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

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.

Figure 1. Evolution of tumor suppressor mechanisms

a, Slow aging and resistance to cancer have evolved multiple times in rodents. Numbers following the species name indicate maximum lifespan in years/body mass in grams^, . Red font highlights slow aging species with maximum lifespan greater than 20 years. Asterisks indicate species for which cancer resistance had been documented. b, Strong negative correlation between telomerase activity in somatic tissues and body mass. Telomerase is repressed in somatic tissues of large rodents. Adapted from. c, Cell proliferation patterns of primary fibroblasts isolated from species depending on their body mass and maximum lifespan. Small body mass and short lifespan 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 summarizing evolution of tumor-suppressor strategies depending on lifespan and body mass. When species evolve large body mass the cancer risk is increased due to increased number of cells. To mitigate this risk large body mass coevolves with repression of telomerase activity and replicative senescence. Small and short lived-species require fewer tumor suppressors. Finally, evolution of longer lifespan in small-bodies species is associated with telomere-independent tumor-suppressor mechanisms that stringently control cell proliferation and are characterized by very slow proliferation rate in vitro. Adapted from.

Figure 2. Longevity and anticancer adaptations in two mole rat species that independently evolved longevity and resistance to cancer

a, The naked mole rat is the longest lived rodent that is virtually cancer-proof^, . Cancer resistance in the naked mole rat is mediated by high molecular weight hyaluronan resulting in “early contact inhibition” — that is, hypersensitivity of naked mole rat cells to contact inhibition. High molecular weight hyaluronan may also contribute to naked mole rat longevity by increasing stress resistance due to hyaluronan’s antioxidant and cytoprotective properties. 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 high molecular weight hyaluronan, but in contrast to the naked mole rat, do not display early contact inhibition. Antioxidant properties of high molecular weight hyaluronan in the blind mole rat can increase stress resistance and contribute to longevity in this species.

Figure 3. Comparative genomics of aging

The figure illustrates strategies for comparative genomic analyses of rodents, starting with the genomes of organisms with widely different lifespans and focusing on genetic adaptations of long-lived species, such as the naked mole rat and the blind mole rat. Approaches are shown that 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 associated with longevity and cancer resistance. In addition, the use of omics approaches may support analyses across rodents, thereby characterizing common strategies employed by these organisms to regulate species lifespan and cancer susceptibility.

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 part of the figure depicts three groups of species whose ecology or phenotype is associated with evolution of longevity and anticancer adaptations. The blue banner below highlights such adaptations. On the left, body size >10 kg is associated with evolution of replicative senescence. The giant mammals such as elephants and whales are hypothesized to evolve novel tumor suppressor mechanisms that are absent in smaller species including human. Shown in the middle are small long-lived species. This group is characterized by diverse anticancer adaptations such as high molecular mass hyaluronan (HMM-HA), interferon (IFN)-triggered necrosis, or stringent cell cycle control. On the right, are long-lived bats that possibly evolved more efficient DNA repair and DNA damage systems and alterations in IGF1–GH axis. Question marks indicate adaptations for which exact molecular mechanisms are still unknown.