A preprint published in bioRxiv has partially explained the lifespan of the bowhead whale through its duplication of CDKN2C, which regulates how cells divide.
Peto’s paradox
It would be logical for longer-lived animals to be more susceptible to cancer than shorter-lived animals over time, as they have longer to develop the mutations that lead to cancer. However, this is not the case; there is no correlation between lifespan and cancer. This counterintuitive finding is known as Peto’s paradox, which was originally discovered in 1975 [1] and backed up by studies performed this year [2].
This fact can be explained by genes that increase resilience to genomic instability. Mice that overexpress the tumor suppressor p53 and the cell cycle regulator CDKN2A live longer and are more resistant to cancer [3], despite the fact that CDKN2A is associated with cellular senescence. Increasing the presence of SIRT1, which protects against telomere attrition, protects mice against some aging-associated diseases, including cancer [4].
A whale of a lifespan
Unlike most cetaceans, which normally live between 50 and 70 years, the bowhead whale is estimated to have a lifespan of over two centuries [5]. It is far longer-lived than the right whale, which it diverged from between four and five million years ago. To live this long, it must have some extra resistance to cancer, even beyond the formidable cancer protection of other cetaceans.
Comparing the genes of the bowhead and its nearest relatives, the researchers found that CDKN2C is duplicated in a way that does not occur in related whales. Retrotransposition, a form of genetic mutation, had copied this gene into the cetacean-specific LINE L1 genetic sequence, which drives its substantial expression. Previous research has shown that this gene suppresses cancerous tumors [6].
This abundance of CDKN2C also dramatically slows down the cellular cycle of division and replication. In a way, this is related to the maxim ‘live slow, die old’ in longevity research, but this extra slowdown also gives cells more time to prevent cancerous mutations from occurring. While the researchers have not fully explored the biochemistry involved, they hypothesize that this extra time allows two related genes to do more work: CDKN2A, which inhibits cellular death by apoptosis, and CDKN2D, which enhances DNA repair mechanisms. Apparently, the cells are not just dividing more slowly; they are being more careful in their division.
On the other hand, the researchers also hypothesize that this protection leads to trade-offs in other areas (antagonistic pleiotropy). While it has not been proven, they suggest that this mutation may lead to slow maturation and reduced male fertility in these whales.
Conclusion
It is, of course, completely infeasible to do direct lifespan experiments on whales, even moreso than on humans; any such experiment would take mutliple (current) human lifetimes to complete. However, the gene CDKN2C exists in mice and in people. If this approach can be proven to work through trials, genetic or RNA-based therapies that cause the overexpression of this gene may become part of a near-term approach towards extending human lifespan.
Literature
[1] Peto, R., Roe, F. J., Lee, P. N., Levy, L., & Clack, J. (1975). Cancer and ageing in mice and men. British journal of cancer, 32(4), 411-426.
[2] Vincze, O., Colchero, F., Lemaître, J. F., Conde, D. A., Pavard, S., Bieuville, M., … & Giraudeau, M. (2022). Cancer risk across mammals. Nature, 601(7892), 263-267.
[3] Matheu, A., Maraver, A., Klatt, P., Flores, I., Garcia-Cao, I., Borras, C., … & Serrano, M. (2007). Delayed ageing through damage protection by the Arf/p53 pathway. Nature, 448(7151), 375-379.
[4] Palacios, J. A., Herranz, D., De Bonis, M. L., Velasco, S., Serrano, M., & Blasco, M. A. (2010). SIRT1 contributes to telomere maintenance and augments global homologous recombination. Journal of Cell Biology, 191(7), 1299-1313.
[5] George, J. C., Follmann, E., Zeh, J., Sousa, M., Tarpley, R., Suydam, R., & Horstmann-Dehn, L. (2011). A new way to estimate the age of bowhead whales (Balaena mysticetus) using ovarian corpora counts. Canadian Journal of Zoology, 89(9), 840-852.
[6] Franklin, D. S., Godfrey, V. L., O’Brien, D. A., Deng, C., & Xiong, Y. (2000). Functional collaboration between different cyclin-dependent kinase inhibitors suppresses tumor growth with distinct tissue specificity. Molecular and cellular biology, 20(16), 6147-6158.
