Updated: Aug 10
Drugs, surgery, & radiation have failed to realize the promise of a cure for cancer.
Metabolic therapies may be at least as potent as most anticancer drugs.
A new study of deliberate cold exposure therapy for cancer is the most comprehensive and convincing explanation yet for the remarkable remissions experienced by some cancer patients.
Cold exposure therapy could inhibit tumor growth by activating brown fat, starving tumor cells, killing them with ketones, and stimulating secretion of cold shock proteins that repair nucleic DNA.
Current cancer research fails to improve treatment
Allopathic medicine has failed to cure cancer
While progress has been made in allopathic (drugs, surgery, & radiation) therapies for some specific cancers, none of the 200+ potentially fatal types can be described as "cured" in humans (Farelly 2021). As a consequence, cancer costs over $200 billion per year in medical expenses, and yet still remains the second leading cause of death in the United States, behind heart disease.
That wasn't what we expected from more than fifty years of intensive research funding. Back in 1971, it seemed to medical researchers like a cure for cancer was imminent.
"We are so close to a cure for cancer. We lack only the will and the kind of money and comprehensive planning that went into putting a man on the moon." Dr. Sidney Farber, Past-President American Cancer Society, c. 1971
Since President Nixon signed the National Cancer Act that same year, government funding for cancer research has ballooned to over $7 billion per annum -- without managing to improve the life expectancy of cancer patients by much more than a single year (e.g., Lichtenberg 2009, using data from 1978-2004).
Although it is true that mortality from cancer has declined, most of the improvement has come from reduced rates of smoking -- not improved allopathic cancer therapies (American Cancer Society 2022).
How did 50 years and billions of dollars spent on research investment fail to make a significant improvement in cancer treatment outcomes?
According to Thomas N. Seyfried, PhD it is because the National Cancer Institute (NCI) has been looking in the wrong place the entire time (Cancer as a Metabolic Disease, Seyfried 2012).
The dominant scientific theory of cancer underpinning NCI research is that defects in replication of DNA in the nucleus of the cell can cause unregulated growth of cancer cells into metastatic tumors that eventually impinge on essential bodily functions. According to this theory, therapies must remove or destroy the defective DNA to restore the body to good health. For example, in cases where tumor cells can be separated from healthy tissues, surgery cuts them out from the body. Similarly, radiation therapy uses focused high-frequency electromagnetic energy to destroy cancer cells, while sparing the surrounding healthy tissues by subjecting them to lower radiation doses. Finally, chemotherapy poisons the body in the hope that cancer cells will be disproportionately destroyed, without damaging healthy cells beyond the point of their recovery.
Each of these therapies are expensive, and profitable. In other words, the genetic theory of cancer provides a financial incentive to conduct research into the discovery, improvement, and commercialization of increasingly sophisticated technologies for cancer detection, diagnosis, and destruction.
The problem is that none of these therapies work in harmony with the body's natural corrective functions, or heal the underlying health conditions that allowed the cancer to form in the first place.
A metabolic theory of cancer
In contrast, Seyfried is a proponent of an alternative theory that suggests cancer is a disorder of metabolism. According to this theory, damage to the DNA in the nucleus is the result of metabolic disorders, rather than the cause.
How could this be?
It turns out that there are two sources of DNA in almost every cell in your body. The first is the most familiar -- the DNA in your cell nucleus.
The second is the DNA in your mitochondria, which is inherited only from your Mother. Less than a few millionths of a meter long, there can be thousands of mitochondrial organelles in a single cell of your body. They reside outside the cell nucleus, but within the cell membrane. Mitochondrial DNA are essential for synthesizing enzymes and other molecules that speed the conversion of glucose (sugar) and lipids (fats) carried into the cell from the bloodstream into the energy on which all bodily functions rely.
The problem is that mitochondrial DNA are more vulnerable to damage and less amenable to repair, compared to nucleic DNA (Singh et al. 2015). As the locus of energy-converting chemical reactions that enable muscle movement, thermogenesis, and nearly every other human function, over-taxed mitochondria are subject to injury by intracellular reactive oxygen species (ROS) produced during energy conversion.
And nothing overtaxes mitochondria like excess glucose.
In fact, Type 2 diabetes may be a natural adaptation for protecting mitochondria from glucose overload. When carbohydrate intake is too high and blood glucose spikes, cells respond by becoming resistant to insulin, the hormone that transports glucose across the cell membrane from the blood into the body of the cell. By keeping the glucose in the bloodstream for later processing (e.g., into synthesis of fat), insulin-resistant cells protect their precious mitochondria from being inundated with glucose that could cause overproduction of mitochondria-damaging ROS.
Most cancer cells run exclusively on glucose, using an alternative metabolic pathway that bypasses mitochondria called the Warburg Effect (e.g., Tripping Over the Truth, Christofferson 2014). When the mitochondria in a cell become damaged by excess ROS production, one way that a cell can continue to grow and metabolize is to switch to the Warburg Effect for extracting energy. This pathway is less efficient, but as much as 10-100 faster than mitochondrial respiration. That extra speed of the Warburg Effect is what fuels rapid growth and reproduction of cancer cells -- as long as excess glucose for fermentation is available in the bloodstream.
The metabolic theory helps explain why we observe increased cancer rates in people who suffer from diseases characteristic of excess blood glucose, including obesity and Type 2 diabetes. And why we see lower cancer rates in people who maintain low blood glucose levels by practicing low-carb dieting, intermittent fasting, regular exercise, and deliberate cold exposure.
Can cold exposure cure cancer?
In Mitochondria, Cold, Cure for Cancer I speculated about the mechanisms by which Dean Hall (pictured) drove his incurable leukemia into remission. Following his terminal cancer diagnosis, Dean began training to swim the entire length of the Willamette River in Oregon. Having lost his wife to a brain tumor a few years earlier, Dean said he wanted to do something to inspire other cancer patients before he died.
Based on Dean's testimony and the concerns expressed by the medical team that supervised his swim, there can be no doubt that Dean spent days in a continuous state of glucose-depletion. When the diet does not include sufficient carbohydrates to support energy expenditure, the body will switch to fat-burning metabolic pathway called ketosis.
According the metabolic theory of cancer, the extreme glucose deprivation and ketone production of his intensive cold water swimming constituted a state of natural metabolic therapy that killed his cancer.
Cold exposure inhibits tumor growth
Now, a new study of the effects of deliberate cold exposure on tumor growth and cancer-related mortality has appeared in the prestigious science journal Nature that helps explain Dean's experience (Seki et al. 2022). An international team of researchers investigated the effects of cold exposure on glucose metabolism, brown fat, tumor growth, and cancer in mice and in a human being.
They found that mice implanted with colorectal tumors and subjected to 4C cold air exposure lived longer and experienced slower tumor growth than mice kept at warmer temperatures. The researchers attribute this to the fact that cold exposure activates and recruits new brown fat, and clears glucose from the blood stream.
In an extensive series of clever experiments, the researchers isolated the activation of brown fat via cold exposure as the essential mechanism that inhibited tumor growth. Moreover, they reversed the inhibitory effect by feeding cold-exposed mice a diet so high in glucose that even cold exposure could not consume it all -- suggesting that the glucose-clearing properties of the brown fat are responsible for tumor inhibition.
Ketones & cancer
It is already well established that brown fat cells are densely packed with mitochondria to facilitate cold thermogenesis (Lee et al. 2019). In fact, deliberate cold exposure has been suggested as therapy for correction of mitochondrial disorders, based on the idea that recruiting new brown fat cells for cold thermogenesis stimulates mitochondria biogenesis. The combination of exercise during cold exposure appears to be particularly powerful -- at least in mice (Chung et al. 2017).
Therefore, the new research from Seki et al. supports Seyfried's prior work on the Warburg Effect and the metabolic origins of cancer. However, Seyfried is silent on cold exposure and brown fat activation as potential treatments for cancer. He instead emphasizes the benefits of fasting, calorie and carbohydrate restriction, and a ketogenic (i.e., low carbohydrate) diet.
Several studies support Seyfried's assertion that ketosis is therapeutic for cancer patients. For example, a review of more than 50 studies found that ketogenic diets can result in anti-tumor effects in both animals and humans, without causing serious side effects (Klement 2017). Moreover, the ketones need not be produced endogenously as a consequence of a carbohydrate-restricted diet. Having observed that ketones inhibit tumor growth in laboratory cultures, another study hypothesized that exogenous ketones (via dietary supplements) may also have anti-tumor effects. A research team that included Seyfried found that they could extend the lives of mice with systemic metastatic cancer by administering ketone supplements, independent of glucose levels (Poff et al. 2014).
More recently, researchers compared the response of pancreatic cancer in mice to chemotherapy alone, and chemotherapy in combination with a ketogenic diet. They found that survival in the mice on the keto diet was nearly triple those on a standard diet (Yang et al. 2022).
In other words, there may be two anticancer mechanisms by which cold exposure inhibits tumor growth. The first is by starving the cancer cells -- i.e., reducing blood glucose, as suggested by Seki et al. The second may be by production of ketones -- i.e., by killing cancer cells through direct exposure to ketones in the bloodstream, as suggested by Poff et al.
Because Seki et al. (2022) did not monitor for ketone levels, they cannot rule out that the tumor inhibition they observed benefited from both effects. After all, deliberate cold exposure may be the fastest way to increase ketones in the bloodstream.
Cold exposure in human cases
Dean Hall is not the only improbable case of improvement in incurable cancer resulting from a combination of carbohydrate restriction, exercise, and deliberate cold exposure. In fact, Seki et al. enrolled an 18-year-old human Hodgkin's lymphoma patient into a pilot study of cold exposure.
Hodgkin's is one of the few types of cancer for which increased research funding has resulted in improved prognoses. The most famous Hodgkin's survivor of my lifetime may be Hall of Fame hockey player Mario Lemieux. If ever there was a case against the merits of the metabolic approach, Lemieux is it. Given the intense exercise regimen and regular cold exposure Lemieux experienced as a professional winter sport athlete, it should be obvious that cold exposure is neither a cure for cancer, nor a guaranteed cancer preventative. Lemieux's Hodgkin's was treated with radiation, after which he continued to perform at the highest level of his sport.
Nonetheless, the Hodgkin's patient Seki et al. chose to enroll in their pilot study had already undergone five cycles of chemotherapy and still had active tumors. Because human cancer patients can not be expected to tolerate the same degree of cold exposure to which mice may be subjected, the human study did not seek to replicate the animal studies. Rather, it sought to answer the question "What metabolic effects can be observed in human cancer cells at tolerable temperatures?"
After 7 days of acclimation to cool air at 22C (about 71 F), researchers measured significant activation of brown fat in the patient supraclavicular region and "reduced glucose uptake in the tumor tissue." That is, although the patient was not "cured" of Hodgkin's, the study successfully observed a shift in glucose metabolism away from the tumor cells an into brown fat at an ambient air temperature that was well tolerated by the patient. Moreover, when the patient was warmed to 28 C (about 82 F) for 4 days, brown fat activation ceased -- suggesting that it was the mild cold that caused the metabolic adaptation.
"Exposure of a patient with cancer to mild cold conditions markedly reduced glucose uptake in the tumour tissue." Seki et al. 2022
My own experience is different from the patient in the Seki et al. study. When I was confronted with test results that show elevated levels of prostate specific antigen (PSA -- a marker for increased risk of prostate cancer) I resolved to treat myself with ice baths and carbohydrate restriction for ketosis. I cycled in and out of a low-carb diet, practiced deliberate cold exposure in my ice bath for 4-5 minutes every day, and performed light exercise after my ice bath to help me rewarm. As I wrote in What Happened to my Testosterone After Using Ice Baths to Treat my Prostate, the results were stunning. Not only did my PSA come down to levels well below what would be considered "normal," but my testosterone shot up to levels that would be considered high for men half my age.
Still, my experience is nothing compared to AJ Kay's.
How a Mom shrank her inoperable liver tumor
In December of 2018, I was in Texas when I got a call from my close friend AJ Kay, who was recently divorced and trying to figure out how to raise her four daughters by herself.
She said she was doubled over in abdominal pain, and suspected an ovarian cyst.
I asked her to get to the hospital immediately, but she was reluctant to go. She had no back-up care for her children, and worried that it would scare them if she were admitted to the hospital. She rationalized that her pain tolerance was pretty high and that the discomfort would likely pass soon, anyway.
It did not. Hours later when the pain became unbearable and she could no longer put on a brave face for the kids, she checked herself into the emergency room (ER).
After undergoing blood tests, an ultrasound, a CT, and an MRI the night before, she woke up the next morning to "Oncology Consult" written on the white board daily care plan in her hospital room. The oncologist explained to her that what had been noted as "incidental, sub-centimeter spot on her liver" on a CT several years ago had grown into a complex, inoperable mass spanning more than half the diameter of her liver. Even if it weren't malignant (which was unclear from the imaging), should the tumor continue to grow, it could pretty quickly impair her liver function, impinge on critical vascular pathways, and cause her early death. (She was 38 at the time).
She feared that, should "the worst come to pass" her four daughters would be left motherless and in the custody of a father from whom two of them were already estranged.
The tumor board at the hospital met to review her case and opted to discharge her from the hospital when the immediate problem, which was caused by the tumor bleeding into her abdomen, resolved. The plan was to follow her with oncology and order several MRIs per year to track the growth. Even a biopsy to rule out malignancy (one of three tumor markers for which they tested came back positive) would have been too risky so they advised watchful waiting.
I wasn't satisfied with that.
Remembering my experience with my PSA, and that she had recently reversed her Type 2 diabetes (a risk factor for cancer), I implored her to:
eliminate all concentrated carbohydrates & alcohol from her diet (no soda, no sugar, no fruit juice),
begin a program of intermittent fasting & cycling in and out of ketosis,
She tweeted out the results of her next blood test in Feb 2019, barely two months later. As she said then, it was "three pages of perfect."
"It’s been 2 months since I was gut punched into getting serious about my health. "I eliminated refined sugar from my diet and got into ketosis and fasting. "I took up aerial yoga and recently did my first Cold Water Immersion & plan to do more. My latest bloodwork came back... "...with no signs of the Type 2 diabetes, hypothyroidism, autoimmune markers, imbalanced hormones, or inflammation that plagued me previously. "No migraines. No Raynaud's. No anemia. No arrhythmia. "It was 3 pages of perfect." #ketodiet #coldwaterimmersion #anticancer #healing - https://twitter.com/AJKayWriter
Several months after, she had her first follow up scan.
Her tumor had shrunk.
If there's one thing that spontaneous, inoperable tumors are not expected to to do after three years of rapid growth, it's shrink.
On top of that, nearly all of her seemingly unrelated health issues resolved as well.
She has not gone back to the hospital since then, despite experiencing another episode of abdominal pain that reminded her of the first. It was less intense the second time, she reasoned, and maybe it happened because she relaxed her low-carb regimen, the yoga studios had closed for COVID, and as part of that she was no longer doing a weekly ice bath-hot yoga workout.
So she returned to what worked for her the first time and hasn't experienced a relapse since.
New directions for cancer research and clinical practice?
One of the most remarkable findings in the Seki et al. (2022) study is the suggestion that "cold-induced antitumour activity is at least equivalently potent to most anticancer drugs."
"This therapeutic approach is simple, cost-effective and feasible in almost all hospitals and even at home, and is most likely omnipresent for all cancer types. As adult humans have a sufficient amount of brown adipose (fat) tissue that effectively takes up blood glucose after cold exposure, we reasonably speculate that a similar anticancer activity should also be seen in human patients with cancer. "Our findings represent a new concept for cancer therapy that patients with cancer could potentially benefit from." Seki et al. 2022
UPDATE 30 Oct 2022
Exercise kills cancer
Epidemiological evidence has long supported the hypothesis exercise reduces cancer risks (Moore et al. 2016), but the mechanisms remain speculative.
When researchers isolated blood serum from men who performed high intensity exercise and injected it into a culture of lung cancer cells, they discovered that he blood could kill the cancer cells.
Blood was collected from male subjects prior to, 5 min, 1 hr, and 24 hr after a single bout of high intensity interval exercise on a cycle ergometer. Exposure of (cancer) cells to post exercise serum resulted in the inhibition of cell proliferation... compared to cells treated with serum taken pre-exercise. - Kurgan et al. 2017.
The authors speculate that reduced levels of insulin-like growth factor (and increases in insulin-like growth factor binding protein) in the blood serum of post-exercise individuals is critical to the effect on cancer cell growth and survival.
Which may amount to identifying a third mechanism by which cold exposure inhibits tumor growth, because at least one study demonstrated (in pigs) that cold exposure at 4°C resulted in lower basal plasma IGF-1 concentrations (Ozawa et al. 1994).
Cold may act to inhibit cancer in a way that is similar to exercise, independent of the mechanisms of glucose starvation and ketone production.
UPDATE 30 JUNE 2023
Cold shock proteins repair nucleic DNA defects
There is a third mechanism by which cold water immersion might help manage cancers risks -- cold-induced RNA-binding protein (CIRBP). I've written about it in greater detail in a new article called Cold Shock Protein Critical for Cancer? but I'll summarize it here.
One of the pernicious problems with the nucleic DNA defect theory of cancer is that it fails to explain how large, long-lived animals like whales manage to live up to two hundred years without developing cancer. Given the enormous number of cells in their body, there is a greater probability that an accumulation of random defects somewhere in their nucleic DNA that would cause "all whales should have colorectal cancer by age 80" (Caulin & Maley 2012).. The fact that they don't is called "Peto's Paradox."
Researchers at the University of Rochester now suggest that production of cold-shock proteins for repair of damaged DNA may further inhibit tumor proliferation, accounting for the extreme longevity of the bowhead whale (Firsanov et al. 2023). If that's true, then it could support Seyfried's assertion that cancer originates in the mitochondria, not the nucleus, because cells with healthy mitochondria are capable of repairing problems with nucleic DNA.
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