Article series: Disease mechanisms

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

Journal name:
Nature Reviews Genetics
Volume:
15,
Pages:
531–540
Year published:
DOI:
doi:10.1038/nrg3728
Published online

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.

At a glance

Figures

  1. Evolution of tumour suppressor mechanisms.
    Figure 1: Evolution of tumour suppressor mechanisms.

    a | Slow ageing and resistance to cancer have evolved multiple times in rodents. Maximum lifespan in years (yr) and body mass in grams of each of these species are shown1, 81. Red shading highlights slow-ageing species with maximum lifespans >20 years. Stars indicate species for which cancer resistance had been documented. b | Correlation of telomerase activity with body mass is shown. A strong negative correlation is observed between telomerase activity in somatic tissues and body mass. Telomerase is repressed in somatic tissues of large rodents. Error bars represent one standard deviation. c | Cell proliferation patterns are shown for primary fibroblasts isolated from species with different body mass and maximum lifespans. Small body mass and short lifespans correlate with rapid cell proliferation in vitro and the absence of replicative senescence. Large body mass (>10 kg) correlates with rapid cell proliferation in vitro followed by replicative senescence due to telomere shortening. Finally, cells of small but long-lived (maximum lifespan >10 years) animals tend to proliferate very slowly but do not enter replicative senescence. d | The model summarizes evolution of tumour suppressor strategies depending on lifespans and body mass. When species evolve large body mass, the cancer risk is increased owing to increased number of cells. To mitigate this risk, large body mass co-evolves with repression of telomerase activity and with replicative senescence. Small short-lived species require fewer tumour suppressors. Finally, evolution of longer lifespans in small species is associated with telomere-independent tumour suppressor mechanisms that stringently control cell proliferation, and the cells of these species are characterized by very slow proliferation rates in vitro. MYA, million years ago; N., north. Part b reproduced from Springer Age (Dordr.), 30, 2008, 111119, Rodents for comparative aging studies: from mice to beavers., Gorbunova, V., Bozzella, M. J. & Seluanov, A., figure 2a. With kind permission from Springer Science and Business Media. Part d reproduced with permission from Ref. 15 © 2008 Seluanov, A. et al. Aging Cell © Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland 2008.

  2. Two mole rat species independently evolved longevity and resistance to cancer.
    Figure 2: Two mole rat species independently evolved longevity and resistance to cancer.

    a | The naked mole rat is the longest-lived rodent that is almost cancer-proof11, 41. Cancer resistance in the naked mole rat is mediated by high-molecular-mass hyaluronan (HMM-HA), which results in early contact inhibition (that is, hypersensitivity of naked mole rat cells to contact inhibition). HMM-HA may also contribute to longevity by increasing stress resistance as a result of the antioxidant and cytoprotective properties of hyaluronan. b | The blind mole rat is one of the longest-lived rodents that is also resistant to cancer. Cancer resistance in the blind mole rat is mediated by an interferon-mediated necrotic cell death mechanism. Blind mole rat cells produce HMM-HA but, in contrast to naked mole rat cells, do not show early contact inhibition. Antioxidant properties of HMM-HA in the blind mole rat can increase stress resistance and contribute to longevity in this species. RB, retinoblastoma protein.

  3. Comparative genomics of ageing.
    Figure 3: Comparative genomics of ageing.

    Strategies for comparative genomic analyses of rodents are shown. Such analyses begin with the genomes of organisms with widely different lifespans and focus on genetic adaptations of long-lived species, such as the naked mole rat and the blind mole rat. These may lead to the identification of functionally relevant genes that contribute to the examined traits. For example, these approaches may uncover lineage-specific genetic changes that are associated with longevity and cancer resistance. In addition, the use of 'omic' approaches may support analyses across rodents, thereby characterizing common strategies used by these organisms to regulate species lifespan and cancer susceptibility. SNP, single-nucleotide polymorphism.

  4. Lineage-specific mechanisms of longevity and cancer resistance that evolved in species with diverse ecology could be adapted to benefit human health.
    Figure 4: Lineage-specific mechanisms of longevity and cancer resistance that evolved in species with diverse ecology could be adapted to benefit human health.

    The upper panel depicts three groups of species with an ecology or a phenotype that is associated with the evolution of longevity and anticancer adaptations, which are shown in the lower panel. Large body size (>10 kg) is associated with the evolution of replicative senescence (left panel). The giant mammals such as elephants and whales are hypothesized to evolve novel tumour suppressor mechanisms that are absent in smaller species, including humans. Small long-lived species are characterized by diverse anticancer adaptations, such as high-molecular-mass hyaluronan (HMM-HA), interferon-triggered necrosis and stringent cell cycle control (middle panel). Long-lived bats possibly evolved more efficient DNA damage repair systems, as well as alterations in the insulin-like growth factor 1 (IGF1)–growth hormone (GH) axis (right panel). Question marks indicate adaptations for which exact molecular mechanisms are still unknown. These longevity and anticancer mechanisms hold promise to benefit human health.

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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

Competing interests statement

The authors declare no competing interests.

Corresponding author

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Author details

  • Vera Gorbunova

    Vera Gorbunova is Professor at the Department of Biology at the University of Rochester, New York, USA, and co-director of the Rochester Ageing Research Center. She received her Ph.D. at the Weizmann Institute of Science, Rehovot, Israel, in 2000. She developed reporter systems for analysing the efficiency of DNA double-strand break repair and used them to study the changes in DNA repair capacity during ageing. She integrated evolutionary and molecular biology approaches to understand longevity and cancer resistance using a collection of rodents with diverse lifespans. She is currently studying molecular mechanisms that are responsible for more efficient genome maintenance in several long-lived mammalian species. Vera Gorbunova's homepage.

  • Andrei Seluanov

    Andrei Seluanov is Assistant Professor at the Department of Biology at the University of Rochester, New York, USA. He received his Ph.D. at the Weizmann Institute of Science, Rehovot, Israel in 1999. He applied comparative biology approaches to understand anticancer adaptations that evolved in diverse mammalian species. He determined mechanisms that are responsible for cancer resistance in the naked mole rat and the blind mole rat. He is currently investigating the role of hyaluronan in longevity of these species. Andrei Seluanov's homepage.

  • Zhengdong Zhang

    Zhengdong Zhang is an assistant professor in the Department of Genetics at Albert Einstein College of Medicine, New York, USA. He received his M.S. in computer science in 1998 and Ph.D. in biochemistry in 2002, both from the University of Houston, Texas, USA. His research interests are bioinformatics and systems biology, with a focus on algorithm development, data integration and software implementation. Zhengdong Zhang's homepage.

  • Vadim N. Gladyshev

    Vadim N. Gladyshev is Professor of Medicine at the Genetics Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. He is also an associate member of the Broad Institute, Cambridge, Massachusetts. He received his Ph.D. from Moscow State University, Russia, in 1992. He used genomic approaches to define mammalian selenoproteomes and to identify redox-active cysteine residues. Recently, he led efforts to sequence the genomes of exceptionally long-lived mammals — namely, the naked mole rat and the Brandt's bat. He is currently applying methods of comparative and functional genomics across mammals to identify genes and processes that contribute to longevity of these animals. Vadim N. Gladyshev's homepage.

  • Jan Vijg

    Jan Vijg is Professor and Chairman of the Department of Genetics at the Albert Einstein College of Medicine, New York, USA. He received his Ph.D. at the University of Leiden, The Netherlands, in 1987. He developed the first transgenic reporter mouse and Drosophila melanogaster models for studying mutagenesis in vivo, and subsequently used these models to study frequency and spectra of somatic mutations in different organs and tissues during ageing. He is currently developing single-cell, whole-genome sequencing methods to study somatic mutations and epimutations in cancer and ageing. Jan Vijg's homepage.

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