Tuesday, December 8, 2009

Nutrients and Longevity

Today I read an interesting article in the New York Times that reminded me of earlier studies I had read. To read the full article you need to register with the NY Times. That is free and I recommend it because the health articles are amongst the best I've encountered in the mass media. (They will protect your privacy.) Balanced, referencing actual research, and the articles are very easy to read. The companion articles in relation to this issue can be read here, and here.

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.

Sunday, June 14, 2009

Autophagy, Aging, ATP, and AMD

Over recent months I have being trying to deepen my understanding of autophagy. For a good overview of autophagy check out this site. The nutshell goes like this:

Autophagy is an intra cellular process whereby cellular contents are degraded and then either recycled or expelled from the cell. Autophagy is mediated by organelles called lysosomes, which have a high internal acidity of 4.5 so as to allow the degradation of many molecules and organelles such as mitochondria; the latter process being mediated via macroautophagy, the former through chaperone mediated autophagy.

Autophagy can induce cell death in cancer cell lines though exactly how this happens is not understood. This issue has been bugging me for some time now, I'll come back to it later.

Under most circumstances however autophagy is protective for many cell types and improving autophagy, particularly in the aging cell, is fundamental to preserving cellular health. Autophagy tends to decrease with age, probably concurrently with the increase in lipofuscin waste products in cells. Lipofuscin is undegraded waste products that accumulate in the lysosomes. Lipofuscin can occupy a very large intra cellular volume and will inhibit lysosomal function. This can create a vicious feedback cycle as more lipofuscin will acccumulate, eventually causing the lysosome to rupture and spill the contents into the cytoplasm. Lysosomes used to be known as "suicide vesicles" and with good reason, the degradative enzymes and a pH of 4.5 do a lot of damage in the cytoplasm, potentially killing the cell.

Why does autophagy decrease with age? Speculations:

To maintain an internal pH of 4.5 lysosomes have proton pumps which are ATP dependent. "ATP" is an acronym for a molecule the provides energy in various chemical reactions. It is produced predominantly by mitochondria. ATP levels tend to fall with age and strategies to promote ATP production are vital in maintaining cellular health. If lysosomes cannot maintain an appropriate pH then lipofuscin accumulation will be accelerated.

An aging cell requires more house keeping. Protein production is not as good as it used to be, thereby placing more work on lysosomes and the ubiquiotin - proteasome processes to degrade damaged or dangerous molecules. These two degradative pathways must also contend with the problems created by various irritants that have entered the cell. While these irritants may never actually kill a cell there is the potential for the disruption of any number of processes that could perturb cellular functions.

Nuclear DNA Damage. Again, essentially the aging cell is confronted with increased maintenance. More aberrant proteins are transcribed which requires more degradation by the ubiquitin - proteasome system.

Mitochondrial DNA damage. Mitochondria have DNA more typical of bacteria than mammals. It is single stranded and circular, encoding only 13 proteins, the other proteins required by mitochondria are provided by nuclear DNA. Mitochondrial DNA is much more susceptible to damage than nuclear DNA and lacks the repair enzyme capacity of nuclear DNA. This is unfortunate because mitochondria are the major source of all oxidants created in our cells. The consequent of this is reduced ATP production and all the downstream consequences that entails.

Before Autophagy There Must be ATP

While small amounts of ATP are produced in the cytoplasm it is the ATP production of mitochondria that can determine the health of a cell. Following the ideas of Lynn Marguilis, mitochondria appear to be ancient cells that took up residence in another cell type, thereby allowing a powerful symbiosis that underlies the increasingly complexity of cells through evolution. Various studies have indicated that targeting mitochondrial function could have considerable clinical value.

Professor Bruce Ames was so impressed with his results that he started a company, Juvenon, to market a product specifically aimed at "rejuvenating" mitochondria. The active components of this product are Alpha Lipoic Acid and Acetyl L Carnitine. For an overview of their research refer to this page where you can download various scientific articles. Alpha Lipoic Acid is a very powerful antioxidant that can "regenerate" vitamins C and E. Acetyl L Carnitine transports fatty acids into mitohondria, thereby providing the essential substrates for ATP production.

In the work of Ames et al there is a striking recovery of mitochondrial structure. The internal cristae are like those from the mitochondria of young cells. There are a number of issues here that baffle me. I find it hard to believe that mitochondria, with a genome encoding only 13 proteins, can initiate repair processes. Alternatively this recovery of structure may reflect a simple reiterative process of molecular dynamics that gives rise to the structure. Chaperones and heat shock proteins, typically providing a protective effect for cells, often play important roles in folding proteins and unfolding misfolded proteins. As many of these functions are ATP dependent, increased ATP availability will enhance the protective effects of chaperones and heat shock proteins.

As the principal mode of house keeping for lysosomes is chaperone mediated autophagy, an important chaperone here being HSC70, and the ATP dependent proton pump in lysosomes, improved ATP levels will enhance autophagic processes. This raises the question as to whether the improved mitochondrial structure arose because the increased "house keeping" activities removed various misfolded proteins and irritants thereby allowing mitochondrial structure to become more like that associated with healthy mitochondria. This suggests a complex interplay between mitochondrial and lysosomal functions. Aging and rejuvenation studies clearly indicate that mitochondrial and lysosomal functions are linchpins of health.

The decline in ATP production with age is probably occurring through the gradual loss of mitochondrial numbers and efficiency. (And, I just stumbled upon this, for a laugh, read it.) However, according to this article at least, under the right conditions it does seem possible that mitochondrial structure can be repaired. Note the chaperone and heat shock protein involvement in these processes and also the "spontaneous" macromolecule assembly that occurs.
The article addresses mitochondrial replication, an ongoing process in our cells.

The Retina as a Model of Autophagy and Aging

While enhancing cellular house keeping functions is essential to warding off damage and maintaining optimal cellular metabolism there remains the problem that lipofuscin accumulation is almost inevitable. These are chemical processes after all and there are always residues that are not excreted as digested products from lysosomes. lipofuscin accumulates, not only in lysosomes but also in other cellular regions including mitochondria, where it directly impacts on ATP production. Lysosomal degradation results in the expelling of the digested products for recycling. There is also evidence for some of these products being "packaged", transported to the cell surface, and expelled.

In one hypothesis, what I consider to be an exquisite process that gives me a moment's sympathy with Intelligent Design, it is put forward that lysosomes and\or the waste products are transported to the cell surface, excreted, absorbed by microglia, which then move to the capillary and dump the contents into the general circulation. As hard as I find that to believe recently I read a study addressing the contents of drusen, the waste products that builds up in the retina and beyond a certain level is a key marker for Age Related Macular Degeneration, is composed of molecules that are related to autophagic processes, including mitochondrial related proteins. That finding suggests that the waste products of lysosomal processes are being excreted. In relation to the retinal pigment epithelium the finding is not surprising because these are probably the cells that do the most degradation work of any cells in the body; at least in terms of constancy of demand.

That study raises the interesting question: why are the RPE cells expelling these materials into Bruch's Membrane, which lies between the RPE cells and the choroid, the blood supply? I hate to so obviously invoke intentionality but I trust you'll understand my point: Bruch's Membrane is a two way transport membrane, allowing nutrients to reach the RPE and waste products to be excreted into the bloodstream. In one study I read it was found that with age the permeability of Bruch's Membrane decreases by many orders of magnitude. In many perhaps most people over 50 there are some traces of drusen. In AMD drusen is all over place and where drusen is present the underlying photoreceptors cells are either suffering or dying; probably both.

A very interesting aspect of that study is the finding of mitochondrial related proteins. Such contents may have been expelled from the cell in vesicles. Mitochondria are degraded by a complicated process called macroautophagy. from what I can presently understand this process requires a lot of energy and makes big demands on a lysosome. Thus any strategy which can reduce the overall rate of mitochondrial turnover could have value in retinal and neural degenerative conditions. This may explain some experimental and clinical results suggesting improving mitochondrial function can impede disease progression.

With the decreasing permeability of Bruch's Membrane larger particles may effectively become trapped in the membrane. However all is not lost for this is where the little appreciated aspects of immune function come into play. There are various types of immune cells that carry what is called a "scavenger receptor". These cells move through tissues and do the extra-cellular equivalent of house keeping. Extra cellular debri is removed, dead or dying cells are absorbed and digested, cell health in the tissues is monitored through MHC class I receptors.

When the Peace Corps Come Marching In

At this point we need to enter into immunology. Here's the nutshell. Cytokines are a class of molecular messengers with far ranging effects, mostly immunological but that can get difficult ... . The types of immune cells that are engaged in the above functions are helped along by cytokines il4 and il10. These are typically perceived as anti-inflammatory cytokines. It appears to be the case that inflammation and house keeping don't go together(males may disagree). That makes sense, you don't vacuum the carpet when there's a burgler in the house.

In times of peace the immune system is cleaning up the area. This is a natural extension of an important process in limiting inflammation. As the inflammatory process progresses there must eventually be an elimination of inflammatory signals. This will involve the elimination of various proteins and lipids that signals danger and so invites an inflammatory response. For example, heat shock protein 60, expressed at very high levels, can and will drive inflammatory signals. The more quickly proteins like hsp 60 are removed from the extra cellular environment the more quickly inflammation will recede and then the repair processes can begin.

It is important to remember that "inflammation" is a word describing a series of processes. Unfortunately it is a loaded word. "Inflammation" can play important roles in initiating cellular repair, providing nutrients, and some so called "inflammatory mediators" are important in regulating neural transmission. (That's a whole fascinating other subject, the many relationships between the the nervous systems and the immune "system".) Take heed of Wittgenstein's Wisdom: "Words are posts on which we hang meanings".

In studies of Age Related Macular Degeneration there is are clear genetic linkages with immunological function and susceptibility to AMD. In particular, Complement Factor H, an inhibitor of complement function, is strongly implicated. The general trend suggests that a persistently elevated level of systemic inflammation is a considerable risk factor for AMD. Systemic inflammation is driven by two principal cytokines: tnf a and il1. A current model popular in immunology is the Th1 - Th2 paradigm. Th 1 is typically perceived as inflammatory and driven by by tnf a and il1, whereas Th 2 is driven by il4 and il10. Echinacea can cause a distinct shift towards the Th 2 type of function, and vitamin D also plays an important role here. Even omega 3's can be important as these fats will, over time, alter the production of prostaglandins, the downstream effect of this being to inhibit the production of il1 and tnfa.

As a general rule the studies suggest that our physiology, particularly with age, is too inclined to shift towards an inflammatory state. The possible explanations for this, while plausible, are long winded and tedious so I'll avoid that aspect.

Our evolution predisposed towards a balance of fat intakes that is out of kilter in modern diets. There is too much omega 6 to omega 3, the consequence being that while omega 3's inhibit potentially inflammatory prostaglandins, omega 6 fats do the exact opposite. At the immunological level this involves a shift towards higher expression of il1 and tnfa. Hence there have been some very surprising results in treating early AMD with omega 3 fats and other nutrients. There is already one supplement out there that appears to even reverse early AMD, while another recent study suggest that even in juvenile retinal degenerative conditions nutrient support can delay disease progression.

With age there is a general increase for more house keeping functions. This arises as cell damage occurs and DNA damage, at both the nuclear and mitochondrial sites, induces aberrant protein production that places additional loads on the ubiquitin proteasome degradation pathway.

With age people can lose the capacity to produce vitamin D from sunlight exposure. Recent epidemiological studies suggest widespread vitamin D deficency. This has all sorts of worrying implications for general health but of particular relevance here is that vitamin D is very important in moving the immune balance towards a less inflammatory state.

Thus studies indicating the protective effects of vitamin D and omega 3's might be converging on the general metabolic effect this has and how this impacts of autophagy and immunological extra cellular house keeping functions. What is interesting about the successful supplement regimes is the specific targets the researchers had in mind: antioxidant strategy, omega 3s'(mininum of two functions here: DHA is a substrate for NPD1, an important neuroprotectant, and EPA works at the prostaglandin level), and mitochondrial enhancement.

And to Wrap Up ... .

This brings us all the way back to what I mentioned earlier about the susceptibility of mitochondrial DNA to oxidative damage. Mitochondria absorb nutrients and eventually divide but as the DNA is damaged the new mitochondria are effectively aged. Fortunately genes aren't everything, ongoing studies indicate that the astute use of nutrients can impact on cellular functions at such fundamental levels so as to provide cells with protective functions that may increase their lifespan and function.

Inducing autophagy is not easy but obviously a desired goal. Rapamycin, an antibiotic of all things, induces autophagy. Nutrient deprivation, as in Caloric Restriction where autophagy has long been recognised as an important antiaging component of this strategy, can induce autophagy but it is very difficult to know just how much nutrient deprivation ... . It might just be amino acid deprivation, or the deprivation of fuel. Indeed, it is known that rapamycin induces autophagy by inhibiting the receptor mTOR, which is a nutrient receptor. Interesting concordance with Caloric Restriction dynamics there. This is how in the earlier study I cited on cancer cells killed by autophagy the process unfolded. Now there's another fascinating mystery, why does autophagy kill cancer cells but not other cells; though it can kill other cells sometimes ... . It's just too difficult. At present, just today I managed to dream up at least one plausible approach to that challenge. "Plausible" don't mean that much though!

My other specific goal in relation to this is to find strategies that address the exocytosis of waste products from cells concurrently with a distinct immunological shift to induce a heightened state of extra cellular house keeping. It probably can be done to some decent extent but will require lots of discipline. Don't have much of that and besides I need to keep reading.

Saturday, June 6, 2009

Those Mad Neuroscientists

A Critique of "The Madness of Neuroscience" by Dale Atrens, Quadrant, May 2009.

Quadrant is an Australian journal typically devoted to addressing issues in social science and economics. In this regard it does a good job. With regard to neuroscience, psychiatry, and psychology, if this article is any guide, it is obvious the editors don't have a clue about these disciplines.

Whether treated scientifically or by any of the myriad alternatives, the prognosis for the afflicted remains bleak. Some get better; some don't. Whether any treatment substantially alters these grim odds is questionable.
No-one is denying that there exists some psychiatric conditions for which treatment is management of the symptoms not addressing the cause. In medicine that is not an unusual practice. For the vast majority of psychiatric patients the prognosis is much better than the mentally ill who do not receive treatment. Even most critics who claim psychiatry is drug addicted admit that drugs are an essential component to treating a great many mental health issues. For example, in as yet unpublished research Nancy Andreasen has established that schizophrenics experience ongoing cell loss at an accelerated rate. Her findings also established that this cell loss is greater in those who receive higher doses of anti-psychotic drugs. Her advice is not to stop administering these drugs but to keep the dosages as low as possible. What is interesting here is that she does advocate cessation of these drugs, most probably because she is well aware the benefits far outweigh the potential risks. Additionally there could be a chicken and egg question here. That is, the cell loss might be a function of the severity of pathology, hence those receiving the higher doses would experience greater cell loss irrespective of the drugs. We shall have to wait for her results to be published but already I can hear various individuals proclaiming that these results are proof that psychiatrists are evil individuals who are functioning as an arm of the State who have little regard for the welfare of their patients.

The efficacy of various treatments is questionable but the weight of evidence clearly supports the importance drugs play in managing mental illness. The problem with the author's claim is that he lumps all psychiatric conditions under one umbrella when the prognosis for many conditions can vary from careful management of symptoms to complete cure. "Madness" is a hopelessly ambiguous term but that is consistent with often ambiguous nature of the author's arguments.

Madness is increasingly depicted as a disorder of brain chemistry that is best treated by drugs. The conception of madness as a brain disease is said to be both scientific and humane.
A long time ago the "chemical imbalance" hypothesis regarding depression immediately caught the attention of my critical faculties. Unfortunately there were enough "authorities" from neuroscience, psychology, and psychiatry to publicly proclaim an understanding of the neurobiology of depression. It's all about serotonin! Even when many antidepressants also targeted norepinephrine suddenly everyone was talking about serotonin and depression.

Many years later I was exploring a neuroimmunological perspective and reading some very interesting neuroscience literature. Endocrinology also becomes relevant. In the 1960's, in yet another display of exuberant confidence, it was believed that a biological marker for depression had been discovered. It was found that up to 40% of major depressives display glucocorticoid resistance. Now we know that people reporting depression can also have very low cortisol levels, whereas glucocorticoid resistance typically arises from chronically high cortisol. To cut a very long story short all these factors seem to create a environment in the hippocampus that suppresses neurogenesis through reduced GABA expression, GC-NfKB mutual transcriptional antagonism(facilitating either il1 or NO), and increased glutamate expression. If there is a final common pathway here, and I suspect there isn't, BDNF, a trophic factor strongly implicated in depression, may well be it. (Note: I will not bother to explain the above acronyms, that would require many pages.) My thinking shifted from thinking about depression as a neurobiological disorder to a neuroimmunologicalendocrinologicaltrophicenvironmental disorder. That is, I don't have a clue. To fully appreciate my ignorance we need to look at the other aspects of depression.

The concept of "depression" is further complicated by the singular tense of the word. There are a number of types of depression and treatment needs to be tailored to the type of depression.

Depression is reaching epidemic proportions and imposes tremendous costs on society. It is a condition that occurs at the interface of the individual and environment. Stress is the primary driver of depression but a host of other causative factors can be involved.

One causative factor that is virtually ignored is the role culture can play in the frequency of depression. The British celebrity psychologist, Oliver James, has argued that our society is making too many people mentally ill. If the trends in depression incidence are to be believed he may well have a point. Nancy Andreasen, former Professor of Psychiatry at Harvard, at the end of her text "Brave New Brain", eloquently argues for a fundamental rethink of what it means to be a "self". I have some sympathy with their views but I think Andreasen is dreaming, albeit a good and proper dream.

That stress and culture can be caused factors in depression makes it clear that depression cannot be defined as a "brain disease".

We should not yet expect to find reliable biomarkers for depression. Depression arises from so many different causative factors and human physiology is so flexible and responsive to the world that expecting symptoms verbally reported will have correspondence with various biomarkers is a highly questionable assumption. In time we will more clearly delineate markers for depression but I suspect we will never achieve the precision we would like.

My reading clearly indicates that at the primary literature level there are some very promising progress being made at both the molecular and clinical levels. In Australia at least there is a trend away from solely drug based treatments and a host of peer reviewed literature over the last several years has provided a range of therapeutic options; from insight mediation to maintaining good vitamin D status. If clinicians choose to still rely predominantly on drugs it is not because of lack of choice or some maddening drug promoting rant from the neuroscience community.

There has been and probably still is a problem with the prescribing of antidepressants. The problem is not going to be solved by erecting some straw man argument that purports to prove that the reason for this drug dependency is because the neuroscience community has foisted upon all and sundry a massive global wide conspiracy to the effect that they really do know what is going on inside our heads.

Nor I am sure which neuroscientists he is making reference too. In my experience neuroscientists and psychiatrists are the amongst least likely to play Dr. Freud, Dr. Darwin, or Dr. Pauling. They admit to ignorance and make no apologies for that. As one neuroscientist commented on bionet.neuroscience: at this stage they are basically "butterfly collecting". Hopes for finding the precious "neural code" have been dashed too many times and the vast majority of neuroscientists have no interest in such questions. Their attention is directed to the discrete elements involved in nervous function. Good science starts there and it will may take decades before more powerful concepts and hypotheses can be explored. We don't know, there could be a paper published tomorrow the casts illuminating light on these issues.

Nonetheless, human beings being what they are, there are those who believe that in every instance there is no time like the present. Over recent decades there have been a variety of popular texts that were widely discussed at both academic and coffee shop levels. The professions involved were neuroscientists, philosophers, psychologists, artificial intelligence researchers, and probably many others I don't about. With the exception of Damasio's, The Feeling for What Happens", these texts remind me of a statement I read in a great book by Francis Crick, "The Astonishing Hypothesis: The Scientific Search for the Soul."

"At times I even persuade myself that I can glimpse some of the answers, but this is a common delusion experienced by anyone who dwells too long on a single problem."
I read the texts, I enjoyed many of them, and the forewords of most texts I read made it perfectly clear that authors were aware that this was an "adventurous exploration" into the question of "consciousness and associated neural events". Nonetheless I think Daniel Dennett(Consciousness Explained) and Steven Pinker(How the Mind Works), and many other less well known texts, have done a disservice to such investigations.

The problem here is not that these all authors are deluded but that those listening to and reading them can be left with the impression that the "big questions" of neuroscience are about to be solved. Yet solving the question of consciousness, if it is worth the effort, is not going to help us address Alzheimers or Multiple Sclerosis or Parkinson's Disease or help find strategies to preserve brain function well into old age and a great many other important matters. These are much more important challenges and a great deal of research is directed towards those challenges.

As for the questions addressing human behavior I'm not going to address that because I have absolutely no idea how to think about that. I gave up that little adventure a long time ago, too many times lost in the forest.

As for the author's claim that madness is increasingly perceived as a disorder of brain chemistry this is just plain wrong. There WAS the dopamine hypothesis(note: hypothesis! not explanation) regarding schizophrenia but in recent years accumulating evidence suggests schizophrenia is a developmental disorder resulting in widespread cell death in the neocortex. Parkinson's Disease is perceived primarily as a mitochondrial dysfunction disorder, though a paper by the Australian neuroscientist, G. Willis, offers a fascinating hypothesis regarding the etiology of Parkinson's Disease.

The above examples are much more illustrative of what is going on in neuroscience and psychiatry than the conspiratorial idea that neuroscience is a monolithic entity attempting to delude us all with grand proclamations of understanding.

I'm not sure what neuroscience literature the author reads but he either needs to read more carefully or learn to read more widely.

A frightening proportion of the population in developed countries uses some form of prescription drug claiming to be psychotherapeutic. Why waste time lying on a couch or go to the bother of changing ways when you can pop a pill and get on with living. It's a seductive promise. Young, old, or in between. no matter what problem you may have, there is a drug that promises quick and easy relief.
Is this a problem of neuroscience and psychiatry or of culture? Neuroscience as a discipline has nothing to with this question, psychiatry does. Western Medicine very much fights a rear guard action. A former Australian Health Minister, Michael Wooldridge, once stated that the Department of Health should be called the Department of Disease. A very valid point. Since he made that statement the general level of health awareness has substantially increased. Strike up one for the old wisdom: prevention is better than cure.

Unfortunately this trend towards prevention has been slow to penetrate into the mental health realm. Psychiatrists and psychologists are called upon to treat people who are mentally ill but do so in an environment where "quick and easy relief" is not so much an option as an imperative. Psychotherapy is time consuming, expensive, and slow. However if on the basis of the empirical results the author doubts of efficacy of drug treatments then he should be in no doubt that psychotherapy is a complete waste of time.

Our culture does not allow us the option of taking time out to engage in such "luxuries". Mental Health professionals are already busy enough, they too are under pressure to provide the quick and easy relief. There are many reasons why the excessive use of antidepressants has arisen but trying to sheet all the blame back to neuroscience or psychiatry is to engage in some very selective cherry picking.

It is worth remembering that mental health professionals are required to enter into an extremely difficult endeavour. They must attempt to fix problems with the most complex known phenomenon in the universe: human behavior. We should not be surprised that their success rates are less than enviable. The vast majority of clinicians are painfully aware of the shortcomings in the available therapeutic options.

There has been far too much prescribing of antidepressants, this in part driven by a culture which suggests we should always be happy. Life was not meant to be easy nor was it meant to be managed by popping powerful psychotropic drugs that full effects of which can never be completely anticipated.

There are millions of people who will attest that lives have been saved by psychotropic drugs. The author's assertion flies in the face of conventional medical practice and as such requires more than an outright repudiation of that practice. The author should also consider that if not for modern psychiatric drugs mental institutions would be dotted all over the landscape.

Lithium, for all its problems, has been a valuable treatment. The mode of action remains a mystery. That is no big deal, it was discovered quite by accident by the Australian psychiatrist John Cade in 1949. At the cellular level lithium has some very interesting effects. One being the emergence of trophic factors issues, this being consistent with data on some antidepressants.

Antidepressants are the most widely used psychiatric drugs and have revolutionised the treatment of depression. Unfortunately the biologic-reductionist model of understanding depression has led to an over emphasis on drug based treatments. Prescribing of these drugs, more often done by general practitioners than specialists, has been too frequent and often on the flimsiest of evidence. In recent years the trend has moved away from drugs and a more balanced approach to treating depression. In the majority of cases it should be taken as a given that the treatment has succeeded only when the drug is no longer required.

As for the all the other mental health issues out there, and there are a great many of them, each must be addressed at the clinical level. The clinician is well aware of the theoretic limitations underpinning the therapeutic strategy but over the course of years, hopefully, the experience enriches and improves their clinical practice.

Dale Atren claims it is "not rational" to prescribe drugs that affect neurotransmitter levels because there is no theoretic basis for the same. In Science, Mr. Atrens, experience is rather useful. Clinicians don't know why drug A helps patient B but they do know it may very well help the patient. What is important here is the clinical outcome, if the patient improves then who gives a hoot that we don't understand the molecular underpinnings of the same? If medicine had proceeded on the premise of "must be rational" as defined by Mr. Atrens then we'd be asking chimps for advice concerning medicinal plants.

Taking a home grown example, the below is from ADHD treatment in the Royal College of Physicians Draft Document of 2008

Over the past 30 years there has been extensive scientific research published into ADHD causes, associations, outcomes, and treatments. ADHD continues to be a subject of great interest in the community, with frequent discussion in the media. Diverse and strong opinions are often expressed, particularly about causes and treatments.
That is, modern neuroscience does not present a consensus on the cause and treatment of ADHD. In fact this document makes specific reference to a number of potential processes at play. The same is true of of schizophrenia and depression. For example, there is even a Swedish study demonstrating that in a subset of schizophrenics the causative factor is celiac disease. This example highlights the tremendous difficulties in understanding psychiatric illnesses. There are so many potential causative factors involved that only through disciplined ongoing research and analysis is progress going to be possible. Engaging in Coffee Shop Logic, as Mr. Atrens obviously enjoys doing, is a facile and pusillanimous activity best left to those who have no experience and little if any understanding of neuroscience, psychiatry, and psychology.

In the public realm neuroscience, psychiatry, and psychology are typically addressed through Coffee Shop Logic. Consequently the general public is often completely misinformed about what is happening in these disciplines. My suspicion is that the general public likes it this way because it gives warrant to engaging in endless specious speculations about brain function and how to address abnormalities. It is also true that far too many professionals in the relevant fields fall prey to these desires. All of us are susceptible to this cognitive deficiency and must be on guard against it. It is both frustrating and difficult to be constantly saying, "I don't know" but that is all too often what should be said. Instead over the years we have been confronted with the following examples of Coffee Shop Logic:


This concept is flawed at the philosophical, conceptual, empirical, and perceptual levels. It is ludicrous.

Emotional Intelligence

A load of bollocks.


Another bloody ghost, at least as it is commonly understood. It is as if the famous text, Ghost in the Machine(1949) by the British philosopher, Gilbert Ryle, has never been read.

The Emotional Brain

That concept just makes me angry.

Repressed memory syndrome.

Some truth to this, perhaps. Its significance is vastly over rated.

Consciousness studies

Ideal for the coffee shop, it makes one sound so profound and insightful. Long ago I wrote:

If, and we all do occasionally, you need to sound like you know what you're talking about when pondering the great mysteries, quantum-mechanically indeterminately chaotically insert the words, quantum, Einstein, Heisenberg et al, indeterminacy, chaos, and consciousness, into your dialogue.

We only use 10% of our brain

Speak for yourself.

We never forget anything, we just can't recall it.

Specious nonsense with not one iota of empirical support.

The Right-Left duality of brain function

One could just as easily argue for a balance between the frontal and posterior regions of the brain, or the neocortical and basal ganglia dynamics. One is better off not saying a single word.

Evolutionary Psychology

Was a big deal for a time but is now, thankfully, relegated to the huge garbage dump of stupid models concerning human behavior.

Global models of brain function

Dreamer, silly little dreamer, can you put your hands in your head oh no("Dreamer", Supertramp)

Those who wish to engage in Coffee Shop Logic and ponder the great mysteries of neuroscience and psychology will do well to heed the following.


A Buddhist Master was seeking a replacement for his monastery so he asked all the most promising monks to provide an explanation as to why they should take over his role. Many came forth with erudite accounts of Buddhist scriptures and principles. Then one monk came up to him and silently proffered a single flower. He got the job.


One day the Zen master Hakuin was teaching a teenage girl from the the local village a particularly difficult sutra. After he finished explaining it she asked if he could explain it again. As Hakuin commenced to recount his explanation the girl, without saying a word, stood up and left the room. Hakuin burst out laughing and exclaimed, "I've made a fool of by this girl!".


"We may differ in what we know but in our infinite ignorance we are all equal." (Karl Popper)


There is nothing intrinsically wrong with Coffee Shop Logic but it must always be exercised with the recognition that we are engaging in an "adventurous explanation" rather than a rigourous analysis. Sadly Coffee Shop Logic is all too often mistaken as "good thinking". It is nothing of the kind, I typically engage in it to help me get to sleep or when taking cheap shots at people on blogs. Now that is fun. If blogs are indicative of the general state of human intelligence we are in big trouble.

There are many other statements by Mr. Atrens that are contemptible and foolish but I've wasted enough time on this. At present my focus is on an intra-cellular process, autophagy, and how this relates to preserving neural health and enhancing longevity. I have a great deal of work to do here and consider those investigations far more valuable than wasting my time addressing the failures of Coffee Shop Logic.

Mr Atrens is a Reader Emeritus in Psychobiology at the University of Sydney. That Doofus of Inter-Galactic proportions, Tom Cruise, will love Mr. Atrens. I advise Mr. Atrens to become a spokesman for the Scientologists.

Thursday, May 28, 2009

Type 1 Diabetes on the Rise

28/05/2009 5:39PM

Type 1 childhood diabetes is increasing. Type 2 actually has a closer genetic connection than type 1, at least that is what one doctor told me. There was an interesting Italian study sometime ago which found that in obese individuals the risk of type 2 was 49 times higher for those in the highest 10% (I think) then the lowest group for organic pollutant measurements in their body tissues. Another study found increased complications in diabetes individuals if they lived close to a dump.

Type 1 diabetes is perceived as a Th 1 inflammatory mediated autoimmune disease, the beta cells appear particularly sensitive to oxidative attack. However the cytokine profile goes across the board. The Th 1-Th 2 stuff is useful but not the real thing. There might be an epigenetic process going on here because I recall one study which indicated that if the grandmothers had gone through a severe famine this increased the risk of diabetes but only in the grandchildren line(so far measured). I can think of two possible causes, there must be more. The point is this: Across wide populations, if we increase the potential risk factors through environmental changes, we can then create epidemics. It's a neat trick and we're pulling it off.

Strange stuff but just today I read this:

The water flea, daphnea will develop large defensive spines when predators are around. If they then reproduce, their off spring develop these spines even when not exposed to predators.

New Scientist May, 2008l p 31

There is a way to understand this but you have to give up the one gene - one protein idea. It's wrong so you may as well.

Now, speaking of persistent organic pollutants, has anyone bought any bottled water lately?