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.
Sunday, June 14, 2009
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.
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.
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."
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.
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
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:
Self-esteem
This concept is flawed at the philosophical, conceptual, empirical, and perceptual levels. It is ludicrous.
Emotional Intelligence
A load of bollocks.
Rationality
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:
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.
1.
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.
2.
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!".
3.
"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.
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:
Self-esteem
This concept is flawed at the philosophical, conceptual, empirical, and perceptual levels. It is ludicrous.
Emotional Intelligence
A load of bollocks.
Rationality
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.
1.
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.
2.
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!".
3.
"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?
John.
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?
John.
Thursday, November 20, 2008
Diabetes and Pollution
To yet again highlight the ever increasing dangers of pollution, this article puts forward a very worrying hypothesis that is cause for concern. This is not the first study to find a link between diabetes and pollution and it will not be the last.
Potassium, Sodium, and Blood Pressure
Low Potassium is linked to high blood pressure
Most of us have heard about the dangers of excessive salt consumption in relation to blood pressure. While salt consumption needs to be carefully monitored it is equally as important to ensure that we receive adequate potassium intake. This can be quite a challenge as recommended potassium intake is quite high. Bananas, potatoes, Tomato juice, orange juice, are all good sources of potassium. This article, from the ever reliable NIH institute, provides a good overview of potassium and its dietary sources. Note the daily requirement for potassium is a whooping 4.7 grams. To achieve this, have a look at this site for more detailed guidelines on potassium dietary sources. Look at the table at the bottom of the page. They have excluded meat sources but these are also valuable sources of potassium.
Remember, the potassium - salt(ie sodium) balance is very important, so if you eat lots of processed food, which is typically far too high in sodium and\or salt, you need to counter balance this with substantial potassium intake.
Most of us have heard about the dangers of excessive salt consumption in relation to blood pressure. While salt consumption needs to be carefully monitored it is equally as important to ensure that we receive adequate potassium intake. This can be quite a challenge as recommended potassium intake is quite high. Bananas, potatoes, Tomato juice, orange juice, are all good sources of potassium. This article, from the ever reliable NIH institute, provides a good overview of potassium and its dietary sources. Note the daily requirement for potassium is a whooping 4.7 grams. To achieve this, have a look at this site for more detailed guidelines on potassium dietary sources. Look at the table at the bottom of the page. They have excluded meat sources but these are also valuable sources of potassium.
Remember, the potassium - salt(ie sodium) balance is very important, so if you eat lots of processed food, which is typically far too high in sodium and\or salt, you need to counter balance this with substantial potassium intake.
Stop Killing the Frogs
There is a prevailing mythology that if bodily concentrations of a particular compound are below the "safety threshold" then no damage is being done. Even a basic understanding of biological processes should reveal how dangerous and misleading that notion is. As this recent indicates, cumulative exposure of various compounds that are well below the safety threshold for each compound are more than capable of killing amphibians. We should all be very worried about the amount of junk humanity is pouring into the environment because this has serious implications not only for the other animals but as increasing numbers of studies are indicating this also has serious implications for human health.
Marijuana and Dementia
Over the years there have been multiple studies indicating the potential of cannabinoids across a wide range of conditions. This latest study provides further weight as to the therapeutic potential of cannabinoids. It is high time that the public was made aware of the considerable therapeutic potential of these compounds. As for the psychosis\schizophrenia risk, that has been too much overblown and the risk is virtually negligible post 21 years of age. The reasons for this therapeutic potential are:
- The two principal cannabinoids, THC and cannabidiol, have very strong antioxidant capacity.
- These two compounds are lipophilic, that is lipid soluble, hence will remain in the body for extended periods. For pot smokers, typical wash out periods are 90% after one week, though this can greatly vary.
- Both of these compounds target specific receptors. THC will target CB1 and to a lesser extent CB2(controversial), while cannabidiol is very specific for CB2 and hence is non-psychoactive.
- Both compounds will bind to the anion site of ACHe, an enzyme that breaks down acetylcholine. This neurotransmitter is markedly reduced in some dementias, particularly Alzheimers.
- ACHe is also strongly implicated in amyloid production, both cannabinoids reduce the production of amyloid, an early step in Alzheimers because this production seems contingent on the anion site.
- Activation of the CB2 receptor limits the expression of pro-inflammatory cytokines, excess production of these cytokines being implicated in everything from atherosclerosis to cancer to dementia.
Sunday, November 9, 2008
Vitamin B3 and Alzheimers Disease
9/11/2008 4:37PM
Vitamin B3 and Alzheimers Disease
Nicotinamide is a form of Vitamin B3. This is a promising study because this compound was found to target a key and early initiator of amyloid plaque formation in the brain. That process is tau phosphorylation which is implicated in many neurodegenerative conditions. Nicotinamide can be purchased as supplement and is generally safe but at very high doses can be toxic.
The Science Daily news release is available here.
The Journal of Neuroscience, November 5, 2008, 28(45):11500-11510; doi:10.1523/JNEUROSCI.3203-08.2008
Nicotinamide Restores Cognition in Alzheimer's Disease Transgenic Mice via a Mechanism Involving Sirtuin Inhibition and Selective Reduction of Thr231-Phosphotau
Kim N. Green,1 Joan S. Steffan,2 Hilda Martinez-Coria,1 Xuemin Sun,3 Steven S. Schreiber,3,5 Leslie Michels Thompson,1,2,4 and Frank M. LaFerla1
Departments of 1Neurobiology and Behavior, 2Psychiatry and Human Behavior, 3Neurology, 4Biological Chemistry, and 5Anatomy and Neurobiology, University of California, Irvine, Irvine, California 92697-4545
Correspondence should be addressed to Frank M. LaFerla, Department of Neurobiology and Behavior, University of California, Irvine, 1109 Gillespie Neuroscience Building, Irvine, CA 92697-4545. Email: laferla@uci.edu
Memory loss is the signature feature of Alzheimer's disease, and therapies that prevent or delay its onset are urgently needed. Effective preventive strategies likely offer the greatest and most widespread benefits. Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance memory and synaptic plasticity. We evaluated the efficacy of nicotinamide, a competitive inhibitor of the sirtuins or class III NAD+-dependent HDACs in 3xTg-AD mice, and found that it restored cognitive deficits associated with pathology. Nicotinamide selectively reduces a specific phospho-species of tau (Thr231) that is associated with microtubule depolymerization, in a manner similar to inhibition of SirT1. Nicotinamide also dramatically increased acetylated -tubulin, a primary substrate of SirT2, and MAP2c, both of which are linked to increased microtubule stability. Reduced phosphoThr231-tau was related to a reduction of monoubiquitin-conjugated tau, suggesting that this posttranslationally modified form of tau may be rapidly degraded. Overexpression of a Thr231-phospho-mimic tau in vitro increased clearance and decreased accumulation of tau compared with wild-type tau. These preclinical findings suggest that oral nicotinamide may represent a safe treatment for AD and other tauopathies, and that phosphorylation of tau at Thr231 may regulate tau stability.
Vitamin B3 and Alzheimers Disease
Nicotinamide is a form of Vitamin B3. This is a promising study because this compound was found to target a key and early initiator of amyloid plaque formation in the brain. That process is tau phosphorylation which is implicated in many neurodegenerative conditions. Nicotinamide can be purchased as supplement and is generally safe but at very high doses can be toxic.
The Science Daily news release is available here.
The Journal of Neuroscience, November 5, 2008, 28(45):11500-11510; doi:10.1523/JNEUROSCI.3203-08.2008
Nicotinamide Restores Cognition in Alzheimer's Disease Transgenic Mice via a Mechanism Involving Sirtuin Inhibition and Selective Reduction of Thr231-Phosphotau
Kim N. Green,1 Joan S. Steffan,2 Hilda Martinez-Coria,1 Xuemin Sun,3 Steven S. Schreiber,3,5 Leslie Michels Thompson,1,2,4 and Frank M. LaFerla1
Departments of 1Neurobiology and Behavior, 2Psychiatry and Human Behavior, 3Neurology, 4Biological Chemistry, and 5Anatomy and Neurobiology, University of California, Irvine, Irvine, California 92697-4545
Correspondence should be addressed to Frank M. LaFerla, Department of Neurobiology and Behavior, University of California, Irvine, 1109 Gillespie Neuroscience Building, Irvine, CA 92697-4545. Email: laferla@uci.edu
Memory loss is the signature feature of Alzheimer's disease, and therapies that prevent or delay its onset are urgently needed. Effective preventive strategies likely offer the greatest and most widespread benefits. Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance memory and synaptic plasticity. We evaluated the efficacy of nicotinamide, a competitive inhibitor of the sirtuins or class III NAD+-dependent HDACs in 3xTg-AD mice, and found that it restored cognitive deficits associated with pathology. Nicotinamide selectively reduces a specific phospho-species of tau (Thr231) that is associated with microtubule depolymerization, in a manner similar to inhibition of SirT1. Nicotinamide also dramatically increased acetylated -tubulin, a primary substrate of SirT2, and MAP2c, both of which are linked to increased microtubule stability. Reduced phosphoThr231-tau was related to a reduction of monoubiquitin-conjugated tau, suggesting that this posttranslationally modified form of tau may be rapidly degraded. Overexpression of a Thr231-phospho-mimic tau in vitro increased clearance and decreased accumulation of tau compared with wild-type tau. These preclinical findings suggest that oral nicotinamide may represent a safe treatment for AD and other tauopathies, and that phosphorylation of tau at Thr231 may regulate tau stability.
A "Fat Burning" Drug?
Experimental Drug Spurs Fat Burning
This is all becoming rather silly. That so many valuable research resources are being wasted on what is essentially a behavioral problem is a poor reflection on society and the state of biomedical research. The last fat burning drug promising miracles was fenfluramine. It was discontinued in 1997 because it was found to induce heart valve damage, this damage lasting years after use was ceased.
This drug targets SIRT1, a gene transcription regulator that is strongly associated with the beneficial effects of caloric restriction. A word of warning about the caloric restriction craze: recent studies have indicated that it will probably not prolong life in humans and it does carry some risks, including infertility, immunosuppression, hypoglycemia, and there is some suggestion it may damage the brain over the long term. Not surprising really, animals living in cages on CR is something entirely different from the real world experience. I suspect this drug will never reach the market.
To use drugs to address what is essentially a behavioral problem is both dumb and dangerous. Sure, it can be very difficult to lose weight. Many years ago I began to pile on the weight. It took time but I now have reduced my weight to a very good level. I could probably lose a few more kilos but I'm not obsessive about weight, in fact I think the Body Mass Index is silly and misleading. What many are loathe to say is that being a little overweight is probably better than being underweight. Some studies do support this.
If you are gaining weight don't run to the doctor for a magic bullet. In this age of ballooning health care costs and innumerable accounts of so called "scientifically tested" drugs proving to have worrying side effects prudence and common sense dictates that we should take charge of our health instead of seeking magic bullets from the biomedicine industry. You know what you have to do: change your lifestyle and diet. Don't try to lose weight quickly, don't diet, change your lifestyle and diet so the weight is gradually shed until you reach the weight you think is good for your body type. The BMI is a useful guide but don't take it as an absolute. There are no dietary or health secrets and anyone who tells you differently is probably trying to sell you something.
This is all becoming rather silly. That so many valuable research resources are being wasted on what is essentially a behavioral problem is a poor reflection on society and the state of biomedical research. The last fat burning drug promising miracles was fenfluramine. It was discontinued in 1997 because it was found to induce heart valve damage, this damage lasting years after use was ceased.
This drug targets SIRT1, a gene transcription regulator that is strongly associated with the beneficial effects of caloric restriction. A word of warning about the caloric restriction craze: recent studies have indicated that it will probably not prolong life in humans and it does carry some risks, including infertility, immunosuppression, hypoglycemia, and there is some suggestion it may damage the brain over the long term. Not surprising really, animals living in cages on CR is something entirely different from the real world experience. I suspect this drug will never reach the market.
To use drugs to address what is essentially a behavioral problem is both dumb and dangerous. Sure, it can be very difficult to lose weight. Many years ago I began to pile on the weight. It took time but I now have reduced my weight to a very good level. I could probably lose a few more kilos but I'm not obsessive about weight, in fact I think the Body Mass Index is silly and misleading. What many are loathe to say is that being a little overweight is probably better than being underweight. Some studies do support this.
If you are gaining weight don't run to the doctor for a magic bullet. In this age of ballooning health care costs and innumerable accounts of so called "scientifically tested" drugs proving to have worrying side effects prudence and common sense dictates that we should take charge of our health instead of seeking magic bullets from the biomedicine industry. You know what you have to do: change your lifestyle and diet. Don't try to lose weight quickly, don't diet, change your lifestyle and diet so the weight is gradually shed until you reach the weight you think is good for your body type. The BMI is a useful guide but don't take it as an absolute. There are no dietary or health secrets and anyone who tells you differently is probably trying to sell you something.
Antioxidants - A Risk Benefit Profile
Antioxidants are all the rage these days. Paradoxically, while there are many in vitro studies demonstrating potential benefits from antioxidants, and many studies indicating their utility in various pathologies, there is scant evidence that antioxidant supplementation prolongs life.
I have concerns about the absorbing huge doses of antioxidants. Oxidation is an intrinsic and vital physiological process, filling up your body with antioxidants may sound like a good idea but how often have we been subjected to the latest nutrition craze only to find that it was nonsense? Far too many times, there needs to be much caution in the use of antioxidants. This recent study highlights that while antioxidants have considerable therapeutic promise, indiscriminate use of antioxidants can also lead to pathological processes.
One thing not mentioned in this study but is very important is the use of alpha tocopherol, typically and misleading referred to as Vitamin E. There are in fact a number of types of vitamin E and high consumption of alpha tocopherol can reduce the concentrations of gamma tocopherol and delta tocopherol, both of which are better variants than alpha tocopherol. . This may explain why some studies have found that high dosages of alpha tocopherol can increase mortality. The reason why most vitamin E supplements only contain alpha tocopherol is simple: it is the cheapest to manufacture. If you want a good source of vitamin E use wheatgerm. Note what the below study found in relation to wheatgerm:
Note that last sentence, that the antioxidants in wheat germ "recover" their antioxidant activity. Now whether or not this happens in the body is another question but given that wheat germ is cheap and a valuable nutrient source why bother with all those expensive supplements?
This study also highlights that certain antioxidants, at high doses, can actually induce oxidation. Ever since that now famous study on beta carotene which found it increased the rate of lung cancer in smokers(as if that were possible!) I have harbored suspicions that beta carotene should not be added to multi vitamins. Smokers should definitely avoid beta carotene in vitamin pills and problem be careful about the intake from natural sources. As for non smokers, the data is equivocal. Beta carotene does not appear to be a causative factor for or against developing cancer.
Ascorbic acid, a variant of vitamin C, appears to be a double edged sword. At high doses it can stimulate the production reactive oxygen species, particularly in the presence of free iron, the latter often being present in inflammatory conditions. Mega dosing of vitamin C is a waste of money and can damage the gut. Once tissue saturation of vitamin C is achieved there is little point in swallowing vitamin C tablets because it will not pass the gut wall. Smokers should increase their intake of vitamin C has it has been shown to help preserve vitamin E levels. As with most antioxidants, it is generally better to consume these throughout the day because this will help maintain tissue levels through the course of the day, whereas consuming antioxidant rich foods or supplements at one time of the day will lead to depletion until topping up occurs at the next meal.
The flip side of megadosing for vitamin C is recent studies which found that intravenous injections of vitamin C may have therapeutic use in treating some cancers.
The below study can be downloaded at this site.
Reading
Article
The role of antioxidant supplement in immune system, neoplastic,
and neurodegenerative disorders: a point of view for an assessment
of the risk/benefit profile
Authors
Daria Brambilla1, Cesare Mancuso2, Mariagrazia Rita Scuderi1, Paolo Bosco3,
Giuseppina Cantarella1, Laurence Lempereur1, Giulia Di BenedettoLL0000001,
Salvatore Pezzino1 and Renato Bernardini*1
Journal
Nutrition Journal 2008, 7:29 doi:10.1186/1475-2891-7-29
Location
Life\Nutrition\
Date obtained
2/11/2008
Date Read
7/11/2008
Date to Review
Web Page
http://www.nutritionj.com/content/7/1/29
Keywords
Printed
Notes
Abstract
This review will discuss some issues related to the risk/benefit profile of the use of dietary antioxidants. Thus, recent progress regarding the potential benefit of dietary antioxidants in the treatment of chronic diseases with a special focus on immune system and neurodegenerative disorders will be discussed here. It is well established that reactive oxygen species (ROS) play an important role in the etiology of numerous diseases, such as atherosclerosis, diabetes and cancer. Among the physiological defense system of the cell, the relevance of antioxidant molecules, such as glutathione and vitamins is quite well established. Recently, the interest of researchers has, for example, been conveyed on antioxidant enzyme systems, such as the heme oxygenase/biliverdin reductase system, which appears modulated by dietary antioxidant molecules, including polyphenols and beta-carotene. These systems possibly counteract oxidative damage very efficiently and finally modulate the activity of oxidative phenomena occurring, for instance, during pathophysiological processes. Although evidence shows that antioxidant treatment results in cytoprotection, the potential clinical benefit deriving from both nutritional and supplemental antioxidants is still under wide debate. In this line, the inappropriate assumption of some lipophylic vitamins has been associated with increased incidence of cancer rather than with beneficial effects.
I have concerns about the absorbing huge doses of antioxidants. Oxidation is an intrinsic and vital physiological process, filling up your body with antioxidants may sound like a good idea but how often have we been subjected to the latest nutrition craze only to find that it was nonsense? Far too many times, there needs to be much caution in the use of antioxidants. This recent study highlights that while antioxidants have considerable therapeutic promise, indiscriminate use of antioxidants can also lead to pathological processes.
One thing not mentioned in this study but is very important is the use of alpha tocopherol, typically and misleading referred to as Vitamin E. There are in fact a number of types of vitamin E and high consumption of alpha tocopherol can reduce the concentrations of gamma tocopherol and delta tocopherol, both of which are better variants than alpha tocopherol. . This may explain why some studies have found that high dosages of alpha tocopherol can increase mortality. The reason why most vitamin E supplements only contain alpha tocopherol is simple: it is the cheapest to manufacture. If you want a good source of vitamin E use wheatgerm. Note what the below study found in relation to wheatgerm:
Intriguingly, the combined treatment with wheat germ and vitamin C profoundly inhibited metastasis formation in various tumor models of different origin (Lewis lung carcinoma, B16 melanoma and human colon carcinoma xenografts [HCR25]) [61]. On the contrary, wheat germ had no toxicity on peripheral blood leukocytes (PBLs) at doses that affected tumor cells. The crude powder extract of fermented wheat germ inhibits nucleic acid ribose synthesis primarily through the non-oxidative steps of the pentose cycle [60]. Curiously, another quinone compound, carnosic acid quinone, like wheat germ, recovers potent antioxidant activity upon standing [62].
Note that last sentence, that the antioxidants in wheat germ "recover" their antioxidant activity. Now whether or not this happens in the body is another question but given that wheat germ is cheap and a valuable nutrient source why bother with all those expensive supplements?
This study also highlights that certain antioxidants, at high doses, can actually induce oxidation. Ever since that now famous study on beta carotene which found it increased the rate of lung cancer in smokers(as if that were possible!) I have harbored suspicions that beta carotene should not be added to multi vitamins. Smokers should definitely avoid beta carotene in vitamin pills and problem be careful about the intake from natural sources. As for non smokers, the data is equivocal. Beta carotene does not appear to be a causative factor for or against developing cancer.
Ascorbic acid, a variant of vitamin C, appears to be a double edged sword. At high doses it can stimulate the production reactive oxygen species, particularly in the presence of free iron, the latter often being present in inflammatory conditions. Mega dosing of vitamin C is a waste of money and can damage the gut. Once tissue saturation of vitamin C is achieved there is little point in swallowing vitamin C tablets because it will not pass the gut wall. Smokers should increase their intake of vitamin C has it has been shown to help preserve vitamin E levels. As with most antioxidants, it is generally better to consume these throughout the day because this will help maintain tissue levels through the course of the day, whereas consuming antioxidant rich foods or supplements at one time of the day will lead to depletion until topping up occurs at the next meal.
The flip side of megadosing for vitamin C is recent studies which found that intravenous injections of vitamin C may have therapeutic use in treating some cancers.
The below study can be downloaded at this site.
Reading
Article
The role of antioxidant supplement in immune system, neoplastic,
and neurodegenerative disorders: a point of view for an assessment
of the risk/benefit profile
Authors
Daria Brambilla1, Cesare Mancuso2, Mariagrazia Rita Scuderi1, Paolo Bosco3,
Giuseppina Cantarella1, Laurence Lempereur1, Giulia Di BenedettoLL0000001,
Salvatore Pezzino1 and Renato Bernardini*1
Journal
Nutrition Journal 2008, 7:29 doi:10.1186/1475-2891-7-29
Location
Life\Nutrition\
Date obtained
2/11/2008
Date Read
7/11/2008
Date to Review
Web Page
http://www.nutritionj.com/content/7/1/29
Keywords
Printed
Notes
Abstract
This review will discuss some issues related to the risk/benefit profile of the use of dietary antioxidants. Thus, recent progress regarding the potential benefit of dietary antioxidants in the treatment of chronic diseases with a special focus on immune system and neurodegenerative disorders will be discussed here. It is well established that reactive oxygen species (ROS) play an important role in the etiology of numerous diseases, such as atherosclerosis, diabetes and cancer. Among the physiological defense system of the cell, the relevance of antioxidant molecules, such as glutathione and vitamins is quite well established. Recently, the interest of researchers has, for example, been conveyed on antioxidant enzyme systems, such as the heme oxygenase/biliverdin reductase system, which appears modulated by dietary antioxidant molecules, including polyphenols and beta-carotene. These systems possibly counteract oxidative damage very efficiently and finally modulate the activity of oxidative phenomena occurring, for instance, during pathophysiological processes. Although evidence shows that antioxidant treatment results in cytoprotection, the potential clinical benefit deriving from both nutritional and supplemental antioxidants is still under wide debate. In this line, the inappropriate assumption of some lipophylic vitamins has been associated with increased incidence of cancer rather than with beneficial effects.
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