Cancer is a numbers game; mutations occur at some rate, and some of those mutations result in a cancerous cell. The more cells an individual has, the greater the risk of cancer, all other factors being equal. Of course those factors are not equal. For a physically large species to evolve to become physically large, it must also have evolved superior means of cancer suppression. As researchers explore the biochemistry of large and small mammals, from mice to whales, they are uncovering the mechanisms employed by large species to resist cancer, and which never evolved in smaller species. It is possible that some of these discoveries may lead to ways to prevent or treat cancer in humans, but practical applications resulting from the study of comparative biology remain a future prospect at the present time. Even where specific genes and interactions are identified, it remains unclear as to how best to make use of them in human medicine in a sufficiently safe way to pass muster with the very conservative regulatory bodies.
Across the animal kingdom, cancer risk should, in principle, scale with increasing body size and lifespan. Larger animals contain vastly more cells, and longer lives permit many rounds of cell division, both of which increase the probability of accumulating mutations and undergoing malignant transformation. However, this expectation does not always hold in nature. Some of the largest and longest-lived animals, such as whales and elephants, exhibit a remarkably low cancer incidence.
This incongruency, known as Peto's paradox, suggests that evolutionary pressures have endowed these animals with unusually potent anticancer mechanisms to counteract the mutational burden associated with large bodies and extended lifespans. Indeed, studies in elephants revealed that these large animals have evolved multiple copies of the tumor suppressor TP53 gene, which is associated with an increased apoptotic response that allows the prompt elimination of damaged cells before they become precancerous. Interestingly, sequencing and analysis of several whale genomes, including the bowhead whale - known to live for over 200 years - did not reveal the TP53 duplications seen in elephants, suggesting that whales rely on alternative, previously uncharacterized, anticancer strategies.
In this commentary, we discuss a recent study showing that a key contributor to bowhead whales' exceptional lifespan and cancer resistance is their superior genome maintenance capacity. We further discuss DNA repair as a determinant of longevity in other long-lived species and explore how these naturally occurring mechanisms could be harnessed to improve genome integrity, reduce cancer risk, and promote healthy aging in humans.
Link: https://doi.org/10.1002/1878-0261.70250
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