limbs, snout, and throat (Rudolph et al. 1999). Additionally, old telomerase deficient mice had slow wound healing. In contrast, they did not suffer generalized effects of aging to other organ systems -- the effects seem to be concentrated in the skin. This makes some sense because the skin functions by attrition -- constantly wearing off into the environment and fixing itself based on environmental insults. The other system that depends on constant loss, the blood, was also affected by the lack of telomerase, with the rate of blood cell replenishment significantly lower in older telomerase-knockout mice.
Kim and colleagues (2002) presented a good review of the relation of telomeres to cancer and aging, and mention the relation to wound healing from several different studies. It's a good review of the literature to that point, and they also discuss a number of other proteins besides telomerase that are associated with maintaining telomere structure or function.
The evolution of telomere stabilization has involved multiple pathways, and that does generate an apparent paradox: a deficiency in telomerase helps to trigger certain cancers. These manage to spread by a telomerase-independent pathway, which enables cell replication to continue without telomerase. In other words, there is no single cancer switch involving telomere length, and the removal of the ordinary regulator protein may cause other pathways to spiral out of control.
Kim S-H, Kaminker P, Campisi J. 2002. Telomeres, aging and cancer: in search of a happy ending. Oncogene 21:503-511. DOI link
Rudolph KL, Chang S, Lee H-W, Blasco M, Gottlieb GJ, Grieder C, DePinho RA. 1999. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96:701-712. DOI link
Seluanov A and 7 others. 2006. Telomerase activity coevolves with body mass not lifespan. Aging Cell (online early) DOI link
Shay JW, Zou Y, Hiyama E, Wright WE. 2001. Telomerase and cancer. Hum Mol Genet 10:677-685. Free full text