What is Known of Anti-Cancer Mechanisms in Longer-Lived Species

Risk of cancer is a function of cell numbers and division rates, but also of the efficiency of cancer suppression mechanisms. In order for a species to evolve a longer life span, cancer suppression must improve. In order for a species to evolve a larger body mass, cancer suppression must improve. As this paper notes, comparatively little is definitively known of the anti-cancer strategies of various long-lived mammals. Elephants duplicate the tumor suppressor gene TP53, but that doesn't occur in other large and long-lived species, so it is likely that each species takes its own path. It is far too early to say whether what can be learned from this line of research into comparative biology might lead to ways to suppress cancer risk in humans.

The first indications that elephant lineage contains genetic strategies to enhance cancer protection mechanisms came from studies that found that elephants have a lower cancer rate than expected based on their body size compared with other mammalian species. This was related to multiple copies of the TP53 gene, widely known as a crucial tumor suppressor gene (TSG), preventing the growth and survival of potentially malignant cells. While most mammals have only one TP53 copy in their genome, the African bush elephant genome contains 19 extra copies of TP53, 9 to 20 copies were identified in the Asian elephant genome, and 21 to 24 copies were found in the African forest elephant genomes.

Many genomes of giant whales have been sequenced thus far but did not reveal duplications of TP53 similar to those in elephants, suggesting that they evolved different anticancer adaptations. Comparative genomics in the bowhead whale, the longest-lived whale, identified genes under positive selection and specific mutations in genes linked to cancer, aging, the cell cycle, and DNA repair, but without conclusive experiments. Researchers reported signals of positive selection in seven TSGs: CXCR2, ADAMTS8, ANXA1, DAB2, DSC3, EPHA2, and TMPRSS11A. Moreover, they revealed that the turnover rate of TSGs was almost 2.4 times faster in cetaceans than in other mammals, showing 71 duplicated genes in at least one of the Cetaceans species. Most duplication events and positively selected genes were identified in the lineage of large baleen whales, suggesting that they have evolved additional anticancer mechanisms.

As in other mammalian lineages, the maximum life span and body mass are correlated in primates, and the great apes are the largest body size and long-lived species among them. Researchers found only five genes with positive selection signals for the great ape lineage (IRF3, SCRN3, DIAPH2, GASK1B, and SELENO), all of which have functions related to cancer development and inflammatory responses. The results show that the evolution of strategies for cancer resistance in the primate lineage is quite diverse, with modifications that can be found at the coding, expression, and regulatory levels, and that although the great apes lineage provides evidence of specific changes capable of giving greater longevity to the species of the group, the understanding of the relationship with cancer resistance is still developing for nonhuman species and needs to be further investigated.

Bats have exceptional longevity given their body size, but there is still little data on how they evolved their extended lifespan and resisted cancer. Previous studies found reduced GH-IGF1 signaling associated with increased resistance to cancer. Additionally, it has been reported that long-lived bats have resilient telomeres that remain long despite advanced age. Also, bats do not show an increased level of mitochondrial damage given their metabolic rate, suggesting that this group evolved adaptations in their DNA repair and maintenance mechanisms. These molecular adaptations were underpinned by a study showing that bats exhibit a unique age-related regulation of genes associated with DNA repair, immunity, and tumor suppression that underlies extended bat longevity. Furthermore, it was reported that long-lived bats possess specific miRNAs that function as tumor suppressors. This provides a new potential molecular mechanism to decrease cancer risk not yet identified in any other lineage.

Link: https://doi.org/10.1590/1678-4685-GMB-2022-0133

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