Note: I have been thinking about these ideas over some weeks and how they might apply to complement my therapeutic approach to my prostate cancer (HSPC T3cN1M0). Nothing here should be taken as suggesting an epigenetic and phytochemical approach as an alternative for optimally selected and medically administered optimal treatment(s) that have been proven in the highest quality clinical trials. Much of this is emerging science that has not yet proven efficacy in human prostate cancer (with a few exceptions). So please take this as it is offered, just one patient's opinions and not anyone's prescription. - Paul
The "Hallmarks of Cancer" is a roadmap of the sequence of changes in cells as they progress down a slippery slope from minimally abnormal cells, to cancer in situ, to invasive cancer, metastasis and treatment resistance. (Hanahan and Weinberg 2000, updated in 2011).
Specifically, the hallmarks are: 1) Sustained proliferative signaling. 2) Evading growth suppressors. 3) Resisting cell death. 4) Enabling replicative immortality. 5) Inducing angiogenesis. 6) Activating invasion and metastasis. And more recent additions: 7) Reprogramming of energy metabolism. 8) Evading immune destruction. Underlying this view is the understanding that cancers are not homogenous masses of proliferating cells, but rather complex tissues with multiple distinct cell types that interact with each other. And they recruit normal cells to help them acquire the hallmarks, creating the "tumor microenvironment". Hence the apt analogy: "Cancer is a meadow and not a cornfield."
What captured my interest most keenly, and gave me a new perspective on cancer altogether was this: That the progression through these hallmarks, or stages of malignancy, are underlain by just two factors, genome instability and inflammation. Genome instability is the progressive accumulation of very many random point mutations giving rise to genetic diversity, exploring every pathway with Darwinian selection that will find pathways to eventually progress in face of any therapeutic or protective mechanisms. So my key question is: Might I adapt strategies to maximally protect my body's genome and minimize inflammation? These not only for slowing the evolution of my cancer, but also for protecting the 99.9% of my cells that are not cancerous but still subject to genetic degradation causing the declines of aging (bodily senescence as opposed to cellular senescence).
I presume from this model that if someone has cancer that has already progressed through all of the hallmarks and has reached the end stage, meaning metastatic and multiply castrate and treatment-resistant, then this may not be possible in theory. But if one is still hormone sensitive, or not metastatic and especially if just biochemically recurrent, then perhaps such strategies could slow the progression through the hallmarks, thereby affording longer survival with better functioning as we age. And even if one is metastatic castrate-resistant it could still be beneficial in principle to protect against further mutations leading towards even more treatment resistances and the emergence of neuroendocrine and small cell transformations.
These are unknown and certainly unproven.
So what are the pathways of lifestyle, nutrition and therapeutics that could contribute to this approach? What are the known elements with the best scientific evidence? Since placebo controlled randomized clinical trials are mostly not yet done for these factors we must rely on lesser evidence. But weighing the risk to possible benefits can provide guidance. It is nonetheless mostly uncharted territory as far as long term human trials are concerned.
Much of the basic science in protecting the genome comes from longevity research as much as from cancer research. Epigenetic factors and their pathways such as the Sirtuin mediated mechanisms of histone deacetylation, and others, are involved in balancing gene DNA protections and accessing repair mechanisms. These are also intimately involved with epigenetic control of mitochondrial function, responding to oxidative stress and modulating immune function.
For an easy to read and accessible primer on these mechanisms from the longevity perspective I recommend the book "Lifespan, Why we Age and Why we Don't Need To" by David Sinclair. For going deeper into the cellular science and pathways I suggest "Epigenetic Control of Mitochondrial Function in the Vasculature" by Mohammed et al. Applies just as well to cancer and aging.
Some interventions that are well documented to activate these protective mechanisms have been verified in a large body of research on aging, mostly done on animals including mammals. These include caloric restriction (hard to do); Intermittent fasting (IMF -much easier to do); Regular low level exercise; And more powerful is High Intensity Interval Training (HIIT); Exposures to cold temperatures (Walking in cold air or cold water immersions); An "Epigenetic Diet" rich in plant based phytochemicals; and possibly a ketogenic diet which acts by different mechanisms. Although high animal protein and fat seems to be counter-productive in the animal studies. (Problematic for me on my ketogenic diet with IMF!); Metformin, or its phytochemical equivalent Berberine, are beneficial therapeutics for genetic and mitochondrial protection, even for non-diabetics.
For reducing inflammation, first eliminate identifiable sources of inflammation such as low-grade infection and immune/autoimmune processes. Optimize the micro-biome of the gut through nutrition (soluble fiber!) and probiotics if needed. Avoid environmental pollutants and unnecessary radiation exposure. Effective pharmacologic anti-inflammatories include low-dose aspirin, NSAIDS, especially the COX2 inhibitor celecoxib, and statins, among others. Overall inflammatory status can be checked with simple blood tests such as CRP and ESR among others.
Most of the phytochemical agents that positively impact epigenetic and other pathways are also anti-inflammatory. For a review of the most well-established and relevant phytochemicals and their food sources I suggest the following articles as a good starting place:
The most relevant and "generally recognized as safe" phytochemical supplements include: Sulforaphane, Resveratrol or Pterostilbene, Curcumin, EGCG from Green Tea, Quercetin. These, along with Acetyl-L-Carnitine and Alpha Lipoic acid, I would consider the "top tier" and are in my own regimen. Further candidates include Genistein from soy (not without controversy), Diallyl disulfide; Indol-3-carboinol and Procyandin. These I have not investigated in depth. There are many others with their mechanisms described in the above articles and elsewhere. Of course a diet rich in a wide variety of natural antioxidants, anti-inflammatories and flavonoids, etc. is the best foundation and can provide most of these. Supplementation, of course, is a personal decision. And one's oncologic medical team needs to be aware of any supplements being taken.
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MateoBeach
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Paul...Many thanks for this really meaningful post. The most impressive line I found was "We can stop the 99.9% cells which are still normal from becoming cancerous and prevent more point mutations " (not exact words)
I have been working on these lines in my own treatment and therefore emphasizing role of resveratrol ,Sulforaphanes. Phytosterols, Flavonoids,, Gingerols, Curcuminoids ,anthocyanins, EGCG and many many more dietary substances along with 4 to 5 miles walk daily.. I believe in medical treatment BUT it needs to be supported by keeping our cancer fighting capability intact by all the other means as mentioned by you in this post. Once more: Judicious medical treatment PLUS complementary supportive action is the way to go.
BTW, Today only I found and bought a bag of Dried, White Mulberry fruits ..an anti cancer superfood rich in anthocyanins, Cyanidins and Resveratrol.
Even Medical treatments might work better when we have solid healthy body and robust immune system. Enjoyed your great post.
Great post, thank you. With regard to the fact that "high animal protein and fat seems to be counter-productive in the animal studies" some have noted that many studies of "high-fat" diets (in both humans and animals) neglect to emphasize the different possibilities of what that term can mean.
A "high-fat" diet COULD be high in both fat AND carbs, or high in both fat AND protein. And there are, of course, many different types of fats, and they can be natural or highly processed. So the devil will be in the details, so far as both study diets and individual diets go. (If they ever do a "high-fat" study where instead of highly processed chow the mice get a whole-food diet of grass-fed animal products, nuts, olives, avocado, etc. I'll bet those mice do just fine!)
Modern adults of industrialized societies have an energy intake that is sub-optimal in terms of amounts of food, and/or types of food, and/or the timing and frequency of feedings. As infants and toddlers and youths, this pro-growth intake is the very thing that we NEEDED, to optimize growth and development. But as aging men, stuffing our faces 16 hours a day with simple sugars and refined starches seems like it might lead to gene/cellular signaling and up-regulated metabolic pathways that promote... well, things like sustained proliferation, evasion of growth suppressors, resisting cell death, enabling of replicative immortality, etc.
I think you are on the right track, with both IMF and keto. I intend to resume both, but find for myself that giving up a carb addiction is an awful process... a hell of a lot harder than when I gave up booze for a few years. (And of course, how did I get through the process of not drinking? By eating more carbs!)
Nope, just carb counting. I began by fasting for three days, which seemed to work pretty well for me in making the transition to low carb. But after a few months I began to cheat at social events (family dinners, pizza parties, etc.) and reverted to more of a Mediterranean diet, and then slowly slipped closer to a SAD diet.
I first tried cutting sugar and bread from my diet nearly forty years ago, when I suspected a carb addiction was leading to mood swings and a constant feeling of "hunger." I have always been amazed every time I make that attempt at how intense and persistent the carb-cravings are. It is not true hunger for food that I experience, but the insatiable desire for the dopamine rush of a temporary sugar-high. Endorphins are terrible, wonderful things.
When Ed Bradley asked Eric Clapton if his drug addiction started with heroin he answered: “No, it started with sugar. When I was 5 or 6 years old I was cramming sugar down my throat, sugar on bread and butter, sweets, soda – I was using it to change how I felt.” Carbs are a drug.
Brain can only use sugar ,(glucose) to keep it functioning normally. As soon as sugar level goes down below normal level, brain receptors get stimulated demanding sugar and that's the reason for craving carbs. The best way to deal with this is to provide brain with very low amounts of sugar...by long acting sugar foods such as apples. During carb craving if we eat a lot of carbs..a lot of Insulin will get secreted aburuptly lowering sugar level ...thus..intensifying craving for Carb. In medical terms ,it is known as "Reactive Hypoglycemia" We need to block reactive hypoglycemia by eating small amounts of Carbs each time we have carb craving...just enough to bring blood sugar tiny bit above the baseline.
"Brain can only use sugar ,(glucose) to keep it functioning normally."
Not so!
A standard approach for young children prone to seizures is a ketogenic diet, because the brain does very well on ketones & they do not induce seizures.
When blood sugar dips...cognitive capacity dips too.
In absense of Glucose, the liver creates Glucose out of fat and protein. A phenomenon called "Gluconeogenesis" to supply brain with glucose because it is so critical for cognitive functioning.
Ketogenic diet is great. It does cause weight loss and help in many ways. Once Glycogen storage is depleted....ketosis starts in order to provide energy.
But for brain workers, low levels of glucose can impair mental performance and therefore , a small amount of long active carbs like in apples etc maintain blood sugar from dipping too low and thus keeping brain functioning sharp.
Many people feel irritable, short fused and have difficulty thinking once sugar level drops below 100.
Beta-Hydroxybutyrate is the main blood and brain form of ketone in ketosis. It can provide up to 70% of the energy requirements for the brain with no cognitive impairment.
But it has other actions that could favorablly impact prostate cancer progression and longevity. This is from the article linked above on Epigenetic Control of Mitochondrial Function . .
"b-Hydroxybutyrate
The ketone body b-hydroxybutyrate (bOHB) modulates several
signalling pathways with implications for metabolic disease and
Yes, but perhaps they feel irritable, short fused and have difficulty thinking not simply because the brain is not getting enough glucose, but because it is not getting the glucose it is USED to getting?
Consider also that many people (NON-diabetic) have some degree of brain insulin resistance, arising from the constant intake of carbs that has become their lifelong habit.
If one was to fight through being irritable, short fused and cognitively impaired as the short term response, the body and brain and insulin sensitivity can re-adjust to the new normal of low/no carb intake. This may take days (at least) but may take weeks for some.
You are correct that the brain needs SOME glucose. But the body always provides it, so long as there is sufficient intake of healthy fats and proteins. ZERO carb intake is required for the body to supply the sugar the brain needs. (And it can apparently be powered at very high-functioning levels with up to about 70% ketones as fuel.)
Actually, there is no requirement to consume ANY carbs at all to get glucose to the brain... the liver can make all the glucose needed through the process of gluconeogenesis, using dietary proteins and fats (or the proteins and fats stored in the body).
In addictive-like craving, I think it is not a shortage of glucose driving the "hunger" for carbs, but rather the withdrawal effect of not having your dopamine buzz.
Eating some carbs is one way to deal with craving, but I would not suggest apple or anything even modestly likely to provoke a significant insulin response. I would want something lower on both the glycemic index and the insulin index. For fruit, that might be raspberry or blackberry or sour cherry.
Carb craving can go away altogether by consuming very few net carbs in the form of those lower indexed foods. Since part of the craving is learned/psychological, it is a bit like abstaining altogether from any other addictive substance. If I am going low/no-carb and have a bite of a juicy, sweet apple, the cravings will reappear for sure! (Speaking here as a carb-addict, not as a "normal" non-bingeing person.)
I went full keto with net carbs 20 gm or less. First days were a bit rough but once I was in true ketosis ( verified by urine keto strips) all hunger and cravings went away and I had unlimited energy burning fat. Amazing. Lost 42 pounds effortlessly and am now near 12% body fat. I can be more flexible with carbs now, up to 50gm some days so I can have more meal flexibility a few times per week. Dry wines are ok too. Just have to be vigilant about habits of craving that are conditioned not true hunger.
"habits of craving that are conditioned not true hunger"
Yup, that's the real challenge for me. Eating is a main way for many of us to mediate emotion. (They don't call it "comfort food" for nothing!)
My first experience also resulted in a 40 lb loss, but I wouldn't quite call it effortless, for me. Falling off the wagon WAS effortless! It's getting started that is toughest, kind of like when you have been working out regularly and then quit for a few months: being exhausted and out-of-breath in no time can put you right back on the couch if you are easily frustrated and discouraged (as I sometimes can be).
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