The naked mole rat (Heterocephalus glaber) displays exceptional longevity, with a maximum lifespan exceeding 30 years1, 2, 3. This is the longest reported lifespan for a rodent species and is especially striking considering the small body mass of the naked mole rat. In comparison, a similarly sized house mouse has a maximum lifespan of 4 years4, 5. In addition to their longevity, naked mole rats show an unusual resistance to cancer. Multi-year observations of large naked mole-rat colonies did not detect a single incidence of cancer2, 6. Here we identify a mechanism responsible for the naked mole rat’s cancer resistance. We found that naked mole-rat fibroblasts secrete extremely high-molecular-mass hyaluronan (HA), which is over five times larger than human or mouse HA. This high-molecular-mass HA accumulates abundantly in naked mole-rat tissues owing to the decreased activity of HA-degrading enzymes and a unique sequence of hyaluronan synthase 2 (HAS2). Furthermore, the naked mole-rat cells are more sensitive to HA signalling, as they have a higher affinity to HA compared with mouse or human cells. Perturbation of the signalling pathways sufficient for malignant transformation of mouse fibroblasts fails to transform naked mole-rat cells. However, once high-molecular-mass HA is removed by either knocking down HAS2 or overexpressing the HA-degrading enzyme, HYAL2, naked mole-rat cells become susceptible to malignant transformation and readily form tumours in mice. We speculate that naked mole rats have evolved a higher concentration of HA in the skin to provide skin elasticity needed for life in underground tunnels. This trait may have then been co-opted to provide cancer resistance and longevity to this species.
At a glance
- The naked mole rat—a new record for the oldest living rodent. Sci. Aging Knowl. Environ. 2002, pe7 (2002) &
- Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species. J. Comp. Physiol. B 178, 439–445 (2008)
- Genome sequencing reveals insights into physiology and longevity of the naked mole rat. Nature 479, 223–227 (2011) et al.
- Growth curves and survival characteristics of the animals used in the Biomarkers of Aging Program. J. Gerontol. A 54, B492–B501 (1999) et al.
- HAGR: the Human Ageing Genomic Resources. Nucleic Acids Res. 33, D537–D543 (2005) , &
- Spontaneous histologic lesions of the adult naked mole rat (Heterocephalus glaber): A retrospective survey of lesions in a zoo population. Vet. Pathol.. http://dx.doi.org/10.1177/0300985812471543 (2013) , , &
- Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat. Proc. Natl Acad. Sci. USA 106, 19352–19357 (2009) et al.
- Contact inhibition and malignancy. Nature 281, 259–262 (1979)
- Hyaluronan: from extracellular glue to pericellular cue. Nature Rev. Cancer 4, 528–539 (2004)
- Hyaluronan and CD44 antagonize mitogen-dependent cyclin D1 expression in mesenchymal cells. J. Cell Biol. 176, 535–544 (2007) et al.
- Rheostatic signaling by CD44 and hyaluronan. Cell. Signal. 21, 651–655 (2009) &
- Hyaluronic acid in human articular cartilage. Age-related changes in content and size. Biochem. J. 250, 435–441 (1988) , &
- Hyaluronan in tissue injury and repair. Annu. Rev. Cell Dev. Biol. 23, 435–461 (2007) , &
- Molecular identification of a putative human hyaluronan synthase. J. Biol. Chem. 271, 22945–22948 (1996) &
- Hyaluronidases: their genomics, structures, and mechanisms of action. Chem. Rev. 106, 818–839 (2006) &
- CD44: from adhesion molecules to signalling regulators. Nature Rev. Mol. Cell Biol. 4, 33–45 (2003) , &
- The NF2 tumor suppressor gene product, merlin, mediates contact inhibition of growth through interactions with CD44. Genes Dev. 15, 968–980 (2001) et al.
- Enumeration of the simian virus 40 early region elements necessary for human cell transformation. Mol. Cell. Biol. 22, 2111–2123 (2002) et al.
- Species- and cell type-specific requirements for cellular transformation. Cancer Cell 6, 171–183 (2004) , , &
- Resistance to experimental tumorigenesis in cells of a long-lived mammal, the naked mole-rat (Heterocephalus glaber). Aging Cell 9, 626–635 (2010) , , , &
- An agarose gel electrophoretic method for analysis of hyaluronan molecular weight distribution. Anal. Biochem. 219, 278–287 (1994) &
- Supplementary Figures (7.5 MB)
This file contains Supplementary Figures 1-9.