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.

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:

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.

With Reckless Abandon We Contaminate Our Home

Yet another study has emerged indicating that reckless disregard towards the consequences of environmental pollution is a health hazard for all of us. Libertarians and their ilk may argue that property rights will afford protection against pollution but this is unmitigated piffle. Pollution does not recognise boundaries or property rights and it can take decades for the full consequences of a pollutant to become apparent. Methylmercury is an excellent example of that.

Wines and Heavy Metals

For years we have been advised that a glass or two of wine is good for us and then this pops up. The basic message is: some European wines have such extraordinarily levels of heavy metals that even a single glass could be bad for our health.

There is an important nutritional lesson here and it is this: we're ignorant. For all the research that goes on we are a very long way of knowing what exactly constitutes good living. The research must proceed but please be very careful with health reporting. It is so very difficult to draw conclusions from a group of studies let alone a single study. Whatever you do with regard to your health always stick to the essentials. Experiment with diet and supplements, where possible do this in the context of regular blood tests so as to determine the effects. Remember, studies are statistical, the results of a particular study may be completely you irrelevant for someone living your life and with your physiology.

At the end of the day, all of us have to find out what works for us healthwise.

SAM-e can be Dangerous

SAM-e is being widely promoted as a "natural antidepressant". Quite by accident I recently stumbled upon some data which indicated that sustained use of SAM-e is potentially very dangerous.

SAM-e is S-adenosylmethionine. Part of its known actions is to act as a methyl donor. If you are using SAM-e you must make sure your vitamin B levels are adequate. The use of SAM-e has been associated with hyperhomocysteinemia, excess SAM-e is associated with Parkinson's Disease like disorders, excess methyl donation is a risk factor for some cancers, and the hyperhomocysteinemia that can arise from unwise use of SAM-e can induce atherosclerosis. It has also been found that in the brains of schizophrenic patients there is an over expression of SAM-e. Excessive SAM-e also induces oxidative stress and lipid peroxidation.

If you are taking S-adenosylmethionine be absolutely certain you have a very good intake of the B vitamin group, particularly folate, and you have a good antioxidant intake as well.

NEVER take SAM-e in conjunction with any antidepressants, "natural" or otherwise. It is probably advisable that before taking SAM-e you should have your homocysteine levels checked. If these levels are high then do not take it and immediately boost your intake of B vitamins and folate.

If you are using SAM-e for depression you might want to consider an "unnatural antidepressant" prescribed by your doctor. Antidepressant drugs are amongst the most widely prescribed drugs and have been subject to extensive trials and analysis. They have an excellent safety profile but it can take quite some experimentation to find the antidepressant that works for you. As recent studies have indicated the efficacy of antidepressants appears contingent on the induction of neurogenesis. This is probably a downstream effect from antidepressant use. At present I am taking an antidepressant. No, I'm not depressed, I just prefer the occasional dosing of an antidepressant because the one I am using has a number of favourable qualities.

Ideally if you are suffering from depression you should first try strategies that do not require taking anything. Check your diet, get some regular exercise, spend time with positive people, stabilise your sleep patterns if need be, get out in the sun occasionally(yes, sunshine, probably via circadian regulation and vitamin D, can give a slight boost to serotonin levels), and find ways to reduce your stress levels.

A brief overview of SAM-e is available at Wikipedia.

Brain Aging in Relation to Genes, Diet, and Behavior

Over recent years there has been tremendous progress in our understanding of brain aging and neurodegeneration. Whereas in times past it was presumed that little could be done to forestall the onset of age associated cognitive impairment it is now obvious that there is a welter of strategies we can utilise to markedly slow down the rate of age associated cognitive impairment.

This review article from Mark P. Mattson et. al. is a good starting point for enhancing your understanding of brain aging and the strategies that can help in slowing that trend. Some even claim that one can completely forestall brain aging. I remain very cynical of that possibility but hey it is worth a try so give it a go!

In brief, the following strategies are advisable:

• Regular light aerobic exercise.
• Moderate fasting a couple of times a week appears to be beneficial. Caloric Restriction, however, is ill advised as there is some suggestion that over the long term it can damage the brain.
• A good diet, obviously.
• Avoiding saturated fats and trans fats. Do not eliminate saturated fat, just reduce it.
• Maintaining an appropriate balance of omega 3 to omega 6 fats.
• Regular sleeping patterns.
• Avoiding excessive stress.
• Treat depression quickly. Numerous studies now indicate that depression damages the brain and the body. In fact sustained major depression is a significant risk factor for Alzheimers and a minor risk factor for heart disease.
• Avoid knocks to the head. Even mild brain injury can pave the way for latter dementia.

The abstract:

Mattson, Mark P., Sic L. Chan, and Wenzhen Duan. Modification of Brain Aging and Neurodegenerative Disorders by Genes, Diet, and Behavior. Physiol. Rev. 82: 637-672, 2002; 10.1152/physrev.00004.2002.Multiple molecular, cellular, structural, and functional changes occur in the brain during aging. Neural cells may respond to these changes adaptively, or they may succumb to neurodegenerative cascades that result in disorders such as Alzheimer's and Parkinson's diseases. Multiple mechanisms are employed to maintain the integrity of nerve cell circuits and to facilitate responses to environmental demands and promote recovery of function after injury. The mechanisms include production of neurotrophic factors and cytokines, expression of various cell survival-promoting proteins (e.g., protein chaperones, antioxidant enzymes, Bcl-2 and inhibitor of apoptosis proteins), preservation of genomic integrity by telomerase and DNA repair proteins, and mobilization of neural stem cells to replace damaged neurons and glia. The aging process challenges such neuroprotective and neurorestorative mechanisms. Genetic and environmental factors superimposed upon the aging process can determine whether brain aging is successful or unsuccessful. Mutations in genes that cause inherited forms of Alzheimer's disease (amyloid precursor protein and presenilins), Parkinson's disease (-synuclein and Parkin), and trinucleotide repeat disorders (huntingtin, androgen receptor, ataxin, and others) overwhelm endogenous neuroprotective mechanisms; other genes, such as those encoding apolipoprotein E₄, have more subtle effects on brain aging. On the other hand, neuroprotective mechanisms can be bolstered by dietary (caloric restriction and folate and antioxidant supplementation) and behavioral (intellectual and physical activities) modifications. At the cellular and molecular levels, successful brain aging can be facilitated by activating a hormesis response in which neurons increase production of neurotrophic factors and stress proteins. Neural stem cells that reside in the adult brain are also responsive to environmental demands and appear capable of replacing lost or dysfunctional neurons and glial cells, perhaps even in the aging brain. The recent application of modern methods of molecular and cellular biology to the problem of brain aging is revealing a remarkable capacity within brain cells for adaptation to aging and resistance to disease.

Placebo Power

Henry Beecher would have been pleased with these findings. He pioneered the concept of the placebo effect. A surgeon in World War 2, he found that simply giving wounded soldiers a sugar pill alleviated their pain. Fascinated by this after World War 2 he began research into the Placebo Effect.

Sadly the Placebo Effect is often perceived as a statistical artefact rather than a real phenomenon. However it can be very powerful. Even classical conditioning has been shown to induce altered immune responses in humans and rats. In fact in humans one can induce immunosuppression through behavioral conditioning. Now before you start thinking something spooky is going on here, you should read this article which indicates that there is a physical basis for this phenomenon.

There needs to be greater attention to the potential of the Placebo Effect in clinical practice. As this news item indicates, many doctors are not adverse to using the Placebo Effect in their daily practice.

For an introduction to the work of Henry Beecher, read this Wikipedia entry.

Eat Smart, Be Smart

They like to say that we cannot improve our intelligence. Recent studies have contradicted this as has my personal experience. There are a great many things we can do to improve our intelligence but to achieve maximum benefit requires careful management and a holistic approach to health. By "holistic" I do not mean that New Age crap or the continual popping of pills, but rather an integrated approach where we address many aspects of our lives. This includes:

• Being happy. If you are lacking happiness then this is the first challenge you must address.
• Sound sleep. There used to be the boast of how little sleep one could get by on. Great, welcome to future dementia.
• Aerobic fitness. Absolutely essential.
• Don't just exercise your brain, push it. Make it work. Read material that you find challenging, that makes you think, that challenges your preconceptions. One of my favourite quotes is:*Gelett Burgess: "If in the last few years you haven't discarded a major opinion or acquired a new one, check your pulse. You may be dead."
• Remember that exercising the brain is not just about conceptual work, bodily exercises that require co-ordination and timing can also be very important. This is further highlighted by recent research indicating that simple physical training in co-ordination appears to be beneficial for some children with ADHD. This appears to be related to the cerebellum(little brain). This part of the CNS has been neglected for too long.
  
• Eat well.

This study from the FASEB journal involved the administration of some supplements to gerbils. It was found that these readily available compounds enhanced their cognition. The nutshell goes like this:

DHA: an important omega 3 fat that is a substrate for NPD1, a neuroprotective compound that prevents apoptosis(programmed cell death).
Choline: an important component in cell walls and also a substrate for acetylcholine, the "memory neurotransmitter".

A news item on the study can be read here.

FASEB, July 2008

Dietary uridine enhances the improvement in learning and memory produced by administering DHA to gerbils

Abstract:

This study examined the effects on cognitive behaviors of giving normal adult gerbils three compounds, normally in the circulation, which interact to increase brain phosphatides, synaptic proteins, dendritic spines, and neurotransmitter release. Animals received supplemental uridine (as its monophosphate, UMP; 0.5%) and choline (0.1%) via the diet, and docosahexaenoic acid (DHA; 300 mg/kg/day) by gavage, for 4 wk, and then throughout the subsequent period of behavioral training and testing. As shown previously, giving all three compounds caused highly significant (P<0.001)>

The Mediterranean Diet

You may have heard about the Mediterranean Diet and its implications for health. This meta-analysis confirms previous findings, including reductions in mortality from cardiovacular disease(9%), cancer(6%), Parkinson's Disease, and Alzheimers(13%).

In short, the diet focuses on high intakes of legumes vegetables, high cereals, relative absence of red and processed meats, a high ratio for Monunsaturated vs. Saturated Fat, low milk and dairy products.

I have concerns about a high cereal diet and suggest that this is not a necessary component in relation to the health benefits derived from the Mediterranean diet. Cereals tend to contain high levels of omega 6 and this may create an unbalance in relation to omega 3 levels. Additionally, cereals are often high in carbohydrates, thus potentially leading to excess caloric intake.

However I do agree that in general we consume too much processed and red meat. As recent studies have indicated simply reducing protein intake, as opposed to adopting a torturous caloric restriction regime, can confer substantial benefits. We need to be cautious here, in reducing protein intake we may also be depriving ourselves of some essential amino acids.

An important component of the Mediterranean diet is the large amounts of olive oil used. Monounsaturated fats tend to be ignored these days, in my view there is too much emphasis on omega 3's and I have some concerns about high levels of omega 3's in the diet. After all, eskimos may be relatively free of conditions associated with an imbalance of the omega 3 and omega 6 fats, but they also tend to suffer from cerebral hemorrhages in their 60's and 70's. This propensity to bleeding first came to my attention is a wonderful text on lipids: The Fats of Life by Caroline M Pond. You can preview this text at this site. Thanks Google! The Australian Cardiologist, Ross Walker, also makes reference to this in his text The Cell Factor. I highly recommend this text, it contains abundant useful advice and for anyone with a cardiovascular condition it should be recommended reading.

Another reason I am interested in the role of monounsaturated fats is a study I read wherein they induced a cortical lesion in animals and then gave a massive intravenous infusion of monounsaturated fats. The results were remarkable, a huge reduction in lesion size. Unfortunately I cannot find it in my archives. It seems my memory is still better than my damned database.



Adherence to Mediterranean diet and health status: meta-analysis

Updated information and services can be found at:
http://bmj.com/cgi/content/full/337/sep11_2/a1344

ABSTRACT
Objective To systematically review all the prospective cohort studies that have analysed the relation between adherence to a Mediterranean diet, mortality, and incidence of chronic diseases in a primary prevention setting.

Design

Meta-analysis of prospective cohort studies. Data sources English and non-English publications in PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials from 1966 to 30 June 2008.

Studies reviewed Studies that analysed prospectively the association between adherence to a Mediterranean diet, mortality, and incidence of diseases; 12 studies, with a total of 1 574 299 subjects followed for a time ranging from three to 18 years were included.

Results

The cumulative analysis among eight cohorts (514 816 subjects and 33 576 deaths) evaluating overall mortality in relation to adherence to a Mediterranean diet showed that a two point increase in the adherence score was significantly associated with a reduced risk of
mortality (pooled relative risk 0.91, 95% confidence interval 0.89 to 0.94). Likewise, the analyses showed a beneficial role for greater adherence to a Mediterranean
diet on cardiovascular mortality (pooled relative risk 0.91, 0.87 to 0.95), incidence of or mortality from cancer (0.94,0.92 to 0.96), and incidence of Parkinson’s disease and
Alzheimer’s disease (0.87, 0.80 to 0.96).

Conclusions

Greater adherence to a Mediterranean diet is associated with a significant improvement in health status, as seen by a significant reduction in overall mortality (9%), mortality from cardiovascular diseases (9%), incidence of or mortality from cancer (6%), and
incidence of Parkinson’s disease and Alzheimer’s disease (13%). These results seem to be clinically relevant for public health, in particular for encouraging a Mediterranean-like dietary pattern for primary prevention of major chronic diseases.

Power Napping

Sleep deprivation is chronic in our society and this has important implications for our health. Chronic sleep deprivation typically increases the production of proinflammatory cytokines. Chronic sleep deprivation will induce increased production of cortisol and interleukin 6. Both have a number of functions in physiology.

Cortisol is a key stress hormone that is important in suppressing excessive inflammatory responses and helping us to maintain alertness. Throughout the 24 hour period both cortisol and interleukin 6, along with a host of other physiological mediators, vary in accordance with our circadian rhythms. Cortisol rises in the early hours of the morning, helping us to wake up, climbs through the morning, then starts a gradual decline through the evening and night. At basal physiological levels it plays important roles.

Interleukin 6 is a perplexing cytokine, it has been associated both with inflammatory and growth processes, my guess is that its function is contingent on the expression of inflammatory mediators like tumour necrosis factor. That is, in the presence of tumour necrosis factor at elevated levels, in can promote inflammation. It is worth noting that in this study at least the levels of tumour necrosis factor were largely unaffected.

In this study the human subjects were sleep deprived for a number of days and then allowed to nap for 2 hours. The effects were minor, statistically significant yes but physiologically significant? Not so sure about that. Napping does help but it cannot make up for maintaining good sleeping patterns.

The Lesson

Don't fall for the idea that you can catch up on sleep and no harm done. Sleep deprivation is a stressor and will impact your performance. Chronic sleep deprivation will do you no good at all. It will do the exact opposite. During the deepest phases of our sleep cycle growth hormone levels are elevated, and various repair processes come into play. As high cortisol is often found in depression, chronic sleep deprivation can pave the way for depression. Indeed it can be the final straw that breaks the camel's back. So if you are experiencing chronic sleep deprivation try to find ways to change that.

I take good quality sleep so seriously that I wear a sleep mask and ear plugs. This has a wonderful effect on my sleep cycle and I typically wake up wonderfully refreshed. A great change from years gone by when I would wake up feeling like death. I am a night owl who likes to stay up late, typically reading, studying, or just playing computer games. However I do make sure I get a good night's sleep and this has substantially improved my productivity and cognition.

If you're interested in learning about sleep and the importance of maintaining regular sleeping patterns I highly recommend The Promise of Sleep by William C. Dement and Christopher Vaughan. Dr. Dement commenced the Stanford Sleep Centre and is a leading authority on sleep. The text is very accessible. Here is a link to it.

You can download the full paper here.

Am J Physiol Endocrinol Metab 292: E253–E261, 2007.
Daytime napping after a night of sleep loss decreases sleepiness,improves performance, and causes beneficial changes in cortisol and interleukin-6 secretion

A. N. Vgontzas,S. Pejovic, E. Zoumakis, H. M. Lin, E. O. Bixler, M. Basta, J. Fang, A. Sarrigiannidis, and G. P. Chrousos

Daytime napping after a
night of sleep loss decreases sleepiness, improves performance, and
causes beneficial changes in cortisol and interleukin-6 secretion. Am J
Physiol Endocrinol Metab 292: E253–E261, 2007. First published August
29, 2006; doi:10.1152/ajpendo.00651.2005.—Sleep loss has been
associated with increased sleepiness, decreased performance, elevations
in inflammatory cytokines, and insulin resistance. Daytime napping has
been promoted as a countermeasure to sleep loss. To assess the effects of
a 2-h midafternoon nap following a night of sleep loss on postnap
sleepiness, performance, cortisol, and IL-6, 41 young healthy individuals
(20 men, 21 women) participated in a 7-day sleep deprivation experiment
(4 consecutive nights followed by a night of sleep loss and 2 recovery
nights). One-half of the subjects were randomly assigned to take a
midafternoon nap (1400–1600) the day following the night of total sleep
loss. Serial 24-h blood sampling, multiple sleep latency test (MSLT),
subjective levels of sleepiness, and psychomotor vigilance task (PVT)
were completed on the fourth (predeprivation) and sixth days (postdeprivation).
During the nap, subjects had a significant drop in cortisol and
IL-6 levels (P < 0.05). After the nap they experienced significantly less
sleepiness (MSLT and subjective, P < 0.05) and a smaller improvement
on the PVT (P < 0.1). At that time, they had a significant transient
increase in their cortisol levels (P < 0.05). In contrast, the levels of IL-6
tended to remain decreased for ~8 h (P < 0.1). We conclude that a 2-h
midafternoon nap improves alertness, and to a lesser degree performance,
and reverses the effects of one night of sleep loss on cortisol and IL-6.
The redistribution of cortisol secretion and the prolonged suppression of
IL-6 secretion are beneficial, as they improve alertness and performance.