Sunday, September 27, 2009

Melatonin, Molecules, and Models

Melatonin is a health supplement promoted for its anti aging properties. There is a substantial body of evidence suggesting melatonin can confer a wide range of protective benefits. Melatonin is a potent antioxidant, promotes the immune response, demonstrates anticancer properties, and plays an important role in regulating the sleep wake cycle.

As we age our melatonin levels tend to drop, this probably playing some role in the increased incidence of cancer with age. To cite one of many examples:

Therapeutic actions of melatonin in cancer: possible mechanisms.

From the abstract:

The anticarcinogenic effect of melatonin on neoplastic cells relies on its antioxidant, immunostimulating, and apoptotic properties. Melatonin's oncostatic actions include the direct augmentation of natural killer (NK) cell activity, which increases immunosurveillance, as well as the stimulation of cytokine production, for example, of interleukin (IL)-2, IL-6, IL-12, and interferon (IFN)-gamma.


The increased incidence of breast cancer and colorectal cancer seen in nurses and other night shift workers suggests a possible link between diminished secretion of melatonin and increased exposure to light during nighttime. The physiological surge of melatonin at night is thus considered a "natural restraint" on tumor initiation, promotion, and progression.

There can be little doubt that at a population level melatonin levels have markedly declined. The reasons for this relate to our current lifestyles relative to the greater part of our evolutionary history. It wasn't that long ago that when night came so did darkness. A primary regulator of melatonin production is blue light. Exposure to blue light rapidly diminishes melatonin production. This effect is so pronounced that in the excellent text: The Promise of Sleep, the authors argue that if you get up in the middle of the night you should not use full lighting. The idea behind this advice is that because blue light so quickly diminishes melatonin, and melatonin helps keep us asleep and maintain appropriate sleep cycles, any disruption to the sleep cycle can have repercussions throughout the following day.

Perhaps they are being a little extreme, I'm doubtful the momentary perturbation can be that disrupting but the research does make it abundantly clear that maintaining good sleeping patterns is essential to present and future health. As the authors state in that excellent text,

"If you are serious about your health, nutrition, and fitness, you need to be serious about your sleep." (p. 423)
For a set of abstracts addressing melatonin's role in preventing cancer development have a look at this page. Shift work and cancer rates have long been in the literature. While shift workers do not necessarily sleep less than the rest of the population their sleep is less efficient and higher rates of cancer are observed. This is particularly true of breast cancer but that may reflect and experimental bias because nurses do shiftwork, are still predominantly female, work in hospitals making access to them much easier and cheaper, and will be willing to participate in such studies.

It is not enough to get the requisite 7 hours sleep. It is equally important that the sleep pattern is maintained and undisturbed. One striking example of this is a study of aircrews found that those on trans meridian flights had elevated levels of cortisol, poorer working memory performance, and and a follow up study fond reduced hippocampal volume, the latter findings often being consistent with elevated levels of cortisol.

Cortisol is another good example of an idea I am exploring on this peaceful Sunday afternoon. We hear about the need to keep cortisol down but that in itself can represent a misunderstanding of physiological processes. "Homeostasis" is a misleading concept, biological processes are almost invariably in constant states of change. Cortisol levels are generally inversely proportional to melatonin levels. Cortisol is an arousal hormone released by the adrenal glands, throughout the day the levels fluctuate in what may be described as a "broad expectancy strategy" for the upcoming time.

Approximately 2 hours before awakening our cortisol levels begin to rise. This is important because cortisol is an arousal hormone that helps us wake up. Melatonin does the opposite, it inhibits dopamine and by stimulating some immunological messengers(il1,il2, il6,il8) it induces fatigue. As the sunlight hits the eyes, even the closed eyes, melatonin production is now being suppressed by an external signal, with the intrinsic circadian rhythms already lowering its production sometime beforehand. The organism is being primed to wake up and the physiology is being moved in anticipation of a changing environment.

Why sleep in the first place? There is a lot of debate about this and it is very hard to to present a clear picture of why we need to sleep. A recent paper argues that sleep is a form of behavioral adaptation, that the organism is better off sleeping as it is primarily adapted to being a creature of the day or vice versa. It is well known that chronic sleep deprivation as a form of torture is a very good way to induce psychosis and so some surmise that sleep must play some fundamental role in cognitive processes, either by way of "fine tuning" what was learnt during the day or allowing repair and nutrient provision to consolidate what was learnt during the day. There is plenty of evidence to support these ideas but I wonder if the approach is couched in a poor frame of reference.

As previously mentioned, in physiological processes there is a persistent shifting set of rhythms that regulate not only external behavior but internal behavior. The organism's physiology is adapted to respond to the most probable environmental demands that occur with the passage of time. The sleep wake cycle is not just about regulating the level of awareness it is about the whole organism. Cortisol levels fall in the evening to reduce alertness and energy levels, growth hormone levels rise during deep sleep to promote repair and growth, dopamine and acetylcholine levels rise in the morning, albeit that given the popularity coffee all too slowly for the modern world; but decline in the evening hours.

The picture is one of a vast set of physiological processes broadly co-ordinated by the "central" circadian clock, located in the brain and called the suprachiasmatic nucleus. This is a remarkable and tiny body of cells. Their rhythm is regulated by the degradation and production of various intra-cellular molecules(BMAL, CLOCK, PER and ... ) in a process so simple but replicated so many times it can achieve remarkable stability. Take 10,000 of these cells put them in a culture dish and they will entrain their rhythms to something just over 24 hours, 24.8 hours comes to my mind but I can't find the reference and I've seen others indicating different times but always just over 24 hours. It is almost as if evolution destined us to regretting waking up.

Those cells are also influenced by a plethora of molecules from the CNS and the bloodstream which can change the rates of degradation and production. Additionally, there are various types of "circadian clocks" throughout the body and I even recall one study citing a different circadian time across the right and left hemispheres. So it would seem remarkable that for the greater part these processes keep the organism's function and behavior concordant with the day night cycle. (There are broader rhythms which help regulate behavior across the climatic seasons.) This appears remarkably precise and helps explain why some people take a liking to intelligent design. In this case however evolution has cheated.

We come back to melatonin and blue light. The only reason we maintain circadian stability(hopefully!) is because early morning exposure to blue light quickly shuts down melatonin production, this being concordant with other physiological changes occurring at that time. As numerous studies on blind people have established, without the regular stimulus of light circadian rhythms soon shift to be markedly out of kilter with the day night cycle. Interestingly, retinally blind individuals, those whose retinas transmit no information to the CNS or central clock, do have lower rates of some cancers and this might be explained by the finding that their bodies produce melatonin for up to 12 hours per 24 hours whereas typically light regulation of melatonin production reduces it to 8 hours per 24 hours. Given melatonin's potential to increase pro-inflammatory mediators, I would be interested to see studies on this demographic addressing dementias, autoimmune diseases, and atherogenesis.

Within the mammalian retina there is a specialised set of cells that specifically respond to blue light and transmit a signal to initiate the shutdown of melatonin production. The route of this signal is torturous and hopelessly inefficient, a good example of how clumsy evolution can be in getting things done. This is not a simple on or off signal, it is graded but even that probably isn't linear. Even this regulation of melatonin can be insufficient to maintain circadian stability.

Chronic stress is very good at inducing circadian dysregulation, is the primary driver of depression, and depression is often marked by elevated cortisol and even more worryingly glucocorticoid resistance, a condition in which the cortisol levels have been elevated for so long that cortisol no longer plays an immunosuppressive role but rather an immuno destructive role, inducing programmed cell death in various immunological cells and also shrinking some regions of the brain. The lack of immunosuppression leads to increased expression of pro-inflammatory mediators which are implicated in atherogenesis, dementias, and tumour promotion by angiogenic factors. As the studies make very clear chronic major depression is not just about the neck up but a whole body response to the environment. It needs to be taken very seriously because the individual is not only "feeling blue" but damaging their present health and markedly increasing their risks for future health problems. The "mind" is destroying the body. While some perceive depression as an adaptive response in my view it is a response that confers no benefit on the organism. The physiological changes are damaging and represent a change being driven by a failure of the adaptive processes to address the present environmental contingencies.

Interestingly chronic depression is often marked by temporal lobe atrophy, the same type of neurological change seen in trans meridian aircrews. Chronic disruption of circadian rhythms is an intrinsic stressor and is very common in major depression. The air crews demonstrated elevated cortisol levels at certain circadian times. Similiar results are found in major depression and traumatic brain injury. Intriguingly the elevated cortisol levels are not consistent throughout the day but may be confined to some portion of circadian time. It is as if the physiological processes have been shunted into a new rhythm but the transformation was incomplete and induces some inefficiencies.

The loss of efficency is to be expected because the physiological processes represent an anticipated response. The physiological processes, while capable of preparing the organism for a wide range of environmental contingencies, have a relatively narrow range of optimal function but a broad range of mediocre function. Evolution enjoys mediocrity because it is relatively easy to stumble upon and in a numbers game mediocrity will not only predominate but also tend to crowd out better solutions because probabilities are that the mediocre solutions will be the first solutions encountered. This explains the public service.

The physiological processes do not "adapt" or even "respond" to the changed circumstances, there is merely a change that is driven without intent or purpose. Physiological processes are about as intelligent as a mouse trap. These processes are not trying to do anything. If you wish to be a strict materialist and become deeply disturbed consider that even us, as conscious individuals, are not trying to do anything, we are just another type of adaptive process. We can honestly state this flies directly in the face of our personal experience but many known facts about the universe do exactly the same. That an idea contradicts our most immediate experience does not invalidate the idea but it can raise some interesting quandaries. Of molecules and men, is there any real difference?

Melatonin has a dark side and that is Light. Melatonin likes the night, taking it approximately 2 hours before bedtime is a good way to promote sleep. Various studies indicate that high melatonin levels during light hours can induce increased rates of photoreceptor death in the retina. The risk is sufficient that individuals with any type of retinal degeneration are advised to avoid melatonin supplements. There are other potential contraindications for melatonin supplements: those with autoimmune diseases or at risk of the same, the immuno stimulatory role of melatonin may predispose individuals towards some types of leukemia; and if Greg Willis, an Australian neuroscientist is to be believed, melatonin levels may play a role in the etiology of Parkinson's Disease.

In my view these are relatively small risks and there are many reports of supplements having a potential downside. Melatonin is a good example of how even the slightest changes in context, in in this case light exposure, can induce significant changes in results. There is a small mountain of literature proclaiming the various beneficial properties of melatonin the molecule that in no way suggest melatonin could carry the above risks. It is only when we consider its mode of action within specific contexts that we can begin to appreciate how these risks may arise.

This, however, is largely beside the point. Melatonin is a hormone the function of which is tightly tied to the physiological and environmental conditions prevailing at night. That melatonin demonstrates seemingly favourable effects does not immediately mean it should be of benefit. There can be benefits to melatonin administration but given its physiological activity my view is that it should only be taken at night. That is, these physiological agents need to be understood within an overall context rather than specific properties like antioxidant capacity, immuno modulatory functions, etc etc. A classic example for models that are context based is antioxidants because most antioxidants, melatonin included, can demonstrate pro oxidant activities. Even the appellation "inflammation" carries a multitude of connotations that can easily mask the crucially important roles so called inflammatory mediators can play in a very large range of physiological processes.

Language can be a problem in our descriptions of physiological processes if only because the structure of language very much predisposes us towards thinking about properties rather than contexts and dynamics. We need to keep in mind that the appellations of various biological objects are conceptual conveniences that do not necessarily elucidate the full function and significance of the object. We need to also recognise that the function of any biological object can be contingent on the current physiological state. This, of course, makes the conceptual challenge that much greater and demanding. That is going to take some time ... .

Tuesday, September 22, 2009

A Little Stress Goes a Long Way: 26 weeks of anti-tumour activity

Short Term Stress Enhances Anti-tumor Activity In Mice, Study Shows.


Researchers at the Stanford University School of Medicine have shown that, at least in laboratory mice, bouts of relatively short-term stress can boost the immune system and protect against one type of cancer. Furthermore, the beneficial effects of this occasional angst seem to last for weeks after the stressful situation has ended.


The abstract for the research piece can be downloaded here.

The results of the above study remind of a wonderful review by Sapolsky et al wherein they put forward a model addressing such issues. That was in the days when I was stupid enough to believe I might learn something about what the hell is going on around me. The logic is simple, we don't have to go to acronym city.

The review is somewhat dated now but can be downloaded here:

Stress of just about any kind will activate the stress response axis in our brains. This will induce the release of Corticotrophin Releasing Factor, a hormone that stimulates the adrenal glands to start pumping out cortisol and other stress hormones. Corticotrophin Releasing Factor is released at the base of the brain and must travel via the bloodstream to the adrenal glands which sit on top of our kidneys. This hormone not only stimulates the adrenal glands to pump out immune dampening cortisol it also activates a variety of immunological cells and will promote inflammation until such time as cortisol levels rise to dampen the response. Whereas inflammatory mediators are stored in various cells and can be immediately released through the appropriate signals, it can take several hours for cortisol levels to reach sufficiently high levels to dampen the immunological activation.

Therein lies the beauty of this evolutionary strategy because stress implies injury so you want the immune system primed to address injuries. It is important to remember that the "immune system" and "inflammation" play essential roles in healing, nutrient provision, and growth factors to injured tissues. If there is an injury a great many inflammatory mediators will be released at the site of injury. So even by the time cortisol comes into play, this region will be loaded up with immunological warriors and repair crews while the inflammatory response in the rest of the body is being suppressed by the cortisol. If there is no injury, things settle back to the forever wavering physiological changes that make a mockery of "homeostasis".

So short term stress has the benefit of occasionally raising the alert status of the immune system, thereby enabling it to identify and target pre cancerous and cancerous cells. This touches on something I have often wondered about: it may be a good idea not to try and fixate a physiological state because most such states have upsides.

As to the sustained effects of the response, I can make no theoretical sense of that which means it is time to get off my lazy arse and start learning again(Ha!). I suspect the cause of the sustained response is that every time the researchers approached the cages to take more blood samples the mice looked up and thought, "SHIT, here we go again." After six months they got used to it.