Saturday, July 31, 2010

2- Enriched environment, stress, inhibits cancer?

In a previous post I mentioned the new research showing how an enriched environment can markedly impede the development of cancer. This research, the abstract of which is available here. (This research is concordant with research I earlier addressed, you can read it here.)The results of this current research indicate that a key variable is leptin. Leptin is a hormone released by fat cells(and other cells) that suppresses appetite. When writing up that previous post I was in a hurry so did not have time to think about it. As I driving over to a friend's place I had a petit epiphany, realising that there could very well be a linkage between the findings of this study and another post I put up on the same day that indicated regular coffee consumption is associated with cancer reduction. The typical assumption is that coffee confers this protection because it is extremely high in antioxidants, but together with the above research we can see another way in which coffee exerts its anti-cancer effects. There are some important lessons here, both in relation to the dangers of extrapolation when dealing with complex adaptive systems and the need to constantly re-evaluate our assumptions. I know, whilst thinking about this during the week I made some silly logical errors.

My first error was to assume that the cancer reduction associated with coffee was primarily being driven by the very high antioxidant content of coffee. This is a common assumption but that is no excuse. Common assumptions are a great source of fallacies. My petit epiphany was the realisation that the common linkage between these two studies is norepinephrine, typically regarded as a neurotransmitter but like a great many biological messengers it can have a wide range of functions in various tissues. Norepinephrine expression in the hypothalamus causes a marked reduction in the expression of leptin from adipose tissue(fat). As the above study indicated this big drop in leptin expression resulted in very strong reductions in tumor size. Coffee does elevate norepinephrine expression. Coffee is also an appetite suppressant so it might encourage reduced eating. I had made a stupid logical error, for some reason I assumed that caloric restriction would lead to increased leptin expression. I did a data check, caloric restriction reduces leptin expression. I should have known better because I regular starve myself, often going 24 hours without food(currently at 22 hours, with the exception of 3 cups of coffee) and have noticed that with practice I have become used to it, not really experiencing hunger but I do experience a mild fatigue and some brain fogginess on occasion, probably due to slightly low blood sugar. Talk about a fistful of ignorance!

In studies of caloric restriction, a regime which typically suppresses cancer, leptin levels take a big dive. Understandable because leptin is released during feeding and activates the mTOR pathway, the major route by which nutrients enter cells.  Leptin also stimulates the production of pro-inflammatory cytokines, molecules which are associated with cancer because these molecules promote angiogenesis - the production of new blood vessels, which is a critical requirement for tumor growth. Inhibiting the mTOR pathway is currently a strategy in cancer treatment. It can literally starve cancer cells to death, though I should add that there is  evidence to suggest that for some cancer types inhibiting this pathway can accelerate cancer growth. This highlights an important principle that is rarely addressed: "cancer" should be "cancers", each cancer has differing metabolisms and this has serious implications for treatment regimes. So if you ever hear anyone talking about a "magic bullet" or "universal anti-cancer agent", walk away in silence, or, if you are like me, shout, "stop selling snake oil you charlatan!".

The mTOR pathway is currently a research area of major interest. Generally speaking, the evidence points to inhibition of this pathway can play a major role in longevity and maintaining cellular health. Of course you don't want to starve the cells to death but periodic starvation appears to be a very good thing. It doesn't matter apparent sense, one would be inclined to think that inhibiting nutrients would damage cells. Aye, another danger of extrapolation when dealing with complex adaptive systems. As it turns out, when the mTOR pathway is inhibited, this accelerates a key intra-cellular function that is consistently demonstrating to be a major regulator of cellular health. That function is autophagy, which I have addressed in this post.

Autophagy is attracting great interest because it plays a prominent role in removing "debri" from cells. This debri, if it becomes too large, can eventually overload the house keeping functions of cells, leading to lipofuscin accumulation. Lipofuscin accumulates in lysosomes and can be rightly regarded as a key marker for cell aging. It has long been assumed that once lipofuscin accumulation has occurred it cannot be undone. However in recent years there is research indicating that lipofuscin reduction is possible and this have major implications not only for aging but for macular degeneration, a key feature of this condition being the very large accumulation of lipofuscin which seriously impedes cellular function, especially the production of the major energy molecule, ATP. As this recent study demonstrates, it is now conceivable that we can develop strategies to eliminate lipofuscin. That study was on a locust species, for obvious reasons we can't go around opening up peoples' heads to determine if lipofuscin reduction can be achieved. Additionally there are other studies in various species indicating that lipofuscin reduction is possible.

So here we see a "great chain of causation", from and enriched environment, which induces stress, which in turn elevates norepinephrine, which inhibits leptin, which increases autophagy, decreases angiogenesis, starves cancer cells, and thereby provides an anti-cancer effect. Note that in this study it was not the physical activity that provided the benefit, it was the enriched environment and subsequent stress it created as stress does induce norepinephrine release.

As a matter of further investigation it is interesting to note that depression does increase the risk of cancer. Anti-depressant drugs often target norepinephrine, increasing its levels in the synapse and while in treating depression the preferred loci of action should be in the limbic and neocortical regions, it will be interesting to see if depression involves a general reduction in norepinephrine expression including the hypothalamus. Additionally, given the role of Brain Derived Neurotrophic Factor(BDNF) in mediating norepinephrine expression, and that BDNF reduction very strongly correlates with depression, it may well be the case the increased cancer risk in depression is a direct consequence of reduced norepinephrine expression.

The above paragraph is an exercise in Extrapolation City. Interesting idea worthy of investigation. At this point, that is all it is.

Given the above we should not be surprised that cancer rates are rising and that overall public health appears to be degenerating. When searching through my archives I came across something that directly touches on this. It is from "Living to 100", a text addressing research into centenarians wherein this observation was made:

  1. Many of the subjects had limited diets suggestive of nutrient deficiencies, yet these centenarians were in good health, active, and obviously had something going for them. 
  2. As these centenarians experienced the Great Depression, two World Wars, and a differing diet in their younger years, they experienced periods  of famine, there were no trans fats, no processed food, and fat was regarded as a treat. 

So what are the lessons here?

  1. Learn to stay hungry but maintain good nutrient intake. 
  2. Don't avoid stress, manage it. In fact in the studies of centenarians it is often found that these individuals lived in very stressful times. Stress is not the problem, stress management is. 
  3. Recognise the modern Western Diet is pathological. 
  4. When thinking about complex adaptive systems don't be afraid to extrapolate but only if you then follow through with empirical support! Plausibility is not Proof! 


Pbef said...

I tend to appreciate people with your kind of tenacity and toughness. I also wish that you go on surveying and sampling and try to digest philosophically unripe fruits (or facts) from biological fields of sciences for as long as possible; So, I end by saying: Take care not to starve yourself too long and too often.

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