Longevity Briefs: Do Bowhead Whales Hold The Secret To Lifespan Extension?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Larger organisms have more cells, and more cells mean more opportunities for cancer to occur, since cancer is an inherently random process. Yet the incidence of cancer in larger organisms is generally no higher (and is often lower) than it is in smaller organisms. This observation is known as Peto’s paradox, though it appears less paradoxical when you consider things from the perspective from an evolutionary perspective. Large organisms invest lots of time and energy into growing large, while producing fewer offspring than small animals in a ‘quality over quantity’ evolutionary strategy. While an elephant might produce fewer offspring than a rabbit, it’s a lot more likely to survive a harsh winter or a surge in predator population, for example.

Given that this evolutionary strategy relies on longevity, it’s perhaps more understandable why larger organisms might have evolved systems to mitigate the increased cancer risk that comes from having more cells. The question is, what are these systems and can we humans harness them in some way? Cancer is ultimately the result of damage to the DNA molecule, which is constantly occurring and being repaired within each of our cells. In this study, researchers examine DNA damage, repair, and cancer incidence in the cells of bowhead whales. Bowhead whales are the longest-lived species of mammal, attaining lifespans of over 200 years.

The discovery:

Researchers conducted their experiments in both human and bowhead whale fibroblast cells. Some large organisms like elephants achieve cancer resistance partly by shutting down cancer cells as soon as they mutate, thanks to increased activity of a critical cancer-suppressing protein called p53. However, the researchers found no evidence of increased p53 activity in bowhead whale fibroblasts, meaning this was unlikely to be the mechanism they were looking for.

They then asked whether bowhead whale fibroblasts could sustain more cancer-causing mutations or ‘oncogenic hits’ than human fibroblasts. Somewhat surprisingly, they found that the reverse was true – it took fewer oncogenic hits to turn bowhead whale fibroblasts cancerous than it took in human fibroblasts (though this might not hold true for other cell types). Since bowhead whales seemed neither more resilient when faced with oncogenic hits, nor more capable of shutting down cancer cells, the researchers suspected that the whales might be accumulating mutations at a lower rate, and this suspicion turned out to be correct. Upon exposing whale fibroblasts to various sources of DNA damage, researchers found that the whale cells sustained fewer mutations than human cells treated the same way.

Upon investigating further, the bowhead whale’s secret to success appeared to be more efficient DNA repair, specifically thanks to higher levels of a protein called CIRBP (cold-inducible RNA-binding protein). This protein helps to fix double-stranded DNA breaks, where both strands of the DNA double helix are broken. This is the most dangerous type of DNA damage, because there is no intact template to facilitate accurate repair (unlike in the case of a single stranded break). This means that repairs of double-stranded breaks are more likely to introduce large, disastrous mutations. To test whether the beneficial effects of CIRBP could be conferred to other species, researchers genetically modified fruit flies to express increased levels of either human or bowhead whale versions of CIRBP. Remarkably, not only did the modified fruit flies outlive controls after being exposed to radiation (suggesting improved DNA repair), both versions of CIRBP also increased life expectancy in non-irradiated flies.

The implications:

This study suggests that bowhead whales achieve their resistance to cancer in part thanks to more efficient DNA repair. It also provides a proof of concept that other species could benefit from this increased DNA repair efficiency. DNA repair isn’t just important for preventing cancer, but also for preserving cell function in general. Even genetic mutations that don’t lead to cancer can be harmful, causing proteins to not function correctly and potentially leading cells to enter senescence, a state in which they can no longer divide and instead pump out inflammatory signals. One of the proposed ways of slowing human ageing is to somehow enhance DNA repair, for example by enhancing the production of proteins like CIRBP.

While we are a long way from humans receiving CIRBP gene therapy, there may be something you can do to enhance CIRBP activity. As you may have already guessed from the name, CIRBP production is triggered upon cold exposure, which may explain why bowhead whales have so much of it, given their Arctic habitat. Exposure to cold temperatures increases CIRBP levels in humans as well, and there is increasing interest in using controlled cold exposure to promote general health. Unfortunately, there’s currently not nearly enough data concerning the merits of different methods of cold exposure.