Distinct tumor suppressor mechanisms evolve in rodent species that differ in size and lifespan

Aging Cell. 2008 Dec;7(6):813-23. doi: 10.1111/j.1474-9726.2008.00431.x. Epub 2008 Sep 5.


Large, long-lived species experience more lifetime cell divisions and hence a greater risk of spontaneous tumor formation than smaller, short-lived species. Large, long-lived species are thus expected to evolve more elaborate tumor suppressor systems. In previous work, we showed that telomerase activity coevolves with body mass, but not lifespan, in rodents: telomerase activity is repressed in the somatic tissues of large rodent species but remains active in small ones. Without telomerase activity, the telomeres of replicating cells become progressively shorter until, at some critical length, cells stop dividing. 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. Here, we examined the proliferation of fibroblasts from 15 rodent species with diverse body sizes and lifespans. We show that, consistent with repressed telomerase activity, fibroblasts from large rodents undergo replicative senescence accompanied by telomere shortening and overexpression of p16(Ink4a) and p21(Cip1/Waf1) cycline-dependent kinase inhibitors. Interestingly, small rodents with different lifespans show a striking difference: cells from small shorter-lived species display continuous rapid proliferation, whereas cells from small long-lived species display continuous slow proliferation. We hypothesize that cells of small long-lived rodents, lacking replicative senescence, have evolved alternative tumor-suppressor mechanisms that 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Evolution*
  • Body Size / genetics*
  • Body Size / physiology
  • Cells, Cultured
  • Cellular Senescence / genetics
  • Cricetinae
  • Genes, Tumor Suppressor / physiology*
  • Guinea Pigs
  • Longevity / genetics*
  • Longevity / physiology
  • Mice
  • Mice, Inbred C57BL
  • Rats
  • Rats, Inbred BN
  • Rats, Inbred F344
  • Rodentia / genetics*
  • Rodentia / physiology
  • Telomerase / physiology
  • Telomere / metabolism


  • Telomerase