Review Article | Published:

Comparative genetics of longevity and cancer: insights from long-lived rodents

Nature Reviews Genetics volume 15, pages 531540 (2014) | Download Citation

Abstract

Mammals have evolved a remarkable diversity of ageing rates. Within the single order of Rodentia, maximum lifespans range from 4 years in mice to 32 years in naked mole rats. Cancer rates also differ substantially between cancer-prone mice and almost cancer-proof naked mole rats and blind mole rats. Recent progress in rodent comparative biology, together with the emergence of whole-genome sequence information, has opened opportunities for the discovery of genetic factors that control longevity and cancer susceptibility.

Key points

  • Comparative biology provides a powerful tool for understanding mechanisms of longevity and cancer resistance. The rodent clade is particularly suitable for the comparative study of ageing, as it contains species that differ nearly 10-fold in longevity and >1,000-fold in body mass.

  • Replicative senescence and repression of telomerase activity evolve in species with body mass greater than ~10 kg to counteract increased cancer risk that is conferred by larger numbers of cells. Small species with lifespans greater than ~10 years evolve additional telomere-independent tumour suppressor mechanisms.

  • There is evidence that long-lived species have more efficient genome maintenance mechanisms.

  • Different cancer-resistant species evolve distinct anticancer mechanisms. Cancer resistance is mediated by high-molecular-mass hyaluronan in the naked mole rat and depends on the interferon-mediated elimination of precancerous cells in the blind mole rat.

  • Recent advances in whole-genome sequencing open new avenues for identifying genes and pathways that are responsible for longevity and cancer resistance in exceptionally long-lived animals.

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Acknowledgements

The authors thank D. Promislow and M. van Meter for comments on the manuscript, and I. Seim for help with the figures. The work in the authors' laboratories is supported by the US National Institutes of Health (all authors); the Life Extension Foundation (V.G. and A.S.); and the Glenn Foundation for Medical Research (J.V.). The authors thank past and present members of their laboratories for their insights.

Author information

Affiliations

  1. University of Rochester, Rochester, New York 14627, USA.

    • Vera Gorbunova
    •  & Andrei Seluanov
  2. Albert Einstein College of Medicine, Bronx, New York 10461, USA.

    • Zhengdong Zhang
    •  & Jan Vijg
  3. Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Vadim N. Gladyshev

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Vera Gorbunova.

Glossary

Maximum lifespans

The maximum documented lifespans achieved by representatives of various species. They are typically documented in a captive environment protected from predators.

Telomerase

A ribonucleoprotein enzyme that elongates telomeres by synthesizing the telomeric repeat sequence using an RNA templete.

Pseudogenized genes

Genes that have lost their functional gene products, for example, through accumulation of frameshifts or stop codons. They also arise when a gene is processed by a retrotransposon such that a portion of the mRNA transcript of a gene is reverse transcribed back to DNA and inserted into chromosomal DNA.

Synteny

Shared genomic organization between related species. It is usually seen as a shared relative order of genes or other functional elements on a portion of a chromosome.

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DOI

https://doi.org/10.1038/nrg3728

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