Cold-induced RNA-binding protein (CIRBP) improves repair of nucleic DNA defects in long-lived bowhead whale
Summary
The dominant theory of cancer claims that it originates in defects of nucleic DNA that appear during cell replication -- but this fails to explain "Petos' Paradox." That is, how can large, long-lived mammals like bowhead whales live for two centuries free of cancer, when their accumulated DNA defects must be much greater than that in humans?
New research suggests that cold shock proteins modulate nucleic DNA defect repair in both whales and human beings.
If that research is true, then it adds a third mechanism by which deliberate cold exposure will help manage cancer risks.
Metabolic therapies for cancer
In Cryotherapy for Cancer, I wrote about the two metabolic mechanisms by which deliberate cold exposure inhibits the growth of tumor cells:
By activating non-shivering thermogenesis in brown fat cells to clear glucose from the bloodstream and starve tumor cells of their essential energy source, and
By stimulating endogenous production of ketones (see Ice Bath for Fast Keto), which have been shown to have anticancer effects in mouse models and human trials (e.g., Poff et al. 2014).
Further, in Mitochondria, Cold, and Cancer, I suggested that these two mechanisms might be responsible for the miraculous recovery from incurable, inoperable cancers that Dean Hall and others have experienced after adopting a practice of cold water swimming. At the time, I considered these two mechanisms sufficient to explain the salubratory effect that deliberate cold exposure can have for management of cancer risks.
Could cold shock proteins provide cancer protection?
Now, a new study lead by a team of researchers at the University of Rochester suggests that production of cold-shock proteins for repair of damaged DNA may be a third mechanism by which deliberate cold exposure might be critical to inhibition of cancer (Firsanov et al. 2023). Their discovery started by examining the extreme longevity of the bowhead whale, which has been documented to have a maximum life span of over 200 years.
According to the nucleic DNA defect theory of cancer that currently dominates centralized medicine, such long lifetimes in a mammal as massive as the bowhead whale should be impossible. That is, if cancer originates in the random mutations and defects of the DNA in the nucleus of each cell, then the risk of cancer increases with the number and age of cells in the body. By this logic, researchers have estimated that "all whales should have colorectal cancer by age 80" (Caulin & Maley 2012).
Rather than question the nucleic DNA defect theory of cancer, centralized medicine invented a term called "Peto's Paradox" to describe the conundrum presented by the discordance between theory and the long, cancer-free lifespans of whales and elephants.
If every cell has some chance of becoming cancerous, large, long-lived organisms should have an increased risk of developing cancer compared to small, short-lived organisms. The lack of correlation between body size and cancer risk is known as Peto’s Paradox. Animals with 1,000 times more cells than humans do not exhibit an increased cancer risk, suggesting that natural mechanisms can suppress cancer 1,000 times more effectively than is done in human cells. - Caulin & Maley 2012.
The research team at the University of Rochester began their investigations of the so-called Paradox by testing existing hypotheses regarding cancer suppression. They ruled out several ideas that would have supported the nucleic DNA defect theory, including the hypothesis that somehow whale DNA is less prone to errors of replication.
Instead, they discovered that whales have more effective mechanisms of repairing errors that do occur, thus explaining their relatively cancer-free existence despite their long lives and large size.
Cancer originates in disorders of mitochondria
This new realization is consistent with the much more convincing theory of cancer described by Dr. Thomas Seyfried, Professor of Biology at Boston College. In his book Cancer as a Metabolic Disease, Seyfried explains that cancer originates not in defect of the nucleic DNA, but in defects of the mitochondrial DNA (Seyfried 2012).
Mitochondria are organelles that exist in almost every cell of human body (an exception is red blood cells - Power, Sex & Suicide: Mitochondria and the Meaning of Life, Lane 2005). The whole purpose of mitochondria is to convert food energy, such as glucose, triglycerides (fats), and ketones into the energy required by the human body to fuel movement, growth, wound repair, and thermogenesis. Rather than rely exclusively on nucleic DNA, the mitochondrial maintain their own DNA for synthesis of proteins that are essential to energy conversion, thereby keeping the source of these proteins in close proximity to the site at which they must act.
The greater the energy requirements of a cell, the more mitochondria are packed inside the cell walls. For example, muscle and brain cells have lots of mitochondria, while white fat cells have very few. That's because the purpose of white fat is to store energy, not consume it. By contrast, brown fat cells are dense with thousands of mitochondria, because the purpose of brown fat is to support non-shivering thermogenesis -- i.e., produce heat to keep your body warm when exposed to cold.
There is no cell inside the body that has a greater concentration of mitochondria than the retina, in the back of the eye. Evidently, processing of light and maintenance of photoreceptor cells is extremely energy intensive, which may explain why eyesight degrades as mitochondrial quality declines (Eells 2019).
Cancer cells typically have dysfunctional mitochondria, and consequently draw their energy from an alternative process of glucose fermentation called The Warburg Effect (Liberti & Locasale 2016). Whereas most researchers believe the mitochondrial damage in cancer cells is caused by defects in nucleic DNA, Seyfried suggests that the mitochondrial damaged precedes the nucleic defects, not the other way around.
Because mitochondria provide the energy required for all cell replication and repair, it stands to reason that defects in mitochondrial DNA would impair the processes of cell division and result in increased rates of nucleic DNA defects for which little energy is available to repair. The problem is that existing outside the protection of the cell nucleus makes mitochondria ten times more susceptible to damage from the reactive oxygen species (ROS) that are an inevitable byproduct of energy conversion.
Mitochondrial therapy
A long life span and large body size requires protecting mitochondria from damage. One the best things you can do to maintain a high quality and quantity of mitochondria is a regular practice of ice baths. As I wrote in Ice Baths for Mitochondrial Therapy:
When mitochondria are damaged, mechanisms exist to repair them. When they are damaged beyond repair, the body is capable of selecting the best, least damaged mitochondria for replication so that new mitochondria can replace the old. As you might imagine, this process is stimulated by exercise, cold thermogenesis, and growth -- all the functions that demand energy. Of the three, the most powerful may be the cold. Nothing stimulates mitobiogenesis quite like an ice bath. - Ice Baths for Mitochondrial Therapy, Seager 2023.
Cold shock protein modulates nucleic DNA repair rates
Intrigued by their findings that ruled out the reduced rate of nucleic defect production hypotheses, the University of Rochester team sought alternative explanations that would resolve Peto's Paradox in the bowhead whales. That's how they discovered that, compared to humans, mice, and cows, these whales have much higher levels of a cold shock protein called cold-inducible RNA-binding protein (CIRBP) that is responsible for nucleic DNA repair. Previous experiments at the University of Texas Austin had already established the efficacy of CIRBP for repair of breaks in DNA double-strands (Chen et al. 2018), so discovery of the elevated levels of CIRBP in whales suggested that their unlikely, cancer-free existence must be due to more efficient repair of DNA defects.
And what stimulates expression of CIRBP? Cold exposure, of course.
The evolution of constitutively high CIRBP expression in the bowhead whale is likely to have been driven, at least in part, by the unique physiological stresses this Arctic cetacean (i.e., marine mammal) must endure. This naturally includes the extremely cold water in which it is constantly immersed. Interestingly, beneficial effects of cold as a therapeutic agent have been known for a long time with brief cold-water immersion believed to promote health and hardening in Nordic cultures. Currently, whole body cryotherapy is widely used in sports medicine to reduce inflammation and facilitate recovery after exercise or injury... . We speculate that increased CIRBP expression may contribute to health benefits by facilitating DNA repair. - Firsanov et al. 2023.
Hypothermia for human cells?
To test the hypothesis that these findings in whales might also be transferable to humans, the University of Rochester team kept human cells in a state of hypothermia (91F) for two days, then measured the efficiency of non-homologous end-joining (NHEJ) of double-strand breaks in the human DNA.
They found a two-fold increase, modulated by expression of CIRBP.
If the researchers are right about this third mechanism by which cold fights cancer, and that it applies not just to whales, then we should be able to observe the effect in the human beings who live in the same cold, Arctic regions occupied by the whales, right?
Those people are called the Inuit, and epidemiological study of cancer rates in their population is riddled with confounding factors related to changes in diet, exercise, housing, exposure to pollutants, and other factors. Nonetheless, malignant disease is "believed to be almost non-existent in Inuit populations during the beginning of the 20th century" (Friborg & Melbye 2008).
Only as the Inuit became more industrialized in their housing, their habits (e.g., smoking) and their diet, did rates of certain "lifestyle" cancers skyrocket.
During the second half of the 20th century, Inuit populations underwent major changes concerning a wide range of exposures. These changes included the establishment of larger urban communities, improvement of housing standards, and a transition from traditional fishing and hunting subsistence to a society where most people are employed in public administration, service, and trade. - Friborg & Melbye 2008
While the data regarding the Inuit may be ambiguous, previous studies have linked CIRBP to tumor suppression in humans (Lujan et al. 2018). For example, CIRBP was associated with slower growth of ovarian cancer cells and a reduction in malignancy, compared to benign tumors (Biade et al 2006). Nonetheless, I'm not aware of any clinical trials investigating CIRBP as a therapy for cancer.
Protocols for cold shock proteins?
CIRBP is just one of many cold shock proteins expressed within the body in response to deliberate cold exposure. For example, another RNA-binding protein called motif protein 3 (RMB3) is "a molecular marker of hypothermia that has proved neuroprotective in neurodegenerative disease models" (Avila-Gomez et al. 2020). However, we so far haven't described just how cold the body must become during deliberate cold exposure to simulate cold shock.
Thus far, studies describe the conditions that stimulate expression of CIRBP as "mild hypothermia," (e.g., Corre & Lebreton 2023). That description is unhelpful, even for experienced cold plungers, as it can take more than 30 minutes of whole-body immersion in frigid water to induce mild hypothermia and typically cold plunge times range between 2-4 minutes at a time. (See How Often Should You Ice Bath for an explanation of dose-response in cold water immersion). Other sources also report that exposure to UV light and hypoxia can also stimulate CIRBP expression, although neither of these are necessarily stacked with an ice bath.
The more relevant question that the literature has yet to answer is, "What's the minimum effective dose to stimulate expression of meaningful concentrations of cold shock protein?"
While it's tempting to say "Well, I feel shocked when I get into the cold, so I must be producing cold shock proteins, right?" according to my current understanding of the scientific literature, no one knows for sure whether the levels produced in a 4 min ice bath are clinically relevant for suppressing tumor growth -- although it does seem clear that it's not going to make anything worse.
About the Author
Thomas P Seager, PhD is an Associate Professor in the School of Sustainable Engineering at Arizona State University. Seager co-founded the Morozko Forge ice bath company and is an expert in the use of ice baths for building metabolic and psychological resilience.